Headache

Oxford Textbook of

Headache Syndromes

EDITED &v Michel Ferrari

Joost Haan

AndrewCharles
David W. Dodick SEGlES EDITOR Fumihiko Sakai Christopher Kennard

ALL CONTENT AVAILABLE AT OXFORDMEDICINE .COM

Oxford Textbook of

Headache Syndromes

OXFORD TEXTBOOKS IN CLINICAL NEUROLOGY

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Oxford Textbook of

Headache Syndromes

EDITED BY

Michel Ferrari

Department of Neurology, Leiden University Medical Centre, The Netherlands

Joost Haan

Associate Professor, Leiden University Medical Centre and Alrijne Hospital Leiderdorp, The Netherlands

Andrew Charles

Professor of Neurology, Director, UCLA Goldberg Migraine Program, Meyer and Renee Luskin Chair in Migraine and Headache Studies, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

David W. Dodick

Professor, Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA

Fumihiko Sakai

Department of Neurology, Kitasato University, Sagamihara, Kanagawa, Japan

Series Editor

Christopher Kennard

Great Clarendon Street, Oxford, OX2 6DP, United Kingdom

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Contents

Abbreviations ix 11. Contributors xiii

PART 1

General introduction

1. Classi cation and diagnosis of headache disorders 3
Jes Olesen and Richard B. Lipton

2. Taking a headache history: tips and tricks James W. Lance and David W. Dodick

3. Diagnostic neuroimaging in migraine 17 Mark C. Kruit and Arne May

4. Headache mechanisms 34 Andrew Charles

5. Headache in history 45 Mervyn J. Eadie

PART 2

Migraine

6. Migraine: clinical features and diagnosis
Richard Peat eld and Fumihiko Sakai

7. Migraine trigger factors: facts and myths Guus G. Schoonman, Henrik Winther Schytz,
and Messoud Ashina

Non-vascular comorbidities and complications 110

Mark A. Louter, Ann I. Scher, and Gisela M. Terwindt

12. Migraine and epilepsy 120
Pasquale Parisi, Dorothée Kasteleijn-Nolst Trenité,
Johannes A. Carpay, Laura Papetti, and Maria Chiara Paolino

13. Migraine and vertigo 128 Yoon-Hee Cha

14. Treatment and management of migraine:acute 138
Miguel J. A. Láinez and Veselina T. Grozeva

15. Treatment and management of migraine:preventive 152
Andrew Charles and Stefan Evers

16. Treatment and management: non-pharmacological, including neuromodulation 165
Delphine Magis

PART 3

Trigeminal autonomic cephalgias

17. Classi cation, diagnostic criteria, and
epidemiology 177
Thijs H. Dirkx and Peter J. Koehler

18. Cluster headache: clinical features and management 182
Ilse F. de Coo, Leopoldine A. Wilbrink, and Joost Haan

19. Paroxysmal hemicrania: clinical features and management 190
Gennaro Bussone and Elisabetta Cittadini

20. SUNCT/SUNA: clinical features and management 196
Juan A. Pareja, Leopoldine A. Wilbrink, and María-Luz Cuadrado

8. Hemiplegic migraine and other monogenic migraine subtypes and syndromes 75
Nadine Pelzer, Tobias Freilinger, and Gisela M. Terwindt

9. Retinal migraine 92
Brian M. Grosberg and C. Mark Sollars

10. Migraine, stroke, and the heart 98 Simona Sacco and Antonio Carolei

61 67

Contents

21. Hemicrania continua 203 Johan Lim and Joost Haan

22. Cluster tic syndrome and other combinations of primary headaches
with trigeminal neuralgia 208
Leopoldine A. Wilbrink, Joost Haan, and Juan A. Pareja

PART 4

Other primary short-lasting and rare headaches

23. Primary stabbing headache 215 Rashmi B. Halker, Esma Dilli, and Amaal Starling

24. Cough headache 220
Julio Pascual and Peter van den Berg†

25. Exertional and sex headache 225 Shih-Pin Chen, Julio Pascual, and Shuu-Jiun Wang

26. Hypnic headache 230 Dagny Holle and David W. Dodick

27. Cranial neuralgias and persistent idiopathic facial pain 237
Aydin Gozalov, Messoud Ashina, and Joanna M. Zakrzewska

28. Some rare headache disorders, including Alice in Wonderland syndrome, blip syndrome, cardiac cephalalgia, epicrania fugax, exploding head syndrome, Harlequin syndrome, lacrimal neuralgia, neck–tongue syndrome, and red ear syndrome 248
Randolph W. Evans

PART 5

Tension-type and other chronic headache types

29. Tension-type headache: classi cation, clinical features, and management 259
Stefan Evers

30. New daily persistent headache 267
Kuan-Po Peng, Matthew S. Robbins, and Shuu-Jiun Wang

31. Chronic migraine and medication overuse headache 275
David W. Dodick and Stephen D. Silberstein

32. Frequent headaches with and without acute medication overuse: management and international differences 284
Christina Sun-Edelstein and Alan M. Rapoport

33. Nummular headache 298
Juan A. Pareja and Carrie E. Robertson

PART 6

Secondary headaches: Diagnosis and treatment

34. Thunderclap headache 307 Hille Koppen, Agnes van Sonderen, and Sebastiaan F. T. M. de Bruijn

35. Headache associated with head trauma 314 Sylvia Lucas

36. Cervicogenic headache 322 Nikolai Bogduk

37. Headache and neurovascular disorders 334 Marieke J. H. Wermer, Hendrikus J. A. van Os,
and David W. Dodick

38. Headache attributed to spontaneous intracranial hypotension 346

Farnaz Amoozegar, Esma Dilli, Rashmi B. Halker, and Amaal J. Starling

39. Headache associated with high cerebrospinal uid pressure 356

Ore-ofe O. Adesina, Sudama Reddi, Deborah I. Friedman, and Kathleen Digre

40. Headache associated with systemic
infection, intoxication, or metabolic derangement 367
Ana Marissa Lagman-Bartolome and Jonathan P. Gladstone

41. Headache associated with intracranial infection 384

Matthijs C. Brouwer and Jonathan P. Gladstone

42. Remote causes of ocular pain 392 Deborah I. Friedman

43. Orofacial pain: dental head pains, temporomandibular disorders, and headache 399
Steven B. Graff-Radford† and Alan C. Newman

44. Headache with neurological de cits and cerebrospinal uid lymphocytosis (HaNDL) syndrome 403
Germán Morís and Julio Pascual

45. Nasal and sinus headaches 409 Vincent T. Martin and Maurice Vincent

46. Giant cell arteritis and primary central nervous system vasculitis as causes of headache 418
Mamoru Shibata, Norihiro Suzuki, and Gene Hunder

47. Headache related to an intracranial neoplasm 428
Elizabeth Leroux and Catherine Maurice

48. Headache and Chiari malformation 442 Dagny Holle and Julio Pascual

49. Reversible cerebral vasoconstriction syndrome 447
Aneesh B. Singhal

PART 7

Special topics

50. Headaches in the young 459
Vincenzo Guidetti, Benedetti Bellini, and Andrew D. Hershey

51. Headaches in the elderly 470
Jonathan H. Smith, Andreas Straube, and Jerry W. Swanson

52. Headache and psychiatry 475
Maurizio Pompili, Dorian A. Lamis, Frank Andrasik, and Paolo Martelletti

53. Headache and hormones, including pregnancy and breastfeeding 484

Sieneke Labruijere, Khatera Ibrahimi, Emile G.M. Couturier, and Antoinette Maassen van den Brink

54. Headache and the weather 494
Guus G. Schoonman, Jan Hoffmann, and Werner J. Becker

55. Headache and sport 502 David P. Kernick and Peter J. Goadsby

56. Headache attributed to airplane travel 508 Federico Mainardi and Giorgio Zanchin

57. Headache and sleep 514 Stefan Evers and Rigmor Jensen

58. Headache and bromyalgia 523 Marina de Tommaso and Vittorio Sciruicchio

59. Visual snow 530
Gerrit L. J. Onderwater and Michel D. Ferrari

Index 535

Contents

vii

Abbreviations

5-HT 5-hydroxytryptamine (serotonin) [18F]-MPPF [18F]-2’-methoxyphenyl-(N-2’-pyridinyl)

-p- uoro-benzamidoethyipiperazine [18F]-FDG udeoxyglucose

AAION arteritic anterior ischaemic optic neuropathy AAN American Academy of Neurology
ACE angiotensin-converting enzyme
ACR American College of Rheumatology

ACTH adrenocorticotropic hormone
ADHD attention-de cit hyperactivity disorder AED antiepileptic drug
AGES-Reykjavik Age, Gene/Environment

Susceptibility–Reykjavik study AGS Aicardi-Goutières syndrome

AH airplane headache
AHC alternating hemiplegia of childhood AHI apnoea/hypopnea index
AHS American Headache Society
AIDS acquired immune de ciency syndrome AMPA α-amino-3-hydroxy-5-methyl-4-

isoxazolepropionic acid
AMPP American Migraine Prevalence and

Prevention Study
ARIC Atherosclerosis Risk in Communities study

AR allergic rhinitis
ARS acute rhinosinusitis
ASA acetylsalicylic acid
aSAH aneurysmal subarachnoid haemorrhage AUC area under the curve
AVM arteriovenous malformation
BBB blood–brain barrier
BMI body mass index
BOEP benign occipital epilepsy of childhood with

occipital paroxysms BoNT-A botulinum toxin type A

BPD bipolar disorder
BPPV benign paroxysmal positional vertigo
BSR British Society for Rheumatism
CAD cervical artery dissection
CADASIL cerebral autosomal dominant arteriopathy with

subcortical infarcts and leukoencephalopathy CAI carbonic anhydrase inhibitor

CAMERA Cerebral Abnormalities in Migraine, and Epidemiological Risk Analysis

cAMP cyclic adenosine monophosphate CBCT cone beam computed tomography CBF cerebral blood ow
CBT cognitive behavioural therapy CBZ carbamazepine

CCH chronic cluster headache
CCL chemokine (C-C motif) ligand
CCR7 C-C chemokine receptor type 7
CDH chronic daily headache
cGMP cyclic guanosine monophosphate
CGRP calcitonin gene-related peptide
CHARM CHroni cation And Reversibility of Migraine CI con dence interval
CM chronic migraine
CM1 Chiari malformation type I
CNS central nervous system
COCP combined oral contraceptive pill
COL4 type IV collagen
COMOESTAS Continuous Monitoring of Medication

Overuse Headache in Europe and Latin America: development and STAndardization of an Alert and decision support System

COX cyclooxygenase
CPAP continuous positive airway pressure CPCH chronic post-craniotomy headache
CRP C-reactive protein
CSD cortical spreading depression
CSF cerebrospinal uid
CRS chronic rhinosinusitis
CT computed tomography
CTA computed tomography angiography
CTM computed tomography myelography CTTH chronic tension-type headache
CVST cerebral venous sinus thrombosis
CXCL10 C-X-C motif chemokine ligand 10
DBF dermal blood ow
DBS deep brain stimulation
DHE dihydroergotamine
DNA deoxyribonucleic acid
dr-CCH drug-refractory chronic cluster headache DSA digital subtraction angiography
DSM digital subtraction myelography
DSM-5 Diagnostic and Statistical Manual of Mental

Disorders, h edition DWI di usion-weighted imaging

EA2 episodic ataxia type 2
EA6 episodic ataxia type 3
EAAT1 excitatory amino acid transporter 1
EBP epidural blood patch
EBV Epstein–Barr virus
ED emergency department
EEG electroencephalography
EFNS European Federation of Neurological Societies EM episodic migraine

Abbreviations

EPC endothelial progenitor cell ID-CM ER endoplasmic reticulum IEH

. ERα oestrogen receptor alpha IFN

. ERβ oestrogen receptor beta IGF-1

ESR erythrocyte sedimentation rate IHA EU European Union IHL EULAR European League Against Rheumatism IIH EVA Epidemiology of Vascular Aging study IIHTT FASPS familial advanced sleep phase syndrome

FCL familial chilblain lupus IL FDA US Food and Drug Administration ILAE FHM familial hemiplegic migraine IM

. FHM1 familial hemiplegic migraine type 1 IOI

. FHM2 familial hemiplegic migraine type 2 IPS

. FHM3 familial hemplegic migraine type 3 IPSYS

FLAIR uid-attenuated inversion recovery ITT
FM bromyalgia IV
fMRI functional magnetic resonance imaging IVC GABA γ-aminobutyric acid JBD GCA giant cell arteritis LAMI GCS Glasgow Coma Scale LASIK GEFS+ generalized epilepsy with febrile seizures plus LDLPFC GFR glomerular ltration rate LP
GH growth hormone LPS GnRH gonadotropin-releasing hormone LSD GOM granular osmiophilic material Mφ GTN glyceryl trinitrate MA GWAS genome-wide association studies mAb HANAC hereditary angiopathy, nephropathy, aneurysms, MARD

and muscle cramps MBI HaNDL headache and neurological de cits associated MCM

with CSF lymphocytosis MELAS HC hemicrania continua

HH hypnic headache MI
Hib Haemophilus in uenzae type b MIDAS HIV human immunode ciency virus MISP HM hemiplegic migraine MIST HR hazard ratio
HRT hormone replacement therapy MMP HUNT-3 Nord-Trøndelag Health Survey MO IBMS International Burden of Migraine Study MOH IBS irritable bowel syndrome MR ICA internal carotid artery MRA ICH intracerebral haemorrhage MRI ICHD International Classi cation of Headache MRM

Disorders mRNA ICHD-2 International Classi cation of Headache mRS Disorders, second edition MRV

ICHD-2R International Classi cation of Headache MS Disorders, second edition revised mTBI

ICHD-3 International Classi cation of Headache mtDNA Disorders, third edition MTHFR

ICHD-3B International Classi cation of Headache MTT Disorders, third edition, beta version NAR

. ICD-10 Tenth Edition of the International Classi cation NDPH of Diseases NH

. ICD-11 Eleventh Edition of the International NIH Classi cation of Diseases NNT

ICP intracranial pressure NO ICVD International Classi cation of Vestibular NOMAS

Disorders NREM ID Identify Migraine NSAID

Identify Migraine–Chronic Migraine ictal epileptic headache
interferon
insulin-like growth factor 1

ictal headache
infratentorial hyperintense lesion
idiopathic intracranial hypertension Idiopathic Intracranial Hypertension Treatment Trial
interleukin
International League Against Epilepsy intramuscular
idiopathic orbital in ammation
intermittent photic stimulation
Italian Project on Stroke in Young Adults intention to treat
intravenous
inferior vena cava
juvenile bipolar disorder
low- and middle-income
laser in situ keratomileusis
le dorsolateral prefrontal cortex
lumbar puncture
lumboperitoneal shunt
lysergic acid diethylamide
macrophage
migraine with aura
monoclonal antibody
migraine anxiety-related dizziness mindfulness-based intervention
major congenital malformation
mitochondrial myopathy with encephalopathy, lactic acidosis, and stroke
myocardial infarction
Migraine Disability Assessment
mean intrasellar pressure
Migraine Intervention With STARFlex Technology
matrix metalloproteinase
migraine without aura
medication overuse headache
mixed rhinitis
magnetic resonance angiography
magnetic resonance imaging
menstrually related migraine
messenger ribonucleic acid
modi ed Rankin Scale
magnetic resonance venography
multiple sclerosis
mild traumatic brain injury
mitochondrial DNA methylenetetrahydrofolate reductase
mean transit time
non-allergic rhinitis
new daily persistent headache
nummular headache
National Institutes of Health
number needed to treat
nitric oxide
Northern Manhattan Study
non-rapid eye movement
non-steroidal anti-in ammatory drug

nVNS non-invasive vagal nerve stimulation rTMS OA osteoarthritis RVCL OCT optical coherence tomography
ONS occipital nerve stimulation RVCL-S ONSF optic nerve sheath fenestration

ONSTIM Occipital Nerve Stimulation for the Treatment SAH of Intractable Migraine SC

OR odds ratio SCA6 OSAS obstructive sleep apnoea syndrome SD OTC over-the-counter SE OXC oxcarbazepine SHM OXVASC Oxford Vascular study SIFAP1 PACAP pituitary adenylate cyclase-activating peptide SIH PACNS primary angiitis of the central nervous system SLE PAG periaqueductal gray SMEI PCA posterior cerebral artery SNP PCNSV primary central nervous system vasculitis SNRI

. PCR polymerase chain reaction

. PCS post-concussion syndrome SNS

PDGF platelet-derived growth factor SPECT PDPH post-dural puncture headache SPG PedMIDAS Pediatric Migraine Disability Assessment SRHA PET positron emission tomography SSRI PFO patent foramen ovale sTMS PG prostaglandin STN PGE2 prostaglandin E2 SUNA PGI2 prostaglandin I2

PH paroxysmal hemicrania SUNHA PHN postherpetic neuralgia
PI3K phosphoinositide 3-kinase SUNCT PIFP persistent idiopathic facial pain

PIHA pre-ictal headache
PMD perimetric mean deviation TAB PMH perimesencephalic subarachnoid haemorrhage TAC PMR polymyalgia rheumatica TBI PNS peripheral nerve stimulation TCH PO per os tDCS PPR photoparoxysmal EEG response TED PPV positive predictive value TENS PREEMPT Phase 3 REsearch Evaluating Migraine TH1

Prophylaxis erapy TH17 PREMICE PREvention of MIgraine using Cefaly THIN PRES posterior reversible encephalopathy syndrome TIA PRISM Precision Implantable Stimulator for Migraine TLR PROSPER Prospective Study of Pravastatin in the Elderly TM

At Risk TMD PSG polysomnographic TMJ PTCS pseudotumour cerebri syndrome TMS

PTH post-traumatic headache TN PWI perfusion-weighted imaging TNC QP quadripulse TNF RA rheumatoid arthritis TOV

. RBC red blood cell TREX1

. RBD REM sleep behaviour disorder TRT

RCT randomized controlled trial tSNS RCVS reversible cerebral vasoconstrictor syndrome TTH REM rapid eye movement tVNS RFT radiofrequency thermocoagulation TVS RLS restless legs syndrome VAS RNA ribonucleic acid VEGF RNFL retinal nerve bre layer VEMP RPON recurrent painful ophthalmoplegic neuropathy VIP

repeated-stimulation TMS
retinal vasculopathy with cerebral leukodystrophy
retinal vasculopathy with cerebral leukodystrophy and systemic manifestations subarachnoid haemorrhage
subcutaneous
spinocerebellar ataxia type 6
spreading depolarization
status epilepticus
sporadic hemiplegic migraine
Stroke in Young Fabry Patients
spontaneous intracranial hypotension systemic lupus erythematosus
severe myoclonic epilepsy of infancy
single nucleotide polymorphism
serotonin and norepinephrine reuptake inhibitor
supraorbital nerve stimulation
single-photon emission CT
sphenopalatine ganglion
seizure-related headache
selective serotonin reuptake inhibitor single-pulse TMS
spinal trigeminal nucleus
short-lasting unilateral neuralgiform headache attacks with cranial autonomic features short-lasting unilateral neuralgiform headache attacks
short-lasting unilateral neuralgiform headache attacks with conjunctival
injection and tearing
temporal artery biopsy
trigeminal autonomic cephalgia
traumatic brain injury
thunderclap headache
transcranial direct current stimulation
thyroid eye disease
transcutaneous electrical nerve stimulation type 1 helper T cell
type 17 helper T cell
e Health Improvement Network
transient ischaemic attack
Toll-like receptor
transformed migraine
temporomandibular dysfunction temporomandibular joint
transcranial magnetic stimulation
trigeminal neuralgia
trigeminal nucleus caudalis
tumour necrosis factor
transient obscurations of vision
three prime repair exonuclease 1
total retinal thickness
transcutaneous supraorbital nerve stimulator tension-type headache
transcutaneous supraorbital nerve stimulator trigeminovascular system
visual analogue scale
vascular endothelial growth factor
vestibular evoked myogenic potential vasoactive intestinal peptide

Abbreviations

xii

Abbreviations

VNS vagus nerve stimulation VPS ventriculoperitoneal shunt vSMC vascular smooth muscle cell VZV varicella zoster virus

WADA World Anti-Doping Agency WHO World Health Organization WHS Women’s Health Study WML white matter lesion

Contributors

Ore-ofe O. Adesina Ruiz Department of Ophthalmology and Visual Science, Houston, TX, USA

Farnaz Amoozegar Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary and Hotchkiss Brain Institute, Canada

Frank Andrasik Department of Psychology, University of Memphis, Memphis, TN, USA

Messoud Ashina Department of Neurology & Danish Headache Center, Righospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

Werner J. Becker Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Canada

Benedetti Bellini Department of Human Neuroscience, Sapienza University di Roma, Rome, Italy

Nikolai Bogduk University of Newcastle, Newcastle, Australia

Matthijs C. Brouwer Academic Medical Center, Department of Neurology, Amsterdam, e Netherlands

Gennaro Bussone Clinical Neuroscience Department, Neurological Institute IRCCS C. Besta, Milano, Italy

Antonio Carolei Institute of Neurology, Department of Applied Clinical Sciences and Biotechnology, University of L’Aquila, L’Aquila, Italy

Johannes A. Carpay Department of Neurology, Tergooiziekenhuizen, Hilversum, e Netherlands

Yoon-Hee Cha University of Minnesota, Minneapolis, MN, USA

Andrew Charles David Ge en School of Medicine at UCLA, Los Angeles, CA, USA

Shih-Pin Chen Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan

Elisabetta Cittadini Wandsworth Complex Needs Service, South West London, and St George’s Mental Health Trust, Spring eld University Hospital, London, UK

Emile G.M. Couturier Boerhaave Medisch Centrum, Amsterdam, e Netherlands

María Luz Cuadrado Headache Unit, Department of Neurology, Hospital Clínico San Carlos, Universidad Complutense, Madrid, Spain

Sebastiaan F.T.M. de Bruijn Department of Neurology, Haga Hospital, e Hague, e Netherlands

Ilse F. de Coo Department of Neurology, Leiden University Medical Centre, Leiden; Basalt Medical Rehabilitation, e Hague, e Netherlands

Marina de Tommaso Neuroscience and Sensory System, Department Bari Aldo Moro University, Policlinico General Hospital, Neurological Building, Bari, Italy

Kathleen Digre Department of Ophthalmology, John A Moran Eye Center, University of Utah Health Sciences Center, Salt Lake City, UT, USA

Esma Dilli Neurology, University of British Columbia, Canada

Thijs H. Dirkx Department of Neurology, Laurentius Hospital, Roermond, e Netherlands

David W. Dodick Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA

Mervyn J. Eadie University of Queensland, Brisbane, Australia

Randolph W. Evans Baylor College of Medicine, Houston, TX, USA

Stefan Evers Department of Neurology, Lindenbrunn Hospital Coppenbrügge, and University of Münster, Münster, Germany

Michel D. Ferrari Department of Neurology, Leiden University Medical Centre, Leiden, e Netherlands

Tobias Freilinger Department of Neurology, Passau Hospital, Passau; Zentrum für Neurologie und Hertie-Institut für Klinische Hirnforschung Universitätsklinikum Tübingen, Tübingen, Germany

Deborah I. Friedman Departments of Neurology, Neurotherapeutics, and Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX, USA

Jonathan P. Gladstone Gladstone Headache Clinic, e Hospital for Sick Children, Sunnybrook Health Sciences Centre, Toronto Rehabilitation Institute and Cleveland Clinic Canada,

Toronto, Canada

Peter J. Goadsby Headache Group, NIHR– Wellcome Trust Clinical Research Facility, King’s College London, London, UK

Aydin Gozalov Danish Headache Center and Department of Neurology, Rigshospitalet, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

Steven B. Graff-Radford† e Program for Headache and Orofacial Pain, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Brian M. Grosberg Hartford Healthcare Headache Center, Department of Neurology, University
of Connecticut School of Medicine, Hartford, CT, USA

Veselina T. Grozeva Servicio de Neurología. Hospital Clínico Universitario, Valencia, Spain

Vincenzo Guidetti Department of Human Neurosciene, Sapienza University di Roma, Rome, Italy

Joost Haan Leiden University Medical Centre, Leiden, and Alrijne Hospital Leiderdorp, Leiderdorp, e Netherlands

Rashmi B. Halker Department of Neurology, Mayo Clinic Hospital, Phoenix, AZ, USA

Andrew D. Hershey Department of Pediatrics, Division of Neurology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, College of Medicine, Cincinnati, OH, USA

Jan Hoffmann Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

Dagny Holle Department of Neurology, University Hospital Essen, Essen, Germany

Gene Hunder Division of Rheumatology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA

Khatera Ibrahimi Department of Internal Medicine, Division of Pharmacology, Erasmus Medical Center, Rotterdam, e Netherlands

Rigmor Jensen Danish Headache Centre, Copenhagen, Denmark

Dorothée Kasteleijn-Nolst Treni Child Neurology, Pediatric Headache Centre,
Sleep Disorders Centre, Chair of Pediatrics, NESMOS Department, Faculty of Medicine and Psychology, Sapienza University, Rome, Italy

xiv

Contributors
David P. Kernick St omas Health Centre,

Exeter, UK

Peter J. Koehler Department of Neurology, Zuyderland Medical Centre, Heerlen, e Netherlands

Hille Koppen Department of Neurology, Haga Hospital, e Hague, e Netherlands

Mark C. Kruit Department of Radiology, Leiden University Medical Centre, RC Leiden, e Netherlands

Sieneke Labruijere Department of Internal Medicine, Division of Pharmacology, Erasmus Medical Center, Rotterdam, e Netherlands

Ana Marissa Lagman-Bartolome Department
of Pediatrics, e Hospital for Sick Children; Pediatric Headache and Concussion Program, Center for Headache, Women’s College Hospital, University of Toronto, Toronto, Canada

Miguel J.A. Láinez Servicio de Neurología. Hospital Clínico Universitario, Valencia, Spain

Dorian A. Lamis Department of Psychiatry and Behavioural Sciences, Emory University School of Medicine, Atlanta, GA, USA

James W. Lance University of New South Wales, Sydney, New South Wales, Australia

Elizabeth Leroux Departement de Neurologie, Hopital Notre-Dame du CHUM, Montreal, Quebec, Canada

Johan Lim Department of Neurology, Haga Teaching Hospital, e Hague, e Netherlands

Richard B. Lipton Monte ore Headache Center, Albert Einstein College of Medicine, Bronx, NY, USA

Mark A. Louter De Viersprong Institute for Personality Disorders, Rotterdam, e Netherlands

Sylvia Lucas University of Washington Medical Center, Harborview Medical Center, Seattle, WA, USA

Antoinette Maassen van den Brink Department of Internal Medicine, Division of Pharmacology, Erasmus Medical Center, Rotterdam, e Netherlands

Delphine Magis Neurology and Pain Units, CHR East Belgium, Verviers, Belgium

Federico Mainardi Headache Centre, Department of Neurology, SS Giovanni e Paolo Hospital, Venice, Italy

Paolo Martelletti School of Health Sciences, Sapienza University of Rome, Department of Medical and Molecular Sciences, Rome, Italy

Vincent T. Martin University of Cincinnati, Cincinnati, OH, USA

Catherine Maurice Neuro-Oncology/Neurology Division, Princess Margaret Cancer Centre, Department of Medicine, University Health Network, University of Toronto, Toronto, Canada

Arne May University Medical Center Hamburg- Eppendorf, Hamburg, Germany

Germán Morís Neuroscience Area, Service of Neurology, Asturias Central University Hospital, Oviedo, Spain

Alan C. Newman e Program for Headache, Orofacial Pain, and Dental Sleep Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Jes Olesen Department of Neurology, Glostrup Hospital, Glostrup, Denmark

Gerrit L. J. Onderwater Department of Neurology, OLVG West, Amsterdam, e Netherlands

Maria Chiara Paolino Child Neurology, Pediatric Headache Centre, Sleep Disorders Centre, Chair of Pediatrics, NESMOS Department, Faculty of Medicine and Psychology, Sapienza University, Rome, Italy

Laura Papetti Department of Pediatrics, Child Neurology Division, ‘Sapienza’ University of Rome, Rome, Italy

Juan A. Pareja Department of Neurology, University Hospital Fundación Alcorcón, Madrid, Spain

Pasquale Parisi Child Neurology, Pediatric Headache Centre, Sleep Disorders Centre, Chair of Pediatrics, NESMOS Department, Faculty of Medicine and Psychology, Sapienza University, Rome, Italy

Julio Pascual Service of Neurology, University Hospital Marqués de Valdecilla and IDIVAL and Departament of Medicine, University of Cantabria, Santander, Spain

Richard Peat eld Princess Margaret Migraine Clinic, Charing Cross Hospital, London, UK

Nadine Pelzer Department of Neurology, Leiden University Medical Centre, Leiden, e Netherlands

Kuan-Po Peng Department of Systems Neuroscience, University Medical Center Hamburg Eppendorf (UKE), Hamburg, Germany; Brain Research Center, National Yang- Ming University, Taipei, Taiwan

Maurizio Pompili Department of Neurosciences, Mental Health and Sensory Organs, Suicide Prevention Center, Sant’Andrea Hospital, Sapienza University of Rome, Italy

Alan M. Rapoport e David Ge en School of Medicine at UCLA, Los Angeles, CA, USA

Sudama Reddi Department of Neurology and Neurotherapeutics, UTSW, Dallas, TX, USA

Matthew S. Robbins Department of Neurology, Weill Cornell Medicine, New York, NY, USA

Carrie E. Robertson Department of Neurology, Mayo Clinic, Rochester, MN, USA

Simona Sacco Institute of Neurology, Department of Applied Clinical Sciences and Biotechnology, University of L’Aquila, L’Aquila, Italy

Fumihiko Sakai Saitama International Headache Centre Saitama Neuropsychiatric Institute, Saitama, Japan

Ann I. Scher Department of Preventive Medicine and Biometrics, Uniformed Services University, Bethesda, MD, USA

Guus G. Schoonman Department of Neurology, Elisabeth-Tweesteden Hospital, Tilburg, e Netherlands

Henrik Winther Schytz Danish Headache Center, Department of Neurology, Righospitalet Glostrup, University of Copenhagen, Copenhagen, Denmark

Vittorio Sciruicchio Children Epilepsy and EEG Center, Bari, Italy

Mamoru Shibata Department of Neurology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan

Stephen D. Silberstein Je erson Headache Center, omas Je erson University, Philadelphia,
PA, USA

Aneesh B. Singhal Department of Neurology, Stroke Service, Massachusetts General Hospital, Boston, MA, USA

Jonathan H. Smith Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA

C. Mark Sollars Projects Department, McMahon Publishing Group

Amaal Starling Department of Neurology, Mayo Clinic Hospital, Phoenix, AZ, USA

Andreas Straube Department of Neurology, University of Munich, Munich, Germany

Christina Sun-Edelstein Department of Clinical Neurosciences, St Vincent’s Hospital Melbourne, Fitzroy, Victoria, Australia

Norihiro Suzuki Department of Neurology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan; Department of Neurology, Shonan Keiiku Hospital, Kanagawa, Japan

Jerry W. Swanson Department of Neurology, Mayo Clinic, Rochester, MN, USA

Gisela M. Terwindt Department of Neurology, Leiden University Medical Centre, Leiden, e Netherlands

Peter van den Berg† Department of Neurology, Isala kliniek, Zwolle, e Netherlands

Hendrikus J. A. van Os Leiden University Medical Center, Department of Neurology, Leiden, e Netherlands

Agnes van Sonderen Department of Neurology, Haga Hospital, e Hague, e Netherlands

Maurice Vincent Neuroscience Research, Eli Lilly and Company, Indianapolis, IN, USA

Shuu-Jiun Wang Brain Research Centre and School of Medicine, National Yang-Ming University; Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan

Marieke J.H. Wermer Leiden University Medical Center, Department of Neurology, Leiden, e Netherlands

Leopoldine A. Wilbrink Department of Neurology Leiden University Medical Centre, Leiden, e Netherlands

Joanna M. Zakrzewska Facial Pain Unit, Division of Diagnostic, Surgical and Medical Sciences, Eastman Dental Hospital, UCLH NHS Foundation Trust, London, UK

Giorgio Zanchin Padua University, Padua, Italy

PART 1

General introduction

1. Classi cation and diagnosis of headache 3. disorders 3

Diagnostic neuroimaging in migraine 17 Mark C. Kruit and Arne May

Jes Olesen and Richard B. Lipton

2. Taking a headache history: tips and tricks James W. Lance and David W. Dodick

4. Headache mechanisms 34 Andrew Charles

5. Headache in history 45 Mervyn J. Eadie

Classification and diagnosis of headache disorders
Jes Olesen and Richard B. Lipton

Introduction

Disease classi cation systems delineate a group of related disorders and provide operational rules for de ning the boundaries among them. Diagnosis refers to the assignment of a particular individual to a particular diagnostic category (1). A robust disease classi – cation system provides a framework for standardizing diagnosis, studying epidemiology, predicting prognosis, assessing treatment, and implementing therapy in practice (2). Disease classi cation is therefore crucial for both clinical practice and research.

e rst modern attempt to classify headache disorders was undertaken by the National Institutes of Health (NIH) in the United States in 1962 (NIH classi cation) (3). is classi cation described 15 headache disorders but was neither operational nor evidence- based. Operational criteria identify features, or combinations of fea- tures, that establish or exclude a particular diagnosis. In the NIH classi cation, migraine was de ned as a subtype of vascular head- ache characterized by recurrent headache, of various durations, in- tensity, and frequency, usually unilateral, associated with nausea/ vomiting and sensory, motor, and mood disturbances (3). is lan- guage is not speci c; as a consequence, two clinicians may assign di erent diagnoses to the same patient using these criteria.

e International Classi cation of Headache Disorders (ICHD), now in its third edition, was designed to address the limitations of the NIH classi cation. First published in 1988 (4), all editions of the ICHD provide operational diagnostic criteria for a broad range of headache disorders. e second edition, ICHD-2 (5), was pub- lished in 2004 and ICHD-3 (6) was published in 2013. All editions have been translated into multiple languages. e ICHD also pro- vides a common language, which facilitates communication world- wide. ICHD-based diagnoses have been used to study epidemiology, natural history, biology, and treatment, leading to many advances in headache medicine. is research has been the foundation for treatment guidelines developed in many countries. roughout this period, the ICHD system has remained the undisputed gold standard for headache classi cation.

ICHD-3 was published in a ‘beta’ version, to facilitate eld-testing. Because the classi cation committee anticipated that changes in the nal version of ICHD-3 would be minor, they encouraged im- mediate use of the beta version both in practice and in research. Publication of the nal ICHD-3 was coordinated with release of the eleventh edition of the International Classi cation of Diseases (ICD-11) from the World Health Organization (WHO). Early adop- tion of ICHD-3 by clinicians generated familiarity and ease of use of the ICD-11. In this chapter, we will review some of the important aspects of the ICHD-3 classi cation and then discuss an approach to its application in clinical practice.

All versions of the ICHD system have many features in common. e basic structure and format of the diagnostic criteria remain unchanged. e ICHD-3 criteria de ne three major categories of disorders: primary headaches; secondary headaches; and cra- nial neuralgias and facial pain (4–6). For primary headache dis- orders, the headache disorder is the problem; the clinical pro le is a manifestation of a condition with a unique pathogenesis, such as migraine with aura or cluster headache. For secondary head- ache disorders, headaches are attributed to an underlying condi- tion such as a disease, trauma, or a drug. Cranial neuralgias and face pain are a distinctive set of disorders described further on in this chapter.

e classi cation speci es that many individuals have more than one type of headache. As a consequence, each type of headache should be diagnosed. Some individuals may have two primary headache dis- orders (migraine and tension-type headache). Others may have a pri- mary headache disorder and a secondary headache disorder (chronic migraine and medication overuse headache). Still others may have a primary headache disorder and a cranial neuralgia (migraine with aura and trigeminal neuralgia). Diagnosis can be di cult in a patient

The ICHD-3 system has continuity with earlier versions

ParT 1 General introduction

with more than one disorder as they may not classify their headache experiences in the same way a headache specialist might.

e ICHD system in all of its incarnations is hierarchical, organ- izing diagnostic entities into major categories with several levels of subcategories, denoted by a multidigit codes (4–6). As a conse- quence, diagnoses can be assigned with a level of precision appro- priate to the diagnostic setting. In general practice, a two-digit code may su ce (e.g. migraine without aura). In neurological practice, two- or three-digit codes can be used. In headache practice or re- search, additional digits of diagnostic coding allow even greater pre- cision. ese hierarchical diagnoses make the ICHD system exible and broadly applicable to a range of settings and purposes.

For both primary and secondary headache disorders diagnostic criteria comprise a series of lettered headings, each of which must be ful lled to make a diagnosis. O en, the lettered criteria can be met in several ways (i.e. two of four pain features), a structure termed ‘polythetic’. Other letter headings can only be ful lled in a single way, a structure termed ‘monothetic’.

Several kinds of features are not generally used in diagnostic criteria. Inheritance is usually avoided as that would create circu- larity in studies of familial aggregation. Treatment responses are also typically not used as no treatment works in every patient with a particular disorder. Requiring a response to a single drug makes diagnosis di cult in patients unable to take that drug. In addition, including treatment as part of the case de nition may interfere with the development of alternative treatments. e only exceptions to this rule are the requirement for an indomethacin response in pa- tients with certain indomethacin-responsive disorders, such as hemicrania continua. e hope is that these exceptions will be re- placed by better operational rules not based on treatment response, as classi cation science advances.

e ICHD-3 classi cation includes important changes for the classi- cation of migraine with aura, chronic migraine (CM), hemicrania continua, nummular headache, hypnic headache, new daily per- sistent headache (NDPH), primary stabbing headache, and primary thunderclap headache (6). We will consider these changes one at a time. Criteria for migraine without aura and tension-type headache remain unaltered and will not be discussed.

Changes in the classi cation of migraine

Migraine with aura

Migraine with aura (1.2) is now de ned at the two-digit level using the criteria speci ed in Box 1.1. Speci c subtypes of migraine with aura are de ned at the third digit level.

Chronic migraine

Classi cation of CM has been very controversial (7). In the ICHD- 3, CM was moved from the Appendix to the main body of the classi cation, based on the criteria shown in Box 1.2. In the re- vision, CM and medication overuse headache can be diagnosed in patients who meet criteria for both disorders—a crucial change from ICHD-2.

In the ICHD-2, CM could not be diagnosed in the presence of acute medication overuse (5). is rule was modi ed for a number of reasons and is consistent with one of the pre-existing classi cation rules: if a primary headache disorder is made signi cantly worse (at least a doubling of headache days) by a secondary cause, then both the primary headache and the secondary headache should be diagnosed and coded. In addition, CM and medication overuse headache occur together with a very high frequency, both in clinic-based and popu- lation studies (8,9). Medication overuse is a risk factor the develop- ment of CM in a person with episodic migraine (EM) (10). In a patient with CM and medication overuse headache, if medication withdrawal is associated with a reversion of CM to EM (<15 headache days per month), then the diagnosis would change to episodic migraine. e separation of migraine into a chronic and an episodic form has been criticized because headache days per month varies within patients with migraine over time. Nonetheless, it is important to distinguish this severely a ected group of patients, who require intensive treat- ment. In addition, there are di erences among persons with EM and CM in terms of epidemiology, imaging, and treatment response.

Familial hemiplegic migraine

Familial hemiplegic migraine can be subtyped based on speci c genetic abnormalities (11). In this sense the disorder is the only pri- mary headache attributed to an underlying cause.

Vestibular migraine

Vestibular migraine is included in the appendix with diagnostic cri- teria developed in collaboration with the Barany Society. ey will serve a useful purpose in the further exploration of this enigmatic and disputed entity.

Box 1.1 Criteria for migraine with aura

. A At least two attacks ful lling criteria B and C.

. B One or more of the following fully reversible aura symptoms:
1 Visual
2 Sensory
3 Speech and/or language 4 Motor
5 Brainstem
6 Retinal.

. C At least three of the following six characteristics:

. 1 At least one aura symptom spreads gradually over ≥5 minutes

. 2 Two or more aura symptoms occur in succession

. 3 Each individual aura symptom lasts 5–60 minutes1

. 4 At least one aura symptom is unilateral2

. 5 At least one aura symptom is positive3

. 6 The aura is accompanied, or followed within 60 minutes, by
headache.

. D Not better accounted for by another ICHD-3 diagnosis.

Notes

1 When, for example, three symptoms occur during an aura, the ac- ceptable maximal duration is 3 × 60 minutes. Motor symptoms may last up to 72 hours.

2 Aphasia is always regarded as a unilateral symptom; dysarthria may or may not be.

3 Scintillations and pins and needles are positive symptoms of aura.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Changes in the ICHD-3 classi cation of primary headache disorders

CHaPTEr 1 Classi cation and diagnosis of headache disorders

Box 1.2 Criteria for chronic migraine

. A Headache(migraine-likeortension-type-like)1on≥15days/month for >3 months, and ful lling criteria B and C.

. B Occurring in a patient who has had at least ve attacks ful lling cri- teria B–D for 1.1 Migraine without aura and/or criteria B and C for 1.2 Migraine with aura.

. C On ≥8 days/month for >3 months, ful lling any of the following:2
1 Criteria C and D for 1.1 Migraine without aura.
2 Criteria B and C for 1.2 Migraine with aura.
3 Believed by the patient to be migraine at onset and relieved by a
triptan or ergot derivative.

. D Not better accounted for by another ICHD-3 diagnosis.3–5

Notes

. 1 The reason for singling out ‘1.3 Chronic migraine’ from types of epi-
sodic migraine is that it is impossible to distinguish the individual episodes of headache in patients with such frequent or continuous headaches. In fact, the characteristics of the headache may change not only from day to day, but even within the same day. Such pa- tients are extremely dif cult to keep medication-free in order to observe the natural history of the headache. In this situation, attacks with and those without aura are both counted, as are both mi- graine-like and tension-type-like headaches (but not secondary headaches).

. 2 Characterization of frequently recurring headache generally requires a headache diary to record information on pain and associated symptoms day-by-day for at least one month.

. 3 Because tension-type-like headache is within the diagnostic criteria for ‘1.3 Chronic migraine’, this diagnosis excludes the diagnosis of ‘2. Tension-type headache’ or its types.

. 4 ‘4.10 New daily persistent headache’ may have features suggestive
of ‘1.3 Chronic migraine’. The latter disorder evolves over time from ‘1.1 Migraine without aura’ and/or ‘1.2 Migraine with aura’; therefore, when these criteria A–C are ful lled by headache that, unambigu- ously, is daily and unremitting from <24 hours after its rst onset, code as ‘4.10 New daily persistent headache’. When the manner
of onset is not remembered or is otherwise uncertain, code as
‘1.3 Chronic migraine’.

. 5 The most common cause of symptoms suggestive of chronic mi-
graine is medication overuse, as de ned under ‘8.2 Medication- overuse headache’. Around 50% of patients apparently with
‘1.3 Chronic migraine’ revert to an episodic migraine type after drug withdrawal; such patients are in a sense wrongly diagnosed as ‘1.3 Chronic migraine’. Equally, many patients apparently overusing medication do not improve after drug withdrawal;
the diagnosis of ‘8.2 Medication-overuse headache’ may be in- appropriate for these (assuming that chronicity induced by drug overuse is always reversible). For these reasons, and because of the general rule to apply all relevant diagnoses, patients meeting criteria for ‘1.3 Chronic migraine’ and for ‘8.2 Medication-overuse headache’ should be coded for both. After drug withdrawal, mi- graine will either revert to an episodic type or remain chronic, and should be re-diagnosed accordingly; in the latter case, the diag- nosis of ‘8.2 Medication-overuse headache’ may be rescinded.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Box 1.3 Criteria for nummular headache

. A Continuous or intermittent head pain ful lling criterion B.

. B Felt exclusively in an area of the scalp, with three of the following
four characteristics:
1 Sharply-contoured
2 Fixed in size and shape 3 Round or elliptical
4 1–6 cm in diameter.

D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Nummular headache

Nummular headache was added to Chapter 4. is entity is charac- terized by a ‘coin-shaped’ spot on the scalp, o en in parietal head regions (Box 1.3).

Nummular headache may arise as a response to trauma or surgery but most o en occurs spontaneously (13). It is relatively rare but may be severe and debilitating.

Primary headache associated with sexual activity

e criteria for primary headache associated with sexual activity have been simpli ed. e division into pre-orgasmic headache and orgasmic headache is not supported by prospective studies (14–16).

Hypnic headache

Although hypnic headache retains its onset during sleep, the cri- terion based on age has been removed, as have the requirements for severity and type of headache (Box 1.4).

New daily persistent headache

e criteria for NDPH have changed markedly (6,17,18). e diag- nostic criteria focus exclusively on the sudden onset within 24 hours of a continuous headache, which must have been present for at least three months and is not better accounted for by another diagnosis (Box 1.5).

Primary stabbing headache

Primary stabbing headache has re ned criteria, which are presented in Box 1.6 (19).

Primary thunderclap headache

Primary thunderclap headache has headache features identical to those of headache attributable to subarachnoid haemorrhage but

Box 1.4 Criteria for hypnic headache

. A Recurrent headache attacks ful lling criteria B–E.

. B Developing only during sleep, and causing wakening.

. C Occurring on ≥10 days per month for >3 months.

. D Lasting from 15 minutes up to 4 hours after waking.

. E No cranial autonomic symptoms or restlessness.

. F Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Hemicrania continua

Hemicrania continua has been moved from Chapter 4 (Other Primary Headaches) to Chapter 3 (Trigeminal Autonomics Cephalgias). is change is justi ed by the fact that hemicrania continua and the other trigeminal autonomic cephalgias are characterized by trigeminal pain and ipsilateral autonomic features (12).

ParT 1 General introduction

Box 1.5 Criteria for new daily persistent headache

. A Persistent headache ful lling criteria B and C.

. B Distinct and clearly remembered onset, with pain becoming con-
tinuous and unremitting within 24 hours.

. C Present for >3 months.

. D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Box 1.7 Criteria for primary thunderclap headache

. A Severe head pain ful lling criteria B and C.

. B Abrupt onset, reaching maximum intensity in <1 minute.

. C Lasting for ≥5 minutes.

. D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

without evidence of such haemorrhage. is is a diagnosis of in- clusion that requires a very speci c clinical phenotype, described in Box 1.7, and a diagnosis of exclusion, in that underlying causes have to ruled out by extensive investigation, including magnetic resonance imaging or computed tomography angiography and venography (20).

Part of the problem may be in the de nition of the primary thunderclap headache. Diagnostic criteria require that headache be maximal within 1 minute. e impression is that the true time from onset to peak intensity (i.e. as opposed to the use of the word ‘sudden’, for example) is not always accurately elicited in emer- gency departments and therefore headaches that take longer to develop may mistakenly be categorized as primary thunderclap headache. Future prospective studies regarding this issue are necessary.

In the ICHD-2, a secondary headache diagnosis became de nite if the headache disappeared or greatly improved, either spontaneously or following treatment of the secondary cause. e general format for secondary headache disorders in the ICHD-3 are summarized in Box 1.8 (16).

Remission of headache with improvement of the causative dis- order is not a reliable sole diagnostic criterion for secondary head- ache. Headache may persist a er trauma for more than 3 months (21), and parallel patterns may occur with other secondary head- ache disorders. e temporal relationship of headache onset and remission in relation to the emergence and remission of disorders thought to cause secondary headache is a fertile area for future research.

Headache attributed to trauma or injury to the head and/or neck

Chronic post-traumatic headache was renamed ‘persistent headache attributed to traumatic injury to the head’ to parallel the naming of other secondary headache disorders. e criteria require headache onset within 7 days of trauma or within 7 days of becoming able to communicate the history clearly (21). As the period of increased risk of headache onset following head injury is uncertain, the Appendix provides criteria for delayed onset persisting headache attributed to traumatic injury.

Headache attributed to cranial or cervical vascular disorder

Accumulating evidence con rms that headache is a frequent symptom of many types of cerebrovascular disorders, including disease of large and small arteries, veins, and dural sinuses. Based on accumulating knowledge, disorders have been regrouped and names have been changed. e term reversible cerebral vasocon- strictor syndrome (RCVS) is now applied to the disorder previously known as benign vasculopathy of the brain (Box 1.9) (20).

e disorder is o en benign but may be associated with pos- terior reversible encephalopathy syndrome, arterial dissection, and ischaemic and haemorrhagic stroke (20,22–25). If recurrent thun- derclap headaches occur in the absence of other causes, a diagnosis of RCVS should be considered. RCVS may be responsive to oral or parenteral calcium channel blockers.

Changes to the ICHD-3 classi cation of secondary headache

Box 1.8 Criteria for general diagnostic criteria for secondary headaches

. A Any headache ful lling criterion C.

. B Another disorder scienti cally documented to be able to cause
headache has been diagnosed. Evidence of causation demonstrated by at least two of the following:

. 1 Headache has developed in temporal relation to the onset of the
presumed causative disorder

. 2 One or both of the following:
• headache has signi cantly worsened in parallel with worsening of the presumed causative disorder
• headache has signi cantly improved in parallel with improve- ment of the presumed causative disorder

. 3 Headache has characteristics typical for the causative disorder

. 4 Other evidence exists of causation.

. C Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Box 1.6 Criteria for primary stabbing headache

. A Head pain occurring spontaneously as a single stab or series of stabs and ful lling criteria B–D.

. B Each stab lasts for up to a few seconds.

. C Stabs recur with irregular frequency, from one to many per day.

. D No cranial autonomic symptoms.

. E Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

CHaPTEr 1 Classi cation and diagnosis of headache disorders

Headache attributed to arterial dissection was well de ned in the ICHD-2, but evidence supporting this entity has accumulated (26). Some rare disorders have been assembled under the title headache attributed to genetic vasculopathy.

Headache attributed to non-vascular intracranial disorder

Criteria were revised for a number of disorders in this broad chapter.

Idiopathic intracranial hypertension

e revised criteria for idiopathic intracranial hypertension (IIH) are provided in Box 1.10. e criteria no longer require speci c headache features, headache relief with removal of cerebrospinal uid (CSF), or the presence of papilloedema. To make the diagnostic criteria more speci c, the requisite opening pressure on lumbar puncture was raised to 250 mm water. It was also noted that in some people, particularly children, normal opening pressures may be as high as 280 mm water. Body mass index-strati ed criteria for opening pres- sure were removed. By not requiring papilloedema, the classi cation acknowledges that IIH without papilloedema can exist; a position held among experts and corroborated by the literature (27–29). e neuroimaging ndings associated with IIH are acknowledged (empty sella turcica, distension of the peri-optic subarachnoid space, attening of the posterior sclerae, and protrusion of the optic nerve papillae into the vitreous) but not part of the formal criteria (30).

Headache associated with spontaneous (or idiopathic) low CSF pressure

Criteria for low-pressure headache were changed as indicated in Box 1.11. Requirements for orthostatic headache associated with speci c symptoms were dropped because CSF leaks occur in the ab- sence of a postural headaches (31,32). Now the diagnosis requires any headache associated with low CSF pressure or imaging ndings that document a CSF leak.

Headache and neurological de cits associated with CSF lymphocytosis

Revised criteria emphasize that headache and neurological de cits associated with CSF lymphocytosis (HaNDL) is associated with sensory, language, or motor de cits that last four or more hours in contrast with the typically shorter-lived de cits that typify transient ischaemia attacks and migraine with aura (Box 1.12).

Headache attributed to a Chiari malformation type 1

Criteria for headache attributed to Chiari malformation type 1 are provided in Box 1.13. e criteria require short-lived headache, lasting less than 5 minutes, provocation by Valsalva, or posterior

Box 1.9 Criteria for headache attributed to reversible cerebral vasoconstriction syndrome (RCVS)

. A Any new headache ful lling criterion C.

. B RCVS has been diagnosed.

. C Evidence of causation demonstrated by at least one of the following:

. 1 Headache, with or without focal de cits and/or seizures, has led to angiography (with ‘strings and beads’ appearance) and diag- nosis of RCVS

. 2 Headache has either or both of the following characteristics: • recurrent during ≤1 month, and with thunderclap onset
• triggered by sexual activity, exertion, Valsalva manoeuvers,
emotion, bathing and/or showering

. 3 No new signi cant headache occurs >1 month after onset.

. D Not better accounted for by another ICHD-3 diagnosis, and aneur- ysmal subarachnoid haemorrhage has been excluded by appro- priate investigations.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Box 1.10 Criteria for headache attributed to idiopathic intracranial hypertension (IIH)

. A New headache, or a signi cant worsening1 of a pre-existing head- ache, ful lling criterion C.

. B Both of the following:
1 Idiopathic intracranial hypertension (IIH) has been diagnosed2 2 Cerebrospinal uid (CSF) pressure exceeds 250 mm CSF (or
280 mm CSF in obese children)3

. C Either or both of the following:
1 Headache has developed or signi cantly worsened in temporal relation to the IIH, or led to its discovery
2 Headache is accompanied by either or both of the following: • pulsatile tinnitus
• papilledema4

. D Not better accounted for by another ICHD-3 diagnosis.5,6

Notes

. 1 ‘Signi cant worsening’ implies a twofold or greater increase in fre- quency and/or severity in accordance with the general rule on distinguishing secondary from primary headache.

. 2 IIH should be diagnosed with caution in those with altered mental status.

. 3 For diagnostic purposes, CSF pressure should be measured in the absence of treatment to lower intracranial pressure. CSF pressure may be measured by lumbar puncture performed in the lateral de- cubitus position without sedative medications or by epidural or intraventricular monitoring. Because CSF pressure varies during the course of a day, a single measurement may not be indicative
of the average CSF pressure over 24 hours: prolonged lumbar or intraventricular pressure monitoring may be required in cases of diagnostic uncertainty.

. 4 Papilloedema must be distinguished from pseudopapilloedema
or optic disc oedema. The majority of patients with IIH have papilloedema, and IIH should be diagnosed with caution in patients without this sign.

. 5 ‘7.1.1 Headache attributed to idiopathic intracranial hyperten-
sion’ may mimic the primary headaches, especially ‘1.3 Chronic mi- graine’ and ‘2.3 Chronic tension-type headache’; on the other hand, these disorders commonly co-exist with IIH.

. 6 82 Medication-overuse headache should be excluded in pa- tients lacking papilloedema, abducens palsy or the characteristic neuroimaging signs of IIH.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Box 1.11 Criteria for headache attributed to low cerebrospinal uid pressure

. A Any headache ful lling criterion C.

. B Either or both of the following:
1 Low cerebrospinal uid (CSF) pressure (<60 mm CSF)
2 Evidence of CSF leakage on imaging.

. C Headache has developed in temporal relation to the low CSF pres-
sure or CSF leakage, or led to its discovery.

. D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

ParT 1 General introduction

Box 1.12 Criteria for syndrome of transient headache and neurological de cits with cerebrospinal uid lymphocytosis (HaNDL)

. A Episodes of migraine-like headache ful lling criteria B and C.

. B Both of the following:
1 Accompanied or shortly preceded by the onset of at least one of the following transient neurological de cits lasting >4 hours
• hemiparaesthesia • dysphasia
• hemiparesis.
2 Associated with cerebrospinal uid (CSF) lymphocytic pleocytosis (>15 white cells per μl), with negative aetiological studies.

. C Evidence of causation demonstrated by either or both of the
following:

. 1 Headache and transient neurological de cits have developed or
signi cantly worsened in temporal relation to onset or worsening
of the CSF lymphocytic pleocytosis, or led to its discovery

. 2 Headache and transient neurological de cits have signi cantly improved in parallel with improvement in the CSF lymphocytic
pleocytosis.

. D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Box 1.14 Criteria for medication-overuse headache

. A Headache occurring on ≥15 days per month in a patient with a pre- existing headache disorder.

. B Regular overuse for >3 months of one or more drugs that can be taken for acute and/or symptomatic treatment of headache.

. C Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

location. As Chiari malformations may be incidental, characterizing the headache may help avoid unnecessary decompressive surgery. An important di erential diagnostic point is that tonsillar descent may occur in low-pressure headache.

Headache attributed to a substance or its withdrawal

e requirements in the ICHD-2 for changes in headache days in re- lation to changes in medication taking were removed, because they were di cult to ascertain and hard to interpret. Medication overuse headache is now diagnosed in all patients who take medication at a level that exceeds speci ed limits if they have a primary headache that occurs on 15 or more days per month (Box 1.14).

Acute headache induced by substances have emerged as im- portant experimental models providing insights into the mech- anisms of migraine. In particular, calcitonin gene-related peptide (CGRP)-induced headache is important because it was a major stimulus for the development of CGRP receptor antagonists and CGRP antibodies for the acute and preventive treatment of mi- graine, respectively.

Headache attributed to disorder of homeostasis

e criteria for high-altitude headache were re ned based on re- cent papers (33,34). Headache attributed to airplane travel has been added to the ICHD-3 (Box 1.15) (35).

By definition, these headaches occur during plane travel and arise or remit during take-off, or, in the vast majority of cases, during landing. Criterion D requires the exclusion of sinus disorders.

Headache attributed to sleep apnoea was retained in the ICHD-3, but the published evidence supporting its existence is considered weak.

Headache attributed to autonomic dysre exia

Headache attributed to autonomic dysre exia, a new disorder, oc- curs in patients with spinal cord injury. e headache is of sudden onset and di use, typically associated with autonomic symptoms, including a rise in blood pressure o en accompanied by bladder or bowel symptoms (36,37). Triggers include bladder distention, urinary tract infection, bowel distention or impaction, or urological

Box 1.13 Criteria for headache attributed to Chiari malformation type I

. A Headache ful lling criterion C.

. B Chiari malformation type 1 (CM1) has been demonstrated.

. C Evidence of causation demonstrated by at least two of the following:

. 1 Either or both of the following:
• headache has developed in temporal relation to the CM1 or
led to its discovery
• headache has resolved within 3 months after successful treat-
ment of the CM1

. 2 Headache has at least one of the following three characteristics:
• precipitated by cough or other Valsalva-like manoeuvre • occipital or suboccipital location
• lasting <5 minutes

. 3 Headache is associated with other symptoms and/or clinical signs of brainstem, cerebellar, lower cranial nerve and/or cervical spinal cord dysfunction.

. D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Box 1.15 Criteria for headache attributed to airplane travel

. A At least two episodes of headache ful lling criterion C.

. B The patient is travelling by airplane.

. C Evidence of causation demonstrated by at least two of the following:
1 Headache has developed exclusively during airplane travel 2 Either or both of the following:
• headache has worsened in temporal relation to ascent after take-off and/or descent prior to landing of the aeroplane
• headache has spontaneously improved within 30 minutes after the ascent or descent of the aurplane is completed
3 Headache is severe, with at least two of the following three characteristics:
• unilateral location
• orbitofrontal location (parietal spread may occur)
• jabbing or stabbing quality (pulsation may also occur).

. D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

procedures, among others. e dysautonomia can be life threatening. Exclusion of RCVS is important (36).

Headache or facial pain attributed to disorder of the cranium, neck, eyes, ears, nose, sinuses, teeth, mouth, or other facial or cervical structures

is chapter was minimally revised as new data are lacking.

Cervicogenic headache

Criteria for cervicogenic headache in the ICHD-2 required de nite structural lesions in the cervical spine. e criteria have now been broadened to include so tissues of the neck and not exclude tender- ness of cervical muscles (Box 1.16).

As tension-type headache may arise from the myofascial tissues in the head and/or neck distinguishing these disorders may be prob- lematic. Headache attributed to cervical myofascial tenderness has been added to the Appendix, adding additional complexity. If the source of pain is in the muscle, then tension-type headache is the preferred diagnosis. e overlap of these disorders represents an im- portant area for future research.

Headache attributed to temporomandibular disorder

e diagnostic criteria for headache attributed to temporoman- dibular disorder are shown in Box 1.17.

If there are abnormalities of the temporomandibular joint then the diagnosis can be straightforward. If the only abnormality is tenderness of the muscles of mastication it may be di cult to dis- tinguish this disorder from tension-type headache. Strongly held positions and regional dogmatic tradition continue to impede a so- lution to these issues.

Headache attributed to psychiatric disorder

is chapter remains essentially unchanged as almost no new evi- dence has appeared. It is, however, the opinion of the experts that psychiatric disorders, particularly depression and anxiety, may be a cause of headache. A large section in the Appendix concerning headache attributed to psychiatric disorder is designed to stimulate research.

Cranial neuralgias and facial pain

is chapter has been considerably revised in collaboration with col- leagues from the International Association for the Study of Pain.

Classical trigeminal neuralgia

Firstly, we consider the new criteria for classical trigeminal neur- algia (Box 1.18).

ese criteria are very speci c, although speci city may have been achieved at the price of sensitivity. A patient whose pain radiates outside the trigeminal distribution may respond to trigeminal neur- algia therapy. Similarly, although the criteria require the absence of a neurological de cit, using quantitative sensory testing, documented

CHaPTEr 1 Classi cation and diagnosis of headache disorders

Box 1.17 Criteria for headache attributed to temporomandibular disorder

. A Any headache ful lling criterion C.

. B Clinical evidence of a painful pathological process affecting elem-
ents of the temporomandibular joint(s), muscles of mastication, and/
or associated structures on one or both sides.

. C Evidence of causation demonstrated by at least two of the following:

. 1 Headache has developed in temporal relation to the onset of the temporomandibular disorder

. 2 The headache is aggravated by jaw motion, jaw function (e.g. chewing) and/or jaw parafunction (e.g. bruxism)

4 The headache is provoked on physical examination by tempor- alis muscle palpation and/or passive movement of the jaw.

D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Box 1.18 Criteria for trigeminal neuralgia

Recurrent paroxysms of unilateral facial pain in the distribution(s) of one or more divisions of the trigeminal nerve, with no radiation beyond,1 and ful lling criteria B and C.

. A Pain has all of the following characteristics:
1 Lasting from a fraction of a second to 2 minutes2
2 Severe intensity3
3 Electric shock-like, shooting, stabbing, or sharp in quality.

. B Precipitated by innocuous stimuli within the affected trigeminal distribution.4

. C Not better accounted for by another ICHD-3 diagnosis.

Notes

1 2

3 4

In a few patients, pain may radiate to another division, but it remains within the trigeminal dermatomes.

Duration can change over time, with paroxysms becoming more prolonged. A minority of patients will report attacks predominantly lasting for > 2 minutes.
Pain may become more severe over time.

Someattacksmaybe,orappeartobe,spontaneous,buttheremust be a history or nding of pain provoked by innocuous stimuli to meet this criterion. Ideally, the examining clinician should attempt to con- rm the history by replicating the triggering phenomenon. However, this may not always be possible because of the patient’s refusal, awk- ward anatomical location of the trigger and/or other factors.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Box 1.16 Criteria for cervicogenic headache

. A Any headache ful lling criterion C.

. B Clinical and/or imaging evidence of a disorder or lesion within the
cervical spine or soft tissues of the neck, known to be able to cause
headache.

. C Evidence of causation demonstrated by at least two of the following:

. 1 Headache has developed in temporal relation to the onset of the cervical disorder or appearance of the lesion

. 2 Headache has signi cantly improved or resolved in parallel with improvement in or resolution of the cervical disorder or lesion

. 3 Cervical range of motion is reduced and headache is made sig- ni cantly worse by provocative manoeuvres

. 4 Headache is abolished following diagnostic blockade of a cer- vical structure or its nerve supply.

. D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

ParT 1 General introduction
sensory abnormalities in the a ected area are not rare in classical

trigeminal neuralgia (38).

Ophthalmoplegic migraine

Ophthalmoplegic migraine is no longer in the migraine chapter and is instead regarded as a cranial neuropathy, although this decision remains controversial (39–43).

Persistent idiopathic facial pain

Atypical facial pain is now called ‘persistent idiopathic facial pain’. is disorder is characterized by constant boring, burning, pressing facial pain, which contrasts with the electrical, paroxysmal, stabbing, and radiating quality of trigeminal neuralgia. Drugs known to be ef- fective for classical trigeminal neuralgia are generally not e ective.

relation to the ICD-11 and validity testing

Work on the ICHD-3 began before the major structure of the ICD- 11 was decided by the WHO. e WHO has long recognized the enormous importance of headache disorders, as re ected by their Global Burden of Disease study, demonstrating that migraine is the seventh most disabling medical illness in the world (44). e same study shows that headache is the world’s most disabling neurological disease (44).

Given their emphasis on common disorders and diagnosis in general practice, headache disorders are very important to the development of the ICD-11. WHO representatives agreed to use the ICHD-3 in a simpli ed form. In the neurology section of the ICD-11, headache disorders have their own section and all primary headaches are included. e important secondary headaches are also included using cross reference to the causative disorder. is is of tremendous importance to the elds of neurology and headache medicine as all headache disorders will be classi ed in the neur- ology chapter.

Field testing of the ICHD-3 will occur in collaboration with the WHO as they test the ICD-11. The emphasis will be on the clinical utility of ICD-11 in comparison with the ICD-10, based on the evaluation of case vignettes presented online. Field testing will include physicians from all fields including headache experts. Systematic data will be used to determine whether all patients can be classified (completeness) and whether clinicians evaluating the same vignette assign the same diagnosis or diagnoses (reli- ability). Validity will be examined using demographic profile, disability, family history, treatment response, comorbidities, and biomarkers as external validators. Generalizability will be as- sessed by applying the criteria to patients from different settings such as primary care, neurological practice, and headache spe- cialty practice.

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. (5) Headache Classi cation Committee. e International Classi cation of Headache Disorders, 2nd Edition. Cephalalgia 2004;24(Suppl. 1):1–160.

. (6) Headache Classi cation Subcommittee of the International Headache Society. e International Classi cation of Headache Disorders, 3rd edition. Cephalalgia 2018;38:1–211.

. (7) Silberstein SD, Lipton RB, Dodick DW. Operational diag- nostic criteria for chronic migraine: expert opinion. Headache 2014;54:1258–66.

. (8) Chiang CC, Schwedt TJ, Wang SJ, Dodick DW. Treatment of medication-overuse headache: a systematic review. Cephalalgia 2016;36:371–86.

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Taking a headache history Tips and tricks
James W. Lance and David W. Dodick

Introduction

Long before the arrival of computed tomography and magnetic resonance scanning, the most useful diagnostic tool was freely available—a comprehensive case history.

Clinicians vary the order in which they take a history, but it does not matter as long as it covers all the important points that de ne clearly the pattern of headache, helping to place symptoms in an ap- propriate group for diagnostic purposes.

If the headaches are of recent onset or there is a dramatic single episode like a thunderclap headache or acute head injury, we may wish to enquire rst about the patient’s past health, family history, and personal background before obtaining a detailed description of the incident and headache characteristics. One then has a mental picture of the patient’s life before the onset of headache and can com- pare this with their life a erwards.

More o en, when headaches are recurrent and their frequency has progressively increased we prefer to establish the evolution of the headache before dealing with the patient’s past health, and gen- etic and social background.

The headache history

If the patient has more than one type of headache, such as the common combination of migraine and tension-type headache, each should be analysed separately.

A template is now suggested.

Length of illness

• Acute: hours or days.
• Subacute: weeks or months.
• Chronic:years(chronicisusedinamorespeci csensein‘chronicmi-

graine’ to indicate 15 or more migraine-like headaches each month).

Frequency and duration of headaches

ese characteristics establish the temporal pattern of headaches. Check that the answers make sense. Four headaches a week, each lasting 2 days, does not compute, whereas many attacks in a single day, each lasting minutes to hours, may re ect accurately the pattern of cluster headache and other trigeminal autonomic cephalgias (TACs) (Figure 2.1).

Time and mode of onset

Premonitory symptoms:
Many migrainous patients recall familiar sensations the evening

before awakening with a headache the next morning, or in the hours preceding a headache such as:

• neck sti ness;
• yawning;
• drowsiness;
• a sense of elation; • hunger;

• a craving to eat chocolate or other sweet foods.

e sequence of a morning headache following eating chocolate is sometimes mistaken for chocolate being a trigger factor, whereas craving for chocolate may be the rst symptom of a migraine attack.

ese are clear markers for migraine and their recognition opens the way for nocturnal medication to prevent a headache developing the following day, or earlier treatment with acute migraine therapies.

Aura:

Aura symptoms may include visual, sensory, language, motor, or vestibular dysfunction.

e most common aura is a visual disturbance, a zig zag shim- mering ‘forti cation spectrum’ (teichopsia), a ecting some 10% of migrainous patients, with unformed ashes of light (photopsia) being experienced by another 25%. Forti cation spectra usually move slowly across a visual half eld for 10–60 minutes, leaving an area of impaired vision behind them. ey usually precede the onset of headache but may persist until the headache fades, appear during headache, or even without headache as a relatively uncommon ‘mi- graine equivalent’ (acephalgic migraine) (Figure 2.2). Paraesthesia, aphasia, and hemiparesis may also form part of the aura (1). e fea- ture of migraine equivalents that distinguishes them from transient ischaemic attacks is their slow progressive march over the visual elds or body and leisurely disappearance.

Headache characteristics

Headache can be either unilateral or bilateral in migraine patients but is unilateral in nearly all those with cluster headache, TACs,

Thunderclap headache

Migraine

Chronic tension-type headache

Transformed migraine

Cluster headache

Intracranial lesion

Time

Figure 2.1 Temporal patterns of headache.
Reproduced from Lance JW, Migraine and other headaches, Simon & Schuster

(Australia) Pty Limited. Copyright (1998) Lance JW.

trigeminal neuralgia, and, by de nition, all those with hemicrania continua (Figure 2.3). Pain in cluster headache is usually felt deep behind one eye. If the pain is felt mainly below the eye it is known as ‘lower half headache’ or facial migraine and may be confused with sinusitis. Many migraine patients with a recurrent frontal pain are also o en misdiagnosed as having chronic sinusitis.

Quality

Headache may be described as being:

• sudden in onset and explosive (‘thunderclap headache’);

• a tight internal pressure sensation as though the head were being
in ated;

• external pressure like a weight on the head, a band around the
head, or the head being held in a vice;

• intense, stabbing, or boring (cluster headache and TACs);

• throbbing (pulsatile).

Beware of the patient’s description of ‘throbbing’, which is often used to indicate severity or fluctuation in intensity rather than any relationship to the cardiac rhythm. Migraine may start as a dull constant headache but usually becomes pulsatile as severity increases.

‘Ice cream headaches’ from swallowing cold liquids or foods are commonly mid-frontal but may be referred to another part of the head if the su erer is also subject to migraine that habitually a ects that particular area.

Neuralgic pain is usually stabbing as in trigeminal neuralgia but is occasionally constant and burning as in some cases with occipital neuralgia.

Patients with chronic tension-type headache or migraine may also be subject to sudden jabs of pain in the head known as ‘ice-pick pains’.

Associated features

Nausea and vomiting are common accompaniments of migraine. Sensitivity to light, sound, and smells is characteristic of migraine. Touching the scalp or skin may feel painful (allodynia) (2). e super cial temporal arteries may be seen to dilate and become tender to touch. It is as though the normal inhibitory control of af- ferent impulses from the special senses, skin, and blood vessels has been withdrawn as part of a ‘nerve storm’ (3).

Tension-type headache is notable for the absence of these dis- tinctive features, although some patients do complain of a constant mild photophobia or occasional nausea.

Patients with cluster headache and the other TACs commonly experience cranial autonomic symptoms, including Horner’s syn- drome on the side a ected by headache, and are commonly associ- ated with redness and watering of the eye with blockage or running of uid from the nostril on the a ected side.

Headaches secondary to pathological conditions are more likely to be associated with more dramatic symptoms or signs. Neck rigidity is present in most, but not all, cases of subarachnoid haemorrhage, meningitis, or encephalitis. The sudden headache caused by a colloid cyst blocking the flow of cerebrospinal fluid (CSF) in the third ventricle may be accompanied by a ‘drop at- tack’—sudden loss of power in the legs, without necessarily impairing consciousness because of a rapid increase in intra- cranial pressure. Patients may become drowsy, yawn, or vomit without preliminary nausea. Progressive dilatation of one pupil can be seen with a space-occupying lesion such as an extradural or subdural haematoma, causing tentorial herniation to com- press the third cranial nerve, a signal for urgent action.

Skin rashes may be observed in childhood infections, septicaemia, and meningitis. Bony tenderness may be present over the forehead and cheeks in acute sinusitis even if there is no obvious nasal ob- struction, and circumcorneal injection in glaucoma may also indi- cate the source of headache.

Precipitating or aggravating factors

e onset and nature of an aura may be determined by a erent input directed to a speci c part of the cerebral cortex. For example, sun- light ickering through trees when driving along a tree-lined street or ashing lights in a disco can trigger a visual aura. One of our col- leagues reported that holding a vibrating object such as the handle of a motor-powered lawn mower would induce tingling in that hand,

CHaPTEr 2 Taking a headache history: tips and tricks

Premonitory
symptoms Aura

Headache

Migraine with aura

Migraine without aura

Aura alone

Figure 2.2 Classi cation of migraine syndromes according to the appearance of neurological symptoms (shaded areas) in relation
to headache. Premonitory symptoms include changes in mood, alertness, and appetite that may precede migraine by a day or so.

Reproduced from Lance JW, Migraine and other headaches, Simon & Schuster (Australia) Pty Limited. Copyright (1998) Lance JW.

ParT 1 General introduction

Figure 2.3 What part of the head aches? Regions commonly affected by six varieties of head pain are illustrated. Reproduced from Lance JW, Migraine and other headaches, Simon & Schuster (Australia) Pty Limited. Copyright (1998) Lance JW.

spread up his limb on the a ected side, and then develop into a fully blown sensory aura.

Common trigger factors include the following:

• Stress (migraine and tension-type headache). One patient devel- oped a migrainous aura within minutes of receiving a threatening letter from a lawyer.

• Relaxation a er stress (migraine), known as ‘weekend headaches’.

• Phases of the menstrual cycle (premenstrual and mid-cycle when
the blood oestradiol level drops in women).

• Excessive a erent stimuli (glare, ickering light, noise, and strong
perfumes).

• Vasodilator drugs, alcohol (particularly cluster headache) or spe-
ci c foods (migraine).

• Hypoglycaemia or dehydration.

• Excessive intake of tea or co ee (ca eine withdrawal headache).

• Exercise (exertional vascular headache).

• Sexual activity (‘benign sex headaches’, orgasmic headaches).

• Coughing (intracranial vascular headaches, ‘benign cough head-
ache’, and raised intracranial pressure).

• Sustained neck posture or neck movements (upper cervical syn-
drome and tension-type headache).

• Talking,chewing,swallowing,touchingtheface,orfeelingwindonthe
face (trigeminal neuralgia and short-lasting unilateral neuralgiform
headache attacks with conjunctival injection and tearing).

• Change in sleep pattern, too little or oversleeping in the morning
(migraine).

• Extreme weather changes (migraine and tension headache).

• Medications—exacerbation of headache may be caused by medi-
cations. It is important to determine if worsening of headache is temporally correlated with any new medications taken for other conditions, or change in the dosage of medications.
Patients with raised intracranial pressure or space-occupying lesions may complain that the headache is made worse by jolting or jarring of the head, sudden movements, coughing, or straining. Headache

present on standing but eased by lying down suggests a state of low CSF pressure. Facial pain arising from the temporomandibular joints is made worse by chewing, jaw clenching, or grinding the teeth during sleep. Pain may develop in the temporal and masseter muscles (‘claudication of the jaw muscles’) when their blood supply is compromised by temporal arteritis.

Relieving factors

• During migraine headache the patient usually wishes to sit or lie quietly in a darkened room and nds bene t from sleeping, whereas a patient with cluster headache prefers to stand or pace the oor, holding one hand over the a ected eye.

• Pressure on dilated scalp vessels and the use of hot or cold com- presses are o en soothing in migraine and cluster headache.

• Inhaling 100% oxygen through a mask at about 7 litres a minute relieves most patients with cluster headache.

• Relaxation of forehead and jaw muscles reduces the severity of tension-type headache.

• Tension-type headache is o en relieved by drinking alcohol, in contrast to its adverse e ect in migraine and cluster headache.

• Medications—the medications that provide relief from headache are o en informative as to the nature of the headache.

Previous treatments

Any type of treatment tried previously should be listed, with a note about its success or failure. In recording medications used in acute treatment or prophylaxis it is important to ascertain the dosage where ever possible. Some patients may have been prescribed subtherapeutic doses, whereas others may have been consuming large amounts of analgesics without supervision.

Past health

Any illness associated with or preceding the onset of headaches should be listed together with any accident, injury, or operation.

Ice Cream Headache

Sinusitis

Migraine

1 kg

Cluster Headache

Tension Headache

Trigeminal Neuralgia

Headaches may be a feature of infections, acquired immune de – ciency syndrome (AIDS), malignancy, blood dyscrasias, vasculitis, polymyalgia rheumatica, and endocrine disorders. A system re- view for patients with headache should include eyes, ears, nose and throat, teeth, and neck.

Recurrent abdominal pain, vomiting attacks, and motion sickness in childhood are o en precursors of migraine in later life.

A past history of asthma in a patient with migraine cautions against the use of beta blockers, which cause bronchoconstriction, in management.

If there is a past history of a thunderclap headache it is useful to enquire whether spinal root pains, in the buttocks and thighs some hours or days a er the onset of headache, developed (as a pointer to blood tracking down the subarachnoid space to the cauda equina a er haemorrhage).

Family history

More than half of migrainous patients have a positive family his- tory. Twin studies have shown that approximately half of the sus- ceptibility to migraine is of genetic origin and the other half is possibly determined by environmental in uences. Familial hemi- plegic migraine is inherited as a dominant gene. A positive family history for cluster headache has been reported to vary from 3% to 20%.

Personal background

It has been argued in legal circles that only factors of relevance should be included in a medical history. For any physician interested in headaches, any of the facts elicited in obtaining a detailed picture of each individual’s personality, educational background, and life- style may prove to be relevant to his or her susceptibility to head- aches. e following headings may prove useful:

• place of birth and cultural background;

• education (primary, secondary, or tertiary level achieved); when
appropriate, the age of leaving school;

• occupational history;

• marital history, when appropriate;

• lifestyle;

• habits;

• extent of consumption of tea, co ee, ca eine-containing so
drinks, and alcohol, and the history of cigarette smoking, con- sumption of prescribed drugs, and the use of so-called ‘recre- ational drugs’;

• social life, involvement in community a airs;

• hobbies, recreations, and sports.
Unresolved problems may become apparent that could underlie chronic tension-type headache and the increasing frequency of mi- graine attacks. ere may be nancial or sexual problems, a sense of inadequate achievement, and other causes of resentment that may prove important in the psychological aspect of treatment. Some insight is usually gained into whether the patient’s symptoms

are exaggerated by loneliness and introspection, or whether they are being played down by somebody who has an active and interesting life.

Diagnosis based on the history

Onset of headache

e sudden onset of severe headache (thunderclap headache; see Chapter 34) may be the presentation of:

• subarachnoid haemorrhage;

• reversible segmental cerebral vasoconstriction (Call–Fleming
Syndrome; see Chapter 49);

• sexual orgasm headache (which may be associated with the above
form of cerebral vasospasm; see Chapter 25);

• meningitis, encephalitis (see Chapter 41);

• pressor responses as in patients with phaeochromocytoma, or in-
gestion of incompatible medications or tyramine-containing sub-
stances while on monoamine oxidase inhibitors;

• obstructive hydrocephalus (e.g. colloid cyst of the third
ventricle);

• dissection of the carotid or vertebral arteries.
Subacute onset of headache
Possible causes include:
• an expanding intracranial lesion;
• progressive hydrocephalus;
• temporal arteritis in patients older than 55 years (see Chapter 46); • idiopathic intracranial hypertension (see Chapter 39);
• intracranial hypotension (see Chapter 38).
recurrent discrete episodes of headache or facial pain
• Migraine, including ‘lower half headache’ (facial migraine; see Chapter 6).
• Cluster headache (see Chapter 18).
• Trigeminal and other cranial neuralgias (see Chapter 27).
• Transient ischaemic attacks.
• Intermittent obstructive hydrocephalus.
• Paroxysmal hypertension.
• Tolosa–Hunt syndrome.
• Cough; exertional and benign sex headaches (see Chapter 25).
• Hypnic headaches (see Chapter 26).
• Ice cream headache
• Ice pick pains.
• Sinusitis as a cause of facial pain, rarely a cause of episodic head-
ache (see Chapter 45).
Chronic headache or facial pain
• Tension-type headache (see Chapter 29).
• Chronic migraine (see Chapter 31).
• New daily persistent headache (see Chapter 30). • Post-traumatic headache (see Chapter 35).

CHaPTEr 2 Taking a headache history: tips and tricks

ParT 1 General introduction
• Posterior idiopathic (atypical) facial pain (see Chapter 27).

• Postherpetic neuralgia. Conclusion

Well, there it is then, a simple and logical approach that may enable a rm diagnosis to be made on the history alone. If not so, it should at least identify which patients require investigation to identify or eliminate a structural cause for the headaches. Along the way, it is hoped that we have got to know our patient better, avoid some tricks. and obtain some tips for treatment.

rEFErENCES

. (1) Russell MB, Olesen J. A nosographic analysis of the migraine aura in the general population. Brain 1996;119:355–61.

. (2) Selby G, Lance JW. Observations on 500 cases of migraine and allied vascular headaches. J Neurol Neurosurg Psychiatry 1960;23:23–32.

. (3) Liveing E. On Megrim, Sick-headache and Some Allied Disorders. A Contribution to the Pathology of Nerve-storms. London: J &
A Churchill, 1873.

Diagnostic neuroimaging in migraine

Mark C. Kruit and Arne May

Introduction

Migraine is a multiphasic disorder and understanding of its patho- physiology starts with the acknowledegment that migraine is not simply a disease of intermittently occurring pain, but that it involves processes that a ect the brain over time (see Chapters 4 and 6). ese processes seem to lead to increased sensitivity or hyperexcitability of di erent brain regions, facilitating paroxysmal headache and aura (1). E ects on the brain (structure, neurochemistry, function) and neurovascular system have been widely documented during the dif- ferent phases of migraine, and neuroimaging has played a signi – cant role in the current understanding of the pathophysiological processes behind migraine. However, these processes are still only partially understood, are likely multifactorial, and involve several brain structures.

e pathophysiological mechanism behind migraine aura symp- toms is cortical spreading depression (CSD; see Chapter 4). is is a transient activation followed by depression of activity in neural tissue, which slowly propagates in brain tissue (2, 3). CSD most o en involves the occipital lobe, leading to visual symptoms in about 30% of patients. During CSD regional brain hyper- and hypoperfusion reductions of blood–brain barrier integrity and plasma extravasa- tion have been described (see subsection ‘Neuroimaging ndings in (prolonged) aura’).

Neuroimaging has contributed signi cantly to the current neuroscienti c knowledge of structural and functional brain changes during the ictal phase (aura and headache) of migraine (4– 6). It is, however, largely unknown which parts of the brain struc- turally, functionally, or biochemically change earlier on, during the premonitory phase (7). e thalamus, hypothalamus, and prob- ably other deep brain and brainstem structures seem to play a role. Further research focusing on such early changes in the premoni- tory phase may provide insight into when and why brainstem nu- clei and pain networks become paroxysmally dysfunctional, how the trigeminovascular system becomes activated, and what patho- physiological changes precede and characterize the aura symp- toms. Given the diagnostic focus of this chapter, the neuroscienti c neuroimaging ndings (based on, e.g., voxel-based morphometry, di usion tensor imaging, magnetic resonance spectroscopy, etc.) underlying migraine pathophysiology are considered out of scope here, and will therefore not be discussed further.

Diagnostic neuroimaging indications in migraine

e diagnosis of primary headaches is primarily a clinical task, based on history-taking and careful neurological examination. No single instrumental examination has yet been able to de ne or en- sure the correct diagnosis, or to di erentiate idiopathic headache syndromes. However, it is common knowledge that some patients with migraine display irregularities on Doppler ultrasound of cra- nial vessels, abnormalities in electroencephalography readings between and during attacks, and occasionally unspeci c white matter changes on magnetic resonance imaging (MRI). ese white matter changes have been linked with an increased risk of brain lesions in patients with migraine. Although the interpret- ation of nding such white matter changes in individual patients with migraine is clinically challenging, given that functional cor- relates are completely lacking, it may be that they are a markers that indicate risk factors for future stroke or for the development of chronic headache. Longitudinal studies are certainly crucial in assessing whether these lesions are progressive and need the atten- tion of clinicians.

In cases of acute headache (like primary thunderclap headache or a er trauma, etc.) or suspected symptomatic headache, the need for neuroimaging is clearly evident, and will not be discussed further in this chapter. For non-acute headache, as applies to most migraine patients, neuroimaging is overused and is only in selected cases con- sidered to be appropriate.

Computed tomography (CT) and MRI scans are frequently re- quested and performed in migraine patients who seek medical help. O en this is driven by the patient’s anxiety about having an underlying pathological condition, or to improve the patient’s overall satisfac- tion and medical care. e fact that radiological examinations are not particularly invasive or uncomfortable reduces thresholds fur- ther. In selected patients, like those with chronic daily headache with anxiety disorders, it has been shown that neuroimaging reassures patients e ectively and signi cantly reduces costs, possibly by chan- ging the subsequent referral patterns of the general practitioner (8).

However, particularly in patients presenting with typical pri- mary headaches, the very low likelihood of detecting explanatory underlying diseases that change treatment or diagnosis must be con- sidered. Combined results of imaging studies (CT and MRI) in over 3700 headache patients (not exclusively ‘typical migraine’) together

ParT 1 General introduction

shows a low yield of about 0.4% in those with migraine (9–11). In patients with ‘typical migraine’, the yield is likely to be even lower.

A potential risk of unnecessary imaging is the discovery of an in- cidental nding, which eventually needs further diagnostic work- up or follow-up. Further potential problems include false-positive studies, false reassurance from an inadequate study, allergic reaction to contrast agent, and so on (12). Furthermore, the current resource- restricted medical environment requires more and more evidence- based justi cation for diagnostic imaging.

american academy of Neurology recommendations

In 2000, the quality standards subcommittee of the American Academy of Neurology (AAN) published an evidence-based guide- line on the role of neuroimaging in patients with headache to assist physicians in making appropriate choices in diagnostic work-ups (13). A total of 28 studies (from 1966 to 1998) were reviewed. Based on reported rates of ‘abnormalities related to headache that may re- quire further action’ (e.g. acute cerebral infarct, neoplastic disease, hydrocephalus, aneurysm, or arteriovenous malformation) com- bined with data from patient history and neurological examination, the following symptoms were identi ed to increase signi cantly the odds of nding a signi cant abnormality on neuroimaging in pa- tients with non-acute headache (13):

• rapidly increasing headache frequency;

• history of lack of coordination;

• history of localized neurological signs or a history such as sub-
jective numbness or tingling;

• history of headache causing awakening from sleep (although this
can occur with migraine and cluster headache).
Based on these ndings, the following AAN recommendations for non-acute headache were formulated:

• consider neuroimaging in patients with an unexplained abnormal nding on the neurological examination (grade B);

• consider neuroimaging in patients with atypical headache features or headaches that do not ful l the strict de nition of migraine or other primary headache disorder (or have some additional risk factor, such as immune de ciency), when a lower threshold for neuroimaging may be applied (grade C);

• neuroimaging is not usually warranted in patients with migraine and a normal neurological examination (grade B).
European Federation of Neurological Societies guidelines
e European Federation of Neurological Societies (EFNS) pub- lished a similar guideline for the management of non-acute head- ache (revision in 2010) (14), which was also mainly based on a review of published evidence (9, 10). e EFNS guideline includes the following summarized statements relevant for migraine (grade B recommendations):

• in adult and paediatric patients with migraine, with no recent change in pattern, no history of seizures, and no other focal neuro- logical signs or symptoms, the routine use of neuroimaging is not warranted;

• exceptions to this rule should be made in the diagnosis of trigem- inal autonomic headaches and headaches that are aggravated by exertion or a Valsalva-like manoeuvre (11);

• in patients with atypical headache patterns, a history of seizures, or neurological signs or symptoms, or symptomatic illness such as tumours, AIDS, and neuro bromatosis, MRI may be indicated;

• when neuroimaging is warranted, the most sensitive method should be used, and MRI (not CT) is recommended in these cases; • with a normal unenhanced MRI, in the absence of other disease and suspicion on metastasis/vasculitis/etc., there is no need for

additional scanning with gadolinium;
• there is no role for conventional Röntgen techniques;
• digital subtraction angiography is not appropriate in the screening

of patients with headache for intracranial disease.

Summarized recommendations

In the recent meta-analysis by Detsky et al. (11), data from more than 3700 patients were included. e recommendations from this meta-analysis are consistent with the AAN and EFNS guidelines, although additional recommendations were included to perform imaging in cases with (i) non-visual aura (sensory or motor); (ii) an aura that has changed in character; or (iii) an aura that cannot be clearly described as typical of migraine aura.

Since a 2007 case series demonstrated that even cluster headache with a typical time pattern and an excellent response to typical treat- ment can still be caused by underlying structural pathology such as a pituitary tumour, patients with trigeminal autonomic headaches should be considered for neuroimaging (15).

No evidence exists that elderly patients who experience headache, but have normal ndings in a neurological examination, should undergo neuroimaging. However, when patients who are older than 50 years present with a rst or a new type of headache, neuroimaging may be considered.

In summary, patient history, details of symptoms, and careful clin- ical neurological examination are together the most important tools in diagnosing and treating migraine. In most patients with non- acute headache this will lead to a reliable diagnosis (applying the International Classi cation of Headache Disorders (ICHD) criteria) and do not require any further laboratory tests or neuroimaging. While positron emission tomography and functional MRI are of little or no value in the typical clinical setting of primary headaches, they are believed to have vast potential to aid exploration of the pathophysiology of headaches and the e ects of pharmacological treatment.

Box 3.1 summarizes the combined recommendations on the use of neuroimaging in patients with non-acute headache.

Migraine and stroke

Accumulating evidence from the last three or four decades has ex- panded the spectrum of neurovascular pathology linked to migraine (see also Chapters 10 and 37). Initial case reports of ‘migrainous stroke’ were followed by retrospective and prospective, mostly hospital-based, case–control studies assessing the prevalence of clinical ischaemic and haemorrhagic stroke in migraine patients, showing a consistent association between migraine with aura and stroke; the association with migraine without aura is less evident (16,17). MRI studies have further identi ed that migraine is also associated with markers of small vessel disease, including (progres- sive) white matter lesions (WMLs), brainstem T2 hyperintensities,

CHaPTEr 3 Diagnostic neuroimaging in migraine

Box 3.1 Recommendation on the use of diagnostic neuroimaging in non-acute headache

A Consider neuroimaging in non-acute headache patients with ‘red ags’:

• unexplained abnormal ndings on neurological examination;

• (atypical) headaches that do not ful l ICHD-2 criteria for primary
headaches;

• additional risk factors (e.g. immune de ciency, tumours, etc.);

• history of (associated) seizures;

• recent changes in headache pattern;

• non-visual (e.g. sensory or motor) or atypical aura pattern.
B Neuroimaging in not usually warranted in patients with typical mi- graine with or without aura and normal neurological examination. C When neuroimaging is warranted, magnetic resonance imaging is
the primary method of choice.

Box 3.2 Diagnostic criteria for migrainous infarction

. A A migraine attack ful lling criteria B and C.

. B Occurring in a patient with 1.2 Migraine with aura and typical of
previous attacks except that one or more aura symptoms persists for
>60 minutes.1

. C Neuroimaging demonstrates ischaemic infarction in a relevant area.

. D Not better accounted for by another ICHD-3 diagnosis.

1 There may be additional symptoms attributable to the infarction.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

posterior circulation subclinical infarcts, and microbleeds (18–20). And, nally, reports from epidemiological studies on associations between migraine and coronary events (21,22) and all-cause mor- tality (23) further illustrate the broad spectrum of lesions associated with migraine, likely to be explained via complex relationships (24).

e relationship between migraine and stroke is complex, and the following paragraphs will expand on di erent aspects of this relation- ship; neuroimaging examples will illustrate how migraine patients with (suspicion of) haemorrhagic or ischaemic stroke may present.

Firstly, migrainous infarction and its imaging appearances will be described, followed by a section on ‘aura-related’ neuroimaging ndings, because the clinical symptoms of either ‘infarction’ or ‘aura’ are o en very similar in the acute and sub-acute moments of presentation.

Migrainous infarction

Kurth et al. (24) suggested that the rst report on migrainous infarc- tion was probably by Féré (25), who, in 1883, described a patient with migraine who died a er 2 months of headache, visual disturbances, and hemiplegia. Various case reports of migrainous infarction have been published since then, and have made clear that migraine can act as a direct cause of ischaemic stroke. In such cases stroke is as- sumed to be directly and causally related to an acute migraine attack.

Because it is o en impossible by clinical examination alone to di erentiate between transient ischaemic attack, prolonged aura, and migrainous infarction, MRI (notably with di usion weighting) today plays a key role in the diagnosis of migrainous infarction. e current ICHD-III criteria strictly de ne migrainous infarction as ischaemic stroke that occurs when, during a typical migraine with aura attack, one or more migrainous aura symptoms persist longer than 60 minutes, with neuroimaging proof of an associated is- chaemic brain lesion in an appropriate region, and absence of other underlying causes (see Box 3.2) (27).

Based on this de nition, it is indirectly evident that migraine patients who present with ‘prolonged aura symptoms’ require an appropriate neuroimaging work-up with MRI and, when an acute is- chaemic lesion is present, additional diagnostic work-up to exclude other underlying disorders. In cases of co-existing other causes (e.g. cardiac arrhythmia, coagulation disorders, embolism through a pa- tent foramen ovale, cervical artery dissection), the diagnosis then

has to be (changed to) ischaemic stroke co-existing with migraine. e same applies when in a patient with a history of migraine without aura, an ischaemic lesion develops during or a er a migraine attack. In other cases, when criteria are not completely ful lled, ischaemic stroke in a patient with migraine may be categorized as cerebral in- farction of other cause presenting with symptoms resembling migraine with aura (26).

In past decades, the diagnostic criteria for migrainous infarc- tion have been changed (ICHD-1 vs ICHD-2) and studies incon- sistently applied the criteria. is probably explains the relatively wide range (0.8–3.4 per 100,000) of reported annual incidences (28–31), and points at a probable amount of overdiagnosis (32). Although this implies that migrainous infarction is a rare condi- tion, which is further illustrated by Wolf et al. (33), who estimated that it accounts for approximately 2 in 1000 ‘overall’ strokes per year, it needs to be considered that migrainous infarction predom- inantly a ects younger patients. In that age category migrainous infarction was estimated to account for 13% of rst-ever ischaemic strokes (34).

Neuroimaging ndings in migrainous infarction

e largest series of migrainous infarction cases to date have been reported by Wolf et al. (17 cases)(33) and Laurell et al. (33 cases) (33,35). In both reports patients underwent an appropriate stroke work-up, and were diagnosed according to ICHD-2 criteria (Table 3.1) shows the main ndings of the studies.

Both studies reported a clear predominance of infarcts in the pos- terior circulation, supporting previous observations. e low age at stroke onset is a further key nding in both studies; therefore, when treating a young patient presenting with stroke, migrainous infarc- tion should be kept in mind. In both studies, outcome was relatively favourable. Although no studies have systematically examined the appearance of migrainous infarcts, from a number of case reports it is suggested that the ischaemic insults predominantly a ect the cortex when supratentorial. Similarly, cortical ischaemia that crosses di erent vascular territories may also point to a migrainous infarct mechanism, but this is probably an infrequent nding, as in the study by Wolf et al. (33) no such ‘crossing’ lesions were identi ed, neither on di usion-weighted imaging (DWI) nor on perfusion- weighted imaging (PWI). However, aura-related hypoperfusion typ- ically seems to cross territories.

e underlying mechanisms of migrainous infarction are un- known but are probably related to CSD-related changes, including hypoperfusion and changes in blood–brain barrier permeability (which might lead to an exacerbation of local cellular injury caused

ParT 1 General introduction
Table 3.1 Recent case series of migrainous infarction

by ischaemia). Together with factors predisposing to coagulopathy and release of vasoactive neuropeptides, further changes in cere- bral haemodynamics, arterial thrombosis, and infarctions may be explained (19).

In Figures 3.1–3.4 case descriptions illustrate various presentations and appearances of migrainous infarcts. In Figure 3.5 a case with ‘Cerebral infarction presenting with symptoms resembling migraine with aura’ is described, and illustrates that it can be di cult to apply a correct and meaningful diagnosis, given the strict ICHD-2 criteria.

Neuroimaging ndings in (prolonged) aura

According to the ICHD-2 criteria, a diagnosis of persistent aura without infarct can be applied when aura symptoms remain pre- sent for longer than 1 week and when there is no neuroradiological evidence of ischaemia. is is a rare condition that seems to a ect genetic forms of migraine (such as familial hemiplegic migraine) somewhat more o en.

Incidentally, in ‘regular’ migraine with aura patients, aura symp- toms also persist for longer than 60 minutes. When more than one

(b1)

Laurell et al. (34)

Wolf et al. (32)

Cases

n = 33 (all ICHD-2)

n = 17 (n = 11 ICHD-2)*

M:F (%)

39:61

23:77

Age at stroke onset (y)

19–76, median 39

20–71, mean 45

Posterior circulation (%)

Cerebellum (%)

Multiple lesions (%)

Family history of migraine (%)

Patent foramen ovale (%)

* n = 6 had a history of migraine without aura (thus not ful lling the ICHD-2 criteria in the strict sense) and presented with rst-ever neurological symptoms compatible with migraine with aura and concomitant migraine headaches.

(a1) (a3)

(a2) (a4)

(b2)

Figure 3.1 Bilateral occipital migrainous infarction.

A 33-year-old woman with migraine without aura since childhood, and also, since the age of 21, attacks with visual aura. She presented with the usual visual aura symptoms but now has a persisting visual eld defect, and persisting positive scintillating scotoma, accompanied by migraine headache. There were no other neurological signs or symptoms. Family history for migraine with aura was positive. A magnetic resonance imaging (MRI)
scan performed after 1 day of symptoms revealed, bilaterally in the occipital lobe, small cortical areas of diffusion restriction. There were no other abnormalities. Computed tomography angiography of the cervical and intracranial arteries was negative (not shown). There were no other underlying causes. Follow-up MRI after 3 weeks showed only minimal residual hyperintensity on the uid-attenuated inversion recovery (FLAIR) images, consistent with near normalization of the ischaemic foci. Images: (a1) and (a2) FLAIR images; (a3) and (a4) corresponding B1000 diffusion-weighted images in the acute setting; (b1) and (b2) FLAIR images after 3 weeks of follow-up.

Figure 3.2 (see Colour Plate section)

Bilateral occipital and thalamic migrainous infarction.

CBV

TTP

A 61-year-old woman with a long history of migraine with aura presented with a persisting left upper quadrant visual eld defect that had developed during a regular migraine with visual aura attack. (a) Initial non-contrast computed tomography (CT) dubiously showed some reduced grey–white matter differentiation in the right occipital lobe. CT angiography (not shown) showed normal calibre of the carotids, the vertebrobasilar system, and the posterior cerebral arteries; the posterior communicating arteries were not identi ed. (b) Whole-brain perfusion CT demonstrated reduced cerebral blood volume (CBV) and cerebral blood ow (CBF), and prolonged mean transit time (MTT) and time to peak (TTP) values in the right occipital lobe, but also to a lesser degree in the left occipital lobe. (c) Magnetic resonance imaging after 1 day con rmed recent bilateral infarction, with signs of haemorrhagic transformation on the left side (arrowhead), but also identi ed right-sided thalamic infarction. In the following diagnostic work-up, no other underlying causes were identi ed.

aura symptom is present (e.g. visual and sensory symptoms together or in succession), for each type 60 minutes may be accepted. When aura persists for longer, this might point to migrainous infarction, although most o en the symptoms spontaneously normalize, and patients will probably only be scanned incidentally. By de nition, imaging studies in such ‘non-infarct’ cases do not show ischaemic changes, but various case reports and series have described other CSD- or aura-related e ects on the brain tissue and neurovascular system, which will be discussed in the following paragraphs.

Cutrer et al. (36) and Sanchez del Rio et al. (37) studied spontan- eous migraine episodes with perfusion-weighted MRI, including six patients studied during regular (not-prolonged) visual aura, within 31 ± 6 minutes a er the onset of visual symptoms. In all studies perfusion de cits were observed in the occipital visual cortex from which the hemi eld defect was originating. Maximum measured changes were a 37% decrease in cerebral blood ow (CBF), a 33% decrease in relative cerebral blood volume, and an 82% increase in mean transit time (MTT). Several small series and case reports have been published since then, mostly with consistent ndings of mild regional hypoperfusion, uni- or bilaterally a ecting overlapping vascular territories.

Förster et al. (38) reported a prospective study in which pa- tients with suspected acute ischaemic stroke were evaluated. In this study, 33 patients with a nal diagnosis of migraine with aura were

compared with age-matched patients with a nal diagnosis of acute ischaemic stroke. As a consequence of the study methodology, in this cohort the number of patients with ‘rare’ aura symptoms (like hemihypaesthesia, hemiparesis, and aphasia) was over-represented, as well as ‘acute onset’ of symptoms. In 54% (n = 18) of migraine with aura PWI showed hypoperfusion, which involved more than the posterior cerebral artery (PCA) territory in all but one of the patients, although the PCA territory was predominantly involved in 61% of cases. In seven patients (39%) the hypoperfusion extended to the parietal, temporal, or frontal lobe. ere was no clear associ- ation between clinical symptoms and location of perfusion changes. ere were no DWI abnormalities related to the aura symptoms, and there were no vessel occlusions or stenoses on magnetic resonance angiography (MRA). In comparison with acute ischemic stroke pa- tients, the aura patients more o en had hypoperfusion involving more than one territory, and less increased time to peak and MTT ratios. Figure 3.6 (from the original publication by Förster et al. (38)) illustrates a typical ‘prolonged aura’ case with parieto-occipital hypoperfusion without di usion abnormalities, and with subtle dilation of the regional vasculature on MRA.

A few reports pointed to the occurrence of ‘crossed cerebellar diaschisis’ in cases with aura-related perfusion changes. Dodick and Roarke (39) reported a migraine patient with typical attacks of sensory aura for 30–60 minutes followed by headache, who showed

CHaPTEr 3 Diagnostic neuroimaging in migraine

(a) (b) CBF

MTT

(c)

ParT 1 General introduction

Figure 3.3 Bilateral cerebellar migrainous infarction.

A 45-year-old man with migraine with aura, who had visual aura attacks since the age of 35, with an average attack frequency of two per year, presented with the usual visual aura symptoms, which had lasted longer than normal and were accompanied by sensory symptoms over his whole body, and diplopia and dysarthria. Non-enhanced computed tomography (upper row) was performed after a few hours, and showed bilateral cerebellar hypodensities consistent with bilateral cerebellar infarction. A subsequent magnetic resonance imaging scan (T2 images, lower row) con rmed the presence of three cerebellar and one vermian infarct. Magnetic resonance angiography of the cervical and intracranial arteries was negative (not shown). No other underlying causes were found.

reversible reduction in CBF in the le cerebral hemisphere and asso- ciated crossed-cerebellar diaschisis (hypoperfusion in the right cere- bellar hemisphere) during a typical attack on a brain single-photon emission CT (SPECT) scan. Iizuka et al. (40,41) observed in a case with prolonged aura crossed cerebellar hyperperfusion on brain SPECT scan on day 2 a er symptom onset, which was explained as a consequence of uncoupled hyperperfusion with low function in the le cerebral hemisphere (corresponding to the neurological de cits). Both the crossed hyperperfusion and hypoperfusion il- lustrates the possibility of associated ow (and metabolic) alter- ations distant to and opposite of the primary site of disturbances, which could be relevant in understanding the occurrence of silent ischaemic lesions in the cerebellum in migraine patients (see later).

Besides ow alterations, a variety of other imaging ndings have been described on brain imaging during (prolonged) migraine aura, which together may be explained by temporary changes in blood–brain barrier function, which are probably secondary to aura-related CSD and/or spreading hypoperfusion. A number of re- ports described ‘vasogenic leakage’, which may present as regional sulcal hyperintensity on native uid-attentuated inversion recovery (FLAIR) MRI images (42) as (delayed) subarachnoid (sulcal),

leptomeningeal, or cortical gadolinium enhancement on FLAIR or T1-weighted MRI scans (40,41,43,44), or as increased vascular per- meability on perfusion-weighted MRI (45). In a few cases with (pro- longed) aura, symptoms may be associated with reversible cortical swelling and hyperintense signal changes on FLAIR images, distrib- uted along the regional cortical ribbon corresponding to the symp- toms, without clear di usion restriction (vasogenic oedema) (46). Figure 3.7 provides an examples of ‘increased vasogenic leakage’ as presented in the literature.

Besides the (rare) presentation of ‘migrainous infarction’ (i.e. dir- ectly related to a migraine attack), migraine patients also have a higher chance of presenting with an ischaemic or haemorrhagic stroke unrelated to a migraine attack.

Over the past four decades, many observational studies, hospital- based stroke case–control studies, and population-based studies have evaluated the association between migraine and clinical

Migraine as a risk factor for clinical ischaemic stroke

CHaPTEr 3 Diagnostic neuroimaging in migraine

Figure 3.4 Subacute right occipital migrainous infarct.

A 58-year-old man with migraine with aura, with visual and sometimes sensory aura attacks since childhood, presented with a history of recent persisting visual aura symptoms for >1 week, followed by partial spontaneous recovery. Magnetic resonance imaging was performed to exclude ischaemia or other underlying causes. The scan was performed 12 days after the start symptoms, and showed a subacute occipital corticosubcortical infarct on the right: hyperintensity on FLAIR and T2 slices (open arrows); cortical diffusion restriction and signs of cortical necrosis (arrows). Note a small lipoma in the vermis, initially diagnosed as suspicious for an arteriovenous malformation (arrowhead).

ischaemic stroke. Meta-analyses of these studies revealed that mi- graine patients are about at doubly increased risk (16,47,48), which notably applies to patients with migraine with aura. Schürks et al. (16) calculated a pooled relative risk of 1.7 (95% con dence interval (CI) 1.3–2.3) for migraineurs versus controls (16). Data speci ed by migraine subtype were available from eight studies, resulting in a pooled relative risk of 2.2 (95% CI 1.5–3.0) for patients with mi- graine with aura and 1.2 (95% CI 0.9–1.7) for patients with migraine without aura versus controls. A higher migraine frequency seems also to further increase the risk of ischaemic stroke (49,50). Owing to the lower prevalence of migraine in men, the association between migraine and ischaemic stroke is less certain in men.

e risk is highest in women, notably at younger age (<45 years), and in this group the risk further increases (up to 10 times in- creased risk) with concurrent use of oral contraceptives. In indi- vidual studies the e ects of concurrent hypertension and heavy smoking showed a greater than multiplicative e ect on risk (51,52). Associations with markers of endothelial dysfunction and factors linked to prothrombotic or pro-in ammatory conditions have also been suggested as explanatory for the increased stroke risk in mi- graine (53). Genetic factors, including polymorphisms in MTHFR, ACE, MEPE, and IRX4, g have been linked with both migraine and

ischaemic stroke, but further studies are needed to assess the patho- physiological relevance of such ndings.

Topographical and pathophysiological considerations

Few structured data exist on the topography of non-migrainous infarcts in migraine patients. In a large series of 3500 patients with acute stroke, 130 (3.7%) had active migraine, and about 50% of these were <45 years of age. In the younger patients, posterior circulation involvement (55%) was characteristic (54). From case reports and small series is was also suggested that the occipital lobe and/or the posterior cerebral artery territory seem to be over- represented in migraine patients with clinical ischaemic stroke (55). Øygarden et al. (56) retrospectively investigated whether the lesion pattern on DWI MRI scans was di erent between mi- graineurs (with and without aura; n = 196) and non-migraineurs (n = 720) with clinical ischaemic stroke. In the migraine group, younger patients and women were over-represented, and in- farcts were more o en due to cardio-embolism and less o en due to small vessel disease, than in the control group. Migraine pa- tients presented more o en with symptoms from the posterior circulation and had more cortical (odds ratio (OR) 1.8, 95% CI 1.3–2.5), small (OR 1.9, 95% CI 1.04–3.5), cerebellar (P = 0.026),

ParT 1 General introduction

(a) (b) (c) (d)

Figure 3.5 Cerebral infarction presenting with symptoms resembling migraine with aura.

A 46-year-old woman with migraine with aura, with regular attacks of (left-sided) visual aura since the age of 22, woke up in the morning with right-sided hemiparesis and aphasia, with associated migraine-like headache, which was followed in the hospital by a unilateral pulsating headache with nausea and vomiting, resembling her prior migraine attacks. The non-contrast computed tomography scan in the acute setting showed slight hypodensity (not shown). A magnetic resonance imaging (MRI) scan 1 day later con rmed a cortically restricted zone of cytotoxic oedema in the left middle cerebral artery (MCA) territory involving parts of the frontoparietal and insular cortex, consistent with her symptoms ((a) T2-weighted images; (b) B1000 diffusion-weighted images; (c) sagittal and coronal uid-attenuated inversion recovery (FLAIR) images). Additional diagnostic work-up remained negative for other underlying causes. The patient recovered completely, although a follow-up MRI scan after 1 year ((d) FLAIR images) showed postischaemic cortical parenchymal loss. The cortically restricted infarct was considered somewhat unusual for ordinary MCA stroke and might have been due to aura-related cortical spreading depression. However, because the infarction was not clearly temporally related to a migraine with aura attack that was similar to previous attacks, the diagnosis was ‘Cerebral infarction presenting with symptoms resembling migraine with aura’, and not ‘migrainous infarction’.

(a) (b) (c) (d) (e)

Figure 3.6 (see Colour Plate section) Regional hypoperfusion in prolonged aura.

Example of multimodal magnetic resonance imaging in migraine aura. (a) Diffusion-weighted imaging is unremarkable, while (b–d) perfusion maps (time to peak, cerebral blood ow, cerebral blood volume) demonstrate an extensive hypoperfusion in the left frontal, parietal and occipital lobes. (e) Magnetic resonance angiography demonstrates subtle dilation of the left middle cerebral artery branches.

Figure 3.7 Reversible disturbed blood–brain barrier in (prolonged) aura

Fluid-attenuated inversion recovery images acquired 10 hours after
onset of sensory aura symptoms (numbness around the lips on the
right side of the face that spread to the right hand within 5 minutes and lasted for more than 1 hour) in a 22-year-old woman with a history of migraine without aura. Images show (arrows) linear hyperintensity in several parietotemporal sulci, without signal changes in the underlying parenchyma. There were no diffusion- or perfusion-weighted imaging abnormalities and there was no gadolinium enhancement (not shown).
A lumbar puncture ruled out a subarachnoid haemorrhage; cerebrospinal uid was normal. Follow-up after 4 days showed normalization of the magnetic resonance imaging scan (not shown).

Reproduced from Neurology, 70, 24, Gómez-Choco, M., Capurro, S. & Obach,
V., Migraine with aura associated with reversible sulcal hyperintensity in FLAIR,
pp. 2416–2418. Copyright © 2008, American Academy of Neurology. DOI: https:// doi.org/10.1212/01.wnl.0000314693.57386.f0.

and occipital infarcts (13.3% vs 8.6%; P = 0.05). Migraine patients with infarcts had a three-times-higher chance of having a patent foramen ovale.

Øygarden et al. (56) suggested that the higher frequency of smaller lesions in migraineurs with aura may point at a higher vulnerability to damage following minor ischaemic insults (as was similarly de- scribed in experiments in mice with familial hemiplegic migraine) (57), or that ischaemia in migraineurs may simultaneously lead to a small, ‘clinically silent’ ischaemic lesion (that normally would not be noticed) and ischaemia-triggered CSD resulting in ‘clinical’ stroke- like neurological de cits leading to hospital admission (56).

Although the earlier study results were criticized (e.g. because of potential misclassi cation, referral bias, lack of neuro-imaging proof, etc.), the consistent ndings in several studies over the years have migraine set today as an acknowledged ischaemic stroke risk factor. It has to be noted that in absolute terms stroke in young women with migraine (estimated at 5.5/100.000 annually) (58) re- mains rare, although at the same time, in this age group migraine should be considered an important risk factor.

Data on a possible association between migraine and haemorrhagic stroke have remained inconsistent for years. However, in 2013, Sacco et al. (17) meta-analysed a total of four case–control (59–61) and four cohort studies (62–65) that together included 320,539 individ- uals in whom 1600 intracerebral or subarachnoid haemorrhages oc- curred. Migraine patients were found to be at signi cantly increased

risk for haemorrhagic stroke (OR 1.48, 95% CI 1.2–1.9; P = 0.001). ere was no clear di erence between migraine with aura (OR 1.6, 95% CI 0.9–3.0; P = 0.13) or migraine without aura (OR 1.4, 95% CI 0.7–2.62; P = 0.3), male and female patients, or younger and older subjects with migraine, although Kuo et al. (65) reported higher risks in migraine with aura, men, and patients <45 years of age. A limitation in the review by Sacco et al. (17) was that subarachnoid and intraparenchymatous haemorrhages could not be separated. Next to ischaemic stroke, patients are thus likely to be at increased risk for haemorrhagic stroke, although the mechanisms likely di er and remain to be elucidated, and subgroups most at risk still need to be identi ed.

Migraine as a risk factor for subclinical stroke

Posterior circulation infarcts

e population-based cross-sectional Cerebral Abnormalities in Migraine, and Epidemiological Risk Analysis (CAMERA) MRI study (n = 435) assessed whether people with migraine were are at increased risk for several types of ‘silent’ (or subclinical) brain le- sions and whether certain areas of the brain were particularly vul- nerable (66). None of the participants reported a history of stroke or transient ischaemic attack, or showed relevant abnormalities at standard neurological examination.

In the migraine with aura group, 8% of patients had one or more posterior circulation infarcts. is was signi cantly higher com- pared with controls (0.7%; P = 0.005) and migraineurs without aura (2%). e highest risk was found in those with migraine with aura with ≥1 attack per month (OR 15.8, 95% CI 1.8–140). Infarct size ranged from 2 to 21 mm. Most lesions were located in the cere- bellum, typically in a border zone location (Figure 3.8). e average number of lesions per patient was 1.8. Although migraine-related clinical strokes seem to have a predilection for the occipital lobes, in the CAMERA study none of the posterior circulation infarcts was in the occipital lobes.

Migraine patients with posterior circulation infarcts were signi – cantly older, but cardiovascular risk factors were not more prevalent, and the presence of these lesions was not signi cantly associated with supratentorial brain changes, such as WMLs. ese two obser- vations suggest that the lesions are not atherosclerotic in origin. e combination of vascular distribution, deep border zone location, shape, size, and imaging characteristics on MRI makes it likely that the lesions have an ischaemic origin. e most likely aetiological mechanism seems to be hypoperfusion and/or embolism rather than atherosclerosis or small vessel disease.

e higher risk for those with a higher attack frequency may point to migraine-attack related mechanisms. During and a er migraine attacks, low cerebral ow below an ischaemic threshold has been described (36,37,67–69). eoretically, a decrease in brain perfu- sion pressure (e.g. during migraine) a ects the clearance and des- tination of embolic particles; narrowing of the arterial lumen and endothelial abnormalities stimulate formation of thrombi; and oc- clusive thrombi further reduce blood ow and brain perfusion (70). Because the deep cerebellar territories have a pattern of progres- sively tapering arteries with only few anastomoses present, they are likely to be particularly vulnerable to hypoperfusion-related border

CHaPTEr 3 Diagnostic neuroimaging in migraine

Migraine as a risk factor for clinical haemorrhagic stroke

ParT 1 General introduction (a)

(b)

(c)

Figure 3.8 Cerebellar infarcts in patients with migraine with aura.

Corresponding T2-weighted (left) and uid-attenuated inversion recovery (right) magnetic resonance images showing (multiple) cerebellar infarcts (arrowheads) in three migraine with aura patients from the CAMERA study.

zone infarct mechanisms (71,72). is hypoperfusion-related con- cept matches the ndings of previous studies in which the small cerebellar border zone infarcts, in particular when multiple, were strongly associated with severe occlusive and/or (artery-to-artery) embolic disease based on vertebrobasilar atherosclerosis, likely to result in hypoperfusion and infarction.

e population-based Age, Gene/Environment Susceptibility (AGES)-Reykjavik study (n = 4689) con rmed these ndings, and also reported a signi cantly higher prevalence of cerebellar infarcts on MRI scans in female migraine with aura patients in later life (23% vs 15%; P <0.001) (73). In that study, there was no increased risk for cortical or subcortical infarcts on MRI for migraine patients.

In the 9-year follow-up CAMERA-2 study, 66% of the original sample was rescanned with the same MRI scanners and protocols. None of the infarcts present at baseline had disappeared. Only in the migraine group had new posterior circulation infarcts occurred (5% vs 0%; P = 0.07) (20).

Other population-based evidence for silent infarcts in migraine

In the Epidemiology of Vascular Ageing study (EVA; n = 780) mi- graine with aura patients (n = 17) had over a threefold increased risk (OR 3.4, 95% CI 1.2–9.3) vs controls (n = 617) for any infarct on MRI, and there was a suggestion that migraine with aura patients were at increased risk for multiple infarcts (OR 3.7, 95% CI 0.8–17) (74). In this study, most infarcts were located outside the cerebellum or brainstem, and the number of patients was, unfortunately, too small for further statistical testing of speci c infarct locations like cerebellum (5.9% vs 2.8%) and thalamus (11.8% vs 2.1%) in mi- graine with aura versus control participants.

e MRI substudy of the Northern Manhattan Study (NOMAS) included 546 racial/ethnically diverse population-based partici- pants; 65% were Hispanic. Migraine patients had a signi cantly higher risk of subclinical brain infarcts (OR 2.1, 95% CI 1.0–4.2), which was even higher in migraineurs without aura (OR 2.6, 95% CI 1.3–5.5). In the groups of participants aged >75 years, 30% of mi- graineurs had at least one infarct on MRI versus 15% of controls. In this study, infarcts were found most commonly in the white matter (13%) and cerebellum (10%) (75).

In summary, an association between migraine and subclinical infarcts is well established by now. Similarly to clinical ischaemic stroke, migraine with aura patients are at highest risk. e exact mechanisms and potential consequences need further evaluation and research. e posterior circulation territory is probably most vulnerable in migraine patients.

Migraine and T2 hyperintensities on MrI

White matter lesions in migraine

From the early days of MRI, reports exist on the presence of WMLs on T2-weighted images in migraine patients. Initial clinic-based studies presented data on WMLs in migraine patients, but results were o en uncontrolled, inconsistent, or con icting. Some studies evaluated migraine subtypes, also with inconsistent results. One

study found that migraine attack frequency was related to an in- creased prevalence of WMLs. Despite the various limitations and discrepancies in those MRI studies, a meta-analysis summarized the results of seven case–control studies, and reported that migraine pa- tients were at four times increased risk (OR 3.9, 95% CI 2.3–6.7) for WMLs, regardless of comorbidities like cardiovascular risk factors, demyelinating disease, in ammatory conditions, and valvular heart disease (18).

White matter lesions in migraine: the CaMEra- 1 and CaMEra-2 studies

Because the clinic-based studies mentioned in the previous section su ered from methodological di culties, and might have evaluated a more severe than average subgroup of migraine patients (due to their ‘clinic-based’ origin), the cross-sectional population-based CAMERA MRI study was carried out (see ‘Migraine as a risk factor for subclinical stroke’). In women of the CAMERA cohort, the risk of having a high deep WML load (top twentieth percentile of the dis- tribution of deep WML load; Figure 3.9) was increased in migrain- eurs versus controls (OR 2.1, 95% CI 1.0–4.1). is risk was higher in those with a higher attack frequency (≥1 attack/ per month; OR 2.6, 95% CI 1.2–5.7), and was similar among women with migraine with and without aura. Among men, the prevalence of deep WMLs did not di er between controls and migraineurs. No association was found between the severity of periventricular WMLs and migraine, irrespective of sex or migraine frequency or subtype.

e nding of higher risks in those with a higher attack fre- quency was suggestive of a potential causal relationship between migraine attacks or attack severity and the development of WMLs. erefore, the 9-year follow-up CAMERA 2 study (n = 286, mean age 57±8 years) was carried out to test for accumulative e ects of recurrent attacks and to study the underlying mechanisms and possible cognitive consequences (20).

In the follow-up study, again there were no di erences in WMLs between male participants with migraine versus controls. However, deep WML volume was higher in female migraineurs than in con- trols (P = 0.04), and their deep WML progression was more severe (77% vs 60%; P = 0.02), which was highest in those with migraine without aura (83%). Multivariate logistic regression showed that mi- graine was independently associated with deep WML progression (OR 2.1, 95% CI 1.0–4.1; P = 0.04). e increase in total deep WML volume was explained by an increased number of new lesions, rather than by an increase in size of pre-existing lesions. Figure 3.10 shows an example of incident lesions in a female migraine patient a er 9 years of follow-up. e mean size of individual hyperintensities at follow-up did not di er between participants with migraine and controls. Among females with migraine, deep WMLs appeared to be more di usely distributed than in controls (Figure 3.11). Hypertension and diabetes were not associated with a higher inci- dence of deep white matter hyperintensity progression. Exploratory analyses showed no association of number of migraine attacks, mi- graine attack duration, migraine frequency, type of attack, or mi- graine therapy with deep WML progression. ere was also a lack of signi cant decline in cognitive function correlated with WMLs in the CAMERA-2 study.

CHaPTEr 3 Diagnostic neuroimaging in migraine

ParT 1 General introduction

Figure 3.9 Focal small-to-medium-sized deep white matter lesions in a 47-year-old woman with migraine.

White matter lesions in migraine: other population-based evidence

In the longitudinal EVA study (n = 780; mean age 69 ± 3 years), participants with a history of any severe headache (including mi- graine) were at increased risk of higher WML volumes (OR 2.0, 95% CI 1.3–3.1) versus controls, with similar ndings for deep and peri- ventricular WMLs (74). In participants with migraine with aura the associations with WMLs were strongest.

A subset of participants of the Atherosclerosis Risk in Communities (ARIC) cohort study (n = 1028) received two MRI examinations, 8–12 years apart. e authors also showed, in a cross- sectional analysis, that migraine without aura is associated with WMLs (OR 1.9, 95% CI 1.0–3.4). However, they failed to demon- strate that migraine was associated with WML volume progression. Di erences in lesion-quanti cation methodology, in the de nition of progression, in the older age, size and other characteristics of the cohort, and so on, might explain why the ndings seem to contrast with the ndings of the CAMERA-2 study.

Unexpectedly, in the NOMAS study (n = 546; two-thirds of parti- cipants were >60 years of age), no association between WML volume

Figure 3.10 Fluid-attenuated inversion recovery images showing pre- existing (arrowhead) and newly developed (arrows) deep white matter lesions after 9 years of follow-up in a 37-year-old (at baseline) female migraine without aura patient.

and migraine or its subgroups was found. e authors suggested that no di erence was detected because of the high burden of other car- diovascular risk factors in the racially diverse older cohort.

Pathophysiological mechanisms?

Although the pathological substrate of WMLs in migraine re- mains unknown, the most likely histological substrate of these ab- normalities is incomplete infarction with changes such as gliosis and demyelination (76). e causative mechanisms, however, re- main largely unknown. Di erent explanatory options have been described.

Attack-related mechanisms may play a role, as was suggested by the higher risk of WMLs in the CAMERA-1 study, and as seems likely given the occurrences of migrainous infarcts. During attacks, reduced blood ow in large and/or small arteries (37,69), possibly in combination with vasoconstriction or activation of the clotting system/platelets (77,78), might lead to formation of local thrombi. Alternatively, local tissue changes during migraine attacks, such as excessive neuronal activation, neurogenic in ammation, neuropep- tide and cytokine release (79), or excitotoxity (80), may occur and such changes may lead directly to tissue damage. Reversible MRI abnormalities during migraine aura, including areas of increased vasogenic leakage (46) and evidence of blood–brain barrier dys- function in prolonged aura (40,41,44) seem to illustrate the possi- bility of direct e ects to the brain during attacks, most likely rst acting on the level of the microvasculature (81), and possibly being enhanced by other factors like a matrix metalloproteinase-9 de- pendent cascade mechanism, which may increase the risk of local tissue damage (82).

However, because the progression of WMLs and occurrence of infarcts in the CAMERA cohort was not dependent on persisting migraine activity, and also because of the attack-unrelated increased risk of clinical ischaemic strokes in migraineurs, attack-unrelated factors also seem to play a role. With increasing age, when attacks generally diminish, other systemic migraine ‘disease-related’ condi- tions leading to WMLs are possibly increasing, and likely compli- cate the detection of attack-related mechanisms. Attack-unrelated factors could, for example, include chronic procoagulatory or pro- in ammatory changes due to endothelial dysfunction (83,84), ele- vated homocysteine levels (85–87), or recurrent paradoxical (micro-)

Baseline

Follow-up (9 years)

Controls Migraine with aura

CHaPTEr 3 Diagnostic neuroimaging in migraine Migraine without aura

Figure 3.11 (see Colour Plate section) Topography and progression of deep white matter lesions (WMLs) in female migraine patients and controls

Baseline and follow-up deep WMLs are projected on transparent three-dimensional maps (normalized for differences in group size; controls, n = 52; migraine with aura, n = 75; migraine without aura, n = 57).

emboli due to right-to-le shunts (88). In addition, population-based evidence that migraine (with aura) is associated with a higher car- diovascular risk pro le might contribute to the risk of (ischaemic) brain lesions (89).

Brainstem lesions

In the CAMERA-1 study, infratentorial hyperintense lesions (IHLs) were also signi cantly more prevalent in migraine patients (4.4.%) compared with controls (0.7%; P = 0.04) (67). e ma- jority of the IHLs were located in the pons. e CAMERA-2 study showed that a er 9 years of follow-up the prevalence of IHLs re- mained higher in women with versus without migraine (21% vs 4%; adjusted OR 6.5, 95% CI 1.5–28.3 (P = 0.01)), and that they also more o en showed progression of IHLs (15% vs 2%; adjusted OR 7.7, 95% CI 1.0–59.5 (P = 0.05)) (20). Figure 3.12 shows typ- ical examples of T2 hyperintensities in the brainstem and their progression over time.

Typically, brainstem lesions were located in the dorsal basis pontis, adjacent to the tegmentum, at the level of, and slightly cranial to, the entry zone of the trigeminal nerve. In nearly all cases lesions were located bilaterally, sometimes extending to the midline; none reached the surface of the pons. Hyperintensities seem to involve the pontocerebellar bres, the pontine nuclei, or the nucleus reticularis tegmenti pontis, and, in some cases, parts of the corticopontine (pyr- amidal tract) or medial lemniscus bres. ese anatomical locations

are supplied by the anteromedial and anterolateral groups arising from the basilar artery.

Earlier reports in non-migraineurs linked pontine IHLs to patients with cardiovascular risk factors, leukoaraiosis, lacunar infarcts, and poor clinical outcome a er stroke (90–92). Histopathologically, pon- tine IHLs correspond to myelin pallor and reactive astrocytosis. e pathophysiology of these lesions is assumed to be comparable as for lesions in subcortical arteriosclerotic encephalopathy (i.e. ischaemia secondary to small artery sclerosis). ere is a good correlation be- tween MRI ndings and histopathology (90). Similar hyperintense brainstem lesions are also frequent in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a disorder in which migraine with aura is o en the pre- senting symptom (93). In CADASIL, decreased cerebral perfusion secondary to changes in the wall of cerebral arteries leads to early damage of the white matter. Regions that are irrigated by the longest perforating arteries are most vulnerable to hypoperfusion. is is particularly the case for the central part of the pons. Similarly, as discussed earlier for deep WMLs, migraine attacks might causally be related to the brainstem lesions, because repeated or prolonged reduced perfusion has been described in migraine attacks, although not speci cally in the pons (69). Alternatively, attack-unrelated ‘sys- temic’ factors could also explain the association, maybe in combin- ation with suggested impaired adaptive cerebral haemodynamic mechanisms in the posterior circulation of migraine patients (94).

ParT 1 General introduction
(a) (b) (c)

Figure 3.12 Infratentorial hyperintense lesions (IHLs) in migraine.
T2-weighted images of baseline and 9-year follow-up of three migraine patients from the CAMERA study, showing increasing loads of IHLs: either

(a) newly developed lesions (arrowheads), (b) additional lesions (open arrows), or (c) increases in size (arrows), compared to baseline.

‘Subclinical’ MrI ndings in the individual migraine patient

e knowledge from hospital- and population-based studies that mi- graine is an independent risk factor for deep WMLs, IHLs, and sub- clinical infarcts does not imply that when such lesions are identi ed on a brain MRI scan in a migraine patient that migraine is ‘the cause’. In routine neuroradiological practice, T2 hyperintense lesions in the white matter are frequently encountered in those older than 50 years of age, but also appear in younger individuals. No studies found clear preferential locations or distribution patterns for patients with mi- graine with WMLs. erefore, in most patients with migraine and WMLs, the lesions will remain ‘non-speci c’. e identi cation of a limited number of small-to-medium-sized lesions in adults with mi- graine does therefore generally not need further medical attention.

Incidentally, WMLs are observed on MRI scans in relatively young patients (e.g. <40 years of age). In such cases, the number, location, aspect, and distribution of the lesions have to be care- fully evaluated, and based on the images and clinical history to- gether, the likelihood of other diseases that are associated with WMLs (such as multiple sclerosis; vasculitis; CADASIL; mito- chondrial encephalomyopathy, lactic acidosis, and stroke-like epi- sodes; coagulation disorders; cardiac abnormalities, etc.) has to be

considered. ‘Migraine’ is part of this di erential diagnostic list, but other options should never be disregarded.

Similarly, the identi cation of one or more silent cerebellar in- farcts on an MRI scan cannot directly be attributed to ‘migraine’, although this nding—with the data from the CAMERA stud, showing that 8% of patients with migraine with aura from the gen- eral population a ected—is not so unusual in migraine patients with aura. In such cases, if the observation is incidental, no direct clin- ical consequence seems to be necessary. If future research indicates that there is a risk of progression of number or size of lesions, or if there are associated functional consequences, an additional study of causes and evaluation of the usefulness of preventive therapy has to be initiated. However, a patient who presents with an acute cere- bellar infarct, irrespective of the size of the lesion or presence of mi- graine, has to be screened for (embolic) sources of the infarction, and treated accordingly.

Conclusion

Migraine is a prevalent disorder. Knowledge of the pathophysiology of migraine allows better interpretation of neuroimaging ndings in migraine patients, who may present both in acute situations and in regular outpatient settings.

Follow-up (9-years) Baseline

A migraine patient may present during a migraine attack with neurological de cits. Normal neurological aura symptoms need to be di erentiated from ‘prolonged aura’ and ischaemic stroke. When a clinical diagnosis is not possible, urgent neuroimaging is mandatory. Neuroimaging may show heterogeneous changes during ‘prolonged aura’, which can mostly be di erentiated from ndings in true ischaemia. If ischaemia is identi ed during a mi- graine attack, this might be either due to true migrainous infarc- tion, to ischaemic stroke co-existing with migraine, or to cerebral infarction of other cause presenting with symptoms resembling migraine with aura.

Migraine patients, notably those with aura, and in the younger age category, are also at increased risk of clinical ischaemic or haemor- rhagic stroke unrelated to a migraine attack. e exact mechanisms behind these associations are still unknown, although attack- unrelated ‘systemic’ pro-in ammatory, prothrombotic, endothelial, cardiac, and genetic factors probably play a role, and may be part of ‘migraine as a disease’. Migraine is associated with subclinical in- farcts, and supratentorial and infratentorial T2 hyperintense lesions on MRI. e higher prevalence of such lesions is probably explained by similar pathophysiological mechanisms.

Neuroimaging in migraine patients is overused in non-acute situ- ations; recommendations have been formulated to identify patients in whom neuroimaging is warranted.

CHaPTEr 3 Diagnostic neuroimaging in migraine

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Headache mechanisms

Andrew Charles

Changing paradigms regarding headache mechanisms: moving away from vascular hypothesis

Migraine and cluster headache were, for decades, considered to be ‘vascular headaches’, based on the presumption that the vasculature played a primary role in headache pain in these disorders. However, extensive recent studies have shown that changes in the calibre of either extracranial or intracranial vessels are neither necessary nor su cient to cause migraine pain. Recent high-resolution magnetic resonance angiography studies have shown that the neither evoked nor spontaneous migraine headache are correlated with the dilation of intracranial or extracranial arteries (1,2). Furthermore, signi – cant vasodilation evoked by substances such as vasoactive intestinal peptide is not necessarily correlated with headache (3). us, while signi cant vascular changes may occur with some types of primary headache, it is likely that these changes are a re ection of activity in the brain and in perivascular nerves that are responsible for head- ache, rather than representing a primary cause of pain. It is now clear that acute and preventive headache therapies do not work primarily by constricting blood vessels or by preventing vasodilation (2).

Consistent with the vascular hypothesis of headache, the throbbing quality of migraine and other types of headache was presumed to be a re ection of aberrant sensitivity to vascular pulsation. Recent studies, however, provide strong evidence against this presumption. When examined quantitatively, the ‘throb rate’ of migraine pain is generally signi cantly slower than that of the arterial pulse, and their phase is not consistently correlated (4). is observation indicates that other mechanisms must be involved in the throbbing nature of migraine headache; one possibility is that this could be a re ection of slow oscillations in cellular activity in the thalamus or brainstem.

Migraine mechanisms

The predisposition to migraine

e genetics of migraine provide important information about mi- graine pathophysiology. Migraine has a substantial genetic com- ponent, but apart from the rare hemiplegic migraine syndromes, most familial migraine is unlikely to involve a single gene. Rather,

combinations of multiple genes and epigenetic factors are involved. Of the genes that predispose to migraine that have been identi ed thus far, there is no single unifying mechanism that is common to all of them. It is interesting to consider how such a diverse array of genes can ultimately contribute to the same clinical phenomenon. A better understanding of the nal common pathways through which these genes predispose to migraine is likely to lead to more de nitive acute and preventive therapies (see Figure 4.1).

Neurophysiological changes in migraine patients

A variety of clinical neurophysiology approaches indicate alterations in brain excitability, connectivity, and sensory processing between attacks in migraine patients. Among these alterations are increased photic driving and synchronization of speci c electroencephalog- raphy (EEG) rhythms between attacks (5–8). Between attacks, mi- graine patients have also been found to have reduced habituation of cortical responses and re exes evoked by either repetitive noxious or non-noxious stimuli (9–13). e habituation of cortical responses to non-noxious stimuli normalizes during attacks. Further, the amp- litude of high-frequency oscillations in somatosensory-evoked re- sponses, a pattern of activity believed to re ect connectivity between the thalamus and cortex, is higher in migraine patients between attacks than in controls, and also normalizes during attacks (14,15). Whether these di erences between migraine patients interictally and controls re ect increased or decreased brain excitability re- mains the subject of debate, but it seems clear that the excitability of the ‘migraine brain’ is more variable that that of those without migraine. Taken together, the di erences suggest that migraine in- volves dysregulation of normal coordination between the activity of the thalamus and the cortex (16).

The serotonin hypothesis

A number of studies, primarily measuring serum and platelet levels of serotonin, have suggested that interictal serotonin levels are lower in patients with migraine than in controls (17,18). Functional imaging studies also suggest alterations in serotonin and/or its recep- tors in migraine patients between attacks. A single photon emission computed tomography study using a radioactive ligand targeting the brain serotonin transporter found signi cantly increased binding of the ligand in the brainstem as compared with controls, consistent with either low levels of serotonin or higher levels of the transporter

CHaPTEr 4 Headache mechanisms

CORTICAL WAVES

• Cortical spreading depression • Astrocyte waves
• Vascular waves

?↑ BBB permeability

AURA

• Visual
• Sensory • Cognitive • Motor

HEADACHE

PREDISPOSING FACTORS

• Genes
• Sex/Hormones • Drugs
• Environment

DYSREGULATION OF EXCITABILITY

• Brainstem
• Hypothalamus • Thalamus
• Cortex

ACTIVATION OF PAIN PATHWAYS

• Activation of trigemino-cervical complex, periaqueductal gray, thalamus, sensory cortex

• Release of CGRP
• ? Release of PACAP, NO, ATP

ACTIVATION AND SENSITIZATION

Brainstem Hypothalamus Thalamus Cortex

ASSOCIATED SYMPTOMS

• Photo/phonophobia • Cutaneous allodynia • Nausea
• Vertigo

• Fatigue

PREMONITORY SYMPTOMS

Yawning Polyuria Fatigue
Neck pain Photophobia Mood change

Figure 4.1 Schematic of basic mechanisms of migraine.
BBB, blood–brain barrier; CGRP, calcitonin gene-related peptide; NO, nitric oxide; ATP, adenosine triphosphate.

(19). Similarly, a positron emission tomography (PET) study showed increased brain binding of a ligand speci c for the 1A subtype of sero- tonin receptors (5-hydroxytryptamine (5-HT)1A receptors) between attacks in patients with migraine without aura, consistent either with reduced levels of serotonin or an increased density 5-HT1A receptors in migraine patients (20). A PET study using a radioactive marker of 5-HT synthesis found that global brain 5-HT synthetic rate was slightly but not signi cantly reduced in migraine patients between attacks compared with controls (21). Administration of the 5-HT1 agonist buspirone was reported to evoke a signi cantly greater re- lease of prolactin in migraine patients in the interictal state compared with controls, suggesting increased central 5-HT1 receptor sensitivity in migraine patients between attacks (22). ese studies all point to- ward low levels of serotonin in migraine patients between attacks, suggesting that these reduced central nervous system serotonin levels could increase the propensity to migraine. As with many of the neurochemical and physiological changes observed in migraine, it is not clear whether these observed changes in serotonin are a cause or e ect of migraine. While the e cacy of triptans, selective agonists of 5-HT1B, D, and F receptors, suggests a role for serotonin in mi- graine therapy, the lack of e cacy of most selective serotonin uptake inhibitors as migraine preventive therapies argues against low levels of brain serotonin as a primary causative mechanism of migraine. Regardless of the exact role of the serotonin system in migraine, it clearly remains a critically important therapeutic target.

The premonitory phase

A signi cant percentage of migraine patients consistently experi- ence multiple symptoms prior to the onset of aura or headache

(see also Chapter 6), including light sensitivity, neck pain, fatigue, yawning, mood change, and polyuria, among others (23–25). ese symptoms may occur up to several hours before headache, and some individuals can reliably identify the onset of a migraine attack based on these symptoms (26). PET studies in the premonitory phase in triggered migraine have now identi ed changes in brain activity that are correlated with these symptoms, including the posterolateral hypothalamus, midbrain tegmental area, periaqueductal gray, dorsal pons, and cortical areas, including occipital, temporal, and prefrontal cortex (27). As discussed earlier, electrophysiological studies also indicate signi cant changes in brain function in the hours prior to headache.

Although both imaging and clinical neurophysiological studies indicate that widespread changes in brain excitability occur be- fore headache, one particular brain region that may play a critical role is the hypothalamus. Changes in mood, appetite, and energy that precede headache are suggestive of alteration in hypothalamic function, and functional imaging studies demonstrating increased blood ow in the hypothalamus both before and during migraine attacks support an important role for this brain region (27,28). is is of particular interest because multiple hypothalamic peptides may therefore represent novel targets for therapies that could be adminis- tered during the premonitory phase of headache, rather than during later phases of an attack during which all therapies may be less ef- fective. One example of a such a hypothalamic target is the orexins, which show promise in animal models as potential mediators of mi- graine and therapeutic targets (29).

e fact that some of premonitory symptoms can also be evoked by dopamine agonists led to the hypothesis that the premonitory phase

ParT 1 General introduction

of migraine involves the release of dopamine (30,31). e observa- tion in a small study that the dopamine antagonist domperidone could abort an impending attack even when taken before headache supported this hypothesis (32), although this nding has not been validated in further studies.

Migraine and other primary headache disorders commonly have sensitivity to light, sound, touch, and smell as prominent symptoms. is increased sensory sensitivity is generally considered to re ect ‘central sensitization’, i.e. changes in sensory processing in the brain or spinal cord that amplify peripheral sensory signals. In traditional pain models, central sensitization occurs as a secondary consequence of the transmission of pain signals from the periphery. In migraine and other headache disorders, however, sensory sensitivity may pre- cede pain by up to hours (26,33), and this prodromal sensory sensi- tivity may be correlated with changes in the activity of related brain regions (27). e early occurrence of sensory sensitivity before pain indicates that, contrary to traditional pain models, central sensitiza- tion in headache can be a primary event rather than a secondary con- sequence of painful input from the peripheral nervous system.

Migraine aura

Migraine aura is de ned as a transient change in vision, somatic sensation, language, motor function, or brainstem function that precedes or accompanies headache. Approximately 30–40% of mi- graine patients experience at least two auras in their life, and there- fore qualify for a diagnosis of migraine with aura (34,35). e visual, sensory, language, and motor symptoms are caused by alterations in cortical function that may propagate from one region to another. While traditionally considered to be a distinct phase of a migraine at- tack that triggers subsequent symptoms, including pain, prospective examination of the timing of migraine symptoms relative to aura indicates that headache and other migraine symptoms commonly occur simultaneously with aura (36). ese observations suggest that the pain and associated symptoms of migraine may occur in parallel with aura, rather than as a direct downstream consequence of the aura phenomenon.

Clinical features of the visual aura

e classic migraine visual aura is a ‘scintillating scotoma’, a ick- ering, bright, typically jagged front that expands in multiple direc- tions over a few minutes to 30 minutes, leaving its wake an area of decreased or absent vision (37) (see also Chapter 6). It is important to recognize, however, that this visual phenomenon is, in fact, only one of a variety of visual phenomena that can be part of the mi- graine visual aura. Flashing lights, scotomas without a positive edge, colours in the visual eld, or simply distortion of vision are also commonly reported (38,39). It is also common for these visual phe- nomena to be stationary and xed in size, rather than the classically expanding visual percept.

Systematic detailed recording of migraine aura percepts by indi- viduals have revealed a number of important features (40). Firstly, they may begin in di erent regions of the visual eld, indicating that the underlying phenomenon is not invariably initiated at a single cortical focus. Secondly, the pattern of spread in the visual eld is not necessarily consistent with a concentric spread in the visual cortex, but rather may be more consistent with a wave of xed width travelling along a single sulcus or gyrus. irdly, even with an atten- tive observer, the visual phenomenon may disappear for minutes at

time, before reappearing in a location consistent with the concept that the wave has propagated through a region of cortex without producing any symptoms. is observation raises the possibility that ‘silent aura’ may, indeed, occur when the underlying change in cor- tical activity occurs in a region of cortex that does not generate any positive or negative neurological symptoms.

Imaging studies of the migraine aura

Functional imaging studies have shown signi cant changes in brain metabolism and blood ow in some patients during migraine aura (41–43). e most commonly seen change is hypoperfusion (44), although hyperperfusion may also occur (45). PET studies have also shown decreased metabolism in association with migraine aura (46). It is not clear whether or not these changes occur uni- versally in patients with migraine aura, as clinical experience and case reports (47) indicate that many patients have normal com- puted tomography and magnetic resonance imaging (MRI) scans while experiencing aura. In cases of prolonged aura or hemiplegic migraine, vasogenic oedema and breakdown of the blood–brain barrier may be observed (48–50). ere may be disruption of the normal coupling between brain activity and blood ow during migraine aura. Hypometabolism in the presence of normal blood ow has been reported (46,48,51), and studies using transcranial Doppler have shown impaired vascular reactivity during a migraine aura or headache (52).

Cortical spreading depression

Cortical spreading depression (CSD) is a wave of excitation followed by inhibition of neural and glial activity that propagates slow across the brain surface. e temporal characteristics of CSD are very similar to those of the spread of the visual percept of the migraine aura across the visual cortex. is similarity led to the assumption, which has been held since the original description of CSD in the 1940s, that CSD is the physiological substrate of the migraine aura (53). CSD in humans with brain injury has now been extensively characterized using electrodes placed directly on the brain surface (54,55). While changes suggestive of CSD have been observed with magnetoencephalography in migraine patients (56), the de nitive electrophysiological features of CSD have never been observed in migraine. is may be because standard surface EEG recordings do not detect the phenomenon. Regardless, it is important to recognize that we are still without de nitive proof that CSD, as it is observed in animal models or in brain injury, is the same physiological phenom- enon that underlies migraine aura.

Evidence from experimental models provides strong circum- stantial support for a role of CSD in migraine. ree di erent gene mutations associated with familial hemiplegic migraine, as well as one mutation associated with familial migraine with and without aura, each reduces the threshold for induction of CSD (57–60). e threshold for induction of CSD is also reduced by female sex, as well as by oestrogen, consistent with the signi cantly higher prevalence of migraine in women compared with men (58,61). Finally, multiple established migraine preventive medications with diverse mechan- isms of action have all been reported to inhibit CSD, whereas related medications that do not prevent migraine do not inhibit CSD (62– 64). While there are some exceptions to CSD as a predictive model (65), the majority of known migraine preventive therapies tested to date have been reported to inhibit CSD.

In rodents or other animal models which have a lissencephalic cortex (no sulci or gyri), CSD expands as a concentric wave, like that produced by a pebble in a pond. As discussed, however, ana- lysis of the percept of the visual aura suggests that the alteration in cortical activity underlying migraine aura may travel with more limited expansion along individual sulci or gyri. Several experi- mental triggers can evoke CSD in animal models, including local mechanical stimulation or injury, tetanic or DC electrical stimu- lation, KCl, CaCl2, hypo-osmotic medium, metabolic inhibitors, ouabain, glutamate receptor agonists, endothelin, and micro- emboli (66). Elevations in extracellular K+ and activation of glu- tamate receptors appear to play key roles in the initiation of CSD (67–73). As discussed, it is well demonstrated that brain injury can trigger CSD in humans. For migraine, however, the mechanisms underlying the spontaneous occurrence of CSD are not clear. It is possible that multiple di erent cellular pathways, perhaps driven by di erent genetic variations, could lead to spontaneous increases in K+ and glutamate release through distinct mechanisms in dif- ferent individuals.

Neurovascular uncoupling with CSD

Both in rodent models and in humans, the propagated wave of CSD can be followed by sustained uncoupling of the normal vas- cular response to neural activity. In rodents, vasoconstriction and decreased blood ow persist for up to an hour in the face of a pro- longed membrane depolarization and recovery of neuronal activity (74,75). Delayed activation of trigeminal nociceptors following CSD has been reported, raising the possibility that the prolonged neurovascular uncoupling that follows CSD contributes to the acti- vation of pain by this phenomenon (76).

CSD as a cause of headache?

CSD in animal models is associated with release of a number of messengers that could be involved in the generation of headache, including nitric oxide (77,78), adenosine triphosphate (79), calci- tonin gene-related peptide (CGRP) (80–83), and high-mobility group box 1 (84). CSD has been shown to cause activation of tri- geminal nociceptive neurons as indicated by immunohistological labelling for c-Fos in the brainstem (85), as well as by electrophysio- logical recording of neurons in the trigeminal ganglion and brain- stem (76,86). CSD has also been reported to cause changes in the activity of brainstem neurons responsible for trigeminal pain pro- cessing directly via descending central pathways (87,88), indicating that CSD may in uence subcortical regions implicated in migraine headache directly, without the requirement for trigeminal or other peripheral input.

Whether or not CSD as it occurs in animal models is, indeed, the mechanism underlying the migraine aura remains an open question. Similarly, the potential role of CSD as a trigger for the headache of migraine remains unresolved. It is possible that CSD is a manifestation of neurochemical and cellular changes that are occurring di usely in the brain during a migraine attack, ra- ther than it being a fundamental cause of headache. Advances in imaging and non-invasive electrophysiological techniques are likely to provide more de nitive information about the occurrence of CSD in migraine and its role in causing the symptoms of a mi- graine attack.

CHaPTEr 4 Headache mechanisms The headache phase

The anatomy of headache

The trigeminal nerve

e trigeminal nerve is believed to be primarily responsible for carrying pain signals that are responsible for headache for migraine and other primary headache disorders. e ophthalmic division (V1) of the trigeminal nerve innervates the dura of the anterior cra- nial fossa (89). Branches of V1 travel with branches of the middle meningeal artery, and also along the superior sagittal sinus. A re- current meningeal branch of V1, the nervus tentorii of Arnold, innervates the dura mater of the parieto-occipital region, the ten- torium cerebelli, the posterior third of the falx cerebri, and the su- perior sagittal and transverse sinuses (89). Branches of the V2 and V3 divisions of the trigeminal nerve are also believed to innervate the middle cranial fossa. Recent studies in humans and rodents have shown that trigeminal meningeal a erents may have extracra- nial projections (90,91), raising the possibility that this could be a pathway by which extracranial triggers (and therapies) could modu- late intracranial mechanisms of migraine.

The cervical nerves and the trigeminocervical complex

Although multiple primary headache disorders are commonly re- ferred to as ‘trigeminovascular’ disorders, it is important to recog- nize that other nerves apart from the trigeminal nerve may also play important roles. e rst three cervical nerves (C1, C2, and C3), in particular, may be important mediators of primary headaches. Patients commonly report neck pain in the premonitory phase or the postdromal phase of migraine, as well as during the headache phase. Animal studies and some human studies indicate that C1–C3 in- nervate the dura of the posterior cranial fossa (89,92,93). Pain input from the C1–C3 nerves converges with input from the trigeminal nerve in the caudal portion of the trigeminal nucleus caudalis in the medulla and cervical spinal cord, known as the trigemino-cervical complex. Animal studies indicate that stimulation of the occipital nerve (comprised of branches of C2 and C3) leads to increased ring of second-order neurons receiving trigeminal input from the sagittal sinus, and the reverse is also true (94,95). Interestingly, stimulation of rostral structures in the cervical spine in humans may evoke pain that radiates to the frontal or periorbital region (96). Selective stimulation of the C1 nerve, but not the C2 and C3 nerves, has also been shown to evoke pain around the eye in individuals with migraine (97). One explanation for these referral patterns may be the sensitization of central neurons in the trigemino-cervical complex, with overlapping central representations of input from trigeminal and cervical inputs.

Other brain regions implicated in migraine pain include the periaqueductal gray, the dorsolateral pons, the rostral ventromedial medulla, the thalamus, and the parietal cortex (98). Stimulation of the periaqueductal gray in the brainstem has been reported to evoke migraine-like headache (99), and in animal models this region con- tains 5-HT1B and 5-HT1D receptors that are activated by triptans (100). PET studies have consistently shown activation of the dorso- lateral pons during migraine attacks, particularly on the side ipsi- lateral to the pain (101). Increased activation of the thalamus has been visualized with functional MRI (fMRI) in migraine patients who have widespread allodynia associated with their attacks (102).

ParT 1 General introduction

Whether activation of these regions is a cause or a consequence of migraine headache, or activation of any region is speci c to mi- graine as compared with other types of pain, remain open questions.

The pharmacology of headache

e triptans, selective agonists at 5-HT1B, 5-HT1D, and 5-HT1F recep- tors, are remarkably e ective in aborting a migraine attack, indicating a key role for serotonin in the inhibition of migraine. Despite their clear role as a potent modulator of migraine, however, the location and mechanism of action of the triptans remains uncertain. A key unanswered question is whether the primary site of the therapeutic action of triptans is outside of the brain, within the brain, or both. Triptans were developed as migraine therapeutics based primarily on their actions as constrictors of meningeal vessels (103). Animal studies, however, have shown that 5-HT1B, 5-HT1D, and 5-HT1F re- ceptors are all expressed in the brain and have antinociceptive func- tions at multiple central sites (104). In animals models, triptans have been shown to inhibit nociceptive signalling in the trigeminal nu- cleus caudalis, periaqueductal gray, and thalamus (100,105,106). Whether or not triptans in fact reach these central sites of action, and whether one or more of them is a critical site responsible for therapeutic e cacy, remains unknown. e reported e cacy of lasmiditan, a non-triptan selective 5-HT1F receptor agonist, indi- cates a non-vascular mechanism of action given that 5-HT1F recep- tors are not widely expressed in the vasculature, and activation of these receptors does not cause any change in vascular calibre (107– 109). Further, the dose-dependent dizziness, vertigo, and fatigue as- sociated with this therapy indicate a central mechanism of action (108). Nonetheless, whether the triptans act centrally or peripherally continues to be the subject of ongoing debate.

PET studies have also provided evidence regarding serotonin re- ceptor involvement in a migraine attack. Studies using the 5-HT1A receptor-speci c ligand [18F]-2’-methoxyphenyl-(N-2’-pyridinyl) -p- uoro-benzamidoethyipiperazine ([18F]-MPPF) indicate in- creased 5-HT1A receptor availability in the several brain regions in triggered migraine attacks (110). ese studies suggest a generalized reduction in serotonergic activity during a migraine attack, and raise the possibility that in addition to other 5-HT1 receptor subtypes, the 5-HT1A receptor may play a signi cant role in migraine.

Calcitonin gene-related peptide

CGRP is a neuropeptide that is found throughout the body and is believed to play a variety of physiological roles, particularly in the recovery of normal vascular calibrw a er vasoconstriction (111). Substantial human evidence indicates that CGRP plays a primary role in migraine. Levels of CGRP in serum have been reported to be elevated during both spontaneous and nitroglycerin-evoked migraine and cluster headache attacks versus baseline (112–115). Salivary CGRP levels have also been reported to be elevated during migraine attacks in patients with episodic migraine (116), and both serum and salivary CGRP levels may be reduced in association with pain relief achieved by treatment with a triptan (113,114,116,117). Administration of intravenous CGRP causes a delayed migraine attack in susceptible individuals, and this migraine can be e ect- ively treated with sumatriptan (118–120). Finally, CGRP receptor antagonists and antibodies targeting CGRP have been shown to be e ective as acute and preventive migraine therapies. An initial study with the CGRP receptor antagonist olcegepant delivered intraven- ously (121), and subsequent studies of the oral CGRP antagonist

telcagepant (122,123), all showed e cacy of these agents as acute migraine therapies. More recently, antibodies to the CGRP peptide delivered either intravenously or subcutaneously have shown e – cacy as preventive therapies for migraine (124–127).

e location of CGRP’s e ects in migraine remain unclear. As with 5-HT1B, 5-HT1D, and 5-HT1F receptors, CGRP and its receptors are found in multiple locations in peripheral and central nociceptive and pain-modulating pathways that could play a role in migraine. CGRP and/or its receptors have been identi ed in sensory bres in the dura, in neurons and satellite glia in the trigeminal ganglion, in the trigeminal nucleus caudalis, in multiple nuclei in the thalamus, and in the somatosensory cortex, insula, amygdala, hypothalamus, and nucleus raphe magnus (128–130). ese locations indicate functions of CGRP in peripheral and central pain transmission, and potentially in descending modulation of pain, the response to stress and anxiety, and visual and auditory perception.

A PET study with a CGRP ligand indicating brain CGRP receptor occupancy found that the ligand was not displaced by therapeutic concentrations of telcagepant, suggesting that telcagepant could be e ective without acting centrally (131). Similarly, the preventive ef- cacy of anti-CGRP antibodies, which presumably do not cross the blood–brain barrier, indicate that ‘neutralizing’ CGRP peripherally can e ectively prevent migraine. While these results suggest that peripheral sites of CGRP are most important with migraine, it may be that, as with triptans, CGRP receptor or peptide antagonists may exert their therapeutic e ects through duplicative actions at mul- tiple peripheral and central sites.

Pituitary adenylate cyclase-activating peptide

Pituitary adenylate cyclase-activating peptide (PACAP) is a pep- tide similar to CGRP that has also been implicated in migraine. Like CGRP, administration of PACAP to susceptible individuals triggers a delayed migraine attack (132,133). Serum PACAP levels were also reported to be elevated during a migraine attack, as compared with between attacks in patients with episodic migraine (134), and ad- ministration of PACAP38 results in an increase in plasma levels of PACAP38 prior to the onset of migraine (133). As with CGRP, PACAP and its receptors are expressed in multiple regions be- lieved to involved in migraine, including the trigeminal ganglion, sphenopalatine ganglion, trigeminal nucleus caudalis, hypothal- amus, and thalamus (135–137).

PACAP binds to three di erent receptors, two of which are also activated by vasoactive intestinal peptide (VIP) (138). Interestingly, administration of VIP causes signi cant cerebral vasodilation but does consistently cause migraine, even in susceptible individuals (3). is has led to the conclusion that the PAC1 receptor, which is bound with signi cantly higher a nity by PACAP compared with VIP, is the receptor primarily involved in PACAP’s role in migraine (133).

Prostaglandins

Triggered migraine studies also indicate that prostaglandins may play a key role in migraine.

Infusion of either prostaglandin (PG) E2 or I2 evokes a migraine- like headache in individuals with migraine (139). Interestingly, the migraine attack evoked by PGE2 occurred immediately a er infu- sion in the majority of patients, in contrast to the 2–4-hour delay be- fore the occurrence of migraine that was more commonly observed with PGI2 or with all other reported migraine triggers (140). PGs are synthesized from arachidonic acid by activated cyclooxygenase.

Elevated levels of PGE2, PGD2, and PGF2α in saliva have been re- ported in migraine patients during attacks, and these levels may be normalized coincident with headache relief (141,142). Levels of PGE2 and PGI2 have also been reported to be elevated in blood from the external jugular blood during migraine attacks (143). e e cacy of non-steroidal anti-in ammatory drugs as acute and pre- ventive therapies and for migraine supports a role for PGs in mi- graine. Speci c receptors for PGs, particularly PGE2 and PGEI2, are appealing targets for migraine therapy (139).

Migraine-associated sensory sensitivity

ere is growing insight into the sensory sensitivity that is associated with migraine. Migraine pain continues to be worsened by light in patients in whom rod and cone damage cause blindness, indicating that there are alternative pathways for mediating light sensitivity in migraine, possibly a direct pathway from the retina to a region of the posterior thalamus that also responds to stimulation of the dura (144). ese ndings demonstrate the existence of non-trigeminal pathways that in uence migraine pain.

e occipital cortex has also been shown to be hyperexcitable in association with migraine photophobia independent of headache. An H215O PET study in migraineurs showed that low-intensity light stimulation activated the visual cortex during spontaneous mi- graine attacks associated with photophobia and a er treatment with sumatriptan, but not during the attack-free interval (145). e thal- amus may also play a key role in sensory sensitivity during migraine. Mechanical and thermal allodynia (the perception of ordinarily in- nocuous stimuli as uncomfortable) associated with migraine are as- sociated with increased thalamic responses to sensory stimulation based on fMRI blood oxygen level-dependent imaging (102).

The migraine postdrome

A number of symptoms of a migraine attack may occur following resolution of a headache, also known as the ‘postdrome’ (24,146,147). ese symptoms include tiredness, weakness, cognitive di culties, mood change, residual head pain, lightheadedness, and gastro- intestinal complaints. Some of these symptoms may become ap- parent upon treatment of headache, leading to the impression that they are an adverse e ect of migraine therapy rather than a part of the attack (148). Functional imaging studies indicate that either hyperperfusion or hypoperfusion may persist beyond the headache phase, either with spontaneous resolution of headache or with suc- cessful treatment with sumatriptan (149). PET studies have shown that activation of the dorsolateral pons in non-trigeminal-triggered migraine persists a er amelioration of headache with sumatriptan (101). Similarly, midbrain and hypothalamic activation, as well as increased light-induced activation of the visual cortex, may also persist- a er headache relief (28,150). ese observations clearly demonstrate that changes in brain activity may continue for ex- tended lengths of time a er either spontaneous or therapeutic reso- lution of headache.

Chronic changes with chronic headache

Structural and functional imaging studies indicate that migraine may be associated with long-lasting changes in regions of the brain that are involved in the processing and modulation of pain (98). ese changes consistently include a decrease in gray matter volume in the anterior cingulate and insular cortex, and in some studies also include decreased gray matter volume in thalamus,

orbitofrontal, prefrontal, and somatosensory cortex among other regions (151,152–154). In the majority of these studies the ex- tent of gray matter decrease was correlated with the duration of the disorder. Some studies have also reported an increase in gray matter volume in the periaqueductal gray and in the dorsal pons in the brainstem (152). A decrease in gray matter volume has also been reported in similar regions in patients with chronic tension- type headache (155). Key questions regarding these morphological and functional changes include whether or not any are speci c to headache, and whether they represent a cause or a consequence of chronic headache. A number of chronic pain syndromes other than headache are associated with similar changes in the structure and function of brain regions involved in nociceptive processing, sug- gesting that they may be a general response to pain rather than spe- ci c to migraine (156). e observation that some of the changes are reversible upon e ective treatment of pain suggests that the changes are a response to pain rather than a cause of it (157,158). Regardless of what role they play in headache, however, it is clear that signi – cant changes in brain structure may occur in the setting of headache disorders. ese observations suggest that structural plasticity of the brain may accompany worsening or improvement of headache. is concept raises the speculative possibility that mechanisms of brain plasticity that are therapeutic targets for other neurological disorders such as stroke and neurodegenerative disorders could also represent targets for headache, particularly chronic headache.

Recent studies have also examined chronic changes in poten- tial neurochemical mediators in patients with chronic migraine. Interictal levels of CGRP in peripheral blood have been reported to be signi cantly higher in patients with chronic migraine compared with healthy controls or those with episodic migraine, and CGRP levels were particularly increased in patients with chronic migraine who had a history of migraine with aura (159). ese ndings add to studies implicating CGRP in an acute migraine attack, and provide support for preventive therapies targeting CGRP and its receptor.

Cluster headache

While there is some overlap between mechanisms of cluster head- ache and those of migraine described above, cluster headache clearly involves distinct anatomical, neurochemical, and physiological fea- tures (see also Chapter 18). e prominence of cranial autonomic features in cluster headache indicates a greater role for the autonomic nervous system, particularly the sphenopalatine ganglion (160).

Another distinguishing feature of cluster headache is the involve- ment of the posterior hypothalamus as indicated by chronic changes in gray matter density, as well as functional activation during cluster attacks (161). A primary role for the hypothalamus in cluster head- ache is consistent with the circadian rhythmicity that is a common characteristic of the disorder. e responsiveness of cluster head- ache attacks to oxygen is another distinguishing feature. Rodent studies indicate that oxygen inhibits activation of the trigemino- cervical complex triggered by parasympathetic stimulation but not by stimulation of meningeal a erents (162). is selective e ect of oxygen on activation of brainstem pain processing neurons by a trigeminal autonomic re ex may be responsible for its speci c e – cacy as a therapy for cluster headache. A better understanding of the commonalities and di erences between the mechanisms underlying cluster headache, migraine, other headache disorders, and pain

CHaPTEr 4 Headache mechanisms

ParT 1 General introduction
disorders in general has the potential to yield important insight into

each of them.

Conclusion

e mechanisms underlying headache disorders are extraordinarily varied and complex. Given the heterogeneity of their clinical fea- tures, it is likely that distinct mechanisms are involved in di erent individuals with the same disorder. e processes involved in head- ache are unlikely to occur as a linear cascade of events, but rather as parallel and overlapping phenomena that occur as a consequence of di use alterations in chemical and physiological function. Advances in genetics, imaging, clinical neurophysiology, and pharmacology will help us to further unravel the speci c mechanisms responsible for these common and disabling disorders.

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Headache in history

Mervyn J. Eadie

Introduction

Humans almost certainly experienced headaches in prehistorical times. e nding of human skulls from around 10,000 bc that con- tained apparent trepanning openings made during life has led to speculation that the operations may have sometimes been carried out for headache relief. However, the rst reasonably de nite surviving written record of human headache originated in Mesopotamia some six millennia ago.

ancient times

Mesopotamia

Israel

e Old Testament book of Kings II, Chapter 4 (c. 800 bc) describes how one morning the only son of a Sunammite woman went to his father in the elds, and cried out ‘My head, my head!’ e boy was taken back to his mother, sat on her knee, and died. e prophet Elisha was summoned, and seems to have resuscitated the boy, who was mentioned as being alive 7 years later (II Kings 8.5). e medical nature of this episode is uncertain, for example possibly childhood migraine, but obviously headache was known in ancient Israel.

India

Headache received mention at various places in the writings attrib- uted to Charaka (probably 500–300 bc). Numerous possible causes of headache were mentioned, for example retained urine and faeces, sexual excess, drinking cold water, smoke exposure, and cloudy wea- ther. Various remedies were described (4).

Greece

An ancient Greek myth described how the god Zeus experienced headache before his head split open to allow Athena to emerge. us, there was awareness of headache in Greek society well before the writings of Socrates, Plato, Aristotle, and Hippocrates (fourth and h centuries bc). One of the Dialogues of Plato contains Socrates’ advice to Charmides concerning cure of his headache. It mentions that the attempt at cure should assess the whole body, not merely the a ected part (5). Aristotle’s e History of Animals (c. 350 bc) men- tioned postpartum headache and a sense of darkness before the eyes (possibly migraine with aura). However, the main medically sig- ni cant ancient Greek writings on headache are in the Hippocratic corpus, although they contain no consolidated account of headache, as such. In these accounts, supernatural causes of headache gave way to physical factors, for example wine drinking. ere were observa- tions on headache prognosis and treatment, for example dividing the vessel running vertically in the forehead to relieve pain at the back of the head. One of the later Hippocratic writings (6), not in- cluded in Adams’ translation of the Genuine Works of Hippocrates (7), contained two very similar accounts of almost certain migraine with aura:

In 1903, R. Campbell ompson translated an eighth century bc Mesopotamian cuneiform text that dealt with material that he thought had originated around 4000 bc (1). Part of the material in- dicated a belief that headache arose from the in uences of invisible supernatural beings, or powers (demons and evil spirits). Headache occurred unpredictably and followed courses ranging from the be- nign and self-limited to the lethal. Various spells and magic rituals for headache relief were described, and also temporary binding of the head.

Texts originating from the Sumerian city of Nippur between 2113 and 2038 bc also re ected a belief that demonic activities caused headache (2).

Egypt

From the middle of the second millennium bc onwards, various Egyptian papyri mentioned headache. ey mostly considered the considerable variety of treatments proposed for the symptom. Certain Egyptian deities, for example the sun-god Ra, were stated to su er headaches (3). It appears that headache was still being at- tributed to supernatural in uences. ere was no indication that varieties of headache were recognized. e symptom was treated with incantations and spells, while numerous substances of animal, vegetable, or mineral origin were applied locally to the head, for ex- ample cat sh skull, sh bones, root of the castor oil plant, worm- wood, and clay.

ParT 1 General introduction

Phoenix’s problem: he seemed to see ashes like lightning in his eye, mostly the right. And when he had su ered that a short time, a ter- rible pain developed toward his right temple and then around his whole head and on to the part of the neck where the head is attached behind the vertebrae. And there was tension and hardening around the tendons. If he tried to move his head or opened his teeth, he could not, as being violently stretched. Vomits, whenever they oc- curred, averted the pains I have described, or made them gentler (6).

Smith WD. Hippocrates. Vol 7. Cambridge, Mass. Harvard University Press; 1994.

e Hippocratic writings mark the beginning of an acceptance, at least in Western medicine, that headache has physical causes. From here on, the present account deals only with headache not due to organic disease, i.e. primary headache. is avoids the need to con- sider the numerous individual diseases, which, taken collectively, still cause only a small minority of all headaches.

Early Christian era

ere seems little evidence that distinct headache syndromes were recognized until the writings of Celsus in the early rst century ad (8). Celsus described cephalalia (headaches of various patterns, sites, and prognoses) and hydrocephalus (headache associated with swelling of the scalp). He wrote a great deal about headache treat- ment, and there was even more in Pliny’s Natural History (9) and in the great Herbal of Dioscorides (c. 40–90 ad) (10). In the second century surviving writings of Aretaeus (11), and the probably slightly later works of Galen, a classi cation of headache types ap- peared and was to endure for many centuries.

Aretaeus

In part of his lost writings, Aretaeus probably dealt with cephalalgia, a short-lived headache. Elsewhere, he distinguished it from cephalaea, chronic or recurrent headache, that, if strictly one sided, he termed heterocrania. His description of the latter suggests that it included both migraine and other one-sided head pains. Aretaeus based his interpretation of headache mechanisms on humoral pathology, not on supernatural in uences, cephalaea being due to coldness and dryness. His recommendations for headache treatment involved correcting the postulated imbalance of the responsible humours by employing measures such as bleeding, cupping, enemas, or sternu- tatories (to promote sneezing).

Galen

Galen’s (121–c. 200 ad) ideas on headache appear at various places in his Omnia Opera (12). He recognized cephalalgia (dolor capitis) and cephalaea, and at places seemed to regard hemicrania (Aretaeus’ heterocrania) as a separate headache entity (a recogni- tion usually attributed to Alexander of Tralles, c. 600 ad). us originated the triad of headache types, viz., cephalalgia, cephalaea, and hemicrania, that persisted in medical terminology for almost two millennia. Over that long period the terms were not always used consistently, and cephalalgia gradually subsumed the head- aches originally termed cephalaeas. is venerable terminology does not t particularly well with modern-day headache types. us, hemicrania would exclude migraine with bilateral headache, and includes one-sided headache due to organic disease. Galen recognized that external factors (e.g. heat, cold, inebriation, ex- ercise) and internal disturbances (e.g. stomach disorders, uterine

‘irritation’, suppression of the menses) could cause headache, and described an extensive array of headache medications (in volume 12 of the Omnia Opera (12)).

Subsequent Byzantine medical writers (e.g. Caelius Aurelianus, Oribasius, Paul of Aegina, and Alexander of Tralles) added little of major conceptual importance to Galen’s ideas, although some of their anti-headache pharmacopoeias were more extensive. ey too employed humoral concepts of headache pathogenesis, sometimes with di erent details. However, in the general community, ideas of supernatural origins of headache lingered, with treatment attempts being directed accordingly, e.g. utilizing charms.

The Middle ages

e medieval Arab physicians wrote on headache, but their ideas largely depended on Galen’s concepts from long before. ey em- ployed the familiar triad of headache types, naming simple non- re- current headache seda, continued bilateral or recurrent headache bayzeh, and recurring pulsatile one-sided headache shaqhiqheh. ey understood that headache could arise from brain disease, sys- temic disorders, and psychological factors (13). Haly Abbas thought that headache originated either in the head itself, or in the stomach, and then a ected the head via the agency of ‘sympathy’.

ere has been recent interest in the writings and illustrations of the medieval mystic abbess, Hildegard of Bingen (1098–1711). Charles Singer (14) suggested that the zig-zag patterns forming parts of her illustrations raised the possibility that she had experi- enced migrainous visual auras (Figure 5.1). If so, there seems no evidence that her writings had any contemporary impact on head- ache knowledge.

Figure 5.1 Illustration from Hildegard of Bingen’s writings, showing a V shape with serrated edges resembling a migrainous visual aura phenomenon, but with a face and attached wings at the apex of the V. The original appeared in Hildegard’s Scivias (c. 1180).

Reproduced from Singer C. The scienti c views and visions of Saint Hildegard (1098– 1180). In Singer C (Ed) Studies in the history and methods of science, Clarendon Press. 1917; pp. 1–55.

Fernel

In mid-sixteenth-century Paris, Jean Fernel (Fernelius) stated that all headache arose from the meninges, the headache features depending on the type of humour that impacted on these mem- branes (15). Sharp bilious vapours produced sharp bilious head- ache, cold phlegmatic humours heavy headache, and atulence or less malign vapours, when insinuated between skin and pericra- nium or between skull and dura, caused tense headache. Distended pulsating arteries produced tight pulsatile headache. Such ideas about headache mechanisms might have provided a basis for a classi cation of headache types based on mechanism, but none appeared.

Despite such more scienti c attitudes appearing, the majority of headache su erers probably still held supernatural concepts re- garding headache production. us, Martin Luther (1483–1546) at- tributed his headaches to the malice of the Devil (16).

The scienti c revolution

At the end of the sixteenth century, Phillip Barrough (17), still heavily dependent on Galen, stated of hemicrania that: ‘this griefe in English is called Migrime.’ He described cephalaea in a way that strongly re- sembled (non-unilateral) migraine without aura, stating that it oc- curred more frequently in women because of their long hair.

Le Pois

In 1618, Charles Le Pois (Carolus Piso, 1563–1613), himself a head- ache su erer (18), published ideas of headache pathogenesis resem- bling those of Fernel. Le Pois provided probably the rst reasonably convincing description of a migraine aura to appear since the later Hippocratic corpus (c. 200 bc). is aura was a le -sided somatic sensory one. No associated visual phenomena were mentioned.

Wepfer

Later in the seventeenth century two major, near contemporaneous, authors wrote on headache, although the ideas of the Swiss, Johann Jakob Wepfer (1620–1695), appeared posthumously, in 1727 (19). Nearly 100 pages of Wepfer’s Observationes medico-practicae de a ectibus capitis were devoted to descriptions of individual instances of headache and his commentaries on their causes and mechanisms. Wepfer used the cephalalgia, cephalaea, hemicrania classi cation and dealt with a mix of primary and symptomatic headache entities. His Observation 54 described a hemicrania with a visual aura (moving objects resembling ies) that developed in parallel with the headache. Some of his 14 instances of hemicrania were due to de- tected organic disease. ere was a possible account of trigeminal neuralgia. Isler (20) suggested that Wepfer’s Observation 108 may have been an instance of subsequently so-called ‘basilar artery mi- graine’. However, a previous hemiplegia in the su erer raises suspi- cion that organic basilar artery disease was present. Wepfer provided no overview of headache mechanisms, but proposed that a chylous humour from the stomach could cause head pain that originated in the meninges, and that the pain of hemicrania was of vascular origin and due to defective serum, or over lled vessels. He thus provided early descriptions of some headache entities and perceived a role for vascular events in hemicrania pathogenesis.

Willis

In his De Anima Brutorum, which appeared in 1672 (21), Thomas Willis (1621–1675) devoted two chapters to De Cephalalgia, words ‘English’d’ by Samuel Pordage in 1683 as ‘Of the Headach’ (Figure 5.2). The translation suggests that cephalalgia had be- come the general term for headache in everyday English. Pordage also rendered Willis’ ‘hemicrania’ as ‘Meagrim’. Although phys- icians cherished the Latin headache terms for another couple of centuries, by the seventeenth century the ordinary Englishman seems to have recognized the distinctive features of the disorder called ‘megrim’. The French laity spoke of ‘migraine’ as early as the twelfth century.

It is di cult to do justice to Willis’ headache writings in a short space. ey contain not only important original insights, but also apparent inconsistencies, and are based on Paracelsian iatrochem- ical thinking that does not equate readily with modern knowledge. Willis related sites of headache occurrence to the richness of the local innervation, and considered that headache originated in the meninges (in particular), pericranium, nerve ‘coats’, muscle bellies, and skin. In discussing what probably was migraine, he postulated that ‘morbi c matter’ (circulating material of unspeci ed chemical nature) a ected the meninges and their nerves to produce pain, with repeated chemical insults permanently altering the dura to cause chronic headache. Elsewhere Willis seemed to attribute headache to altered intracranial arterial blood ow, and explained localized headache and hemicrania by increased ow in individual arteries. us, it can be argued that Willis was the progenitor of both the neural and the vascular theories of migraine pathogenesis, although he wrote concerning headache in general.

Willis described a ‘venerable matron’ who, over more than 3 weeks, experienced daily head pain from around 4pm until mid- night. She then slept, and woke well next morning to repeat the cycle of events. No further useful details were provided, but this may be an early record of cluster headache, although Koehler sug- gested that Nicholas Tulp had described a similarly possible ex- ample in 1641 (22).

Sydenham

omas Sydenham (1624–1689), in writing on ‘an a ection called hysteria in women and hypochondriasis in men’, described a very localized form of headache associated with vomiting (his clavus hystericus) (23). Authors as late as 1894 (24) continued to mention it (e.g. Tissot’s (1778–1780) ‘le clou’). It may be the forerunner of today’s ‘nummular headache’.

The eighteenth century

As mentioned, eighteenth-century medical authors usually em- ployed the cephalalgia, cephalaea, hemicrania terminology, with cephalalgia increasingly becoming the general term for headache, and hemicrania equivalent to the layman’s ‘migraine’.

In the latter part of the eighteenth century, major texts, such as Cullen’s First Lines of the Practice of Physic (25), o en contained no consolidated account of headache, while Boissier de Sauvages’ at- tempted comprehensive classi cation of headache varieties in 1772 proved prohibitively complex (26).

CHaPTEr 5 Headache in history

ParT 1 General introduction

Figure 5.2 The title page of Samuel Pordage’s (1683) translation of Willis’ De Anima Brutorum with Willis’ portrait from the frontispiece of The Remaining Medical Works of That Famous and Renowned Physician Dr Thomas Willis.
Reproduced from Willis T. De anima brutorum quae hominis vitalis ac sensitive est. 1672.

Fothergill

e London Quaker physician John Fothergill (1712–1780) de- scribed the visual aura of his own migraine in a posthumous publication (27):

is has o en been considered the rst account of trigeminal neur- algia (tic douloureux), although, as o en happens a er a new dis- ease entity achieves wider recognition, earlier reports are traced. Lewy (30) thought Avicenna (980–1036) may have described it as ‘Levket’, and noted an account of its occurrence in Johanes Lauentius Bausch (1605–1665), founder of the Imperial Leopoldian Academy for Natural Sciences. e English philosopher (and occasional phys- ician) John Locke had recorded in his diary its probable occurrence in the Countess of Northumberland, wife of the English Ambassador to France, in 1677 (31,32).

Parry

In 1792 Caleb Hillier Parry, of Bristol, noted that compression of the carotid artery on the headache side a orded temporary pain relief (33), an observation subsequently proved to be important in identifying a role for vascular mechanisms in hemicrania and bilious headache. Actually, long before, Galen, in De locis a ectis, noted that the now-lost works of Archigenes (late rst or early second-century ad) mentioned that strong compression of blood vessels (presum- ably in the scalp) relieved headache (34). Parry (35) also described an episode of probable migraine with a visual aura followed by right upper limb and facial sensory symptoms, then inability to speak and mental confusion, culminating in headache.

Tissot

In the 1778–1780 period the rst edition of Samuel Tissot’s (1728– 1797) highly in uential Traité des nerfs appeared (36). In it, he dis- missed in a few lines of text all varieties of headache except migraine.

It begins with a singular kind of glimmering in the sight; objects swi ly change their apparent position, surrounded with luminous angles, like that of a forti cation. Giddiness comes on, head-ach and sickness.

Fothergill J. Remarks on that complaint commonly known under the name of the sick headach. Medical Observations and Inquiries. 1784; 6:103–137.

A er many centuries of silence since the later Hippocratic writings this was an early reappearance of mention of a migraine visual aura, although, according to Rucker (28), Vater and Heinicke had de- scribed an instance in 1723 that long went unnoticed.

In 1783 Fothergill (29) had also described 14 instances of ‘a painful disorder of the face’ in which:

a pain attacks some part or other of the face, or the side of the head: sometimes about the orbit of the eye, sometimes the ossa malarum. sometimes the temporal bones, are the parts complained of. e pain comes suddenly, and is excruciating. It lasts but a short time, perhaps a quarter or half a minute, and then goes o ; it returns at irregular intervals, sometimes in half an hour, sometimes there are two or three repetitions in a few minutes.

Fothergill J. Of a painful a ection of the face. Medical Observations and Inquiries. 1773; 5:129. Reprinted in Lettsom, J C. e works of John Fothergill MD. Vol 2. London. Dilly. 1783:179–189.

He wrote at considerable length on the latter, providing the rst major account of this particularly common type of headache that grasped the attention of the contemporary medical profession, at least in his native Switzerland and France. Tissot considered migraine and hemicrania synonymous, but pointed out that he had seen instances of non-unilateral headaches that were otherwise identical with mi- graine. He drew on the earlier literature and described the clinical features of the disorder much more comprehensively than hitherto, mentioning the presence of vision changes, scintillations, and bright lines during the attacks. He described in detail two instances of mi- graine with aura, one both visual and hemi-sensory, the other hemi- sensory only (probably Le Pois’ case of 1618, mentioned earlier). Tissot did not comment that aura phenomena o en preceded the headache, and that the pain was o en pulsatile in character. He thought migraine arose from a stomach disturbance that a ected the head by means of ‘sympathy’ mediated via nerve connexions (pre- sumably the vagus). e sympathy a ected the brain, causing nausea and perhaps vomiting, and reached trigeminal branches, mainly one supraorbital nerve, to produce unilateral headache. His ideas were derived from earlier writings and theoretical considerations, more than from experimental observation. Tissot’s advice on treatment was mainly drawn from the literature, although he tended not to rec- ommend over-vigorous measures.

Tissot’s writings, given time for the medical profession to absorb their import and for the knowledge to spread into the lay commu- nity, seem to have awakened a surge of interest in headache, almost exclusively migraine. is began in the French-speaking world of the nineteenth century, and later extending into English-speaking and other nations. is interest is re ected in the appearance of etch- ings and cartoons such as those shown in Figures 5.3 and 5.4.

The nineteenth century

Migraine

Much nineteenth-century French-language publications concerning migraine, particularly the numerous theses, tends to be repetitive, although some new insights emerged. By the end of the century mi- graine was a generally accepted major headache entity. e more signi cant French work on migraine began with Piorry.

Piorry

In 1831 and again in 1835 Pierre-Adolphe Piorry (37) described in some detail his ‘iridial’ or ‘ophthalmic’ migraine, i.e. migraine with a visual aura. He suggested that hemicrania was a one-sided head neuralgia. Some initiating factor, probably ambient light, acted on the retina and iris diaphragm of the eye to alter local nervous ac- tivity. is alteration set the pupil into a state of oscillating con- striction and dilatation that was responsible for producing a zig-zag pattern of light on the retina. e altered neural activity extended into trigeminal territory, causing a supraorbital neuralgia. He thus explained the pathogenesis of both the migraine visual aura and the unilateral headache. Spread of the abnormal neural activity to vagal and sympathetic innervated structures could produce nausea and vomiting. Piorry’s was an ingenious, comprehensive, but highly speculative, hypothesis. Some four decades later, in 1875, Piorry (38) reiterated the idea, adding the suggestion that the connection between the vagus and the trigeminal nerves occurred through the spheno-palatine ganglion. Migraine was, for him, an ‘irisalgia’.

In 1832 Jules Pelletan de Kinkelin published a modi ed neural type of hypothesis of migraine pathogenesis (39). He suggested that neural inputs from various peripheral organs whose dysfunc- tion seemed related to the onset of migraine (the iris, stomach and uterus, and congested blood vessels) were transmitted through the brain to rst-division trigeminal branches in whose territories of supply pain was experienced. e idea did not survive. Anatomical evidence of the proposed cerebral connections was lacking.

Seven years later, Louis-Florentin Calmeil (40) reversed the pos- tulated sequence of neural events, hypothesizing that migraine arose from a brain disturbance that spread from its cerebral origin along anatomically veri ed nerve pathways to the trigeminal system and, mainly via the vagus, to abdominal organs. e Londoner Francis Anstie, in 1866, also considered migraine headache neuralgic in na- ture, but originating in trigeminal branches themselves (41).

Vascular hypotheses of migraine pathogenesis also appeared. Marshall Hall in 1849 suggested that peripherally initiated a erent nerve activity re exly produced neck muscle spasm that obstructed venous out ow from the head (42). e consequent cranial venous congestion caused headache. In that same year Auzias-Turenne (43) postulated that mainly unilateral venous congestion in the cavernous sinus caused trigeminal nerve ( rst division) compression. is ex- plained unilateral headache, with carotid artery pulsation within the sinus making the pain throb. Ophthalmic vein congestion caused red- dening of the eye and possibly blurred vision, while jugular venous distension within the carotid sheath could compress the vagus nerve to produce nausea and vomiting. Turenne’s was another ingenious idea that accounted for numerous clinical phenomena, but perished from want of con rmatory evidence of the postulated mechanism.

Du Bois Reymond

In 1861 a less speculative hypothesis appeared when Emil Du-Bois Reymond (1818–1896), the Berlin physiologist, published an ana- lysis of his own migraine phenomena (44). He speci ed that his ex- planation did not necessarily apply beyond his personal situation, a stipulation largely ignored by those who cite his idea. e headaches in his right temple increased with each beat of his super cial tem- poral artery, the artery felt harder than its le -sided counterpart, his face was pale, and his right conjunctiva appeared slightly injected. Recently available knowledge of cervical sympathetic function al- lowed him to suggest that right-sided sympathetic overactivity caused his early symptoms, the basic disturbance being at the origin of the cervical sympathetic trunk in the upper thoracic spinal cord. Brown-Séquard almost immediately rejected this interpretation, ar- guing that cervical sympathetic excitation in animals did not appear to cause pain, and that, in his experience, migraine manifestations more o en were consistent with cervical sympathetic paralysis (45). Möllendorf’s clinical experience, described in a 1867 paper (46), supported Brown-Séquard’s view. Two years later Jaccoud, to an extent, reconciled these apparently contrary neurovascular in- terpretations by proposing that during a migraine attack cervical sympathetic over-action might be followed by under-action (47). en Eulenburg, in 1877, stated that there was no marked vaso- motor change in some migraine attacks, and proposed that any rapid change in scalp arterial calibre might irritate nearby trigem- inal nerve terminals to cause headache (48). e Cambridge aca- demic P. W. Latham, in 1872 and 1873, had also suggested that initial cervical sympathetic overactivity in migraine attacks produced cra- nial vasospasm, the resulting brain ischaemia being responsible for

CHaPTEr 5 Headache in history

ParT 1 General introduction

Figure 5.3. Etching of a man with a splitting headache.
Courtesy of the Wellcome Collection, Attribution 4.0 International (CC BY 4.0), https://creativecommons.org/licenses/by/4.0

CHaPTEr 5 Headache in history

Figure 5.4 Lithograph of a man whose headache was experienced as if his head was being repeatedly hammered by devils. Courtesy of the Wellcome Collection, Attribution 4.0 International (CC BY 4.0), https://creativecommons.org/licenses/by/4.0

ParT 1 General introduction

Figure 5.5 The title page of Liveing’s monograph on migraine.
Reproduced from Liveing E. On megrim, sick-headache, and some allied disorders: a contribution to the pathology of nerve-storms. London. Churchill; 1873.

any migraine aura that occurred (49,50). Subsequent sympathetic exhaustion produced headache as cranial arteries then dilated. e ideas of Latham, and before him, of Jaccoud, re-emerged three- quarters of a century later in the writings of Harold Wol (51), who is now o en credited with devising the vascular hypothesis of mi- graine pathogenesis.

Liveing

Almost simultaneously to Latham, Edward Liveing in 1873 wrote the great classic of migraine literature, a monograph On Megrim, Sick Headache, and Some Allied Disorders (Figure 5.5) (52). is work contained Liveing’s clinical observations and a thorough and detailed literature review. Liveing wrote at a time when medicine was

becoming increasingly aware of the existence of localized represen- tation of function in the brain and proposed that migraine resulted from a ‘nerve storm’ or ‘neurosal seizure’ within the brain. Liveing postulated that his nerve storm could occur anywhere between the thalamus and the vagal nuclei in the brain stem. A thalamic discharge accounted for the visual aura, a vagal nuclear disturbance for nausea and vomiting, and a discharge in intermediate areas somehow ex- plained the headache itself. Liveing’s idea was developed before the course of the optic pathway beyond the thalamus was known.

Airy

In 1870 another Cambridge man, Hubert Airy (1838–1903), described his own migraine aura and illustrated its evolution (Figure 5.6) (53).

CHaPTEr 5 Headache in history

Figure 5.6. Hubert Airy’s drawing of the evolution of his migraine aura from its beginning (top left corner). Reproduced from Philosophical Transactions, 160, Airy H, On a distinct form of transient hemiopsia, pp. 247–264, 1870.

ParT 1 General introduction

Figure 5.7 George Airy’s drawings of the development of his scintillating scotoma.

Reproduced from Philosophical Magazine, 30, Airy GB, The Astronomer Royal on hemianopsy, pp. 19–21, 1865.

He reviewed the relevant literature and described the auras of a number of contemporary Fellows of the Royal Society, whether or not their auras were accompanied by headache. One of the Fellows was Airy’s father, the British Astronomer Royal, Sir George Biddell Airy, who in 1865 had already illustrated the evolution of his visual auras (Figure 5.7) (54). e younger Airy did not propose a mech- anism for the aura or headache, but posed questions for his readers that suggest that he believed the aura arose within the brain. His paper, more than the occasional earlier mentions of migraine auras in the late-seventeenth- and eighteenth-century literature, probably made English-language neurology as aware of migraine phenomena as the French literature already was. Indeed, a French librarian, Louis Hyacinthe omas, in 1887 authored a monograph on mi- graine in which he divided the topic into migraine vulgaire (common migraine, migraine without aura) and migraine ophthalmique (es- sentially, migraine with aura) (55). is classi cational distinction remains widely accepted.

Liveing’s domestic neighbour William Gowers (1845–1915), in volume 2 of his great Manual of Diseases of the Nervous System, which rst appeared in 1888, provided a wonderfully clear, crit- ical, and comprehensive account of migraine phenomena (56). Gowers believed that migraine originated in the cerebral cortex, but was circumspect regarding the initiation of the postulated cortical disturbance, possibly knowing that his London colleague Sidney Ringer in 1877 had suggested that migraine was not due to Liveing’s ‘nerve storms’, but resulted from a local loss of cerebral cortical ‘resistance’ (a concept akin to loss of inhibition) (57). In his 1895 Bowman Lectures (58), Gowers discussed migraine visual auras in considerable detail and illustrated their appearances with drawings made by a patient (Figure 5.8), and also by Hubert Airy (Figure 5.9).

Non-migrainous headache

By the late nineteenth century, migraine was reasonably rmly es- tablished as a distinct headache entity and it was increasingly ac- cepted that migraine headache did not have to be strictly one-sided. e old cephalalgia, cephalaea, hemicrania classi cational triad was proving increasingly unsatisfactory in the light of growing know- ledge of the pathological basis of disease. Various new headache classi cations were proposed, partly to accommodate the residue of headache patterns that remained a er migraine was excluded. Some of these classi cations were based on presumed headache cause, or mechanism or site of pain origin. Entities such as rheumatic, neur- algic, and congestive headache were proposed, but no headache clas- si cation achieved any sustained popularity.

The twentieth century

An important new headache syndrome, later termed cluster headache, was recognized early in the twentieth century. From mid-century onwards, there were great advances in knowledge con- cerning migraine and reasonably satisfactory headache classi ca- tions appeared (59–61).

Cluster headache

In 1926 Wilfred Harris (1869–1960) described ‘migrainous neur- algia’ in his monograph Neuritis and Neuralgia (62). Some of his case histories probably represented migraine. Others were instances of ‘periodic migrainous neuralgia’ or what he later called ‘migrainous (ciliary) neuralgia’ (63). e clinical features of this disorder, viz. attacks of localized unilateral anterior head pain with a particular set of accompaniments and a tendency to recur in periodic bouts, were those of what was later termed ‘cluster headache’.

Apparently initially unaware of Harris’ work, Bayard Horton (1895–1980), from 1939 onwards, described ‘histaminic cephalalgia’(64). Its clinical features also were those of cluster head- ache. Horton erroneously believed that this disorder responded spe- ci cally to courses of histamine injections. It was for Kunkle and his colleagues in 1952 to describe additional cases and coin the name ‘cluster headache’ (65). Once the entity was recognized, earlier in- stances were traced in the literature, including those mentioned pre- viously in this chapter, and ones described by von Swieten in 1745 (66), Whytt in 1768 (67), and Morgagni in 1779 (68). Relatively recently, what could be considered cluster headache variants have been recognized and embraced in a designation of trigeminal auto- nomic cephalalgia (69).

Migraine

In the early decades of the twentieth cntury new hypotheses ap- peared accounting for the pathogenesis of the migraine attack. Some were vascular or neural-type hypothesis variants. Others invoked novel factors such as choroid plexus herniating into and obstructing a narrow foramen of Monro (70), episodic brain swelling (71), pitu- itary swelling (72), allergy (disproven in the case of milk by Loveless (73)), and errors of refraction (74), while Freud devised a psycho- dynamic interpretation (75). None of these ideas proved persuasive, and major progress did not occur until the work of Harold Wol , in New York, appeared mid-century.

Figure 5.8 Drawing made by William Gowers’ patient Beck of a scintillating scotoma in the upper part of his visual eld.

Reproduced from Lectures on Diseases of the Nervous System. Second Series. Subjective Sensations of Sight and Sound, Abiotrophy, and Other Lectures. By Sir William Gowers, M. D. (Philadelphia: P. Blakiston’s Son & Co., 1904). American Journal of Psychiatry, 61(2), pp. 372–373.

Wolff

A sustained program of experimental studies, many of them in human migraine su erers, provided Harold Wol (1898–1962) with a scienti c basis from which to re-enunciate ideas proposed on much less adequate data by Jaccoud and Latham nearly a century before. Local cerebral arterial constriction produced the migraine aura and, as the constriction passed o , arterial dilatation caused the head- ache. To this Wol added a signi cant new idea, viz. that the pain from the vasodilatation triggered painful contraction of head and neck muscles, a second pain-producing mechanism in the attacks. Wol ’s contribution to knowledge about headache, and particularly migraine, was amassed in the second, posthumously published, edi- tion of his Headache and Other Head Pain (51).

Following Wol ’s work, knowledge about headache and head- ache mechanisms and treatment grew apace. Perhaps the main advances in relation to migraine arose from recognition of the phe- nomenon of cortical spreading depression by Leão in 1944 (76), and

identi cation of the roles of serotonin and other neurotransmitters in the pathogenesis of the disorder. ese advances are too recent for their consequences to be fully worked out and their historical signi cances appropriately assessed.

Tension headache

e numerous su erers of primary non-migrainous headaches seemed largely to escape sustained medical interest in the earlier part of the twentieth century. Shortly a er the end of World War II an entity of tension headache began to be mentioned in the medical literature. e origin of the concept is di cult to trace. e term may have been used informally by physicians before it began to appear in print with its present meaning (earlier, ‘tension headache’ had occasionally referred to headache associated with high arterial tension, i.e. raised blood pressure). Early accounts suggested that tension headache arose from psychological factors (77,78). Wol (51) thought that the pain was produced by neck and

CHaPTEr 5 Headache in history

ParT 1 General introduction

Figure 5.9 Another of Hubert Airy’s unpublished drawings of the evolution of one of his migraine auras.
Reproduced from Lectures on Diseases of the Nervous System. Second Series. Subjective Sensations of Sight and Sound, Abiotrophy, and Other Lectures. By Sir William

Gowers, M. D. (Philadelphia: P. Blakiston’s Son & Co., 1904). American Journal of Psychiatry, 61(2), pp. 372–373.

scalp muscle tension. Aring (79) believed that tension headache had earlier been called indurative, nodular, myalgic, or rheumatic headache. Currently, the headache mechanisms involved and the limits of the entity do not seem adequately understood.

Headache treatment

e account in this chapter contains little regarding headache treat- ment. is is not because there was little medical interest in the matter but because, over the many centuries, there had been a vast array of chemical substances administered locally, orally, rectally, intranasally, or systematically, and various physical manipulations of various degrees of violence employed to relieve headaches or pre- vent further attacks, but none had achieved any consistent or spe- ci c bene t. is situation altered when the ergot alkaloid derivative ergotamine came into use in the 1920s (80), although it had been available, unidenti ed, in ergot extracts since 1868 (81). In the 1970s part of the structure of the ergotamine molecule provided a basis for synthesizing a number of migraine-speci c triptan derivatives (82).

Conclusion

e recorded saga of the human encounter with headache is already a lengthy one, and also one unlikely to be near its end.

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CHaPTEr 5 Headache in history

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PART 2

Migraine

6. Migraine: clinical features and diagnosis 61 Richard Peat eld and Fumihiko Sakai

7. Migraine trigger factors: facts and myths 67 Guus G. Schoonman, Henrik Winther Schytz, and
Messoud Ashina

8. Hemiplegic migraine and other monogenic migraine subtypes and syndromes 75
Nadine Pelzer, Tobias Freilinger, and Gisela M. Terwindt

9. Retinal migraine 92
Brian M. Grosberg and C. Mark Sollars

10. Migraine, stroke, and the heart 98 Simona Sacco and Antonio Carolei

11. Non-vascular comorbidities and complications 110
Mark A. Louter, Ann I. Scher, and Gisela M. Terwindt

12. Migraine and epilepsy 120

Pasquale Parisi, Dorothée Kasteleijn-Nolst Trenité, Johannes A. Carpay, Laura Papetti, and
Maria Chiara Paolino

13. Migraine and vertigo 128 Yoon-Hee Cha

14. Treatment and management of migraine:acute 138

Miguel J. A. Láinez and Veselina T. Grozeva

15. Treatment and management of migraine: preventive 152

Andrew Charles and Stefan Evers

16. Treatment and management: non-pharmacological, including neuromodulation 165
Delphine Magis

Migraine
Clinical features and diagnosis Richard Peat eld and Fumihiko Sakai

Introduction

Headache is by far the commonest presenting symptom in neuro- logical clinics, and the idea is gaining popularity that the vast ma- jority of such patients have migraine, be it mild or severe, with or without an aura. In assessing such patients, the clinician has two principal tasks—to ensure that there is no alternative explanation for the headache requiring speci c treatment, and to assess the ex- tent to which the headache is disrupting the patient’s life and work in order to o er appropriate abortive medication or preventative treat- ment. Imaging and appropriate blood tests may be absolutely neces- sary to exclude other conditions, but the vast majority of patients seen in the neurology clinic with a long history of typical migraine and no physical signs on examination do not need any investigation. ere is as yet no test for migraine, which has to be diagnosed from a typical history and negative investigations for alternatives when thought necessary.

e International Classi cation of Headache Disorders (ICHD) is intended to standardize the diagnostic criteria for headache dis- orders (1–3). ey are also of some value in attempting to make the diagnosis of migraine more evidence based. In routine clinical prac- tice, however, clinicians must have discretion in interpreting these criteria, and it is o en appropriate to treat an atypical patient for migraine once realistic alternative diagnoses have been excluded.

Gender ratio

Migraine is predominantly a disease of women—most population- based epidemiological series suggests a ratio of 2–3:1 (4). Migraine is actually commoner in young boys than young girls, and the vast majority of women develop migraine at or soon a er puberty. e incidence of new cases of migraine in males rises steadily at least until the 30s, whereas there is an unequivocal peak in women (4– 7). Most migraine will have revealed itself by the age of about 30 in women and 40 in men, and it is appropriate to undertake more investigations in new cases of headache in patients older than this.

Frequency

The frequency of migraine is very variable, and is necessarily de- pendent on the source of the patients. Some have only one or two attacks per year, and will only rarely see the need for medical advice. The majority of patients with episodic migraine seen in a typical neurology clinic have between one attack every 2 months and two attacks weekly (8). It has recently become accepted that headache more frequent than this can still be migrainous (‘chronic migraine’) (4,9–11). In most cases episodic attacks gradually be- come more frequent, and this apparent ‘transformation’ can be explained by, for example, the overuse of potentially addictive analgesics such as codeine or triptans (12,13), female hormones such as the contraceptive pill or hormone-replacement therapy, or a depressive state. Recent epidemiological studies do suggest, however, that there are also patients with chronic migraine that seems to occur spontaneously without these exacerbating factors (11). Other risk factors for chronic rather than episodic migraine include a high body mass index, a lower level of education, and smoking (11).

Duration

e duration of migraine is equally variable. It can be as short as 1 hour in young children, although the majority of adult pa- tients with migraine have headaches lasting at least 4 hours when untreated, and many last rather longer. ICHD-3 speci es that a typical migrainous headache lasts for 4–72 hours (untreated or unsuccessfully treated). e patient o en describes the pain being situated in only one part of the head at the onset of the attack, and shi ing to another part of the head as the attack evolves. Very short, well-localized pains lasting no more than a few seconds— ‘jabs and jolts’, or ‘ice pick pains’ (14), are seen in patients o en with a personal or family history of migraine, and should be con- sidered migrainous in aetiology. Little treatment for these may be required.

Part 2 Migraine Location

In about 60% of cases the headache of migraine is unilateral, usually hemicranial, although the pain may be con ned to only one part of the head such as the le frontal or right temporal regions (8,15). Most patients will describe at least a minority of attacks occurring in a symmetrical position on the other side of the head and, as already mentioned, some pains can switch sides during an attack. e use of unilaterality as a diagnostic criterion for migraine makes assessment of this in large populations di cult, but it must be borne in mind that at least 40% of patients with unequivocal migraine have bilateral headache (8).

Undue scalp sensitivity (‘allodynia’) is experienced by over 60% of migraine patients (16). It usually starts about an hour a er the onset of the headache, and there is evidence that the response of the headache to triptans is less good if treatment is delayed until a er this time (17).

e pain is characteristically throbbing or pulsating, and wors- ened by physical activity, such as climbing stairs (8,15). Nausea and vomiting, the latter occasionally profuse, are again a diagnostic cri- terion for migraine; about 90% of patients are at least nauseated and 50% have vomited (8,15).

Early premonitory symptoms

Many patients have vague and non-speci c symptoms preceding the onset of more overt migrainous ones with or without a typical aura (18). ese can include an ill-de ned feeling of well-being, as well as yawning, thirst, fatigue, dizziness, and muscle aching. In a study of 97 patients given electronic diaries, Gi n et al. (19) demonstrated that 72% had some type of premonitory symptom, most commonly fatigue, poor concentration, and a sti neck. Yawning, irritability, and emotional changes were also common, as well as the photo- phobia, phonophobia, and nausea that are considered part of the headache phase. ese symptoms usually lasted less than 12 hours, although they were occasionally much longer (20). e symptoms at the end of a migraine attack o en seem to ‘mirror’ those of the pre- monitory symptoms (see Figure 6.1) (21).

aura symptoms

Perhaps 30% of population-based series of migraine patients ex- perience aura symptoms of some kind (6,7,22). Auras usually pre- cede the headache, although they can occur during it, and very occasionally a patient will describe repeated auras during a single headache (23). Migraine aura may be associated with a headache that does not ful l the criteria used for migraine without aura (24); a small but de nite minority of patients experiencing auras have no headache at all (25). Many of these are older patients who have had migrainous headache with preceding aura throughout their lives, and the headache has faded as they grow older while the aura has remained unchanged. ere are other patients who present in later life with aura symptoms alone (26,27)—while many are typical, it is not always straightforward to distinguish all of these symptoms

The five stages of an attack
Anorexia/nausea/vomiting Vomiting

Headache

Food carving Tired/yawning

Heightened perception

Fluid retention

Malaise/lethargy Sensitive to light/sound

Heightened sense of smell Difficulty focusing Poor concentration

Deep sleep Medication

Limited food tolerance

Tired Hungover

Diuresis

I II III IV V
Normal prodrome aura headache resolution recovery Normal

Figure 6.1 Pathophysiology of migraine.

Reprinted from The Lancet, 339, Blau JN, Migraine: theories of pathogenesis,
pp. 1201–1207. Copyright (1992), with permission from Elsevier. DOI: https://doi. org/10.1016/0140-6736(92)91140-4.

from those of transient ischaemic attacks (25), as is discussed in the section ‘Sensory aura’.

Visual symptoms

Many of the earliest descriptions of migrainous aura phenomena were published by articulate migraine su erers, many themselves medically quali ed. ese include Hubert Airy (28), Karl Lashley (29), Walter Alvarez (30), and Edward Hare (31). ere is an excel- lent account in the book by Oliver Sacks (32). It is generally held that photophobia and blurring of vision are not wholly typical mi- grainous aura symptoms, and should not be labelled as such. Some patients complain of persistent visual a erimages or disturbances of the visual eld akin to a ‘broken windscreen’ or a ‘wet windscreen’, while others have scotomas, or visual loss with or without a bright zigzag disturbance sometimes in a curve, usually on the temporal side of the eld. is is believed to re ect the way visual cortical cells are arranged to respond to the orientation of an object seen. In many cases the visual disturbance moves across the visual eld from close to the xation point towards the periphery over 20–40 minutes (22,28,33). Very rarely it is apparent that this disturbance has mi- grated out of the visual areas of the brain completely, as the patient goes on to develop dysphasia rst and then even a sensory disturb- ance in a sequence re ecting the location of these areas within the cerebral cortex. is wave of malfunction is followed by a further wave in which normal cerebral function and normal vision is re- stored. It is unusual but not impossible for a second wave to follow the rst (see Figures 6.2 and 6.3).

Lashley (29) and Peter Milner (34) calculated that the disturbance runs across the cerebral cortical surface at a rate of 2–3 mm per mi- nute, which is the strongest evidence that the spreading depression phenomenon described by Aristides Leao (35) is the cause of this. e likely mechanism of the aura is discussed by Whitman Richards (36), by Andrew Charles and Serapio Baca (37), and elsewhere in this book.

CHaPtEr 6 Migraine: clinical features and diagnosis

Figure 6.2 The visual aura drawn by Hubert Airy in 1870.
Reproduced from Philosophical Transactions of the Royal Society, 160, Airy H, On a distinct form of transient hemiopsia. pp. 247–264,1870.

Part 2 Migraine

Figure 6.3 Map of Vaubon’s new forti cations of the city of Lille. Galeazzo Gualdo Priorato’s Teatro Del Belgio, 1673.

Sensory aura

Many patients complain of paraesthesiae or numbness, most com- monly in the parts of the body most heavily represented on the cortex—the lips, the face, and the ngertips. It is typical and almost pathognomonic of migraine that the sensory disturbance should migrate, taking perhaps 20–30 minutes to pass from the shoulder to the ngertips or vice versa. e symptoms of transient ischaemic attacks, in contrast, usually appear all at once and the vast majority of these last only a few minutes before resolving in a comparable manner.

Speech disturbances, including expressive and/or receptive dysphasias and paraphrasia are also commonly found. ey usu- ally also last for 20–40 minutes before resolving. Dysarthria can also occur.

Motor disturbances are rather rarer, with the exception of those seen in familial hemiplegic migraine (see Chapter 8) in which weakness can be the predominant symptom, although sometimes this is preceded by visual or speech disturbances (38). It has been argued that the motor cortex is separated from the parts of the brain most commonly a ected by migraine by the Sylvian ssure, which seems to have an inhibitory e ect on the disturbance passing across the brain surface. at the motor and sensory cortices are supplied by the middle cerebral artery and the visual cortex by the posterior cerebral artery, while migraine is most commonly seen in

the visual, speech, and sensory cortices, has to be evidence that aura symptoms are not triggered by disturbances in ow within major blood vessels.

Transient global amnesia is much commoner in patients with a history of migraine (39). e memory disturbance usually lasts for several hours, which is longer than a typical aura and the attacks only rarely occur more than once in a lifetime. Visual hallucinations and confusion have been recorded (40), and even olfactory hallu- cinations (41). Vertigo as a symptom of migraine is dealt with in Chapter 13—whether there is a genuine constellation of posterior fossa symptoms that can be entitled vertebrobasilar migraine is problematic, and this term has now been replaced by ‘migraine with brainstem aura’ in ICHD-3, as involvement of the basilar artery is unlikely.

Many patients have more than one migrainous symptom (22,42), the commonest combination being visual and sensory symptoms. It has been recognized for a long time that patients can develop dysphasia at the same time as paraesthesiae and numbness in the non-dominant arm, which suggests that the neurophysiological disturbance can occur simultaneously in both hemispheres, albeit in a patchy manner. ere is no clear relationship between the lat- eralization of the aura symptoms and the lateralization of the sub- sequent headache, which seems to be randomly distributed at least in many series (43). is certainly makes it di cult to o er a patho- genetic mechanism of migraine that relates the neurophysiological

disturbance of the presumed spreading depression in the cortex to a painful vasodilatation of the meninges overlying the cortex on the same side.

Speci c migrainous syndromes, including hemiplegic migraine, both familial and sporadic, ophthalmoplegic migraine, and ret- inal migraine are covered elsewhere in this book (see Chapters 8 and 9).

the long-term prognosis

Migraine has a gratifying tendency to improve as the patients grow older. Many women, especially if their attacks have been linked to the menstrual cycle, nd that they fade a er the menopause, par- ticularly if they are able to avoid hormone-replacement therapy. is is supported by cohort-based follow-up studies of migraine patients over many years, but the phenomenon is less easily demonstrated in epidemiological studies done at a xed point in time, which sug- gests that there may be as many women who start at the menopause as there are those whose headaches settle down. e prevalence in older men, in contrast, is certainly lower than in younger men (44). It is o en possible to withdraw prophylactic medication from pa- tients as they grow older.

Complications of migraine

ICHD-3 lists four complications of migraine including status migrainosus, persistent aura without infarction, migrainous infarc- tion, and migraine aura-triggered seizure.

Death in a wholly typical attack is exceptionally rare. e risk of ischaemic stroke in migraine is covered in Chapters 3, 10, and 37. All neurologists would be well advised to investigate any patient presenting with a permanent de cit a er a typical migrainous at- tack with great care, to exclude cerebrovascular disease and car- diac disease, and particularly a persistent foramen ovale, as these seem to have an association with migraine with aura (45). It is only exceptionally that wholly uncomplicated migraine is followed by a permanent de cit. Haemorrhagic stroke is very rare but has been described (46). e association of migraine with epilepsy, and abnormalities of the cerebrospinal uid are, likewise, covered elsewhere.

Conclusion

Migraine is a clinical diagnosis, and is perhaps the disease most clearly diagnosed by the history and examination, and not by in- vestigation. ere is an extraordinary variety of focal symptoms, as well as degrees of distress, which must be carefully evaluated before recommending treatment.

CHaPtEr 6 Migraine: clinical features and diagnosis

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Migraine trigger factors
Facts and myths
Guus G. Schoonman, Henrik Winther Schytz, and Messoud Ashina

Introduction

In second-century Rome, Galen of Pergamon suggested that mi- graine was triggered by yellow bile irritating the brain and meninges (1). Today, atmospheric, nutritional, hormonal, physiological, and pharmacological triggers are suspected, and have been investigated in numerous clinical studies. A trigger for migraine is any factor that upon exposure or withdrawal can lead to the development of a mi- graine attack (2). According to the International Headache Society (IHS) (3), trigger factors increase the probability of a migraine at- tack usually within 48 hours. A trigger factor is not regarded as a necessary causative agent in migraine and therefore the presence of a trigger factor may not always induce an attack and patients may have attacks without trigger. e majority of studies on trigger factors are retrospective surveys hampered by recall bias, multiple signi – cance errors, and questionnaire design, which may explain di er- ences between studies. ere is only a limited number of prospective studies and these show con icting results. In this chapter we will present and describe the present knowledge on migraine triggers, highlighting both facts and myths. In addition, we will discuss the clinical implications of identifying triggers, and whether there is any rationale for avoidance of triggers, which has been a classic strategy and recommendation for migraine treatment (4–6).

atmospheric trigger factors

In this section we will only brie y summarize the ndings regarding weather and migraine, as Chapter 54 deals with the relation between weather and headache (including migraine) in greater detail.

In short, many patients have the impression that changes in the atmosphere are able to trigger a migraine attack. Retrospective ques- tionnaires showed that between 7% and 52% of migraine patients identi ed weather changes as a possible trigger factor (7). ese questionnaire studies, however, are hampered by a variety of bias (8). Prospective studies, combining objective weather data from meteorological institutes with information from headache diaries or visits to the emergency room for migraine, showed no positive

associations (9–11). Other studies found a triggering e ect for tem- perature and relative humidity (11,12). It seems that there is a sub- group of migraine patients that might be susceptible to changes in weather (13).

Food and migraine

Between 10% and 50% of migraine patients are convinced part of their migraine attacks are triggered by certain food products (14). Based on retrospective questionnaires, a long list of possible mi- graine triggers has been formulated (Table 7.1). Among the most frequently mentioned products are alcohol (including wine), cheese, and chocolate, as well as withdrawal of ca eine and missing a meal. Prospective studies in which the intake of food and the occurrence of migraine attacks are scored independently using diaries are scarce. A large Austrian study included 327 migraine patients and assessed several potential trigger factors on a day-to-day basis. In that study the e ect of nutritional factors was very limited. In fact, the consumption of beer even decreased the risk of getting a mi- graine attack (15).

Provocation trials in migraine

So far three food substances have been tested in a small randomized clinical trial for their migraine provoking abilities: red wine, choc- olate, and tyramine. Red wine provoked migraine in nine of 11 mi- graine patients who were preselected on being sensitive for red wine (16). Chocolate triggered migraine in ve of 12 ‘chocolate-sensitive’ migraine patients, whereas in a second study the headache response a er chocolate did not di er from placebo (17,18). Tyramine (200 mg), a naturally occurring catecholamine analogue-releasing agent found in fermented food, has also been tested in a provocation study in 80 migraine patients and there was no di erence in the occurrence of headache between tyramine and placebo (19). is is in agree- ment with the fact that noradrenaline infusion, under controlled conditions, does not induce headache in healthy subjects (20).

In conclusion, questionnaire studies reported several migraine- provoking food products, but prospective and provocation studies

Part 2 Migraine
table 7.1 Potential triggers for migraine

Psychosocial stress

Both acute and chronic exposure to psychosocial stress have been linked to a whole range of diseases, including multiple sclerosis, asthma, and migraine. e current understanding of the relation- ship between stress and migraine is represented in Figure 7.1. Almost 1000 papers have reported on the relation between stress and migraine (21). e studies di er a lot in terms of design and can roughly be placed in two groups. e rst group consists of retro- spective and prospective questionnaires looking at stressor load and the perception of the patient. In the second group there are provoca- tion trials and studies looking at the stress response.

Stressor load and patient perception

Many migraine patients consider mental stressors as a strong trigger factor for migraine. In retrospective questionnaire studies, between 31% and 82% of patients reported psychosocial stressors as trigger factor (17,18). ese studies only give a global impression regarding the perception of patients and it is di cult to draw clear conclusions. A few studies have addressed the link between the load of poten- tial stressors and migraine prospectively. ree studies looked at the number of life events or job strain and migraine and failed to nd a relation (22–24). Prospective studies using diaries looking at the relation between the number of daily hassles and the onset of mi- graine showed a positive result in two studies (22,25) and a negative result in one (26). Interestingly, in this latter study the number of potential stressors did not change prior to a migraine attack, but the patient perception of the stressors increased. It seems that it is not the number of potential stressors that is changing prior to a migraine attack, but the way patients cope with potential stressors.

Provocations and stress response

ere have been few attempts to study the e ect of mental stress in migraine under experimental conditions. e cardiovascular

OUTPUT CHRONIC CONSEQUENCES

Weather and other atmospheric variables

Temperature
Relative humidity
High altitude (hypoxia)
Possibly other variables (see Chapter 54)

Nutritional

Alcohol
Beer
Wine (red and white)
Cheese
Chocolate
Caffeine
Ice cream
Meat
Fish
Milk (and other dairy products) Vegetables
Citrus fruits
Lipids
Aspartame
Monosodium glutamate
Sugar
Fasting or skipping meals
Fluid deprivation

Stress

Psychological stressors

Hormonal

Female hormones

Lifestyle

Fatigue and sleep Smoking Physical activity Sexual activity

Pharmacological

Nitric oxide donors
Calcitonin gene-related peptide
Pituitary adenylate cyclase-activating polypeptide Prostaglandins

demonstrated only limited evidence of a causal relation. Many pa- tients report a craving for certain food products prior to the mi- graine attack, so these factors could be considered premonitory factors instead of trigger factors.

INPUT

MODULATION

Figure 7.1 Stress cascade and migraine.

Psychosocial stressors:
-daily life
-major life events

Coping styles and individual susceptibility

Authors’ impression of the relationship between stress and migraine. Daily life stressors and major life events are well-known stressors that activate
the stress system in humans. The response (both psychological and physiological) is modulated by coping styles and individual susceptibility. Speci c disease states such as migraine render the brain more vulnerable to potential stressors. Long-term activation of the physiological stress system results in an increased allostatic load (85) and might, in turn, serve as aggravating factor for migraine.
SAM, sympathetic adrenal medullary axis; HPA, hypothalamic–pituitary adrenal axis.

Psychosocial: -perceived stress -behaviour

Psychosocial: -SAM axis -HPA axis

Allostatic load and response

Disease such as migraine and depression

response to public speaking, low-grade cognitive testing, Stroop test, cold pressor, or a mental arithmetic stressor were not (or only mildly) di erent between migraine patients and controls (27–29). All of these studies were done interictally. If it were true that coping strategies fail in the hours prior to an attack, it would be of interest to study migraine patients during the onset of an attack.

Female hormones

e menstrual cycle lasts about 28 days and can be divided into the follicular and the luteal phase (see also Chapter 5). e luteal phase starts just a er ovulation where the follicle secretes progesterone and oestrogen. If no pregnancy occurs, the corpus luteum persists for 14 days and then degenerates, which leads to a fall in blood oes- trogen and progesterone levels, resulting in menstruation.

Changes in female hormones and migraine

e female preponderance in migraine is intriguing and is likely related to female hormones as the male/female (M/F) ratio in mi- graine changes from childhood (M/F = 1:1) to adults (M/F = 1:3) (30–32). e IHS de nes pure menstrual migraine without aura (MO) as attacks occurring exclusively on day 1 ± 2 of menstru- ation in at least two out of three menstrual cycles and at no other times of the cycle, whereas patients with menstrual-related migraine may also have attacks outside menstruation (3). Two US studies re- ported that 53–62% of actively cycling patients reported menses as a trigger (33,34). Sixty-seven per cent of women with menstrual- related migraine reported their menstrual migraine to be more severe, more refractory to symptomatic therapy, or of longer dur- ation than their non-menstrual attacks (34). In fact, 25% reported their menstrual migraine to be at least occasionally manifested as status migrainosus (34). Other studies from Europe reported lower incidences of menstruation as a trigger, ranging from 24% to 51% (27,30,31), whereas a study from India reported an incidence of only 13% (35). It appears that menstruation as a trigger appears more fre- quent in MO (36), and that the resulting attacks are predominately without aura (37). e PAMINA study (38) prospectively analysed data from migraineurs and reported that day 1–3 of menstruation was associated with a hazard ratio of 2.0 for developing migraine attacks in migraineurs. Hormonal alterations during ovulation do not seem to trigger migraine, as shown in two negative studies (39). Oral contraceptives may worsen migraine frequency and intensity in up to 50% of subjects, with no di erences between MO and mi- graine with aura (MA), whereas few improve (40). Furthermore, migraine is more prevalent in postmenopausal women using oral hormone replacement (41). An improvement in migraine is well known during pregnancy, with reports of 80% of women showing complete remission or a higher than 50% decrease in the number of attacks (42). e improvement is most likely during the third tri- mester (37,38). However, some patients with MA may experience onset or worsening during pregnancy (40).

Potential mechanism

e mechanism behind female hormones as a migraine trigger is likely due to oestrogen withdrawal. us, MacGregor et al. (43) pro- spectively assessed, via daily urine samples, migraine during phases

CHaPtEr 7 Migraine trigger factors: facts and myths 40 50

E1G PdG

30 20 10

40 30 20 10

0–15 –10 –5 1 5 10 150 Day of cycle

Figure 7.2 Migraine incidence and menstrual cycle.

Incidence of migraine, urinary estrone-3-glucuronide (E1G) and pregnanediol-3-glucuronide (PdG) levels on each day of the menstrual cycle in 120 cycles from 38 women.
Reproduced from Neurology, 67, MacGregor EA, Frith A, Ellis J et al., Incidence
of migraine relative to menstural cycle phases of rising and falling estrogen,
pp. 2154–2158. Copyright © 2006, American Academy of Neurology. DOI: 10.1212/ 01.wnl.0000233888.18228.19.

of rising and falling levels of oestrogen across the menstrual cycle (Figure 7.2). e study showed that migraine was signi cantly more likely to occur in association with falling oestrogen in the late lu- teal/early follicular phase of the menstrual cycle, and that migraine was signi cantly less likely during phases of rising oestrogen (43). Withdrawal of oestrogen and progesterone leads to endometrium breakdown and thereby release of prostaglandins into the circula- tion (37). In support, infusions of prostaglandins induce immediate migraine-like attacks (44,45) and the prostaglandin inhibitor, na- proxen, may be e ective as short-term prophylaxis in pure men- strual migraine (46).

Lifestyle factors

Fatigue and sleep

Sleep has been documented as an important migraine trigger. Fatigue, and sleeping di culties as a whole, has been reported as a trigger factor by up to 80% of migraine patients versus 56% without migraine (25). Interestingly, both sleep excess and deprivation have been reported as migraine triggers. us, studies reported that lack of sleep is a potential migraine trigger in 20–84% of patients (32,47); in contrast, excess sleep has been reported in one study as a trigger by 32% (48). e relationship between sleep and mi- graine is complex. Migraine is positively associated with a general lack of refreshment a er sleep (31), and polysomnographic record- ings showed a decrease in cortical activation on nights preceding migraine attacks versus nights without a following attack (49). Furthermore, headache upon awakening has also been reported by 71% of patients in a large clinical sample of migraineurs (17,44), and a prospective study using an electronic diary identi ed tired- ness as a premonitory symptom in 72% of migraineurs (50). e lateral hypothalamus and perifornical area contain hypocretinergic neurons that become active during sleep deprivation (46,51). Such

Mean hormone metabolite concn ng/mL E1G and μg/mLPdG

% Days with reported migraine

Part 2 Migraine

hypocretinergic neurons may mediate the triggering of a migraine attack when the patient is mildly sleep deprived (52). In conclusion, sleep disturbances are present in many migraine patients and are frequently reported as a migraine trigger. However, it is di cult to di erentiate whether sleep disturbances may be a true trigger factor or a premonitory symptom. It is possible that sleep disturbances may be both a trigger factor and an integrative part of the patho- physiology of migraine.

Smoking

Smoke from cigarettes contains many compounds that may be po- tential migraine triggers. Inhaling smoke also leads to an increase in arterial carbon monoxide, which may induce dilatation of cere- bral vessels (53). Smoking has been reported in one retrospective study to be more common in MO than in MA, whereas another study has shown the opposite (48). Whether smoke has a clinical impact was questioned in a prospective study by Chabriat et al. (25), who reported that only 2% of migraineurs experienced smoking as a trigger. Interestingly, a large prospective study showed that smoking increases the risk of aura but decreases the risk of MO, according to multivariate analysis (38). Salhofer-Polanyi et al. (38) hypothesized that avoidance of smoke may be a premonitory symptom characterizing MO patients, but two former studies in a large cohort of patients did not regard changes in smoking habits as a premonitory symptom (45,50). In summary, smoke is a potential trigger in MO and MA, but it is uncertain to what degree. It may also be questioned whether smoke might be a part of premonitory symptoms.

Physical activity

Retrospective studies have reported physical activity as a mi- graine trigger with a frequency ranging from 13% to 42% (17,54). It is important to differentiate this potential trigger from primary exertional headache, which is defined as a pulsating headache lasting from 5 minutes to 48 hours brought on by and occurring only during or after physical exertion (3). In one prospective study (55) the risk of migraine aura was increased significantly by physical exhaustion on univariate analysis (odds ratio 1.96), but when performing multivariate analysis, taking into account other trigger factors, this trigger was not significantly related to MA (38). Hougaard et al. (56) reported that in MA patients who reported physical activity as a migraine trigger, only one in 12 reported migraine aura after physical activity under controlled conditions in the laboratory. Interestingly, migraine patients have been shown to be significantly more likely to avoid physical activity compared with tension-type headache patients (55), and Wöber et al. (57) also prospectively showed that lack of phys- ical activity increased the risk of headache in migraineurs. In addition, a cross-sectional epidemiological study demonstrated that the level of physical activity showed no association with mi- graine. Thus, it is likely that physical activity is not in itself a trigger, but avoidance of physical activity may be a premonitory symptom in migraine patients. Furthermore, physical activity may lead to other potential triggers such as stress, heat, and fa- tigue (17,54).

Sexual activity

ere are a few studies reporting sexual activity as potential trigger (see also Chapter 25). e studies have reported relatively low trigger frequencies among migraine patients, ranging from 3% to 5% (17,58). Interestingly, sexual activity may also have a positive e ect on migraine headache. Hambach et al. (59) reported in an observa- tional study that 34% of migraine patients had experience with sexual activity during an attack, and out of these patients 60% reported an improvement of their headache. Some patients, in particular male migraine patients, even used sexual activity as a therapeutic tool.

Pharmacological factors

Pharmacological migraine triggers have been systematically exam- ined for many years to study migraine pathophysiology (60). ese experiments yield important clues to possible brain structures that may be activated during spontaneous attacks, which may also be used to explain the e ect of potential migraine triggers.

Nitric oxide

Nitric oxide (NO) is a well-known migraine trigger. It is a signalling molecule that has many biological functions and has been identi- ed in trigeminal C- bres (61) and parasympathetic nerve bres (62) innervating cranial vessels. Food may contain nitrite and ni- trate, which are possible exogenous sources of NO. Nitrite and ni- trate are food additives (labelled E249–E252) for preserving meat to prevent botulism, and the amounts of nitrite and nitrate in food are controlled by national and European Union authorities to avoid formation of carcinogenic nitrosamines in meat, possibly the reason why there is only a single 1972 case report on ‘hot-dog headache’ (63). NO may also be delivered via glyceryl trinitrate (GTN), a pro- drug used to treat angina and heart failure. Intravenous administra- tion of GTN has been reproducibly shown to induce migraine-like attacks in 80–83% of MO patients (64–66) and 50–67% of MA pa- tients (64,67). Patients typically develop a delayed migraine-like at- tack, peaking 5 hours a er the end of an infusion (66). e exact neurobiological mechanisms of GTN-induced migraine-like attacks have not been fully clari ed (62,63). GTN serves as a vasodilator because it is converted to NO in the body. NO is highly lipid sol- uble and easily penetrates membranes, including the blood–brain barrier. us, NO may trigger migraine through peripheral and/or central modulation of the brain. NO also activates intracellular sol- uble guanylate cyclase and catalyses the formation of cyclic guano- sine monophosphate (cGMP). Sildena l, a selective inhibitor of phosphodiesterase 5, which is the major enzyme responsible for the breakdown of cGMP, has been demonstrated to induce migraine- like attacks in 83% of migraine patients (68), which suggests that migraine might be provoked by upregulation of intracellular cGMP.

Calcitonin gene-related peptide

Trigeminal sensory C- bres innervating the cranial vessels con- tain the neuropeptide calcitonin gene-related peptide (CGRP) (69), and electrical stimulation of the trigeminal ganglion liberates vaso- active peptides into the perivascular space (70). e importance of

CGRP in migraine became rmly established when Lassen et al. (71) conducted a double-blind crossover study, where CGRP or placebo was infused for 20 minutes in 12 MO patients. Following CGRP infusion, 67% experienced migraine-like attacks versus only one a er placebo. A study by Hansen et al. (72) revealed that CGRP induced MO attacks in 57% of MA patients. Mechanisms respon- sible for CGRP-induced migraine attacks has not yet been clari ed, but CGRP receptor activation leads to increased cyclic adenosine monophosphate (cAMP) levels (73). Cilostazol is an inhibitor of phosphodiesterase 3 that is known to increase intracellular cAMP, and when cilostazol is given to healthy subjects, 92% develop head- ache, of which 18% have migraine-like features such as pulsating pain quality and aggravation by physical activity (74). ese data suggest that the cAMP pathway may play an important role in trig- gering migraine.

Pituitary adenylate cyclase activating polypeptide

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a signalling molecule found in sensory (75) and parasympathetic nerve ganglia (62) with perivascular nerve bre projections to intra- cranial vessels. PACAP38 infusion induced migraine attacks in 58% of MO patients (76). It has been suggested that PACAP38-induced migraine might be caused by selective activation of the PACAP type 1 receptor (77), which, interestingly, shares the same cAMP intracel- lular signalling pathway as CGRP.

Prostaglandins

Prostaglandins are important mediators of pain and in amma- tion, and considerable evidence implicates their involvement in the pathogenesis of migraine. us, experimental studies have showed that prostaglandin I2 (PGI2) (45) and prostaglandin E2 (PGE2) (44) induce migraine-like attacks in MO patients. Interestingly, in con- trast to delayed NO, CGRP, and PACAP38 migraine attacks, PGI2 and PGE2 initiate immediate migraine symptoms during infusion. is suggests that prostaglandins might have modulatory e ects in the late course of spontaneous migraine.

Several endogenous signalling molecules found in perivascular intracranial compartments have been identi ed as migraine triggers. us, the described hormonal, nutritional, and physiological trig- gers may all eventually lead to endogenous release to some of these signalling molecules during spontaneous migraine attack. Drugs targeting blockade of these signalling molecules, before exposure to a certain trigger, may be pursued experimentally to investigate the causative relationship between a trigger and a signalling molecule.

Migraine triggers: many myths and few facts

ere is some discrepancy between patient perception of migraine triggering factors (as measured by retrospective questionnaires) and prospective studies. e consistency between retrospective ques- tionnaire studies in various countries is limited. For instance, eating too late or fasting is considered a trigger in 57% of US migraine patients (48) and 1% of Japanese patients (78). Menstruation is a trigger for 65% of US patients and 9% of Chinese patients (79). In a review paper, the prevalence of several non-dietary factors were compared and consistency was also rather low (7). A second ex- ample of discrepancy is found in a study concerning Chinook winds. In Canada there is a strong believe that Chinook winds are strong

triggers for migraine. In a prospective study, 88% of 34 migraine pa- tients said their migraines were weather sensitive, but an objective correlation could only be con rmed in 21% (80). A third example is chocolate. In retrospective questionnaires around 25% of patients indicated that chocolate is a trigger factor (14). Prospective clinical trials, however, are either negative (17) or show a trend (18).

Potential sources for disagreement between patients’ perceptions and prospective studies

Differences in study design

Comparing questionnaire studies with prospective studies is a bit like comparing apples and pears. Questionnaire studies are good for assessing patient perception but that is something di erent than nding a factual association. e problem with measuring percep- tion is that it can be in uenced by, for instance, symptoms generated by the migraine attack. During the onset of a migraine attack pa- tients become sensitive to external stimuli like light and sound, but they can also become sensitive to potential stressors, which, under normal conditions, would not be considered stressful (26).

Variability in migraine susceptibility

e probability of a migraine attack at a certain point in time de- pends on the severity of the trigger and individual susceptibility. For instance, a female migraine patient might only get a migraine a er drinking red wine when she has her menstrual period. In a retrospective questionnaire study she will respond that red wine is a trigger. However, if you do a provocation trial on day 8 of her cycle she will not have an attack.

Clinical implications

Classic advice has been to instruct patients to identify and avoid triggers (4,5). is is despite a very limited amount of research on the e ect of coping with migraine triggers by avoidance. Blau and avapalan (81) investigated 14 MA and nine MO patients and identi ed 127 provoking factors. e patients were then instructed to avoid triggers, which led to a 50% reduction in attack frequency within 3 months. However, the patients were also instructed to abort attacks by quickly taking antiemetic and analgesic tablets, which may have been a very important confounder. Martin (82) suggested that migraine patients may, in fact, bene t from exposure to triggers, based on experience from cognitive behavioural therapy in treat- ment of anxiety and stress. However, whether exposure to a poten- tial trigger may actually be e ective as migraine therapy has not yet been investigated.

It is di cult to di erentiate between what might be premonitory symptoms or triggering factors in migraine, which seems clear from the reviewed data in this chapter. Hougaard et al. (56) recruited 27 MA patients who reported that bright or ickering light or strenuous exercise triggers their migraine attacks. e patients were experimentally provoked by di erent types of photo stimulation, strenuous exercise, or a combination of the two. Interestingly, only three patients (11%) reported attacks of MA following provocation. An additional three patients reported MO attacks. us, the study shows that experimental provocation using self-reported natural trigger factors causes MA only in a small subgroup of MA patients. In addition, possible migraine triggers may occur at the same time, which makes it di cult for the patient and the treating physician to identify the appropriate trigger. For example, how do we identify and decipher the exact triggering factor if a migraine attack occurs

CHaPtEr 7 Migraine trigger factors: facts and myths

Part 2 Migraine

following jogging for 1 hour, which may induce heat, mild dehydra- tion, and hypoglycaemia, resulting in consumption of a chocolate bar and a feeling of general fatigue? It is also possible that this cas- cade of possible triggers needs to occur in combination to induce migraine or may depend on the migraine patient’s conviction that this may trigger an attack.

Oestrogen withdrawal leading to menstruation-induced mi- graine is a clear migraine trigger, for which there is evidence that maintaining a stable oestrogen level (83) or prophylactic treatment during oestrogen withdrawal is e ective in preventing the attack. Pharmacological triggers such as NO, CGRP, PACAP38, and pros- taglandins have also been shown to induce migraine in a controlled experimental setting. Yet, at present, there is no scienti c evidence that avoiding or coping with most known migraine trigger factors is e ective in migraine treatment. We suggest that patients are advised and informed that some factors may occur prior to a migraine attack but that these factors are not necessarily responsible for the migraine attack. Some of these factors may be symptoms of a developing mi- graine attack. ere is a great demand for future prospective and experimental studies on migraine triggers.

Conclusion

Migraine triggers are identi ed by many migraine patients and trigger avoidance is recommended as a rst step in migraine man- agement. However, prospective studies showed only weak correl- ations between migraine and weather, food, stress, or lifestyle factors. Only pharmacological triggers like nitroglycerin are able to trigger an attack in more than 75% of patients. ere are no convincing clinical trials showing the e cacy of trigger-avoidance strategies as prophylactic treatment for migraine. When instructing a patient it is important to explain the substantial discrepancy between patient perception and objective studies. Many potential triggers can be re- garded as premonitory symptoms, but trying to avoid them will not work. For instance, psychosocial stressors are not increased in the 24–48 hours prior to a migraine attack, but the migraine patient is less able to cope with these stressors.

Future studies should focus on both prospective cohort studies and clinical provocation trials. ere is no need for new retro- spective questionnaires. Before starting a large-scale prospective study on trigger factors, it makes sense to look at the methodology used in genetic studies, such as genome-wide association studies. In fact, environment-wide association studies have revealed new pieces of information for multifactorial diseases like diabetes mellitus type 2 (84) and, hopefully, they will do the same for migraine.

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Hemiplegic migraine and other monogenic migraine subtypes and syndromes
Nadine Pelzer, Tobias Freilinger, and Gisela M. Terwindt

Introduction

Migraine with aura (MA) and migraine without aura (MO) both have a strong genetic component. Population-based family studies showed that the familial risk of migraine is increased (1–3). Genome- wide association studies (GWAS) have recently led to the identi ca- tion of several genetic risk factors for migraine, which con rms that these common forms have a complex genetic background (4–7). To identify pathophysiological mechanisms of a complex genetic dis- order it is useful to study monogenic subtypes. Hemiplegic migraine (HM) is such a rare monogenic subtype of MA. Apart from HM, other monogenic syndromes are associated with migraine (Figure 8.1). Migraine seems to be part of the clinical spectrum of several monogenic vascular syndromes. Other monogenic syndromes in- clude symptoms that mimic migraine headache or migraine auras, or these syndromes are associated with one of the three known HM genes. Because of these overlapping features, these monogenic syn- dromes are part of the di erential diagnosis when a patient pre- sents with migraine (-like) symptoms. Genetic testing and other diagnostics such as imaging, cerebrospinal uid (CSF) analysis, or electroencephalography (EEG) may sometimes help to di eren- tiate between these disorders. Making a correct diagnosis is crucial to inform patients not only about the natural history and prognosis of their disease, but also about its heritability and thus the conse- quences for the patient’s relatives. Several genes showed associations with migraine in only a few patients with familial migraine without motor auras (KCNK18 (8), CSNK1D (9)), or in a few patients with HM, o en with comorbid disorders (SLC1A3 (10,11), SLC4A4 (12)). ese genes and disorders are not discussed further in this chapter.

HM is a monogenic syndrome in which migraine is the key in- herited disorder. HM is considered an o cial subtype of MA in the International Classi cation of Headache Disorders (ICHD) (13). HM is rare, with an estimated prevalence of 0.01% (14). Beside

common aura symptoms and migraine headaches, attacks include transient hemiparesis varying from mild paresis to hemiplegia. Two types of HM are recognized. In familial HM (FHM) there is at least one rst- or second-degree family member with HM attacks. FHM shows autosomal dominant inheritance, which means that any o spring of a patient with HM has a 50% chance of inheriting the genotype. In the third version of the ICHD, FHM is categor- ized according to the results of genetic testing. FHM1 is associated with mutations in CACNA1A, FHM2 with ATP1A2 mutations, and FHM3 with SCN1A mutations (Figure 8.1) (see section ‘Genetic testing in hemiplegic migraine’). In sporadic HM (SHM), the family history is negative for HM, but migraine o en runs in the family (13). Some patients with SHM have de novo mutations and thus a new FHM family may develop if the mutation carrier has o spring in the future (15). e core pathophysiological mechanisms of HM are considered to be similar to those of migraine, especially MA, and patients with HM report similar trigger factors as patients with common subtypes of migraine (16), although experimental studies also showed di erent triggering e ects in HM (17–20).

Clinical symptomatology of hemiplegic migraine

Clinical diagnosis of HM is based on the ICHD criteria of the International Headache Society (Box 8.1), which makes the physician’s interview the most important step of the diagnostic pro- cess (13). A physical examination is mainly performed to exclude other disorders. To distinguish familial HM from sporadic HM, obtaining the family history is essential.

Compared with the general population, patients with HM have an increased risk of also su ering attacks of the common forms of migraine with and without aura, with a co-prevalence risk of 55% for MA and 25% for MO (21). Because of this co-occurrence of several migraine subtypes in one patient, it may be di cult for patients to discern which symptoms occur during which type of attacks, and the interview can therefore be complicated.

To conclude whether a patient su ers from HM, a motor aura must be present. When patients experience complete hemiplegia, they o en report these symptoms spontaneously, but a mild par- esis that is, for example, limited to one extremity may be di cult

Hemiplegic migraine: a monogenic migraine subtype

Part 2 Migraine

AHC

ATP1A3

MIGRAINE SHM/FHM1

CACNA1A

EA2

CACNA1A

SCA-6

CACNA1A

SHM/FHM2

ATP1A2

COL4A1

syndromes

MELAS

mtDNA genes

GEFS+/SMEI

SCN1A

CADASIL

NOTCH3

RVCL

TREX1

FHM3

SCN1A

during attacks. To diagnose FHM it is therefore always necessary to obtain a direct interview from all family members to verify whether multiple relatives do indeed su er from motor auras, and not common MA.

Apart from the HM-speci c motor auras, the symptoms and their order of appearance during attacks are very similar for HM and MA (22). Possible clues towards HM are the occurrence of two or more aura subtypes (e.g. visual, sensory, and motor auras), aura symptoms of longer duration, and brainstem auras (i.e. dysarthria, vertigo, tinnitus, hypacusis, diplopia, ataxia, and/or decreased level of consciousness) (13,22,23). In addition, the attack frequency of HM is variable, but with an average of three attacks per year it is much lower than that of MA and MO (24). e mean age at onset of FHM is lower than the average in common migraine subtypes. In familial MA, a mean age at onset of 21 years has been reported versus 17 years (95% con dence interval 15–18; range 1–45 years) or even 11.7 years (standard deviation 8.1, range 1–51) in FHM (22,25). Similar to common migraine subtypes, HM is 2–4 times more prevalent in females (14,22). A typical HM feature is triggering of attacks by a minor head trauma, with an average prevalence of 9% in a large FHM cohort (25).

Severe HM attacks may be prolonged (up to 6 weeks) and accom- panied by confusion, decreased consciousness, fever, seizures, and even coma (25–27). ese severe symptoms and also the typical HM symptoms may divert physicians to other diagnoses, resulting in a need for additional diagnostics.

role of additional diagnostics and differential diagnosis of hemiplegic migraine

Imaging and vascular events or structural abnormalities

Especially in the acute phase of a rst HM attack, a transient is- chaemic attack (TIA) or stroke is o en part of the di erential diag- nosis. A discerning factor is that migraine auras o en start gradually, with a series of consecutive and spreading symptoms, in contrast to the sudden onset of vascular events.

Genetic testing can solve the diagnostic problem, but it may take up to several months before the results are available. In the mean- time, it is important to consider other diagnoses. When HM attacks always occur on the same side, underlying pathologies, including arteriovenous malformations, arterial dissections, and cerebral vas- culitis, must be excluded by magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). ere are only a few permanent imaging abnormalities (i.e. abnormalities that are also present in the interictal phase) that can support the diagnosis of HM. In patients with FHM type 1 (FHM1) patients with pro- gressive cerebellar ataxia, cerebellar atrophy has been described (Figure 8.2) (28,29). In a few cases, di use cortical and subcortical hyperintensities on T2-weighted MRI (30–32), signs of ischaemic necrosis (33), or cortical cerebral atrophy (30–32,34) were still vis- ible in the previously a ected hemisphere.

e majority of radiological abnormalities in HM have been found during or shortly a er a HM attack. Even during an attack, however, it is di cult to determine whether the observed abnormal- ities are primary or secondary. e ictal computed tomography (CT) or MRI abnormalities are reversible and may be linked to both vas- cular and neuronal mechanisms. Di use (cortical) oedema of the hemisphere contralateral to the motor de cit is the most prevalent observation (Figures 8.2 and 8.3) (31,35–37). e oedema may be

Neuronal

Figure 8.1 Monogenic syndromes associated with migraine (and their

causative genes).

CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts
and leukoencephalopathy; RVCL-S, retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations; MELAS, mitochondrial myopathy with encephalopathy, lactic acidosis, and stroke (associated with mutations in mitochondrial DNA (mtDNA); GEFS+/SMEI, generalized epilepsy with febrile seizures/severe myoclonic epilepsy of infancy; SCA-6, spinocerebellar ataxia type

6; EA2, episodic ataxia type 2; SHM/FHM, sporadic hemiplegic migraine/familial hemiplegic migraine; AHC, alternating hemiplegia of childhood.

to establish retrospectively. e biggest di culty is to distin- guish complaints of sensory disturbances from those of a mild paresis, because sensory auras may cause the sensation of being unable to grasp or li objects and might be interpreted as mild motor auras. is diagnostic problem also arises when patients are asked whether relatives with migraine su er from motor weakness

Box 8.1 Criteria for hemiplegic migraine

1.2.3 Hemiplegicmigraine

Description:

Migraine with aura including motor weakness.

Diagnostic criteria

A Attacks ful lling criteria for 1.2 Migraine with aura and criterion B below.

. B Aura consisting of both of the following:

. C fully reversible motor weakness;

. D fully reversible visual, sensory and/or speech/language symptoms.

Notes:

1 The term plegic means paralysis in most languages, but most attacks are characterized by motor weakness.

2 Motor symptoms generally last less than 72 hours but, in some pa- tients, motor weakness may persist for weeks.

Comment:

It may be dif cult to distinguish weakness from sensory loss.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Vascular

Glial

(a) (b)

CHaPtEr 8 Hemiplegic migraine and other monogenic migraine subtypes and syndromes (c) (d)

Figure 8.2 Consecutive magnetic resonance imaging (MRI) scans over a 10-year follow-up period in familial hemiplegic migraine.

The patient carries the p.Ser218Leu CACNA1A mutation and suffers from psychomotor retardation and progressive cerebellar ataxia. (A, C) Axial T1- weighted MRIs during ictal phases showing diffuse cortical swelling of both the (A) right and (C) left hemisphere during separate hemiparetic attacks with a 9-year interval. (B, D) Sagittal T1-weighted inversion recovery MRI showing progressive cerebral and cerebellar atrophy with a 2-year interval.

cytotoxic, as is suggested by MRIs that show reversible decrease in water di usion (35,38). Mild gadolinium enhancement on MRI has also been reported, which indicates opening of the blood–brain bar- rier and thus points towards vasogenic oedema (38–40). Reported abnormalities in cerebral perfusion during a HM attack are diverse and de nite conclusions cannot be made (31,40,41).

Both conventional angiography and MRA have shown narrowing or even obliteration of intracranial arteries during a HM attack, but subsequent signs of ischaemia were not observed (42,43). In con- trast, a case report demonstrated dilatation of the middle cerebral artery (40). Conventional cerebral angiography via a catheter is contraindicated in HM, because it has been reported to provoke HM attacks, or worsen a patient’s condition dramatically (25,27,32,44). Modern alternatives such as MRA or CT angiography are therefore recommended.

Electroencephalography and epilepsy

Epilepsy and HM o en co-occur, mainly in FHM type 2 (FHM2) and FHM type 3 (FHM3). Patients may su er from migraine and epileptic features during the same episode, or experience separate

(a) (b)

Figure 8.3 Magnetic resonance imaging (MRI) during the ictal phase of a hemiplegic migraine attack.

Patient with right-sided hemiparesis, aphasia, and migraine headache. (A) T2-weighted and (B) uid-attenuated inversion recovery T2-weighted MRI showing generalized cortical swelling of the left hemisphere.

migraine attacks and epileptic seizures. It may be di cult to deter- mine whether visual symptoms are auras or epileptic phenomena, and Todd’s palsies may be confused with motor auras (25,45,46). Epilepsy symptoms can be distinguished by their more sudden onset than migrainous symptoms.

EEGs during and a er HM attacks have shown di use one-sided slow waves (theta and/or delta activity) in the hemisphere contralat- eral to the side of the motor symptoms (47). Epileptic features such as spike-and-wave complexes have only been found in cases with simultaneous HM attacks and epileptic seizures (29,45).

Cerebrospinal uid analysis and meningo-encephalitis or transient headache with neurological de cits and CSF lymphocytosis

Patients with HM may present with confusion, altered conscious- ness, and fever during an attack, which warrants a lumbar puncture to exclude an infectious aetiology. Lumbar punctures performed during HM attacks have revealed CSF lymphocytosis of up to 350 cells per mm3 and elevated protein levels of up to 228 mg/dl in pa- tients who occasionally had fever but no meningeal signs (28,48–51). CSF cultures and virological tests subsequently turned out negative. is phenomenon is probably a meningeal reaction secondary to a migraine attack or, less likely, the migraine may be secondary to an aseptic meningitis. To establish the diagnosis, it is important to note that increased CSF cell counts and protein levels may occur during HM attacks.

e condition of transient headache with neurological de cits and CSF lymphocytosis (HaNDL) shows a remarkable resem- blance to HM (see also Chapter 44) (52,53). Approximately 100 cases have been described with CSF lymphocytosis, o en with in- creased protein levels, and normal neuroimaging, CSF culture, and virological tests. Additional characteristics, such as transient, focal, non-epileptiform EEG changes, provocation of attacks by cerebral angiography, and even reversible radiological abnormalities, are also reported (52–55). Visual auras are a very common feature in HM (89–91% of patients), but were only reported by 18% of patients with HaNDL (24,52). Approximately half of patients with HaNDL de- scribe a viral prodrome and fever, which is not as common in cases of HM, although an incidental fever has been described. e only HaNDL criterion that truly con icts with HM is that HaNDL, by

Part 2 Migraine

de nition, has to resolve spontaneously within 3 months. Although the duration of follow-up in some patients with HaNDL was up to 3 years, it remains di cult to determine whether the symptoms really did not recur. Because of the many overlapping features be- tween HM and HaNDL, it may be considered that HaNDL is part of the HM phenotypic spectrum. One study evaluated this hypothesis by screening the CACNA1A gene in patients with HaNDL, but no mutations were found. However, this study only included eight pa- tients, and the other HM genes have not yet been tested in patients with HaNDL (56).

Genetic testing in hemiplegic migraine

So far, three genes have been associated with HM, indicating that HM is genetically heterogeneous (Box 8.2). PRRT2 (also associated with benign familial infantile seizures, paroxysmal kinesigenic dys- kinesia, and infantile convulsion choreoathetosis syndrome (57)) has been suggested as the fourth HM gene, but further evidence is needed to support this claim (58). Based on clinical symptoms during HM attacks alone, subtypes of HM cannot be distinguished, but the presence of additional symptoms (such as chronic progres- sive ataxia or epilepsy) may be suggestive of certain genetic sub- types. FHM1 and SHM type 1 are caused by mutations in CACNA1A on chromosome 19p13, encoding the ion-conducting α1A -subunit of P/Q-type voltage-gated Ca2+ channels (59). ese channels are localized in dendrites and presynaptic nerve terminals of cen- tral neurons and trigger neurotransmitter release (60). Over 25 CACNA1A missense mutations, leading to a gain of function of the Ca2+ channels, have been associated with FHM1 (60). Apart from the pure HM symptoms described in the ICHD criteria, the clinical spectrum of reported FHM1 families includes chronic progressive

cerebellar signs, permanent cognitive de cits, and decreased level of consciousness and seizures during HM attacks (25,28,61). e p.Ser218Leu CACNA1A mutation is associated with a very severe phenotype of seizures triggered by minor head trauma, followed by cerebral oedema and even fatal coma (26).

e second HM gene, ATP1A2 on chromosome 1q23, encodes the α2-subunit of Na+/K+-ATPase. is pump creates a steep sodium gradient by exchanging Na+ ions for K+ ions, thereby facilitating the removal of K+ and glutamate from the synaptic cle into glial cells (60). e majority of the total number of HM mutations has been identi ed in ATP1A2, with nearly 50 unique ATP1A2 mutations, mostly missense mutations, reported so far. e mutations appear to result in a loss of function of the Na+/K+-ATPase (60,62). Additional paroxysmal neurological symptoms have been described in patients with FHM2, including epilepsy, confusion, decreased conscious- ness, or even coma and prolonged hemiplegia, and also permanent neurological symptoms such as mental retardation (27,46,47,60,63). Progressive cerebellar signs that have frequently been reported with CACNA1A mutations are rarely seen in patients with ATP1A2 mutations (64).

In a few families, missense mutations in a third gene have been detected. SCN1A on chromosome 2q24 encodes the α-subunit of voltage-gated Na+ channels (65). It has been suggested that the voltage-gated Na+ channels are primarily expressed on inhibitory central neurons (66). When these channels are dysfunctional, as suggested by experiments in heterologous expression systems, this is predicted to lead to neuronal hyperexcitability and FHM attacks (65,67). Of note, SCN1A is an important epilepsy gene, with hun- dreds of mutations identi ed in monogenic epilepsy syndromes, including Dravet syndrome (also known as severe myoclonic epi- lepsy of infancy (SMEI)) and generalized epilepsy with febrile seiz- ures plus (GEFS+). e functional e ects associated with epilepsy mutations are usually more pronounced than in FHM3; however, the pathophysiological basis of mutations in the same gene leading to migraine versus epilepsy still remains incompletely understood (68). As SCN1A mutations were not identi ed in large groups of SHM patients, it can be justi ed to refrain from systematic screening of SCN1A in SHM (69,70).

e main pathophysiological mechanism thought to underlie HM is that all mutations lead to increased cerebral levels of K+ and glutamate in the synaptic cle , which would increase neuronal ex- citability, and thereby can explain the increased susceptibility to cor- tical spreading depression (CSD) (Figure 8.4) (60).

When a patient exhibits a typical HM phenotype, it is di cult to predict whether a mutation in one of the HM genes will be de- tected. In large FHM cohorts CACNA1A mutations were detected in 4–7% (71,72) and ATP1A2 mutations in 7% (71). Mutation de- tection rates in SHM vary even more, with CACNA1A mutations in 1–36% (69,70,73,74) and ATP1A2 mutations in 1–56% (69,70,73). A likely cause for the reported low detection rates is that severe mi- graine with aura may be confused with HM. Detection rates in SHM appeared to be higher in early-onset SHM, especially when associ- ated with additional neurological symptoms, which con rms that an early age at onset is a feature that may distinguish HM from mi- graine with aura (69). It appears that not all individuals carrying an HM mutation develop the HM phenotype, as una ected relatives of patients with HM also carried CACNA1A or ATP1A2 mutations (63,70,71). is reduced penetrance has not yet been reported in

Box 8.2 Criteria for the subtypes of hemiplegic migraine based on genetic testing and family history

1.2.3.1 Familial hemiplegic migraine (FHM)

. A Attacks ful lling criteria for 1.2.3 Hemiplegic migraine (see Box 8.1).

. B At least one rst- or second-degree relative has had attacks ful lling
criteria for 1.2.3 hemiplegic migraine.

1.2.3.1.1 Familial hemiplegic migraine 1 (FHM1)

. A Attacks ful lling criteria for 1.2.3.1 Familial hemiplegic migraine.

. B A mutation in the CACNA1A gene has been demonstrated.

1.2.3.1.2 Familial hemiplegic migraine 2 (FHM2)

. A Attacks ful lling criteria for 1.2.3.1 Familial hemiplegic migraine.

. B A mutation in the ATP1A2 gene has been demonstrated.

1.2.3.1.3 Familial hemiplegic migraine 3 (FHM3)

. A Attacks ful lling criteria for 1.2.3.1 Familial hemiplegic migraine.

. B A mutation in the SCN1A gene has been demonstrated.

1.2.3.1.4 Familial hemiplegic migraine (FHM) other loci

. A Attacks ful lling criteria for 1.2.3.1 Familial hemiplegic migraine.

. B Genetic testing has demonstrated no mutation in the CACNA1A, ATP1A2, or SCN1A genes.

1.2.3.2 Sporadic hemiplegic migraine

. A Attacks ful lling criteria for 1.2.3 Hemiplegic migraine.

. B No rst- or second-degree relative ful ls criteria for 1.2.3 Hemiplegic
migraine.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Inhibitory neuron

FHM3 Nav1.1

Excitatory neuron

Presynaptic terminal

FHM2 Na+/K+-ATPase

Na+

K+ Glial cell

CHaPtEr 8

Hemiplegic migraine and other monogenic migraine subtypes and syndromes

FHM1 Cav2.1

Postsynaptic terminal

Figure 8.4 Schematic representation of a glutamatergic synapse and the functional roles of proteins encoded by the familial hemiplegic migraine types 1, 2, and 3 (FHM1, FHM2, and FHM3) genes.

In response to an action potential, calcium enters the presynaptic terminal of excitatory neurons via voltage-gated calcium channels (Cav2.1), encoded by CACNA1A. As a result, glutamate will be released into the synaptic cleft. Glial cells (astrocytes) contain Na+/K+-ATPase, which is encoded by ATP1A2 and aids in removing potassium from the synaptic cleft. The removal of extracellular potassium creates a Na+ gradient, which leads to the uptake of glutamate by other transporters. The voltage-gated sodium channels (Nav1.1) encoded by SCN1A play a major role in the generation and propagation of action potentials. FHM1 mutations cause a gain-of-function effect, and FHM2 and FHM3 mutations likely have loss-of-function effects. All FHM mutations appear to result in increased cerebral levels of K+ and glutamate in the synaptic cleft, and thereby cause an increased excitability, which may explain the increased susceptibility to cortical spreading depression, which is thought to be the underlying mechanism of the migraine aura.

FHM3, although only ve clear FHM-associated SCN1A mutations have been described so far (60).

It is likely that more HM genes remain to be identi ed, as some clinically a ected individuals do not have a mutation in any of the known genes. Negative test results for mutations in CACNA1A, ATP1A2, and SCN1A therefore do not exclude the clinical diag- nosis of HM. Over the past years, GWAS have been successful in identifying susceptibility loci for the common forms of migraine, but HM is too rare to perform such studies (4–7). New analytic techniques such as next-generation sequencing may enable the identi cation of novel HM genes in the near future (75,76). e im- portance of taking comorbid disorders into account is illustrated by the nding that mutations in CSNK1D, associated with familial ad- vanced sleep phase syndrome, may also contribute to the pathogen- esis of migraine (9).

treatment of hemiplegic migraine

Before considering medication to treat HM, some lifestyle advice can be discussed. Various trigger factors, such as stress, sleep dis- turbances, physical exertion, bright lights, drinks, and food prod- ucts, have all been reported in HM (16). However, especially stress, but possibly other trigger factors as well, is suggested to be part of the premonitory phase of the migraine attack, rather than a true

trigger factor (77). is does not apply to the triggering of attacks by (minor) head trauma, which is o en and convincingly described in HM. e head trauma-triggered attacks are o en reported to be severe, sometimes including coma, or even fatal in speci c cases with the p.S218L CACNA1A mutation (25,26,28,41,45,47). Because of these reports, patients with HM must be advised not to practice contact sports, or, for example, avoid heading balls when playing soccer. No evidence-based advice can be given about other lifestyle or dietary factors.

Because of the rarity of HM, large clinical drug trials have not been performed and treatment largely follows guidelines for the common forms of migraine. Preference for certain drugs is mostly based on empirical data and the personal experience of the treating neurologist. ere are no speci c treatments for patients with known mutations. Although the aura symptoms in HM are o en more debilitating than the headache, most migraine-speci c drugs for acute treatment unfortunately only a ect headache.

e rst choice in acute treatment is usually acetaminophen or a non-steroidal anti-in ammatory drug. When these do not relieve headaches su ciently, triptans can be prescribed. e use of triptans was previously controversial because of a fear of migrainous strokes or aggravation of auras, but as CSD is now thought to underlie auras, this contraindication does not apply anymore. Several studies in

Na+

Ca2+

Part 2 Migraine

patients with HM showed that side e ects of triptans were rare and minor (78,79).

e evidence for alternative options in acute treatment of HM is limited. A few case reports suggested the possible e cacy of abortive treatment with intravenous verapamil and acetazolamide in HM (80–83). Other studies have reported some bene cial e ects of acute treatment with ketamine nasal spray in HM (84,85). Although these results appear promising, these drugs are not yet considered suitable for widespread use in HM (86).

Prophylactic treatment is o en prescribed to reduce high attack frequencies, and may also be considered with low-frequent but se- vere attacks. Lamotrigine, unarizine, sodium valproate, verapamil, and acetazolamide can be tried, in no strictly preferred order (86). Other migraine prophylactics, such as topiramate, candesartan, and pizotifen can also be considered, although there is less evidence for the e cacy of these drugs. Reports of adverse e ects in HM makes propranolol more controversial, but the evidence of these e ects is insu cient to contraindicate beta blockers (see Box 8.3) (86).

Some monogenic syndromes show a higher prevalence of migraine than would be expected based on the population risks. Other symp- toms of these disorders are primarily vascular, and unravelling pathophysiological mechanisms of these disorders may reveal vas- cular mechanisms that also play a role in migraine pathophysiology. e following syndromes should be considered when a family his- tory not only includes many migraine patients, but also many re- latives with (early-onset) (cerebro)vascular disease and dementia. Radiological imaging is o en helpful in the diagnostic process of these syndromes.

Cerebral autosomal dominant arteriopathy
with subcortical infarcts and leukoencephalopathy

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common familial small-vessel disease, with an estimated prevalence of approximately two per 100,000 adults (87). e disease has previously been de- scribed as hereditary multi-infarct dementia, chronic familial vas- cular encephalopathy and familial subcortical dementia, but a er the discovery of mutations in NOTCH3 in 1993 has primarily been referred to as CADASIL (88,89).

Clinical symptomatology of CADASIL

CADASIL is a systemic vascular disease, with varying clinical presen- tation, even among relatives with the same mutation. Approximately 20–40% of patients su er from migraine, predominantly MA (90). In half of these cases, attacks are atypical with prolonged, brainstem or hemiplegic auras (or even confusion), fever, meningeal signs, or coma (91,92). During gestation and shortly a er childbirth there appears to be an increased risk of transient neurological symp- toms, which are later o en labelled as migraine auras (93). In these women, and also in other cases, migraine is o en the presenting symptom, with a mean age at onset of 26 years (90,94). Mood dis- turbances occur in 20% of cases, including severe depressive epi- sodes. Apathy is observed in about 40% of patients with CADASIL, which may be accompanied by depressive symptoms, but also oc- curs without depression (89). A key symptom that should raise the suspicion of CADASIL is the occurrence of TIAs and ischaemic stroke before the age of 50 years (mean age at rst event is 48 years, range 19–67 years) (95). A er recurrent (lacunar) strokes and cere- bral microangiopathy, patients o en develop progressive cognitive disturbances, which have also been observed as an isolated nding in 10% of patients (89). About three-quarters of patients eventually develop (vascular) dementia (95).

In patients presenting with MA, especially with the aforemen- tioned atypical features, it is thus important to obtain a thorough family history of cerebrovascular events and early-onset dementia. If a pattern of autosomal-dominant inheritance can be derived, this further points towards CADASIL. However, the disease can also re- sult from a de novo mutation, in which case the family history is negative (96).

Treatment options for CADASIL are limited and non-speci c. Migraine attacks can be treated according to common guidelines. In contrast to what is o en thought by clinicians, acute antimigraine

Vascular monogenic syndromes associated with migraine

Box 8.3 Recommendations for clinical practice when suspecting hemiplegic migraine (HM) in a patient

Patient interview

• Con rm the presence of motor aura symptoms and distinguish these from sensory aura symptoms.

• Identify additional features during attacks that point towards HM: — epilepsy;
— confusion;
— fever;
— decreased consciousness;
— other symptoms of brainstem auras; — prolonged aura symptoms.

• Identify additional features outside attacks that point towards HM: — epilepsy;
— ataxia.

• Obtain family history:

— direct interview with rst- and/or second-degree relatives to inves-
tigate familial occurrence of HM;

— take into account the possibility of reduced penetrance in relatives
(63,70,71).
Additional diagnostics

• Molecular genetic testing:
— mutations in CACNA1A, ATP1A2, or SCN1A.

• MRI:

— progressive cerebellar (and cerebral) atrophy;

— diffuse (cortical) oedema of the hemisphere contralateral to the
motor de cit during attacks.

• Cerebrospinal uid analysis:
— pleocytosis during attacks.

• Electroencephalography:
— diffuse one-sided slow waves (theta and/or delta activity) in the hemisphere contralateral to the motor de cit during attacks.
Treatment

• Acute treatment (86):
— conform treatment of common migraine types, including triptans.

• Prophylactic treatment (in no strictly preferred order) (86): —lamotrigine, unarizine, sodium valproate, verapamil, and

acetazolamide.

medication, such as triptans, can be safely prescribed. Other co- occurring disorders, such as hypertension, hypercholesterolaemia, and diabetes, should also be treated symptomatically. As in other cerebrovascular diseases, patients should be advised to refrain from smoking, as smoking increases the risk of stroke, also for CADASIL speci cally (97). Antiplatelet treatment may be used, but its e cacy is not proven in CADASIL. Anticoagulants may pro- voke cerebrovascular accidents and are therefore contraindicated. Conventional angiography is contraindicated for the same reasons (98). Intravenous thrombolysis is thought to increase the risk for cerebral haemorrhage, which should be conveyed to the treating physicians in the acute phase of a CADASIL-related stroke.

A study of over 400 patients with CADASIL revealed a reduced life expectancy, especially in men. e median age at death was 68 years. e most frequent cause of death was pneumonia; other causes were sudden unexpected death and asphyxia. Most patients were completely dependent or even con ned to bed during the nal stage of the disease (95). Although there is some therapeutic advice to be given, CADASIL is an incurable and fatal disease. When there is a clear clinical suspicion of CADASIL, (genetic) counselling in a specialized centre is therefore strongly advised before any diagnos- tics (MRI, skin biopsy, or genetic screening) are performed.

Imaging in CADASIL

e suspicion of CADASIL o en arises when MRI reveals symmet- rically distributed MRI white matter hyperintensities in the peri- ventricular and deep white matter. T2 signal abnormalities in the white matter of the temporal pole and in the external capsule have frequently been described (Figure 8.5). ese hyperintensities may be subtle, but are consistently seen from 21 years of age onwards. Distinctive white matter lesions o en rst appear in the anterior temporal lobes, while the remaining white matter appears una ected (99). e load of white matter hyperintense lesions increases during the course of the disease, to a state where all white matter appears to be a ected (100). Additional radiological ndings include sub- cortical lacunar lesions at the junction of the grey and white matter in approximately two-thirds of patients and cerebral microbleeds, which mainly occur in the thalamus (98,101,102). Haemodynamic

(a) (b)

Figure 8.5 Magnetic resonance imaging abnormalities in a patient with CADASIL.

Axial T2-weighted uid-attenuated inversion recovery images showing extensive symmetric white matter abnormalities in (A) the periventricular areas and in (B) the temporal poles.

imaging studies reported decreased total cerebral blood ow and decreased cerebral perfusion in normal and abnormal appearing white matter (103,104). Also, areas of white matter lesions exhib- ited decreased vasoreactivity, which would be consistent with the expected degeneration of vascular smooth muscle cells (vSMCs) (105). Cerebrovascular reactivity measurements a er acetazolamide administration in patients with CADASIL were of prognostic value regarding cerebrovascular pathologies (106).

Pathophysiology of CADASIL

NOTCH3 is predominantly expressed in vSMCs, preferentially in small arteries. NOTCH3 encodes a single-pass transmembrane re- ceptor, composed of an intra- and extracellular domain. Most iden- ti ed NOTCH3 mutations lead to a loss or gain of a cysteine residue in one of the epidermal growth factor repeats of NOTCH3 (107). e mutations are thought to a ect folding of the protein by disrupting disulphide bonding of the cysteine residues. Other hypotheses sug- gest the receptor cannot be internalized properly, which could result in enhanced ligand binding or toxic e ects (108). e majority of NOTCH3 mutations are clustered in exons 2–6 (109). Microscopic and ultrastructural investigations show a speci c arteriopathy af- fecting mainly the small cerebral and leptomeningeal arteries, characterized by a thickening of the arterial wall leading to lumen stenosis, a largely normal endothelium, the appearance of pathogno- monic granular osmiophilic deposits, termed granular osmiophilic material (GOM) within the media extending into the adventitia, and degeneration of vSMCs. e GOM is extracellular, located close to the cell surface of vSMCs, but it can occasionally be found in capil- laries. e presence of GOM is highly speci c for CADASIL and can be con rmed with electron microscopy of small vessels obtained via a skin biopsy, which may serve as an alternative diagnostic method besides screening of NOTCH3. It should be noted, however, that the deposition can be focal and could be missed if the specimen is not thoroughly evaluated (110). Exclusion of the diagnosis based only on a negative skin biopsy is therefore not recommended. DNA ana- lysis is the gold standard.

Although the same morphological changes have been estab- lished repeatedly, the pathophysiological mechanisms that eventu- ally cause the CADASIL phenotype remain elusive. Mutations in NOTCH3 in patients with CADASIL may lead to dysfunction of the blood–brain barrier due to degeneration and loss of pericytes (111,112). A remarkable nding that illustrates the unanswered questions in CADASIL pathophysiology is the fact that clinical manifestations are only cerebral, although arteriopathy is also pre- sent in other organs, such as the spleen, liver, kidneys, muscle, aorta, and skin (90,113).

retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations

A collection of hereditary neurovascular syndromes with retinal in- volvement and other systemic symptoms all appeared to be associ- ated with mutations in TREX1. A er this discovery in 2007, these syndromes (cerebroretinal vasculopathy; hereditary vascular ret- inopathy; and hereditary endotheliopathy with retinopathy, neph- ropathy, and stroke) were designated as retinal vasculopathy with cerebral leukodystrophy (RVCL) (114). Heterozygous mutations in TREX1 have been found in 11 families from Europe, North America, Asia, and Australia (115–121). Although RVCL currently appears

CHaPtEr 8 Hemiplegic migraine and other monogenic migraine subtypes and syndromes

Part 2 Migraine

to be very rare—the gene was discovered only a few years ago— the condition is therefore likely still underdiagnosed. e acronym ‘RVCL’ has recently been replaced by ‘RVCL-S’ (for ‘RVCL and sys- temic manifestations’) (122).

Clinical symptomatology of RVCL-S

RVCL-S is primarily characterized by progressive loss of vision due to a retinal vasculopathy. In addition, a wide range of cere- bral and systemic conditions, including intracerebral mass lesions and white matter lesions with associated focal neurological symp- toms and cognitive impairment, migraine (primarily without aura), Raynaud’s phenomenon, anaemia, and liver and kidney dysfunction can be detected (118). Especially in a large Dutch RVCL-S family, MA and Raynaud’s phenomenon—an abnormal vasomotor reac- tion in response to cold exposure—are prominent in the phenotype (123). A genetic association study demonstrated an increased sus- ceptibility for both Raynaud’s phenomenon and migraine for the RVCL-S haplotype (124). A treatment to cure RVCL-S is not avail- able, but some symptomatic treatment can be tried. e common policy for migraine treatment can be followed, and the retinopathy can be halted by laser therapy. e anaemia, liver, and kidney dys- function o en do not appear to require treatment, but it remains unclear if this applies to all patients with RVCL-S. e consecutive disease stages of RVCL-S, especially the early stages, remain to be identi ed. Life expectancy in RVCL-S patients is decreased, with an average age at death of 53.1 years (range 32–72 years). In most de- scribed cases the cause of death was a pneumonia or sepsis in the setting of general debilitation (122).

Imaging in RVCL-S

When a patient presents with symptoms suggestive of RVCL-S, radiological imaging can strengthen this suspicion, or other syn- dromes, such as CADASIL, may become a more likely diagnosis. All abnormalities on CT and MRI that have so far been described in patients with RVCL-S are restricted to the white matter. e le- sions are non-speci c but remarkable for the patients’ relatively young age. Two types of lesions have been observed: (i) focal, non- enhancing T2-hyperintense lesions scattered throughout the peri- ventricular and deep white matter; (ii) hyperintense mass lesions on T2 and hypointense lesion on T1-weighted images, enhanced with gadolinium contrast, and o en surrounded by extensive oe- dema, displacing adjacent structures and leading to sulci e ace- ment (Figure 8.6) (117,118). ese mass lesions are o en referred to as ‘pseudo-tumours’ (119,125). Mass lesions have been reported in 75% of patients with RVCL-S, most o en in later stages of the disease. Lesions are localized in the frontoparietal lobe in all pa- tients, sometimes with additional lesions in the cerebellum and oc- cipital lobe. ese lesions have been observed to increase in size, remain stable, or diminish in size. Restricted di usion has occa- sionally been observed, mainly in the centre of these lesions, but it remains unclear whether this re ects local ischaemic changes or demyelination. In approximately half of patients, mass lesions are associated with calci cations on CT. In some cases, mass lesions de- velop superimposed on pre-existing aspeci c non-enhancing white matter hyperintensities, sometimes associated with pre-existing or developing calci cations. Haemorrhage is reported only very rarely (122). Imaging in presymptomatic TREX1 mutation carriers has

(a) (b)

Figure 8.6 Magnetic resonance imaging abnormalities in patients with retinal vasculopathy with cerebral leukodystrophy and systemic manifestations.

(A, B) Axial gadolinium-enhanced uid-attenuated inversion recovery images showing periventricular white matter lesions in two separate patients. (C, D) Axial gadolinium-enhanced T1-weighted images showing two mass lesions in the same patient, enhanced with gadolinium contrast and with surrounding oedema.

not been performed systematically, and it is unclear whether mild intracerebral lesions may already be present in these individuals.

Pathophysiology of rVCL-S

When a TREX1 mutation is found in a patient with symptoms sug- gestive of RVCL-S, the diagnosis is thereby con rmed. So far, all TREX1 mutation carriers appear to develop the RVCL-S phenotype, indicating 100% penetrance (122). TREX1 is the most abundant 3 ́–5 ́ exonuclease in mammalian cells. Normal three prime repair exonuclease 1 (TREX1) protein resides in the cytoplasm in a protein complex attached to the endoplasmic reticulum (ER) membrane and likely translocates across the cell to clear products of DNA repair, replication, and retrotranscription (126,127). Truncating RVCL-S TREX1 mutations result in mutant TREX1 that lacks the carboxyl terminus and can no longer bind to the ER membrane. While this mutant TREX1 retains its exonuclease activity, it is thought to lack proper subcellular context and to be located throughout the nucleus and cytoplasm (121). It is still unknown how the mutated TREX1 protein leads to a microvasculopathy.

TREX1 mutations have not only been found in RVCL-S, but also in Aicardi-Goutières Syndrome (AGS) (128,129), familial chil- blain lupus (FCL) (130,131), and (neuropsychiatric) systemic lupus erythematosus (SLE) (132,133). TREX1 consists of a catalytic do- main, involved in enzymatic activity, and a C-terminal domain,

probably in uencing the location of the TREX1 protein (114). Mutations in FCL and AGS are primarily found in the catalytic do- main, while mutations in RVCL-S and SLE are most o en found in the C-terminal domain. All RVCL-S-causing mutations that have been identi ed so far result in frameshi s and truncated TREX1. In AGS, FCL, and SLE, several types of mutations have been reported, including missense and frameshi mutations (134). e exact func- tional e ects of these di erent types of mutations on these di erent locations of the TREX1 gene remain to be elucidated.

As AGS, FCL, and SLE are all associated with a disruption of type 1 interferon (IFN) metabolism, this has incited research into the link between TREX1 and (auto)immunity. De ciency of TREX1 is pos- tulated to cause accumulation of intracellular nucleic acids, which initiates an IFN-α-mediated innate immune response leading to in ammation and autoimmunity (135–137). Trex1-de cient mice have, for example, been shown to develop in ammatory myocarditis (138). A CSF lymphocytosis is common in patients with AGS, who are homozygous for TREX1 mutations (128). More importantly, in patients with AGS expression of certain IFN-stimulated genes was found to be elevated in serum and CSF (139,140). In addition, a substantial increase in the release of pro-in ammatory cytokines (interleukin-6) and chemokines (C-X-C motif chemokine ligand 10 (CXCL10) and chemokine (C-C motif) ligand 5 (CCL5)) was de- tected (140). A similar IFN signature was described in a case report of a patient with RVCL-S, albeit using slightly di erent methods (141). Another recent study found that the carboxyl terminus of TREX1 is important in the regulation of oligosaccharyltransferase activity in the ER, and thereby in preventing glycan and glycosylation defects that can lead to immune disorders (142).

Autoimmune dysfunction in RVCL-S may lead to endothe- lial dysfunction, which has been suggested to occur in RVCL- S. Activation of the endothelium results in a pro-in ammatory, procoagulatory, and proliferative milieu (143). Clinical features of RVCL-S suggest the involvement of small vessels of several organs (vascular retinopathy, cerebral white matter lesions, and kidney and liver dysfunction). e presence of Raynaud’s phenomenon points even more towards endothelial dysfunction. Both impaired endothelial-dependent vasodilatation and a mismatch between endothelium-derived vasoconstrictors (primarily endothelin-1) and vasodilators (primarily nitric oxide and prostacyclin) was dem- onstrated in Raynaud’s phenomenon (144). Similar mechanisms may be involved in RVCL-S. A recent study demonstrated endothe- lial dysfunction in patients with RVCL-S and impaired endothelial independent vasoreactivity of dermal microvasculature in patients with CADASIL. An increased vascular sti ness is seen in both disorders (145). In addition, patients with RVCL-S had abnormal increased circulating levels of the markers of endothelial function— angiopoietin-2, and Von Willebrand Factor antigen and propeptide (146). A few studies in migraine also point towards endothelial dysfunction. Circulating endothelial progenitor cells (EPCs) are suggested to provide valuable information about endothelial regen- eration capacity. Unfortunately, the cultured EPC type that probably best re ects ‘real’ EPCs has not been investigated in migraine (147). Circulating numbers and function of another EPC-like cell type have, however, been suggested to be reduced in migraine, meaning that patients with migraine may exhibit dysfunctional endothe- lial regeneration (148,149). Markers of endothelial activation were

found to be increased in premenopausal women with migraine, and biomarkers of hypercoagulability and in ammation have also been associated with migraine in a population-based study (150–152). By unravelling overlapping mechanisms in the hypothesized endothe- lial dysfunction in RVCL-S and migraine, new pathophysiological mechanisms for both diseases may be revealed.

Small-vessel diseases associated with COL4A1 mutations

A group of autosomal dominant syndromes in which the retinal and cerebral vasculature is also a ected are the COL4A1-associated syndromes (153–155). COL4A1 on chromosome 13 encodes the α1 chain of type IV collagen (COL4), which is a basement membrane protein that is also present in the vascular basement membrane. Co- occurrence of COL4A1 mutations and migraine has been described in a few studies.

Reported phenotypes of COL4A1 mutation carriers are peri- natal haemorrhage with porencephaly, and also sporadic late-onset intracerebral haemorrhages (156–160). HANAC syndrome (heredi- tary angiopathy, nephropathy, aneurysms, and muscle cramps) is a COL4A1-associated phenotype that has many systemic features. HANAC patients may have aneurysms within the intracranial seg- ment of the internal carotid artery, muscle cramps, Raynaud’s phe- nomenon, kidney defects, and cardiac arrhythmias (161). Another study suggested that COL4A1 is associated with muscle–eye–brain/ Walker–Warburg syndrome, which is characterized by ocular dysgenesis, neuronal migration defects, and congenital muscular dystrophy, and as such suggested that COL4A1 may also play a role in cortical and muscular development (162). Ocular features in COL4A1-associated syndromes are variable and include retinal arteriolar tortuosity, cataracts, glaucoma, and anterior segment dysgenesis of the eye (the Axenfeld-Rieger anomaly) (154,163). Neurological symptoms include infantile hemiparesis (persistent, not intermittent), seizures, visual loss, dystonia, strokes, mental retardation, cognitive impairment, and dementia (155). A speci c and curative treatment for the COL4A1-associated syndromes is not available.

Considering COL4A1 mutations and migraine: a co-occurrence has been described in a few studies. One patient with MO and two relatives with unspeci ed migraine were described in a family with porencephaly (158). In a family with recurrent strokes and cata- ract without porencephaly, but with di use leukoencephalopathy and microhaemorrhages, one mutation carrier su ered from MA (164). MA was observed in three out of six mutation carriers in a family with hereditary infantile hemiparesis, retinal arteriolar tor- tuosity and leukoencephalopathy (165,166). As only 10 COL4A1 mutation carriers with migraine have been described, without clear co-segregation in any of the families, this co-occurrence may well be coincidental. Although the COL4A1-associated syndromes show overlapping symptoms with the small-vessel diseases CADASIL and RVCL-S, the association with migraine is far less clear.

Imaging will reveal features such as di use leukoencephalopathy with the involvement of posterior periventricular areas, subcortical infarcts, cerebral microbleeds, and dilated perivascular spaces. In patients with porencephaly, large periventricular uid- lled cav- ities are seen, and schizencephaly has also been observed (155,167). COL4A1 screening can thus be considered when these features are seen on MRI, especially when ocular features are also present.

CHaPtEr 8 Hemiplegic migraine and other monogenic migraine subtypes and syndromes

Part 2 Migraine
Mitochondrial myopathy with encephalopathy, lactic

acidosis, and stroke syndrome

In patients with migraine-like headaches in combination with epi- sodes of hemiparesis at a young age, mitochondrial myopathy with encephalopathy, lactic acidosis, and stroke (MELAS) syndrome should also be considered. MELAS is caused by mutations in mito- chondrial DNA (mtDNA) and is maternally inherited (168). Early development is usually normal, but MELAS can manifest in child- hood. Although the clinical criteria for MELAS used to include an onset of symptoms before the age of 40 years, an onset later in life has also been reported (169). Patients o en experience a prodrome that resembles a migraine episode and consists of nausea, vomiting, throbbing headache, and abdominal complaints. e prodrome is followed by a sudden neurological de cit within hours or days. e neurological de cit can include hemiplegia, hemianopia, ataxia, or aphasia (170). In contrast to symptoms of (hemiplegic) migraine, the onset of the neurological de cit is sudden and the de cit is not (fully) reversible, causing patients to show progressive neurological dysfunction, including cognitive decline. In addition, patients can su er from generalized seizures, muscle weakness, hearing loss, and a typical short stature (171–173).

In combination with the clinical ndings, the diagnosis is pri- marily based on genetic testing. Mutations in several mtDNA genes have been found in MELAS, but most patients have a mutation in tMT-TL1 (168,174). Because of skewed heteroplasmy, the mutation may not be found in leukocytes (175). A er a negative genetic test result in blood, the pathogenic mutation may therefore still be de- tected in a biopsy of skin tissue or skeletal muscle, which can also reveal ragged red bres. In addition, an elevated lactate can be dem- onstrated in blood and/or CSF (175).

Radiological imaging may reveal symmetric and progressive basal ganglia calci cation, focal lesions, and, at a later stage, cerebral and cerebellar atrophy (170). Apart from white matter changes, deep grey matter changes have also been observed (176). e focal le- sions do not always match a vascular territory, and may result from a mitochondrial cytopathy and angiopathy. A mitochondrial dys- function may lead to energy depletion and neuronal necrosis (177). e occurrence of abnormal mitochondria and a respiratory chain de ciency have been demonstrated in the cerebral and cerebellar microvasculature of patients with MELAS, a ecting not only the vas- cular smooth muscle cell layer, but also the endothelium (178,179). Because of the rather severe abnormalities on MRI, MELAS can be easily distinguished from other disorders, especially HM.

e following monogenic syndromes do not always include mi- graine, but symptoms that mimic migraine or migraine auras may be present. e conditions are closely associated or even allelic with FHM1 and FHM2.

Episodic ataxia type 2

Episodic ataxia type 2 (EA2) is a rare disorder, characterized by attacks of ataxia lasting hours to days, accompanied by severe ver- tigo, nausea, and vomiting. A gaze-evoked, rebound, or downbeat

nystagmus can occur not only during, but also in between attacks. A broad range of ictal symptoms, including dysarthria, tinnitus, dystonia, diplopia, and also hemiplegia and headache, may be pre- sent. Approximately 50% of patients with EA2 have migraine head- aches (180). Cases with episodic hemiplegia have been described in a large EA2 family (181). Like HM, attacks usually start at a young age, during childhood or (early) adolescence (182,183). Stress, ex- ertion, ca eine, and alcohol may precipitate attacks and patients o en develop persistent cerebellar symptoms and cerebellar ver- mian atrophy (184). EA2 is caused by mutations in the FHM1 gene CACNA1A, which can not only be inherited autosomal domin- antly, but also occur de novo (59,185–188). In EA2, missense muta- tions have been found in CACNA1A, and also deletions, leading to frameshi s and truncated proteins (189). In FHM1, CACNA1A mu- tations appear to result in a gain of function e ect, while mutations in EA2 appear to lead to a loss-of-function e ect (59). Patients with the recurring p.Arg1347Gln CACNA1A mutation may su er from symptoms of both FHM and progressive ataxia, with temporary worsening a er attacks, and also showed cerebellar atrophy (190). Although the exact molecular mechanisms may be di erent, there is thus marked clinical overlap of FHM1 and EA2.

Other ndings that illustrate the overlap of episodic ataxia and HM are related to SLC1A3, which encodes the glial glutamate trans- porter excitatory amino acid transporter 1 (EAAT1). Mutations in this gene were found in patients with episodic ataxia, in a case with episodic ataxia, hemiplegia, and seizures, and in a case with pure HM (10,11,191). As functional studies demonstrated reduced glutamate uptake, involvement of the EAAT1 transporter could t into the overall hypothesis that increased cerebral levels of K+ and glutamate in the synaptic cle increase neuronal excitability, leading to increased susceptibility to CSD. Episodic ataxia associated with SLC1A3 muta- tions is designated as episodic ataxia type 6 (EA6) (191).

As in most subtypes of episodic ataxia, acetazolamide is o en e ective for reducing the frequency of EA2 attacks (180). In add- ition, a randomized controlled trial of 10 patients with EA, including seven patients with CACNA1A mutations, showed that the potas- sium channel blocker fampridine (4-aminopyridine, in a dosage of 5 mg three times daily) was signi cantly more e ective in redu- cing attack frequency than placebo (192). In an earlier pilot study, fampridine completely prevented attacks of ataxia in two patients and markedly reduced attacks in one (193). Two of these patients had previously developed an increased frequency of attacks, des- pite treatment with acetazolamide (193). No trials have compared fampridine with acetazolamide in EA2.

Spinocerebellar ataxia type 6

Another disorder that is allelic with FHM1 is spinocerebellar ataxia type 6 (SCA6). Instead of point mutations that occur in FHM1 and also in EA2, SCA6 is associated with polymorphic, unstable, and expanded CAG repeats in exon 47 of CACNA1A. Patients carry 21–28 CAG triplets, compared with 4–16 in healthy individuals (194,195). Inheritance is autosomal dominant. A population-based study in England showed a point prevalence of 1.59 in 100,000 and the prevalence of the CAG repeat was approximately ve in 100,000 (196). e SCA6 phenotype is characterized by a slowly progressive cerebellar ataxia, dysarthria, and nystagmus. e reported ages at onset vary between the second decade to even 70 years, which may di er signi cantly even among relatives with the same mutation, but

Neuronal and glial monogenic syndromes associated with migraine

appears to be inversely correlated with the repeat length (197–199). e rst symptoms are o en complaints of gait unsteadiness and stumbling; sometimes a patient may rst present with dysarthria. ese symptoms may initially be episodic, at which stage there is marked overlap with the EA2 phenotype (200,201). e progression of symptoms is slow, but eventually all patients show gait ataxia, in- tention tremor, incoordination of the upper limbs, and dysarthria. Dysphagia is also rather common, as well as diplopia. A gaze-evoked or downbeat nystagmus may cause visual disturbances caused by di culty xating on moving objects (197,198). Cognitive function appears preserved in patients with SCA6 (202).

Although migraine does not appear to be particularly prevalent in patients with SCA6, a CACNA1A missense mutation was found in members of a family including several individuals with both pro- gressive cerebellar ataxia and HM, and also individuals with pro- gressive cerebellar ataxia alone, indicating the close association of the phenotypes (203).

MRI in patients with SCA6 has demonstrated atrophy of the cere- bellar vermis and hemispheres, with sparing of the brainstem and cerebral cortex (197–199). Pathological examinations have revealed that the neurodegeneration is more widespread and also includes the cerebral cortex, thalamus, midbrain, pons, and medulla oblongata, but it is less severe than in other spinocerebellar ataxias (204). e cerebellar atrophy appears to result mainly from degeneration of Purkinje cells and, to a lesser extent, from granule cells (199,205). e neurodegeneration may be associated with cytoplasmic aggre- gations of the α1a calcium channel protein (206).

e management of the disease is entirely supportive. Like in EA2, acetazolamide may help to eliminate episodes of ataxia. ere are no treatments to delay or halt the progression of the disease. Patients with SCA6 have a normal life expectancy.

alternating hemiplegia of childhood

Alternating hemiplegia of childhood (AHC) is an extremely rare dis- ease (estimated incidence of one in one million births) and occurs before the age of 18 months. AHC is characterized by episodic hemi- plegia or quadriplegia lasting a few minutes to several days. Other paroxysmal symptoms include tonic/dystonic attacks, nystagmus, strabismus, and dyspnoea. Typically, all symptoms disappear im- mediately on going to sleep, and may recur a er awakening, in long-lasting attacks. Between the episodes, patients o en show developmental delay, a learning disability, dystonia, ataxia, and choreoathetosis (207,208). When episodic hemiplegia occurs be- fore the age of 18 months, AHC may be considered. A mutation in the FHM2 ATP1A2 gene has been demonstrated in a patient with AHC, which suggested a close association with HM (209). Recently, however, mutations in ATP1A3, encoding the Na+/K+-ATPase α3 subunit, were discovered in AHC. Approximately 70% of patients carried an ATP1A3 mutation, and genetic screening thus enables con rmation of AHC and di erentiation from HM (210).

Mouse models have been developed for several monogenic dis- eases that are associated with migraine. e FHM1 mouse model’s phenotype is very similar to the human FHM1 phenotype and has

been studied extensively. e knock-in mouse models carry, for ex- ample, the human R192Q FHM1 CACNA1A mutation or the S218L FHM1 CACNA1A mutation (211,212). Knockdown CACNA1A mouse models can contribute to research into EA2 and SCA-6 (213). Homozygous FHM2 knock-out and knock-in mouse models were found to die immediately a er birth, but heterozygous mice were viable (214,215). As increased susceptibility to CSD was demon- strated in the heterozygous knock-in mouse model, this model may be used for further in vivo research (215). Mouse models associated with the FHM3 SCN1A gene have so far only focused on the epilepsy phenotypes SMEI and GEFS+ (216,217). Transgenic mouse models for the vascular migraine models CADASIL and RVCL-S, but also mouse models with COL4A1 mutations, have been developed as well (218,219). Although an association with CSNK1D and familial migraine (and advanced sleep phase) was reported only once, mice harbouring a CSNK1D mutation did exhibit a reduced threshold for CSD (9).

All these di erent mouse models are very useful to study genotype–phenotype correlations. Moreover, a translational re- search approach using monogenic human and mouse migraine models opens many possibilities for functional studies of migraine pathophysiology, aiming to develop new treatments in the future.

CHaPtEr 8 Hemiplegic migraine and other monogenic migraine subtypes and syndromes

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Retinal migraine

Brian M. Grosberg and C. Mark Sollars

Introduction

Retinal migraine is characterized by attacks of monocular visual impairment associated with migraine headache. It is rare and poorly understood. Retinal migraine was rst described by Xavier Galezowski in the late nineteenth century as ‘ophthalmic megrim’ (1). Since then, patients with monocular visual defects beginning before, during, or a er attacks of otherwise typical migraine have been reported with various designations. Desmond Carroll intro- duced the term ‘retinal migraine’ to describe episodes of transient and permanent monocular visual loss in the absence of migraine headache (2). Subsequently, ‘retinal migraine’ has been applied to those cases of monocular visual impairment temporally associated with attacks of migraine. Noting that unilateral visual loss is not re- stricted exclusively to the retina, some advocated the term ‘anterior visual pathway migraine’ or ‘ocular migraine’ (3,4). e authors prefer the term ‘migraine associated with monocular visual symp- toms’ because it distinguishes between the loss of vision in one hom- onymous hemi eld and that of one eye and includes sites other than the retina, such as the choroid or the optic nerve.

Several de nitions of retinal migraine have been proposed over the past 20 years. B. Todd Troost de ned retinal migraine as a tran- sient or permanent monocular visual disturbance accompanying a migraine attack or occurring in an individual with a strong history of migraine-like episodes (5). e International Headache Society established more rigorous criteria with the publication of the rst edition of the International Classi cation of Headache Disorders (ICHD-1), which required at least two attacks of fully reversible monocular scotoma or blindness lasting less than 60 minutes asso- ciated with headache (type unspeci ed) (6). Criteria were revised in the 2018 third edition of the ICHD (ICHD-3) (Box 9.1) (7).

e literature includes positive and negative visual phenomena as symptoms of retinal migraine (8,9). Standard accounts of positive visual phenomena include ashing rays of light, zigzag lightning, and other teichopsia, whereas perceptions of halos, diagonal lines, and bright-coloured streaks are less commonly described (10,11). e negative visual losses include blurring, ‘grey-outs’, and ‘black- outs’, causing partial or complete blindness (12,13). Elementary forms of scotoma have been perceived as blank areas, black dots, or spots in the eld of vision (14,15). Visual eld defects can be alti- tudinal, quadrantic, central, or arcuate. Less frequently noted are

complex patterns of monocular visual impairment, such as tunnel vision, the coalescence of peripherally located spots, and the appear- ance of ‘black paint dripping down from the upper corner of my le eye’ (16).

In most cases, the migraine headache was ipsilateral to the visual loss. Nearly 50% of patients with monocular visual loss had a his- tory of migraine with typical visual aura. Rare cases of transient monocular visual loss have also been reported with cluster head- ache, idiopathic stabbing headache, chronic daily headache, cere- bral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, and an unspeci ed headache type (17–21).

Recurrent monocular visual disturbances are strictly unilateral and without side shi in most patients, although some experi- ence side-alternating attacks. e temporal relationship between the visual loss and the headache is variable. Usually, the onset of visual loss precedes or accompanies the headache; less o en, the visual loss follows an attack of migraine headache. By de nition, the visual symptoms occur within 1 hour of the headache. e dur- ation of transient monocular visual loss vary widely between pa- tients and within individual patients. e duration of the visual symptoms may be as short as a few seconds but usually last many minutes to 1 hour. Prolonged but fully reversible monocular visual loss rarely occurs, sometimes lasting hours, days, or even weeks (16,17,22–26). Only a few patients have had ophthalmological examinations during an attack. Examinations, when performed, were usually normal, suggesting retrobulbar involvement. One self-reported case of retinal migraine cited multiple ophthalmo- logical examinations during attacks, as well as one performed by a retinal specialist (27). is patient was a 71-year-old male oph- thalmologist who had su ered from attacks of migraine with and without aura since the age of 16 years. His conventional visual aura consisted of homonymous scintillating scotomas lasting 15–20 minutes. Beginning at the age of 56 years, he experienced recurrent monocular visual events, which were stereotypic, short-lived, and mostly isolated in nature. e patient reproduced the scotomas of some of these events using Amsler grids. With the exception of one episode, all of these events involved his le eye, lasted 10–11 min- utes, and were not associated with headache. During one of these episodes, a retinal specialist examined him 6–7 minutes into the ictus. No evidence of retinal vasospasm, embolic phenomena, or other abnormalities was found.

Box 9.1 Criteria for the diagnosis of retinal migraine

A Attacks ful lling criteria for 1.2 Migraine with aura and criterion B below.

B Aura characterized by both of the following:
1 Fully reversible, monocular, positive, and/or negative visual phe-

nomena (e.g. scintillations, scotomata, or blindness) con rmed during an attack by either or both of the following:
a. Clinical visual eld examination
b. The patient’s drawing of a monocular eld defect (made after

clear instruction).
2 At least two of the following:

a. Spreading gradually over >5 minutes
b. Symptoms last 5–60 minutes
c. Accompanied, or followed within 60 minutes, by headache.

C Not better accounted for by another ICHD-3 diagnosis, and other causes of amaurosis fugax have been excluded.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

In nearly half of reported cases of retinal migraine, patients ul- timately experienced permanent monocular visual defects, but no consistent pattern of visual eld loss was noted. Severe narrowing or occlusion of retinal arteries and veins was observed rarely (1,2,17,23,28–39). e diagnoses of anterior or posterior ischaemic optic neuropathy were reported in about a dozen (4,40–50). Other ndings included cotton wool spots (51), retinal pigmentary change (29), central retinal venous occlusion (52–54), central serous retin- opathy, optic nerve atrophy (52), optic disc oedema (40), and haem- orrhages of the optic nerve, retina, or vitreous (55,56).

Clinical vignette

A 44-year-old woman su ered from attacks of migraine without aura since the age of 30. e headaches began in the right nuchal and temple regions, typically lasted 1–2 days, and occurred an average of 1–2 times per month, usually in association with her menses. Associated features included photophobia, phonophobia, osmophobia, nausea, vomiting, facial pallor, and dysarthria. One year before presentation, the patient experienced 1–2 attacks per week of her otherwise typical migraine headache associated with recurrent bouts of monocular visual loss ipsilateral to the head- ache. Complete blindness of the right eye always began 30 minutes into the headache. Alternately covering each eye during attacks con rmed that the visual changes were limited to the right eye. e monocular visual loss lasted the entire duration of the headache, ranging from 8 hours to 3 days, and then fully resolved. ere was a strong family history of migraine. Past history included asthma and abnormal uterine bleeding. e patient drank alcoholic bever- ages occasionally but denied cigarette smoking and illicit drug use.

Her general medical, ophthalmological, and neurological examinations were normal. Investigations included a computed tomography (CT) scan of the brain, magnetic resonance imaging (MRI) and magnetic resonance angiogram (MRA) of the brain, MRA of the neck, echocardiography, and extensive haemato- logical tests, all of which were within normal limits. e patient was treated with topiramate 300 mg daily with complete cessation of her recurrent bouts of monocular visual loss, as well as a reduc- tion of headaches.

CHaPtEr 9 Retinal migraine Pathogenesis and pathophysiology

e underlying pathophysiology of retinal migraine remains largely unknown. Bouts of transient monocular visual loss lasting less than 1 hour, transient monocular visual loss of prolonged duration, and transient monocular visual loss that later becomes permanent correspond clinically to the typical visual aura of mi- graine, prolonged aura, and migrainous infarction, respectively. Perhaps these three phenomena a ecting the cerebrum (espe- cially the cortex) or the eye (especially the retina) share common pathophysiological mechanisms (9). Spreading depression of cor- tical neurons is the broadly accepted basis of the typical aura of migraine and perhaps a similar mechanism a ects the retina. is phenomenon has been noted in the retina of the chicken (57). e expression of major N-methyl-d-aspartate receptor subtypes, NR1, NR2A, and NR2B (58), and calcitonin gene-related peptide receptors (59) in the chick retina makes them pertinent targets for pharmacological inhibition of spreading depression (58). One pa- tient who described her transient monocular visual loss as black paint slowly dripping down from the corner of her monocular visual eld may well be describing spreading depression of the retina.

Primary vascular dysregulation is associated with retinal vascular disease and is comorbid with migraine. eoretically, it could be a factor in the pathogenesis of retinal migraine (60). Ischaemia is the other mechanism commonly invoked to explain permanent mon- ocular visual loss in the setting of migraine. Vasospasm of retinal arterioles and veins has been demonstrated in cases of transient monocular visual loss, where no other predisposition to vascular disease was discovered (61,62). Vasospasm during migraine head- aches has also been documented angiographically (63). Although vasospasm is no longer considered the primary cause of the focal neurological de cits of migraine, this older concept of migraine may account for the visual loss in some cases (9).

Some studies, such as kinetic arc perimetry (64), measurements with ickering light stimuli (65), motion coherence perimetry (66), and measurements of contrast thresholds for static and moving stimuli (67), implicated both cortical and precortical visual sites. A reduction in nerve bre layer thickness has been found in mi- graine patients in contrast to control subjects (68). e signi cance of these ndings to retinal migraine is uncertain.

Epidemiology

Retinal migraine is thought to be a rare disorder, but its true preva- lence and incidence are unknown. In a review of the literature, Hill and associates applied strict International Headache Society criteria in a broad-based review of the reported cases of transient monocular visual loss, nding only ve of 142 cases that met the de nite criteria for retinal migraine. e authors attributed the other cases of tran- sient monocular visual loss to retinal vasospasm (69,70). In another review, nearly two-thirds of patients with retinal migraine were found to be female (9). More than half of the patients experienced only transient monocular visual loss, whereas the remainder later developed permanent monocular visual loss in association with otherwise typical attacks of migraine. Men and women were equally a ected in the transient group, whereas the permanent group showed

Part 2 Migraine

a female preponderance, with a female-to-male ratio of 2.5:1. Age at onset of retinal migraine ranged from 7 to 54 years. Mean age at onset was similar in both groups (24.7 years for the transient group, 23 years for the permanent group). e duration of retinal migraine before diagnosis ranged from days to several decades. Similarly, the evolution from transient to permanent attacks of monocular visual loss in the permanent group was variable, occurring within the same year of retinal migraine onset and up to 52 years later. With the ex- ception of one case, in which attacks of transient monocular visual loss ceased a er oral contraceptives were discontinued, no speci c precipitating events were identi ed. irty per cent of patients had a documented family history of migraine. Because many cases did not include information on family history, this number may be under- estimated. Only two patients had familial retinal migraine (71).

Minor risk factors for vascular disease were identi ed in only a few patients with transient and permanent monocular visual loss. ey included hypertension, hyperthyroidism, pregnancy, diabetes, oral contraceptive use, smoking, and increased levels of factor VIII. ese conditions were not thought to be the main cause of the visual loss (9).

Prevention

One treatment approach focuses on the avoidance of potential mi- graine triggers (i.e. stress, use of oral contraceptives, smoking) by patients with infrequent attacks. It has been suggested that prophy- lactic therapy should be deferred when patients have infrequent attacks, i.e. less than one attack per month (72). However, this course of action may not be prudent because episodes of permanent mon- ocular visual loss can occur in migraineurs with and without prior attacks of transient monocular visual loss (73).

Differential diagnosis

Patients o en have di culty distinguishing between the loss of vision in one homonymous hemi eld and the loss of vision in one eye. To make this distinction accurately, the patient must alternately cover each eye and compare their views. e description of hemi eld loss with both eyes open is characteristic of a homonymous hemianopia rather than monocular visual loss. If monocular visual loss is con- rmed, one must attempt to exclude other causes of transient or per- manent monocular visual loss. e di erential diagnosis of retinal migraine includes amaurosis fugax. In retinal migraine, visual loss typically evolves slowly and o en lasts longer than amaurosis fugax of carotid artery origin. e ‘shade dropping over a visual eld’, typ- ical of micro-embolization, was not reported by patients with retinal migraine. Other causes of transient monocular visual loss include atherosclerosis; thrombus originating from the carotid artery, heart, or great vessels; giant cell arteritis; other vasculitic diseases with or without autoimmune diseases; primary vascular disease of the cen- tral retinal artery or vein; illicit drug use; demyelinating disease; and hypercoagulable states, such as macroglobulinaemia, polycy- thaemia, anticardiolipin antibody syndrome, and sickle cell disease. Less common causes are orbital diseases, including mass lesions, retinal detachment, and intermittent angle-closure glaucoma (9,74).

Diagnostic work-up

e clinician needs to identify or exclude secondary causes of tran- sient monocular blindness because retinal migraine is a diagnosis of exclusion (see Table 9.1). If a patient’s history or general physical, ophthalmological, or neurological examination includes atypical features, imaging studies or other diagnostic testing are warranted. Features that should prompt concern for an underlying secondary cause of headache with transient monocular blindness include ab- sence of a typical migraine history, onset a er the age of 50 years, incomplete resolution of monocular visual loss, concomitant med- ical problems that can precipitate attacks of transient monocular blindness, and the presence of atypical neurological signs or symp- toms. All cases with persistent monocular visual loss should be fully investigated. To exclude the possibility of a cardio-embolism, investigations such as electrocardiography, echocardiography, and Holter monitoring need to be performed. Diagnostic testing of pa- tients with suspected ischaemic disease of the eye or brain should include duplex ultrasound, CT, MRI and MRA, uorescein angi- ography, and, in uncertain cases, conventional catheter angiog- raphy. Neuroimaging can exclude an orbital or intracranial mass. Other diagnostic possibilities, such as vasculitis, hypercoagulable states, illicit drug use, and rheumatological disorders, require a complete laboratory evaluation, consisting of a complete blood count with di erential and platelet count, prothrombin time, par- tial thromboplastin time, toxic drug screen, lupus anticoagulant and anticardiolipin antibody levels, erythrocyte sedimentation rate, rheumatoid factor, antinuclear antibody titre, antiphospholipid antibodies, protein C and S, antithrombin III levels, and serum pro- tein electrophoresis (73).

Prognosis and complications

Although retinal migraine has traditionally been viewed as a benign condition, it appears that patients with migraine may have subclin- ical precortical visual dysfunction and permanent attacks of partial

table 9.1 Clinical factors favouring retinal migraine versus other causes of monocular visual loss.

Factors favouring other diseases

Factors favouring retinal migraine

Age ≥ 50 years

Age ≤40 years

No history of migraine

History of migraine

PMVL

Migraine with TMVL

Hypercoagulable state

TMVL

Embolic source

Drugs (OCPs, cocaine)

Increased intracranial pressure

Atypical neurological signs

Vascular disease • Dissection
• Occlusion
• Vasculitis

PMVL, permanent monocular visual loss; TMVL, transient monocular visual loss; OCPs, oral contraceptive pills.

or complete monocular visual loss occur more o en than generally appreciated. Studies with automated perimetry have demonstrated subclinical visual eld defects in some asymptomatic patients with migraine (75). ere was a correlation between these ndings and duration of disease and advancing age.

Some patients with retinal migraine who experience transient monocular visual loss may present with considerable variation in phenotype (either continuing to have transient visual loss or experi- encing new attacks of permanent visual loss), whereas others only experience permanent monocular visual loss without a pre-existing history of transient visual loss. No speci c factor has been identi ed to account for this variation in phenotype or for the heterogeneity of this condition (73). Just as migraine aura sometimes gives rise to migrainous infarction, the authors believe that irreversible visual loss is part of the spectrum of retinal migraine and perhaps a form of migrainous infarction.

Patients with retinal migraine appear to have prolonged and per- manent monocular visual loss much more commonly than those with migraine who experience prolonged typical aura or migrainous infarction. e high number of patients with transient monocular visual loss who eventually develop permanent monocular visual loss makes retinal migraine a less benign condition than migraine with typical visual aura. erefore, although there are no data to deter- mine the e cacy of preventive treatment for this entity, preventive drug therapy seems prudent, even if attacks are infrequent (9).

Management

No clear guidelines exist regarding the management of patients with retinal migraine. In an attempt to prevent irreversible ocular damage, early medical management with daily aspirin and a mi- graine preventive agent may be advisable (73). Prophylactic medi- cations that anecdotally have provided bene t include calcium channel blockers (i.e. verapamil, nifedipine, nimodipine), tricyclic antidepressants (i.e. nortriptyline), beta blockers (i.e. propran- olol), and neuromodulators (i.e. divalproex sodium, topiramate). Aspirin is a logical agent because of its antiplatelet activity. In a few cases, simple monotherapy reduced the frequency of mi- graine with and without monocular visual defects. e authors favour antiepileptic drugs (i.e. topiramate or divalproex sodium) and tricyclic antidepressants (i.e. amitriptyline or nortriptyline). Although some patients respond to beta blockers, we do not usu- ally recommend beta blockers because of their theoretical poten- tial for arteriolar constriction. Although episodes of vasospastic amaurosis fugax appear to have been successfully treated with calcium channel blockers (76), they were not e ective in the few patients the authors treated. Several patients, unfortunately, were refractory to many migraine preventive medications given as monotherapy or in combination.

ere is currently insu cient clinical information to support speci c recommendations for acute medical therapy in the treat- ment of retinal migraine. Given the potential risk of worsening any underlying vasospasm, medications with vasoconstrictive proper- ties (i.e. ergotamines, triptans) should not be used (73). Only a few patients were treated with acute medication during the attack of retinal migraine. Inhaled carbon dioxide improved vision ‘slightly’ in a single patient during a single attack, whereas amyl nitrate and

isoproterenol via inhaler showed ‘good e cacy’ in improving the visual loss in a few patients. None of these medications helped re- lieve the headache (77,78). Patients who experienced permanent monocular visual loss showed no consistent bene t from cal- cium channel blockers, oral and intravenous corticosteroids, or vasodilators.

CHaPtEr 9 Retinal migraine

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. (68) Gipponi S, Scaroni N, Venturelli E, Forbice E, Rao R, Liberini P,
et al. Reduction in retinal nerve ber layer thickness in migraine
patients. Neurol Sci 2013;34:841–5.

. (69) Hill DL, Daro RB, Ducros A, Newman NJ, Biousse V.
Most cases labeled as “retinal migraine” are not migraine. J
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. (70) Winterkorn JM. “Retinal Migraine” is an oxymoron. J

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CHaPtEr 9 Retinal migraine

. (71) Lewinshtein D, Shevell MI, Rothner AD. Familial retinal mi- graines. Pediatr Neurol 2004;30:356–7.

. (72) Hupp SL, Kline LB, Corbett JJ. Visual disturbances of migraine. Surv Ophthalmol 1989;33:221–36.

. (73) Grosberg BM, Solomon S. Retinal migraine. In: Lipton RB, Bigal ME, editors. Migraine and Other Headache Disorders. New York: Taylor and Francis Group, 2006, pp. 213–22.

. (74) Maggioni F, Dainese F, Mainardi F, Lisotto C, Zanchin G. Intermittent angle-closure glaucoma in the presence of a white eye, posing as retinal migraine. Cephalalgia 2005;25:622–6.

. (75) Lewis RA, Vijayan N, Watson C, Keltner J, Johnson CA. Visual eld loss in migraine. Ophthalmology 1989;96:321–6.

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of migraine. Neuroophthalmology 1987;7:1–10.

Migraine, stroke, and the heart

Simona Sacco and Antonio Carolei

Migraine and stroke

Accumulating data have linked migraine to stroke. e relationship between migraine and stroke is complex and bidirectional (1,2). A stroke, either ischaemic or haemorrhagic, may produce symptoms mimicking a migraine attack; a migraine attack may mimic a stroke; migraine may be directly associated with an ischaemic stroke (mi- grainous infarction); migraine may represent a risk factor for stroke; several diseases, mostly genetically determined, include among their clinical manifestations attacks of migraine and stroke; lastly, mi- graine has been associated with subclinical infarct-like brain lesions and white matter hyperintensities.

A stroke, either ischaemic or haemorrhagic, may produce symp- toms mimicking a migraine attack (see also Chapter 37). A migraine- like headache may occur especially when lesions are located in the posterior circulation, in cortical areas, or when the ischaemic event is caused by an arterial dissection (3–6). In these instances the head- ache should not be diagnosed as migraine, but rather as a secondary headache and coded according to the International Classi cation of Headache Disorders, 3rd edition, (ICHD-3) as ‘Headache attrib- uted to ischaemic stroke or transient ischaemic attack’ (code 6.1) or ‘Headache attributed to non-traumatic intracranial haemorrhage’ (code 6.2) (7). In those secondary headaches, the pain develops in close temporal relationship with other symptoms and/or clinical signs of the vascular event or leads to its diagnosis and improves in parallel with stabilization or amelioration of other symptoms or clinical or radiological signs of the vascular event (7). In patients with a previous history of migraine, the onset of a stroke may trigger an acute attack (8); in these circumstances the symptom should not be misinterpreted as being involved in the mechanism of ischaemia (9). Likewise, cases of migraine that resolved or ameliorated a er stroke have also been reported.

A migraine attack may also mimic a stroke. In fact, aura symp- toms resemble the symptoms of transient ischaemic attack (TIA) (10). Di erential diagnosis may be challenging when the aura oc- curs for the rst time, when it is not followed by headache, or when it a ects older patients. e mode of onset is crucial: the focal de cit is typically sudden in a TIA and with a slower evolution and a serial progression of symptoms in a migrainous aura. Furthermore, posi- tive phenomena such as scintillating scotoma or paraesthesia are far more common in migrainous aura than in TIA, whereas negative

phenomena are more usual in TIA. When people present with symptoms of an aura that persists much longer than usual, magnetic resonance imaging (MRI) of the brain may be required to di eren- tiate between an acute infarction and a persistent aura. Hemiplegic migraine and basilar migraine also pose a challenge to the appro- priate diagnosis as they can resemble an acute stroke.

Migraine may be directly associated with an ischaemic stroke (migrainous infarction; ICHD-3 code 1.4.3) (see also Chapter 37) (7,11). is condition is very rare, with an estimated incidence of 0.8 per 100,000 cases annually (12), but in the past, before the development of the ICHD diagnostic criteria, it was vastly over- estimated. Epidemiological studies have shown that 0.5–1.5% of all ischaemic strokes are migrainous infarctions; in younger pa- tients, migrainous infarction was reported to account for 13% of rst-ever ischemic strokes (12–15). Migrainous infarction can be diagnosed only in patients with a de nite history of migraine with aura (MA). To meet the diagnostic criteria, the stroke must occur during a migraine attack that is typical of previous attacks, except for the persistence for more than 60 minutes of one or more of the aura symptoms; brain neuroimaging must demonstrate an is- chaemic infarction in a relevant cerebral area (Figure 10.1), and the clinical condition must not be attributed to another disorder, even though stroke risk factors may be present (7). In patients with migrainous infarction, symptoms are visual in 82.3%, sensory in 41.2%, and dysphasic in 5.9% (16). If a concomitant aetiology is detected (e.g. cervical arterial dissection), or if a patient with a history of migraine without aura (MO) develops an ischaemic stroke a er a migraine attack, the disease cannot be classi ed as migrainous infarction. As most strokes in migraineurs occur out- side the migraine attacks, only a minority of ischaemic strokes in migraineurs meets these criteria. Migrainous infarctions usually occur in young people, are mild at onset, and the corresponding lesions are located mainly in the posterior circulation territory (16,17). e prognosis in terms of survival and functional out- come is usually good. A high prevalence (64.7%) of patent foramen ovale in those with migrainous infarction has been reported (16), but the causal link is not clear. e pathogenesis of an infarction is probably related to severe hypoperfusion occurring during the aura phase, even though the precise causative mechanism remains to be established. A er a migrainous stroke ergotamine or triptans use should be avoided (18).

Figure 10.1 Brain magnetic resonance imaging showing a migrainous infarction in a patient diagnosed with migraine with aura who presented a persisting right hemianopia.
Courtesy of Stefano Bastianello, Professor of Neuroradiology, University of

Pavia, Italy.

Migraine is also a risk factor for stroke (Box 10.1), as a large body of published data indicates an increased risk of ischaemic stroke in migraineurs, illustrated in three meta-analyses (Table 10.1) (19–21). All of them found a signi cant increase in the risk of ischaemic stroke in patients with any migraine, with a pooled adjusted e ect estimate between 1.73 and 2.16 (Table 10.1) (19–21). Whereas this increased risk has been statistically proven in MA, only a non-signi cant trend towards the association has been observed in MO. e American Migraine Prevalence and Prevention study (AMPP), a population- based investigation involving 120,000 US households (22), which became available only a er the publication of the aforementioned meta-analyses (19–21), con rmed the above reported evidence. In detail, the AMPP study found an association between any mi- graine and ischaemic stroke and between MA and ischaemic stroke, but no association between MO and ischaemic stroke (22). More recently, the Northern Manhattan Study (NOMAS), a prospective population-based study including 1292 participants with a mean age of 68 years followed for a mean of 11 years, evaluated the possible association between migraine and cardiovascular events, including stroke (23). e study was unable to demonstrate an association between migraine, either MA or MO, and stroke (23). Notably, the authors found that migraineurs, as compared to non-migraineurs, had an increased risk of stroke if they were also current smokers (23). A further study including 1,566,952 children aged 2–17 years was unable to demonstrate an association between migraine and ischaemic stroke in the same age group (24). Besides, a post-hoc analysis of the same adolescents showed a threefold increased risk of ischaemic stroke among those with migraine (24). A recent add- itional study based on administrative coding data of nearly 50,000 patients hospitalized for a rst stroke indicated an increased risk of ischaemic stroke in migraineurs versus non-migraineurs (25). e Oxford Vascular Study (OXVASC), a population-based study including 1810 participants with TIA or ischaemic stroke, showed that as compared to events with determined aetiology, patients with cryptogenic events most o en had a history of migraine. e same association was seen for MA and MO in an analysis strati ed by sex

and vascular territory (26). In this study, as expected, the frequency of migraine decreased with age in the overall cohort; however, the frequency of history of migraine did not fall with age in patients with cryptogenic TIA or stroke, such that with an analysis strati ed by age, the association of migraine and cryptogenic events was strongest at older ages (26). e Italian Project on Stroke in Young Adults (IPSYS) demonstrated that in young patients with ischaemic stroke, MA represented an independent risk factor of overall recur- rent vascular events and of recurrent ischaemic stroke (27).

Intriguingly, the severity of a migraine attack is not associated with an increased risk of ischaemic stroke; on the contrary, a high frequency of attacks (>12 attacks per year) and a recent onset of mi- graine (lifetime duration of <1 year before the stroke event) have been related to an increased risk (28,29). As the early studies focused on women (30–32), there exists a huge body of evidence linking is- chaemic stroke with migraine in women; data on migraine in men are scarce and lacking in detail. As no direct estimates of the risk in men versus women are available, it is impossible to establish whether it is higher in one sex. Also, the risk of having a TIA seems to be in- creased in migraineurs, although this issue has not been extensively investigated. Misdiagnosis of migrainous aura as TIA may represent a limitation in the proper study of this association. In a case–control study, women with MA versus non-migrainous women had a two- fold increase in the risk of having a TIA; this was con rmed by data from the Women’s Health Study (WHS) (30,33). Only one of the aforementioned studies found an increased risk of TIA in women who had MO instead of MA (30).

Several studies also addressed the possible association between migraine and haemorrhagic stroke, but with con icting results. A meta-analysis of those studies disclosed a signi cant association between the two conditions (Table 10.1) (34). e risk of haemor- rhagic stroke increased by 50% in patients with any migraine versus non-migraineurs. e overall risk of haemorrhagic stroke, however, was lower than that reported for ischaemic stroke in other meta- analyses (19–21). e risk of haemorrhagic stroke was increased when female migraineurs of any age and female migraineurs aged <45 years were compared with control subjects. e meta-analysis could not prove an association of either MA or MO with an in- creased risk of haemorrhagic stroke, as only three studies collected data on the risk of haemorrhagic stroke according to migraine type (35–37). Two of these studies showed an association between MA and haemorrhagic stroke (36,37), while only one of them showed an association between MO and haemorrhagic stroke (37). However, as MA was the smaller subgroup and the e ect size esti- mate was higher than that for MO, the meta-analysis might have had insu cient power to detect a possible association. Regarding haemorrhagic stroke type, available data suggest that the associ- ation between migraine and haemorrhagic stroke is driven by an increase of intracerebral, but not subarachnoid, events (36). Other authors performed a case–control study using data from 1797 pa- tients with intracerebral haemorrhage and 1340 patients with sub- arachnoid haemorrhage and frequency-matched controls from a large epidemiological dataset, e Health Improvement Network (THIN) (38). In this study, the authors were unable to demonstrate an increased risk of overall haemorrhagic stroke or of intracerebral haemorrhage or subarachnoid haemorrhage in those with migraine versus non-migraineurs. e analysis performed according to mi- graine type showed that neither MA nor MO were associated with

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Box 10.1 Evidence referring to the association between migraine and the risk of vascular disease

Ischaemic stroke

• Numerous studies have demonstrated an association with any migraine.

• De nite association with migraine with aura (MA).

• No de nite association with migraine without aura (MO).

• Association with MA con rmed by three meta-analyses.
Transient ischaemic attack
• The risk seems to be increased in migraineurs, although this issue has not been extensively investigated owing to a challenging overlap of symptoms with migraine aura.
Haemorrhagic stroke

• Several studies have addressed the topic and provided inconsistent results.

• A meta-analysis of those studies indicated a small but signi cant association.

• No de nite conclusion regarding migraine type. Cardiac events

• Two large studies have indicated an association with any migraine in men and women and with MA in women (data not available for men).

• An additional study has reported an association between migraine (any migraine, MA, and MO) and myocardial infarction.

• Con icting results provided by other available studies.

• Association with migraine con rmed in a meta-analysis.
Vascular death

• A meta-analysis and a large study have supported an association with MA.

• No association with any migraine according to meta-analysis of data. Other vascular diseases
• Studies indicated a possible association with any migraine and ret- inal disease and peripheral artery disease.
Brain lesions

• Migraine has been associated with white matter hyperintensities and infarct-like lesions.

• Association of migraine with white matter hyperintensities has been con rmed in two meta-analyses.
Adapted from The Journal of Headache and Pain, 14, 80, Sacco S, Ripa P, Grassi D et al., Peripheral vascular dysfunction in migraine: a review. © Sacco et al.; li- censee Springer, 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0). Doi: [10.1186/1129-2377-14-80].

an increased risk of haemorrhagic stroke. Only patients with a long history (≥20 years) of migraine had an increased risk of intracerebral haemorrhage versus control subjects. e already reported study including 1,566,952 children aged 2–17 years was unable to dem- onstrate an association between migraine and haemorrhagic stroke (38). Another recent study did not demonstrate an increased risk of haemorrhagic stroke in migraineurs; however, in this same study the subanalysis by sex suggested an increased risk for haemorrhagic stroke in women migraineurs versus non-migraineurs but no di er- ence by migraine status in men (25).

ere are several diseases, mostly genetically determined, that include among their clinical manifestations migraine and cere- brovascular events (39). e best known of those diseases is

cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (Figure 10.2), although other conditions have also been recognized and are listed in Table 10.2 (see also Chapter 8) (40–44).

Migraine has also been associated with subclinical infarct-like brain lesions and white matter hyperintensities (Figures 10.3 and 10.4) (45–49). Infarct-like lesions appear as small infarcts on brain MRI mostly in the absence of a clinical history of stroke. eir exact nature still remains elusive, as some of them may represent enlarged perivascular spaces or, alternatively, might be of a dif- ferent nature than ischaemic. Even in this case, data point toward a clear association with MA, while data referring to any migraine or MO are controversial (46–50). e Cerebral Abnormalities in Migraine, and Epidemiological Risk Analysis (CAMERA) study showed that subjects with migraine had a sevenfold increased risk for infarct-like lesions in the cerebellum compared with controls, an association that was stronger for patients with MA and for those with a high attack frequency (46,47). ose ndings are in agree- ment with the Reykjavik study, which found that women with MA in mid-life had an increased risk of cerebellar infarct-like lesions in later life (49). In that study, the risk was independent of the pres- ence of cardiovascular risk factors. In the Epidemiology of Vascular Aging (EVA) study, participants with MA had over a threefold in- creased risk of brain infarcts (48). Furthermore, there was a sug- gestion that participants with MA were at increased risk of multiple infarcts (48). Data from the NOMAS indicated that participants re- porting migraine overall had double the odds of infarct-like lesions (odds ratio 2.1; 95% con dence interval 1.0–4.2) when compared with those reporting no migraine (51). Recently, data from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), a placebo-controlled trial assessing e ects of pravastatin on car- diovascular disease, showed no association between migraine (ei- ther MA or MO) and infarct-like lesions (52). e 9-year follow-up data from the CAMERA study found that migraine was not asso- ciated with the progression of infarct-like lesions (53). Available evidence mostly suggests that infarct-like lesions are particularly common in the posterior circulation and cerebellar border zone (54–57). At variance, the results of the EVA study indicated that most of the infarcts were located outside of the cerebellum or the brainstem (48). White matter abnormalities in migraineurs have an uncertain clinical signi cance. eir pathological correlates may correspond to gliosis, demyelination, and loss of axons; this set of ndings has been attributed to microvascular damage. Prevalence of white matter abnormalities in migraineurs ranges from 4% to 59% (58). Regarding white matter hyperintensities, the CAMERA study indicated that in women the prevalence of deep white matter abnormalities was higher in migraineurs than controls (46). e association was independent of the presence or absence of aura and the risk increased with attack frequency. In men, deep white matter abnormalities were not in uenced by the presence, subtype, or frequency of migraine. e EVA study con rmed the associ- ation of migraine with white matter abnormalities (48). e asso- ciation with deep white matter abnormalities was stronger for MA than MO. e association was not speci c to migraine headaches but extended to non-migraine headaches, especially tension-type headaches. e meta-analysis of available studies showed an as- sociation between white matter abnormalities and MA and no association with MO (Table 10.1) (58). More recently, data from the NOMAS indicated no association between MA or MO and

CHaPtEr 10 Migraine, stroke, and the heart table 10.1 Risk of cardiovascular diseases in migraineurs according to the available meta-analyses

Any migraine vs control

Migraine with aura vs control

Migraine without aura vs control

Ischaemic stroke

Etminan et al., 2005 (19)

2.16 (1.89-2.48)

2.88 (1.89-4.39)

1.56 (1.03-2.36)

Schürks et al., 2009 (20)

1.73 (1.31-2.29)

2.16 (1.53-3.03)

1.23 (0.90-1.69)

Spector et al., 2010 (21)

2.04 (1.72-2.43)

2.25 (1.53-3.33)

1.24 (0.86-1.79)

Haemorrhagic stroke

Sacco et al., 2013 (34)

1.48 (1.16-1.88)

1.62 (0.87-3.03)

1.39 (0.74-2.62)

Myocardial infarction

Schürks et al., 2009 (20)

1.12 (0.95-1.32)

–

Sacco et al., 2015 (64)

1.33 (1.08-1.64)

2.61 (1.86-3.65)

1.14 (0.81-2.45)

Angina

Sacco et al., 2015 (64)

1.29 (1.17-1.43)

2.94 (1.59.5.43)

1.45 (1.06-2.00)

Vascular death

Schürks et al., 2009 (20)

1.03 (0.79-1.34)

–

Schürks et al., 2011 (61)

1.09 (0.89-1.32)

–

Stroke-like lesions

Bashir et., 2013 (58)

–

1.07 (0.87-1.33)

0.76 (0.56-1.03)

White matter hyperintensities

Swartz et., 2004

3.9 (2.26-6.72)

–

Bashir et., 2013 (58)

–

1.68 (1.07-2.65)

1.34 (0.96-1.87)

Data are effect size (95% con dence interval)

white matter hyperintensity volume (51). A further analysis of data from a subset of 506 participants included in the PROSPER study was unable to demonstrate an association between migraine either MA or MO and white matter hyperintensities (52). e 9-year follow-up data from the CAMERA study found that mi- graine was associated with signi cantly greater white matter ab- normality progression in women (53). Progression of white matter hyperintensities was not associated with attack frequency, duration, or severity, or antimigraine therapy (53). At variance, a further re- cent population-based study showed that migraine is associated with white matter hyperintensities cross-sectionally but not with their progression over time (45). e available studies do not sup- port that migraineurs with white matter abnormalities are at risk of cognitive impairment (48,53,59). A further analysis of data from the PROSPER study was unable to demonstrate any association be- tween overall migraine with cerebral microbleeds (52). However, analysis strati ed by migraine type and cerebral microbleeds loca- tion (lobar, basal ganglia, infratentorial) indicated an association between MO with infratentorial microbleeds (52).

Migraine and cardiovascular diseases

e risk of cardiac events in migraineurs varies greatly among studies, ranging from a lower-than-average to a moderately in- creased risk (20,50). A major limitation is represented by the avail- ability of data disaggregated for migraine type only from two studies (22,60). With those limitations, evidences suggest an increased risk of myocardial infarction (MI) in patients with MA, while no con- clusion can be drawn referring to any migraine and MO. A meta- analysis did not show an increased risk of MI in patients with any

migraine versus no migraine (Table 10.1) (20). In fact, only one of the studies included in the meta-analysis reported disaggregated data for migraine type (60); in that study, which was part of the WHS, at the end of a mean 10-year follow-up, MO was not associ- ated with an increased risk of any vascular event, whereas MA was associated with an increased risk of MI, coronary revascularization, angina, and death due to vascular disease. A er the publication of the aforementioned meta-analysis (20), the AMPP study found an association between migraine (any migraine, MA, and MO) and MI (22). A further meta-analysis showed that the presence of any mi- graine did not alter the risk of coronary artery disease mortality (61); only MA increased the risk of coronary artery disease mortality (62). In addition some data are reported on the association of migraine with angina. A cohort of >12,000 individuals participating in the Atherosclerosis Risk in Communities (ARIC) study found an asso- ciation between migraine (particularly MA) with Rose angina that, in the absence of a corresponding association with coronary artery disease, suggested that the association between migraine and an- gina was not mediated by coronary artery disease (63). However, the ARIC study did not allow for a de nite conclusion, mostly because of a possible bias related to the assessment of the headaches. A more recent meta-analysis indicated a 30% increase in the risk of MI in pa- tients with migraine versus non-migraineurs (Table 10.1) (64). e analysis strati ed according to aura status indicated an increased risk of MI in patients with MA versus non-migraineurs, while the meta-analysis was unable to show an increased risk of MI in those with MO (64). is same meta-analysis also indicated that migrain- eurs versus non-migraineurs had an increased risk of angina (64). In the case of angina, the risk was increased in both migraineurs with MA and MO (64). Both for MI and angina, the meta-analysis indicated that the overall increased risk was mostly driven by the

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Figure 10.2 Brain magnetic resonance showing white matter hyperintensities in a patient diagnosed with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).
Courtesy of Stefano Bastianello, Professor of Neuroradiology, University of Pavia, Italy.

table 10.2 Genetic diseases including among their clinical features stroke and migraine

Disease

Genetics

Clinical features

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Mutation of the NOTCH3 on chromosome 19

Attacks of migraine with and without aura, mood disturbances, transient ischaemic attacks or strokes (usually lacunar infarcts), progressive cognitive decline; less common clinical features are epilepsy, acute reversible encephalopathy, and myopathy

Mitochondrial encephalopathy lactic acidosis with stroke-like episodes (MELAS)

Mutation at position 3243 of the mitochondrial genome

Seizures, encephalopathy, stroke-like episodes, migraine mostly associated with vomiting and aura, short stature, cognitive impairment, depression, cardiomyopathy, cardiac conduction defects, and diabetes mellitus

Autosomal-dominant retinal vasculopathy with cerebral leukodystrophy (AD-RVCL)

Mutation of TREX1 on chromosome 3

Systemic microvasculopathy with adult-onset retinal vasculopathy and cerebrovascular disease variably associated with migraine, mainly without aura

Hereditary infantile hemiparesis, retinal arteriolar tortuosity and leukoencephalopathy (HIHRATL)

Mutation COL4A1 on chromosome 13

Cerebral small-vessel disease, including subcortical haemorrhagic and ischaemic lacunar strokes and leukoaraiosis. Patients usually suffer also from migraine, mostly MA, seizures, infantile hemiparesis, developmental delay, neuropsychological abnormalities, and ocular, renal and cardiac involvement

MA, migraine with aura.

Figure 10.3 White matter hyperintensities in a patient with migraine headache. They are small, punctate lesions in the deep and periventricular structures. They appear as hyperintense on uid- attenuated inversion recovery (left image) and T2 sequences, and hypointense on T1 sequences (right image).
Courtesy of Stefano Bastianello, Professor of Neuroradiology, University of Pavia, Italy.

association in women, while the meta-analysis was unable to dem- onstrate the same association in men (64).

e mechanisms underlying the relationship between migraine and cardiovascular diseases are cryptic and there are possible hypoth- eses (Figure 10.5). Concerns were raised on an increased vascular risk attributable to the di erent pharmacological agents used to treat migraine that might be responsible for the increased cardiovascular risk in migraineurs. e concerns particularly included triptans and compounds containing ergotamine because of their vasoconstrictive properties. However, neither ergots nor triptans have been consist- ently linked to an increased risk of stroke or other ischaemic events, at least when taken at recommended doses (65,66). Moreover, as

MO and MA are similarly treated and the data on the association between migraine and stroke refer to the pretriptans era, the hypoth- esis seems even more unlikely. Concerns have also been raised on the vascular safety of non-steroidal anti-in ammatory drugs. A re- cent network meta-analysis concluded that although uncertainty re- mains, little evidence exists to suggest that any of the investigated drugs are not safe in cardiovascular terms (67). Comorbid condi- tions may complicate matters further. Migraine is positively related to anxiety and depression (68), which, in turn, are positively related to cardiovascular diseases (69).

A higher burden of comorbid vascular risk factors in migrain- eurs than in non-migraineurs has been reported by some studies and used to explain the increased cardiovascular risk (70). In these studies migraineurs were more likely to have an unfavourable cholesterol pro le; to have elevated blood pressure; to have an in- crease in total cholesterol, non-high-density lipoprotein choles- terol, apolipoprotein B100, C-reactive protein and/or body mass index; to report a history of early-onset coronary heart disease or stroke; to have had an elevated Framingham risk score; to use oral contraceptives; and to have the methylenetetrahydrofolate reduc- tase (MTHFR) C677T genotype (70–75). However, in most of the studies that found an association between migraine and cardiovas- cular disease, at least the conventional vascular risk factors were present in the multivariate model that showed the association (76). Any increased burden of conventional vascular risk factors in mi- graineurs would have led to an increased atherothrombotic load, but, as already reported, no such increase has been documented and there is actually evidence for the contrary (33,63,77,78). Several studies indicated that the migraine–stroke association was present in the absence of traditional vascular risk factors and that the type of stroke was less frequently a large-vessel stroke or a small-vessel stroke when compared with strokes in the general stroke population (29,33). Cardiac events observed in migraineurs did not seem to be attributable to atherothrombosis. e ARIC study, having found that migraine was associated with Rose angina, but not with cor- onary artery disease, proposed a generalized vasospastic disorder as a putative mechanism underlying both migraine and angina (63). is hypothesis was further supported by the nding that in women

CHaPtEr 10 Migraine, stroke, and the heart

Mechanisms linking migraine to cardiovascular diseases

Figure 10.4 Infarct-like lesion in a patient with migraine. A brain infarct appears as focal lesions of ≥3 mm with the same signal characteristics as cerebrospinal uid on T1 (left image), T2 (central image), and uid-attenuated inversion recovery (right image) sequences. Infarct-like lesions can be discriminated from dilated vascular space (Virchow-Robin space) according to their shapes and locations.
Courtesy of Stefano Bastianello, Professor of Neuroradiology, University of Pavia, Italy.

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1. Migraine

Cardiovascular disease

The association may be only apparent for a bias or the disorders co-exist in a non-casual manner

Migraine itself or its consequences on the vasculature are responsible for the increased cardiovascular risk

3. Migraine

Comorbid disorder

4. Unknown disorder

Cardiovascular disease

Migraine Cardiovascular disease

2. Migraine

One or more comorbid conditions with migraine are responsible for the increased cardiovascular risk

A common underlying disorder leads to both migraine and cardiovascular disease

Figure 10.5 Possible hypotheses to explain the association between migraine and cardiovascular diseases.
Reproduced from Cardiology & Clinical Practice – La Cardiologia nella Pratica Clinica, 2,1, Sacco S and Carolei A, Migraine: An emerging cardiovascular risk factor, pp. 53-65.

undergoing coronary angiography, those with migraine had less se- vere coronary artery disease and lower coronary severity scores than those without migraine (78). Moreover, cases of non-atherosclerotic vasospasm of the coronary arteries have been documented in mi- graineurs with cardiac symptoms (72,79,80).

Migraine has also been associated with an increase in prothrombotic factors, including prothrombin factor, factor V of Leiden, elevations in von Willebrand factor antigen and activity, decreased platelet haemostasis time, clotting time and collagen- induced thrombus formation time, and MTHFR and angiotensin- converting enzyme (ACE) insertion or deletion polymorphisms (81–87). e role of these uncommon vascular risk factors remains to be clari ed, even if they can be associated only with a minority of vascular events. Migraine has also been associated with cervical arterial dissection, an acknowledged cause of ischaemic stroke, es- pecially in the young (see also Chapter 37) (88,89). A meta-analysis showed that migraine is associated with a doubling of the risk of cervical artery dissection (88). Although the association was some- what stronger for MA, there was no signi cant di erence according to aura status (88). Shared genetic susceptibility (90) and increased serum elastase in migraine (91) might be involved. Cervical artery dissection, however, may explain only a minority of the ischaemic strokes occurring in migraineurs.

Attention was given to the involvement of cortical spreading de- pression (CSD) in the pathogenesis of ischemic stroke in migrain- eurs (92,93). In CSD the intense neuronal and glial depolarization acts as a potent stimulus to increase regional cerebral blood ow in the cortex (spreading hyperaemia) in order to meet the increased neuronal energy demand. is is followed by more prolonged but moderate hypoperfusion (spreading oligaemia) generally well above the ischaemic threshold (94). A failure of neurovascular coupling to provide a su cient increase in blood ow for the raised energy use in CSD may lead to neuronal death (95). However, it is more di cult

to implicate CSD in vascular events outside the brain (i.e. ischaemic heart disease) and even if it cannot be excluded that other mechan- isms may be of importance, it is unlikely that di erent mechanisms may contribute to the association between migraine and vascular events in and outside the brain. An experimental study suggested that glutamatergic hyperexcitability associated with migraine mu- tations renders the brain more susceptible to ischaemic depolar- izations (96). As a result, the minimum critical level of blood ow required for tissue survival (i.e. viability threshold) is elevated and infarction ensues, even in mildly ischaemic tissues. is represents a paradigm shi in the search for a mechanism for increased stroke risk in migraineurs and di ers from those previously postulated on the basis of clinical data alone. e genetic mouse models ex- pressing migraine mutations (e.g. familial hemiplegic migraine and CADASIL) show a faster onset of ischaemia-triggered spreading de- polarization; an increased frequency of ischaemic depolarization; enlarged infarcts with worse neurological outcomes (which could be prevented by anti-excitatory treatment); and more severe spreading of depolarization-induced oligaemia (97). As a result, the minimum critical level of blood ow required for tissue survival is elevated and infarction occurs, even in mildly ischaemic tissues. Recently, some authors investigated the hypothesis that history of migraine predis- poses to faster acute cerebral infarct growth (98). ey performed a case–control study of patients with acute stroke (45 migraineurs and 27 controls), including chart documentation of migraine status and brain MRI within 72 hours of the stroke. In this study, migraine, particularly MA, more frequently showed the no-mismatch pattern with brain di usion and perfusion MRI. is suggests accelerated loss of viable tissue at risk, as shown in the migraine mouse model (99). In addition, several lines of evidence for vascular dysfunction have been identi ed in migraineurs and there is increasing evidence to suggest that in migraineurs the vascular system is impaired not only within the brain, but rather in the entire body (100). However,

while several studies support an alteration of arterial function among patients with migraine, ndings on the endothelial function are less clear. Endothelial function in migraineurs has occasionally been reported as impaired or altered, while some studies found no di erence compared with endothelial function in controls (100). Regarding arterial function, most of the available evidence sup- ports greater sti ness or impaired compliance of the arterial system in migraineurs (100). Possible clinical implications of arterial dys- function in migraineurs need to be clari ed. In the general popu- lation, arterial dysfunction has been linked to an increased risk of vascular disease through an atherothrombotic mechanism (101), but, as already reported, migraineurs do not seem to be at increased atherothrombotic risk. Additionally, alteration of circulating fac- tors linked to vascular dysfunction has been found in migraineurs (102–105). Electrophysiological changes could be present not only within the brain, but also in other tissues (e.g. the heart) and a com- plimentary hypothesis may rely on a systemic peculiar vascular vul- nerability of migraineurs that may contribute to the pathogenesis of migraine and over time, to the development of vascular events (106).

Management of the cardiovascular risk of migraineurs

To date, no speci c features have been reported that indicate which subjects of the overall migraine population are at the highest risk of vascular events. As stated, the risk of ischaemic stroke in migrain- eurs is magni ed in the presence of some acknowledged vascular risk factors (29,32,35,107,108). In women with migraine, cigarette smoking increases the risk of ischaemic stroke three- to ninefold and oral contraceptive use four- to eightfold (19,20,21,31,32,35). e combination of smoking and oral contraceptive use is associ- ated with a 10-fold increase in risk (31,35). Unfortunately, there are no adequately powered studies to separately determine ischaemic stroke risk for MO and MA patients taking oral contraceptives. Some studies also indicate that arterial hypertension, MTHFR gene polymorphisms, and procoagulant states may a ect the risk of is- chaemic stroke in migraineurs (109). ere are, however, no data on vascular risk factors in migraine that are di erent from those in stroke. Patients with migraine are mostly treated for their pain, but it may be appropriate to manage factors that may increase their basic vascular risk as well (110, 111). Cigarette smoking and arterial hypertension represent well-documented risk factors for cardio- vascular disease in the general population and, consequently, basic recommendations about their management should be given to mi- graineurs e prescription of combined oral contraceptives also de- serves special caution (112). As MO is not a de nite risk factor for stroke, no speci c restrictions are warranted in women with MO, especially in the absence of comorbidities. Oral contraceptives use should, however, be discouraged in women with MA as they have an increased vascular risk. Prescription should be withheld in women with MA, especially when they have comorbid vascular risk factors or congenital or acquired thrombophilia (112).

So far, no drugs are currently recommended for vascular preven- tion in migraineurs. Indeed, as the risk of developing a stroke in this population is small in terms of absolute numbers, no studies on vas- cular risk reduction in migraineurs have been conducted (50). It is

not known whether treatments used to prevent migraine can also reduce the risk of ischaemic stroke and of other vascular diseases (113,114). If stroke would occur as a consequence of repeated mi- graine attacks, it could be hypothesized that any treatment able to reduce migraine frequency would be able to reduce the risk of is- chaemic stroke. However, drugs that reduce the frequency of mi- graine attacks would hardly reduce the risk of systemic vascular events. e use of drugs that both treat migraine and prevent stroke should, at least in theory, be more reasonable. To date, however, the available migraine prevention treatments do not show vascular pro- tective e ects. ACE inhibitors and angiotensin receptor blockers, which, in preliminary studies, seemed promising in preventing mi- graine attacks (115,116), were associated with a reduction in the risk of vascular events in normotensive subjects in the presence of bene- ts beyond those that could be expected only by the reduction of blood pressure values, suggesting the presence of a peculiar e ect on arterial or endothelial function (117). However, the e ectiveness of these drugs has not been consistently demonstrated for migraine prevention and we do not have any evidence indicating that they may contribute to favourable modulation of the vascular function of migraineurs (118).

Migraine and patent foramen ovale

Initial evidence from case–control studies suggested that migraine and patent foramen ovale (PFO) are associated to an extent that goes beyond what would be predicted by the chance co-occurrence of two common conditions (119–126).

In case–control studies, MA has been found to be associated with PFO in nearly 50% of cases—twice the gure usually re- ported in non-migraineurs (120–123)—and in patients with PFO migraine has been found twice as frequently as in patients without PFO (124–126). A large population-based study (127) and a hospital-based case–control study (128) questioned the associ- ation. Non-blinded and non-randomized studies have suggested bene ts of PFO closure on migraine occurrence (129–132). A vari- able proportion of patients who underwent PFO closure for non- migraine indications reported cessation or improvement of their migraine attacks a er the procedure (119). e e ect was evident in patients with MO (frequency reduced by 54%) or MA (fre- quency reduced by 62%) but not for patients with non-migraine headaches (131). However, these studies were limited by being predominantly retrospective, non-randomized, and conducted in highly selected populations of patients. Furthermore, the highly variable course of migraine and the known placebo e ects of inter- vention in previous migraine trials preclude any rm conclusion. e Migraine Intervention With STARFlex Technology (MIST) trial (133), a prospective, randomized, sham procedure controlled trial, was the rst randomized controlled study designed to assess the e ect of PFO closure on migraine headache in patients with frequent, disabling, and drug-resistant MA (133). In the trial, pa- tients with MA who experienced frequent migraine attacks, had previously failed two or more classes of prophylactic treatments, and had moderate or large right-to-le shunts consistent with the presence of a PFO, were randomized to transcatheter PFO closure with the STARFlex implant or to a sham procedure. No signi – cant di erence was observed in the primary end point of migraine

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headache cessation between implant and sham groups. Secondary end points also were not achieved. Only in an exploratory ana- lysis, excluding two outliers, did the implant group demonstrate a greater reduction in total migraine headache days. As expected, the implant arm experienced more transient procedural serious adverse events. However, the results of the MIST trial did not allow de nite exclusion of any bene t of the PFO closure. In fact, the included patients were selected because they had particularly se- vere and refractory migraine, which is less amenable to treat than mild or moderate migraine; the continued use of prophylactic mi- graine medication throughout the trial in both treatment arms may have limited the impact of PFO closure; and the primary study end point of migraine cessation may have been unrealistic and less clinically relevant than reduction in migraine frequency. It should also be tested whether PFO closure may have an impact on aura rather than on pain. Finally, in the MIST trial, the bene ts of PFO closure were analysed 3–6 months a er device implant. e e ect of PFO closure during this relatively early analysis phase may have been confounded by clopidogrel use, incomplete closure of the defect, concomitant pulmonary shunt, and a possible early transient adverse e ect of device implant. erefore, a longer follow-up might have demonstrated additional bene t accrued over time. Residual shunts were assessed by the investigators using contrast transthoracic echocardiography at 6 months. However, it is likely that more residual shunts persisted earlier during the ana- lysis phase, and atrial or pulmonary shunts below the detection threshold of this technique might have had an impact on the treat- ment e ect in this population. us, evidence that PFO closure reduce migraine frequency is scarce and this treatment should not be used for the prophylaxis of migraine (134). However, further research on this issue is needed because of the aforementioned limitations of the MIST trial and of experimental evidences that small particles and air bubbles can trigger CSD (135,136), a likely pathophysiological correlate of the migraine aura.

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109

Non-vascular comorbidities and complications
Mark A. Louter, Ann I. Scher, and Gisela M. Terwindt

Migraine comorbidity

Comorbidity was de ned in 1970 by Alvan Feinstein as ‘any distinct additional clinical entity that has existed or that may occur during the clinical course of a patient who has the index disease under study’ (1). In this de nition the term comorbidity could be used for any entity that occurs before the diagnosis, during the disease, or a er treatment of the disease. Even ‘non-disease’ clinical entities such as pregnancy or dieting were included by Feinstein’s de nition. Nowadays, the term comorbidity is used mostly for associations be- tween disorders that are greater than could be expected based on the usual individual prevalence of both diseases in the given population.

e interpretation of comorbidity between two disorders is not always simple. In fact, (true) comorbidity can be caused by di erent mechanisms (Figure 11.1). e rst mechanism is that there is a unidirectional causation, which states simply that migraine may be a risk factor for another disease. In this case, it would be predicted that migraine would occur rst. Secondly, when not only migraine increases the risk for a certain disease, but also vice versa (the dis- ease increases the risk for migraine), this is called ‘bidirectional comorbidity’. Such a bidirectional relationship is strongly suggestive for shared (environmental and/or genetic) risk factors. In diseases where genetic factors unmistakably play a role, the shared genetic factors hypothesis is particularly attractive (2). Classical twin studies can be used to test whether shared genetic and/or environmental factors underlie the two disorders (3), but direct identi cation of genetic factors can also be successful when studying cases with both disorders. As a third mechanism of comorbidity, migraine is part of the clinical spectrum of a clear monogenetic disease (i.e. CADASIL, familial advanced sleep phase syndrome (FASPS)).

e number of suggested migraine comorbidities as reported in the scienti c literature has increased immensely over the past dec- ades. Research into comorbidity and its underlying mechanisms has become increasingly challenging. Furthermore, migraine pa- tients presenting at a headache clinic or neurology department will o en show multiple problems (4). Knowledge about and recogni- tion of this phenomenon has grown among clinicians. Still, the clin- ical comorbidities create new challenges for patient management,

education, and treatment. From a scienti c point of view, we note that patient samples are prone to selection (Berkson’s) bias, which is the reason why population-based studies are preferable to clinical studies in this instance.

Among the most reported migraine comorbidities, clear associ- ations in population studies have been reported for ischaemic stroke, epilepsy, vertigo, psychiatric diseases, sleep disorders, and pain disorders. Whereas ‘migraine, stroke and the heart’ (Chapter 10), ‘migraine and epilepsy’ (Chapter 11) and ‘migraine and vertigo’ (Chapter 13) are separate chapters in this textbook, we will focus on migraine and psychiatric comorbidity (see also Chapter 52), migraine and sleep disorders (see also Chapter 57), and migraine and pain disorders. Other reported comorbidities o en lack con- vincing evidence because of inconsistent results, study designs with poor statistical power, or highly selected patient populations. Many potential comorbidities have not yet been investigated or have only sparsely been explored. See Table 11.1 for a list of all clinically rele- vant investigated comorbidities of migraine and primary references.

Migraine comorbidities have been investigated in both clin- ical and population-based studies. One of the advantages of clin- ical studies is that migraine diagnoses are o en reliable. One of the main disadvantages is that migraine patients who consult phys- icians have more frequent and severe attacks than migraineurs in the general population, thereby o en overestimating the presence of comorbidities (especially when the comorbidity is associated with migraine severity and frequency). Population-based studies o er a more balanced view on the real extent of the association, although de nitions of disease o en are less reliable.

Of all studies on comorbidities of migraine most are cross- sectional, complicating the causal interpretation of the results. Only when prospective cohort studies have been done, in which the rst onset of disease in a population of migraineurs has been studied, can rm statements on causality be made. e best example in the eld of migraine comorbidity is the relationship between migraine and depression. First onset of depression is not only increased in mi- graineurs, but also rst onset migraine is increased in depressive pa- tients. is has led to the recognition of a bidirectional comorbidity, possibly due to shared genetic factors or environmental triggers.

1. Unidirectional causation

Migraine Comorbid disease

2. Bidirectional comorbidity, due to shared (environmental or genetic) risk factors

Shared risk factors

Migraine

3. Monogenetic disease theory

Comorbid disease

Monogenetic disease

Migraine as part of the clinical spectrum

Figure 11.1 Mechanisms of migraine comorbidity.

Migraine and psychiatric comorbidity

e relationship between migraine and psychiatric disorders has been extensively investigated in both population-based and clinical studies (see also Chapter 52). With the development of improved diagnostic criteria and statistical methodology, observations from case series have been con rmed. Multiple studies in particular have focused on the bidirectional association between migraine and depression.

Understanding the associations between migraine and psychi- atric disorders is important for various reasons (5). Both migraine and depression are ranked in the top 10 disorders with high dis- ability and burden (6). e presence of psychiatric conditions, es- pecially depression, is a risk factor for migraine chroni cation (7). In addition, comorbid migraine is associated with poorer func- tioning and increased somatic complaints in depressed patients (8). Migraine patients with comorbid psychiatric disorders are greater health resources users than migraineurs without psychiatric condi- tions (9). Lastly, treatment choices for both migraine and psychi- atric disorders can be in uenced by the presence of comorbidity. Prescription of beta blockers is (although debated) relatively contraindicated as a migraine prophylactic in patients with a comorbid depression. Migraine prophylaxis with selective sero- tonin re-uptake inhibitors is still controversial because of the sug- gested risk of developing a serotonin syndrome when prescribed together with triptans, especially when used frequently. However, in our experience this is not a problem in practice. Valproate as prophylactic treatment for migraine may be favoured owing to its stabilizing e ect on depressive symptoms.

CHaPtEr 11 Non-vascular comorbidities and complications Depression

Migraine and depression show a bidirectional comorbidity. Population-based studies have shown that persons with a lifetime history of depression have an increased risk of rst onset migraine (odds ratio (OR) 3.0, 95% con dence interval (CI) 1.2–7.6) and, vice versa, persons with migraine have an increased risk of rst-onset major depression (OR 5.2, 95% CI 2.4–11.3) (10). Such bidirec- tional association suggests a shared aetiology, which is at least partly explained by genetic factors (11–13). Indeed, evidence suggests that migraine and depression share genetic factors. In a large twin study, 20% of the variability of comorbid migraine and depression was estimated to be due to shared genetic factors and 4% to unique shared environmental factors (14). A study performed in a genet- ically isolated Dutch population investigated the extent to which the comorbidity of migraine and depression could be explained by shared genetic risk factors. Clear indications were found for shared genetic factors in depression and migraine, especially in migraine with aura (15). Future research should clarify the speci c genetic factors that increase liability to both disorders.

e presence of depression is a risk factor for increasing frequency of migraine attacks, thus leading to chroni cation (6). Treatment of patients with (chronic) migraine and depression is o en compli- cated, because migraine chroni cation is strongly associated with the overuse of acute headache medication. Medication overuse is present in up to 80% of patients with chronic migraine who are treated in a specialized headache clinic, and in 33% of chronic mi- graineurs in the general population (6). Depression itself is an im- portant predictor of medication overuse and dependence, and patients with overuse of analgesics are at increased risk of depression (16, 17). Altogether, a triad is suggested of migraine chroni cation, depression, and medication abuse (Figure 11.2). An important clin- ical implication of this triad is that patients with chronic migraine should be screened for both medication overuse and comorbid de- pression. Withdrawal of medication overuse is accepted as a suc- cessful treatment for patients with medication overuse headache (18), and could be o ered to all patients with chronic migraine and medication overuse.

Beside the general determinants of depression, several migraine- speci c determinants involved in this relationship are described. Among others, cutaneous allodynia (the perception of pain in re- sponse to non-noxious stimuli to the normal skin) seems to be in- volved in the relationship between migraine and depression (19,20). Allodynia is considered a clear marker for a central sensitization process of the brain (21). Clinically, central sensitization causes refractoriness to acute treatment. (20). us, allodynia has conse- quences for disease progression and treatment, and it should lead to an increased awareness of comorbidity of migraine and depression, and of risk for chroni cation of migraine (22).

anxiety disorders

A strong relationship between migraine and anxiety disorders has been described in the literature, with ORs ranging from 2.7 to 3.2 (23,24). Current anxiety is associated with an increased migraine at- tack frequency (24). Depression and anxiety are highly comorbid disorders, which could partly explain the relationship between anx- iety disorders and migraine. Patients with a combination of anxiety

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table 11.1 Comorbidities of migraine, with key references

Comorbidity

Key references

Type of study

Number of migraineurs

Remarks

Psychiatric disorders

• Depression

• Anxiety

• Bipolar disorder

• Panic disorder

• Post-traumatic stress
disorder

Breslau et al., 2003 (10)
Stam et al., 2010 (15) Merikangas et al., 1990 (23) Zwart et al., 2003 (24)
Fornaro and Stubbs, 2015 (28) Fasmer 2001 (26)

Oedegaard et al., 2010 (27) Smitherman et al., 2013 (31) Stewart et al., 1994 (106) Peterlin et al., 2011 (32) Peterlin et al., 2011 (107)

Population based, longitudinal Clinic based, cross-sectional Population based, longitudinal Population based, cross-sectional Meta-analysis

Clinic based, cross-sectional Genome-wide association study Review article
Population based, cross-sectional Review article

Population based, cross-sectional

n=496 n=360 n=61 n=6209 n=3976 n=28 n=56

–
Not provided –
n=251

Proves bidirectional comorbidity
Indicates shared genetic factors Distinguishes between depression and anxiety –
Primary bipolar cohorts
Primary bipolar cohort
BPD without headache vs. BPD with migraine –
Primary panic disorder cohort
–
–

Sleep disorders

• Restless legs syndrome

• Narcolepsy

• Insomnia, daytime sleepiness,
sleep apnoea

• FASPS

Rhode et al., 2007 (39)
Chen et al., 2010 (40)
Winter et al., 2013 (44) DMKG Study Group 2003 (50) Dahmen et al., 2003 (51) Barbanti et al., 2007 (55) Odegård et al., 2010 (56) Lateef et al., 2011 (57) Kristiansen et al., 2011 (58) Brennan et al., 2013 (52)

Clinic based, case–control
Clinic based, cross-sectional Population based, cross-sectional Clinic based, case–control
Clinic based, cross-sectional Clinic based, case–control Population based, cross-sectional Population based, cross-sectional Population based, cross-sectional Genetic family study

n=411 n=772 n=2816 n=21 n=37 n=100 n=51 n=373 n=109 n=12

–
Control groups: TTH and cluster headache Self-reported migraine diagnoses
Primary narcolepsy cohort
Primary narcolepsy cohort
Outcome measure: excessive daytime sleepiness Outcome measure: sleep disturbances Outcome measure: Insomnia
Outcome measure: sleep apnoea (no association) –

Pain disorders

• Low back pain • Fibromyalgia
• Abdominal pain

Von Korff et al., 2005 (65) Hagen et al., 2006 (66) Le et al., 2011 (67)
Le et al., 2011 (67)

de Tomasso, 2012 (68) Cole et al., 2006 (71)

Kurth et al., 2006 (72)

Population based, cross-sectional Clinic based, cross-sectional Population based, cross-sectional Population based, cross-sectional

Review article
Health insurance database cohort,

cross-sectional
Clinic based, cross-sectional

Not provided n=17 n=8044 n=8044

– n=5890

n=99

Primary spinal pain cohort, self-reported migraine

Primary low back pain cohort, self-reported migraine

Self-reported migraine, self-reported comorbidities

Self-reported migraine, self-reported

comorbidities –

Primary irritable bowel cohort, weak migraine diagnoses

Outcome measure: upper abdominal symptoms

Gynaecological disorders

• (Pre-)eclampsia • Endometriosis • Premenstrual

syndrome

Facchinetti et al., 2005 (81) Simbar et al., 2010 (82) Tietjen et al., 2007 (83)

Tietjen et al., 2006 (84) Karp et al., 2011 (85)

Facchinetti et al., 1993 (86) Allais et al., 2012 (87)

Clinic based, case–control Clinic based, case–control Clinic based, case–control

Clinic based, case–control Clinical trial

Clinic based, cross-sectional Review article

n=29 n=13 n=171

n=50 n=54

n=34 –

Primary pre-eclampsia cohort
Primary pre-eclampsia cohort
More comorbid conditions in women with

endometriosis –

Endometriosis con rmed by biopsy, no association

Association only signi cant in the menstrual

migraine group –

Movement disorders

• Parkinson’s disease • Essential tremor
• Tourette’s syndrome • Sydenham’s chorea • Dystonia

Barbanti et al., 2000 (108) Barbanti and Fabbrini,

2002 (109)
Barbanti et al., 2010 (110) Duval and Norton, 2006 (111) Kwak et al., 2003 (112) Barabas et al., 1984 (113) Teixeira et al., 2005 (114) Barbanti et al., 2005 (115)

Clinic based, cross-sectional Review article

Clinic based, case–control Clinic based, cross-sectional Clinic based, cross-sectional Clinic based, cross-sectional Clinic based, cross-sectional Clinic based, cross-sectional

n=66 –

n=28
n=30
n=25
n=16
n=12
Not provided

Primary Parkinson’s cohort –

Primary essential tremor cohort, no association No association
Primary Tourette’s cohort
Primary Tourette’s cohort, paediatric population Paediatric population

Primary dystonia population. No evidence for association

table11.1 Continued

disorders and major depression have been shown to be more likely to have migraine than those with only depression or anxiety (24). e interpretation of the relationship between migraine and depres- sion should therefore always be interpreted in the light of probable comorbid anxiety disorders as the association between migraine and depression seems to be stronger in patients with co-existing anxiety disorders (23–25).

Bipolar disorder

A few studies have investigated the relationship between migraine and bipolar mood disorders. In a prospective cohort study among 27- and 28-year-olds in Zurich, Switzerland, the 1-year prevalence of a bi- polar spectrum disorder was 8.8% in migraineurs versus 3.3% in non- migraineurs (OR 2.9, 95% CI 1.1–8.6) (23). In a psychiatric inpatient population, migraine appeared to be most prevalent in patients with a bipolar II disorder (77%), when compared with unipolar depressive disorder (46%) and the bipolar I disorder (14%) groups (26).

A genome-wide association study was performed in a sample of patients with bipolar a ective disorder (using comorbid migraine as an alternative phenotype). A single nucleotide polymorphism was suggested to be associated with bipolar disorder and attention- de cit–hyperactivity disorder in patients with migraine. However, this nding was never replicated by others (27).

A recent systematic review and meta-analysis established that, overall, approximately one-third of people with bipolar disorder are a ected by comorbid migraine (28,29). e nding that migraine is

Chronic migraine

more prevalent among people with bipolar II disorder than in those with bipolar I disorder was con rmed in this studies.

Other psychiatric comorbidities

Relationships have been described of migraine with panic dis- order, obsessive–compulsive disorder, phobias, and post-traumatic stress disorder (23,25,30–32). Only cross-sectional studies were performed, complicating the causal interpretation of these rela- tionships. Further research is needed to enlighten the interaction of di erent psychiatric disorders and their comorbidity with mi- graine. e exact mechanisms underlying most of the psychiatric comorbidities of migraine are poorly understood, with the clear ex- ception of depression for which more clues are provided for shared (genetic) risk factors.

Migraine and sleep disorders

Sleep disorders have been reported to occur more o en in migrain- eurs than in persons without migraine (see also Chapter 57). Among sleep disorders associated with migraine are restless legs syndrome (RLS), narcolepsy, insomnia, and obstructive sleep apnoea (OSAS) (33). Migraine is associated with sleep in di erent ways: patients o en report their migraine attacks to start during nocturnal or di- urnal sleep, on the one hand. On the other hand, many patients re- port sleep as an important factor of relief for their migraine attacks. ese ndings indicate that the physiology of sleep could somehow be related to the mechanisms underlying migraine attacks (34). e frequent association of headache (in general) and sleep might be de- ned by di erent paradigms: rstly, headache as a result of disrupted nocturnal sleep (i.e. OSAS or RLS). Secondly, headache might be the cause of sleep disturbances (i.e. chronic tension-type headache or chronic migraine, and also cluster headache). Lastly, there could be an intrinsic (anatomical and/or physiological) relationship between the headache disorder and sleep, as being suggested for migraine, cluster headache, and hypnic headache (34).

CHaPtEr 11 Non-vascular comorbidities and complications

Comorbidity

Key references

Type of study

Number of migraineurs

Remarks

Other disorders

• Syncope
• Obesity
• Asthma and allergies • Diabetes
• Multiple sclerosis
• Cancer

Thijs et al., 2006 (74) Peterlin et al., 2010 (88) Bigal et al., 2007 (89) Bigal et al., 2006 (90) Aamodt et al., 2007 (79) Burch et al., 2012 (92)

Rainero et al., 2005 (93) Cavestro et al., 2007 (94) Pakpoor et al., 2012 (98) Kister et al., 2012 (99)

Li et al., 2010 (100) Winter et al., 2013 (103) Phipps et al., 2012 (105) Kurth et al., 2015 (104)

Population based, cross-sectional Population based, cross-sectional Review article
Population based, cross-sectional Population based, cross-sectional Population based, longitudinal

Clinic based, cross-sectional Clinic based, cross-sectional Meta-analysis
Population based, longitudinal Population based, longitudinal

Population based, longitudinal Population based, longitudinal Population based, longitudinal

n=323 n=4664 – n=3791 n=5024 n=5062

n=30 n=84
8 studies n = 17,893 n = 10,464

n=7318 n=8598 n = 39,534

–
Self-reported migraine diagnoses
–
–
–
Self-reported migraine. No evidence for an

association
Outcome measure: insulin sensitivity Outcome measure: glucose metabolism Overall OR 2.60 (95% CI 1.12–6.04) Self-reported migraine diagnoses
Incident breast cancer. Self-reported migraine

diagnoses
Incident breast cancer. Self-reported migraine

diagnoses
Incident endometrial cancer. Self-reported

migraine diagnoses
Incident brain tumours. Self-reported migraine

diagnoses

Migraine comorbidities described in literature are summed up with their key references. Comorbidity of migraine with stroke, epilepsy, and vertigo are not mentioned as separate chapters are dedicated to these topics. BPD, bipolar disorder; FASPS, familial advanced sleep phase syndrome; TTH, tension-type headache; OR, odds ratio; CI, con dence interval.

Medication overuse

Depression

Figure 11.2 Triad of migraine chroni cation.

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Part 2 Migraine

e relationship between migraine and sleep, with the occurrence of migraine o en during nocturnal sleep and awakening, as well as the periodic nature of migraine and the premonitory symptoms occurring in migraine, suggest that migraine may be associated with the chronobiology. Also, reported triggers such as hormonal changes (menstruation), jet lag, shi work, seasonal cycles, and work–rest activity (weekends) support the theory that chronobiology plays an important role in migraine pathophysiology. e chronobiology is regulated by the hypothalamus, suggesting involvement of the hypo- thalamus in the pathophysiology of migraine (35). Consequently, associations between migraine and sleep disorders are suggestive of hypothalamic modulation of the trigeminovascular pathway (34,35). Pain signals that originate in the trigeminovascular pathway can alter the activity of hypothalamic and limbic structures that inte- grate sensory, physiological, and cognitive signals that drive behav- ioural, a ective, and autonomic responses (36).

restless legs syndrome

RLS is characterized by an urge to move, mostly associated with unpleasant leg sensations, occurring at rest, in a circadian pattern, diminishing with motor activity (37). RLS hampers sleep and has a negative impact on quality of life (38). Several epidemiological studies have provided evidence for a bidirectional association be- tween migraine and RLS in clinical cohorts (39,40). RLS prevalence rates in migraine populations are about twice as high as prevalence rates in the general Western population: 11–18% in migraine popu- lations versus 5–10% in general populations (39–45). RLS is, ac- cording to a recent cross-sectional study, not only twice as prevalent, but also more severe in migraine patients, and associated with de- creased sleep quality (46).

RLS has long since been considered to be related to dopamin- ergic system dysfunction (47,48). Dopaminergic dysfunction has also been linked to the pathogenesis of migraine, especially to clin- ical premonitory symptoms such as nausea, vomiting, hypotension, and drowsiness (49). Another possible link between migraine and RLS could be that sleep deprivation in patients with RLS triggers migraine attacks. Co-associations are found with depression, which could also in uence this comorbidity (39).

Narcolepsy

Narcolepsy is a disorder of the sleep–wake cycle with a prevalence of approximately 20–60 per 100,000 (50). Only a few studies have been published on the comorbidity of migraine and narcolepsy. e main symptoms are excessive daytime somnolence, cataplexy, hypnagogic hallucinations, sleep paralysis, disturbed nocturnal sleep, and cata- plexy (51). All studies on the comorbidity of migraine with narco- lepsy have been performed in clinical narcolepsy populations, most probably due to the low prevalence of narcolepsy. Con icting results have been reported: some report a clear signi cant association with migraine in a cohort of narcoleptic patients (51), and others report no association with migraine, but only with the occurrence of ‘un- speci c headache’ (50). More investigations are needed to explore the relationship between migraine and narcolepsy.

Familial advanced sleep phase syndrome

Two families were identi ed with both familial migraine with aura and FASPS, which appeared to be inherited in an autosomal dom- inant manner (52). is syndrome is de ned by a profound phase

shi of the sleep–wake cycle. A mutation was identi ed from this family in the casein kinase 1δ gene, being involved in the circadian clock regulation. Testing in transgenic mouse models suggested an increased cortical excitability, consistent with a susceptibility to migraine with aura (53). ese ndings suggest that circadian dysregulation may be common to migraine in general (54). is type of comorbidity, however, in which a single gene seems to increase the sensitivity for both migraine and another disease, is both excep- tional and unique.

Insomnia, daytime sleepiness, and sleep apnoea

Associations of headache with sleep disturbances in general, including excessive daytime sleepiness, insomnia, snoring, and/ or apnoea, have been investigated thoroughly by several studies. However, few of those studies have focused particularly on mi- graine. Sleepiness is considered a possible migraine symptom that can emerge during various phases of a migraine attack, including the premonitory phase, the headache phase and the recovery phase. A case–control study of 100 patients with episodic migraine and 100 healthy controls indicated that daytime sleepiness was more frequently present in migraineurs than in controls (OR 3.1, 95% CI 1.1–8.9) (55). One population-based study evaluated sleep disturb- ances in 297 participants, of whom 51 were diagnosed with migraine. Compared with migraine-free controls, patients with migraine had signi cantly more severe sleep disturbances (OR 5.4, 95% CI 2.0– 15.5), with a stronger association for chronic headache patients (56). Another population-based study including 373 migraineurs indi- cated that migraineurs versus healthy controls had more di culty in initiating sleep (OR 2.2, 95% CI 1.6–3.0), di culty in staying asleep (OR 2.8, 95% CI 2.3–3.5), more early morning awakening (OR 2.0, 95% CI 1.4–2.7), and more daytime fatigue (OR 2.6, 95% CI 2.0–3.3) (57). However, no di erences between migraine and other types of headache were found, nor were there di erences between migrain- eurs with and without aura. No relationship between migraine and sleep apnoea was found in a cross-sectional population-based study (58).

Migraine and pain disorders

Several (chronic) pain syndromes have been described to be comorbid with migraine, including low back pain, bromyalgia, and irritable bowel syndrome (IBS). e fact that many persons with migraine su er from other pain conditions is suggestive of (subtle) changes in the function of the nociceptive system (20). However, willingness to report pain may also play a role. Repeated or pro- longed noxious stimulation may lead to sensitization, a phenomenon de ned by increased neuronal responsiveness within the central nervous system (59). In migraine, the clinical marker for central sensitization is considered to be cutaneous allodynia (the percep- tion of pain in response to non-noxious stimuli to the normal skin). Migraine patients experience an increased sensitivity to the skin for common daily common daily activities during migraine attacks, such as combing of hair, taking a shower, touching the periorbital skin, shaving, or wearing earrings during migraine attacks (60). Prevalence estimates of allodynia in migraine patients range from 50% to 80% (61). Factors that have been reported to increase the likelihood of having allodynia during migraine attacks are female sex, high body mass index, and headache-speci c features such as a low age at onset, high frequency of attacks, and comorbidity with

depression and anxiety (19,20,60,62–64). Allodynia also has been described as a predictor for migraine chroni cation (22).

In a large clinic-based migraine study, several comorbid chronic pain conditions were associated with migraine-related cutaneous allodynia (20). ese ndings support the theory that the pres- ence of allodynia in migraine patients marks an increased risk for other diseases that have been associated with central sensitization. A shared pathophysiological link between migraine and other pain syndromes might be sensitization of central pain pathways. Longitudinal studies are needed to evaluate the temporal relation- ship of chronic pain conditions and migraine.

Low back pain

Chronic low back pain is typically comorbid with a range of other chronic pain conditions. In a large cross-sectional population- based survey, an association was found with migraine (OR 5.0, 95% CI 4.1–6.4) (65). However, migraine diagnoses were self-reported, and chronic back pain was de ned as self-reported ‘chronic back or neck problems’. A smaller association was found in a clinical population of patients with chronic low back pain (OR 1.6, 95% CI 1.1–2.3) (66). However, this study had similar drawbacks, with migraine diagnoses not ful lling International Classi cation of Headache Disorders, second edition (ICHD-2) criteria. Another population-based study found that low back pain was highly prevalent in migraine patients (OR 1.77, 95% CI 1.62–1.94) (67). Altogether, associations between chronic low back pain and mi- graine have been described, but the magnitude and background of this comorbidity remain unclear.

Fibromyalgia

Fibromyalgia is a chronic pain syndrome of unknown aetiology char- acterized by di use pain and the presence of so-called ‘tenderness points’(see also Chapter 58). e most supported hypothesis on the causes of bromyalgia is that central sensitization might cause mus- culoskeletal pain (68). A review study of comorbidity with primary headache syndromes found seven papers investigating the relation- ship of bromyalgia with migraine. e prevalence of bromyalgia appears to be increased in migraine patients (ranging from 10% to 36% versus 3–6% in the general population). Furthermore, chronic headache types show higher prevalence rates than episodic headache types (68). A large Danish migraine comorbidity study presented an increased comorbidity for migraine with aura (OR 6.63, 95% CI 3.74–11.76) when compared with migraine without aura (OR 2.04, OR 1.01–4.13) (67). Patients with migraine and co-existing bro- myalgia have a higher risk of suicidal ideation and suicide attempts compared with migraine patients without bromyalgia (69). e as- sociation is stronger with increasing migraine attack frequency and migraine burden. is nding suggests that patients with migraine should be carefully evaluated for other chronic pain conditions and for their mental health well-being (70).

abdominal pain

IBS is a functional disorder of the gastrointestinal tract, which re- sults in the clinical symptoms of altered bowel habits and abdominal pain (71). People with IBS are reportedly more likely to have other disorders, including migraine. A health insurance database study of 97,593 patients with a medical claim for IBS showed an increased comorbidity of migraine within this population (OR 1.6, 95% CI

1.4–1.7) (71). However, a major drawback of studies of these kind of databases is that prevalence numbers are not reliable. A clinical study of 99 migraineurs showed (in comparison with a population of 488 blood donor controls) an increased prevalence of upper abdom- inal pain, frequent abdominal pain, abdominal pain (in general), night abdominal pain, and periodic abdominal pain (all P-values <0.001) (72). Remarkably, the relationship of abdominal com- plaints and migraine has also been attributed to ‘adult abdominal migraine’ in a case report (73). Abdominal migraine, according to the ICHD-2 criteria, typically occurs during childhood. It remains unclear whether abdominal complaints during attacks in migraine patients can be classi ed as abdominal migraine, but usually these complaints involve not so much as pain, as well as nausea, vomiting, and diarrhoea.

Migraine and other comorbidities

Syncope

Syncope is a paroxysmal symptom consisting of a brief, self-limiting transient loss of consciousness due to global cerebral hypoperfusion (74). Syncope is associated with dysfunction of the autonomic nerve system, which also has been studied in migraineurs (with con icting results). Only one large population-based study investigated both the prevalence of syncope and related symptoms of the autonomic nerve system (74). e prevalence of one or more syncopal events in 323 migraineurs versus 153 controls was higher in migraineurs, both for syncope (46% vs 31%; P = 0.001) and frequent syncope (13% vs 5%; P = 0.02). ere was no signi cant di erence between the migraine and control groups in measurements of autonomic dysfunction. e reason for this association is presently uncertain. e Cerebral Abnormalities in Migraine, an Epidemiologic Risk Analysis (CAMERA) study shows that frequent syncope, orthostatic intolerance, and migraine independently increase the risk of white matter lesions, particularly in females (75).

Two families were reported with migraine and syncope (76,77). is could be an indication that there could be a genetic predis- position for the comorbidity of migraine and syncope. However, additional studies are required to investigate the probable genetic background of this comorbidity.

Movement disorders

Associations with migraine have been reported for Parkinson’s dis- ease, essential tremor, Tourette’s syndrome, Sydenham’s chorea, and dystonia (78). e pathophysiological explanation for these comorbidities has been described as involvement of the basal ganglia in both movement disorders and migraine. To date, however, it is still unclear to what extent the basal ganglia indeed are involved in migraine.

asthma and allergies

A large population-based study from Norway investigated the re- lationship between migraine (and non-migrainous headache) and asthma, hay fever, and chronic bronchitis. is study showed that mi- graine was associated with current asthma (OR 1.5, 95% CI 1.3–1.7), hay fever (OR 1.5, 95% CI 1.4–1.6) and chronic bronchitis (OR 1.6, 95% CI 1.3–1.8) (79). e pathophysiological explanation for these associations is suggested to be that mast cells (which are evidently

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involved in asthma pathogenesis) could also play a role in migraine genesis as well by secretion of vasoactive, pro-in ammatory, and neurosensitizing mediators (80).

Gynaecological comorbidities

Several gynaecological disturbances have been associated with mi- graine. Endometriosis (which also could be considered a chronic pain syndrome), menorrhagia, (pre-) eclampsia, and the premen- strual syndrome all have been reported as being associated with migraine (81–87). However, the scienti c strength of these relation- ships is mostly moderate, with only few reports. Whether central sensitization (in case of endometriosis) the female sex hormones, or altered platelet function play a role in this suggested comorbidity, is to be clari ed by future research.

by comparing the occurrence of migraine in patients with MS versus controls, showing a signi cant association, with patients with MS being twice as likely to report migraine as controls (OR 2.60, 95% CI 1.12–6.04) (98). A large prospective cohort study among nurses (the Nurses’ Health Study II) calculated the relative risk of MS as being 1.39 (95% CI 1.10–1.77) in study participants with versus without migraine (99). Altogether, a clear association between migraine and MS has been proven. Various hypotheses have been proposed that may explain this association, including misdiagnosis of MS (due to non-speci c radiographic ndings in combination with a history of transient neurologic de cits), migraine-like headache as a pre- senting symptom of MS, and changes in the physiology of the mi- graine brain facilitating the pathogenesis of MS (99).

Cancer

Few studies have been performed on the relationship between mi- graine and cancer, all of which focused on ‘female cancers’: breast cancer and endometrial cancer. As a reason for this speci c focus, most papers put forward that migraine predominantly a ects women, with a reported role of hormonal uctuations in a part of these patients. Interestingly, two case–control studies and one pro- spective study suggested that a history of migraine is associated with a reduction in the risk for breast cancer (10–30% reduction) (100– 102). However, the Women’s Health Study showed in a prospective design no signi cant association of migraine with breast cancer risk (HR 1.10, 95% CI 0.99–1.22), nor with the occurrence of brain tu- mours (HR 1.18, 95% CI 0.58–2.41) (103,104). A study on the risk of postmenopausal endometrial cancer in women with a migraine history showed no association (HR 0.91, 95% CI 0.75–1.11) (105). Altogether, the relationship between migraine and cancer is far from evident.

Obesity

e relationship of migraine with obesity has been studied in several large population-based studies (88–90). Interestingly, in one study, the association of migraine with obesity was only signi cant in younger migraine patients (<56 years) (88). ese ndings support not only the association between migraine prevalence and obesity, but also the theory that adipose tissue disposition plays a role in this comorbidity. A systematic review and meta-analysis of obser- vational studies con rms the association between migraine and obesity, likely mediated by sex, migraine frequency, and age (91).

Diabetes

Insulin resistance as a component of metabolic syndrome has been proposed as being a part of the associations between migraine, obesity, and increased cardiovascular disease risk. e Women’s Health Study, a large prospective cohort study of women aged >44 years, investigated the association between migraine status and incident type 2 diabetes (92). No associations were found. Others, however, describe alterations in insulin metabolism in migraineurs, albeit without de ning diabetes (93,94). e other way around, in persons treated for diabetes, a reduced prevalence of migraine medi- cation intake was found, suggesting a reduced migraine prevalence of migraine among (older) patients with diabetes (95). It is plausible that these inconsistent results may be due, in part, to the age of the studied populations. For example, selective mortality, diabetic neur- opathy, or vascular changes suppressing the expression of migraine in later life might lead to a di erent association between migraine and diabetes in younger versus older adults. Consistent with this hypothesis is the previously referenced study showing a di erent relationship between obesity and migraine in younger versus older adults (88). Notably, a longitudinal study from Norway found in- creased incidence of metabolic syndrome in migraineurs compared with others over 11 years of follow-up (96,97). In conclusion, the exact relationship between migraine and diabetes is still very un- clear. e question of whether diabetes is independently associated with migraine, or just as a confounder in the association between migraine and cardiovascular disease, should be studied in longitu- dinal study designs.

Multiple sclerosis

e proposed relationship between migraine and multiple scler- osis (MS) has been investigated in several studies. A recent meta- analysis of studies on this relationship provided an overall estimate

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Migraine and epilepsy

Pasquale Parisi, Dorothée Kasteleijn-Nolst Trenité, Johannes A. Carpay, Laura Papetti, and Maria Chiara Paolino

General concepts

Migraine and epilepsy are both characterized by transient attacks of altered brain function with a clinical, pathophysiological and thera- peutic overlap (1–10). Furthermore, epilepsy and migraine may mimic each other. In particular, occipital lobe seizures may be easily misinterpreted as migraine with visual aura (11)—although there seem to be several clinical characteristics that can di erentiate be- tween visual auras of epileptic and migrainous origin (12).

e frequency of epilepsy in people with migraine (range 1–17%) is higher than in the general population (0.5–1%), just as the preva- lence of migraine among patients with epilepsy is also higher than that reported in healthy individuals (3,13–18). is comorbidity is o en found especially in children (19,20). Some studies of the asso- ciation between migraine and speci c epilepsy syndromes, such as childhood epilepsy with occipital paroxysms and benign childhood epilepsy with centrotemporal spikes, were negative (6,21), but others were positive (3,22–27).

An increase in (usually unspeci c) electroencephalographic (EEG) abnormalities in patients su ering from migraine (9) has been considered as further evidence of a relationship between mi- graine and epilepsy (11,13). e mechanism underlying the onset of a migraine attack is probably cortical spreading depression (CSD). Unlike epileptiform abnormalities in epilepsy attacks, CSD is not demonstrable in the EEG of migraine patients, which clearly ham- pers studies addressing the pathophysiological overlap between mi- graine and epilepsy attacks.

Pathophysiology

Seizures and migraine attacks share several pathophysiological mechanisms (28). Both phenomena may be symptoms of an underlying brain lesion, or have a genetic origin. Lesions in the oc- cipital lobe may be associated with migraine and occipital lobe epi- lepsy (6). Both occipital epilepsy and migraine are characterized by visual symptoms (elementary visual hallucinations vs aura) followed by headache and other autonomic symptoms.

Epileptic seizure—migraine attack: common substrates

Many studies support the hypothesis of excessive neocortical cel- lular excitability as the main pathological mechanism underlying the onset of attacks in both diseases (2). In migraine, however, hyperexcitability is believed to result in CSD rather than in the hypersynchronous activity that characterizes a seizure. Moreover, in migraine hypo- and hyperexcitation occur sequentially as re- bound phenomena (during a spreading depression); hence, the term ‘dis-excitability’ may better describe migraine pathophysi- ology than hyperexcitability (29). CSD could be a connecting point between migraine and epilepsy (30–33). CSD is characterized by a slowly propagating wave of sustained strong neuronal depolariza- tion that generates transient intense spike activity as it progresses into the brain tissue, followed by neural suppression, which may last for minutes. e depolarization phase is associated with an increase in regional cerebral blood ow, whereas the phase of reduced neural activity is associated with a reduction in blood ow (34). CSD causes activation of the trigeminovascular system (TVS), consisting of the cascade release of numerous in ammatory molecules and neuro- transmitters, which results in pain during the migraine attack (35).

In both CSD and a seizure, the onset and propagation of neuronal depolarization are triggered when a certain threshold is reached, which is supposed to be lower for CSD than for a seizure (36–40).

Once the cortical event has started, spreading subsequently de- pends on the size of the onset zone, velocity, semiology, and type of propagation. Moreover, the onset of CSD and that of the epileptic seizure may facilitate each other (29,41). ese two phenomena may be triggered by more than one pathway converging upon the same destination: depolarization and hypersynchronization (29,32,33,41,42). A paroxysmal change in cortical neuronal ac- tivity may occur during a migraine attack or epilepsy seizure; hyperexcitation occurs in epilepsy, whereas in migraine hypo- and hyperexcitation occur sequentially as rebound phenomena (spreading depression) (43,44). e triggering causes may be en- vironmental or individual (genetically determined or not), which result in a ow of ions that mediates CSD, through neuronal and glial cytoplasmic bridges rather than through interstitial spaces, as usually occurs in the spreading of epileptic seizures (29,41,42). e

threshold required for the onset of CSD is likely to be lower than that required for the epileptic seizure. In this regard, a ‘migraleptic’ event (see section ‘Migraine-triggered seizure (migralepsy) and ictal epileptic headache’) would be unlikely to occur. Recurrent seizures might also predispose patients to CSD, thereby increasing the oc- currence of a peri-ictal migraine-type headache, usually a post-ictal headache (29,33,41,45). However, in chronic epilepsy, an intrinsic protection mechanism against CSD may exist, as was suggested by the strongly increased threshold for CSD in brain slices from pa- tients su ering from chronic epilepsy (46).

Epileptic syndromes—primary headache/ migraine: common substrates

In speci c childhood epilepsy syndromes migraine/headaches seem more prevalent (6,23,26,47,48). e best known are benign occipital epilepsy of childhood with occipital paroxysms (BOEP) and benign rolandic epilepsy. e seizures in BOEP usually begin with visual symptoms, including amaurosis, elementary visual hallucinations (phosphenes), and complex visual hallucinations (visual illusions) (47), followed by hemiclonic, complex partial, or generalized tonic- clonic seizures. Approximately 25–40% of these patients develop migraine- like headaches (6). erefore, occipital seizures may be erroneously diagnosed as migralepsy (47,49).

Both migraine and epilepsy have an important genetic compo- nent. e rare monogenic forms of migraine are of the familial hemiplegic migraine (FHM) subtype (50). Strong support for a shared genetic basis between headache and epilepsy comes from clinical/EEG and genetic studies on FHM (51–60)—errors in the same gene may be associated with migraine in some cases and with epilepsy in others (53). Recent data suggest shared genetic sub- strates and phenotypic–genotypic correlations with mutations in some ion transporters genes, including CACNA1A, ATP1A2, and SCN1A (54–59). Several other genetic ndings pointing to a link between migraine and epilepsy have been reported. ey include mutations in SLC1A3, a member of the solute carrier family that encodes excitatory amino acid transporter 1, 57 POLG58, C10, and F259, which encode mitochondrial DNA polymerase and helicase twinkle (59,60).

Although much remains to be understood of the pathophysiology of epilepsy and migraine, glutamate metabolism (61), serotonin me- tabolism (62), dopamine metabolism (63), and ion-channel func- tion (sodium, potassium, and chloride) might be impaired in both (64). In particular, it is likely that voltage-gated ion channels are critically positioned in the pathways associated with migraine and epilepsy (54–60).

Photosensitivity

Intermittent photic stimulation (IPS), may induce photoparoxysmal EEG responses (PPRs), migraine, and epileptic seizures (45). Some patients with ictal epileptic headache (IEH) (21,65) were photosensi- tive (21,66–69). Although occipital lobe epilepsy already has much in common with migraine (visual aura; positive and negative ictal signs; and autonomic disturbances, such as pallor and vomiting), the photosensitive variant of occipital epilepsy and photosensitive epilepsy, in general, share even more similarities, such as a higher prevalence in women (female to male ratio of 3:2) and a sensitivity to ickering light stimuli and striped patterns with provocation of attacks (45).

In children a ected by migraine with aura (MA), a PPR was seen in over one-third (70), which is more than reported in a healthy population of children (1.4%) and in epilepsy patients in general (5%) (71). In another study that investigated the PPR frequency and type in 263 children and adolescents between 7 and 18 years of age a ected by primary headache, Wendor et al. (72) found that the PPR frequency did not di er signi cantly in the three main types of headaches, ranging from 6.7% (tension-type headache) to 8.9% (migraine without aura (MO)). However, PPR was most frequent (17.6%) in the MA group of patients under 12 years of age, and in seven of 17 patients with both migraine and PPR, photogenic stimuli were the most frequent triggering factors of the migraine attack, compared with 10 of 100 controls ( <0.01) (45).

Propagation of PPR is associated with increased excitability of the occipital cortex (73). In this regard, it should be borne in mind that the accumulated burden of migraine seems to cause slight al- terations in the physiology of the visual cortex and an increase in alpha rhythm variability up to 72 hours before the next migraine attack (74). Flashes, phosphenes, and other positive or negative visual manifestations are o en part of the clinical picture in mi- graine and occipital epilepsy (75). Moreover, IPS induces ‘ ashes and phosphenes’, as well as migraine and seizures.

Finally, photophobia is one of the most well-known features of migraine (80% of chronic migraineurs (76)) and also o en found in epilepsy-related headaches (in 50% of cases it occurs in pre-ictal, postictal, or even interictal headache (77)).

In summary, a subclinical spontaneous (epileptic foci or CSD) (41,78,79) or induced (IPS or other visual stimulations) (64,79) cor- tical event might, depending on the cortical or subcortical neural network threshold and on the speed and direction of propagation, result in a seizure, in migraine or in both. In exceptional cases (IEH), which occur almost exclusively in childhood, the subclinical focus might consist of an epileptic focus that activates the TVS, thereby inducing migraine without any other known cortical epileptic signs or symptoms (41,45,78,80).

Drug treatment

e hypothesis that migraine may be related to neurotransmitter or ion-channel dysfunctions makes it interesting to analyse the e ect of antiepileptic drugs (AEDs) on migraines. Several authors have demonstrated the e ectiveness of AEDs (i.e. valproate, topiramate) in preventing migraine attacks (81–83). AEDs reduce neuronal hyperexcitability by various mechanisms (84). Consequently, these results are consistent with the concept that hyperexcitability is re- sponsible for triggering aura and the subsequent headache. However, other AEDs, including phenytoin, oxcarbazepine, vigabatrin, and clonazepam, are not e ective in migraine prophylaxis (9). It is possible that AEDs that act primarily via use-dependent blocking of voltage-gated sodium channels, or that act via γ-aminobutyric acid- ergic (GABAergic) mechanisms, appear to in uence mechanisms that are not relevant to migraine (85).

e use of AEDs for migraine may also elucidate di erences be- tween epilepsy and migraine patients, warranting further studies. Firstly, migraine patients seldom experience remission from attacks when using these drugs, whereas in epilepsy the majority of patients will achieve remission on any AED. Furthermore, migraine patients

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tolerate AEDs less well. Luykx et al. systematically compared the pro le and frequency of adverse reactions to topiramate as reported in six migraine and four epilepsy randomized controlled trials (86). ey found both qualitative and quantitative di erences between the two patient populations. Migraineurs were more likely to drop out because of topiramate-related adverse responses, particularly in the 50 mg group, con rming the clinical impression that migrain- eurs are at higher risk of (unacceptable) adverse drug reactions than epilepsy patients.

Classi cation issues

Peri-ictal and interictal headache

Seizures and epilepsy syndromes are usually classi ed according to the guidelines of the International League Against Epilepsy (ILAE) (87), and headaches according to the International Classi cation of Headache Disorders (ICHD). e current version, the ICHD-3, was published in 2018 (88).

Seizure-related headaches (SRHAs) can be divided into peri-ictal (peri-IHA) and interictal headache (inter-IHA). peri-IHA can be divided into pre-ictal (PIHA), ictal (IHA) and postictal headache (post-IHA). PIHA headaches occur in 5–15% of cases, IHA in 3– 5%, post-IHA in 10–50% of cases, and inter-IHA in 25–60% (89,90). A recent study showed that only one-quarter of peri-IHA episodes can be classi ed according to the ICHD-3 criteria (91). e fact that there is still no consensus on the classi cation of epilepsy-related headaches emphasizes the need to get together experts from both the ILAE and the International Headache Society to come to such a consensus (92).

To date, only three speci c entities of seizure-related headaches are considered in the ICHD-3 classi cations (Box 12.1): hemicrania epileptica (7.6.1), post-HA (7.6.2), and migraine-triggered seizure (migralepsy) (1.5.5). Diagnostic criteria for the new entity ‘ictal epileptic headache’ (IEH) (Box 12.1) have recently been proposed (90).

Hemicrania epileptica/ictal headache

Hemicrania epileptica/ictal headache is recognized as an ipsilateral headache with migraine-like features occurring as an ictal manifest- ation of the seizure discharge. Diagnosis requires the simultaneous onset of headache with epileptiform EEG abnormalities (11).

In published cases, the duration of the ictal headache justi ed their classi cation as non-convulsive status epilepticus (SE) (21,45,65,78). Four patients showed occipital partial SE in the EEG (30,66–69), while bilateral continuous spike-and slow-wave discharges (i.e. ab- sence status) were reported in one case (67). Headache could be ipsi- or contralateral to the ictal epileptiform discharge (21,65–69).

Postictal headache

Post-IHA is the most frequent headache type associated with seiz- ures (93). It is de ned as a headache with features of tension-type headache or of migraine, which develops within 3 hours of a general- ized or partial seizure, and resolves within 72 hours a er the seizure (Box 12.1). Although it is common, occurring in about 50% of epi- leptic patients, it is o en neglected because of the dramatic impact of the preceding seizure. Post-IHA has been reported in patients with symptomatic epilepsy, but it is especially frequent in idiopathic oc- cipital seizures (25). It has been suggested that the seizure discharges

in the occipital lobes trigger a genuine migraine through CSD and activation of trigeminovascular or brainstem mechanisms (5,6).

Interictal headache

Inter-IHA is a headache not temporally related to a seizure. Verrotti et al. (18) analysed the prevalence of peri-IHA and inter-IHA and clinical characteristics and their temporal correlations with seizure onset in a large sample of newly diagnosed children and adoles- cents with idiopathic epilepsy. Post-IHAs and inter-IHAs were the most frequent (62% and 58%, respectively), as in adult studies, while PIHAs were found in only 30% (14,18,94–96). Regarding the burden of SRHA, paediatric studies showed that peri-IHAs were o en se- vere and long-lasting, especially in post-IHA.

Migraine-triggered seizure (migralepsy) and ictal epileptic headache

According to ICHD-2, migralepsy is a recognized complication of migraine (Table 1). Migralepsy does not exist in the classi cations of ILAE. e term ‘migralepsy’ is old, deriving from migra(ine) and (epi)lepsy, used for the rst time by Lennox and Lennox in 1960 (although they attributed it to Dr Douglas Davison), to describe a condition wherein ‘ophthalmic migraine with perhaps nausea and vomiting was followed by symptoms characteristic of epilepsy’ (9). However, most reported cases of ‘migralepsy’ do not allow the dissection of a meaningful and unequivocal migraine–epilepsy sequence (21,64).

ere are at least 50 potential cases of migralepsy reported in the literature (1–3,6,97–107), the majority of which have been the subject of criticism by several authors (11,78,97,106–108). In fact, the diagnosis in the majority of these cases is uncertain because the information available is not clear (38%), the cases do not ful l the current ICHD-3 criteria (30%), or the diagnosis is questionable (28%) (98). Indeed, most of the previous reports of ‘migralepsy’ may have been occipital seizures imitating MA (4,6,7,107–112).

Although unequivocal epileptiform abnormalities in patients with paroxysmal sensations or behavioural changes usually point to a diagnosis of epilepsy, the lack of clear ictal epileptic spike-wave ac- tivity is frequent in autonomic epilepsies, such as Panayiotopoulos syndrome (30,45). In such cases, ictal epileptic EEG activity might be recorded as unspeci c slow-wave abnormalities without any spike activity. Interestingly, there may, on rare occasions (2), be an isolated epileptic headache that has no associated ictal epileptic manifestations or scalp EEG abnormalities but whose ictal epileptic origin can be demonstrated by depth electrode studies (2). e epi- leptic focus that activates the TVS might thus remain purely auto- nomic (it being associated exclusively with migraine complaints), without ictal neuronal activation of non-autonomic cortical areas (di erent neuronal network thresholds appear to be involved); in this case, the focus fails to reach the symptomatogenic threshold required to induce sensory–motor manifestations, as has been de- scribed for other ictal autonomic manifestations in Panayiotopoulos syndrome (41,113).

IEH can be considered an autonomic form of epilepsy, like Panayiotopoulos syndrome (114). Accordingly, cases with long- lasting IEH episodes ful l the criteria to be considered as ‘autonomic status epilepticus’ (115).

Since 1983, 12 cases of IEH according to proposed criteria (Table 1) (35) have been reported (2,21,64,66,68,97,116,117). Parisi et al.

CHaPtEr 12 Migraine and epilepsy

Box 12.1 Classi cation of headache-related seizures (ICHD-3) and the original proposed criteria for ictal epileptic headache

1.4.4 Migraine aura-triggered seizure

Diagnostic criteria:

. A A seizure ful lling diagnostic criteria for one type of epileptic attack, and criterion B below.

. B Occurring in a patient with ‘1.2 Migraine with aura’, and during or within 1 hour after an attack of migraine with aura.

. C Not better accounted for by another ICHD-3 diagnosis.

7.6 Headache attributed to epileptic seizure

Coded elsewhere:

Where migraine-like or other headache and epilepsy are both part of a speci c brain disorder (e.g. MELAS), the headache is coded to that disorder. Where a seizure occurs during or immediately following a migraine aura, it is coded as ‘1.4.4 Migraine aura-triggered seizure’.

Description:

Headache caused by an epileptic seizure, occurring during and/or after the seizure and remitting spontaneously within hours or up to 3 days.

Diagnostic criteria:

. A Any headache ful lling criterion C.

. B The patient is having or has recently had an epileptic seizure.

. C Evidence of causation demonstrated by both of the following:

. 1 Headache has developed simultaneously with or soon after onset of the seizure

. 2 Headache has resolved spontaneously after the seizure has terminated.

. D Not better accounted for by another ICHD-3 diagnosis.

Comments:

Well-documented reports support recognition of the subtypes ‘7.6.1 Ictal epileptic headache’ and ‘7.6.2 Post-ictal headache’, according to their tem- poral association with the epileptic seizure.

Pre-ictal headache has also been described. In a small study of 11 pa- tients with intractable focal epilepsy, frontotemporal headache was ipsi- lateral to the focus in nine patients with temporal lobe epilepsy (TLE) and contralateral in one with TLE and one with frontal lobe epilepsy. More studies are needed to establish the existence of pre-ictal headache, and determine its prevalence and clinical features, in patients with partial and generalized epilepsy. Pre-ictal headache must also be distinguished from ‘1.4.4 Migraine aura-triggered seizure’.

7.6.1 Ictal epileptic headache

Previously used term:

Ictal headache.

Description:

Headache caused by and occurring during a partial epileptic seizure, ipsi- lateral to the epileptic discharge, and remitting immediately or soon after the seizure has terminated.

Diagnostic criteria:

. A Any headache ful lling criterion C.

. B The patient is having a partial epileptic seizure.

. C Evidence of causation demonstrated by both of the following:
1 Headache has developed simultaneously with onset of the partial seizure

2 Either or both of the following:
(a) headache is ipsilateral to the ictal discharge
(b) headache signi cantly improves or remits immediately after the

partial seizure has terminated.
Not better accounted for by another ICHD-3 diagnosis.

Comments:

‘7.6.1 Ictal epileptic headache’ may be followed by other epileptic mani- festations (motor, sensory, or autonomic).

This condition should be differentiated from ‘pure’ or ‘isolated’ ictal epi- leptic headache occurring as the sole epileptic manifestation and requiring differential diagnosis from other headache types.

‘Hemicrania epileptica’ (if con rmed to exist) is a very rare variant of ‘7.6.1 Ictal epileptic headache’ characterized by ipsilateral location of head- ache and ictal EEG paroxysms.

7.6.2 Post-ictal headache

Description:

Headache caused by and occurring within 3 hours of an epileptic seizure, and remitting spontaneously within 72 hours after seizure termination.

Diagnostic criteria:

. A Any headache ful lling criterion C.

. B The patient has recently had a partial or generalized epileptic seizure.

. C Evidence of causation demonstrated by both of the following:
1 Headache has developed within 3 hours after the epileptic seizure has terminated
2 Headache has resolved within 72 hours after the epileptic seizure has terminated.

. D Not better accounted for by another ICHD-3 diagnosis.

Comment:

‘7.6.2 Post-icatal headache’ occurs in > 40% of patients with either temporal lobe epilepsy or frontal lobe epilepsy and in up to 60% of patients with occipital lobe epilepsy. It occurs more frequently after generalized tonic- clonic seizures than other seizure types.

Original proposed criteria for ictal epileptic headache (IEH)

Diagnostic criteria A–D must all be ful lled to make a diagnosis of ‘IEH’: A Headache lasting minutes, hours or days.1
B Headache that is ipsilateral or contralateral to lateralized ictal

epileptiform EEG discharges (if EEG discharges are lateralized).
C Evidence of epileptiform (localized, lateralized, or generalized)2 dis- charges on scalp EEG concomitantly with headache; different types of EEG anomalies may be observed (generalized spike-and-wave or polyspike-and-wave, focal or generalized rhythmic activity or focal subcontinuous spikes or theta activity that may be intermingled with

sharp waves) with our without photoparoxysmal response.
D Headache resolves immediately (within a few minutes) after intra-

venous antiepileptic drugs.

Notes
1 A speci c headache pattern is not required (migraine with or without

aura, or tension-type headache are all admitted).
2 Any localization (frontal, temporal, parietal, occipital) is admitted.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

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(37) published 16 potential cases of IEH from a large multicentric neuropaediatric sample. All 16 patients displayed focal or general- ized ‘ictal EEG abnormalities’ during migraine attacks. A spike or spike-and-wave pattern was the most commonly observed EEG pat- tern, in both MA and MO, whereas EEG theta activity was, surpris- ingly, associated exclusively with MA or a ‘double migraine pattern’ in which MA and MO co-existed. Fourteen of 16 children displayed interictal EEG abnormalities. e use of ‘ictal epileptic headache’ (2,4) may be preferable to the term ‘ictal headache’, as suggested by Parisi et al. (36–40,118–121).

Conclusion

Epilepsy and migraine are both episodic functional disorders in which susceptible brain regions are hyperexcitable and attacks begin with hypersynchronous neuronal ring. e two disorders have a clinical, pathophysiological, molecular, and therapeutic overlap. In epilepsy and migraine, various factors can provoke attacks, but how these factors lead to neuronal hypersynchronous activity and the initiation of an attack is not understood. When CSD is the key event in a migraine attack, it is still unclear how a CSD relates to a seizure. e lack of a practical technique directly measuring CSD in humans makes studies addressing these questions di cult.

e association between migraine and epilepsy seems more ap- parent in children and adolescents, especially in genetic epilepsy syndromes such as juvenile myoclonic epilepsy and benign partial epilepsy of childhood with centrotemporal spikes/rolandic epilepsy. Aversion to visual stimuli, or triggering of attacks through ashes, occurs in both epilepsy and migraine. It is probable that shared gen- etic mechanisms are responsible for this. Epilepsy later in life is more o en related to (new) brain lesions than genetic factors, and there- fore the association between migraine and epilepsy may become less strong.

e clinical di erentiation between migraine and epilepsy is not always easy. Children, in particular, are likely to have autonomic symptomatology both in epilepsy and in headache attacks: they can have isolated, long-lasting ictal autonomic manifestations, while ictal autonomic manifestations (both in epilepsy and in headache) in adults are usually associated, simultaneously or sequentially, with other motor or sensory ictal signs and symptoms. Key unanswered questions are why some individuals are susceptible to migraine and others to epileptic seizures, and in those susceptible to both migraine and seizures, why attacks manifest as one or the other at di erent times.

e present classi cation of conditions in which headache and epilepsy are related (migralepsy, hemicrania epileptic, postictal headache) poses great challenges for the clinician. EEG recordings are not routinely done during presumed migraine attacks, and ictal headache will therefore remain an underdiagnosed condition (122). We are not convinced that the current literature provides clear evi- dence for the existence of a condition named ‘migralepsy’, where a migraine attack triggers a seizure.

erapeutic similarities and di erences between epilepsy and migraine raise interesting questions. AEDs act by in uencing neurotransmitter or ion-channel function in the brain, thus preventing abnormal depolarizations, and some have been shown to be e ective in both epilepsy and migraine. About 60% of patients

with epilepsy achieve remission, and no clear di erences in e cacy have been demonstrated between drugs with di erent mechan- isms of action. In migraine, however, complete remission is seldom achieved, and the mechanism of action seems to be related to e – cacy. Furthermore, tolerance to drug side e ects is better in epilepsy than in migraine.

e clari cation of these issues, as well as of the underlying mech- anisms between these two disorders, may allow both elds (epilepsy and headache) to learn lessons from each other, in order to improve clinical diagnosis and therapeutic strategies.

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127

Migraine and vertigo

Yoon-Hee Cha

Introduction

A relationship between migraine and vertigo has been acknow- ledged for over a millennium, with common references to vertigo and migraine dating back as early as the h century by the phys- ician Caelius Aurelianus to one of the fullest descriptions of this relationship by Edward Liveing in 1873 (1,2). Although the etymo- logical connection did not start out intentionally, the English word megrim at various points in history meant ‘hemicrania’, ‘dizziness (in humans)’, ‘low spirits’, and ‘vertigo (in animals)’ (3). However, it was only in the last 150 years that the systematic study of migraine- related symptoms have helped to clarify some of these associations.

In the modern day, vertigo as a symptom of migraine has re- ceived more formal recognition by the International Classi cation of Headache Disorders (ICHD), through its acceptance of ves- tibular migraine as a migraine subtype in the Appendix section in the third edition (2018) (4). e vestibular symptoms of migraine can be varied and complex, however, and a struggle within the dis- ciplines of neurotology and headache has been in setting limits on the spectrum of what is considered to be vertigo attributable to migraine—limits that have to be set without the availability of bio- logical markers. Like the careful delineation of aura symptoms over time, however, the detailed examination of vestibular symptoms in migraine may also contribute to the overall understanding of mi- graine physiology.

De nitions

Before embarking on a detailed discussion of migraine and vertigo, a clari cation needs to be made that many of the papers referenced in this section do not use the term ‘vertigo’ in the same way. e International Classi cation of Vestibular Disorders (ICVD) criteria set forth by the Committee for Classi cation of Vestibular Disorders of the Bárány Society de ned vertigo as the ‘the sensation of self- motion when no self-motion is occurring or the sensation of dis- torted self-motion during an otherwise normal head movement’ (5). is illusion may be internal or external, meaning that either the self or the environment may be perceived as moving. e term ver- tigo was then subdivided into either a ‘spinning’ illusion or a ‘non- spinning’ illusion. In contrast, dizziness was de ned as ‘a sense of

spatial disorientation without a false sense of motion’. ese de n- itions were set in 2009, a er most papers on migraine and vertigo had already been published.

Most of what is understood about the relationship between mi- graine and vertigo has been culled through a large body of literature that has used a variety of de nitions and terms (6,7). In some works, the term ‘vertigo’ was narrowly de ned as an illusion of actual spinning, whereas in others it has been more broadly used. In some, there was no clear de nition of vertigo given. In 2001, Neuhauser and colleagues published criteria for ‘migrainous vertigo’, de ning both a de nite and probable form (8). Although many researchers subsequently adopted the Neuhauser criteria in the last decade, a need to more precisely de ne a migraine–vertigo syndrome was recognized, leading to these recent de nitions. As more is learned about the pathophysiology of vestibular migraine, however, these clinical criteria will continue to evolve.

e term ‘vestibular migraine’ and its diagnostic criteria were es- tablished in a consensus paper between the Migraine Classi cation Subcommittee of the International Headache Society and the Bárány Society (9). Previous terminologies, such as ‘migraine vestibulopathy’, ‘migraine -associated vertigo’, ‘migraine-related ver- tigo’, and ‘migrainous vertigo’, were replaced. New criteria for what could fall under the de nition of vestibular migraine were devel- oped (Box 13.1).

ese de nitions are now included in Appendix A of ICHD-3, which speci cally adapted the de nition of vertigo from the ICVD. In adapting the de nition of vertigo from the ICVD, only speci c forms of vertigo were accepted as falling under the umbrella of ves- tibular migraine. Speci cally, spontaneous, head-motion-triggered, position-triggered, and visually triggered vertigo were accepted. Sound-induced and ‘other’ triggered symptoms such as those occurring a er passive motion, orthostatic changes, medications, heights, and so on, were speci cally excluded. In addition, only a diagnosis of de nite vestibular migraine was included (4).

Epidemiology

Given the recent changes in both the de nition and nomenclature of vestibular migraine, we would expect that what is understood to be the prevalence of vestibular migraine to change with time.

Recently, vestibular migraine was called ‘the most frequent entity of episodic vertigo’(10). Prevalence measurements may change owing to a growing recognition of the association between migraine and vertigo, and evolving understanding of the relationship between mi- graine and actual inner-ear disorders like Méniére disease and be- nign paroxysmal positional vertigo.

Despite these quali cations, and the range of prevalence statis- tics cited for vestibular symptoms in migraine, there is unequivocal support for a variety of vestibular symptoms being more common in people su ering from migraine headache than those without. Up to 50–70% of patients with migraine have been reported to su er from recurrent episodes of dizziness, with about 9–13% experiencing actual vertigo during migraine headaches (11–13). e spectrum of vestibular symptoms experienced by patients with migraine in- cludes spinning vertigo, imbalance, head motion intolerance, visual sensitivity, or motion sickness.

‘Vestibular vertigo’, de ned as rotational vertigo that can be spon- taneous or position triggered, or recurrent dizziness with nausea and oscillopsia or imbalance, has been reported at a lifetime preva- lence of 7.4% and a 1-year prevalence of 4.9% in a telephone survey involving about a 1000 German citizens (14). In a follow-up analysis

of the same population, 3.2% were found to experience both mi- graine and vertigo in their lifetimes and about 1% speci cally met the Neuhauser criteria for migrainous vertigo (15). is is about three times greater than what would be expected by chance. In diz- ziness clinics, the prevalence of migraine is higher than population baseline; in headache clinics, the prevalence of dizziness is higher than in controls (8).

Natural history

Vertigo associated with migraine appears to follow two di erent life- time courses. In the earliest manifestation, a child between the age of 4 and 8 years develops recurrent, usually short episodes of severe dizziness and imbalance. e term benign paroxysmal vertigo was rst used by Basser to describe this syndrome (16). As very young children o en cannot describe their experiences, the combination of severe imbalance with expressions of fear were inferred to be what adults experience as vertigo. In some cases, the child exhibits nys- tagmus during the episode. In most cases, the episodes last in the order of minutes, but spells that last hours or even days have been reported (17). Despite the term ‘paroxysmal’ a large proportion of these episodes of vertigo follow a known trigger such as stress, fever, motion, or fatigue (17,18). e association between benign parox- ysmal vertigo of childhood and migraine was formally recognized by Fenichel in 1967, and is one of the classical childhood precursors to migraine headaches (19). Whether these children are at higher risk of going on to develop vertigo episodes in adulthood is unknown, but up to 50% of patients in a long-term study were shown to experience continued vertigo into adolescence, and occasionally into adulthood (17). Longer follow-up studies are needed to determine the subse- quent burden of vertigo in this population when they become adults.

e second association involves patients with a previous history of migraine headaches, typically starting in adolescence or young adult- hood, who subsequently develop episodic vertigo attacks roughly a decade a er the headaches start (20,21). In some cases, the vertigo attacks start a er migraine headaches have started to decrease, ob- scuring the association. Vertigo episodes generally decrease with age; new-onset episodic vertigo attributable to migraine appears to be quite uncommon a er the age of 50 years (8,21–23). Given the peak age of onset of Ménière disease in the h and sixth decades of life and the common occurrence of migraine symptoms during Ménière episodes, ruling out Meniere disease is warranted in the older age group (24).

Genetics

A genetic basis for isolated vestibular migraine in the absence of hearing loss or other causes of imbalance is unknown. However, episodic vertigo, as well as migraine headaches, are much more common in blood relatives of probands with migraine and ver- tigo than in unrelated spouses (23). Despite the frequency of mi- graine in patients with spontaneous episodic vertigo, there is so far no evidence that genes implicated in familial hemiplegic migraine (CACNA1A, ATP1A2, SCN1A) are involved in vestibular migraine, even in cases of clear autosomal dominant inheritance (25,26).

To date, there has been one case in which a genetic locus has been identi ed in familial vestibular migraine. A 12.0-Mb region on

CHaPtEr 13 Migraine and vertigo

Box 13.1 Vestibular migraine

. A At least ve episodes ful lling criteria C and D.

. B A current or past history of Migraine without aura or Migraine
with aura.

. C Vestibular symptoms of moderate or severe intensity, lasting be-
tween 5 minutes and 72 hours.

. D At least half of episodes are associated with at least one of the fol-
lowing three migrainous features:
1 Headache with at least two of the following four characteristics:
(a) unilaterallocation (b) pulsatingquality

2 Photophobia and phonophobia

3 Visual aura
E Not better accounted for by another ICHD-3 diagnosis or by an-

other vestibular disorder.

Notes:

1 Code also for the underlying migraine diagnosis.
2 Vestibular symptoms, as de ned by the Bárány Society’s

Classi cation of Vestibular Symptoms and qualifying for a diagnosis of A1.6.6 Vestibular Migraine include:

. (a) Spontaneous vertigo:

• internal vertigo (a false sensation of self-motion);

• external vertigo (a false sensation that the visual surround is
spinning or owing)

. (b) Positional vertigo, occurring after a change of head position

. (c) Visually induced vertigo, triggered by a complex or large moving
visual stimulus

. (d) Head motion-induced vertigo, occurring during head motion

. (e) Head motion-induced dizziness with nausea, dizziness is charac-
terized by a sensation of disturbed spatial orientation.*

*Other forms of dizziness are currently not included in the classi cation of vestibular migraine.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

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chromosome 5q35 with a linkage disequilibrium score of 4.21 was found in a 23-member family in which 10 were diagnosed with mi- grainous vertigo (27). No gene has been identi ed in this pedigree and the study has not been replicated. Identity by descent analysis has revealed a possible shared haplotype on chromosome 11q in six of seven a ected members of a family with migraine-associated vertigo, but most of these individuals would not meet the current criteria for vestibular migraine (28). Similarly, only a subset of 20 families with benign recurrent vertigo showed linkage to chromo- some 22q12 (29). Although 79% of the participants in this study were diagnosed with migraine, the migraine phenotype by itself did not show linkage to this locus. Genome-wide association studies speci cally addressing whether progesterone or oestrogen receptor variants may be di erent in patients with migraine and vertigo versus those with migraine alone revealed one signi cant single nu- cleotide polymorphism di erence in the PROGINs variant of the progesterone receptor in those with migraine and vertigo (30).

Familial aggregation of episodic vestibular syndromes in the con- text of migraine have been described. A family with a history of mi- graine headaches, essential tremor, episodic vertigo, and, in some cases, actual Ménière disease has been reported. Several members of this pedigree responded well to acetazolamide, but a genetic locus was not found (31). One study reported episodic vertigo spells in identical twins, only one of which experienced hearing loss con- sistent with Ménière disease though both experienced migraine headaches and multiple other family members experienced vertigo and migraine (32).

Given the high frequency of concurrent migraine symptoms with Ménière disease, it may be expected that a genetic susceptibility locus for Ménière disease may also help to elucidate a locus for vestibular migraine. However, of the >20 loci that have been reported for both sporadic and familial Ménière disease, only one has been replicated (33). is locus is in COCH gene, mutations in which can cause DFNA9 (autsomal dominant nonsyndromic sensorineural deafness 9). DFNA9 is associated with progressive sensorineural hearing loss and vestibular dysfunction but is not associated with migraine (34).

Episodic vertigo is frequently a symptom of episodic ataxia, in some cases overlapping with migraine headache. e episodic ataxias are a group of paroxysmal disorders of cerebellar dysfunction in which attacks consist of severe imbalance and dysarthria with variable oc- currence of nystagmus or myokymia. Episodic ataxia type 2 (EA2), caused by nonsense mutations in the voltage-gated calcium channel gene CACNA1A, is characterized by prolonged attacks of global cere- bellar dysfunction (nystagmus, dysarthria, truncal and limb ataxia), during which vertigo can be a prominent symptom (35). A history of migraine headaches is seen in over half of patients with EA2, which is consistent with EA2 and familial hemiplegic migraine type 1 being allelic disorders (36). Clinical descriptions of EA types 1, 3, 4, and 7 have included vertigo without an association with migraine (37–41).

Neurochemical links

Both direct anatomical connections between the vestibular and tri- geminal nuclei in the brainstem, as well as shared neurochemical properties within the two systems, support the clinical observation of the co-occurrence of pain and vertigo and the usefulness of some migraine medications in treating episodic vestibular symptoms.

Experimental studies that attempt to co-activate the two systems have shown that inducing facial pain during a motion stimulus en- hances nausea, and creating visual vertigo with optokinetic stimu- lation enhances both facial and body pain sensitivity (42–44). Both monosynaptic pathways between the inferior and medial vestibular brainstem nuclei that synapse with trigeminal nuclei (ipsilaterally and contralaterally) have been described, as well as more elab- orate indirect pathways that involve connections between speci c subnuclei of both the trigeminal and vestibular systems (45).

Given these close anatomical connections, it is not surprising that similar neurotransmitter receptors are expressed on trigeminal and vestibular ganglion neurons. e main target of triptans—5- hydroxytryptamine (5-HT) receptors 5-HT1B, 5-HT1D, and 5-HT1F— are also expressed on both vestibular and spiral (cochlear) ganglion cells. 5-HT1D and 5-HT1F receptors are speci cally expressed on the crista ampullaris of the horizontal semi-circular canal (46). ese serotonergic receptors are heavily expressed on arterioles within the vestibular and spiral ganglia (46). is may be one mech- anism through which triptans can be used to treat both vertigo and headache (47).

Other ligand-gated channels shared by the two systems in- clude transient receptor potential vanilloid 1 (TRPV1), substance P, calretinin, calcitonin gene-related peptide (CGRP), and the purinergic receptor P2X3 (48). CGRP receptors are speci cally lo- cated on vestibular e erent terminals (49). One theory regarding the vestibular e erent system is that it functions to regulate the gain of the a erent system (50). Adding CGRP to the lateral line of frogs (a primitive vestibular organ) increases the spontaneous a erent ring rate but reduces the a erent response to cupular de ection (51). us, the extravasation of CGRP by pain-a erent terminals during a migraine headache may a ect the sensitivity of vestibular a erents. eoretically, this may lead to true vertigo or intolerance to head motion (52). Similarly, the presence of carbonic anhydrase activity in the epithelial cells surrounding the crista ampullaris and within the supporting cells that surround hair cells may represent a pathway through which drugs like topiramate or acetazolamide may be able to a ect vestibular tone and prevent vertigo attacks (31,53–55).

Clinical presentation

A patient with recurrent episodes of vertigo for which migraine is a relevant risk factor may present with vertigo spells in the context of a migraine headache or separate from the migraine headache. Even if a history of migraine headaches is the clear risk factor, a diagnosis of vestibular migraine can only be made if at least two of the epi- sodes of vertigo have occurred temporally with the migraine head- ache (4). is will present a problem in some cases, particularly in men who may not have a personal history of migraine headaches, but whose episodic vertigo attacks behave qualitatively like migraine headaches in terms of triggers, duration, or response to medications. ese patients usually have a strong history of migraine headaches in female rst-degree relatives (21). Roughly, 5–25% of patients with vertigo and migraines always experience them together, whereas at least two-thirds of patients will experience some vertigo spells with headache and some without (11,20,21,23,52).

Patients may present with aura and migraine as part of the migraine with brainstem aura diagnosis, a new entity in ICHD-3, which took

the place of the term basilar-artery-type migraine. In every study of episodic vertigo attributable to migraine, only a minority of patients has been found to meet criteria for what was previously termed basilar-artery-type or basilar-artery migraine. is is mainly because the vestibular symptoms in migraine usually follow a less predictable temporal course than visual aura, are not limited to the 5–60-minute range used to de ne aura, and frequently occur without headache. Although the vertigo in migraine can range from seconds to days, the most common duration is hours to days. Migraine visual aura, however, appears to occur more frequently in patients who also ex- perience vertigo than those who do not (8,13,20,21).

Clinical examination

e examination of a patient with vestibular migraine is most likely to be completely normal. However, both ictal and interictal ocular motor abnormalities can occur in migraine. ese include positional nystagmus that can be horizontal, vertical, or mixed. Nystagmus can be spontaneous or be inducible by head shaking or positional changes. e nystagmus can show either a peripheral or central pattern, or be indeterminant, even in expert hands (56,57). Head-shaking nystagmus can, at times, be ‘perverted’, meaning that horizontal headshaking can cause vertical nystagmus in migraine, indicating abnormal cross-coupling of head motion information in the brainstem (58). e positional nystagmus, however, is not typ- ical of benign paroxysmal positional vertigo, which occurs in a burst and fatigues.

Ictal downbeat nystagmus has been described in vestibular mi- graine, which usually localizes to the caudal cerebellum or brainstem (56,59). It should be noted, however, that headache and positional downbeat nystagmus can occur from caudal cerebellar and brain- stem lesions (60–62). None of the ocular abnormalities in vestibular migraine should be associated with any other central abnormalities such as ataxia or lateralized neurological de cits. erefore, a careful evaluation for other neurological signs and symptoms should be made in cases that include central ocular abnormalities and not be presumed to be from vestibular migraine.

related disorders

Ménière disease

Early in the course of vestibular migraine, it may be di cult, if not impossible, to distinguish from Ménière disease. Triggers and dur- ation can be quite similar between the two (63). Factors that con- tribute to this di culty are that Ménière disease typically occurs in mid-adulthood with age at onset in the range of 38–50 years (64,65). e onset of episodic vertigo from migraine typically follows the onset of migraine headache by about a decade, which is close to the lower end of the Ménière age range.

Auditory symptoms such as a feeling of fullness in the ear and tin- nitus can occur as part of the migraine syndrome, but it is decidedly uncommon for hearing loss to occur in the context of migraine or for migraine to be associated with progressive hearing loss (66,67). It should be noted, however, that if a patient with recurrent vertigo spells developed a persistent low-frequency hearing loss, they would

be diagnosed with Ménière disease regardless of the association with migraine headache. In case series that have noted some pro- gression of hearing loss in vestibular migraine, it has usually been high-frequency sensorineural loss, as seen in ageing. However, there have also been cases of low-frequency hearing loss that were con- sidered to meet criteria for atypical Ménière disease, without further clari cation of what was atypical in those cases (68).

Complicating the picture further is that Ménière attacks them- selves can be associated with severe headache that meet criteria for migraine. One study showed that 56% of patients with Ménière dis- ease had a personal history of migraine and 45% of the attacks ex- perienced by these patients were associated with other symptoms that could be attributable to migraine. In addition to headache, this included photophobia, phonophobia, and even visual aura (24). e baseline prevalence of migraine in patients with Ménière disease has been reported to be in a range that includes no higher than popula- tion baseline to over twice that of population baseline (24,69). What appears to be relevant, however, is that patients with a dual history of migraine and Ménière disease tend to present earlier, with a higher tendency for bilateral disease, and a stronger family history of re- current vertigo (70–72). Genetically identical twins can have one twin a ected with Ménière disease and migraine, and the other with episodic vertigo and migraine (32). erefore, there may, in fact, be more of a continuum in the pathological basis of vestibular migraine and Ménière disease than a clean distinction.

Benign paroxysmal positional vertigo

Patients with migraine have been noted to experience a higher fre- quency of typical benign paroxysmal positional vertigo (BPPV), as well as experiencing BPPV at an earlier age than people without mi- graine (73,74). However, positional vertigo that is not BPPV is also part of the vestibular migraine spectrum. Patients with true BPPV may complain of head and neck pain or sti ness, which should not be confused with migraine.

e positional nystagmus of posterior canal BPPV (the variant in 90% of cases) is a burst of torsional upbeat nystagmus beating toward the lower ear during positional testing. e nystagmus starts a er a short delay and typically does not last for more than 20 seconds and is e ectively treated with the canalith repositioning maneuver (75). In contrast, the positional nystagmus noted in both ictal and interictal vestibular migraine has been noted to be of either a central or peripheral type, but usually has more of a cen- tral pattern. One hallmark feature of nystagmus in vestibular mi- graine is that it is persistent during the entire time that the head is lowered, occurs without a delay, and does not fatigue with repeated positioning (56).

Diagnostic testing

Caloric testing

Vestibular function testing in migraine may be abnormal with or without the presence of vertigo; in some clinical case series, up to 24% of the patients with migraine were reported to have abnormal caloric responses (11,20,52,76–79). In basilar artery migraine, the rate of unilateral paresis is reported to be as high as 60% and the rate of bilateral vestibular paresis as 12% (80,81).

CHaPtEr 13 Migraine and vertigo

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e degree of caloric paresis in vestibular migraine is typically mild and very uncommonly exceeds a 50% asymmetry. Very high degrees of caloric paresis should raise concerns that either there was a problem with the testing (e.g. poor irrigation due to a narrow external canal), or that there is an alternative diagnosis. However, follow-up studies in patients with vestibular migraine show that this disorder can be progressive and be uncommonly associated with bi- lateral vestibular dysfunction (68).

Vestibular hyper-responsiveness has also been reported in both case–control and longitudinal studies (58,82). ese cases are less frequently reported than cases of vestibular hyporesponsiveness. However, they may be in line with a clinical nding that patients who were de ned to have de nite migrainous vertigo by the Neuhauser criteria, were much less tolerant of vestibular stimulation during cal- oric testing, and tended to have a stronger history of motion sickness than those with non-migrainous dizziness (58,83).

Vestibular evoked myogenic potentials

e vestibular evoked myogenic potential (VEMP) exam is a test of the otolith–cervical re ex arc and provides complementary in- formation to traditional caloric testing. In caloric testing, the warm and cold water stimulus to the external ear canal changes the dir- ection of endolymph ow in the horizontal semi-circular canal. is de ects the cupula of the horizontal canal either in the dir- ection of the utricle (stimulates) or away (inhibits). is mechan- ical information is translated into an electrical impulse by the hair cells of the cupula, which travels along the superior branch of the vestibular nerve.

In the VEMP test, a loud sound stimulus in the order of 90–110 dB is presented to the external ear, which stimulates the saccule (an otolith organ) and triggers a saccule–sternocleidomastoid inhibi- tory re ex. e a erent arc of this re ex travels along the inferior branch of the vestibular nerve (84). e VEMP test has typically been reported as being normal in migraine and vestibular migraine, but a few case series have shown that VEMP responses can show low amplitude, long latency, or even be absent in migraine, particularly in those with migraine with brainstem aura (85–88). To some de- gree, some of the variability in the reporting of VEMP responses in migraine-related disorders may be due to di erences in techniques between vestibular laboratories, as some use higher sound stimuli than others.

Low-amplitude and absent VEMP responses have been shown to be features of migraine, regardless of the presence of vestibular symptoms (87,89,90). erefore, VEMPs are not a useful test in determining whether vestibular symptoms can be attributed to a migraine syndrome in a patient with pre-existing migraine. VEMPs, however, have been used in research settings to show that migraine is associated with a lack of the normal habituation to repeated sound stimulation typically seen in patients without migraine (89–91).

audiograms

Audiograms are generally normal in cases of migraine-associated dizziness syndromes that do not clearly t the criteria of Ménière disease (11,67). Hearing function can decrease with time in ves- tibular migraine, but usually involves typical high-frequency hearing loss. In cases in which low-frequency loss has also devel- oped, they are considered to be atypical for Ménière disease (68). Hearing thresholds during migraine headaches have been shown to

both improve and decline relative to baseline hearing levels (56,92). Hearing loss in what was previously known as migraine with brain- stem aura is quite common, noted to be as high as 46% bilaterally and 34% unilaterally (81).

Otoacoustic emissions

Otoacoustic emissions are most commonly used in newborn hearing screening but can also be useful in adults as an additional marker of the intactness of the connection between the cochlear nerve and the inferior colliculi (93). Research on the use of otoacoustic emissions has revealed important di erences in the central processing of audi- tory information in patients with migraine.

When sound energy is transmitted to the inner ear, the cilia of the outer hair cells de ect and emit a tiny fraction of that energy back out of the ear. is tiny otoacoustic emission can be detected by an in-ear microphone (94). When sound is presented to the contralat- eral ear at the same time, the otoacoustic emission of the ipsilat- eral ear decreases. In both migraine and vestibular migraine, there is evidence that baseline otoacoustic emissions are low or absent, suggesting peripheral cochlear injury (95,96). ere is also evidence of less suppression of ipsilateral otoacoustic emissions with contra- lateral stimuli, as well as greater variation in suppression, suggesting impairment of central modulation of sound in migraine, regardless of the presence of vestibular symptoms (95,96).

Words of caution

While the growing recognition of vestibular migraine as a frequent and important cause of vestibular symptoms is important and wel- come, it is equally important to recognize when vestibular symp- toms do not t this pattern. e following are some guidelines of when to consider an alternate diagnosis before presuming a diag- nosis of vestibular migraine.

1. Patients who complain of baseline imbalance early in the course of their disorder
Vestibular migraine is an episodic disorder in which patients should largely be normal in between episodes. One caveat is that patients with migraine o en perceive their imbalance to be worse than objective ndings indicate (82,97,98). Although mild degrees of balance impairment have been noted interictally in patients with migraine, regardless of whether they also ex- perience vertigo, if chronic balance problems present close to the onset of vestibular symptoms, a careful evaluation for other causes should be performed. For example, patients who experi- ence a severe episode of rotational vertigo lasting for several hours or more and take more than several days to recover should undergo a thorough evaluation for an inner ear disorder.

2. Head motion-triggered symptoms that have a clear side predominance
If symptoms are clearly worse when turning the head to one side versus the other, vestibular function testing should be per- formed to evaluate a peripheral lesion. If normal, lesions along the central vestibular pathways including the cerebellum should be considered.

3. Symptoms that are associated with strict unilateral pain in the face or neck.

is clinical feature should raise concerns for a structural lesion, such as seen in thoracic outlet syndrome, skull-based tumours, vestibular paroxysmia, and complex regional pain syndrome all present with unilateral facial pain and episodic vertigo.

4. Episodic vertigo associated with any auditory symptoms such as hearing loss, ear fullness, tinnitus, or sound-triggered symptoms
is symptom complex should trigger a thorough evaluation for an inner ear disorder and may require a referral to an otolaryn- gologist. ese symptoms should start an evaluation for Ménière disease or, in the right clinical context such as barotrauma, a perilymphatic stula. In most cases, the auditory abnormalities in inner-ear disorders will be unilateral.

5. Vertigo episodes that are associated with central ocular abnormalities
Although some studies of patients with vestibular migraine have documented central types of ocular abnormalities, including downbeat nystagmus, this is not the norm in vestibular mi- graine. Interictal central ocular abnormalities like downbeat, upbeat, pure torsional, or gaze-evoked nystagmus should invoke concern for a di erent central cause.

Management

abortive treatment

Patients with migraine experience episodes of acute attacks of ver- tigo, as well as less pronounced vestibular disturbance in between vertigo attacks, such as a tendency toward motion sickness and sen- sitivity to visual motion. erefore, a multipronged treatment ap- proach is required.

When the vertigo spells occur, they can be quite debilitating and can take the form of true rotational vertigo, positional dizziness, oscillopsia, or imbalance with nausea. Depending on the symptom and duration, pharmacological intervention may be warranted. Spells that last less than 20 minutes are generally too short for pharmacological treatment, but most vestibular symptoms in ves- tibular migraine will last on the order of hours. Vestibular suppres- sants such as promethazine, prochlorperazine, or metoclopramide at standard doses are good rst-line agents.

There is relatively less experience in the use of triptans spe- cifically for vestibular symptoms, but the available evidence in- dicates that they are safe to use using the same guidelines as for headache treatment and can be effective for both vertigo and headache (47). Rizatriptan has been shown to help alleviate ro- tational chair-induced motion sickness but not visually-induced motion sickness (99,100). Zolmitriptan was used in a clinical trial of migrainous vertigo, but it was underpowered to detect a clinical difference given that only 10 participants were re- cruited in this placebo controlled trial. However, there were no medication-related side effects noted in its use in treating mi- grainous vertigo (101).

e vestibular symptoms of migraine usually do not follow the pattern observed for the aura phase of migraine, which makes timing of medication use speci cally for the vestibular symptoms challenging. Most patients will experience some episodes of vertigo without accompanying migraine symptoms. In cases in which the

spell comes on suddenly and severely, the use of orally disintegrating medication (e.g. sublingual lorazepam), rectal dosing (e.g. prochlor- perazine or promethazine), or even cutaneous dosing can be con- sidered (e.g. topical promethazine). Cutaneous dosing tends to be slower and less predictable, however.

Preventative treatment

Preventative treatments for vestibular migraine have generally been similar to those used for migraine headache, starting with recog- nition and avoidance of triggers. Stress, dehydration, hormonal changes, certain foods, barometric pressure changes, have all been described as triggers for vertigo spells, although none is speci c enough to be used as part of the diagnostic criteria for vestibular migraine (9).

ere is no evidence from any randomized controlled trials for medications in the preventative treatment of vestibular migraine (102). Similar to the treatment of migraine headache, however, the choice of medication o en depends on concurrent issues such as sleep disturbance, mood disorder, or gastrointestinal tolerance. Tricyclic amines, beta blockers, calcium channel blockers, anticon- vulsants, and benzodiazepines have all been used successfully in the treatment of vestibular migraine (77,103,104). e anticonvulsants topiramate and lamotrigine have been studied in small trials for their e cacy in vestibular migraine (55,105). In the case of topiramate, 50 mg daily was found to be as e ective as 100 mg, with fewer side e ects (55).

Some notable di erences in the treatment of headache versus vertigo are that calcium channel blockers are more frequently used successfully in the treatment of episodic vertigo than head- ache (20,106–108). Studies outside of the United States have used unarizine, lomerizine, and a combination of cinnarizine plus dimenhydrinate, which all have calcium channel blocking properties (20,107,109–111). In the United States, there are re- ported bene ts with other calcium channel blockers (verapamil, diltiazem, amlodipine, nifedipine) (103). It should be noted, how- ever, that calcium channel blocking may be only one of many mechanisms of these medications and it is unclear whether the treatment e ect is directly related to the action on calcium channels.

e carbonic anhydrase inhibitor acetazolamide can be quite ef- fective in treating recurrent vertigo, but its e ect on migraine head- ache is unclear owing to a paucity of literature on its use in migraine and indications that it is not well tolerated by patients with migraine (112–113). In the neurological realm, it has proven to be the most useful in EA2, a disorder of recurrent cerebellar dysfunction that is frequently associated with migraine headaches (35). Its use in the clinical scenario of recurrent vertigo and migraine was introduced by Baloh (31), who described its e cacy in a family with recurrent vertigo, migraine, and essential tremor. Whether the mechanism of action is due to its diuretic e ect, as a driver of metabolic acidosis, its action on inner-ear hair cells and supporting cells, or some other mechanism, is unknown.

When acetazolamide is used to treat vertigo spells, it should be started at a much lower dose than what is typically used to prevent altitude sickness or treat glaucoma (which starts at 250 mg twice daily or three times daily). Patients with migraine appear to have particular sensitivity to bothersome paraesthesia with this medica- tion (112, 113). e consumption of citric juices to help counteract

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the alkalization of urine that promotes the formation of kidney

stones may help.

rehabilitation

ere are situations in which a course of physical therapy may be helpful in patients with vestibular migraine, even if they do not have evidence of inner-ear injury. For some patients, desensitiza- tion to head movement-induced dizziness and visually induced dizziness, as well as strength and gait training, can be bene cial (114,115). Patients with migraine may also perceive their imbal- ance to be greater than how they perform on balance tests (116,117). Regaining con dence in walking by learning techniques to avoid falling during dizzy spells may help patients regain the sense of con- trol they need to prevent fear of falling from becoming a distraction. ere is also a known comorbidity between anxiety disorder, mi- graine, and dizziness, a syndrome termed ‘migraine anxiety-related dizziness’ (or MARD) (118). e anxiety component is important to address because patients with vestibular migraine score higher on anxiety scales, which limits their prognoses for recovery (119,120). Vestibular migraine is recognised as one of the severe potential trig- gers for the development of persistent postural-perceptual diagnosis, a disorder of chronic imbalance and dizzeiness that is worsened by upright posture and visual motion (121). Rehabilitation along with psychological support can play a strong role in managing the interictal symptoms that contribute to overall morbidity and limit quality of life in patients with migraine and vertigo.

Conclusion

Converging lines of evidence from epidemiological, anatomical, neurochemical, and therapeutic experience in treating patients with migraine and vertigo support a close association between the two phenomena. A complete understanding of one phenomenon is not possible without accounting for the behaviour of the other. It is hopeful that the establishment of criteria for vestibular migraine and the inclusion of vestibular migraine in the ICHD Appendix will facilitate the exploration of the link between migraine and vertigo.

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Treatment and management of migraine Acute
Miguel J. A. Láinez and Veselina T. Grozeva

Introduction

Migraine is a highly prevalent and debilitating primary headache, presenting with recurrent pain attacks, associated symptoms of vegetative disturbance, and hypersensitivity of various functional systems of the central nervous system (1,2). e disease is typically characterized by severe headache attacks, lasting from 1 to 3 days, associated with nausea, vomiting, photophobia, phonophobia (migraine without aura), and, in 20–25% of patients, with neuro- logical aura symptoms (migraine with aura) (3). Migraine can be very disabling and it is a disorder usually underdiagnosed and suboptimally treated worldwide (4–7). Migraine has a huge social and economic impact and an appropriate treatment should be ad- dressed to improve patients’ symptoms and diminish the patients’ temporary disability (lost time at work or school; inability to per- form household work, and to take part in social and leisure activ- ities, or to spend time with family; emergency department visits) in a cost-e ective way and with a minimal recurrence rate and adverse e ects (3).

An e ective migraine treatment should be started only when the correct diagnosis is reached, according to the International Classi cation of Headache Disorders-3 criteria (8). All national and international guidelines recommend making a plan of care based on the patient’s preferences and expectations (9–14). A thorough explanation should be o ered by the clinician, ruling out all the al- ternative life-threatening conditions that the patient is concerned about. It has to be made clear to patients that their headache is not caused by a structural disorder (15).

An appropriate treatment consists of pharmacological agents along with the integration of non-pharmacological approaches. Avoidance of triggers such as stress, alcoholic beverages, insu – cient sleep, some speci c foods, frequent travelling/jet lag, skipping meals, and so on, should be recommended (16). Other triggers such as changes in weather conditions and temperature, or hormonal changes in women, are not controllable by the patient (see also Chapter 7). For monitoring progression of disease and acute treat- ment a er initiating therapy, a headache diary could be very useful.

Triggers and potential triggers, headache frequency, intensity, and medication usage should be recorded by the patient (10,15).

Other important non-pharmacological approaches include re- laxation training, biofeedback, and lifestyle modi cation (getting adequate sleep and exercise, stopping smoking, avoiding alcoholic beverages) can signi cantly impact a patient’s overall headache disability (10). During an acute attack some non-pharmacological measures are useful and could help some patients: avoidance of un- comfortable sensory stimuli, rest in a dark and quiet room, ice packs over the head or applying pressure over the super cial temporary artery on the same side as the pain (15).

Goals of management and treatment

Although, migraine cannot be cured, it can be e ectively managed in most cases (11). Periodic follow-up of medical management is re- quired. At each visit, doctors should discuss with patients all bene ts and side e ects of the treatment. e patient’s headache diary should be examined carefully. Education of migraine su erers about their condition and its treatment is crucial part of the management of this disease (9–15).

Two di erent pharmacological strategies are available for treating and preventing this troublesome disorder—abortive/acute and prophylactic. Both approaches are o en needed for patients with frequent and severe migraine attacks (9–15). Acute headache medi- cation is the best option in patients with infrequent attacks and/or bad compliance. In most cases, if the patient has infrequent attacks and is well controlled by acute treatment, preventive medication is not needed (10). e aim of acute medications is to relieve or stop the progression of the attack, eliminating the pain and associated symptoms. It is very important to individualize the treatment and develop a treatment strategy taking into consideration all factors such as co-existent illnesses, the patient’s age, type of migraine, se- verity and disability of the attacks, and associated symptoms (Box 14.1). Medication choice for a patient with migraine must be al- ways individualized. ere are two basic strategies for the acute

treatment of migraine: step care and strati ed care. In step care we recommend that drugs across or within attacks are escalated from simple analgesics to speci c migraine therapies. Strati ed care bases treatment selection on an initial assessment of illness severity. e strati ed care approach is associated with better acute treat- ment e cacy and may be the most appropriate for many patients with severe migraine attacks (17). Treatment selection is based on the patient’s headache characteristics, including frequency, severity of attacks, associated symptoms such as nausea and vomiting, and extent of disability (using instruments like the Migraine Disability Assessment Questionnaire) (17,18). Migraineurs with minimal or no disability may be well controlled only by non-speci c treatment, while patients with signi cant disability may be prescribed a speci c acute and/or preventive treatment medications (10,14).

Medication for an acute attack can be speci c or non-speci c. Speci c medication is useful only for migraine attacks, and non- speci c medication can also control other pain disorders. Migraine- speci c agents include ergotamine, (dihydroergotamine (DHE)) and triptans. Non-speci c agents are non-steroidal anti-in ammatory drugs (NSAIDs), combined analgesics, antiemetics, opioids, and corticosteroids. Non-speci c agents (NSAIDs, combined analgesics, and antiemetics) are indicated for mild or moderate attacks. Speci c agents are used for the treatment of moderate-to-severe migraine and in patients whose mild-to-moderate migraine responds poorly to NSAIDS or combined analgesics. When choosing medication, it is also very important to select an adequate formulation and route of administration, based on severity of the attack, need for rapid relief, or the presence or absence of nausea or vomiting. In the cases with severe nausea or vomiting a non-oral route and antiemetic medica- tion are recommended (10).

In the selection of the drug, treatment attributes (19) and prefer- ences of the patients are also important (20). For doctors, the e cacy attributes are more important than tolerability or consistency (19). For patients, the most important attributes of a migraine medica- tion are complete relief of pain, lack of recurrence, and rapid onset of pain relief. Consistency and lack of adverse events are also con- sidered of great importance.

Another key question is when to start the treatment of the mi- graine attack (21). e evidence supporting early application comes from studies of triptans. A er the rst study with sumatriptan (22), which showed that early treatment is associated with better pain- free rates, data con rming this strategy were published for almost all the triptans. is treatment approach has been also positive when combining triptans with NSAIDs (23), and seems to be cost- e ective (24). e pain-free e cacy of triptan therapy is enhanced

when treating mild attacks versus moderate-to-severe attacks. erefore, treating the attack when the pain is mild improves treat- ment e cacy. Some controversies remain regarding the initiation of treatment during the mild phase of a migraine episode. For ex- ample, the early treatment approach may not be suitable for all migraine su erers, as attacks are highly variable and tension-type headache commonly co-occurs. However, early intervention can improve treatment outcomes and prevent central sensitization and attack progression. It can also increase patient satisfaction (21). One of the disadvantages of this strategy is that it can induce frequent intake of medications and increase the risk of medication overuse. Medication overuse headache has to be prevented. Acute headache medication overuse o en causes treatment failure; for this purpose it is crucial to educate the patient how to use acute agents. To avoid medication overuse headache, it is important to limit the acute headache treatment to 2 days per week (acute treatment should not be taken for more than 9 days per month) and use preventive treat- ment in patients taking acute agents for 1 or more days per week. e desirable goal for acute migraine treatment from a clinical and pa- tient perspective is the rapid and sustained complete removal of pain and restoration of normal functionality. In Box 14.2 we summarize some of the relevant points that have to be taken into account when selecting a symptomatic treatment.

Speci c treatment

Speci c acute headache medications include ergotamine, DHE, and selective 5-hydroxytriptamine (5-HT1) agonists/triptans (Table 14.1) (9–15).

CHaPtEr 14 Treatment and management of migraine: acute

Box 14.1 Factors determining the drug of choice and/or the drug dose

. 1 Age of patient.

. 2 Pain intensity of attack.

. 3 Rapidity of symptom onset.

. 4 Duration of attack.

. 5 Associated symptoms.

. 6 Concomitant diseases.

. 7 Special conditions (gestation).

. 8 Previous treatments experience.

Box 14.2 Ten basic points for the selection of a symptomatic treatment of migraine

. 1 In the clinical practice setting, this is the only management option that most patients really do need.

. 2 Symptomatic treatment should be optimized at its maximum be- fore recurring to prophylactic therapy.

. 3 In the aim of avoiding medication abuse, symptomatic treatment should never be authorised as a single management option if the patient experiences 10 or more days of pain per month

. 4 Any symptomatic treatment should be tailored to each patient’s needs and each crisis’ characteristics: not every patient requires the same management for all episodes.

. 5 When it comes to individualizing treatment, the type of migraine and its co-existence with other headaches should be considered.

. 6 The presence of concomitant disorders and the previous experi- ence of the patient regarding symptomatic treatment are key elem- ents at the time of selecting a speci c pharmacological approach.

. 7 The existence of digestive-related associated symptoms (nausea, vomiting) suggests the need of early administration of prokinetic and antiemetic medications.

. 8 The main reason for treatment failure comes from the use of not suf ciently ef cient medications.

. 9 The choice of administering a certain medicine through an inad- equate formulation (i.e. oral formulation in patients with vomiting episodes) is another frequent reason for treatment failure.

10 Early management of all episodes is highly recommended.

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table 14.1 More common speci c drugs used as acute/abortive treatment in migraine attacks

Drug

Dose

Route of administration

Advantages

Disadvantages

Ergots

Dihydroergotamine: parenteral 0.5–1 mg; intranasal Ergotamine: 1–2 mg in suppositories

Intravenous, intranasal, rectal

Low price
Good ef cacy
Can be combined with antiemetics

Elevated risk of overuse Can increase nausea and

vomiting

Triptans

Depending on type of triptan and route of administration
• Sumatriptan:
• Sc:6mg

• oral 50–100 mg, inhaled 10–20 mg, rectally 25 mg, transdermal patch 6.5 mg

• Almotriptan oral 12.5 mg
• Zomitriptan oral and oral dispersible 2.5–5 mg,

intranasal 5 mg
• Eletriptan oral 20–80 mg
• Naratriptan oral 2.5 mg
• Rizatriptan oral and oral dispersible 5–10 mg • Frovatriptan oral 2.5 mg

Oral, oral dispersible, subcutaneous, intranasal, rectal

The group with highest ef cacy. Speci c treatment for migraine. Able to relieve severe migraine

attacks and associated symptoms

(nausea and vomiting)
Can be combined with NSAIDs and

simple analgesics Different non-oral routes of

administration available

Expensive
Not recommended in

patients with elevated cardiovascular risk

NSAID, non-steroidal anti-in ammatory drug.

Acute treatments taken at the start of the attack are a mainstay of migraine management and this is the best approach in the majority of migraineurs (10,25).

e rst drugs used for migraine were simple analgesics with no migraine-speci c mechanism of action, such as aspirin, which is still widely used (26). Next, ergotamine was isolated from ergots in 1918 (27) and introduced in migraine therapy in 1925 because of its presumed sympatholytic activity (28). e modern era of mi- graine treatment started with the synthesis of the potent 5-HT an- tagonist methysergide from LSD25 by Sandoz in Basel, Switzerland (29). Nowadays, triptans and ergots are the only available migraine- speci c abortive medications.

Table 14.1 summarizes the more frequent speci c drugs used in acute migraine.

Ergots

Ergot alkaloids, such as ergotamine or DHE, have been the only ‘spe- ci c’ treatment for migraine for decades. Ergots have their 5-HT1B/ D receptor agonist action in common with triptans, and that is the concept responsible for the control of migraine-related pain. ey interact with many other receptors such as 5-HT1A, 5-HT2, 5-HT5, 5-HT7, α-adrenergics, and dopamine D2, which is the reason for their varied pro le of adverse e ects, the most common of which are nausea and vomiting. Other frequently observed adverse e ects are cramps, sleepiness, and transitory muscular pains of the inferior limbs. e most feared ergotamine- and DHE-derived secondary e ects are the cardiovascular ones. Elevations in blood pressure have been described, added to cases of angina/heart attack and is- chaemia of the lower limbs. A chronic use of ergotamine is asso- ciated with some speci c adverse e ects. A remarkable one comes from ergotamine’s capacity (and from ca eine incorporated in those formulations, which is authorised in some countries) to induce re- bound headache and trigger the feared ergotic overuse headache. Ergotics are still the cause of one-third of the overuse headache in some countries (30). e e cacy of ergotamine could be posi- tioned in a middle line between NSAIDs and triptans. One of its most serious disadvantages is its low bioavailability (1% orally, max- imum 3% rectal), reason enough for the limited level of e cacy. As

triptans exhibit a larger e cacy and a better, cleaner pro le, expert consensus concluded that ergotic products are not indicated among de novo migraine patients, a group in which triptans should always become rst choice (31). In this sense, ergotic medicines could be maintained in those patients who have used them for a long time; who express a satisfactory response and do not present contraindi- cations; and whose frequency of attacks is low (no more than one per week). An additional indication for ergots could be directed to some patients with long attacks and high rates of pain recurrence.

One option in these cases is the administration of ergota- mine rectal suppositories (1–2 mg) with an antiemetic (10 mg metoclopramide oral tablets, or 25–100 mg chlorpromazine or 25 mg prochlorperazine rectal suppositories if the patient is vomiting). Up to six (1 mg) tablets can be taken or two suppositories over 24 hours for an individual attack. Use should be restricted to one dosage day per week (9).

DHE is available in 1 mg/ml ampules, for intramuscular (IM), subcutaneous (SC), or intravenous (IV) administration, or nasal spray in some countries (15). In clinical trials DHE nasal spray has been superior to placebo, similar to ergotamine and inferior to sub- cutaneous sumatriptan, and therefore in some guidelines this is con- sidered as an alternative in selected patients with migraine (9,13). Ergot compounds, in most of the guidelines published, are con- sidered second-line treatment agents in migraine attacks (9,11,13).

Most of the studies support a therapeutic role of IV and IM admin- istration of DHE in emergency settings. DHE is initially adminis- tered at a test dose of 0.5 mg (0.25 mg for children) given via IV push over 3–5 minutes. If the headache persists, another 0.5 mg DHE is given and 1.0 mg DHE is administered every 8 hours. If nausea per- sists, the next dose can be reduced to 0.25 mg. DHE is tapered down and discontinued in 3–5 days if the patient is headache-free or fails to respond to the medication (15).

An antiemetic should be added to parenteral DHE. An e ective treatment option is to administer 0.5–1 mg IV DHE with 10 mg IV metoclopramide or prochlorperazine (the latter, given alone, is able to reverse a migraine episode by itself in some cases) (32–34).

An orally inhaled and self-administered formulation of DHE delivered to the systemic circulation (known as MAP0004), has

been developed. MAP0004 aerosol DHE provides desirable acti- vation of 5-HT1B/1D receptors, resulting in an e ective antimigraine e ect. Unlike IV DHE, MAP0004 is less likely to bind with other serotonergic, adrenergic, and dopaminergic receptors, resulting in fewer side e ects. MAP0004 administered alone shows no statis- tically signi cant drug-related increase in nausea compared with conventional IV DHE, which is generally administered with an antiemetic medication. MAP0004 is less arterio-constrictive than intravenous DHE. MAP0004 has been proven to be e ective and well tolerated for acute migraine treatment. It provides statistically signi cant pain relief and freedom from photophobia, phonophobia, and nausea compared with placebo. Both phase II and III clinical trials support its antimigraine e cacy. MAP0004 has a superior tol- erability to IV DHE. MAP0004 may be a promising rst-line agent for migraine treatment, with lower rates of nausea and vomiting than other DHE routes of administration (35–37).

e use of ergots is contraindicated when renal or hepatic failure is present, and in pregnancy, high blood pressure, sepsis, and cor- onary, cerebral, and peripheral vascular disease (38). Some formu- lations have been banned by the US Food and Drug Administration (FDA), due to their severe adverse e ects.

triptans

It was known that 5-HT was decreased in blood during a migraine attack and infusion of 5-HT was shown to relieve migraine attacks (39). e studies focusing on the importance of 5-HT inspired the development of sumatriptan by Patrick Humphrey from Glaxo (40).

Triptans are 5-HT agonists with a high a nity for 5-HT1B and 5-HT1D receptors. Triptans were originally thought to provide mi- graine relief by causing cranial vasoconstriction, most likely through action at postsynaptic 5-HT1B receptors on the smooth muscle cells of blood vessels. But it is well known that triptans also block the release of vasoactive peptides from the perivascular trigeminal neurons through their action at presynaptic 5-HT1D receptors on the nerve terminals. In addition, triptans bind to presynaptic 5-HT1D receptors in the dorsal horn, and this binding is thought to block the release of neurotransmitters that activate second-order neurons ascending to the thalamus. Triptans may also facilitate descending pain inhibitory systems (41).

Subcutaneous sumatriptan was the pioneer drug in class and was introduced into clinical practice in 1992 a er it was proved to relieve both migraine and associated symptoms like nausea and vomiting, being superior to placebo in all e cacy parameters (42). A er this rst publication many thousands of patients have been included in clinical trials with oral triptans (43,44).

At present, there are seven triptans available: sumatriptan, rizatriptan, zolmitriptan, naratriptan, almotriptan, eletriptan, and frovatriptan. All of them are shown to o er a favourable response versus placebo, both for headache response and sustained pain-free response (45–47).

Several clinical trials have demonstrated the superiority of triptans over ergots and NSAIDs (43). e triptans became the initial treat- ment choice for acute migraine attacks, when the headache is mod- erate to severe and there are no contraindications for their use. ey are prescribed as rst-line therapy for severe migraine attacks and as back-up medication for less severe attacks that do not adequately respond to simple analgesics (9–14). All triptans are available as oral tablets. In an e ort to deliver more rapid onset of pain relief, a

variety of formulation alternatives to oral triptan conventional tab- lets have been developed, including nasal sprays, suppositories, and rapidly dissolving oral wafers. Di erent ways of administration can be used when nausea and vomiting are present.

Sumatriptan

Sumatriptan is available as a SC injection, an oral tablet, a nasal spray, a dispersible tablet, a transdermal patch, a rectal suppository, and a breath-powered powder intranasal formulation.

It is the only triptan that can be administered as a SC injection, meaning it is the fastest available triptan, as it avoids the gastro- intestinal tract and is rapidly absorbed. It works very quickly to re- lieve pain (>80% headache relief at 2 hours), nausea, photophobia, phonophobia, and functional disability, but it is associated with fre- quent adverse events (48).

erefore, SC sumatriptan is the ideal triptan for patients who need rapid relief or have severe nausea or vomiting. e SC ad- ministration of sumatriptan may cause pain in the site of injection, ushing, burning, and hot sensations. Dizziness, neck pain, and dys- phoria can also be seen. ese adverse events normally disappear in around 45 minutes.

Almost 80% of patients experience pain relief from the ini- tial SC administration, but headache recurs in about one-third of the patients within a day. ese patients respond well to a second dose of sumatriptan and sometimes to simple or combined anal- gesics, but a second dose of oral sumatriptan does not prevent the recurrence (49).

Oral sumatriptan is used for headaches with gradual onset when rapid pain relief is not required; it is available in doses of 100 mg, 50 mg, and in some countries in 25 mg; doses of 50 mg and 100 mg are clearly superior to 25 mg. e headache response at 2 hours for both doses (50 mg and 100 mg) is around 60%.

Sumatriptan is also available as a dispensable tablet; in the studies comparing this formulation with placebo, the results were superior to the conventional tablets.

Sumatriptan 25 mg administered rectally is also an e ective treat- ment for headache relief and functional disability reduction, but the clinical data are limited because this method of administration is not available in many countries (50).

Similarly, intranasal sumatriptan is e ective as an abortive treat- ment for acute migraine attacks, relieving pain, nausea, photo- phobia, phonophobia, and functional disability (51). Although their e ect depends partially on nasal mucosal absorption, a sig- ni cant amount of the drug is swallowed. It transits the stomach and is then absorbed in the small intestine. us, its action also depends on gastrointestinal absorption with the limitations of the oral triptans (52).

e transdermal route of administration by using transdermal iontophoretic patches was approved by the FDA. is method of application bypasses hepatic rst-pass metabolism and avoids gas- tric transit delay. An excellent tolerability (with no triptan-related adverse events) and superior e cacy versus placebo was demon- strated (53). Transdermal sumatriptan was superior to oral triptans for patients with migraine whose nausea is the reason for the delay or avoidance of acute treatment (54). e patches are a promising choice of treatment for patients with intolerable triptan-related ad- verse events, as well as for migraineurs with disabling vomiting and poor absorption of oral medication (55).

CHaPtEr 14 Treatment and management of migraine: acute

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A needle-free device for sumatriptan injection is available in the USA with an e cacy similar to traditional SC administration (56). Also, a new formulation of breath-powered powder sumatriptan for intranasal administration has recently been approved by the FDA. e administration of sumatriptan with this system provides an early onset of e cacy (it is superior to oral sumatriptan at 15 and 30 minutes) with low systemic drug exposure and few triptan- associated adverse events (57).

All these non-oral routes of administration o er a useful alter- native delivery system for patients who have di culty swallowing conventional tablets and for patients whose nausea and/or vomiting impede the swallowing of tablets and/or make the likelihood of complete absorption unpredictable. ese alternative formulations o er migraineurs the possibility of using abortive treatment at the onset of migraine attacks without the need of liquids, anytime and anywhere.

Zolmitriptan

Zolmitriptan was the second triptan introduced to the market. It is available in oral doses of 2.5 and 5 mg in conventional and dis- persible tablets. It has a high oral bioavailability (40%) and a Tmax of around 2.5 hours. It is comparable to sumatriptan in terms of ef- cacy and tolerability. Zolmitriptan 2.5 mg and 5 mg oral tablets are e ective in achieving pain relief within 2 hours (around 60% of patients) following treatment. Both doses are comparable, but the zolmitriptan 5 mg tablet is superior to the zolmitriptan 2.5 mg tablet in achieving 1- and 2-hour pain-free responses (58).

Zolmitriptan as a nasal spray formulation has a proven e cacy, high tolerance, and a very fast onset of action. Zolmitriptan has been detected in plasma only 2 minutes a er intranasal adminis- tration versus 10 minutes a er oral administration, thus achieving faster migraine relief than oral zolmitriptan. It is the triptan with the highest nasal absorption (about 30%). It was found to provide pain relief in some patients as soon as 15 minutes a er administra- tion (59). Good candidates for this treatment formulation are mi- graineurs whose pain escalates rapidly from moderate to severe, and those who have quick time to vomiting or have failed treatment with oral triptans (60).

Naratriptan

Naratriptan has a long half-life and a long Tmax. It is available 2.5-mg tablets. It has the lowest range of e cacy at 2 hours, with a headache response of 48%. Relief rates are lower than with the other triptans, but it is very well tolerated. It could be an alternative in patients with mild or moderate attacks, or in patients with tolerability prob- lems with other triptans. e e cacy of naratriptan 2.5 mg versus NSAIDs has not been su ciently investigated (61). It could have some e cacy in preventing migraine during prodromal phase, but the evidence is low (62).

Rizatriptan

Rizatriptan is a second-generation triptan available in 10 mg and 5 mg tablets, or as an orally disintegrating tablet (wafer) formula- tion (63). It is rapidly absorbed from the gastrointestinal tract and achieves maximum plasma concentrations more quickly than other triptans (shorter Tmax), providing rapid pain relief and a high head- ache response (69%). Clinical trials have shown that rizatriptan is at least as e ective or superior to other oral triptans and has more

consistent long-term e cacy across multiple migraine attacks. Rizatriptan is superior to placebo in achieving total migraine freedom (freedom from pain and absence of associated symptom) dose across all treatment paradigms (64). It has a higher recurrence rate than other triptans. Rizatriptan has a signi cant interaction with propranolol, which is why the dose in patients using this drug should be 5 mg. Patients whose attacks rapidly evolve from mod- erate to severe pain are good candidates for rizatriptan (10).

Almotriptan

Almotriptan is available in oral tablets of 12.5 mg. It shares two common characteristics with sumatriptan: it does not cross the blood–brain barrier and does not produce active metabolites (65). e headache response at 2 hours is 61%. In comparative trials the e cacy has been similar to that of sumatriptan, with better toler- ability (similar to placebo), which has been con rmed in clinical practice (66). A secondary nding in these trials was that patients who took almotriptan early, when the pain was still mild, achieved better outcomes. is prompted the initiation of studies designed to assess the e ect of almotriptan in early intervention. Open-label trials reported improvements in pain-free end points (2 hours and 24 hours), and subsequent randomized clinical trials con rmed these ndings (67). Almotriptan combines good e cacy with ex- cellent tolerability.

Eletriptan

Eletriptan is a second-generation triptan with favourable bioavail- ability and half-life, a high a nity for 5-HT(1B/1D) receptors and se- lectivity for cranial arteries (68). e headache response at 2 hours was 60% for the 40-mg dose and 63% for the 80-mg one. Eletriptan (40 mg and 80 mg) has been shown to be e ective as soon as 30 min- utes a er administration and it is well tolerated when compared to placebo (69). In comparative clinical trials, eletriptan 40 mg and 80 mg were superior or equivalent to other triptans and have shown lower recurrence rates than other triptans (70). e incidence of minor harm was dose dependent, with 80 mg resulting in signi – cantly more adverse e ects than 40 mg. A patient with moderate- to-severe attacks and a tendency to recurrence could be a good candidate for eletriptan.

Frovatriptan

Frovatriptan is an orally administered triptan at doses of 2.5 mg. It has a very long half-life (approximately 26 hours) and the lowest headache response at 2 hours (44%). In randomized trials it was su- perior to placebo and it was generally well tolerated, with an adverse event pro le similar to placebo. Frovatriptan provides an alterna- tive treatment in patients who have had adverse events or frequent headache recurrences (71). If frovatriptan 2.5 mg is taken twice a day during the period of increased migraine vulnerability associ- ated with menstruation, migraine attack occurrence in patients with menstrual migraine is signi cantly reduced (72). Frovatriptan is es- tablished to be e ective for the short-term prevention of menstrually associated migraine (73,74).

Triptans are an appropriate rst-line acute treatment of moderate- to-severe migraine in patients without contraindications such as ischaemic heart disease, angina pectoris or uncontrolled hyperten- sion. For safety, an electrocardiogram is recommended for patients over 40 years of age with risk factors for heart disease (10). Adverse

events like fatigue, dizziness/vertigo, asthaenia, and nausea can be observed with all triptans. e incidence of adverse events is dose dependent with rizatriptan and zolmitriptan. Transient chest symp- toms have also been reported for all treatments in this class. ere is also a risk of serotonin syndrome, when triptans are taken together with other serotonin agonists. e only disadvantage of the use of triptans is their high cost compared with ergots (12,13). Triptans and ergots are both contraindicated when a cardiovascular disease is present (10–15). Triptan product monographs typically state that they are contraindicated in patients with hemiplegic, ophthalmo- plegic, and basilar migraine; these contraindications are theoretical and based on the actions of vasoconstrictors. In small clinical trials, the use of triptans during the aura phase appears to be safe but does not prevent the headache. Because of this, patients with migraine with aura should be advised to take their triptan at the onset of the pain phase. However, if patients nd that treatment during the aura is e ective, there is no reason to discourage this practice (13).

Early triptan intake a er headache onset may help to improve the e cacy of acute migraine treatment (75).

Nowadays, there are seven di erent triptans available on the market with level A evidence for treatment of migraine attack (76). All of them are similar when it comes to their mechanisms of action or pharmaco- dynamics, but they are quite diverse in their pharmacokinetic pro les, which make them suitable for use in di erent types of attacks. Several meta-analysis have been published comparing the di erent triptans with regard to di erent parameters, such as headache response, pain- free rate, recurrence rate, tolerability, and so on (45–47,77). Based on this knowledge and clinical practice, we can make some recom- mendations for the use of the di erent triptans (Table 14.2). It is im- portant to know that the response from one particular patient to one particular triptan is unpredictable and oral triptan therapy does not provide headache relief in one-third of patients. Because of this, in case of no response to one triptan or poor tolerability, other triptans should be tried over time in subsequent attacks.

Migraine patients have to be educated well so that they give up inadequate practices or unjusti ed prejudices about triptan use (15). Triptans are vasoconstrictors and are contraindicated in patients with coronary and cerebrovascular diseases but have been proven remarkably safe in people without vascular disease. ere has been concern about serotonin syndrome in patients taking triptans and selective serotonin reuptake inhibitors and serotonin and norepin- ephrine reuptake inhibitors concomitantly. Although clinical ex- perience indicates that serotonin syndrome is extremely rare with triptan use, patients should be informed about its symptoms.

Triptans combined with NSAIDs

Multiple peripheral and central mechanisms may be involved in mi- graine and a drug combination may potentially achieve better re- sponse rates by combining di erent drug targets (78).

A er some open clinical observations (79) and the rst clinical trial (80), in which the combination of sumatriptan and naproxen sodium was superior to sumatriptan alone, 12 studies have been published testing the combination of sumatriptan 50mg or 85 mg plus naproxen 500 mg to treat attacks of mild, moderate, or severe pain intensity. Using 50 mg sumatriptan rather than 85 mg in the combination did not signi cantly change the results. Treating early, when pain was still mild, was signi cantly better than treating once pain was moderate or severe for pain-free responses at 2 hours

CHaPtEr 14 Treatment and management of migraine: acute table 14.2 Potential indications for each of the different triptans

available

Compound

Formulation

Indication

Sumatriptan formulations

Subcutaneous 6 mg

Severe crises resistant to oral and nasal formulations

Nasal 20 mg

Crises resistant to oral administration

Patients with vomiting episodes

Nasal 10 mg

Children and adolescents

Oral 50 mg

Standard migraine patient Patients with potential risk of

pregnancy

Zolmitriptan

Oral 2.5 mg and 5 mg

Standard migraine patients

Nasal 5 mg

Crises resistant to oral administration

Patients with vomiting episodes

Naratriptan

Oral 2.5 mg

Long-lasting low-to-moderate crises

Adverse effects present with other triptans

Rizatriptan

Oral 10 mg

Serious, fast, short-lasting crises

Almotriptan

Oral 12.5 mg

Standard migraine patients Secondary effects present to other

triptans

Eletriptan

Oral 20 mg and 40 mg

Severe long-lasting crises

Frovatriptan

Oral 2.5 mg

Long-lasting low-to-moderate crises

and in the 24 hours post-dose. e combination seems to reduce the risk of headache recurrence. Where the data allowed direct comparison, combination treatment was superior to either mono- therapy, but adverse events were less frequent with naproxen than with sumatriptan (81).

e association of frovatriptan 2.5 mg with 25 or 37.5 mg dexketoprofen was superior to frovatriptan alone in initial e cacy at 2 hours while maintaining e cacy at 48 hours in in a randomized trial (82).

e combination of triptan with NSAIDs is an alternative in cases of triptan failure or frequent recurrence.

Non-speci c treatment

Over-the-counter (OTC) analgesics are the most used medications for migraine attacks, although their e cacy is limited. However, using the strati ed approach, migraine attacks with no more than mild attack-related disability may be treated with non-speci c medications.

Non-speci c treatment options are also considered when contra- indications or side e ects related to speci c medications are present and when there is a limited supply of these medications; cost issues could be important in some cases and represent the rst line in the therapy of migraine in milder attack (83).

analgesics and NSaIDs

Sometimes rst-line acute treatments of migraine include a var- iety of oral analgesics. If there is no substantial disability present, most patients obtain pain relief by using simple analgesics (9–14).

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NSAIDs are among the most commonly prescribed medications in the world. NSAIDs are non-speci c medications for acute treatment of migraine. ey are used for their anti-in ammatory, antipyretic, antithrombotic, and analgesic e ects, which may be due to some in- hibitory function on both peripheral trigeminal neurons and central neurons (84). e most frequent non-speci c drugs are summarized in Table 14.3.

Various NSAIDs (including ibuprofen, naproxen sodium, diclofenac potassium and others) have been tested in acute mi- graine. In most trials with OTC medications, patients with severe attacks or frequent vomiting were excluded. Apparently, there are no di erences in e cacy between the di erent NSAIDs, but there is a lack of head-to-head comparators. NSAIDs are e ective for mild- to-moderate attacks and in some patients could be e ective also in severe attacks.

NSAIDs should be avoided in patients with gastric ulcers, renal failure, high risk of bleeding, and acetylsalicylic (ASA)-induced asthma (85).

Aspirin

Acetylsalicylic acid (ASA) (900 mg or 1000 mg) has been tested in several trials alone or in combination with metoclopramide 10 mg and compared with placebo or other active comparators, mainly sumatriptan 50 mg or 100 mg. In all studies it has been superior to placebo and similar to sumatriptan 50 mg. Adverse events were mostly mild and transient, occurring slightly more o en with aspirin than placebo. Additional metoclopramide signi cantly reduced nausea and vomiting compared with aspirin alone but without dif- ferences in e cacy (86).

Naproxen sodium

Naproxen (500 mg and 825 mg) was better than placebo for pain- free response and headache relief in the clinical trials. Analysing only the lower dose of 500 mg of naproxen did not signi cantly change the results. Adverse events, which were mostly mild or mod- erate in severity and rarely led to withdrawal, were more common with naproxen than with placebo when the 500 mg and 825 mg doses were considered together, but not when the 500 mg dose was analysed alone.

e only concern is that for naproxen the number needed to treat (NNT) of 11 for pain-free response at 2 hours suggests that it is not a clinically useful treatment. Compared with other commonly used

analgesics for acute migraine, naproxen is inferior for the same out- come (87), although in clinical practice the e cacy of naproxen so- dium is not di erent from other triptans.

Ibuprofen

Ibuprofen has been tried in doses of 200 and 400 mg. Both doses are superior to placebo, but the higher dose was signi cantly better than the lower dose for 2-hour headache relief. Soluble formula- tions of ibuprofen 400 mg were better than standard tablets and provided more rapid relief. Similar numbers of participants experi- enced adverse events, which were mostly mild and transient, with ibuprofen and placebo. Ibuprofen is an e ective treatment for acute migraine headaches, providing pain relief in about half of su erers but complete relief from pain and associated symptoms only for a minority (88).

Diclofenac potassium

e number of patients included in the studies with oral diclofenac is low, but it allows establishment of the e cacy of oral diclofenac potassium at a dose of 50 mg as an e ective treatment for acute migraine, providing relief from pain and associated symptoms, al- though only a minority of patients experience pain-free responses. ere were insu cient data to evaluate other doses of oral diclofenac, or to compare di erent formulations or di erent dosing regimens, although the oral powder solution seems to have a quicker onset (84). Adverse events are mostly mild and transient and occur at the same rate as with placebo (89).

Paracetamol

Eleven studies (2942 participants, 5109 attacks) have compared paracetamol 1000 mg, alone or in combination with an antiemetic, with placebo or other active comparators such as sumatriptan 100 mg. For all e cacy outcomes paracetamol was superior to pla- cebo, when medication was taken for moderate-to-severe pain. Paracetamol 1000 mg plus metoclopramide 10 mg was not signi – cantly di erent from oral sumatriptan 100 mg for 2-hour headache relief, but there were no 2-hour pain-free data. Adverse event rates were similar between paracetamol and placebo.

e NNT of 12 for pain-free response at 2 hours is inferior to all other commonly used analgesics. Given the low cost and wide avail- ability of paracetamol, it may be a useful rst-choice drug for acute

table 14.3 More common non-speci c drugs used as acute/abortive treatment in migraine attacks

Drug

Dose

Route of administration

Advantages

Disadvantages

NSAIDs

Higher than usually used for other types of pain • ASA: 1 g
• Ibuprofen: 800–1200 mg
• Dexketoprofen: 50 mg

• Naproxen 1000 mg
• Ketoprofen 75 mg
• Ketorolac oral 20 mg or intramuscular 60 mg

Indomethacin 50 mg

Oral, rectal, intravenous, intranasal

Can be combined with triptans to achieve better ef cacy

Relief of pain and associated symptoms

Usually not useful for severe attacks

Acetaminophen/ paracetamol

Oral, intravenous

Can be combined with antiemetics (as metoclopramide), increasing considerably its ef cacy (in some studies—similar to sumatriptan)

Generally does not work with moderate- to-severe attacks

NSAIDs, non-steroidal anti-in ammatory drugs; ASA, acetylsalicylic acid.

migraine in those with contraindications to, or who cannot tolerate, NSAIDs or aspirin (90).

Other NSAIDs such as dexketoprofen trometamol (91), and other analgesics such as metamizol, bearing in mind the risk of agranulo- cytosis (92), have shown e cacy in the treatment of acute migraine. Other routes of administration, such as nasal spray, have been tried with good results (93). Recommending one analgesic over another can be di cult because the data that compare these compounds are insu cient; the published clinical trials do not re ect clinical prac- tice particularly well and low doses are probably used. e only clear recommendation in this group of compounds is for paracetamol as a rst-choice drug for migraine attacks during pregnancy, and possibly ASA in patients with cardio- and cerebrovascular comorbidities.

Combination analgesics

Di erent combinations have been tested, with the association of ASA, paracetamol and ca eine showing a signi cant e cacy on mi- graine attacks of moderate intensity and moderate disability (94). Indomethacin, prochlorperazine, propyphenazone, and codeine have also been tested with positive outcomes. eoretically, the combinations have the same indications of simple analgesics and NSAIDs. ese combinations are not recommended as rst-line therapy because the use of ca eine or codeine could increase the risk of medication overuse (10,13,14).

Dopamine antagonists

Dopamine antagonists have an established role in the treatment of migraine. Neuroleptics/antiemetics, which antagonize the dopa- mine D2 receptor, have variable activity as α-adrenergic blockers, antiserotonergics, anticholinergics, and antihistaminergics. eir dopamine-related action is the reason for their e cacy in treating acute migraine and nausea. Antiemetics should be given not only to patients who are vomiting or likely to vomit, but also to those with nausea, which is one of the most disabling symptoms (15). Metoclopramide is recommended as an adjunct in the treatment of nausea associated with migraine, usually in the form of tablets (10 mg); a spray and injectable form (10–20 mg) are also available for the most severe cases. ere is also some evidence for the e cacy of domperidone.

eoretically, owing to the suspected gastric stasis during the migraine attack, the association of an antiemetic with analgesics, NSAIDs, or even triptans could increase the absorption and the ef- cacy of the symptomatic drug; however, in clinical trials the evi- dence for this combination is low.

Metoclopramide, prochlorperazine and chlorpromazine have also shown a modest antimigraine e ect, besides a clear antiemetic e ect (95). Dopamine antagonists are an e ective option in patients who have contraindications for migraine-speci c medications or NSAIDs, or in pregnant women with migraine (15).

Dopamine antagonists are rst-line agents in the emergency room setting, especially for acute migraine patients with nausea and vomiting. Neuroleptic medications are commonly used in status migrainosus or medication overuse headache. Nevertheless, they should be used with caution in order to avoid adverse events such as sedation, akathisia, dystonic reactions, neuroleptic malig- nant syndrome, or movement disorders (usually appearing a er long-term use). Some of the newer atypical neuroleptic agents are promising for both acute and prophylactic migraine treatment with

a lower risk of adverse events (95). Diphenhydramine may be co- administered to avoid the many extrapyramidal adverse e ects of antidopaminergic drugs.

e IV form of metoclopramide (96,97), chlorpromazine, and prochlorperazine are used e ectively in emergency department settings.

Barbiturate hypnotics

Barbiturate hypnotics (butalbital) lead to overuse, dependence, and withdrawal e ects, and may not o er additional pain relief to justify their use. eir use has to be monitored and limited. ey are not recommended as a rst-line therapy for the acute treatment of mi- graine (10–14).

Opioids

Oral opioids and opioid combination products may relieve acute migraine pain, but there is a high risk of overuse and dependency. e association of codeine has demonstrated an increase of the ef- cacy of paracetamol in some studies (98), but not in others (99).

Butorphanol tartrate is a potent synthetic mixed agonist– antagonist, and administered as nasal spray it has been e ective against placebo (100), but there are no studies comparing butorphanol with other non-opioid symptomatic antimigraine drugs.

Tramadol combined with acetaminophen has shown e cacy in a trial against placebo (101), but it had the same risk of dependence and abuse as the other compounds of this group.

For the listed reasons, oral opioids, including codeine, are not re- commended for routine use in migraine (102). Codeine-containing combination analgesics may be considered for patients with mi- graine in case of triptans and/or NSAID failure or contraindication.

Home rescue in acute migraine

In patients with severe attacks treatment with triptans, alone or in combination with NSAIDs, can fail on some occasions and it is important to discuss with the patient a rescue medication strategy. ere are several alternatives.

Oral NSAIDs are unlikely to provide adequate pain relief. Ketorolac IM (the patient should be carefully trained) has provided good results in an open study (103). If the patient is vomiting, the use of suppositories could be considered. Indomethacin supposi- tories in combination with prochlorperazine and ca eine provide a high pain-free score at 2 hours (104). e combination of indometh- acin and prochlorperazine could be an alternative. Prochlorperazine suppositories (at a dose of 25 mg) have been e cacious in pain relief in a small trial (105).

Short-term high-dose steroid treatment has a place in the treat- ment of status migrainosus, although there is a lack of randomized clinical trials (106). By extension, a short course of prednisone or dexamethasone starting with a high dose and tapering down in 2– 3 days’ time might be helpful in a refractory attack. e evidence for the e cacy of corticosteroids alone is very low; only dexamethasone has shown some e cacy in a trial in menstrual-related migraine (107). e frequency of use should be limited to once a month or less.

Opioids and opioid-containing combination analgesics are not re- commended for routine use in migraine, but they could be an alter- native in some refractory attacks. Strong opioids such as morphine

CHaPtEr 14 Treatment and management of migraine: acute

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should be avoided and used only in exceptional circumstances. e frequency of use of all compounds should be carefully monitored and limited to avoid medication overuse headache, abuse, depend- ence, and possible addiction.

DHE applied as a nasal spray (2 mg) or as a SC or IM injection (1 mg) is an option but only in patients who have not taken triptans.

Hospital rescue in acute migraine

Considering hospital rescue medication in acute migraine, the choice of the treatment should be based on e cacy, side e ects, and cost. Headache recurs in more than 50% of patients a er emergency department discharge. Parenteral opioids, NSAIDs, sumatriptan, neuroleptics, and steroids have all demonstrated some e ectiveness in acute migraine treatment (108–110).

Opiates/opioids generally are not recommended as rst-line treat- ment. Meperidine, tramadol, and nalbuphine are most commonly used. ey were all superior to placebo in relieving migraine pain but not superior to other medications such as DHE or prochlorpera- zine. ey can be e ective sometimes, but such rescue therapy may lead to early headache recurrence, central sensitization, sedation, nausea, and dizziness, as well as overuse and abuse. Although, these medications are commonly administered for treatment of acute mi- graine, they should be a last resort (110,111).

NSAIDs (ketorolac IV and IM is the most studied) (112) are well tolerated, and they may provide bene t even when given late in the migraine attack. Ketorolac is appropriate for patients with vascular risk factors and it does not cause sedation. NSAIDs can be com- bined with most other treatments to increase their e cacy. Lysine clonixinate and metamizol (non-NSAID) IV have been superior to placebo in small studies (113). Dexketoprofen IV was also e – cacious in the treatment of acute migraine and similar to IV para- cetamol in a randomized trial (113).

Parenteral administered dopamine antagonists are not only ef- fective antiemetics, but also can reduce or terminate migraine attacks and are recommended as rst-line agents (114). Dopamine antagon- ists can be given alone or with other agents. ey are e ective, even if they are applied late in the migraine attack. ey are not expensive, but they frequently cause sedation, and in some cases akathisia and dystonia that can prolong patients’ functional disability.

Sumatriptan SC is as e ective as droperidol and prochlorpera- zine. When patients have no contraindications, it is very well toler- ated. Sumatriptan was inferior or equivalent to the neuroleptics and equivalent to DHE.

Corticosteroids (dexamethasone and prednisone) are superior to placebo and may prevent headache recurrence a er discharge (115,116), especially if the presenting migraine has lasted longer than 72 hours. IV doses in the emergency department are usually followed by oral dosing for several days postdischarge.

IV sodium valproate has shown good results in acute or prolonged migraine headache (117), although in a recent trial it was inferior to metoclopramide or ketorolac (118). e role of new IV antiepileptics such as lacosamide or levetiracetam is not yet established.

Magnesium IV can be an e ective treatment when aura is pre- sent. It can reduce the photophobia and phonophobia. Magnesium can be added on to any medication. Magnesium also can be useful for pregnancy-associated migraine, although a recent meta-analysis

has failed to demonstrate a bene cial e ect of magnesium in acute migraine (119) and is not recommended in the guidelines (114,116). e following list shows the average percentage of pain relief obtained for all medications for which there were two or more ran- domized trials: droperidol 82%; sumatriptan 78%; prochlorperazine 77%; tramadol 76%; metamizole 75%; metoclopramide IV 70%; DHE 67%; chlorpromazine 65%; ketorolac 30 mg IV 60%; meperi- dine 58%; metoclopramide IM 45%; magnesium 43%; ketorolac 60

mg IM 37%; and valproate 32% (110).
Analysis of a large number of studies con rms that a de nitive

and optimally e ective migraine rescue regimen cannot be deter- mined. e ideal acute migraine rescue therapy administered in urgent settings would provide complete headache relief, possess no side e ects, and prevent early headache recurrence. Because such therapy does not exist, treatment must be tailored to the needs of the individual patient.

e medications more recommended by the guidelines, based on a high or moderate level of evidence, are: prochlorperazine, metoclopramide, and sumatriptan SC (114,116). Lysine ASA and ketorolac are also recommended based on a moderate-to-low level of evidence (114). e guidelines also recommend avoidance of the use of opioids; the use of opioids could be associated with a long stay in the emergency department and higher rates of return (120).

Intravenous treatment in status migrainosus

Status migrainosus refers to severe migraine episodes that last more than 72 hours (8), usually accompanied by severe nausea and vomiting, which can impede oral administration of drugs. Many patients may require hospital admission to achieve an optimal management.

e treatment principles for status migrainosus include the fol- lowing: (i) uid and electrolyte replacement (if indicated); (ii) par- enteral pharmacotherapy to control pain; and (iii) treatment of associated symptoms of nausea and vomiting. In these cases, the IV route, which eliminates the need of absorption and yields a quicker drug e ect (121), can be used for correction of uid and electrolyte imbalances and treating pain. For relieving nausea and vomiting, IV metoclopramide, chlorpromazine, or prochlorperazine can be used. Intravenous or IM metoclopramide has shown a good e cacy for the acute treatment of migraine. ere are few studies suggesting that chlorpromazine IV has a therapeutic role in the acute treatment of migraine in the emergency settings. Metoclopramide, prochlor- perazine, and chlorpromazine all can cause drowsiness or sedation. Acute dystonic reactions and akathisia are rare (32).

Neuroleptics may be useful because of their sedative and antiemetic action (e.g. 100 mg IV tiapride dissolved in dextrose).

IV corticosteroids (4–8 mg of dexamethasone every 6–8 hours or 20–40 mg of prednisolone every 6–8 hours, with a subsequent tapering dose for 3–4 days) are also e ective in controlling headache and accompanying symptoms (122). Analgesics and NSAIDs have a minor role in these cases, but may be helpful as adjuvant therapy when combined. Non-oral triptans, such as 6 mg SC sumatriptan, 10–20 mg intranasal sumatriptan, or 5 mg intranasal zolmitriptan, could be an initial treatment of choice in status migrainosus if the patient has not used triptans or ergotamine for the treatment of the attack (15).

IV DHE (0.5 mg) combined with IV antiemetics is also an e ective option. It can be administered every 8 hours if there is no headache relief (13,15). e peak concentration toxicity should be considered while using IV administration. It can be mitigated by using brief in- fusions lasting 20–30 minutes (15).

Future treatments

Calcitonin gene-related peptide antagonists

Since the triptans were introduced in the 1990s, the calcitonin gene-related peptide (CGRP) blockers are the only new speci c drugs developed for acute migraine treatment with an extensive programme of clinical trials. eir mechanism of action is based on the pathophysiology of the disease (123). Clinical trials have proved that CGRP receptor antagonists/gepants are e ective for treating migraine, and antibodies to the receptor and CGRP are currently under investigation as a preventive treatment. (124) (see Chapter 15). e rst evidence of CGRP receptor blockade in migraine using IV olcegepant was published in 2004 (125). Later studies have been done with the orally administered telcagepant (126,127). CGRP receptor blockers inhibit CGRP-induced vaso- dilatation and they do not seem to exert an e ect on coronary ar- teries, and cardiovascular parameters, and, unlike triptans, they might be a possible option for migraine patients with coronary dis- ease (128). Telcagepant showed liver toxicity in a prophylactic trial and the programme was stopped. Recently, ubrogepant has shown some positive results against placebo (129). GCRP antagonists are superior to placebo, but not superior to 5-HT agonists in the usual indices used in clinical trials (130). 1

Neuromodulation

Neuromodulation is an alternative method for treatment and modi- es pain signals through reversible modi cation of the function of the nociceptive system by exogenous electrical currents application (131). ese techniques are especially used in the preventive treat- ment of refractory patients, but some of them have also been used as acute treatment (see Chapter 16).

Transcranial magnetic stimulation (TMS) is thought to dis- rupt cortical spreading depression by delivering a uctuating magnetic eld from the scalp by which small electrical currents are induced in the brain (132). e single-pulse TMS increased freedom from pain at 2 hours versus sham stimulation in patients with migraine with aura (133). An open postmarketed study has demonstrated some e cacy in acute and chronic migraine, with good tolerability (134).

Vagus nerve stimulation (VNS) is a procedure available for re- sistant epilepsy (135), and it has been recently approved by the FDA as an adjunctive treatment in chronic or recurrent medication- resistant depression (136). In retrospective studies, VNS has been shown to improve episodic migraine (137). A small portable de- vice (gammaCore) has been developed for acute and prophylactic treatment for migraine and cluster headache. Some positive re- sults have been published in open studies of the acute treatment of migraine (138), and an extensive programme of clinical trials is running to explore its utility in acute and preventive migraine treatment.

CHaPtEr 14 Treatment and management of migraine: acute Conclusion

Treatment management and strategies for acute migraine are not uni ed. Certain guidelines and the ‘strati ed care’ principles only as- sist in choosing the best treatment for patients with this troublesome disorder. is literature review focuses on the clinical e cacy and tolerability of the most commonly used drugs for acute migraine treatment, together with their various routes of administration. Descriptions of advantages, disadvantages, and recommended dos- ages are based on human studies and clinical practice. Nevertheless, the individual approach to every patient has to be the key principle in acute migraine management. Treatment strategy should be based on migraine clinical characteristics: severity of the attack, time for peak intensity to be reached, frequency of attacks, severity of other associated symptoms, co-existing conditions and illnesses, other medications/interactions, and prior migraine therapy response (73).

Patients should be educated to recognize the beginning of their attack and to take their medication as soon as possible, before the oc- currence of allodynia, which can possibly attenuate the length of the attack. e best route of drug administration should be chosen, based on the presented symptoms during an attack and the patient’s needs (139,140). If some of the medications fail, the clinician has to make sure that at least two attacks have been treated before deciding that it is ine ective. Clinicians have to ensure that the dose is adequate and that there are no other factors interfering with the drug’s e ects.

A self-administered rescue medication is needed when other treatments fail to work. Although they may not eliminate pain com- pletely or return patients to their normal functioning, they provide a certain relief without visiting the physician’s o ce or the emergency department (13).

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151

Treatment and management of migraine Preventive
Andrew Charles and Stefan Evers

Introduction

A signi cant percentage of individuals with migraine, by some es- timates as many as 25%, are candidates for preventive therapy, also known as prophylactic therapy (1). ese are treatments that are admin- istered to pre-empt headache attacks, as opposed to acute treatments that are administered once a headache attack has occurred (although many treatments may be e ective both as preventive and acute ther- apies). ere are a variety of options for preventive therapy with widely varying mechanisms of action, and there is no clear-cut single choice for any individual patient. Preventive therapies can be broadly grouped as antihypertensive medications, anticonvulsant medications, antidepres- sants, vitamins, natural therapies, neurotoxins, and neuromodulation approaches. Early clinical trials indicate that antibody therapies may play an important role as future migraine preventive therapies. While current therapies are e ective for some patients, there is a critical need for better means of identifying which strategy is the best for each indi- vidual patient, and also for new approaches that are more e ective and better tolerated for the prevention of migraine overall.

Indications for preventive therapy

e decision to begin preventive therapy should be individualized based on a number of factors including:

• frequency and duration of attacks;

• level of disability caused by attacks;

• e cacy of acute therapy;

• co-morbid conditions;

• tolerability of the preventive therapy being considered;

• severely disabling migraine aura;

• lifestyle adjustments, changes in current medications (particularly
addressing acute medication overuse), or behavioural approaches that could be considered before instituting preventive therapy.
Guidelines recommend that preventive medications should be considered if more than 2–3 migraine attacks occur per month, if acute therapy is ine ective, or to try to prevent acute medication

overuse. Other potential indications for preventive therapy in- clude the occurrence of particularly disabling attacks, even if infrequent, or the occurrence of severe or disabling aura, given that aura does not respond to any currently available acute medications.

Because preventive therapies are by their nature designed to have a sustained duration of action, they are also likely to have more sustained and long-term side e ects than acute medications. An interesting unanswered question is whether migraine preventive therapy has any e ect on the progression of the disorder. Some have hypothesized that early use of migraine preventive therapy could re- duce progression from an episodic to a chronic condition (2). One study with topiramate, however, found that it did not prevent pro- gression of migraine despite clear e cacy versus placebo (3), and there is no long-term longitudinal evidence to support the hypoth- esis that preventive therapy protects against progression. Better longitudinal studies of di erent preventive therapies are essential in order to determine the long-term e ects of migraine preventive therapy.

assessing ef cacy/tolerability of therapy

As with the decision to initiate preventive therapy, the assessment of the e cacy of therapy is highly individualized. Parameters that indicate e cacy and tolerability include:

• frequency and duration of attacks;
• severity of attacks;
• acute medication use and e cacy of acute medications; • adverse e ects;
• overall function/disability.

Each of these parameters may carry di erent weight for di erent individuals. In clinical trials of preventive therapies, the per- centage of patients showing a 50% reduction in headache days is a commonly used parameter by which e cacy of therapy is deter- mined. Given the clinical heterogeneity of migraine and the like- lihood that multiple distinct pathophysiological mechanisms exist

in di erent individuals, it may also be useful to examine subgroups of responders, i.e. those with 100% reduction in headache, 75% re- duction, and so on. is may help to identify subgroups of patients for whom a given therapy is particularly e ective. Quality-of-life measures and disability measures may also be highly useful, be- cause they consider both e cacy of medications and adverse e ects. Acute medication use is also an important indicator of the e cacy of therapy.

Duration of therapy

e duration of therapy that constitutes a ‘fair trial’ of a medication varies based on a number of factors. Most clinical trials of migraine preventive therapy have a duration of at least 3 months, and this amount of time is commonly considered to be a minimum duration of therapy to evaluate e cacy. Obviously, this minimum duration may be reduced if the medication is poorly tolerated. A more con- troversial issue is how long therapy should be continued if it is ef- fective. Some evidence indicates that patients may continue to have decreased headache frequency and severity for an extended period a er preventive therapy is stopped (4). ese studies raise the possi- bility that even when a therapy is e ective, it may be advisable to use preventive therapy for months rather than years at a time

Identi cation of migraine preventive therapies

None of the migraine preventive therapies in current widespread use was initially indicated for migraine, and until recently very few ther- apies were developed speci cally to treat the disorder. Some of the earliest identi ed migraine preventive therapies, particularly beta blockers, were hypothesized to work by ‘stabilizing’ blood vessels, a hypothesis that has been challenged by substantial evidence that migraine is not primarily caused by changes in vascular calibre (5,6). Other therapies, such as tricyclic antidepressants, were believed to work by modulating levels of serotonin and norepinephrine. More recently, there has been in increased focus on the possibility that mi- graine preventive therapies may work by reducing brain excitability similar to that underlying seizures. is idea has led to the use of anticonvulsants, such as valproic acid and topiramate, as migraine preventive therapies. In animal models, the ability to suppress cor- tical spreading depression (CSD; the slowly propagated wave of cor- tical activity that may underlie the migraine aura) may have some value as a predictor of the e cacy of migraine preventive therapy (7). However, not all medications that prevent migraine inhibit CSD, and some medications that do not prevent migraine do inhibit CSD (8). e development of new translational models that can reliably identify migraine therapies would represent a valuable step toward.

Choice of preventive therapy

e choice of a preventive therapy for any given migraine patient requires consideration of multiple factors, and may not be straight- forward. Among the guidelines that have been generated by dif- ferent organizations to help clinicians and patients make decisions regarding migraine preventive therapy, there are at least 30 di erent

choices within the top-three tiers of recommendations (Table 15.1) (9–12).

e existence of such a wide array of choices of preventive medica- tions for migraine, with diverse mechanisms of actions, underscores the fact that there is no single medication or class of medications that is consistently e ective and well tolerated for the majority of patients with the disorder. Nonetheless, as indicated by the guide- lines, there are a number of choices that are more consistently re- commended than others. In many cases, the choice of a migraine preventive therapy is based on an individual patient’s comorbidities, rather than by a de nitively superior e cacy of one therapy over another. e features of medications among the top choices for mi- graine prevention are outlined in the following sections.

antihypertensive medications

Beta adrenergic blockers

Several beta adrenergic blockers have been su ciently studied in clinical trials and used extensively in clinical practical such that they can be recommended as migraine preventive therapy. ese include propranolol, metoprolol, nadolol, timolol, atenolol, and bisoprolol. Beta blockers inhibit the action of the endogenous catecholamines epinephrine (adrenaline) and norepinephrine (noradrenaline), on β-adrenergic receptors. Beta blockers are believed to work primarily on two types of β-adrenergic receptor, namely the β1 and β2 receptors (13). Both subtypes are present in the brain. β1-adrenergic receptors are also located primarily in the heart and kidneys, whereas β2- adrenergic receptors are located in other tissues, including smooth muscle, skeletal muscle, lungs, gastrointestinal tract, and liver. Of the medications listed, propranolol, nadolol, and timolol are non- selective beta blockers, whereas metoprolol, atenolol, and bisoprolol are relatively selective B1 blockers. Atenolol and nadolol have low lipid solubility, which may be correlated with reduced blood–brain barrier penetration. Bisoprolol has low-to-medium lipid solubility; metoprolol and timolol have medium lipid solubility; and propran- olol has high lipid solubility (13). Given the fact that a broad range of beta blockers is e cacious in migraine prevention, the receptor speci city and lipophilicity of beta blockers seem not to play a role in their antimigraine action.

e mechanism(s) of action by which beta blockers exert their therapeutic e ects in migraine prevention are not known. In one study, propranolol and metoprolol were found to reduce the ampli- tude of visual evoked potentials in patients with migraine, although this change was not necessarily correlated with the e cacy of these medications as migraine preventive therapy (14). In another study, treatment with either metoprolol or bisoprolol reduced the intensity dependence of the auditory evoked cortical potentials, an e ect that was correlated with clinical improvement (15). In rodent models, propranolol has been shown to inhibit CSD (16). Taken together, these results suggest that at least one mechanism of action of beta blockers may be the modulation of brain excitability.

Propranolol is the most widely studied of the beta blockers. More than 20 placebo-controlled trials showed signi cantly greater e – cacy of propranolol compared with placebo for migraine prevention, and a meta-analysis of studies of propranolol at any dose including more than 600 patients showed a signi cantly greater 50% responder rate and signi cant reduction in headache days (17). Studies com- paring the e cacy of propranolol with metoprolol, unarizine,

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table 15.1 Guidelines for the preventive treatment of episodic

migraine.

Source data from: Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman
E. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78:1337– 45; Evers S, Afra J, Frese A, Goadsby PJ, Linde M, May A, et al. EFNS guideline on

the drug treatment of migraine—revised report of an EFNS task force. Eur J Neurol. 2009;16:968–81; Pringsheim T, Davenport W, Mackie G, Worthington I, Aube M, Christie SN, et al. Canadian Headache Society guideline for migraine prophylaxis. The Canadian journal of neurological sciences. 2012;39:S1–59; Holland S, Silberstein SD, Freitag F, Dodick DW, Argoff C, Ashman E. Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78:1346–53.

amitriptyline, and candesartan showed comparable bene t for mi- graine prevention, whereas one study showed superiority of nadolol over propranolol (18). In clinical trials, propranolol was generally well tolerated with less than 5% drop-out due to adverse events. Common adverse e ects include fatigue, reduction in heart rate, reduction in blood pressure, and sexual dysfunction (13,17,19). Common contra- indications to use of a beta blocker include insulin-dependent dia- betes mellitus and asthma. Beta blockers, particularly those with higher lipid solubility, may have the potential to worsen depression, although this e ect has not been con rmed in a number of studies (19,20). Other relative contraindications to the use of beta blocker for migraine prevention include glaucoma and prostatic hypertrophy.

Practical considerations

ere is strong evidence for the e cacy of beta blockers as migraine preventive therapies. ey may be a good rst choice for individ- uals who have hypertension or who have tachycardia at baseline. It remains unclear whether the more lipid soluble and therefore more centrally acting beta blockers have any advantage over those that are less lipid soluble. It is also not clear whether there is a signi cant di erence between β1 selective blockers and non-selective blockers of β1 and β2 receptors. Recent analyses suggest that there may be in- creased stroke risk associated with non-selective beta blockers versus with β1 selective blockers, possibly related to increased variability of blood pressure with the non-selective blockers (21). Non-selective blockers may therefore be contraindicated in older individuals or those at increased risk of stroke

Candesartan

Mechanism of action

Candesartan is administered as a prodrug, candesartan cilexetil, that is metabolized to candesartan during absorption from the gastro- intestinal tract (22). Candesartan selectively blocks the AT1 subtype of the angiotensin II receptor. AT(1) receptors are located primarily in vascular smooth muscle and adrenal glands, and by activation of these receptors, angiotensin II has a variety of e ects, including contraction of vascular smooth muscle, release of adrenal catechol- amines, augmentation of noradrenergic neurotransmission, and an increase in sympathetic tone (22). AT1 receptors are also located in the brain and spinal cord, where they have been reported to modu- late pain transmission (23,24).

Clinical trial evidence

A crossover study comparing candesartan 16 mg to placebo found a signi cant reduction in the number of days with headache or mi- graine during active treatment compared with the placebo period, as well as a signi cant di erence in 50% responder rate (25). A more recent study comparing candesartan with propranolol and pla- cebo found that the e cacy of candesartan was similar to that of

AHS/AAN

Canadian Headache Society

EFNS

Level A: established as effective;
should be offered Divalproex/sodium valproate 400–1000 mg/day Metoprolol 47.5–200 mg/day Petasites (butterbur) 50–75

mg q12h
Propranolol 120–240 mg/day Timolol 10–15 mg q12h Topiramate 25–200 mg/day

Strong recommendation (level of evidence) Amitriptyline (high) Candesartan

(moderate*) Coenzyme Q10 (low) Gabapentin (moderate) Magnesium (low) Metoprolol (high) Nadolol 80–160

mg/day (moderate) Petasites (moderate) Propranolol (high) Ribo avin 400 mg/

day (low) Topiramate (high)

Drugs of rst choice Flunarizine Metoprolol Propranolol Topiramate Valproic acid

Level B: probably effective; should be considered Amitriptyline 25–150 mg/day Atenolol 100 mg/day Fenoprofen 200–600 mg q8h Feverfew 50–300 mg q12h;

2.08–18.75 mg q8h

for MIG-99 Histamine 1–10 ng SC

twice weekly Ibuprofen 200 mg q12h Ketoprofen 50 mg q8h Magnesium 600 mg/day Naproxen 500–1100 mg/

day Naproxen sodium 550

mg q12h
Ribo avin 400 mg/day Venlafaxine ER 150 mg/day

Drugs of
second choice Amitriptyline Bisoprolol 5–10 mg Naproxen
Petasites Venlafaxine

Weak recommendation Divalproex/sodium

valproate (high) Flunarizine 10 mg/

day (high) Lisinopril (low) Pizotifen 1.5–4 mg/

day (high Venlafaxine (low) Verapamil (low)

Level C: Possibly effective; may be considered Candesartan 16 mg/day* Carbamazepine 600 mg/day Clonidine 0.75–0.15 mg/day Guanfacine 0.5–1 mg/day Lisinopril 10–20 mg/day Nebivolol 5 mg/day Pindolol 10 mg/day Flurbiprofen 200 mg/day Mefenamic acid 500 mg q8h Coenzyme Q10,100 mg q8h Cyproheptadine 4 mg/day

Drugs of third choice Acetylsalicylic

acid 300 mg Gabapentin Magnesium Tanacetum

parthenium

3–6.25 mg Ribo avin Coenzyme Q10 Candesartan Lisinopril Methysergide

4–12 mg

Possibly/probably ineffective;
should not be offered Acebutolol Clomipramine Clonazepam Lamotrigine Montelukast Nabumetone Oxcarbazepine Telmisartan

Recommendation against
Feverfew (high) Botulinum toxin

AHS, American Headache Society; AAN, American Academy of Neurology; EFNS, European Federation of Neurological Societies; SC, subcutaneous.

*Note that an additional study that strengthens evidence for candesartan has been published since these guidelines were developed. Also, importantly, these guidelines did not include studies of monoclonal antibodies targeting calcitonin gene-related peptide for migraine prevention.

propranolol based on reduction in headache days and responder rate, and both were superior to placebo (26). Candesartan was generally well tolerated, although dizziness and paraesthesias oc- curred more commonly with candesartan than with propranolol. Interestingly, telmisartan, another AT(1) receptor antagonist, was not e cacious in migraine prevention.

Practical considerations

Candesartan is generally well tolerated. A trial of candesartan is particularly worth considering in patients with hypertension in addition to migraine, or those who have found other migraine pre- ventive approaches di cult to tolerate. It should not be used during pregnancy because of risk of fetal toxicity (category D).

antidepressants

Amitriptyline

Mechanisms of action

Multiple tricyclic antidepressants are commonly used as migraine preventive therapies (27), but the only one with established e cacy is amitriptyline. Amitriptyline inhibits the transporters for sero- tonin and, to a lesser extent, norepinephrine, which is responsible for uptake of these neurotransmitters from the synaptic cle (28,29). It is metabolized to nortriptyline, which also inhibits serotonin and norepinephrine uptake but is a more potent inhibitor of norepin- ephrine uptake. Amitriptyline also has a variety of other mechan- isms of action that may be relevant to migraine. It inhibits sodium, calcium, and potassium channels, and also acts as an antagonist at serotonin receptors, histamine receptors, and muscarinic acetylcho- line receptors (28,29). Amitriptyline’s inhibition of serotonin and norepinephrine uptake are not correlated with its e cacy as a mi- graine preventive therapy, as other more potent uptake inhibitors do not clearly have greater e cacy for prevention of migraine. e antidepressant e ects of amitriptyline are also not correlated with its migraine preventive e ects (30).

Clinical trial evidence

Amitriptyline has not been as extensively studied in clinical trials as other migraine preventive therapies, and the quality of the studies done has not been as high as that for other therapies (11,30). Amitriptyline had better e cacy than placebo in four placebo controlled trials in adults (31–34). Its e cacy was the same as propranolol and uvox- amine in two trials (33,34). e quality of these studies was not high, and in two of the placebo-controlled trials, the end points make the results di cult to compare with other preventive therapy studies. In the other two placebo controlled trials, however, amitriptyline reduced attack frequency by 42% and by up to 51% versus placebo. In the latter trial, amitriptyline appeared to be superior to propranolol because it improved all e cacy parameters, whereas propranolol improved only a severity and headache score. Two recent trials compared amitrip- tyline to topiramate without placebo control (35,36). Both showed no signi cant di erence in e cacy between topiramate and amitriptyline. Another recent study of young people aged 10–17 years found that ami- triptyline plus cognitive behavioural therapy resulted in a substantially greater responder rate and reduction of headache days versus amitrip- tyline combined with headache education (37).

e doses of amitriptyline used varied considerably in clinical trials, ranging from 10mg to 150 mg. Common adverse e ects of amitriptyline in clinical trials included drowsiness (the most

common adverse e ect), dry mouth, weight gain, skin reactions, orthostatic hypotension, nausea, and constipation.

Practical considerations

While classi ed as an antidepressant, the doses of amitriptyline used for migraine are typically substantially lower than those used for de- pression. Also, as mentioned earlier, migraine preventive e ects are not correlated with antidepressant e ects. us, unlike other medications discussed here such as venlafaxine, amitriptyline is not necessarily a medication that can be recommended to treat depression in addition to preventing migraine. Amitriptyline is also commonly used to treat insomnia, bromyalgia, and irritable bowel disorder. It is worth consid- ering as a migraine preventive therapy in patients with these conditions. Nortriptyline is commonly prescribed as an alternative to amitriptyline with potentially better tolerability. is use of nortriptyline is supported by clinical experience but not by clinical trial data.

Contraindications to the use of amitriptyline include narrow- angle glaucoma, urinary retention, pregnancy, breastfeeding, and concomitant use of monoamine oxidase inhibitors. It should be used with caution in patients with kidney, liver, cardiovascular, and thy- roid disease.

Venlafaxine

Mechanisms of action

Venlafaxine is a serotonin–norepinephrine reuptake inhibitor that, at low doses (< 150 mg/day), primarily inhibits the serotonin trans- porter, whereas at higher doses it also inhibits norepinephrine (> 150 mg/day) and dopamine (> 300 mg/day) transport (38,39). It has other e ects, including modulation of opioid receptors and α2- adrenergic receptors.

Clinical trial evidence

Two trials have evaluated venlafaxine as preventive therapy for mi- graine. Neither is considered to be a high0quality study. One study compared venlafaxine to placebo (40), whereas another evaluated venlafaxine versus amitriptyline (41). In the rst study, patients who received venlafaxine 150 mg daily had a signi cantly greater reduc- tion in the median number of days with headache compared with placebo. Adverse e ects, primarily nausea, vomiting, and drowsi- ness, caused six of 41 venlafaxine-treated patients to discontinue therapy. e trial comparing venlafaxine to amitriptyline found that venlafaxine was equivalent in e cacy to amitriptyline 75 mg daily.

Practical issues

Unlike amitriptyline, venlafaxine has antidepressant e ects at doses typically used to prevent migraine, so is worth considering in pa- tients with comorbid depression. e sustained release preparation of venlafaxine may be associated with reduced nausea, a relatively common adverse side e ect of the medication. Discontinuation of venlafaxine, even missing individual doses, may result in signi – cant withdrawal symptoms. It must therefore be tapered very slowly when therapy is discontinued.

anticonvulsants

Valproic acid (divalproex sodium/sodium valproate)

Valproic acid is a liquid at room temperature, but the salt sodium valproate is a solid. Divalproex sodium is a mixture of the acid and the salt (42). Valproic acid has diverse mechanisms of action that

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may be relevant to migraine. Among other e ects, it inhibits so- dium channels, increases brain levels of the inhibitory transmitter γ-aminobutyric acid (GABA), and inhibits histone deacetylases, a class of enzymes that are involved in expression of DNA (43).

Clinical trial evidence

ere have been three parallel group trials and two crossover studies comparing divalproex sodium with placebo. e parallel group studies included more than 500 participants, and showed that divalproex sodium resulted in a signi cantly increase responder rate and a signi cantly lower number of migraine attacks com- pared with placebo (42,44–47). Adverse e ects, particularly nausea, somnolence, tremor, and dizziness, were consistently higher in the divalproex sodium treatment group than in controls. In one study, 27% of patients taking the 1500-mg dose dropped out because of adverse e ects.

Practical considerations

ere is good-quality evidence to support the use of valproic acid, particularly in the form of divalproex sodium, as a migraine pre- ventive therapy. However, the common occurrence of highly sig- ni cant adverse e ects (including those described in the previous subsection, as well as weight gain) limits more extensive use of this therapy. In addition, it has established teratogenic e ects in preg- nancy (category X), further limiting its potential use in women of childbearing age.

Topiramate

Mechanisms of action

Topiramate has several mechanisms of action that may be relevant to migraine. It blocks voltage-dependent sodium channels, it enhances neurotransmission mediated by the inhibitory transmitter GABA, it inhibits the action of the excitatory transmitter glutamate, the α- amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/ kainate subtype of the glutamate receptor, and it inhibits carbonic anhydrase (48).

Clinical trial evidence

Several large parallel group trials, with varying quality, compared topiramate to placebo for migraine prevention. Topiramate 50 mg, 100 mg, and 200 mg doses have been studied, and at each dose the 50% responder rate was signi cantly higher compared with placebo, with the best response seen with the 100 mg dose (49). Adverse ef- fects were common in the topiramate-treated groups, particularly with the 200-mg dose, leading to signi cant drop-out rates. e most commonly reported side e ects were paraesthesias, weight loss, altered taste, anorexia, fatigue, and memory impairment. One of these studies also had an arm comparing topiramate 100 mg with propranolol 160 mg, which showed similar migraine frequency re- duction, responder rate, and reduction in migraine days (50) . One crossover study compared topiramate to sodium valproate, nding no di erence in e cacy between treatments (51). Another com- pared topiramate 50 mg to placebo and lamotrigine, nding that topiramate had a signi cantly greater responder rate compared with the placebo or lamotrigine treatment phases (52). A large parallel group study comparing topiramate 100 mg with amitriptyline 100 mg (or maximum tolerated dose) found that there was no signi cant di erence in the e cacy of topiramate compared with amitriptyline

(35). Although there was no signi cant di erence in discontinu- ation due to adverse e ects in either group, participants receiving topiramate had signi cant weight loss compared with a signi cant weight gain in those on amitriptyline. A large study designed to de- termine whether treatment with topiramate versus placebo could reduce progression from high-frequency migraine to chronic mi- graine found that topiramate resulted in signi cant improvement in headache frequency compared with placebo but did not have any e ect on progression of migraine (3) .

Practical considerations

Topiramate can cause weight loss, and, in fact, was recently approved by the US Food and Drug Administration (FDA) for use in combin- ation with phentermine for weight loss. It may therefore be appro- priate to consider the use of topiramate for migraine prevention in obese patients. Topiramate was also recently approved by the FDA as a therapy for migraine prevention in adolescents. It is also one of two treatments for which there is e cacy for chronic migraine (see ‘Chronic migraine’). Side e ects are common with topiramate, however, and may limit its use. Cognitive dysfunction, particularly language dysfunction, can be problematic (53), and topiramate has been reported to either exacerbate or cause depression (54,55).

Other special considerations when prescribing topiramate in- clude its interaction with oral contraceptives (decreasing e ective- ness of contraception), potential to predispose to renal calculi, and, rarely, acute angle closure glaucoma, and metabolic acidosis.

Petasites

e plants commonly referred to as butterbur are found in the daisy family Asteraceae in the genus Petasites.

Butterbur was reportedly used by ancient cultures as a treatment for headache, and it has been hypothesized that this e ect is medi- ated by petasin and isopetasin, compounds found in highest concen- tration in the plant’s roots. is is the rationale for the development of butterbur root extract as a migraine preventive therapy (56).

Mechanisms of action

e mechanism of action of butterbur root extract is unknown. Speculated mechanisms of action include anti-in ammatory e ects and inhibition of voltage-gated calcium channels (57,58).

Clinical trial evidence

A small (60 patients) double-blind randomized placebo-controlled trial of a speci c butterbur root extract was performed more than 20 years ago, with recent re-analysis of this data (59). is study found that 100 mg butterbur was superior to placebo in all mi- graine preventive parameters studied. ere were no signi cant ad- verse events or changes of laboratory values observed in this study. A larger (202 patients) study of a butterbur root extract found that 75 mg but not 50 mg daily was superior to placebo during a 4-month treatment period (56). Butterbur root extract was also well tolerated in this study

Practical considerations

Components of the butterbur plant are toxic to the liver, and there have been reports of severe liver toxicity as a consequence of use of extracts of Petasites hybridus. e patented version of butterbur root extract that was studied as described above has not been associ- ated with any reports of liver toxicity, possibly because the extraction

procedure involved in the production of this compound removes toxins that are present in other preparations.

Flunarizine

Mechanisms of action

Flunarizine is calcium channel blocker that may also block sodium channels, inhibit H1 histamine receptors, and modulate dopamine uptake, among other mechanisms (60). It is a vasodilator via its ac- tions on vascular smooth muscle, but it does not inhibit coronary calcium channels. It can cause depression and extrapyramidal symp- toms in humans, clearly indicating that it has actions in the brain (61).

Clinical trial evidence

Six trials of fair-to-poor quality have compared unarizine to pla- cebo (62). Each found a signi cant decrease in migraine frequency with unarizine 10 mg daily compared with placebo. e most common adverse e ects were sedation and weight gain. ree trials have compared unarizine to pizotifen for migraine prophylaxis, all of which reported a reduction in migraine frequency in both treat- ment groups, with no signi cant di erence between groups with re- spect to e cacy or side e ects (63–65).

Practical considerations

While evidence and clinical experience indicate unarizine is ef- fective in migraine prevention, its signi cant side e ects limit its widespread use.

Naproxen

Mechanisms of action

Naproxen is a non-steroidal anti-in ammatory drug (NSAID) that has established e cacy as an acute therapy for migraine, either alone or in combination with triptans. e rationale for its use as a pre- ventive therapy is to prevent in ammatory mechanisms that may be involved in the initiation of migraine. A primary mechanism of action is the inhibition of cyclooxygenase (COX)-1 and COX-2 enzymes, which produce prostaglandins and thromboxanes from arachidonic acid (66). Other potent inhibitors of COX, such as indomethacin, however, have been shown to be ine ective in the preventions of migraine, raising doubts about this as the primary mechanism of action of naproxen in migraine prevention. e in- hibition of platelet aggregation has also been proposed as a mech- anism by which naproxen could prevent migraine. However, studies with high doses of acetylsalicylic acid and dipyramidole as pre- ventive therapy did not indicate a correlation between inhibition of platelet aggregation and migraine prevention.

Clinical trial evidence

Naproxen sodium (1100 mg daily) was found in three trials to be superior to placebo in the prevention of migraine (67–69). In one trial it was comparable to pizotifen (67), and in another trial it was comparable to propranolol (70). e e ects of naproxen sodium as a ‘short-term preventive therapy’ for menstrual migraine have also been investigated.

In one study, naproxen sodium 1100 mg daily was shown to re- duce premenstrual pain, including headache (71). In other studies, naproxen sodium 1100 mg daily taken preventively prior to and during menstruation was found to signi cantly reduce headache severity (70), frequency (72), or both (73) compared with placebo.

Gastrointestinal symptoms were the most common side e ects during NSAID treatment, including dyspepsia and diarrhoea, but their frequencies of occurrence were generally not greater than those encountered in participants who took placebo, probably be- cause of the relatively small size of the trials.

Practical considerations

Naproxen sodium be administered with extreme caution in patients with a history of ulcer disease or gastrointestinal bleeding because of the potential risk of gastrointestinal bleeding caused by its use.

e use of NSAIDS, particularly for long durations or in individ- uals with risk factors, has also been associated with an increased risk of myocardial infarction and stroke (74).

Interestingly, unlike most other preventive therapies, naproxen sodium and other NSAIDS are also used as acute migraine therapies. Paradoxically, when used frequently as an acute therapy, NSAIDS are among the medications that are considered as part of the classi- cation of medication overuse headache. At this stage it is not clear how to reconcile this classi cation with their use as a preventive therapy.

Vitamins and naturally occurring compounds

Ribo avin

Mechanism of action

Ribo avin is a key component of avoproteins, which serve as co- factors in mitochondrial energy metabolism. e rationale for use of ribo avin as a preventive therapy for migraine is based on the hypothesis that de ciency in mitochondrial energy metabolism contributes to migraine, and that oral ribo avin could improve this de ciency (75). Whether or not supplemental ribo avin does im- prove mitochondrial energy metabolism in those with migraine is unclear.

Clinical trial evidence

One study with 55 patients found that ribo avin was superior to pla- cebo in reducing migraine attack frequency and headache days (76). A study comparing a combination of ribo avin 400 mg in combin- ation with magnesium and feverfew versus ribo avin 25 mg alone found no di erence in migraine frequency between the two treat- ment groups (77). A randomized, double-blind study of ribo avin 200 mg in children showed no di erence compared with placebo for end points of 50% responder rate, severity of migraine, associated symptoms, or analgesic use. Similarly, a crossover study of ribo avin 50 mg versus placebo in children showed no di erence between groups for the end point of migraine attack frequency.

Practical considerations

Ribo avin is commonly recommended as migraine preventive therapy because of its exceptional tolerability and low cost, but the evidence for its e cacy is limited to a single study, whereas other studies have shown no bene t.

Coenzyme Q10

Mechanism of action

Coenzyme Q10, also known as ubiquinone, is a component of the electron transport chain in mitochondria. e rationale for its use in migraine is similar to that for ribo avin, i.e. that supplemental oral

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coenzyme Q10 will increase de cient energy metabolism that has

been proposed to be involved in migraine (78).

Clinical trial evidence

One open-label (79) and one randomized, double-blind, placebo- controlled study (80) evaluated the e cacy and tolerability of coen- zyme Q10 100 mg given three times daily as preventive therapy for migraine in adults. In the latter study of 42 patients, treatment with coenzyme Q10 was superior to placebo for the primary end point of improvement in attack frequency a er 3 months versus baseline. ere was also signi cantly greater 50% responder rate for attack frequency in the coenzyme Q10 group (47.6%) compared with the placebo group (14.3%). No signi cant adverse e ects were reported. A placebo-controlled, double-blind, crossover, add-on trial of 100 mg of coenzyme Q10 in 122 children and adolescents found no dif- ferences between treatment and placebo in migraine frequency, se- verity, or duration in last 4 weeks of treatment versus baseline (81).

Practical considerations

Like ribo avin, the evidence supporting coenzyme Q10 is as a migraine preventive therapy is weak, but it is o en prescribed for migraine because of its exceptional tolerability. In the one placebo- controlled study in which it was found to be e ective, a liquid prep- aration was used (80). Whether or not this preparation is superior to a tablet form, and whether or not there is any dose dependence of its potential e cacy, remains uncertain.

Chronic migraine

Patients with very frequent migraine represent a distinct therapeutic challenge, owingto the common occurrence of medication overuse in this patient group, the common association of other comorbidities, and possibly owing to distinct pathophysiological mechanisms that take place when attacks of headache occur very frequently (see also Chapter 31). e classi cation of chronic migraine (15 or more headache days per month, with eight or more of them meeting cri- teria for migraine) was created to acknowledge that individuals with very frequent migraine may have distinct pathophysiological mech- anisms and require di erent therapies (82). e speci c de nition of chronic migraine was based in part on empirical observations of the e ects of onabotulinum toxin, which did not show e cacy in clinical trials for patients in whom headache occurred on less than 15 days per month. us, while the designation of 15 days as a cut-o for the classi cation of chronic migraine has now become widely ac- cepted, it is important to recognize that as far as preventive therapy is concerned, onabotulinum toxin is the only medication for which there is evidence to support speci c therapeutic e cacy based on this classi cation. Other preventive therapies may also be e ective in the setting of chronic migraine, although the e cacy for this in- dication has not been speci cally studied. For example, studies of both sodium valproate (83,84) and amitriptyline (85) suggest bene t for chronic daily headache (including both chronic migraine and tension-type headache). Because of the classi cations used for these studies they cannot be directly compared to those described in the following subsections; nonetheless, they raise the possibility that there may be other medications that are e cacious for chronic mi- graine. Multiple monoclonal antibodies targeting calcitonin gene- related peptide (CGRP) have now also been studied as therapies for chronic migraine. ese are discussed separately.

Topiramate

As described earlier, topiramate was found to be e ective as a preventive treatment for episodic migraine in multiple large, well-designed studies. Topiramate was initially found to be specif- ically e ective as a therapy for chronic migraine in a small placebo- controlled trial of patients with acute medication overuse (86). is study was followed by two large, double-blind, placebo-controlled studies of the e cacy and tolerability of topiramate 100 mg for chronic migraine (87,88). Both studies met their primary end point of reduction in the number of headache days per month. In one study, patients with medication overuse were excluded, whereas in the other they were not. Although topiramate was e ective as pre- ventive therapy even in patients with medication overuse, there was not a signi cant reduction in the mean days of acute medication use in either study. Adverse e ects were similar to those reported in studies of episodic migraine, namely paraesthesias and fatigue.

Botulinum toxin

Botulinum toxin was originally identi ed as a potential therapy for migraine prevention based on anecdotal reports from patients who were receiving it for cosmetic indications. Several clinical trials investigating onabotulinum toxin A injections as preventive therapy for episodic migraine did not show e cacy (89). Because post-hoc analysis of these studies indicated potential e cacy for patients with frequent headache, subsequent studies were performed with pa- tients who had more than 15 headache days per month, and these studies led to international approval of the use of onabotulinum toxin for the prevention of chronic migraine (82).

Mechanisms of action

Botulinum toxin is taken up by cells by binding to cholinergic neurons via a synaptic vesicle protein 2 in conjunction with ganglio- sides (90,91). When administered in vivo, it is taken up primarily by cholinergic neurons, including motor neurons that are responsible for muscle contraction, as well as autonomic neurons that mediate sympathetic and parasympathetic function. ere is some in vivo animal evidence that botulinum toxin can modulate the function of nociceptive neurons relevant to migraine (92). In humans, however, there is no de nitive evidence that botulinum toxin results in any signi cant analgesia or anaesthesia, raising questions about the ex- tent to which its e ects are indeed mediated by uptake into nocicep- tive or sensory neurons. A property of clostridial toxins, including botulinum toxin, is that they undergo retrograde trans-synaptic transport into second-order neurons (93,94). is means that botu- linum toxin may have e ects in the brain, as well as in peripheral neurons.

Clinical trial evidence

ere have been two large multicentre randomized clinical trials of the e cacy and safety of onabotulinum toxin A as a preventive therapy for chronic migraine (> 15 headache days per month) (95,96). e rst study included 679 participants randomized (1:1) to receive injections of onabotulinum toxin A (155–195 U) or pla- cebo every 12 weeks for two cycles (95). e primary end point was mean change from baseline in headache episode frequency at week 24. e study did not meet this end point, but it did meet secondary end points of reduction in headache days and migraine days. e

second study included 705 patients randomized (1:1) to receive in- jections of onabotulinum toxin A (155–195 U) or placebo every 12 weeks for two cycles (96). is study met its primary end point of mean reduction in frequency of headache days per 28 days from baseline to weeks 21–24 post-treatment, as well as multiple head- ache and quality-of-life-related secondary end points. e use of acute medications was not signi cantly reduced in either trial in patients treated with onabotulinum toxin A compared with those treated with placebo.

No serious adverse events were reported in the clinical trials for migraine.

Practical considerations

Medication overuse is common in patients with chronic migraine. Onabotulinum toxin A was found to be e ective in reducing head- ache frequency in patients with medication overuse, but, on average, the onabotulim toxin A group did not have a reduction in acute medication use versus the placebo group. It is not clear whether re- duction in the use of acute medication alone could have the same bene cial e ect as preventive therapy with onabotulinum toxin A in patients with medication overuse, or if it could have an additive ef- fect alongside with preventive therapy (97). Whether or not to with- draw patients from acute medications before initiating treatment with onabotulinum toxin A or any other preventive therapy remains a controversial issue (98).

Onabotulinum toxin A as a preventive therapy for migraine has the advantage that it needs to be administered only every 12 weeks, in contrast to most preventive therapies that are administered on a daily basis. e associated disadvantage is that it cannot be self- administered, requiring the time and expense of a physician visit.

Although few serious adverse e ects have been reported in trials of onabotulinum toxin A for headache, multiple serious adverse ef- fects have been reported with its use for other indications (99). Some adverse e ects of onabotulinum toxin A may be under-reported, in part because of the lack of awareness that they may be associated with the treatment. One such adverse e ect is headache (including ex- acerbation of headache in those with pre-existing headache). Severe headache has been reported as a complication of onabotulinum toxin A in patients receiving it for cosmetic indications (100). e exacerbation of headache as a consequence of onabotulinum toxin A may not be appreciated in patients who are already experiencing frequent headache. Flu-like symptoms have also been reported as a relatively common adverse e ect of onabotulinum toxin A in pa- tients receiving it for other indications (101). Here, again, it may be under-reported by physicians treating migraine patients because of the lack of awareness that this may be a related adverse e ect rather than an unrelated event.

CGRP-targeted therapies

Treatments targeting CGRP are novel because of their speci c devel- opment for migraine.

Monoclonal antibodies (mAbs) targeting CGRP or its receptor have now been studied as therapies for both episodic and chronic migraine in extensive phase II and III studies, involving approxi- mately 10,000 patients to date. ree mAbs targeting CGRP are now approved for use in the United States, and are currently being evalu- ated for approved use worldwide.

Mechanism of action

CGRP release into the extracerebral circulation was observed fol- lowing stimulation of the trigeminal ganglion, rst in animal models then in humans (102), and in the superior sagittal sinus in animals (103). ese ndings led to investigation of migraine patients which showed that CGRP levels were elevated in the jugular blood during migraine attacks, and these elevated levels normalized following treatment of migraine with sumatriptan (104). Human triggering studies have provided evidence for a causative role for CGRP in mi- graine. Infusion of human αCGRP in patients with migraine without aura consistently evoked delayed headache (up to 6 hours a er in- fusion), whereas infusion of placebo did not (105); in some patients the CGRP-evoked attack was consistent with migraine. Infusion of CGRP in patients with a diagnosis of migraine with aura also evoked headache, in some cases including aura (106). is substantial pre- clinical evidence led to the development of migraine therapies targeting CGRP, including both small molecules and mAbs. Four mAbs targeting CGRP have been developed for clinical use thus far. One of these, erenumab, binds to and inhibits the function of the CGRP receptor. e other three, eptinezumab, fremanezumab, and galcanezumab, bind the CGRP peptide and thereby inhibit its binding to cellular receptors.

Representative clinical trial data

Primary end points have been met in all of the clinical trials of the mAbs targeting CGRP thus far. No serious adverse events clearly re- lated to any of the therapies have been identi ed, and overall they are reported to be very well tolerated, with minor skin site reactions representing the only common adverse event. In addition to the rep- resentative clinical trials described, multiple long-term safety and e cacy studies are ongoing.

Erenumab

A study investigating the use of erenumab as a treatment for epi- sodic migraine randomized 317 patients to receive subcutaneous administration of 70 mg erenumab monthly for 3 months, 319 to receive 140 mg monthly, and 319 to receive placebo (107). e mean number of monthly migraine days was signi cantly reduced com- pared with placebo for both doses, and secondary end points of 50% responder rate, reduction in acute medication use, and improve- ment in impairment score were also met for both doses. Similar results were obtained in another randomized trial of erenumab for episodic migraine in which 577 patients were randomized to re- ceive either erenumab 70 mg. subcutaneously or placebo monthly for 3 months (108). In a phase II study of patients with chronic mi- graine, 667 patients were randomized to receive either erenumab 70 mg, erenumab 140 mg, or placebo. Both doses met the primary end point of change in month migraine days from baseline in the last 4 weeks of double-blind treatment (weeks 9–12) (109).

Fremanezumab

A multicentre trial of fremanezumab for episodic migraine ran- domized 875 patients to receive either a single subcutaneous dose of 225 mg fremanezumab monthly, 675 mg quarterly, or placebo (110). Both dosing regimens showed a signi cantly greater reduc- tion of monthly headache days at 12 weeks of treatment compared with placebo. In a study of patients with chronic migraine, 1130 were

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randomized to receive either fremanezumab 225 mg monthly, 675 mg quarterly, or placebo (111). As with the study for episodic mi- graine, both dosing regimens met the primary endpoint of mean change from baseline in the average number of headache days per month during the 12-week study.

Galcanezumab

A 6-month trial examined the e cacy of two doses of galcanezumab, 120 mg and 140 mg delivered subcutaneously, for treatment of epi- sodic migraine (112). In total, 858 patients were randomized to re- ceive either dose of galcanezumab or placebo. Both doses met the primary end point of reduced monthly migraine days versus pla- cebo, as well as all key secondary outcomes. A 3-month trial studied the e cacy and safety of galcanezumab, 120 mg with a 240-mg loading dose (n = 278), or 240 mg monthly (n = 277) versus placebo (n = 558) for the treatment of chronic migraine (113). Both dosing regimens met the primary end point of a signi cant mean reduction in monthly migraine headache days versus placebo.

Eptinezumab

A phase II study examined the e cacy, safety, and tolerability of eptinezumab 1000 mg versus placebo, delivered intravenously, for the treatment of patients with episodic migraine (114). e primary end points were safety at 12 weeks following infusion, and change from baseline in monthly migraine frequency in weeks 5–8 a er the infusions. No safety concerns were identi ed, and there was a sig- ni cant reduction in migraine days, which met the primary e cacy end point.

Practical considerations

e availability of these new therapies targeting CGRP raises im- portant logistical questions regarding the preventive management of migraine. Where in the treatment algorithm for migraine should these new therapies be placed versus currently available therapies? Is there any predictor of response? Is there any advantage of one MAb over another? Is their bene t worth the cost?

As described in this chapter, currently available evidence- based migraine preventive therapies can be broadly categorized as antihypertensives, anticonvulsants, antidepressants, botulinum toxin (for chronic migraine), and neuromodulation devices (115). e choice of which therapy to initiate rst, or second, or third, is not entirely straightforward. is decision is based on multiple fac- tors, including predicted e cacy, tolerability, potential for serious adverse events, comorbid conditions, and cost. ere are presently no ‘biomarkers’ or phenotypic indicators that predict response to speci c therapies, and therefore the choice is o en based on comorbidities (e.g. hypertension, insomnia, obesity) that may also be targeted by these treatments.

ere have thus far been no head-to-head trials comparing ef- cacy, safety, and tolerability of previously available migraine pre- ventive therapies with the mAbs targeting CGRP. e ‘responder rate’ analysis clearly indicates that for a subset of patients the mAbs targeting CGRP are dramatically e ective in reducing migraine frequency—possibly more e ective than any other class of migraine preventive treatments. Regarding cost, they are substantially more expensive than most of the current treatments.

With these considerations in mind, how should the mAbs targeting CGRP be prioritized relative to existing treatments? eir

high cost and relatively limited ‘real-world’ experience with their ef- cacy and safety are factors that would favour their use only in in- dividuals with a threshold frequency of migraine attacks who have failed other therapies. However, because they are the only migraine- speci c preventive therapy that has been developed thus far, and they have the potential for substantially superior e cacy and better tolerability, it is not unreasonable to suggest that they should be con- sidered as a ‘ rst-line’ therapy. ese are very di cult questions that involve complex cost/bene t analyses. Further clinical experience is likely to better inform this analysis.

Neuromodulation therapies

Stimulation of branches of cervical and trigeminal nerves has been tried as an approach to acute and preventive therapy of migraine. Uncontrolled trials of implanted occipital nerve stimulators have shown promise as a treatment for chronic migraine, but no con- trolled study has reached a primary end point, and adverse events are common (116,117). Transcutaneous approaches have been developed as a less invasive and better-tolerated alternative to im- planted stimulators.

Transcutaneous supra-orbital nerve stimulation

A double-blinded, randomized, sham-controlled trial examined the e cacy and safety of transcutaneous supraorbital stimulation as a preventive therapy for migraine (118). In total, 67 were randomized to receive either the treatment or sham stimulation with reduced pulse width, frequency, and intensity. Stimulation was administered daily for 20 minutes over a 3-month period. Transcutaneous supra- orbital stimulation was superior to sham for the two primary end points, namely reduction in mean number of migraine days and 50% responder rate. Treatment was also superior to sham for reduction in monthly migraine attacks, headache days, and acute medication use. No serious adverse events were reported.

In a follow-up observational study, 2573 patients who rented the transcutaneous supra-orbital stimulation device were sur- veyed (119). Of those, 2313 who used triptans as acute therapy were selected for study (as a way of selecting patients with migraine). Of these, 1077 (46.6%) were not satis ed and returned the device a er a 40-day period, whereas 1236 (53.4%) were satis ed and purchased the device. ose who were not satis ed did not use the device for the recommended duration. Adverse events reported included dis- comfort with using the device, sleepiness, headache, and local skin irritation.

Practical considerations

e advantage of this device is that as a non-pharmaceutical ap- proach it does not have the potential for systemic adverse e ects, as is the case with medications. A disadvantage is that a signi cant percentage of patients nd it uncomfortable to use. Also the recom- mended time of administration of 20 minutes per day requires a daily time commitment on the part of the patient

Transcranial magnetic stimulation

Single pulse transcranial magnetic stimulation (TMS) is approved in the United States and Europe for the acute treatment of migraine with aura, based on the results of a randomized, double-blind, sham- controlled study (120). More recent studies have suggested that single-pulse TMS may also have s bene t as a migraine preventive

therapy (121). In a non-blinded, non-controlled study, daily admin- istration of single-pulse TMS was found to reduce headache days and associated symptoms in patients with both episodic and chronic migraine (121). A multicentre prospective open label observational study of 263 patients treated with four TMS pulses twice daily found reduction of headache days compared with a statistically derived placebo estimate (122). No serious adverse events were reported.

Practical considerations

As with supra-orbital nerve stimulation, single-pulse TMS has the advantage that it does not have the potential for systemic adverse events, as is the case for medications. It is therefore an appealing al- ternative for those for whom systemically administered therapies are contraindicated or poorly tolerated. As with other neuromodulation approaches, it does require a commitment of time to administer the treatment unlike self-administration of medications.

Conclusion

Substantial progress has been made in the prevention of migraine, and exciting new approaches have been introduced within the past few years. Despite this progress, however, there continues to be a large number of patients for whom currently available migraine pre- ventive therapies are either ine ective or poorly tolerated. A better understanding of the pathophysiological mechanisms of migraine, including how these mechanisms may vary from patient to patient, is likely to lead to more speci c, more e ective, and better tolerated preventive treatments.

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Treatment and management Non-pharmacological, including neuromodulation Delphine Magis

Introduction

Migraine is a common disabling disorder and can signi cantly a ect the patient’s quality of life. However, according to a re- cent study, it appears that patients su ering from migraine seem reluctant to take preventive medications: 28.3% of episodic (International Classi cation of Headache Disorders, third edition (ICHD-3) beta criteria 1.1 or 1.2 (1)) and 44.8% of chronic mi- graineurs (ICHD-3 beta criteria 1.3 (1)) are current users of pre- ventive drugs (2). Besides a lack of drug e cacy, another main reason for treatment discontinuation is the occurrence of side e ects (range 34.8–49% in episodic migraineurs and 34.2–53.2% in chronic migraineurs, according to the drug class) (2). us, there is room for non-pharmacological migraine therapies with similar e cacies and fewer side e ects than the main drugs usu- ally prescribed for migraine prevention, i.e. beta blockers, anti- depressants, antiepileptics, and calcium channel blockers. Of the available migraine preventive drugs, none was initially designed to treat that disease. Conversely, some non-pharmacological mi- graine treatments reviewed in this chapter opened the way to migraine-speci c approaches.

Based on this author’s experience, several types of patients are identi ed in whom non-pharmacological approaches can be proposed:

• patients who do not want to take any migraine preventive drugs for personal reasons, mainly the fear of harmful side e ects;

• patients who have absolute or relative contraindications to the use of migraine preventive drugs;

• patients who are only partly improved by their migraine preventive medication, in order to avoid an additional preventive drug;

• patients who do not improve when on the main preventive drugs, or are considered as drug-refractory (3).
e topic of this chapter is broad and covers very di erent types of approaches. e more relevant therapies will be addressed and the placebo-controlled evidence, if available, will be concentrated on.

Oral therapies or ‘nutraceuticals’

Oral non-pharmacological migraine preventive treatments can be separated into two main classes: the vitamins and other sup- plements, and the herbal remedies, for which the classi cation as ‘non-pharmacological’ is sometimes questionable, leading to the expression ‘nutraceuticals’. e use of some metabolic enhancers in- volved in the Krebs cycle, like ribo avin, is particularly interesting because the rationale derives from previous migraine pathophysio- logical studies. Recently, this class of treatments was extensively reviewed (4,5).

Vitamins and other supplements

Ribo avin

The rationale for giving high doses of riboflavin (or vitamin B2) in migraine prophylaxis arose from brain spectroscopy studies performed in the early 1990s, which showed a reduction in mito- chondrial phosphorylation potential in migraineurs between attacks (see also Chapter 15) (6). Riboflavin is a precursor of flavin mononucleotide and flavin adenine dinucleotide, which are coenzymes indirectly involved in electron transport in oxi- dation reduction reactions in the Krebs cycle (7). Therefore, riboflavin is an important co-factor of energy generation in the mitochondria, and was chosen for its potential therapeutic prop- erties in increasing the mitochondrial phosphorylation that is supposed to be less effective in migraine patients. Hence, it had already been used in some inherited mitochondrial diseases and was able to improve the clinical and biochemical abnormalities in these patients.

Following an encouraging open pilot trial (8), Schoenen et al. performed a randomized controlled multicentre trial of high-dose ribo avin (400 mg) versus placebo in 55 patients su ering from episodic migraine (9). A er 3 months of daily therapy, ribo avin was signi cantly superior to placebo in reducing attack frequency and headache days. e responder rate (i.e. patients with at least a 50% reduction in headache days) was 59% for ribo avin and 15%

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for placebo (P = 0.002), and the number needed to treat (NNT) for e cacy was 2.3. Another double-blind crossover randomized con- trolled trial (RCT) was recently performed with ribo avin in 42 chil- dren, but only a dose of 50 mg was studied (10). A er 16 weeks of therapy, no di erence was found between real treatment and placebo groups, except for tension-type headache-like symptoms (P = 0.04) (10). e main shortcomings of this study were the young paediatric population (mean age 9 years), in whom the placebo e ect is classic- ally higher and the clinical evaluation more challenging, and the low doses of ribo avin used, which was based on a previous study (11). In that trial, the migraine preventive e ect of a combination of 400 mg ribo avin, 300 mg magnesium, and 100 mg feverfew were com- pared to a placebo containing 25 mg ribo avin in 48 adult patients. ere were no di erences between the real treatment and ‘placebo’ groups, but both clinical outcomes were signi cantly positive (11). Recently, all available trials with ribo avin were reviewed, and it was concluded that ribo avin is a safe and well-tolerated option for preventing migraine symptoms in adults; however, there is insu – cient evidence to make a rm recommendation regarding vitamin B2 as an adjunct therapy in adults and children with migraine (12).

e side e ects of ribo avin are mild: gastrointestinal intolerance (1%), polyuria, and, exceptionally, a reversible cutaneous allergy (personal observation). e physician should inform patients that taking ribo avin, which is a water-soluble vitamin, usually changes the urine colour into a bright yellow/orange, which has no known consequences on health. An important point is that ribo avin does not induce any weight gain (or loss), contrary to most migraine preventive drugs.

e mechanism of action of ribo avin in migraine patients has become partly known from two studies (13,14). Sandor et al. (13) demonstrated that patients treated with daily ribo avin (400 mg) for 4 months did not show any evidence of brain excitability changes a er treatment but it was e ective, contrary to those treated with propranolol, suggesting radically di erent underlying patho- physiological mechanisms. In an elegant pharmacogenetic trial, Di Lorenzo et al. (14) treated 64 migraineurs with 400 mg ribo avin for 4 months, and blindly genotyped these patients for mitochondrial DNA (mtDNA) haplogroups. Forty patients responded to ribo avin (P < 0.001). e mtDNA analysis revealed that the outcome was better in patients with ‘non-H’ mtDNA haplotypes: 67.5% of them were responders, whereas 66.7% of ‘H’ were non-responders. e underlying mechanism is unknown but could be related to the asso- ciation of ‘H’ haplotype with an increased activity in mitochondrial complex I, which is a major target for ribo avin. us, the treatment would be less e ective in ‘H’ patients where complex I activity is op- timal but could have a bene cial e ect in haplotypes associated with a lower complex I activity (14).

Coenzyme Q10 and thioctic acid

Coenzyme Q10 and thioctic (α-lipoic acid) are other ‘metabolic en- hancers’ that improve mitochondrial oxygen metabolism and ad- enosine triphosphate production, similarly to ribo avin (see also Chapter 15). eir e cacy was assessed in two randomized placebo- controlled trials (15,16). A er the encouraging results obtained by Rozen et al. (17) in an open study, Sandor et al. (15) performed a randomized placebo-controlled trial with coenzyme Q10 q8h in 42 patients with episodic migraine. A er 3 months of treatment, co- enzyme Q10 signi cantly reduced attack frequency compared with

placebo (P < 0.01), as well as the number of headache days (P < 0.05). e proportion of responders (who improved by at least 50% in fre- quency) was 47.6% for coenzyme Q10 versus 14.4% for placebo (NNT = 3). e tolerance pro le was also excellent, with the excep- tion of cutaneous allergy in one patient. ioctic acid produces a clin- ical and biochemical improvement in various mitochondriopathies, and its preventive e ect (600 mg/day) on episodic migraine was as- sessed in a double-blind placebo-controlled trial in 44 patients (16). e trial had to be interrupted because of slow recruitment and a time limitation on drug quality. e percentage of responders did not di er between thioctic acid and placebo. However, within-group analyses showed a signi cant reduction of attack frequency (P < 0.01), headache days (P < 0.01), and headache severity (P < 0.05) in patients treated with thioctic acid for 3 months, while these outcome measures remained unchanged in the placebo group. No adverse ef- fects were reported. Larger and longer studies would thus be needed for this metabolic supplement.

Magnesium

e rationale for giving magnesium in migraine comes from mag- netic resonance spectroscopy studies performed during and between migraine attacks (18,19), as well as the nding of low magnesium levels in various biological uids interictally (20,21). Magnesium is mainly involved in energy metabolism and decreases neuronal excitability (22).

ree double-blind placebo-controlled trials have been done in migraine prophylaxis. e rst study was performed in 20 women with menstrual migraine, receiving magnesium (360 mg/ day) or placebo daily from ovulation to the rst day of their next menstruations, over two cycles (23). Patients receiving magne- sium had a signi cant reduction in headache frequency and total pain index. In the study by Peikert et al. (24), magnesium dicitrate (600 mg/dose) was used in 81 patients; the 50% responder rate for attackfrequencywas52.8%,buttheplacebo-subtractedratewas only 18.4%. e last trial, using a drinkable aspartate salt of mag- nesium (20 mmol) was interrupted because of a lack of e cacy (25). In a recent review it was concluded that the evidence sup- porting oral magnesium is low (26). However, despite these mixed results, magnesium deserves to be prescribed for migraine preven- tion in some subsets of patients, for example children or females with menstrual-related migraines, at a recommended dose of 400 mg/day (27).

Intravenous magnesium was also experienced in acute migraine treatment. A recent meta-analysis of ve RCTs using intravenous magnesium failed to demonstrate any bene cial e ect in acute pain relief or need for rescue medication (28).

e usual side e ects of magnesium are gastrointestinal (mainly diarrhoea).

Herbal medicines

Botanical or herbal treatment of headache was described in an Egyptian papyrus dated to 2500 bce (see also Chapter 15). e number of plants believed to have some e cacy in migraine is huge, but evidence is sparse. As underlined in a recent review, there are several ways to prepare oral herbal medicines (dried, teas, infusions, capsules, etc.) and some important pitfalls, among them improperly prepared derivatives, loss of potency due to the method of prepar- ation, ignorance of safety concerns, and unknown interactions with

drugs (29). Only butterbur and feverfew will be considered here as they have been employed in properly designed clinical studies.

Butterbur (Petasites hybridus) is a plant that ourishes in moist areas in Europe, and has been used for its analgesic and spasmo- lytic properties for centuries. Its mode of action is unknown, but it seems to have smooth muscle-relaxing e ects and inhibits leuko- triene synthesis. Its leaves are carcinogenic and hepatotoxic, so it is important to use preparations that only contain a special extract from the underground (rhizome) part of the plant. As far as its e cacy is concerned, Diener et al. (30) re-analyzed the outcome of a randomized placebo-controlled parallel-group study using 25 mg q8h of a special extract of butterbur root (Petadolex) for mi- graine prevention in 60 patients. e 50% responder rate for mi- graine frequency was 45% in the butterbur group and 15% in the placebo group a er 3 months of therapy. Another larger RCT used butterbur extract 75 mg q12h, 50 mg q12h, or placebo q12h in 245 patients for migraine prevention (31). Over the 4 months of treat- ment, the 75-mg extract reduced migraine frequency by 48% (P < 0.01), the 50 mg extract by 36% (non-signi cant), and the placebo by 26%. e 50% responder rate for migraine frequency was 68% in the 75 mg-butterbur group versus 49% in the placebo group. e most frequent adverse events were mild gastrointestinal symptoms (mainly burping).

Feverfew (Tanacetum parthenium) has been known since the middle ages as a remedy against headache. e leaves of the plant (member of the daisy family) contain parthenolide, which inhibits nociception and neurogenic vasodilatation in the trigeminovascular system (32). In the study by Pfa enrath et al. (33), three doses of a carbon dioxide extract of feverfew (MIG-99®; 2.08, 6.25, 18.75 mg q8h) were compared to placebo for migraine prevention for 12 weeks in 147 patients (33). Surprisingly, only the 6.25-mg dose was e ective. e 50% responder rate for attack frequency was 27.8% in a sample of 36 patients, but the placebo e ect turned out to be so high that the placebo-subtracted rate was negative (–3.6%). However, in a subset of 49 patients with at least four attacks/month the 50% responder rate was 36.8% versus 15.4% in the placebo group. In a further study led by the same authors (34), the migraine preventive e ect of the 6.25-mg dose of feverfew q8h was compared to placebo in 170 patients during 16 weeks. e migraine frequency decreased signi cantly in the feverfew compared with the placebo group (P < 0.05). A Cochrane review concluded that the ve eligible RCTs (1996–2003, among them the study by Pfa enrath et al. (33)) pro- vided insu cient evidence to suggest an e ect of feverfew over pla- cebo for preventing migraine (35).

More recently, a double-blind placebo-controlled trial assessed the e cacy of a sublingual association of feverfew and ginger for migraine acute treatment (36). Overall, 151 attacks were analysed in the active and 57 attacks in the placebo arm. At 2 hours, pain- free rates were 32% for feverfew/ginger versus 16% for placebo (P < 0.05), and pain relief occurred in 63% of subjects receiving active medication versus 39% for placebo (P < 0.01). is trial suggests that the association could help some patients treat their headache when the intensity is mild, but this needs to be con rmed by fur- ther studies

e most frequent adverse e ects of feverfew are mouth ulcer- ations or in ammation, and loss of taste.

Exercise

Exercise is recommended and has shown some e cacy in various neurological diseases; therefore, headache specialists commonly advise their patients to practise some regular aerobic exercise, but evidence of e cacy in migraine is lacking. Moreover, exercise per se is a well-known headache trigger (37). As underlined in a review by Busch and Gaul (34), most available studies are small pilot trials or case reports, and to date there have been no randomized placebo- controlled trials. e majority of studies did not nd any signi cant reduction in headache frequency and only suggested an improvement of pain intensity in migraine patients due to regular exercise (5,38). One randomized trial compared the outcome in episodic migrain- eurs treated either with exercise (40 minutes, three times weekly), relaxation therapy, or topiramate (up to 200 mg/day) for 3 months (39). Final results were available for 72 patients. e number of mi- graine attacks signi cantly decreased in all groups when comparing the last month of treatment with the baseline period: –0.93 for ex- ercise, –0.86 for relaxation, and –0.97 for topiramate. No signi cant di erences were observed between groups. Migraine intensity only improved in the topiramate group. e authors concluded that exer- cise could be an alternative for patients who do not want to take or are intolerant to migraine preventive drugs (39).

Behavioural therapies

A meta-analysis of 55 studies reported the e ectiveness of various biofeedback techniques (i.e. peripheral skin temperature biofeed- back, blood volume pulse, and electromyography feedback) in mi- graine preventive management over 17 months of follow-up (40). In a recent RCT, Holroyd et al. (41) compared the e ect of the add- ition of one of four preventive treatments to optimized acute treat- ment in 232 patients with episodic migraine (mean 5.5 migraines/ month): beta blocker (n = 53), matched placebo (n = 55), behav- ioural migraine management plus placebo (n = 55), or behavioural migraine management plus beta blocker (n = 69) (41). e addition of combined beta blocker and behavioural migraine management (– 3.3 migraines/month), but not the addition of beta blocker alone (– 2.1 migraines/month) or behavioural migraine management alone (–2.2 migraines migraines/month), improved outcomes compared with optimized acute treatment alone (–2.1 migraines/30 days). e NNT was 3.1 for the addition of that combined therapy compared with optimized acute treatment alone, and 2.6 compared with beta blocker plus optimized acute treatment. Hence, the association of beta blockers and behavioural migraine management could improve the outcome of patients with frequent migraines (41). In chronic mi- graine with acute medication overuse (n = 84 patients), Grazzi et al. (42) also studied the consequence of adding (or not) a behavioural therapy management to pharmacological prophylaxis. Both groups improved signi cantly a er 1 year, but the addition of behavioural therapy provided no superior bene t. However, these results are in contradiction with clinical data obtained previously by the same authors using a similar study design (43). A er a 3-year follow-up, the population receiving biofeedback-assisted relaxation combined

CHaPtEr 16 Treatment and management: non-pharmacological, including neuromodulation

Exercise, behavioural therapies, and multidisciplinary care

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with preventive drugs had a sustained improvement, contrary to pa- tients taking drugs alone. e di erence would be explained by a dif- ferent relaxation programme between studies, i.e. a higher number of sessions in (43). Taken together, these results suggest that adding behavioural therapy to drug prophylaxis can be a useful and harm- less method to achieve a better outcome in patients with frequent episodic or chronic migraine, although there is a lack of scienti c proof (44).

e mode of action of behavioural techniques in migraine is ob- scure. ey could help improve the global feeling of well-being, as MIDAS (Migraine Disability Assessment) scores appeared lower a er biofeedback sessions (45). Moreover, biofeedback is related to muscle relaxation and decreased oxidative stress (45).

e management of patients su ering from chronic migraine with or without acute drug abuse is o en challenging, as they o en have several comorbidities (psychiatric, other chronic pain syndromes, etc.). e studies reported earlier (41–43) clearly demonstrate the need for a multidisciplinary approach to these patients, involving di erent disciplines, called integrated headache care (46). Structures including in- and outpatient care and treatment were therefore set up in various European countries (mainly Germany and Denmark) and in the United States (46). e outcome of patients treated by integrated headache care at the Essen Headache Centre (Germany) was recently published (47). e clinical data of 841 patients were prospectively collected over a 1-year follow-up period a er the initial management. is management di ered according to the ‘phenotype’ of the patient, ranging from psychologist or physical therapist counselling to a 5-day inpatient multidisciplinary treat- ment programme. e subsequent treatment had been provided by private neurologists. A er 1 year, 36.4% had at least a 50% reduc- tion in headache days, independent of their headache phenotype. An overall reduction of monthly headache days was seen in 57.8% of patients (mean reduction 5.8 ± 11.9 days) (47). Surprisingly, higher headache frequency at baseline and age > 40 years were associated with a better outcome. e 1-year follow-up data of the Headache Centre Berlin (Germany) are also available, but the study only in- cluded 201 patients with di cult-to-treat headaches, among them 11 with tension-type headache alone (48). A reduction of at least 50% in headache frequency was observed in 62.7% of patients, inde- pendent of their headache phenotype. A younger age (contrary to the Essen study) and fewer days lost at work/school were associated with a better outcome. Finally, in the Danish Headache Center’s experi- ence, 1326 headache patients had an overall signi cant reduction in headache frequency from 20 to 11 days/month (P < 0.01) and ab- sence from work from 5 to 2 days/month (P < 0.01) (49). Predictors for good outcome were female sex, migraine, triptan overuse, and a frequency of 10 days/month, whereas tension-type headache and overuse of simple analgesics predicted a poorer outcome.

acupuncture

Acupuncture belongs to the traditional Chinese medical armament- arium and is one of the most widely used non-pharmacological ther- apies in many diseases. In migraine, a recently updated Cochrane

review analysed 22 randomised trials (4419 patients) where acu- puncture was compared to routine care (no treatment), to ‘sham’ acupuncture (placebo), or to pharmacological prophylaxis (50). e rst conclusion was that acupuncture provides additional bene t in the treatment of acute migraine attacks only or to routine care. However, there was no evidence of an e ect of ‘true’ acupuncture over sham interventions. In an update of their Cochrane review, the authors came to a slightly di erent conclusion, i.e. that adding acupuncture to the symptomatic treatment of attacks reduces the frequency of headaches, but that, contrary to the previous nd- ings, there is an e ect over sham, but this e ect is small (50). ey added that available trials also suggest that acupuncture may be at least similarly e ective as treatment with prophylactic drugs (50). Hence, in their large study on 794 episodic migraineurs, Diener et al. (51) demonstrated that the outcome a er 26 weeks did not di er between patients treated with sham acupuncture, real treatment acupuncture, or standard drug preventive therapy (beta blockers, calcium channel blockers, or antiepileptics). e percentage of re- sponders (decrease in migraine days by at least 50%) was 47% in the real treatment group, 39% in the sham acupuncture group, and 40% in the standard group (P > 0.1). In a former trial of migraine preven- tion, 302 patients had also been equally improved by real treatment and sham acupuncture (51% and 53% responders, respectively), but both were superior to a waiting-list group (15% responders) (52). More recently, another study reported only a clinically minor e ect of various subtypes of acupuncture over sham procedures in mi- graine prophylaxis (53).

us, even if acupuncture can be considered as a valuable pre- ventive therapy in migraine (50), this is also true for sham acupunc- ture given that the exact needle location seems to have no or limited importance. In a meta-analysis of relevant migraine studies, Meissner et al. (54) revealed that sham acupuncture was associated with higher responder ratios than oral pharmacological placebos (0.38 vs 0.22), which con rms that a relevant part of its overall e ect may be due to non-speci c—but nevertheless interesting—mechanisms.

Neuromodulation

Peripheral neuromodulation

Electrical stimulation of peripheral nerve(s) is a well-known way to treat pain within the nerve territory. In the rst century ad the physician Scribonius Largus advised putting an electric sh on a painful area of skin in order to make the pain disappear. e an- algesic e ects of electrical stimulation have been attributed to several mechanisms: activation of a erent Aβ bres, gate control in the spinal cord, and descending supraspinal control from the rostroventromedial medulla or the periaqueductal gray (55,56). Peripheral nerve stimulation (PNS) is widely used in chronic pain syndromes like neuropathic pain or the complex regional pain syndrome (57). Along the same line, PNS has been used to treat headaches, especially occipital neuralgia (58). In the last decade new emerging drugs for migraine prevention were quasi inexistent so headache clinical researchers turned to alternative, non-pharmacological therapies, among them PNS. e type of PNS was o en chosen according to the migraine phenotype, as it can be invasive and applied continuously, or non-invasive and applied transcutaneously for short periods.

Integrated headache care and multidisciplinary treatment programmes

Invasive PNS

In migraine, like in other primary headaches, invasive PNS has been studied as a preventive therapy in the most disabled patients, i.e. pa- tients chie y su ering from drug-resistant chronic migraine. e most studied technique is great occipital nerve stimulation (ONS).

ONS

e initial rationale for using ONS came from ndings of basic science studies showing the convergence of cervical, somatic, and dural (trigeminovascular) a erents on second-order nociceptors in the trigeminocervical complex (59,60). e e ectiveness of great oc- cipital nerve steroid injections in the prevention of various primary headaches also supported this rationale (61,62).

Besides small and/or heterogeneous open studies, three short- term (i.e. 3 months each) RCTs have been published (63–65). e preliminary ndings of the Occipital Nerve Stimulation for the Treatment of Intractable Migraine (ONSTIM) study (n = 66 pa- tients) suggested a reduction of at least 50% in headache frequency or a fall of 3 points on the intensity scale in 39% of patients treated with active ONS for 12 weeks, whereas no improvement was seen in sham or ‘non-e ectively’ stimulated groups (64). In the sham- controlled Precision Implantable Stimulator for Migraine (PRISM) study (63), ONS did not produce any signi cant reduction in head- ache days in the 125 patients with drug-resistant migraine who com- pleted the 12-week assessment period. However, this cohort was heterogeneous, as patients su ered either from migraine with or without aura, chronic migraine, and/or medication overuse head- ache. e latter could explain a less favourable outcome. Finally, Silberstein et al. (65) did another large study in 157 patients with chronic migraine, who were randomly assigned to active ONS or to sham stimulation, again for a 3-month period. No di erence was found between the two groups as far as the percentage of responders (i.e. at least a 50% reduction in mean daily visual analogue scale (VAS) scores) was concerned. However, there was a signi cant dif- ference in the percentage of patients that achieved a 30% reduction in VAS scores (P < 0.05). e decrease in the number of headache days was higher in the active group than in the control group (P < 0.01), as well as the decrease in migraine-related disability score (P < 0.01). e long-term results of this study were presented at the last International Headache Congress in Boston, June 2013 (66). A er the 3-month randomized phase, the patients continued in an open- label phase of 40 weeks. Headache days were signi cantly reduced by 6.7 days for the intention-to-treat and 7.7 days for the intractable chronic migraine populations (P < 0.01), as well as disability scores. Patients’ self-assessed relief and satisfaction were improved.

Besides the possible mechanisms of action described, ONS could act via non-speci c modulatory e ect on pain-control systems. Persistent hyperactivity in the dorsal rostral pons was reported with H2 15O positron emission tomography in chronic migraine patients treated with ONS (67).

us, these data highlight that ONS could o er a valuable alter- native or add-on therapy for chronic migraine patients, but only a er failure of several preventive medications and non-invasive, non-pharmacological treatments. Patients must be aware that im- provement may be moderate or absent. Besides its invasiveness and cost, the technique may require several surgeries, which can result in complications like electrode migration or battery depletion (68).

In patients with medication overuse headache, it is crucial to perform e ective detoxi cation before considering ONS, as drug overuse seems to be associated with a less favourable outcome (69).

Other types of invasive PNS

Internal le vagus nerve stimulation (VNS) has shown some e ect- iveness in refractory epilepsy. Only observational case reports or retrospective studies are available in migraine, mainly in patients treated for concomitant seizures. In a retrospective study by Lenaerts et al. (70), eight of 10 patients with migraine had at least a 50% re- duction in headache frequency 6 months a er VNS implantation versus the 3-month baseline period. e other surveys included a smaller number of patients, but reported overall a decrease of mi- graine frequency in about 50% of patients undergoing VNS (68).

e mode of action of VNS is obscure. It is believed to modu- late several cortical and subcortical structures, among them areas involved in nociception.

A combination of ONS with supraorbital nerve stimulation (SNS) was performed by Reed et al. (71,72). In a retrospective study of 44 patients with chronic migraine (mean follow-up 13 months), the frequency of severe headaches decreased by 81% and half of the pa- tients had nearly complete disappearance of headaches.

e sphenopalatine ganglion (SPG) is not a peripheral nerve per se but an extracranial autonomic structure lying in the pterygopalatine fossa, which has connections with the trigeminovascular system. e SPG had thus been previously targeted by various lesional pro- cedures in order to alleviate pain in severe refractory primary head- aches subtypes (68). Percutaneous high-frequency stimulation of the SPG has been performed in an open proof-of-concept study, and was able to relieve acute migraine attacks in ve of 10 drug-resistant chronic migraine patients (73).

Non-invasive PNS

e neurostimulation techniques reviewed in the previous sections are invasive, and thus their use seems unsound in less disabled pa- tients, like episodic migraineurs. e analgesic e ects of transcu- taneous electrical nerve stimulation (TENS) have been known for a long time, and the potential bene t of TENS on headaches have been suggested previously (74), but properly designed trials were lacking (75).

e e ectiveness of a portable transcutaneous supraorbital nerve stimulator (tSNS) on episodic migraine prophylaxis has been re- cently evaluated in a randomized double-blind sham-controlled trial (76). Sixty-seven migraineurs (minimum of two attacks/ month) were treated with daily tSNS or sham sessions of 20 min- utes’ duration. A er 3 months, the mean number of migraine days decreased signi cantly in the tSNS group (6.94 vs 4.88; P < 0.05) but not in the sham group (6.54 vs 6.22 P = non-signi cant). e 50% responder rate was signi cantly greater in the tSNS group (38.1%) than in the sham group (12.1%; P < 0.05). Migraine attack frequency and acute drug intake were also signi cantly reduced in the real treatment but not in the sham group. e safety of tSNS and overall patient satisfaction were recently assessed in a study performed in the patients renting the tSNS device to treat their headaches (77). A er an average testing period of 58.2 days, the majority (53.7%) of this population of 2313 patients were satis ed and kept the de- vice. Among the unsatis ed patients, device analysis showed poor

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compliance, as, on average, these patients used tSNS for less than 50% of the recommended time, and 4.5% of them did not even try the device on. Ninety-nine patients of the 2313 (4.3%) reported one or more adverse event(s), but none of them was serious. e mode of action of tSNS in migraine is currently unknown.

New devices thought to stimulate the vagus nerve transcutaneously (tVNS) have been developed. Preliminary open results have shown that these tVNS devices could help some patients (78). In recent overviews of neuromodulation trials in migraine, focusing on vagal nerve and sphenopalatine ganglion stimulation, it was concluded that these techniques o er promising options for the treatment of migraine (79,80).

us, non-invasive PNS, especially tSNS, may be proposed to a larger population of less disabled migraine patients as preventive or add-on migraine therapy, given that the rate of adverse events is very low and none is serious.

Challenges of PNS in migraine treatment

e use of PNS in migraine and headaches in general is associated with some issues in clinical studies and daily patient management. PNS per se provokes paraesthesia in the stimulated nerve territory, and therefore blinding is a real challenge in PNS sham-controlled trials, as they use the absence of stimulation or infra-threshold in- tensities as sham (68), sometimes a er a rst trial with e ective PNS (65). It is thus imperative to enrol only PNS-naive patients for these studies. Moreover, like sham acupuncture, sham surgical treatments induce a higher response rate than oral drug treatments in migraine (proportion of responders 0.58 vs 0.22) (81). is could explain why the overall results of invasive PNS controlled studies are rather modest. ese data are not available for non-invasive PNS. Finally, the compliance of patients treated with migraine preventive non- invasive PNS appears to be a real challenge. In the sham-controlled PREvention of MIgraine using Cefaly (PREMICE) tSNS study (76), patients applied the device 61% of the recommended time, whereas in the survey of the 2300 patients renting the tSNS device, the rate was 48.6% in patients nding the device ‘ine ective’, knowing that one out of ve of the latter patients used the device for less than 60 minutes (77). is issue is unlikely in patients treated with in- vasive PNS. However, the recommended time of use is purely speculative (76).

Central non-invasive neuromodulation

Up to now only non-invasive central neurostimulation tech- niques have been used in migraine. Two main approaches are cur- rently being studied: transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). Both are thought to be able to modulate the activity of the underlying brain area.

TMS

TMS has been employed in clinical neurophysiology since the late 1950s. It is able to modulate the excitability of the underlying cere- bral cortex (depolarization or hyperpolarization), using a rapidly changing magnetic eld delivered by a coil applied at the scalp sur- face. TMS allows the delivery of a single pulse (sTMS) or trains of repeated stimulations (rTMS). rTMS induces long-lasting changes in the underlying cortex; low stimulation frequencies (i.e. 1 Hz) have an inhibitory e ect (82), whereas high frequencies (≥ 10 Hz) are ex- citatory (83). In healthy volunteers and migraine patients, rTMS was

able to durably modify the excitability of the visual cortex, and, in consequence, to balance the electrophysiological abnormalities usu- ally found in migraineurs (84,85), whereas sTMS disrupted cortical spreading depression in animal models (86). us, the application of TMS to migraine management was worthwhile.

Regarding the place of TMS in acute migraine attacks, a recent randomized sham-controlled trial was performed in 164 migrain- eurs with aura using a portable TMS device delivering two single pulses at 30-second intervals over the visual cortex, within the rst hour of aura onset (87). Pain-free response rates at 2 h were 39% for TMS and 22% for the sham device (P < 0.05), and although sig- ni cant the overall therapeutic gain was of 17% only. Sustained pain-free rates at 24 h and 48 h were in favour of TMS, but headache response at 2 h, use of acute medication, or consistency of response did not di er between groups. e eligible population of this study had between two and eight migraine with aura episodes per month; it was not clearly stated if some patients met the criteria for chronic migraine (ICHD-3) (1). Hence, the e cacy of TMS in the treatment of acute migraine attack needs to be con rmed by further studies.

e e cacy of rTMS in migraine prevention has only been in- vestigated in a few small studies. Based on the hypothesis that the le dorsolateral prefrontal cortex (LDLPFC) would exert a pain- reducing top-down control and is hypoactive in chronic migraine, Brighina et al. (88) applied high-frequency rTMS (20 Hz) or sham stimulation to the LDLPFC in 11 chronic migraineurs. A er 12 sessions of rTMS, the attack frequency, headache index, and use of acute medications were reduced, and this e ect lasted up to 2 months. ere was no signi cant improvement in the ve patients receiving the sham stimulation. ese positive results were not con- rmed by another study where 13 patients with chronic migraine also received high-frequency rTMS (10 Hz) over the LDLPFC, which turned out to be less e ective than placebo (89). In episodic migraine the cortical pre-activation level and the habituation of sen- sory cortices to repeated stimulations seem reduced (90). is is not the case in chronic migraine, where the electrophysiological studies suggest heightened cortical pre-activation levels, like in a ‘never- ending attack’ (90,91). It is likely that the therapeutic e ect of rTMS is not linear and will depend on the baseline activation level of the underlying cortex and thus the stimulation parameters will have to vary according to the migraine subtype (68). Based on this assump- tion, inhibitory quadripulse (QP) rTMS (92) was applied over the visual cortex in 16 chronic migraine patients during a 4-week pilot trial (two rTMS sessions a week as add-on therapy) (93). A majority of patients improved signi cantly a er QP rTMS therapy. Monthly migraine days decreased, on average, from 22 before to 13 a er QP rTMS (–41%; P < 0.05) and severe attacks were reduced by 25% (P < 0.05). e 50% responder rate was 38%, while half of patients re- versed from the chronic to the episodic form of migraine. Acute medication intake was signi cantly decreased (–55.5%; P < 0.05). e clinical improvement remained stable at least 1 month a er the end of QP rTMS, with an average of 10.9 migraine days per month (–50.5% vs baseline; P < 0.05) (93). ere were no adverse events and, interestingly, medication overuse did not modify the response to QP rTMS therapy.

tDCS

tDCS has been known and applied to treat neurological dis- orders since the nineteenth century. Nowadays it is a safe central

neuromodulation technique. tDCS uses weak currents to modify the cell’s resting membrane potential, leading to focal modulation of cortical excitability. As in rTMS, opposite e ects can be obtained with tDCS: cathodal stimulation inhibits neuronal ring, whereas anodal stimulation increases it. In healthy volunteers, tDCS is able to modulate resting electroencaphalography and event-related po- tentials (94), and functional connectivity of corticostriatal and thal- amocortical circuits (95). is is of particular interest for migraine as it is thought to be associated with thalamocortical dysrhythmia (96).

e e ect of tDCS on migraine attack was evaluated in a sham- controlled trial involving 62 patients su ering from chronic mi- graine (97). Surprisingly, both tDCS (so far, this trial is only available in abstract form and thus the polarity is unknown) and sham stimu- lation led to a 54.2% reduction in headache intensity, suggesting a non-speci c placebo e ect.

DaSilva et al. (98) performed another sham-controlled trial in 13 patients, using anodal tDCS applied over the primary motor cortex for chronic migraine prevention. ey noticed a delayed e ect on pain intensity and duration (120 days a er stimulation), which was attributed to slow modulation of central pain-related structures (98).

In a proof-of-concept study, Vigano et al. (99) evaluated the preventive e ect of an 8-week anodal tDCS therapy over the visual cortex in 10 episodic migraineurs (two sessions/week). Migraine attack frequency, migraine days, attack duration, and acute medi- cation intake signi cantly decreased during the treatment period compared with pretreatment baseline (P < 0.05), and this bene t persisted, on average, 4.8 weeks a er the end of tDCS. Moreover, an electrophysiological assessment found that a single session of anodal tDCS over the visual cortex was able to increase ha- bituation to repetitive visual stimuli in healthy volunteers and in episodic migraineurs (99), who, on average, lack habituation interictally (90). at anodal tDCS has a signi cant preventive anti-migraine e ect suggests that the low pre-activation level of the visual cortex in migraine patients can be corrected by an activating neurostimulation (99). A larger sham-controlled trial would thus be worthwhile.

Conclusion

e diversity of non-pharmacological migraine treatments is grad- ually increasing and o ers new therapeutic possibilities and hope for patients. Occipital single-pulse TMS and transcutaneous SNS have the strongest evidence (100). tDCS and repetitive magnetic stimula- tion have been promising in pilot studies, but large sham-controlled trials are not yet available (100). For supraorbital transcutaneous stimulation, TMS, and external VNS, there exists one or two double- blind, sham-controlled RCTs, all with favourable outcomes and no severe or dangerous adverse events (101).

e majority of the treatments reviewed here are harmless and their e cacy o en seems within the range of usual migraine preventive drugs.

In the most disabled patients it would be worthwhile setting up multidisciplinary approaches, including alternative therapies (among them non-invasive neurostimulation), before turning to more invasive and expensive devices in chronic treatment-resistant patients (102).

CHaPtEr 16 Treatment and management: non-pharmacological, including neuromodulation

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PART 3

Trigeminal autonomic cephalgias

17. Classi cation, diagnostic criteria, and epidemiology 177
Thijs H. Dirkx and Peter J. Koehler

18. Cluster headache: clinical features and management 182
Ilse F. de Coo, Leopoldine A. Wilbrink, and Joost Haan

19. Paroxysmal hemicrania: clinical features and management 190
Gennaro Bussone and Elisabetta Cittadini

20. SUNCT/SUNA: clinical features and management 196

Juan A. Pareja, Leopoldine A. Wilbrink, and María-Luz Cuadrado

21. Hemicrania continua 203 Johan Lim and Joost Haan

22. Cluster tic syndrome and other combinations of primary headaches with trigeminal neuralgia 208

Leopoldine A. Wilbrink, Joost Haan, and Juan A. Pareja

Classification, diagnostic criteria, and epidemiology
Thijs H. Dirkx and Peter J. Koehler

Introduction

The trigeminal autonomic cephalalgias (TACs), including cluster headache, paroxysmal hemicrania, SUNCT (short-lasting unilat- eral neuralgiform headache attacks with conjunctival injection and tearing), SUNA (with cranial autonomic symptoms) and hemicrania continua, belong to the primary headaches. They are characterized by severe unilateral headache in association with ipsilateral cranial autonomic features, such as lacrimation, con- junctival injection, and nasal symptoms. The TAC concept was first proposed by Goadsby and Lipton in 1997 (1). They classi- fied short-lasting primary headache syndromes into those ex- hibiting marked autonomic activation (TACs) and those without autonomic activation. They hypothesized a pathway of activa- tion between trigeminal afferents (giving rise to pain) and cra- nial parasympathetic efferents (giving rise to cranial autonomic features), hence the name trigeminal autonomic cephalalgias. Cranial sympathetic dysfunction may also be observed, but this is considered a secondary phenomenon. These headaches are frequently associated with features typically associated with migraine, including nausea, photophobia, and phonophobia, whereas migraine aura is rarely observed. The differences be- tween the various clinical syndromes within the TAC group are mainly based upon differences in attack frequency and duration; they share the typical severe pain and autonomic symptoms. Cluster headache is the best known and most frequent headache type within the group of trigeminal autonomic cephalalgias (see Chapter 18). Cluster headache, sometimes also described as ‘sui- cide headache’, is known as the most painful of head pains and one of the most severe pain disorders known to man. The other TACs have a much lower prevalence, although the epidemio- logical literature on this issue is limited.

In this chapter we will brie y discuss the concept of TACs, the dif- ferent clinical syndromes, diagnostic criteria, and epidemiology. In the following chapters each of the TACs will be discussed separately and in more detail.

Classi cation

According to the most recent International Classi cation of Headache Disorders (ICHD-3) criteria, four types of headache may be distinguished among the TACs, with several subdivisions (Box 17.1) (2). e rst ICHD criteria (1988) described cluster headache (episodic and chronic) and chronic paroxysmal hemicrania (3). e concept of TACs was adopted in the ICHD-2 criteria (4) and, fur- thermore, the diagnoses of episodic paroxysmal hemicrania and SUNCT were added in this edition (2005).

Hemicrania continua (see Chapter 21) was not described as one of the TACs in the ICHD-2 criteria owing to its more or less con- tinuous character and as cranial autonomic features were believed to be ‘less constant’ (4, p.61). At the time, it was classi ed among ‘Other primary headaches’ (4.7). It was included in ICHD-3 as one of the TACs based on the fact that the pain is typically unilateral and during superimposed exacerbations of severe, intense pain, there are typical autonomic symptoms (similar to the other TACs). Brain imaging studies showed activation of the posterior hypothalamic area in hemicrania continua, which is also seen in cluster headache and other TACs. Moreover, the absolute response to indometh- acin is comparable to that in paroxysmal hemicrania (5). However, brain imaging studies also showed activation of the dorsal pons in hemicrania continua, which is more similar to the imaging ndings seen in episodic and chronic migraine (5).

In ICHD-3, short-lasting unilateral neuralgiform headache attacks (SUNHA) are subdivided into SUNA and SUNCT. ‘Probable trigem- inal autonomic cephalalgia’ is mentioned as a separate category in the ICHD-3. ese are headache attacks that are believed to be a type of TAC, but which are missing one of the features required to ful l all the criteria.

Both chronic and episodic forms of cluster headache (see Chapter 18), paroxysmal hemicrania (see Chapter 19), and SUNCT/ SUNA (see Chapter 20) are described. In cluster headache, the epi- sodic form is more frequent than the chronic form. Paroxysmal hemicrania and SUNCT/SUNA usually have a chronic course (6).

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Box 17.1 ICHD-3 criteria for trigeminal autonomic cephalalgias (TACs)

3 Trigeminal autonomic cephalalgias (TACs)

. 3.1 Cluster headache

. 3.1.1 Episodic cluster headache

. 3.1.2 Chronic cluster headache

. 3.2 Paroxysmal hemicrania

. 3.2.1 Episodic paroxysmal hemicrania

. 3.2.2 Chronic paroxysmal hemicrania

. 3.3 Short-lasting unilateral neuralgiform headache attacks

. 3.3.1 Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT)
3.3.1.1 EpisodicSUNCT
3.3.1.2 ChronicSUNCT

. 3.3.2 Short-lasting unilateral neuralgiform headache attacks with
cranial autonomic symptoms (SUNA) 3.3.2.1 EpisodicSUNA
3.3.2.2 ChronicSUNA

. 3.4 Hemicrania continua

. 3.4.1 Hemicrania continua, remitting subtype

. 3.4.2 Hemicrania continua, unremitting subtype

. 3.5 Probable trigeminal autonomic cephalalgia

. 3.5.1 Probable cluster headache

. 3.5.2 Probable paroxysmal hemicrania

. 3.5.3 Probable short-lasting unilateral neuralgiform headche
attacks

. 3.5.4 Probable hemicrania continua

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Remitting and unremitting types of hemicrania continua are also distinguished (2).

Primary or secondary

TACs belong to the primary headaches. However, the typical headache syndromes, fulfilling ICHD-3 criteria, have also been described in association with other disorders (e.g. intracra- nial mass lesions and vascular lesions). If a TAC occurs for the first time in close relation to another disorder that is known to cause headache, it should be diagnosed as a secondary headache (2). In comparison with migraine there is a higher incidence of underlying lesions in TACs, although the exact frequency is unknown. If the prevalence of cluster headache is estimated at 0.1% (7), it is of interest to see that in a series of 84 pituitary tumours, TACs were found in 10% of patients, i.e. 100 times more prevalent (8). Although still rare, cluster headache, in par- ticular, is well known to be secondary to intracranial disorders. A 2010 review identified 156 cases presenting with ‘cluster-like headache’ (9). The most frequent pathologies were of vascular origin, for example aneurysms, arteriovenous malformations, and carotid artery dissection (38.5%, n = 57). Tumours repre- sented 25.7% (n = 38) of the cases, of which five were pituitary tumours. Another review (2014) reported 10 pituitary tumours out of 25 patients developing cluster headache secondary to a tu- mour (10). Of the patients in the 2010 review (9), for whom suf- ficient data were available, 50% matched the ICHD-2 criteria for cluster headache. Because of these perfect mimics, the authors

advised magnetic resonance imaging (MRI) in all patients pre- senting with cluster headache.
As they are less prevalent, not much is known about other TACs with respect to secondary headache; however, multiple secondary cases have been described for all TACs. Symptomatic SUNCT, caused by vascular con ict of the trigeminal nerve with an artery, has been described in numerous case reports (11). To exclude underlying causes, imaging (MRI) is advised in all newly diagnosed TACs.

Epidemiology

Cluster headache is the most frequent type of headache among the TACs and a considerable number of epidemiological studies have been conducted. A meta-analysis of population-based studies in 2008 estimated its lifetime prevalence at 124 per 100,000 persons (95% con dence interval 101–151), or approximately 1:1000 persons. e 1-year prevalence was 53 per 100,000 (7). e male-to-female ratio is 4.3. Episodic cluster headache is much more frequent than chronic cluster headache, with a ratio of 6.0 (7). Cluster headache can develop at any age; peak age of onset is between 20 and 29 years. In women with episodic cluster headache a second peak of onset occurs in the sixth decade. In women with chronic cluster headache, the average age of onset is signi cantly higher, with a mean age of 51 years (12). e exact prevalence of the other TACs is unknown. In a large review on the epidemiology of headache it was stated that insu cient data were available to make a reliable statement on the prevalence and in- cidence of the TACs except for cluster headache (13). e following studies give an estimate on the prevalence of the other TACs.

e reported incidence of paroxysmal hemicrania is around 1–3% of cluster headache (14) or one in 50,000 (15). One study showed that 20% su ered from episodic paroxysmal hemicrania and 80% had a chronic course (16). In their review on TACs (6), Goadsby et al. es- timated a chronic course in 65% of patients. As episodic paroxysmal hemicrania was mentioned for the rst time in the ICHD-2 criteria, older studies focus mainly on chronic paroxysmal hemicrania alone. A 2008 study did not con rm a female predominance in 31 patients (16). Previous studies, however, show a higher prevalence in women. In a study of 74 patients, 62% were female (17). In the same study the mean age of headache onset was 41 years (range 6–75 years).

SUNCT and SUNA have been considered rare conditions. An Australian study estimated the prevalence of SUNCT/SUNA at 6.6 per 100,000. An episodic disease course was evident in 58% of 24 pa- tients; the remaining had a chronic course (18). In another study of 52 patients, 43 had SUNCT and nine SUNA. In contrast to the pre- vious study they found that only 13% of patients with SUNCT and no patients with SUNA had the primary episodic form of the disease (19). In a literature review of 222 cases the mean age at onset was 47.6 years. e SUNCT group consisted of 109 men and 74 women versus 11 men and 19 women with SUNA (20).

Hemicrania continua seems more frequent than SUNCT/SUNA and paroxysmal hemicrania. Some claim it is underdiagnosed, but the exact prevalence is unknown. It may be frequently misdiagnosed as chronic tension type headache or chronic migraine. In one study 24 out of 34 patients were women and the mean age of onset was 28 years (range 5–67 years) (21).

At the level of reference centres, the following gures are avail- able. In a general neurology clinic in the UK, headache was the pri- mary complaint in 23.4% of 3394 patients (22). Forty patients were

diagnosed with a TAC (1.2% of all referrals, 5.3% of all headache pa- tients), of which 36 had cluster headache and four SUNCT/SUNA. None of the patients was diagnosed with paroxysmal hemicrania. ree patients were diagnosed as having hemicrania continua, which was not classi ed as a TAC at the time.

In a large retrospective study in a tertiary headache centre in China, 1843 patients (1152 women) were diagnosed according to the ICHD-2 criteria. Ninety-eight patients (5.3%) were diagnosed as having trigeminal autonomic cephalalgia, and cluster headache was the most common subtype (n = 83). e remaining 15 cases included 10 patients with probable cluster headache and ve with SUNCT. Patients with paroxysmal hemicrania were not found in this study. Hemicrania continua was not speci cally mentioned in this study, but was classi ed under other primary headaches, with a combined prevalence of 1.5% (23).

In a tertiary headache clinic in Spain, 1000 patients were diag- nosed according to the ICHD-2 criteria. Twenty-six (2.6%) were diagnosed as having trigeminal autonomic headaches, including 20 patients with cluster headache, four with paroxysmal hemicrania, and two with SUNCT. Moreover, 16 patients were diagnosed with hemicrania continua, which is a relatively high incidence compared with other studies (24).

Looking at population-based epidemiological studies the fol- lowing data are of interest. In the Vågå study on headache epi- demiology, all residents of the Norwegian town of Vågå aged 18–65 years old, were asked to participate; 1838 persons (88.6%) were included. ey were screened for many types of headache by way of a headache questionnaire. Seven patients with cluster head- ache were found, resulting in a prevalence of 0.3 (25). Two patients with possible SUNCT/SUNA and one possible case of chronic paroxysmal hemicrania was found. Eighteen patients reported a headache syndrome that was suggestive of hemicrania continua. ese diagnoses were labelled probable, because an indometh- acin test (which is necessary for a de nite diagnosis) could not be conducted (26).

To summarize, cluster headache is the most frequent of the TACs. Epidemiological data on the other TACs are scarce and variable. e studies discussed above suggest that hemicrania continua is prob- ably the second most prevalent TAC. SUNCT/SUNA and parox- ysmal hemicrania are very rare.

Distinguishing between the taCs

e various types of TAC are not only distinguished by di erences in attack frequency and duration, but also by di erences with re- spect to the response to treatment (6). Cluster headache has the longest attack duration (15–180 minutes). By de nition, the attack frequency is typically between one attack in 2 days to a maximum of eight attacks a day. Typical for cluster headache is the nocturnal occurrence of attacks and, of course, the cluster periods. Paroxysmal hemicrania has an intermediate attack duration (2–30 minutes) and a median frequency of 11 attacks daily (16). SUNCT/SUNA has the shortest attacks (1–10 minutes) and the highest attack frequency (up to 100 attacks daily). Several di erent attack patterns of SUNCT/ SUNA are described (see Chapter 20). Hemicrania continua has a more continuous dull pain with exacerbations that may include the typical autonomic symptoms and severe pain. e autonomic symp- toms tend to be less prominent than the in other TACs.

e characteristics of these headaches will be further discussed in the next chapters. A conveniently arranged overview with respect to the distinctions between the TACs is presented in Table 17.1.

Differential diagnosis

e TACs can usually be recognized easily by an adequate descrip- tion of attack characteristics, frequency, and duration. No laboratory or radiological tests are available to con rm the diagnosis.

It is of importance to realize that cranial autonomic symptoms, as seen in the TACs, may be observed in other types of headache as well, but usually they are more severe in TACs. A typical feature of TAC is the lateralization of autonomic symptoms ipsilateral to the side of the headache. Likewise, migrainous symptoms (photophobia and phonophobia), are also more frequently ipsilateral to the head- ache in TACs, compared to migraine, where these symptoms are

table 17.1 Characteristics of cluster headache, paroxysmal hemicrania, and SUNCT/SUNA

CHaPtEr 17 Classi cation, diagnostic criteria, and epidemiology

Cluster Headache

Paroxysmal Hemicrania

SUNCT/ SUNA

Sex

3M to 1F

M=F

1.5M to 1F

Pain

Quality

Sharp/stabbing/ throbbing

Sharp/ stabbing/ throbbing

Severity

Very severe

Severe

Distribution

V1> C2> V2> V3

V1 > C2> V2> V3

V1> C2> V2> V3

Attacks

Frequency (typical day)

1-8

100

Length (typical in minutes)

30-180

2-30

1-10

Triggers

Alcohol

+++

–

Nitroglycerin

+++

–

Cutaneous

–

+++

Agitation/restlessness

90%

80%

65%

Episodic vs chronic

90:10

35:65

10:90

Circadian/circannual periodicity

Present

Absent

Treatment effects

Oxygen

70%

No effect

Sumatriptan 6 mg

90%

20%

< 10%

Indomethacin

No effect

100%

No effect

Migraine features with attacks

Nausea

50%

40%

25%

Photophobia/ phonophobia

65%

25%

* Based on several cohorts and patients seen in practice.16,19,33

SUNCT/SUNA, short-lasting unilateral neuralgiforrn headache attacks with conjunctival injection and tearing/short-lasting unilateral neuralgiform headache attacks with cranial autonomic features; M, male; F, female; C, cervical; V, trigeminal

Reproduced from Seminars in Neurology, 30, Goadsby PJ, Cittadini E and Cohen AS, Trigeminal Autonomic Cephalalgias: Paroxysmal Hemicrania, SUNCT/SUNA,and Hemicrania Continua, pp. 186–91. © 2010 Georg Thieme Verlag KG.

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most o en bilateral (6). An important feature of cluster headache (and also other TACs) is a sense of restlessness during attacks. is is a characteristic di erence to individuals with migraine, who tend to remain as still and as quiet as possible.

In some cases it may be di cult to distinguish between the dif- ferent TACs. e clinical syndromes of paroxysmal hemicrania and SUNCT/SUNA may sometimes be very similar. Di erentiating be- tween these is important considering the treatment consequences. As paroxysmal hemicrania has an absolute response to indometh- acin, a trial of indomethacin treatment is recommended when there is clinical uncertainty about the diagnosis.

Hemicrania continua may be confused with other forms of uni- lateral chronic daily headache (e.g. migraine or chronic tension type headache), but also with cluster headache, in which a dull back- ground headache may persist between attacks. If there is one-sided headache and doubt about the diagnosis, again, a trial treatment with indomethacin may be considered (21).

SUNCT/SUNA may be confused with trigeminal neuralgia (TN) (27). In some patients both the ICHD criteria for TN as for SUNCT/ SUNA are ful lled. Autonomic symptoms have been described in TN; however, they are considered to be more prominent in SUNCT/ SUNA. Autonomic symptoms in TN tend to develop a er several years. Furthermore, TN attacks tend to be shorter. e mean dur- ation of a SUNCT attack is 61 seconds (5–250 seconds) (28), while for TN the duration is 1–60 seconds, with most attacks lasting only several seconds (29). In both TN and SUNCT, patients are sensitive to cutaneous triggers. In TN there is typically a refractory period following a trigger; this is not found in SUNCT/SUNA. In TN, < 5% of cases involve the rst trigeminal division (V1) only, whereas in SUNCT, attacks con ned to V1 are typical. Rare cases of patients presenting with cluster headache (or even less frequently parox- ysmal hemicrania) and TN simultaneously have been described (the cluster tic syndrome; see Chapter 22).

Pathophysiology

e pathophysiology of TACs is still not completely understood. e name indicates the hypothesis that activation of the trigemino- autonomic re ex may be part of the pathophysiological mechanism (Figure 17.1). Pain a erents from the trigeminal nerve project to

the thalamus and cortical areas leading to the awareness of pain. Activation of the trigeminal nerve also causes re ex activation of the parasympathetic out ow from the superior salivatory nucleus via the facial nerve. is results in the typical autonomic symptoms, including lacrimation, reddening of the conjunctiva, and nasal con- gestion. It also acts as a positive feedback system resulting in dila- tation of blood vessels, thereby leading to a further stimulus of trigeminal a erent nociceptors (30). is may be the nal common pathway by which the typical symptoms of the TACs develop.

ere is evidence that the hypothalamus plays a central role in the pathophysiology of the TACs. Positron emission tomography and MRI studies show hypothalamic hyperactivity ipsilateral to the side of the headache in cluster headache, contralateral in par- oxysmal hemicrania, and bilateral in SUNCT during attacks (31). A key role of the hypothalamus may explain the typical rhythm of attacks in TACs.

A dysfunction in the hypothalamus, or other areas of the pain ma- trix, may lead to a permissive state, in which the trigeminal auto- nomic re ex is dysregulated, which may cause the typical pain and autonomic symptoms. e posterior hypothalamus may play a part in terminating attacks, thereby regulating the duration of individual attacks and therefore be responsible for the di erent TAC types (32). It is striking, however, to realize that the optimal treatment regimens for the di erent TACs are not the same, which implies a di erent pathogenesis. For example, the excellent response to indomethacin in paroxysmal hemicrania and hemicrania continua is not found in cluster headache or SUNCT/SUNA. Cluster headache attacks respond to oxygen and triptans; furthermore, attack frequency is greatly reduced by verapamil. SUNCT/SUNA has been di cult to treat. Successful results have been described with lamotrigine, gabapentin, and topiramate.

Conclusion

Cluster headache is the most frequent headache type of the TACs. e other TACs are rare, but epidemiological data are scarce and variable. e TACs are characterized by typical unilateral headache attacks with associated ipsilateral cranial autonomic symptoms. e various types of TAC are not only distinguished by di erences in attack frequency and duration, but also by di erences with respect to the response to treatment. ere is some evidence for a shared pathophysiology in all TACs.

V ganglion
Dura mater SSN

Pain

Trigemino- cervical complex

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Pterygopalatine ganglion

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Figure17.1 Trigemino-autonomicre ex.
SSN, superior salivatory nucleus; TNC, trigeminal nucleus caudalis.

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181

Cluster headache
Clinical features and management Ilse F. de Coo, Leopoldine A. Wilbrink, and Joost Haan

Introduction

Cluster headache is a well-de ned primary headache syndrome, characterized by unilateral short attacks of excruciating pain located in the orbital, supraorbital, or temporal region. In the typical form, the attacks are accompanied by ipsilateral cranial autonomic fea- tures of the eye and nose (1,2).

e rst description was probably made by the famous Dutch physician, anatomist, and mayor of Amsterdam, Nicolaes Tulp (1593–1674) in the seventeenth century (3). Over the years the headache was given many names, such as Horton’s disease, mi- grainous neuralgia, and hemicrania neuralgiformis chronica. e name cluster headache was established in 1952 and refers to the typ- ical episodic character of the syndrome such as it occurs in the ma- jority of patients (4,5).

Epidemiology

e prevalence of cluster headache is about 1 in 1000 persons (6), making it much rarer than migraine. e male to female ratio is 4.3:1. Peak age of onset is between 20 and 29 years (6–8), but cluster headache can start at any age. ere are many reports of young chil- dren with cluster headache; descriptions of cluster headache in octo- genarians or older are, however, very exceptional. More about the epidemiology of cluster headache can be found in Chapter 17.

Patients with cluster headache su er from attacks of severe-to-very severe unilateral pain, which is located in the orbital, supraorbital, and/or temporal regions (2). Rarely, patients experience bilateral pain during an attack. Side shi ing between headache attacks or cycles, however, is reported by 14–38% of patients (9,10).

According to the current criteria (Box 18.1), cluster headache attacks last between 15 and 180 minutes, but a longer duration of

attacks has been reported, especially in females (11). Attacks occur from once every other day to a maximum of eight per day. A bout or episode is a period in which frequent cluster headache attacks occur. Such a period may last from weeks to months. Patients with cluster headache are o en restless during an attack, and most have ipsilateral autonomic symptoms such as lacrimation (91%), con- junctival injection (77%), nasal congestion (75%), ptosis, eyelid oedema, rhinorrhoea, forehead and facial sweating, miosis, aural fullness, and/or facial ushing. ese symptoms disappear a er the attack, although ptosis and/or miosis can also persist outside attacks. In a minority of patients, cluster headache attacks can also be ac- companied by nausea and vomiting. Patients can experience an aura preceding their attacks, which can exist of fully reversible visual symptoms, sensory symptoms, speech disturbances, or a combin- ation of these. Motor, brainstem, or retinal symptoms are very rare (12–14). Pre- and postictal symptoms are very frequent (15). During attacks, allodynia can occur (16).

Cluster headache can be divided into an episodic and a chronic form. Most patients (approximately 80%) have the episodic form, which is de ned as a lifetime occurrence of at least two cluster periods lasting more than 7 days to 1 year, separated by pain-free remissions periods of more than 3 months. e remaining 20% are diagnosed with the chronic form, which is de ned as having attacks for more than 1 year without remissions that last longer than 30 days. In the episodic form the mean duration of a bout is around 8.6 weeks (9). Many patients have one bout per year, but patients can also stay attack-free for many years. A change from the episodic to the chronic form (secondary chronic cluster headache) and vice versa (secondary episodic cluster headache) can occur (17–20). In a 10-year follow-up study of 189 patients, about 13% of episodic cluster headache patients became chronic and about 30% of chronic cluster headache patients became episodic (17).

ere are several triggers for individual attacks when patients are in an active episode, such as alcohol, vasodilators, daytime naps, changes in air pressure (airplane, diving), weather changes, and cer- tain odours (1,10,20–23). Remarkably, these triggers do not cause headache outside an active episode/bout.

Clinical features, physical examination, and imaging

Studies of large cluster headache cohorts have shown that pa- tients use more alcohol and co ee than the general population. Surprisingly, males are more likely to have a history of smoking, whereas females smoke less, compared to the general population (21,24). A history of head trauma is more o en reported in patients with cluster headache (19,23,25). However, the causality of these as- sociations is uncertain.

Outside attacks, physical examination is normal in the vast ma- jority of patients, except for ptosis or miosis ipsilateral to the head- ache attacks, which can persist in a minority of patients in the absence of a structural lesion that can cause the symptoms (4). A diagnosis of cluster headache is based on the criteria of the International Criteria of Headache Disorder, third edition (ICHD-3). Contrast-enhanced cerebral magnetic resonance imaging (MRI) should be considered once in every patient, to exclude a causal underlying pathology. A variety of intracranial pathologies have been reported to produce a cluster-like headache phenotype, including cerebral tumours such as prolactinoma or parietal glioblastoma, arteriovenous malforma- tions, and in ammatory conditions (26–28). Repeated contrast- enhanced MRI should be considered if the characteristics of the headache attacks change over time. See Box 18.2 for a comprehen- sive di erential diagnosis.

Cluster headache is thought to be a neurovascular disease, in which the so-called trigeminal autonomic re ex can play a role (29). Experimental stimulation of the trigeminal ganglion leads to an in- crease of intra- and extracerebral cranial blood ow (durovascular complex). e rst division of the trigeminal nerve innervates the dura mater. Its neurons project to second-order neurons in the trigeminocervical complex, which consists of the trigeminal nucleus caudalis and the dorsal horns of C1 and C2. Pain signals from the trigeminocervical complex project to the hypothalamus, thalamus, and cortex via pain processing pathways (30–32). e trigeminocervical complex also activates the parasympathetic auto- nomic out ow, as it projects to the superior salivary nucleus. e su- perior salivary nucleus gives rise to cranial parasympathetic e erents that traverse along with the facial nerve, passing through structures such as the geniculate ganglion and synapsing in the sphenopalatine ganglia. ese neurons project to the cranial vessels and the dura mater, and stimulation results in dilatation of the vessels and irrita- tion of the trigeminal nerve endings (Figure 18.1) (31).

e trigeminal nerve endings contain vasodilator peptides like calcitonin gene-related peptide (CGRP), substance P, neuropep- tide A, and vasoactive intestinal peptide (VIP) that innervate blood vessels (31). During a cluster headache attack, CGRP and VIP levels increase in cranial venous blood, indicating activation of the trigeminovascular system (33,34).

e hypothalamus is also thought to be involved in the patho- physiology of cluster headache. Diurnal and seasonal rhythmicity of cluster headache suggests involvement of the suprachiasmatic nucleus, also known as the biological clock (35). e suprachi- asmatic nucleus projects onto the orexinergic system, which has in uence on functions such as feeding, the sleep–wake cycle, and the ability to modulate trigeminal nociceptive processing. Genetic association studies have suggested a role of the orexinergic system (see ‘Genetics’), as a polymorphism in the OX2R receptor (HCRTR2) was repeatedly found to be associated with cluster headache (36–38).

In positron emission tomography studies a di erence is seen in the hypothalamic grey matter in patients in and outside an active episode of cluster headache (39–41). It has been hypothesized that these hypothalamic volume abnormalities could re ect a dynamic process, which might tend to reverse outside the attack phase.

Genetics

At present, cluster headache is considered to be a complex genetic disorder, i.e. multiple genetic and environmental factors contribute to cluster headache susceptibility. e risk of a rst-degree family member of a cluster headache patient also having cluster headache is 5–18 times higher than in the general population, and for second- degree relatives 1–3 times higher (6). HCRTR2 is so far the only es- tablished susceptibility gene for cluster headache (37,42–44). In a genome-wide association study no variant was statistically signi – cant associated with cluster headache (45). e three most suggestive polymorphisms were repeated in a Swedish cohort of cluster head- ache and controls, but no impact was found on the risk of developing cluster headache in those with these polymorphisms (46).

CHaPtEr 18 Cluster headache: clinical features and management Pathophysiology

Box 18.1 ICHD-3 criteria for diagnosing cluster headache

A B

At least ve attacks ful lling criteria B–D.
Severe or very severe unilateral orbital, supraorbital, and/or tem- poral pain lasting 15–180 minutes (when untreated)
Either or both of the following:

1 At least one of the following symptoms or signs, ipsilateral to the headache:

a. Conjunctival injection and/or lacrimation

b. Nasal congestion and/or rhinorrhoea

c. Eyelidoedema

d. Forehead and facial sweating

e. Miosisand/orptosis.

2 A sense of restlessness or agitation.

D
ENot better accounted for by another ICHD-3 diagnosis.

Occurring with a frequency between one every other day and eight per day.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Box 18.2 Differential diagnosis of cluster headache

• Paroxysmal hemicrania.

• Short-lasting unilateral neuralgiform headache with conjuncitival
injection and tearing (SUNCT).

• Short-lasting unilateral neuralgiform headache with cranial auto-
nomic symptoms (SUNA).

• Migraine.

• Temporal arteritis.

• Trigeminal neuralgia.

• Sinusitis.

• Glaucoma.

• Tumours (particularly parasellar/pituitary).

• Arteriovenous malformations.

• Infarction.

• Dissection of carotid or vertebral arteries.

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Durovascular complex

Cortex Thalamus

Hypothalamus

Greater petrosal nerve

Sphenopalatine ganglion

Dural afferents

Trigeminal nerve

Trigeminal ganglion

– +

TCC Facial (VIIth nerve/parasympathetic outflow)

Superior salivatory nucleus

Figure 18.1 (see Colour Plate section) The trigeminal autonomic re ex. TCC, trigeminocervical complex.

Reproduced from The BMJ, 344, Nesbitt AD, Goadsby PJ, Cluster headache, 344:e2407. Copyright (2012) with permission from BMJ Publishing Group Ltd. doi: https://doi.org/ 10.1136/bmj.e2407.

Diagnosis

A diagnosis of cluster headache is made based on the history of the patient, by applying the ICHD-3 criteria (Box 18.1) (4). Because of the distinct phenotype and the typical annual and circadian pattern, the diagnosis should not pose great problems in typical patients. In daily practice, however, a delay of 3–5 years in making a diagnosis of cluster headache is not uncommon (10,47,48). One of the reasons is that, at rst, the symptoms are ascribed to eye, nose, sinus, jaw, or teeth disorders by patients and physicians. Furthermore, the rela- tive rarity and the episodic nature (attacks o en disappear spontan- eously) also cause di culty in making the correct diagnosis in time.

Differential diagnosis

Cluster headache is one of the primary headaches categorized as tri- geminal autonomic cephalalgias (TACs), which owe their name to the trigeminal distribution of the pain and the accompanying ip- silateral autonomic symptoms. In general, attacks of paroxysmal hemicrania (PH) are shorter than those of cluster headache, but there is an overlap in duration (PH: 2–45 minutes; cluster headache 15–180 minutes) (see Chapter 19). However, in contrast with cluster headache, PH responds dramatically to treatment with indometh- acin. Short-lasting unilateral neuralgiform headache with conjunc- tival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) can be di erentiated from cluster headache by the duration of the attacks. SUNCT and SUNA attacks last between 1 second and 10 minutes, with a median of 1 minute (see Chapter 20).

To di erentiate between migraine and cluster headache is some- times di cult. Two features can be important. Firstly, patients with migraine o en seek rest, whereas most cluster headache patients are restless during an attack. Secondly, the duration of a cluster headache attack is 15–180 minutes and that of a migraine attack 4–72 hours. ere are, however, exceptions with cluster headache attacks being longer and migraine attacks shorter (especially when treated suc- cessfully). Both cluster headache attacks and migraine attacks can be accompanied by nausea, vomiting, photophobia, phonophobia, and osmophobia, but this is more o en the case in migraine. Cluster headache attacks can be preceded by aura symptoms, so that this also cannot be used for a de nite distinction between cluster head- ache and migraine. However, cluster headache can be di erentiated from migraine in the majority of cases by its frequency and the typ- ical time pattern of attacks.

For a comprehensive di erential diagnosis see Box 18.2. treatment

e treatment of cluster headache consists of a combination of acute and prophylactic treatment. Approximately 10% of patients with chronic cluster headache, however, do not respond to pharmaceut- ical prophylactic treatment. In these refractory patients surgical pro- cedures can be considered.

acute symptomatic treatment

Acute treatment aims at reducing the pain of an individual headache attack. e treatment should act rapidly, because of the severity of the pain and its relatively short duration. e most e ective acute

treatments are the 5-HT1B/1D agonist sumatriptan in injectable and intranasal formulations, and inhalation of 100% oxygen.

e rst choice is sumatriptan 6 mg subcutaneous (SC). A double- blind, placebo-controlled trial showed that 46% of the patients are pain-free within 15 minutes (49). In the past, patients were advised to use a maximum of two sumatriptan doses per day, but, based on recent case reports and anecdotal experience, a higher number of doses could be allowed if monitored carefully (50).

Sumatriptan nasal spray can also be e ective, but is probably of use only in longer attacks (> 45 minutes), because it acts slower than the SC form (51). Oral triptans and oral analgesics, like non-steroidal anti-in ammatory drugs, are not e ective in cluster headache, mainly because they act too slowly. Opiate-containing analgesics are also not recommended.

Another option for attack treatment is inhalation of 100% oxygen with a ow rate between 7 and 12 litres per minute for around 15 minutes. It quickly relieves attacks in about 60% of patients, espe- cially in attacks with milder pain (52). In some patients, however, it seems to postpone the attack rather than abort it (53,54).

Intranasal zolmitriptan can be an alternative for patients who do not respond to or cannot tolerate sumatriptan and oxygen. Intranasal zolmitriptan 5 mg, however, is slower than sumatriptan SC. A double-blind placebo-controlled study showed that 38.5% of patients were pain free 30 minutes a er zolmitriptan 5 mg. A dose of 10 mg was also e ective but caused more side e ects than the 5-mg dose (55,56). Remarkably, oral zolmitriptan was also shown to be somewhat e ective in attacks of episodic cluster headache, but not in those with chronic cluster headache (57).

ere is little evidence for the e cacy of dihydroergotamine (DHE) for individual attacks. An open-label study of 54 patients (episodic and chronic) showed an improvement in patients who were repeatedly treated with intravenous DHE. All patients were headache free a er 5 days of treatment (58). DHE is also available in a SC and an intramuscular injectable form.

Prophylactic treatment

e goal of prophylactic treatment is to reduce the number of cluster headache attacks as much as possible. is treatment is given during the bout in patients with episodic cluster headache and continuously in those with chronic cluster headache.

e prophylactic treatment of rst choice is verapamil in both epi- sodic and chronic cluster headache (59). It is generally well tolerated and can be safely combined with sumatriptan. In most patients dos- ages up to 480 mg daily are e ective; however, some patients need dosages as high as 960 mg daily. Electrocardiography should be performed at baseline, before every increase in dose and/or annu- ally to check for atrioventricular cardiac block, which is potentially dangerous and thus a contraindication to continuing verapamil treatment (60). e most common side e ects of verapamil are con- stipation, fatigue, dizziness, and bradycardia (61,62).

Lithium was shown to be e ective in chronic cluster headache, but it is associated with more side e ects than verapamil (61,63). e dose must be based on repeated measurements of the serum level of lithium, which should be between 0.8 and 1.2 mEg/l. Monitoring of renal and thyroid function should be performed on a regular basis. Lithium can cause nausea, vomiting, diarrhoea, tremor, weight gain, and hypo- or hyperthyroidism, especially when taken in high doses (64,65).

Methysergide is o en prescribed for cluster headache, although no controlled double-blind studies have been performed. Open studies have shown the bene t of methysergide in 20–73% of pa- tients. e initial dose is 1 mg daily and can be slowly increased (1 mg for 3–5 days) to a maximum of 12 mg daily (66). Methysergide can only be used for a maximum of 6 months, because of the risk of brotic complications (lung, retroperitoneal, cardiac valvular) a er long-term use (67). A er a ‘drug holiday’ of at least 1 month, the drug can be prescribed again. Unfortunately, the drug is no longer available in Europe or North America.

Topiramate probably has some e cacy. Open-label studies showed a reduction of more than 50% of attacks in 21% of patients. Episodic cluster headache patients tended to respond more o en than chronic cluster headache patients. Side e ects included dizzi- ness, cognitive and language dysfunction, somnolence, ataxia, par- aesthesia, weight loss, and nausea (68–70).

Prednisone was shown to be e ective in open-label studies. In a large study, 60 mg prednisone completely prevented attacks in 77% and partially in 12% of patients (71). Prednisone works rapidly, but it can only be used for a short period owing to side e ects, and in most cases it will interrupt cluster headache only temporarily and not cause complete remission of the episode. It is therefore mostly used for bridging to long-acting prophylactic treatments.

Other preventive drugs sometimes used for cluster headache are ergotamine tartrate, melatonin, sodium valproate, pizotifen, gabapentin, and baclofen, but evidence of e cacy is limited (64,72–74).

Nerve blocks

Occipital nerve injections containing a mixture of local anaes- thetic and corticosteroid were proven to be e ective in episodic and chronic cluster headache patients in a randomized controlled trial (RCT). ere was a reduction of daily attacks in 95% of group receiving cortivazol, a glucocorticoid, versus 55% in the placebo group. ere was no di erence in direct treatment e ect between the chronic and episodic form of cluster headache (75). In another study in chronic cluster headache patients, attacks recurred 3.5 weeks a er injection (76). In episodic patients, however, the e ect lasted longer, and even permanently in the majority of patients (76,77). Like oral corticosteroids, treatment with occipital nerve injections is mainly regarded as a therapy to bridge the time necessary to initiate and ti- trate long-acting prophylactic medications until the right dosage is reached and e cacy is achieved.

Neuromodulation

Unfortunately, a small proportion of chronic cluster headache patients is or becomes intractable or intolerant to medical treat- ment (78). In these patients di erent experimental, invasive, non- pharmacological treatments mainly targeting the trigeminal nerve or the cranial parasympathetic out ow tract have been performed (79). Functional imaging studies in cluster headache have identi ed activations in the region of the posterior hypothalamus, leading to trials of neurostimulation in that area (40).

Hypothalamic deep brain stimulation (DBS) was shown to be ef- fective in some patients with medically intractable chronic cluster headache in small open studies (80). Unfortunately, this treat- ment can lead to high (even fatal) risks (81–84). Retrospectively,

CHaPtEr 18 Cluster headache: clinical features and management

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activation and treatment with DBS was more o en located in the midbrain perimesencephalic grey substance than in the hypothal- amus (85,86).

DBS, with its risks and sometimes lack of e ectiveness, has led sev- eral research groups to investigate extracranial invasive treatments, such as occipital nerve and sphenopalatine ganglion stimulation.

Occipital nerve stimulation is shown as e ective as DBS in the long term. A recent study in chronic cluster headache reported an improvement of 90% in attack frequency in 80% of patients, but o en there is a time delay of several months to reach the optimal e ect (87). Several small, open studies also showed promising re- sults of occipital nerve stimulation in medically intractable chronic cluster headache and related headaches (83,88–90). No serious com- plications were seen. A randomized clinical trial on the e ect and safety of occipital nerve stimulation in medically intractable chronic cluster headache is ongoing (91).

e sphenopalatine ganglion is an extracranial structure lying in the pterygopalatine fossa, containing parasympathetic and sympa- thetic nerves. It is presumed to have a role in cluster headache patho- physiology accounting for the cranial autonomic symptoms during attacks. Intervention procedures including sphenopalatine ganglion blocks and lesions have also demonstrated relief in patients with cluster headache (92). A prospective randomized sham controlled trial in 28 patients with chronic cluster headache showed a reduc- tion of more than 50% of attacks in 12 patients (93).

Vagal nerve stimulation is an invasive neuromodulation therapy that has been used for the treatment of epilepsy and medication- resistant depression. A recent case series reported a decreased frequency and severity of cluster headache a er vagal nerve stimula- tion (94). ere is now a non-invasive vagal nerve stimulator device available. An open-label study with this device showed an subjective improvement in 13 of 14 patients; prophylactic treatment could be reduced in seven of the patients (95). In a recent study this non- invasive vagal nerve stimulator (gammaCore®; Electrocore) was evaluated as adjunctive prophylactic therapy for cluster headache attacks in patients with chronic cluster headache (96). Patients with chronic cluster headache (n = 48) treated with this vagal nerve de- vice plus standard care were compared to standard care (n = 49) alone; vagal nerve-stimulated patients had a signi cantly greater re- duction in the number of attacks per week compared with controls. In addition, 40% of those treated with standard of care plus vagal nerve stimulation versus 8.3% treated with standard care showed a reduction of more than 50% in attacks. ere were no serious treatment-related adverse events. In two RCTs the e ect of non- invasive vagal nerve stimulation as acute therapy was investigated in both episodic and chronic cluster headache (97,98). Vagal nerve stimulation was an e ective acute therapy in episodic cluster head- ache (48% gammaCore® vs 6% sham) (97).

Future treatment options

Monoclonal antibodies directed against the CGRP receptor and mol- ecule have been shown to be e ective for the preventive treatment of migraine. As CGRP is elevated during cluster headache attacks, studies are currently underway to evaluate the safety and e cacy of these biologics for both episodic and chronic cluster headache. A rst study to determine if CGRP itself induces cluster headache attacks showed that CGRP provokes attacks in active phase episodic

and chronic cluster headache, but not during the remission phase in episodic cluster headache (99).

Conclusion

In summary, cluster headache is characterized by unilateral very severe headache attacks lasting 15–180 minutes with ipsilateral autonomic features. Patients are o en restless during an attack. e di erentiation among other paroxysmal headache syndromes is sometimes di cult. Cranial MRI could be considered in patients to rule out intracranial pathology, which can give rise to a headache phenotype that is indistinguishable from primary cluster headache.

e pathophysiology of cluster headache is not known. e tri- geminal autonomic re ex and hypothalamic disturbances are likely involved. Cluster headache is probably a complex genetic disorder.

Treatment consists of a combination of acute and prophylactic treatment. Acute treatment aims at reducing the pain of an indi- vidual headache attack. First choices are oxygen and/or sumatriptan SC. Prophylactic treatment aims at reducing the number of cluster headache attacks as much as possible, with verapamil as the drug of rst choice. Unfortunately, not all patients respond to the available medical treatment options. For those patients, a range of experi- mental therapies may o er possible alternatives.

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189

Paroxysmal hemicrania Clinical features and management Gennaro Bussone and Elisabetta Cittadini

Introduction

Paroxysmal hemicrania (PH) was initially described by Sjaastad and Dale in 1974 (1) and called ‘chronic paroxysmal hemicrania’ 2 years later (2). PH is classi ed as a trigeminal autonomic cephalalgia (TAC) by the International Classi cation of Headache Disorders, third edition (ICHD-3) (see also Chapter 17) (3,4). e current cri- teria require at least 20 attacks of severe unilateral orbital, supra- orbital, or temporal pain, lasting 2–30 minutes, accompanied by ipsilateral cranial autonomic features such as ptosis, eyelid oedema, conjunctival injection, lacrimation, nasal blockage, or rhinorrhoea. Attacks usually have a frequency of more than ve per day, and re- spond exquisitely to indomethacin.

Epidemiology

Patients with PH have been described in di erent countries (5–8). e incidence and prevalence of PH has been reported to be about 1–3% that of cluster headache (5), or about 1 in 50,000 (9), although it may be even rarer (10).

Sex distribution

Initially PH was considered to be predominant in females, with a female-to-male ratio of 7:1 (1). However, in a subsequent review of 84 patients the ratio was 2.36:1 (5), and two recent case series (7,11) did not show a clear female preponderance at all. is di ers from cluster headache (see also Chapter 18), where there is a clear male preponderance. e sex distribution of PH is more similar to that of short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) syndrome (see also Chapter 20). e earlier view of PH as a predominantly female con- dition was probably due to misdiagnosis of male patients with PH as cluster headache (11).

Pathophysiology

e pathogenesis of PH is less well understood than that of other primary headaches, such as migraine (12). Calcitonin gene-related peptide and vasoactive intestinal polypeptide are elevated during PH attacks (13). is release is likely to represent both trigeminovascular and cranial parasympathetic activation, and is similar to what has been observed in patients with cluster headache. e activation of the trigeminal and autonomic systems together seems to be a marker of TACs (14,15). A degree of activation of cranial autonomic response is a normal response to a cranial nociceptive input (16). Useful data to understand more about TACs, and PH in particular, comes from functional imaging studies. Posterior hypothalamus ac- tivation contralateral to the pain has been observed in PH, in add- ition to contralateral activation of ventral midbrain, red nucleus, and substantia nigra (17). Hypothalamic region activation has been also reported in cluster headache (18), SUNCT (19,20), and hemicrania continua (21). In the latter, the ventrolateral midbrain area is also activated (21).Whether the latter region is the key to understanding the therapeutic e ect of indomethacin in these disorders remains a relevant question for future research (11).

e cranial autonomic features may be prominent in these syn- dromes owing to central disinhibition of the trigeminal–autonomic re ex by the hypothalamus (22). ere are direct hypothalamic– trigeminal connections (23), and the hypothalamus is known to play a modulatory role on the nociceptive pathways (24). A positron emission tomography study in patients with chronic cluster head- ache (see also Chapter 18) with hypothalamic deep brain stimulation showed a functional connection between the hypothalamus and the trigeminal system. e hypothalamic stimulation induced activa- tion in the ipsilateral hypothalamic grey at the site of the stimulator tip and the ipsilateral trigeminal system. However, the activation of the trigeminal system did not trigger pain or autonomic cranial fea- tures, suggesting that the activation of the trigeminal system is not su cient to generate pain in cluster headache and perhaps in other TACs (25).

It has been suggested that the posterior hypothalamus area plays a role in terminating the attacks rather than triggering them in cluster headache and the TACs (26).

Recently it has been also argued that hypothalamic activation may not be speci c to TACs but just a part of the general central pain net- work (27). Hypothalamic activation and structural alterations have been also reported in other pain conditions such as migraine (28) and hypnic headache (29) (see also Chapter 26).

In the coming years, further functional neuroimaging and ana- tomical work studies are required to elucidate more clearly the role of the posterior hypothalamic region in the pathophysiology of TACs in general and PH speci cally.

At present it is not known what mechanism of action or inter- action with pathophysiological mechanisms is the key aspect to indomethacin’s unique pharmacology in indomethacin-sensitive headache, including PH (30). Indomethacin inhibits the pro- duction of nitric oxide (NO) by endothelial and inducible nitric oxide synthase (31,32). An animal study (33) showed that indo- methacin inhibits NO-induced dural vasodilation, whereas other cyclooxygenase (COX) inhibitors, such as naproxen and ibuprofen, do not. It is possible that NO plays a relevant part in indomethacin’s e cacy in PH and hemicrania continua, yet its role still needs to be fully understood.

Clinical picture

Site of pain

According to the ICHD-3 criteria (3), the site of the pain is uni- lateral, orbital, supraorbital, or temporal. ree separate case series (4,6,10) of PH con rmed that these are the most frequent locations. Yet, the pain can also be distributed elsewhere in the head (10). e pain is strictly unilateral, although a side shi may occur (10).

autonomic features

e ICHD-3 criteria (3) require at least one cranial autonomic fea- ture with the attacks. Lacrimation, nasal congestion, conjunctival injection, and rhinorrhoea are the most frequent accompanying fea- tures (5). However, a wider range of autonomic features has been reported in a large case series such as facial ushing, sense of aural fullness, or of aural swelling (11).

Laterality and severity of the pain

Typically the attacks of PH are side-locked, but ve cases of bilat- eral pain have been reported (34–38). Interestingly, four of these cases had bilateral pain without cranial autonomic features and the possibility has been raised that these indomethacin-sensitive, short- lasting, bilateral headaches without autonomic symptoms represent a novel headache syndrome (39).

Cluster headache (see also Chapter 18) is typically described as an excruciating syndrome and is o en called ‘suicide headache’ (40), yet data from large case series showed that other TACs such as SUNCT/SUNA (41) (see also Chapter 20) and PH are also extremely painful conditions (11).

Duration and frequency of attacks

e current ICHD-3 criteria (3) require that the duration of each at- tack ranges between 2 and 30 minutes and a that a frequency of more than ve attacks per day for more than half of the time is present.

In a prospective study of 105 attacks in ve patients (42), the mean attack duration was 13 minutes and the range was 3–46 minutes; the mean attack frequency was 14 attacks in 24 hours and the range was 4–38 attacks.

In a large case series the range of the attack duration was between 10 seconds and 4 hours, with a mean of 17 minutes, although the pa- tients with very short attacks also had longer attacks of several min- utes (11). e number of attacks per day in that series was between 2 and 50, with a mean of 11 attacks in 24 hours (11).

Paroxysmal hemicrania and interictal pain

Interictal pain is not a characteristic feature, although it has been re- ported in case series of patients with PH presented in the literature. In a prospective study, one of eight patients reported tenderness between attacks (43), and 28 of 84 patients in a worldwide retro- spective study had interictal discomfort (5). More recently, a large prospective study showed that 18 of 31 patients had background pain (11). Eight (44%) of these 18 patients had medication overuse and 7 (88%) of the 8 patients with overuse had a personal or family history of migraine, or ‘headache not otherwise speci ed’. e re- maining 10 patients (56%) had background pain without analgesics overuse, and seven (70%) of them had a personal history positive for headache, either migraine or ‘headache not otherwise speci ed’. e interictal pain was reported to be relatively mild in comparison to the pain of the attacks, and this feature can be used to di erentiate these patients from those with hemicrania continua (see also Chapter 21). A retrospective study (7) also showed that eight (47%) patients of 17 had interictal pain, which was intermittent in seven (41%) and continuous in one (6%) patient. e interictal pain was not reported during the early phase of the condition. e comparison of patients with interictal pain with those without was statistically signi cant in two parameters. Patients with interictal pain had a longer duration of the chronic form (69.0 vs10.7 months; P = 0.0006), and the dose of indomethacin required was also higher in patients with interictal pain (187.5 vs 113.9; P = 0.0018) (7).

Migrainous features and behaviour

Bilateral phonophobia and photophobia are characteristic symp- toms of migraine (3) (see also Chapter 6), yet can occur unilaterally in some patients (44). Unilateral phonophobia and photophobia have been reported to be common in PH, hemicrania continua (45), SUNCT (41,45), and cluster headache (45,46).

In one study of 31 patients with PH (11), 65% of patients had phonophobia and photophobia, and 39% patients had nausea or vomiting during the attacks, or both; phonophobia was unilateral in 25% and photophobia in 40%. In another study (7), 24% of 17 patients had photophobia and 24% phonophobia and at least one

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Part 3 Trigeminal autonomic cephalgias

migrainous feature such as nausea, or vomiting, photophobia, or phonophobia was present in 53% of patients.

Agitation and restlessness are typical features of cluster headache (40), and aggressive behaviour has also been also described (see also Chapter 18) (47). It has been described that 62% of the patients with SUNCT are also agitated during attacks (41), and in a case series of 31 patients with PH, 80% of patients were agitated or restless, or both, during attacks and one-quarter reported aggressive behaviour during attacks (11). In a case series of 17 patients with PH (7), 76% had agitation or a sense of restlessness.

Circadian and circannual periodicity

PH attacks occur regularly throughout the day, without a nocturnal preponderance (5,7,11,42,43,48). In contrast with cluster headache, a clear circadian and circannual periodicity has not been reported in patients with PH (7,11).

triggers

e majority of attacks are spontaneous, but around 10% of PH pa- tients report provocation of attacks by neck movements and in about 7% of patients alcohol provokes attacks (5). Other frequently men- tioned triggers are stress and exercise (11).

Periodicity and chronicity

e ICHD-3 criteria (3) classify PH as episodic PH and chronic PH. In the episodic form attacks occur in periods lasting 7 days to 1 year, separated by attack free-periods lasting 1 month or longer. In the chronic form attacks occur for more than 1 year without remission or with remission lasting less than 1 month. About 20% of the pa- tients have the episodic form and the remaining 80% the chronic form (11). is is in contrast with CH where the episodic form is more frequent (see also Chapter 18) (47). e reason of this di er- ence in pattern is not understood.

Secondary paroxysmal hemicrania

Probably as a result of publication bias, a number of cases of symp- tomatic PH have been reported in the literature, although a causal relationship with the underlying structural lesion is not clear in many of those cases (11). Di erent pathological processes have been suggested to cause symptomatic PH (48). In side-locked headaches such as (possible) PH, a thorough investigation, including magnetic resonance imaging (MRI), is warranted (49).

Pituitary tumours are o en associated with TAC-like phenotypes, but in the largest study investigating this association, no patients with PH were found (50). In that cohort of 84 patients with a pituitary tu- mour, 5% had SUNCT and 4% cluster headache. However, it is un- known whether the prevalence of pituitary tumours is higher in TAC patients, as no prospective community-based study has been per- formed to address this issue (51). e precise mechanism underlying pituitary tumour-associated headache is still unknown, although it is

likely to be a combination of physical and biochemical tumour charac- teristics, as well as patient predisposition to headache (52).

Differential diagnosis

Distinguishing PH and cluster headache

A clinical overlap exists between PH and cluster headache (see also Chapter 18). In fact, in both conditions the attacks are strictly uni- lateral, relatively brief, and associated with ipsilateral cranial auto- nomic features. At present the absolute response to indomethacin (is the only factor that allows a distinction between these two con- ditions (3,53–55). Nevertheless, there are some other useful clinical clues. Typically, PH is characterized by (i) shorter duration and (ii) high frequency of attacks. In contrast to PH, cluster headache is characterized by the presence of (i) circadian and circannual peri- odicity, and (ii) provocation of attacks by alcohol within 1 hour in 90% of patients during cluster bouts (47).

Distinguishing PH and SUNCT

SUNCT attacks are typically shorter, with a range between 5 and 240 seconds (see also Chapter 20) (3), but longer attacks can occur, with attacks lasting up to 600 seconds having been recorded (41). Additionally, another di erence with PH is the character of the attacks. In SUNCT, attacks are typically described as single stabs, a group of stabs, or long attacks with a saw-tooth pattern of stabs be- tween which the pain does not return to baseline (41). Most SUNCT attacks are triggered by cutaneous triggers such as touching the face or scalp, washing, shaving, eating, brushing the teeth, talking, and coughing (41,56). In contrast, most PH attacks are spontaneous (5,11), and have a longer duration (11).

Distinguishing PH and trigeminal neuralgia

First-division trigeminal neuralgia (see also Chapter 27) attacks last for 5–10 seconds, with a duration of longer than 30 seconds being rare (57). Prominent conjunctival injection is not present with the pain, although slight lacrimation can sometimes be present (58). Typically, trigeminal neuralgia attacks are precipitated by cutaneous stimuli in the trigeminal territory; a feature that is not characteristic of PH (59).

Distinguishing PH with interictal pain and hemicrania continua

e di erential diagnosis between PH with interictal pain and hemicrania continua (see also Chapter 21) can be challenging, and a careful history accompanied with a headache diary is extremely useful during the diagnostic evaluation. e headache diary can provide relevant information regarding temporal aspects of the pain. Some clinical features can also help. In our experience, hemicrania continua typically has less prominent cranial autonomic features than PH. Furthermore, the background pain in hemicrania continua is typically more severe than interictal pain in PH. Painful exacerba- tions in hemicrania continua are long lasting (usually several hours) and less frequent than the short-lasting and frequent attacks associ- ated with PH (60) (Table 19.1).

Family history

A family history of PH has been described (61). Migraine is de- scribed as a genetic headache disorder (62), and mutations have

CHaPtEr 19 Paroxysmal hemicrania: clinical features and management table 19.1 Comparison based on large case series of paroxysmal hemicrania, hemicrania continua of cluster headache and SUNCT/SUNA

present in literature

Cluster headache (47)

Paroxysmal hemicrania (11)

SUNCT/SUNA (41)

Hemicrania continua (83)

Sex

3 M:1 F

M=F

1.5 M:1 F

1 M:1.6 F

Pain

• Quality
• Severity
• Distribution

Sharp/stabbing/throbbing Very severe V1>C2>V2>V3≠

Sharp/stabbing/throbbing Very severe V1>C2>V2>V3

Sharp/stabbing/throbbing Severe
V1>C2>V2>V3

Throbbing/sharp/constant Moderate/severe/very severe V1>C2>V2>V3

Attacks

• Frequency (/day) • Length (minutes)

1–8 30–180

11 2–50

100 1–5

No pattern 30–37 days Background pain

Triggers

• Alcohol
• Nitroglycerin • Cutaneous

+++ +++ –

+ + –

––+++

+ ++ –

Agitation/restlessness (%)

Phonophobia/photophobia (%)

Episodic vs chronic

90:10

35:65

10:90

18:82

SUNCT, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing; SUNA, short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms; M, male; F, female; ≠ C, cervical and V, trigeminal.

been described in patients a ected by familial hemiplegic migraine (see Chapter 10) (63–65). Furthermore, a family history of cluster headache (66) and SUNCT has been described (67). A genetic study of a large group of patients with PH would be important to estab- lish a genetic component, yet this would be a challenge owing to its rarity (11).

Diagnosis

A careful clinical history supplemented with a headache diary, a detailed neurological examination and a trial of indomethacin are needed to make a diagnosis of PH. A brain MRI scan is a reasonable investigation to be performed in all patients with PH.

Natural history

PH can start at any age, even in childhood (68,69). e available data suggest that PH is a lifelong condition, with a mean duration of illness of 13.3 ± 12.2 years (5), although episodic PH can trans- form into chronic PH and vice versa (5,7,11). Patients can ex- perience long-lasting remissions (11,70). Responses and doses of indomethacin tended to be stable over the time and it is in our practice to re-examine and re-image the brain in patients who stop responding (11). Further, a proportion of patients can decrease the dose of indomethacin required to maintain a pain-free state over time (71).

treatment

e diagnosis of PH requires an absolute response to indometh- acin (54,55). e indomethacin test can be performed in two dif- ferent ways: an oral trial or a placebo-controlled Indotest test with

intramuscular indomethacin (21,54). e oral mean daily dosage is 100 mg, with a range of 25–300 mg, although some patients only need 12.5 mg daily (5,55,72,73). Some two-thirds of patients report side e ects at some point, mainly gastrointestinal, which may lead to a discontinuation of the medicine (11). In this context, where gastro- intestinal side e ects are a problem, employing a placebo-controlled Indotest by injection can be very useful. e parenteral trial consists of a single blind administration of 100 mg or 200 mg versus placebo (11). e placebo-controlled indomethacin test may be a suitable aid in the diagnostic evaluation (11).

Patients who develop gastrointestinal problems, are an important challenge for clinicians. Some patients have responded to COX-2 (selective inhibitors (74–76), although their long-term safety makes this option less attractive (77). Topiramate has been reported to be useful in some cases of PH (78,79).

Most PH attacks are too short to be suitable for acute therapy, al- though subcutaneous sumatriptan is reported to be useful in selected group of patients with longer attacks (11). Greater occipital nerve injection with lidocaine and methylprednisolone may be helpful in some patients with PH (80), as is non-invasive vagus nerve stimu- lation (73) . Other (invasive) neuromodulatory procedures, such as blockade of sphenopalatine ganglion, neurostimulation of the pos- terior hypothalamus, and occipital nerve stimulation, are reserved for refractory PH (72,81,82).

Conclusion

PH is classi ed as a TAC by the International Headache Society (3). TACs are a group of primary headaches that include cluster head- ache, PH, and SUNCT/SUNA. ey are characterized by strictly unilateral head pain occurring in association with intense cranial autonomic features. PH is characterized by intermediate duration and intermediate attack frequency (4). e exquisite response to indomethacin is the essential criteria for the diagnosis of PH.

193

194

Part 3 Trigeminal autonomic cephalgias

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195

SUNCT/SUNA
Clinical features and management
Juan A. Pareja, Leopoldine A. Wilbrink, and María-Luz Cuadrado

Introduction

SUNCT syndrome was described in 1978 by Sjaastad et al. (1), and was fully characterized in 1989 under the heading ‘short-lasting uni- lateral neuralgiform headache attacks with conjunctival injection, tearing, sweating, and rhinorrhea’ (2). e acronym SUNCT (short- lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing) was rst used in 1991 (3), and summarizes the clinical features of this syndrome. In 2004, this condition was classi ed in group 3 (trigeminal autonomic cephalalgias (TACs)) of the International Classi cation of Headache Disorders, second edi- tion (ICHD-2) (4). In the vast majority of reported cases, SUNCT attacks lasted 5–240 seconds and were accompanied by both con- junctival injection and lacrimation. ese features were selected as diagnostic criteria at that time, when a conservative and safe pos- ition was convenient.

e restrictive diagnostic criteria for SUNCT led to a less re- strictive syndrome with the acronym SUNA (short-lasting unilat- eral neuralgiform headache attacks with cranial autonomic features) (5,6). SUNA was included in the appendix of ICHD-2 (4), along with other novel entities that had to be validated. According to such a proposal, SUNA could be diagnosed with the presence of just one cranial autonomic feature, and the duration of pain attacks was in- creased up to 10 minutes.

Clinicians familiar with these syndromes have been divided into two groups regarding their nosological view of SUNCT and SUNA. Some authors favour the idea that SUNCT is a subset of SUNA, while others support the idea that both phenotypes are just di erent expressions of the same condition (7,8). e two clin- ical pictures clearly overlap. Most recently, the third edition of the ICHD (ICHD-3) has included both SUNCT and SUNA in the same section of the TACs under the heading ‘short-lasting unilateral neuralgiform headache attacks’ (9). erefore, SUNCT and SUNA are currently classi ed as separate subtypes of the same disorder (Boxes 20.1 and 20.2).

the clinical pictures

SUNCt

SUNCT syndrome is characterized by short-lived unilateral, orbital or periorbital, painful attacks, with prominent autonomic accom- paniments always including both ipsilateral conjunctival injection and tearing (Box 20.3). It is a rare disorder, slightly more common in males (male-to-female ratio 1.4:1), with a mean age of onset around 50 years (range 5–88 years) (10–12). A hereditary component may be present in some patients, as there have been two reports of fa- milial SUNCT (13,14).

Symptoms and signs are strictly unilateral, with the pain usually con ned to the ocular and periocular area (1–3,10–12). Nearly all patients with SUNCT feel the pain within the trigeminal territory, mostly in the area supplied by the rst division of the trigeminal nerve (V1). A spread beyond the midline or co-involvement of the opposite side has occasionally been observed, with the pain still predominating on the originally symptomatic side (10). Exceptional extensions of the pain towards the ear or the occiput, and shi ing side attacks, have also been reported (10–12).

SUNCT attacks are usually characterized by moderate or severe pain. An excruciatingly severe pain is not frequent. Pain quality is commonly described as burning, stabbing, or electric (10– 12). Alternative descriptions are lancinating, piercing, pricking, pulsating, sharp, shooting, spasmodic, steady, or throbbing (10).

Most SUNCT attacks are triggered by mechanical stimuli acting on trigeminal or extra-trigeminal areas (1–3), while only a minority of attacks seem to be spontaneous. Very few patients have entirely spontaneous attacks, with no triggers. Unlike the paroxysms of trigeminal neuralgia, SUNCT attacks are not followed by a refrac- tory period (2,15–17). Only some exceptional patients diagnosed with SUNCT have apparently had refractory periods (6). SUNCT attacks start and cease abruptly. e solitary attacks usually have a ‘plateau-like’ pattern (2), but other temporal pro les have also been described (15,16): ‘repetitive’ (short-lasting attacks in rapid

CHaPtEr 20 SUNCT/SUNA: clinical features and management

Box 20.1 Classi cation of short-lasting unilateral neuralgiform headache attacks

3.3 Short-lasting unilateral neuralgiform headache attacks.

3.3.1 Short-lasting unilateral neuralgiform headache attacks with con- junctival injection and tearing (SUNCT).

3.3.1.1 EpisodicSUNCT.

3.3.1.2 ChronicSUNCT.
3.3.2 Short-lasting unilateral neuralgiform headache attacks with cra-

nial autonomic symptoms (SUNA).

. 3.3.2.1 Episodic SUNA.

. 3.3.2.2 Chronic SUNA.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Box 20.3 Diagnostic criteria for SUNCT

3.3.1 Short-lasting unilateral neuralgiform headache attacks with con- junctival injection and tearing (SUNCT)

Diagnostic criteria
A Attacks ful lling criteria for 3.3 Short-lasting unilateral neuralgiform

headache attacks, and criterion B below.
B Both of the following, ipsilateral to the pain:

1 Conjunctival injection 2 Lacrimation (tearing).

3.3.1.1 Episodic SUNCT
Attacks of SUNCT occurring in periods lasting from 7 days to 1 year, sep- arated by pain-free periods lasting 3 months or more.

3.3.1.2 Chronic SUNCT
Attacks of SUNCT occurring for more than 1 year without remission, or with remission periods lasting less than 3 months.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

succession), ‘sawtooth-like’ (and its variant ‘staccato-like’, in which consecutive spike-like paroxysms occur without reaching the pain- free baseline), and ‘plateau-like plus exacerbations’ (admixture of 1– 2-second jabs superimposed on top of the conventional plateau-like pattern) (Figure 20.1).

e mean length of SUNCT paroxysms is around 1 minute (2,7), with a usual range of 10–120 seconds, and a total range of 1–600 sec- onds as stated by the ICHD-3 criteria (9). Objective measurements of 348 attacks in 11 patients rendered a mean duration of 49 seconds, with a range of 5–250 seconds (18). However, the whole reported range extends from 1–600 seconds according to mostly subjective estimations (6). Only very rarely have long-lasting attacks reaching 1–2 hours’ duration been observed (19). Such prolonged SUNCT attacks should be taken as rare variants, as even in those patients the vast majority of attacks have a typical length.

Between attacks, the patients are normally free of symptoms. However, sometimes the patients feel a very low-grade back- ground pain or discomfort in the symptomatic area throughout

the symptomatic periods (19). is background ache can be rather uctuating or intermittent.

During active periods, the frequency of attacks may vary from less than one attack per day to more than 30 attacks per hour. e attacks predominate during the daytime; nocturnal attacks are seldom reported (18). e natural course of SUNCT is mostly chronic (6), with attacks occurring for more than 1 year without remission, or with remission periods lasting less than 3 months (9). However, the syndrome may occasionally attain an episodic tem- poral pattern (6), with attacks occurring in periods lasting from 7 days to 1 year, separated by pain-free periods lasting 3 months or more (Box 20.3) (9).

Pain attacks are regularly accompanied by prominent, ipsilateral conjunctival injection and lacrimation, with both signs generally appearing in tandem once the attack has started (1,2). e presence of both autonomic signs is a sine qua non diagnostic criterion for SUNCT (Box 20.3). It is worth noting that lacrimation and con- junctival injection are macroscopically evident a few seconds a er the beginning of the pain, and cease just as quickly a er the pain stops. In other words, the ocular accompaniments develop in an ‘explosive’ fashion. Occasionally, SUNCT attacks may be accom- panied by either lacrimation or conjunctival injection alone. is may indicate that the lacking autonomic accompaniment was too subtle to be noticed, or that the patient has been observed for too short a period of time to allow for the development of other auto- nomic features.

Rhinorrhoea and/or nasal congestion are found in approximately two-thirds of patients with SUNCT. Rhinorrhoea takes more time to develop in full, is clinically apparent from the middle part of the at- tack, and then overlasts the pain by some seconds. In addition, there is subclinical increase of forehead sweating, as well as an increase of

Box 20.2 Diagnostic criteria for short-lasting unilateral neuralgiform headache attacks

3.3 Short-lasting unilateral neuralgiform headache attacks

Description

Attacks of moderate or severe, strictly unilateral head pain lasting sec- onds to minutes, occurring at least once a day and usually associated with prominent lacrimation and redness of the ipsilateral eye.

Diagnostic criteria

A B

D E

At least 20 attacks ful lling criteria B–D.
Moderate or severe unilateral head pain, with orbital, supraorbital, temporal, and/or other trigeminal distribution, lasting for 1–600 sec- onds and occurring as single stabs, series of stabs, or in a saw-tooth pattern.
At least one of the following cranial autonomic symptoms or signs, ipsilateral to the pain:

1 Conjunctival injection and/or lacrimation 2 Nasal congestion and/or rhinorrhoea
3 Eyelid oedema
4 Forehead and facial sweating

5 Miosis and/or ptosis.
Occurring with a frequency of at least one a day.1
Not better accounted for by another ICHD-3 diagnosis.

1 During part, but less than half, of the active time course of 3.3 Short-lasting unilateral neuralgiform headache attacks, attacks may be less frequent.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Pain intensity

Severe Moderate Mild

Plateau-like pattern

Repetitive pattern

Saw-tooth pattern

Plateau-like plus exacerbations

Figure 20.1 Temporal pro le of individual SUNCT attacks.

Adapted from Headache, 34, Pareja JA, Sjaastad O, SUNCT syndrome in the female, pp. 217–220. Copyright (1994) with permission from John Wiley and Sons.

197

198

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intraocular pressure and corneal temperature (20), predominating on the symptomatic side.

During periods with a high load of attacks, there may be swelling of the eyelids on the symptomatic side owing to vascular engorge- ment and oedema (20). is produces a decrease in palpebral width, which is not paretic in nature (pseudoptosis). Otherwise, neither ictal nor interictal states of SUNCT are characterized by spontan- eous or pharmacological abnormalities in pupil diameter (21). Only very rarely has miosis been described in patients with SUNCT (22,23).

In addition to the local autonomic accompaniments, SUNCT syn- drome is associated with generalized phenomena. During SUNCT attacks, there may be increased systemic arterial blood pressure to- gether with a decrease in heart rate (24). Moreover, patients with SUNCT hyperventilate during the attacks, and less markedly so in between attacks (25).

SUNa

Unlike SUNCT, SUNA has only one or neither of conjunctival in- jection and lacrimation; otherwise, SUNA may be diagnosed in the presence of one or various autonomic accompaniments (Box 20.4). As there is great overlap between the diagnostic criteria for both SUNCT and SUNA, SUNA has been proposed as a broader category of headache that would include SUNCT (5,6).

Pure SUNA is thought to be very rare, even more than SUNCT. It was rst described in 2005 in an 11-year-old girl su ering from short, sharp headaches located in the back of the eye, which were consistently associated with profuse ipsilateral tearing, but no conjunctival injection or other autonomic features. No refractory periods could be identi ed, but the attacks did not really have any precipitating mechanism (5). Since then, additional reports of pa- tients ful lling the criteria for SUNA have been scarce. To date, only one large series has been published, which included 37 patients with SUNA from multiple centres (26). In that series there were 18 males and 19 females, and the mean age of onset was 45 years (range 15–92 years).

SUNA attacks are similar to SUNCT in location, duration, fre- quency, and severity. Yet, the site of the pain is more varied in SUNA. Compared with SUNCT, SUNA attacks are more o en lo- cated in the temple, the side of the head, V2, and V3 (6). Cranial

autonomic signs are also more varied in SUNA, without the coup- ling of conjunctival injection and tearing characteristic of SUNCT. Lacrimation is the most common autonomic feature, followed by nasal blockage or rhinorrhoea. In the case of SUNA, there are more patients who only have spontaneous attacks, although it is also more common for patients with SUNA to have predom- inantly triggered attacks. As in SUNCT, typical attacks of SUNA are not followed by refractory periods, and this may help to dis- tinguish SUNA from trigeminal neuralgia. Only a small minority of the reported patients had a refractory period a er cutaneous triggers (26).

aetiology: primary and secondary forms

e aetiology and pathogenesis of SUNCT and SUNA are largely un- known. In the majority of cases these conditions cannot be attributed to another disease, so they are regarded as primary. However, some patients showing similar signs and symptoms have an underlying lesion, and are considered to su er from secondary forms.

A typical clinical picture of SUNCT has been described in pa- tients with various types of lesions, which have been mostly located in the posterior fossa or the pituitary region (10–12). ese lesions comprise tumours, vascular malformations, brainstem infarctions, demyelination, traumatic injuries, herpes zoster and other infec- tions, and congenital abnormalities of the skull (27). Some of these lesions may be incidental ndings, but some of them must be re- lated to SUNCT as their suppression may change the clinical course. For instance, the rst known symptomatic case of SUNCT was re- solved a er surgical removal of a cerebellopontine vascular mal- formation (28). In a series of ve patients presenting with SUNCT and an underlying pituitary tumour, three had major improvement a er surgery (29); surprisingly, one patient with a pituitary tumour had the onset of SUNCT a er radiation therapy (30). Symptomatic SUNA has been associated with the presence of an epidermoid cyst in the cerebellopontine angle (31), vertebral artery dissec- tion (32), cranial trauma (33), and herpes zoster (34). e possi- bility of underlying causes makes neuroimaging mandatory as part of the diagnostic work-up in both SUNCT and SUNA, preferably with magnetic resonance imaging (MRI) of the brain and MRI- angiography. Interestingly, MRI-dedicated views of the trigeminal nerve root have shown neurovascular compression in a substantial number of SUNCT or SUNA cases, resembling classical trigeminal neuralgia (35). As dedicated views for the trigeminal nerve are not always obtained, the presence of neurovascular compression may be underestimated.

Pathophysiology

SUNCT and SUNA are conceived as TACs, together with cluster headache, paroxysmal hemicrania, and hemicrania continua. TACs are believed to depend essentially on the activation of the trigeminal system, with pain felt in the area supplied by the rst division (V1) of the trigeminal nerve, together with a disinhib- ition of a trigeminofacial brainstem re ex responsible for the oculofacial autonomic accompaniments (36). Although the lo- cation of the pain and the autonomic accompaniments are quite similar, TACs di er in the duration, frequency, and temporal

Box 20.4 Diagnostic criteria for SUNA

3.3.2 Short-lasting unilateral neuralgiform headache attacks with con- junctival injection and tearing (SUNA)

Diagnostic criteria
A Attacks ful lling criteria for 3.3 Short-lasting unilateral neuralgiform

headache attacks, and criterion B below.
B Not more than one of the following, ipsilateral to the pain:

1 Conjunctival injection 2 Lacrimation (tearing).

3.3.2.1 Episodic SUNA
Attacks of SUNA occurring in periods lasting from 7 days to 1 year, sep- arated by pain-free periods lasting at least 3 months.

3.3.2.2 Chronic SUNA
Attacks of SUNA occurring for more than 1 year without remission, or with remission periods lasting less than 3 months.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

distribution of attacks, as well as the precipitating mechanisms and the response to treatment. Such di erences may depend on the origin of the process and/or the modulation of the pain. Likewise, the pain-modulating system appears to behave di er- ently in SUNCT/SUNA and trigeminal neuralgia, as the attacks of SUNCT/SUNA have longer length and are not followed by a refractory period (12–15).

Functional neuroimaging has shown hypothalamic activation during SUNCT attacks (37). Such activation has been claimed to be pathogenically relevant in SUNCT. Indeed, the hypothalamus is anatomically connected to the pain-modulating system and the superior salivary nucleus, and could therefore modulate both the pain and the autonomic accompaniments. Alternatively, the hypo- thalamus could lead to a permissive stage for the attacks to occur, or just function as a relay station for increased neuronal inputs. Hypothalamic activation is not exclusive to SUNCT, and has actu- ally been observed in all the TACs (38–40).

treatment

As the attacks of SUNCT and SUNA are very short lasting, there are no abortive therapies for individual attacks. e aim of therapy is to prevent or suppress the occurrence of attacks.

No medication is consistently e ective for SUNCT or SUNA (41– 46). Given the rarity of these conditions, most available data come from observational studies, case series, and case reports. To date, only one small placebo-controlled trial of topiramate has been per- formed in patients with SUNCT, with no de nite results (26). Yet, a substantial number of the reported patients with SUNCT or SUNA have seemed to bene t from certain pharmacological and non- pharmacological procedures.

Preventive treatments for SUNCT and SUNA include lamotrigine, gabapentin, and topiramate. Lamotrigine is the drug of choice for the long-term preventive treatment of SUNCT (46– 53). It should be initiated at 25 mg daily and gradually titrated, guided by response and side e ects. Lamotrigine has been the most commonly administered prolonged treatment in patients with SUNCT and, when compared to other therapies, has a higher odds of responders (53). Nevertheless, treatment with lamotrigine has not been as e ective in patients with SUNA (26). Gabapentin may be also e ective for both SUNCT and SUNA (26,54–57). Topiramate is e ective in some patients with SUNCT, but has not shown a reliable e ect on SUNA (26). Carbamazepine has shown e ectiveness in some patients with SUNCT or SUNA. However, it is not recommended as a rst-line treatment as there is a lack of re- sponse in the majority of patients (26). Zonisamide, oxcarbazepine, eslicarbazepine, and pregabalin have been apparently e ective in individual cases (26,58–60). e e ect of verapamil is uncertain (26,61). ere is a report of a patient with refractory SUNCT re- sponding to clomiphene (62).

Both intravenous lidocaine (26,63–65) and intravenous pheny- toin (66) can be useful as transitional treatments during severe ex- acerbations of SUNCT while appropriate preventive therapy is being implemented or just to give the patients some temporary relief. In one case report the positive e ect of lidocaine lasted for 2 months (64). Oral or intravenous corticosteroids have also suppressed severe bouts of SUNCT attacks in a number of cases (67,68). However, not all patients have responded to these therapies.

Greater occipital nerve blocks with local anaesthetics (26,69) and superior cervical ganglion blockade with opioids (70) have been reported as temporally or partially e ective in a few pa- tients. Additionally, peripheral nerve blocks of the supraorbital and infraorbital nerves provided a long-lasting remission in a pregnant patient (71). Likewise, two patients had sustained relief a er botu- linum toxin A injections distributed over the symptomatic area (72,73). Owing to the scarcity of reports, the results of these proced- ures should be taken as preliminary.

Surgical procedures have also been tried in the treatment of med- ically refractory SUNCT or SUNA. For instance, some patients have improved with microvascular decompression of the trigeminal nerve (Janetta procedure) (35,74–76), while others have obtained some bene t with ablative procedures directed to the trigeminal nerve and the sphenopalatine ganglion (percutaneous balloon com- pression, radiofrequency thermocoagulation, glycerol rhizolysis, or stereotactic radiosurgery) (77–80). Nevertheless, these interven- tions do not provide compelling results in all cases. In recent times, both peripheral and central neurostimulation techniques (occipital nerve stimulation, and deep brain stimulation in the posterior hypo- thalamus) have been apparently successful in a few medically in- tractable cases (81–86).

Nosology

SUNCT is a descriptive condition. Descriptive syndromes consist of those observable features by which they are standardly recognized. For clinical and research purposes, operational de nitions must be drawn up from descriptive de nitions. Operational de nitions (i.e. diagnostic criteria) identify the boundaries between a given con- dition and similar entities. Researchers must select the best com- bination of symptoms that are necessary to establish the diagnosis. erefore, diagnostic criteria of a given condition cannot represent the clinical pro le in full, but a practical way to di erentiate similar conditions. A distinction of SUNCT from trigeminal neuralgia (see Chapter 27) may be di cult at times (87,88).

Conjunctival injection, lacrimation, and rhinorrhoea were pre- sent in 100%, 95%, and 63%, respectively, of the rst 21 patients with SUNCT(10). As conjunctival injection and lacrimation were pre- sent in nearly 100%, both features were considered essential for the diagnosis of SUNCT. By the time the ICHD-2 diagnostic criteria of SUNCT were established, there was a need to di erentiate SUNCT from V1 trigeminal neuralgia. Studies on V1 trigeminal neuralgia had shown that attacks might rarely be accompanied by lacrimation without conjunctival injection (89). Otherwise, the duration of tri- geminal neuralgia attacks was considered to range between ‘a few seconds to a few minutes’. erefore, SUNCT attacks accompanied by lacrimation could have been di cult to di erentiate from V1 neuralgia with lacrimation. Including the co-occurrence of conjunc- tival injection and lacrimation as a sine qua non diagnostic criterion would strengthen the di erence with V1 trigeminal neuralgia. Later on, objective duration of V1 neuralgia attacks was assessed (90), thus providing a key feature for the di erentiation between SUNCT and V1 neuralgia accompanied by lacrimation (Figure 20.2). Accordingly, the initial, conservative diagnostic criteria of SUNCT could have been changed for polythetic criteria, as established for the other TACs. In fact, all three TACs seem to exhibit similar auto- nomic features.

CHaPtEr 20 SUNCT/SUNA: clinical features and management

199

200

Part 3 Trigeminal autonomic cephalgias

100 80 60 40 20 0

Figure 20.2 Objective measurement of duration of attacks in SUNCT and V1 neuralgia.

Adapted from Cephalalgia, 25, Pareja JA, Cuadrado ML, Caminero AB et al., Duration of attacks of rst division trigeminal neuralgia, pp. 305–308. Copyright (2005) © SAGE Publications.

e ICHD-2 diagnostic criteria for SUNCT contained only two autonomic features: conjunctival injection and tearing. e two items were connected with ‘and’ and not with ‘and/or’. It was also stated in a note in the appendix that these criteria might be incor- rect, and that only one of the two cardinal features might be present. is problem could have been solved by changing ‘and’ for ‘and/or’. Instead, a broader and more inclusive concept is currently repre- sented in the clinical picture of SUNA.

Admittedly, SUNCT is a rare condition, so the de nition of SUNCT may have been incomplete on the basis of the rst cases ob- served at the time the diagnostic criteria were settled. Nowadays, the clinical picture of SUNCT is vastly known, including variations in the typical features and presence of atypical features. e descriptions of SUNCT and SUNA are rather similar. Minor di erences between those descriptions may partly be due to slight variants of the same disorder. e two clinical pictures largely overlap, thus indicating that both phenotypes could represent complementary clinical pic- tures of the same syndrome. SUNA has been proposed as a broader category that would include SUNCT, but with the same level of cer- tainty or uncertainty SUNA could also be regarded as the whole clin- ical spectrum of SUNCT, i.e. typical, atypical, and fruste forms

e ICHD-3 kept the restrictive diagnostic criteria for SUNCT, and added SUNA in the same subgroup of TACs as a di erent phenotype (9). Both clinical pictures have been classi ed under the nosological structure of short-lasting unilateral neuralgiform head- ache attacks (Box 20.1). For the time being, ICHD-3 has clari ed the taxonomy of these related conditions, providing physicians with a practical distinction between SUNCT and SUNA.

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21–30 >30 Duration of attacks (seconds)

1–10 11–20

V1 Neuralgia SUNCT

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Hemicrania continua

Johan Lim and Joost Haan

Introduction

Hemicrania continua (HC) is an uncommon primary headache disorder characterized by continuous, unilateral cranial pain of moderate intensity, more painful exacerbations with cranial auto- nomic features, and an absolute response to indomethacin (1–5). e unilateral autonomic features and indomethacin responsive- ness, besides the overlap in functional brain imaging, are shared with some of the other trigeminal autonomic cephalalgias (TACs), such as episodic and chronic paroxysmal hemicrania (2,6). Hence, HC has recently been grouped under the TACs in the International Classi cation of Headache Disorders, third edition (ICDH-3) by the Headache Classi cation Committee of the International Headache Society (Box 21.1) (1).

Sjaastad and Spierings were the rst to name the condition HC, in their report on two cases in 1984: a 63-year-old woman and a 53-year-old man with continuous, unilateral pain, which had a dra- matic response to indomethacin (7). Subsequently, nearly 200 cases of HC have been reported from various countries and ethnic back- grounds (2,8–13, 18).

Epidemiology

e incidence and prevalence of HC are unknown (18). Reported numbers vary considerably: while some authors describe the con- dition as not rare (10), the relatively limited cases over the years (nearly 200 reported in approximately 30 years) and experience from clinical practice from tertiary referral sites suggest that HC is a rare condition (2). However, a possible publication bias, an ongoing discussion about its clinical features, and a lack of population-based epidemiological studies in uence these numbers.

Mean age of onset is reported to be in the third decade, but the condition may begin at any age (2,13). e duration of the illness before diagnosis has been reported to be 5 years, on average, ranging from 6 weeks to 19 years (14).

A small female preponderance, with reported ratios of 1.8:1–2.4:1, has been described (2,8,10).

Clinical picture

HC typically presents with unilateral pain (right and le sides being equally a ected) without side shi ing (2,5,15). Only a few patients with alternating headache have been reported (2,16–18). e pain is mostly located in the temporal (82%), orbital (67%), frontal (64%), retro-orbital (59%), or occipital/parietal (54%) regions, or at the vertex/peri-orbitally (51%) (2). However, any part of the head or neck can be a ected (2,19).

e pain is described as throbbing by a majority, while sharp and continuous pain are also reported frequently. e intensity of the background pain is generally described as moderate, whereas the exacerbations are mostly described as severe (2).

e temporal pattern of HC is characterized by daily and con- tinuous pain, generally without pain-free periods for more than 3 months (1). Two types of HC have been described: rstly, an epi- sodic/remitting form with pain-free periods (without treatment) of at least 1 day; and, secondly, a chronic/unremitting form with daily and continuous pain for at least 1 year, without remission periods of at least 1 day (1,2). Evolution from the remitting to the unremitting form, and vice versa, have been reported (2).

Most patients su er from an unremitting form, of which the ma- jority is unremitting from onset (2). e average duration of unre- mitting HC is 12 years, with a range from 3 to 49 years. e interval to progress from remitting to unremitting HC is 8 years, on average, varying from 2 weeks to 26 years.

No clear circadian or circannual preponderance has been described (2).

Exacerbations are daily in about half of the patients, and between one and ve times a week in the majority of the remaining half. Cases without exacerbations have also been reported (2). e length of exacerbations varies considerably, from minutes to months.

Exacerbations can both be triggered or occur spontaneously. Commonly reported triggers are the use of alcohol, irregular sleep, stress, and relaxation a er stress (2). About half of the patients have im- provement of pain a er applying heat around head and/or neck and/or staying in a warm environment, whereas a variety of other maneuvers or positions do not seem to have signi cant e ect on the headache (2).

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Part 3 Trigeminal autonomic cephalgias

Box 21.1. International Headache Socity diagnostic criteria for hemicrania continua

A B

Unilateral headache ful lling criteria B–D.
Present for > 3 months, with exacerbations of moderate or greater intensity.
Either or both of the following:

. 1 At least one of the following symptoms or signs, ipsilateral to the headache:

. (a) conjunctival injection and/or lacrimation

. (b) nasal congestion and/or rhinorrhoea

. (c) eyelid oedema

. (d) forehead and facial sweating

. (e) forehead and facial ushing

. (f) sensation of fullness in the ear

. (g) miosis and/or ptosis.

. 2 A sense of restlessness or agitation, or aggravation of the pain by movement .

Responds absolutely to therapeutic doses of indomethacin.1 Not better accounted for by another ICHD-3 diagnosis.

D E

Hemicrania continua, remitting subtype

. A Headache ful lling criteria for Hemicrania continua, and criterion
B below.

. B Headache is not daily or continuous, but interrupted (without treat-
ment) by remission periods of > 24 hours.

Hemicrania continua, unremitting subtype

. A Headache ful lling criteria for Hemicrania continua, and criterion
B below

. B Headache is daily and continuous for at least 1 year, without remis-
sion periods of > 24 hours.

Probable hemicrania continua

. A Headache attacks ful lling all but one of criteria A–D for hemicrania
continua.

. B Not ful lling ICHD-3 criteria for any other headache disorder.

. C Not better accounted for by another ICHD-3 diagnosis.

1 In an adult, oral indomethacin should be used initially in a dose of at least 150 mg daily and increased, if necessary, up to 225 mg daily. The dose by injection is 100–200 mg. Smaller maintenance doses are often employed.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

While at least one cranial autonomic feature during pain exacer- bations is required for the diagnosis of HC following the ICDH-3 cri- teria (1), cases of phenotypically HC-like, indomethacin-responsive headaches without autonomic features have been reported (2). Lacrimation (73%), nasal congestion (51%), conjunctival injection (46%), ptosis (40%), facial ushing (40%), and rhinorrhoea (38%) are most frequently described (2).

Moreover, a majority of patients are agitated during exacerba- tions, showing restlessness and verbal aggression, but—in contrast to cluster headache—in HC this is not a part of the diagnostic cri- teria (2). Some patients have reported vague ocular discomfort preceding exacerbations (20). Concomitant primary stabbing headache is present in a third of patients (2). Most patients also end up with migrainous features, such as phonophobia, photophobia, osmophobia, motion sensitivity, and nausea or vomiting, rendering the distinction from migraine and chronic migraine di cult in some (2).

A family history of HC has been reported once, but speci c gen- etic studies have not been carried out (2). A majority of patients have a history of migraine and a family history of migraine. In a few cases, abnormal ndings on neurological examination are found, which mainly consist of mild sensory changes in the cra- nial areas a ected by pain (2). Radiologic investigations/magnetic resonance imaging (MRI) are mostly normal, whereas the abnor- malities that are found are mostly considered incidental or non- speci c (2,21).

Pathophysiology

While both peripheral and central components have been discussed as relevant for the pathophysiology of HC, a combination of a cen- tral component predominating in the primary form and a periph- eral component predominating in the secondary form has been argued (22).

Firstly, activation of the trigeminal nerve and the craniofacial parasympathetic nerve in a trigeminal–autonomic re ex seems to play an important role (6). e trigeminal–autonomic re ex consists of a brainstem connection between the trigeminal nerve and facial parasympathic nerves; activation results in pain (exacerbations) and autonomic symptoms, respectively (6). Moreover, stimulation of the trigeminal ganglion is thought to increase extra- and intracerebral blood ow due to a vasodilator response via the parasympathetic out ow (23,24) and propagate local release of calcitonin gene- related peptide, substance P, and parasympathetic (vasoactive intes- tinal peptide) marker peptides (23).

Also, data from functional MRI and neurophysiological studies have raised the hypothesis that activation of the contralateral pos- terior hypothalamic grey seems crucial (25): its central permissive functions as pain modulator and/or terminator possibly deter- mine variation in attack duration and phenotypic expression of the pain (26).

Furthermore, anatomical and physiological investigations in rats have shown direct two-way connections between the two aforementioned systems: the trigeminal nucleus caudalis and pos- terior hypothalamus, which are connected through the trigemino- hypothalamic tract (27).

e pathological activation of the trigeminofacial brainstem re ex and posterior hypothalamic grey are shared with some of the other TACs, along with clinical characteristics (e.g. response to indometh- acin, unilaterality of pain, and autonomic features), thus suggesting a common biological basis (6). Pontine activation in HC, similar to migraine, may explain the frequent occurrence of migrainous fea- tures in this syndrome.

aetiology: primary and secondary cases

e aetiology of HC is unknown and, as such, HC is considered a primary headache. However, symptomatic, cases have been re- ported in association with pituitary abnormalities, a er vitreous haemorrhage, trauma, carotid dissection, and a er cranial surgery (2,12,28). Most authors stress the likelihood of a coincidental asso- ciation of HC and stated abnormalities in these cases (2,14).

Diagnosis

HC should be considered in patients with continuous unilateral pain of varying intensity accompanied by autonomic features. History and physical examination should not suggest any other headache diagnosis. Exclusion of other pathology with full neuroradiological investigation is recommended. A headache diary may prove helpful to assess headache features accurately.

Possible cases should receive an adequate trial of indomethacin (29), for an absolute response to indomethacin is considered to be the hallmark of HC. Indeed, absolute indomethacin responsiveness is a diagnostic criterion for HC (1). However, some patients with (otherwise) phenotypically classic HC-like headaches, do not re- spond to indomethacin (29–31).

A positive response to indomethacin is de ned as an absolute response within 48 hours. However, a trial of up to 2 weeks is re- commended before abandoning the treatment as ine ective. In an adult, oral indomethacin should be at least 150 mg daily (1,32). Pain should promptly recur if indomethacin is stopped (33). Escalating doses or loss of e cacy should be treated with suspicion, as for sec- ondary forms or misdiagnosis (6,34).

Symptomatic HC should be considered in all patients with atyp- ical complaints and those with abnormalities at neurological exam- ination. To consider an underlying lesion as cause of HC complaints, there must be a close temporal relationship between the onset of pain and the onset of the associated lesion, the site of the pain, and the site of the lesion should be in concordance, and—ideally—improvement of the HC symptoms should be achieved a er (surgical or other) treatment.

Other TACs with background pain are important considerations in the di erential diagnosis of HC (2). In contrast to other TACs, the continuous and moderate nature of the background pain (6) and relatively mild nature of the autonomic features (33) are typical for HC. Exacerbations in HC are longer lasting (several hours to days) and less frequent than in paroxysmal hemicrania (< 10 minutes, many times a day) or cluster headache (15 minutes–3 hours). Also, patients with HC are, on average, younger than patients with chronic paroxysmal hemicrania (14). However, di erentiating HC from other TACs might prove di cult, especially when facing chronic paroxysmal hemicrania or cluster headache with interictal pain.

Di erentiating HC from (chronic) migraine can also be compli- cated, as HC frequently presents with migrainous features and ex- acerbations can resemble migraine attacks. Migraine attacks may also be associated with cranial parasympathetic features. e preva- lent autonomic symptoms and ‘unilaterality of photophobia and/or phonophobia’ are mentioned as features possibly to be used in the distinction between HC and migraine (2).

Medication overuse is diagnosed in three-quarters of patients with HC at some point during the course of their disease. Most patients with HC do not show improvement a er medication withdrawal (2).

treatment

By de nition, pain in HC has an absolute response to indomethacin (1,35). e median needed dose is 175 mg, ranging from 50 to 500 mg, but the dose–response relationship has not been systematically

explored (2). Some patients can be maintained on lower doses and pain eradication on the lowest possible doses should be attempted, considering the negative e ects of its possible long-term usage (36). Generally speaking, there is no response to non-steroidal anti- in ammatory drugs (NSAIDs) other than indomethacin (2,14).

e underlying mechanisms of indomethacin e ectiveness are unknown, but recent studies have hypothesized prostaglandin syn- thesis inhibition via cyclooxygenase (COX) and modulation of auto- nomic signalling in the sphenopalatine ganglia, possibly through a nitric oxide-mediated pathway as possible mechanism (37,38).

e main side e ects of indomethacin are dizziness and gastro- intestinal symptoms (e.g. abdominal pain, nausea/vomiting, diar- rhoea, and abdominal bloating) (2). erefore, addition of proton pump inhibitors is advised as it may reduce NSAID-induced gastro- intestinal toxicity (39). Furthermore, while most patients do not seem to develop secondary headache due to extended indomethacin use, a subgroup is prone to developing bilateral headache in the con- text of indomethacin use (2).

Non-indomethacin NSAIDs and other analgesics have o en been tried in cases of indomethacin intolerance (mostly because of gastrointestinal side e ects), but their e cacy is limited (40). Anecdotal evidence of some e cacy exists for gabapentin (41–43) and melatonin (44–46), the latter also as add-on to indomethacin (47). With respect to their relatively good safety pro le, some au- thors recommend their use in cases of indomethacin intolerance (36). e same authors advise caution when using selective COX-2 inhibitors (although they have also shown to be somewhat e ective in individual cases) and opioids for reasons of cardiovascular risks and risk of dependency/addiction. Valproic acid has been used with unclear e cacy (48).

Small series have shown that topiramate and glucocorticoids might prove useful alternatives for indomethacin as prophylactic treatment in some cases (2). Anaesthetic blocks are reported to be e ective in half of patients (49–51). Botox was also described as a potential treatment option in HC (52).

Occipital nerve stimulation (ONS) has been shown to be a safe and e ective treatment in small series, also in the long term (53), although some authors have seen a varying response in prac- tice (35,36,54,55). ONS is realized by a subcutaneously implanted neurostimulation device with a pulse generator placed in the chest wall/abdomen, which is connected to extension leads with elec- trodes that stimulate the occipital nerves. E ect is expected within days to weeks; thus, neuroplasticity might be a mechanism. Most commonly reported complications are lead migration, infection, and sensory symptoms due to overstimulation (53). Radiofrequency ablation of C2 or sphenopalatine ganglion gave long-term improve- ment in some patients (56).

Prognosis

e natural history of HC has not yet been systematically inves- tigated. While HC seems to be, by and large, a chronic condition, some cases of de nitive pain resolution a er indomethacin discon- tinuation have been described (57). Indomethacin therapy is not thought to have disease-modifying e ects, but it enables most pa- tients to be pain-free and lead normal lives (58).

CHaPtEr21 Hemicraniacontinua

205

206

Part 3 Trigeminal autonomic cephalgias Conclusion

HC is characterized by continuous unilateral cranial pain of mod- erate intensity, more painful exacerbations with cranial autonomic features, and an absolute response to indomethacin.

It is considered a primary headache, but possible secondary forms, mostly post-traumatic, have been reported. Activation of the trigeminal–autonomic re ex and the contralateral posterior hypo- thalamic grey, resulting in pain (exacerbations) and autonomic features, respectively, are thought to play an important role in the pathophysiology of HC.

e incidence and prevalence are not known, but HC is generally regarded as an uncommon disorder. e mean age of onset is in the third decade, with a small female preponderance (female-to-male ratio 2:1).

HC can be divided into a remitting and an unremitting type; most patients su er from the unremitting variant. e pain is (by de n- ition) side-locked and mainly described as throbbing. Exacerbations, which can occur both spontaneously and be triggered, are accom- panied by unilateral autonomic symptoms and sometimes by mi- grainous features. Physical and supplementary investigations are by and large normal. Other TACs and migraine are the main di eren- tial diagnostic alternatives.

Indomethacin has an absolute therapeutic e ect on the headache, which can be used for the di erential diagnosis. Lowest possible e ective doses should be used to minimize negative e ects of its possible long-term usage. Dizziness and gastrointestinal symptoms are the main side e ects of indomethacin. Hence, the addition of proton pump inhibitors is advised as it may reduce NSAID-induced gastrointestinal toxicity. Non-indomethacin NSAIDs are generally not e ective. More investigation is needed regarding relatively new invasive techniques, such as ONS.

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207

Cluster tic syndrome and other combinations of primary headaches with trigeminal neuralgia
Leopoldine A. Wilbrink, Joost Haan, and Juan A. Pareja

Cluster tic syndrome: cases reported in the literature

In ‘cluster tic syndrome’, the word ‘cluster’ refers to cluster headache and ‘tic’ to ‘tic douloureux’, a term previously used for trigeminal neuralgia (see also Chapter 27). e term ‘cluster tic syndrome’ was introduced in 1978 in an abstract (1). In this abstract the headaches were very brie y described as having features of both cluster head- ache and trigeminal neuralgia, but it is not clear whether the au- thor described two di erent types of attacks within one patient, or that the attacks had features of both cluster headache and trigeminal neuralgia (‘mixed’ attacks) so that an unequivocal primary head- ache diagnosis was not possible. Since then, the term ‘cluster tic’ has been used in di erent ways in the literature, but less o en to describe these ‘mixed’ attacks.

Most of the time, however, it is used for the ipsilateral co- occurrence of attacks of cluster headache and trigeminal neuralgia within the same patient, although the two components may appear asynchronously. Since 1978, 39 patients have been described under the diagnosis cluster tic syndrome (Table 22.1); 18 male patients and 17 females (sex was not mentioned for four patients), with an age at onset between 20 and 78 years (1–15). In all cases described, tri- geminal neuralgia attacks were ipsilateral to the attacks of cluster headache. is could point to a possible pathophysiological link (see ‘Pathophysiology’, or a publication bias as attacks occurring at dif- ferent sides of the face could have been regarded as unrelated and coincidental. ese 39 patients can be divided into cases described as having co-occurrence of cluster headache and trigeminal neur- algia (according to the International Classi cation of Headache Disorders, third edition (ICHD-3) criteria) (n = 24) and a separate entity consisting of (additional) attacks resembling, but not ful lling all criteria of cluster headache and trigeminal neuralgia (n = 15) (Table 22.1).

Eight cases of ‘secondary’ cluster tic were described (Table 22.1); in three patients the cluster tic syndrome resolved by treatment of a pituitary adenoma, prolactinoma, or epidermoid in the sella turcica,

and in another patient the headaches decreased a er venous decom- pression of the trigeminal nerve (12,13,16,17). In another patient the cluster tic syndrome appeared to be related to multiple sclerosis (18). Basilar artery ectasia and a dural carotid–cavernous stula were sug- gested as underlying cause in two other patients (11,19). In a young child a pontine tumour was the underlying cause (14).

In the majority of published patients (n = 39) (Table 22.1), how- ever, there was no obvious structural lesion explaining the headache syndrome, although—especially in the older studies—one could wonder whether brain imaging was su cient to rule out such a le- sion with certainty. Besides, in most patients with cluster tic syn- drome a speci c magnetic resonance imaging/magnetic resonance angiography to investigate the presence of a vascular compression of the trigeminal nerve root nerve was not performed (20).

Pathophysiology

Some authors question the existence of cluster tic syndrome as a separate entity, because sharp, short pain attacks accompanying the usual longer attacks in cluster headache are o en described and should not receive a separate diagnosis (10). Mulleners and Verhagen (9) reject cluster tic syndrome as a separate entity, illus- trated by the description of a patient su ering from a pain syndrome consisting of anatomical and temporal characteristics of trigeminal neuralgia with the periodicity of cluster headache attacks. e au- thors emphasize that, apparently, there are overlapping pain syn- dromes for which it is not practical to make new diagnostic entities.

Among those who think of cluster tic syndrome as a separate syn- drome, di erent pathophysiological mechanisms have been pro- posed. Firstly, it was suggested that trigeminal neuralgia and cluster headache only co-occur by chance (3). Secondly, some believe that attacks of cluster headache and trigeminal neuralgia are caused by the same underlying pathophysiological mechanism (4,5,7). is is based on the assumption that the concurrence of two rare disorders, such as cluster headache and trigeminal neuralgia, in the same individual, and synchronously occurring on the same side, is more than coincidental.

CHaPtEr 22 Cluster tic syndrome and other combinations of primary headaches with trigeminal neuralgia

table 22.1 Descriptions of the cluster tic syndrome in the literature.

trigeminal sensory pathway with involvement of both myelin- ated and unmyelinated bres is hypothesized to be the underlying mechanism (2).

treatment of the cluster tic syndrome

e third edition of the ICHD (ICHD-3) mentions cluster tic syn- drome as a note in the cluster headache section (21). It de nes cluster tic syndrome as the co-occurrence of trigeminal neuralgia and cluster headache, and advises that these patients should re- ceive both diagnoses, because these two types of attacks each need separate treatments. No randomized clinical trials have been per- formed in cluster tic syndrome, because of its rarity. In the case reports described (Table 22.1), a variety of medication has been tried with variable success. In most cases carbamazepine was ef- fective for trigeminal neuralgia and o en verapamil, lithium, or methysergide for cluster headache. As in cluster headache or tri- geminal neuralgia in daily practice, now and then, di erent kind of medications, dosages, and combinations had to be tried before the attacks ceased. In the literature, some patients are described in whom medication was not e ective and who underwent sur- gical procedures (decompression, section, or thermocoagulation of the trigeminal nerve or root), and these procedures were de- scribed to be o en e ective for both trigeminal neuralgia attacks and cluster headache attacks (2,6,10). However, attacks of cluster headache could eventually reappear a er initial relief of both cluster headache and trigeminal neuralgia a er trigeminal nerve decompression (2,10). One patient with the cluster tic syndrome was described who responded to cervical non-invasive vagal nerve stimulation (22).

Since 1993, 11 patients have been described with a combination of paroxysmal hemicrania and trigeminal neuralgia, called par- oxysmal hemicrania tic syndrome (Table 22.2) (23–28). Most of them were women (nine women, two men), with an age of onset be- tween 40 and 69 years. In three patients an underlying disease was described: a Chiari I malformation and an ecstatic vertebrobasilar junction/basilar artery in close proximity to the le trigeminal nerve root entry zone, and in the third patients the headaches were described as being a clinically isolated symptom, according to the McDonald criteria (27,29–31). As in cluster tic syndrome, in most patients a combination of two treatments was necessary, most of the time a combination of indomethacin and carbamaze- pine. In one patient the attacks of paroxysmal hemicrania were not responsive to indomethacin, which contradicts the diag- nosis of paroxysmal hemicrania, according to ICHD-2 criteria. However, in this patient a combination of carbamazepine and acetazolamide was e ective. ree patients in whom trigeminal neuralgia co-existed with paroxysmal hemicrania and short- lasting unilateral neuralgiform headache attacks with conjunc- tival injection and tearing (SUNCT) have been described (32,33). e authors suggested a pathophysiological relationship between these three short-lasting headaches. is was also the case for a

Reference

Cluster tic as described in ICHD-3 criteria: co-occurrence of cluster headache and trigeminal neuralgia

Diamond et al., 1984 (8) Watson and Evans, 1985 (6) Donnet et al., 2012 (42) Pascual and Berciano, 1993 (7) Klimek, 1987 (4)

Solomon et al., 1985 (10)

Maggioni et al. 2009 (34)

Monzillo et al., 2000 (5)

Haan et al., 2011 (3)

Kinfe et al., 2015 (22)

Bernal Sanchez-Arjona et al., 2009 (15)

Total

Reference

Cluster tic described as separate entity consisting
of (additional) attacks resembling, but not ful lling all the criteria of cluster headache or trigeminal neuralgia

Green and Apfelbaum, 1978 (1)

Mulleners and Verhagen, 1996 (9)

Alberca and Ochoa, 1994 (2)

Total

Reference

Secondary cluster tic

Leone et al., 2004 (16)

González-Quintanilla et al., 2012 (18)

Ochoa et al., 1993 (19) Payán et al., 2012 (11)

Levyman et al., 1991 (12) van Vliet et al., 2003 (14)

Favier et al., 2007 (13) de Coo et al., 2017 (17)

Number M/F

1 0/1

5 3/2

1 0/1

1 1/0

4 2/2

1 0/1

5 3/2

3 2/1

1 1/0

24 14/10

Number M/F

4 NM

1 0/1

10 4/6

15 4/7

Number M/F

1 46 1 29

1 NM 1 69

1 39

1 1

1 31 1 41

8 1–69 M, male; F, female; NM, not mentioned.

Age at onset

28–76

19–40

49–78

60–72

28–78

Age at onset

20–66

Age at onset

Lesion/underlying disease

Pituitary adenoma Multiple sclerosis

Basilar artery ectasia

Dural carotid– cavernous stula

Epidermoid tumour sella turcica

Pilocytic astrocytoma pons

Prolactinoma

Venous compression trigeminal nerve

1/0

0/1

1/0

0/1

4/4

Total

e mechanism behind it is, however, still unknown. irdly, it is asserted that the cluster tic syndrome is a separate entity con- sisting of three types of attacks; trigeminal neuralgia attacks, cluster headache attacks, and mixed attacks. A single lesion a ecting the

Even more rare conditions: paroxysmal hemicrania tic and other ‘tic combinations’

209

210

Part 3 Trigeminal autonomic cephalgias
table 22.2 Descriptions of chronic paroxysmal hemicrania tic syndrome in the literature

Reference

Number

M/F

Age at onset

Paroxysmal hemicrania tic as described in ICHD-2 criteria: co-occurrence of paroxysmal hemicrania and trigeminal neuralgia

Hannerz, 1993 (23)

0/1

Caminero et al., 1998 (24)

0/1

Zukerman et al., 2000 (25)

0/3

47–56

Martinez-Salio et al., 2000 (26)

1/0

Boes et al., 2003 (27)

1/0

Sanahuja et al., 2005 (28)

0/1

No relief from indomethacin

Secondary paroxysmal hemicrania tic

Number

M/F

Age at onset

Lesion/underlying disease

Monzillo et al., 2007 (29)

0/1

Chiari I malformation

Boes et al., 2003 (27)

0/1

Ecstatic vertebrobasilar junction/basilar artery

Ljubisavljevic et al., 2017 (30)

0/1

Hyperintense lesion in the right trigeminal main sensory nucleus and root inlet and right corticospinal tract at the medulla oblongata

Total

2/9

40–69

M, male; F, female.

combination of trigeminal neuralgia, SUNCT, and cluster head- ache, as described by Maggioni et al. (34).

As with cluster tic, ICHD-3 mentions paroxysmal hemicrania tic syndrome in a note to the criteria (21). It is de ned as the co- occurrence of trigeminal neuralgia and paroxysmal hemicrania, and also in these patients the advice is to give them both diagnoses, be- cause these two types of attacks each need separate treatments (21).

e combination of SUNCT and trigeminal neuralgia has also been described in four case reports (Table 22.3) (35–38). Some authors hypothesize that SUNCT may be modi ed trigeminal neuralgia, suggesting a single pathological condition (36). Others, however, state that discrimination between rst division trigem- inal neuralgia and SUNCT is feasible by the presence of autonomic signs at the start of a SUNCT attack, unlike in trigeminal neuralgia in which, if present, these autonomic symptoms are secondary to the head pain (35,39). SUNCT may have been mistaken for trigeminal

table 22.3 Descriptions of SUNCT tic syndrome in the literature

neuralgia when not fully developed, particularly in the initial stages (forme fruste, i.e. with less marked autonomic features) (40).

We found one prospective controlled study giving a hazard ratio for trigeminal neuralgia in migraine to be 6.72 (95% con dence interval 5.37–8.41; P<0.001). e authors conclude that migraine is a previously unidenti ed risk factor for trigeminal neuralgia (41).

Conclusion

Cluster tic syndrome and other combined tic syndromes are very rare and heterogeneously described as case reports in the literature. ree types of cluster tic syndromes can be distinguished: (i) sim- ultaneously occurring trigeminal neuralgia and cluster headache according to the ICHD-3 criteria (most frequent) (21); (ii) attacks not ful lling criteria for either cluster headache or trigeminal neur- algia but having features of both; (iii) secondary cluster tic syn- drome. Trigeminal neuralgia can also co-occur with paroxysmal hemicrania (paroxysmal hemicrania tic) and with SUNCT. In case of co-occurrence of two primary headache syndromes, separate treatments aimed at the two headache syndromes is recommended. e pathophysiology of the tic combination syndromes is unknown.

Reference

Number

M/F

Age at onset

Lesion/ underlying disease

Bouhassira et al., 1994 (36)

1/0

Sesso et al., 2001 (35)

0/1

Secondary SUNCT tic

Eguia et al., 2008 (37)

0/1

Meningitis

Lambru et al., 2017 (38)

1/0

Medullary infarction

Total

2/2

46–58

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211

PART 4

Other primary short-lasting and rare headaches

23. Primary stabbing headache 215 27. Cranial neuralgias and persistent idiopathic

Rashmi B. Halker, Esma Dilli, and Amaal Starling

24. Cough headache 220
Julio Pascual and Peter van den Berg†

25. Exertional and sex headache 225
Shih-Pin Chen, Julio Pascual, and Shuu-Jiun Wang

26. Hypnic headache 230
Dagny Holle and David W. Dodick

facial pain 237
Aydin Gozalov, Messoud Ashina, and

Joanna M. Zakrzewska

Randolph W. Evans

Primary stabbing headache

Rashmi B. Halker, Esma Dilli, and Amaal Starling

Introduction

Primary, or idiopathic, stabbing headache was rst described in 1964 by Lansche in a patient with migraine and stabbing paroxysms as ‘ophthalmodynia periodica’ (1). Various terms have been used to describe primary stabbing headache (PSH), including ice pick head- ache (2), sharp short-lived headache (3), jabs and jolts syndrome (4), and idiopathic stabbing headache (5–7). In this review, we will discuss the epidemiology, clinical features, di erential diagnosis, pathophysiology, treatment, and prognosis of PSH.

Epidemiology

e reported prevalence of PSH varies widely in the currently avail- able studies. Gender and comorbidity with other headache disorders seems to a ect the prevalence.

Two population-based studies reported a prevalence of 0.2–2%. (8,9). In a cross-sectional study of a tertiary neurology clinic in China, the prevalence rate of ‘pure’ PSH (exclusion of other pri- mary headaches disorders) was reported to be 1.5% (10). In Spain, a retrospective review performed in a specialty clinic found only 33/ 100,000 patients with PSH with a mean age of onset of 47.1 years (5). However, the Vågå study, performed in Norway (a large-scale cross-sectional study), reported a PSH prevalence of 35.2%, with a mean age of onset of 28 years (11,12). In a prospective study of 725 patients at a tertiary headache clinic, PSH (based on International Classi cation of Headache Disorders (ICHD)-2 criteria) was re- ported in 36 patients (5%), with a mean age at onset of 34.1 ± 2.9 years (range 10–72 years) (13). It is unclear why the prevalence data, ranging from < 1% to approximately 35%, has such a wide range, but it is possible that changes in diagnostic criteria (see Box 23.1) and selection bias in studies performed in specialty clinics were contributing factors.

In the adult population, PSH is more common in women. e Vågå study demonstrated a female-to-male ratio of 1.49:1 (11). e retrospective review in Spain found a female-to-male ratio of 6.6:1 (5). In a prospective study, where 36 of 725 patients at a tertiary headache clinic were diagnosed with PSH, 26 were females and 10 were males (2.6:1) (13).

PSH also occurs in the paediatric headache population. In a retro- spective review of 548 children and adolescents from a paediatric headache clinic, Fusco et al. (14) reported 23 patients (4.2%) with brief (a few seconds to 15 minutes) attacks of self-limited stabbing headache suggestive of PSH. ere does not appear to be a sex di er- ence in children with PSH (15,16).

PSH is commonly associated with other headache disorders, including migraine and cluster headache (3,17). PSH was found in 12.6% of all headache patients in a Turkish study (18). is was a higher prevalence than found in general population-based studies (8,9), but lower than in the migraine population (19), who followed 280 migraine patients for a 12-month period, noted a high preva- lence of PSH. ey found that 40.4% of their migraine patients pre- sented with idiopathic stabbing headache, with a female-to-male ratio of 3:1. Raskin and Schwartz (3) compared the incidence of PSH in 100 migraineurs and 100 control subjects. ree of the 100 con- trol subjects reported episodes consistent with PSH on at least an annual basis. In contrast, 42 of the 100 migraineurs reported similar episodes, with more than 50% of them experiencing the sharp painful episodes more than once a month. In this study, 45% of the paroxysms of ice pick pain were unifocal at the temple or orbit with 69% of the patients having concurrent headache such as migraine superimposed on the paroxysmal ice pick-like pain. Patients with cluster headache have also reported paroxysms of sharp pain con- sistent with PSH and unique from cluster headache attacks. In an observational study of 33 patients with cluster headache, 11 had par- oxysms of pricking or stabbing sensations in the eye, forehead, and upper jaw (17).

In a clinical series, the incidence of PSH was 33/100,000 per year, while in a population study prevalence was found to be 35.2% (5). e mean age of onset of PSH is 23–47 years, with a female predom- inance in adults and no clear female predominance in children. e prevalence of PSH reported in the literature has varied as a result of reporting bias, particularly as PSH is commonly associated with other headache disorders.

Clinical features

PSH is characterized as paroxysmal attacks of moderate-to-severe stabbing/sharp pain occurring spontaneously in irregular patterns

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Box 23.1 Clinical characteristics

Spontaneous/sporadic attacks/irregular pattern Sharp or stab
1–10 seconds in duration (mean 2 seconds) Unilateral > bilateral

Moderate to severe

(Box 23.1). Typically, the jabbing pain lasts 1–10 seconds, with two- thirds of patients having moderate-to-severe pain of < 1 seconds’ duration (20). Piovesan et al. (19) studied PSH in 280 patients with migraine. In this study the mean duration of pain was 1.42 seconds (1 second in 72.4% of patients, 2 seconds in 18.1%, 3 seconds in 6.3%, 4 seconds in 1%, and 5 seconds in 2%).

e single burst of pain or brief repetitive volleys of pain is similar to an ice pick, needle, or nail jab. In the Vågå population study of PSH, 68% of the 627 jab cases had single jabs, 4% had volleys, and 28% had a mixture of volleys and singlets. Most individuals had ex- perienced only few jabs (11).

e frequency of the attacks can range from one attack per year to 50 attacks daily (20), in a random distribution throughout the day and night in 84%. Chronic occurrence with > 80% attack days per year have been reported in 14% of patients.

Unilateral location has been reported in 59–91.4% of patients.

Paroxysmal stabbing pain occurring in multiple dermatomes has been reported in a prospective study of 28 patients with recurrent stabbing headache. ese patients ful lled the ICHD-2 diagnostic criteria for PSH, except for area of involvement (21).

e pain was originally considered to be in the rst branch of the trigeminal nerve and in previous studies 45–62% of patients with PSH reported a purely V1 distribution of pain (5,22). However, more recent studies report that up to 70% of patients have extra- trigeminal (occipital, nuchal, parietal) stabbing pain from nerves innervated by C2–C4 (22); therefore, the ICHD-3 has removed the criterion requiring stabs to be limited to a V1 distribution (see Table 23.1) (23,24).

Unlike trigeminal autonomic cephalalgias (TACs), there are no cranial autonomic features such as tearing or ptosis associated with the attacks of pain. Nausea, vomiting, and photophobia are un- common; however, accompanying symptoms have been reported in 15–22% (10,22). Although similar ndings have been reported in paediatric studies, in one paediatric study, vertigo, nausea, photo- phobia, and phonophobia have been reported to occur in as high as 47% of children with stabbing headache (25).

table 23.1 Diagnostic criteria for stabbing headache

PSH is commonly associated with other headaches disorders such as migraine. In a study by Fuh et al. (22), 25% of patients with PSH also had migraine. Migraine was less common in patients who had PSH onset a er the age of 50 years (14% vs 38%; P = 0.02) than those who rst experienced PSH before the age of 50. ere appears to be a spatial and temporal relationship to the migraine and stabbing headache as 88% of patients reported an overlap between the loca- tion of the migraine and stabbing pain, and 79% of patients reported stabbing pain during a migraine attack (26).

In most patients, there are no triggers for the paroxysmal stabbing pain. However, a few patients reported provocative factors. ese triggers included physical exertion, head motions, rapid alterations in posture, physical exertion, bright light, and head motion during migraine attacks (3,26). Ammache et al. (27) reported a case of complete vision loss ipsilateral to the pain in a man with idiopathic stabbing headache, but the patient also had a history of migraine with aura.

PSH is rarely reported in the paediatric population. In a retro- spective study in a paediatric neurology service in Saudi Arabia, ve children were identi ed over a 12-year period with PSH, according to the ICHD-2 criteria. ree children had occipital location of their attacks (28). In a retrospective study by Fusco et al. (14), the mean age of onset of stabbing headaches was 9 years, with bilateral distri- bution in 60% and an orbital or temporal location in 60% of patients (14). is predominant bilateral distribution of pain in the paedi- atric population is also seen in paediatric migraine patients.

Differential diagnosis

e di erential diagnosis of PSH consists of all short-lasting stab- like headaches, primary and secondary. As with the diagnosis of all headache disorders, rst an underlying cause for the headache must be ruled out. Several cases of a secondary headache with stabbing- type of pain have been described in the literature, including vascular, autoimmune, infectious, and neoplastic aetiologies (29).

Short lasting, stab-like headaches have been described in both haemorrhagic and ischaemic stroke. Six of the series of 90 patients described a de novo short-lasting, stabbing pain following a haem- orrhagic stroke (30). Paroxysmal sharp pain lasting 1–2 seconds has also been described a er an acute thalamic haemorrhage in an eld- erly patient (31). In a prospective series of > 2000 patients with acute ischaemic stroke, 20% of the patients who presented with headache at onset of their stroke described a stabbing headache (32). In an- other case series, eight patients with stabbing headaches had uni- lateral or bilateral transverse sinus stenosis on magnetic resonance venogram (33).

In a retrospective review of 20,534 patients, 26 patients ful- filled the ICHD-2 diagnostic criteria of stabbing headache and had underlying autoimmune disorders, including multiple sclerosis, Sjögren’s syndrome, systematic lupus erythematous, Behçet’s disease, autoimmune vasculitis, and antiphospholipid antibody syndrome (34). Stabbing headache has also been re- ported with giant cell arteritis (35). Ergün et al. (36) reported that in relapsing remitting multiple sclerosis, stabbing headache (27.8%) was the most common headache in the relapse phase. Klein et al. (37) reported stabbing headache as a sign of relapses in multiple sclerosis.

International Classi cation of Headache Disorders, third edition (ICHD-3) diagnostic criteria for primary stabbing headache

Head pain occurring spontaneously as a single stab or series of stabs and ful lling criteria B and C

Each stab lasts for up to a few seconds.

Stabs occur with irregular frequency, from one to many per day.

No cranial autonomic symptoms.

Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Stabbing headache has been reported as the presenting symptom of a herpes zoster meningoencephalitis (38). e patient presented to the emergency department with complaints of stabbing pain in the right frontal and temporal head regions. Physical examination was signi cant for herpetic lesions on her right chest, as well as neck sti ness and cognitive dysfunction. Further work-up con rmed herpes zoster meningoencephalitis. Treatment with aciclovir re- sulted in resolution of the stabbing head pain.

Stabbing headache has also been the presenting manifestation of intracranial meningiomas (39).

Once secondary headaches have been considered and ruled out, there are multiple primary headache disorders that are included in the di erential diagnosis for PSH. PSH and other primary headache disorders can be di erentiated by determining the location, triggers, duration of attacks, and the presence or absence of cranial auto- nomic features.

e TACs including short unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) should be considered (see also Chapter 20). However, by de nition, the TACs including SUNCT must have unilateral cranial autonomic features. e pres- ence or absence of autonomic symptoms is a key feature that will di erentiate a TAC from PSH.

Trigeminal neuralgia is a unilateral disorder characterized by brief electric shock-like attacks of pain limited to the distribution of one or more divisions of the trigeminal nerve (see also Chapter 27). e attacks of pain are o en precipitated by mechanical stimula- tion such as speaking, eating, or brushing teeth. e distribution of pain and provocative factors di erentiate trigeminal neuralgia from PSH.

Primary cough headache (see also Chapter 24), primary exertional headache, and primary headache associated with sexual activity (see also Chapter 25) are di erentiated from PSH mainly by the presence or absence of provoking factors.

Pathophysiology

e pathophysiology of PSH is unknown. eories include irri- tation of peripheral branches of the trigeminal nerve or other cranial nerves, and/or intermittent dysfunction of central pain processing that results in spontaneous synchronous discharges or hyperexcitability of neurons. e ephaptic impulses are pos- tulated to travel to the corresponding nerve distribution with the sensation of stabbing pain. Selekler and Komsuoglu (26) proposed that the rationale for stabbing pain to occur commonly in areas of the patient’s migraine was the segmental disinhibition of cen- tral pain pathway leading to increased susceptibility to ‘a erent volley of impulses’ (26). Because PSH is more common in patients with migraine, the trigeminal vascular system may play a role, but further studies are required to determine the pathogenesis and pathophysiology of PSH. Other theories include in ammation or focal demyelination within the brainstem in patients with sec- ondary stabbing headache associated with autoimmune disorders (34), although no such nding has been reported in a patient with PSH. Montella et al. (40) suggested that PSH was dural sinus stenosis-associated.

Investigations

Neuroimaging, consisting of either computed tomography or magnetic resonance imaging of the brain, is reasonable in pa- tients presenting with stabbing headache, given that intracranial meningiomas can be a potential secondary cause (39). In elderly pa- tients who present with new-onset headache, additional work-up for secondary causes is important, as there have been cases of thalamic haemorrhage and giant cell arteritis presenting with stabbing head- ache (31,35).

treatment

In patients with infrequent attacks, the explanation that PSH is a be- nign condition can be su cient and treatment may not be necessary. Patients with frequent attacks might require intervention. Acute treatment is not practical given the short duration of the attacks. Consequently, only prophylactic medication can be considered.

PSH, like several other primary headache conditions, is considered indomethacin-responsive. While it is not clear why indomethacin is so e ective and therefore the treatment of choice for these disorders, there is evidence that indomethacin has a few unique properties, particularly compared with other non-steroidal anti-in ammatory drugs (NSAIDs). Indomethacin has been shown to inhibit nitric oxide release, as well as decrease cerebral blood ow and lower cere- brospinal uid pressure. NSAIDs in general, including indometh- acin, reduce in ammatory pathways by inhibiting cyclooxygenase and phosphodiesterase (41). Individuals with PSH have been re- ported to respond quickly to indomethacin ranging from 75–250 mg/day given in divided doses.

Long-term indomethacin use is o en limited owing to gastro- intestinal and renal side e ects. ere are other options for patients who are unable to tolerate indomethacin or have a contraindication to its use. Piovesan et al. (42) presented three patients with PSH who derived a complete therapeutic response to celecoxib 100 mg q12h, respectively, within 3 days, 6 days, and 14 days of starting treatment. O’Connor et al. (43) reported on an 88-year-old woman with PSH who responded to etoricoxib 60 mg daily, with complete cessation of attacks within a week. Rofecoxib 25 mg q12h for 10 days de- creased attack frequency by 50% (44). Etoricoxib and rofecoxib are not available in the USA owing to safety concerns. Indomethacin is not Food and Drug Administration-approved for children < 15 years old. Although there is little literature available about the use of indomethacin in PSH, a trial of indomethacin is recommended by Myers and Smyth (45) in children with severe paroxysmal pain without autonomic symptoms in whom secondary causes have been ruled out.

Melatonin (3–12 mg), nifedipine 90 mg, and gabapentin 400 mg q12h have also been reported to be e ective in isolated cases (44,46,47).

Onabotulinum toxin A (BoNTA) was studied in a prospective, unblinded study in 24 patients with PSH (48). e area of stabbing pain was classi ed based on location (orbital, frontal, temporal, par- ietal, and occipital), and patients received 5 units of BoNTA into each area where they experienced the stabs. Because many patients

CHaPtEr 23 Primary stabbing headache

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had more than one attack zone, the mean dose of BoNTA used was 11.81 ± 7.17 units. Two patients did not experience any bene t from the injections, but the remaining 22 saw improvement, with three individuals noting complete remission. e bene t from BoNTA lasted approximately 63 days. As no patients reported any side ef- fects, BoNTA may be a reasonable therapeutic option for PSH.

Prognosis

Although there have not been any prospective studies on PSH prog- nosis, it is generally considered a benign condition, and may remit with time. Periodic medication tapering trials to evaluate for the possibility of remission is reasonable.

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CHaPtEr 23 Primary stabbing headache

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219

Cough headache

Julio Pascual and Peter van den Berg†

Introduction

Headaches related to exertion can be brought on by Valsalva man- oeuvres (‘cough headache’), prolonged exercise (‘exercise headache’), and sexual excitation (‘sexual headache’) (1). ese conditions are a challenging diagnostic problem. ey can be primary or sec- ondary, and their aetiologies di er depending on the headache type. Historically, cough headache has been included in the broader context of exercise-induced headache, but clinical features of cough headache are clearly di erent from those of exertional and sexual headache, which do have many properties in common (2) (see also Chapter 25).

Tinel, in 1932, reported several patients with intermittent, par- oxysmal headaches following exertion and manoeuvres that in- creased intrathoracic pressure (3). In the 1950s, Symonds called the disorder ‘cough headache’ and demonstrated that it may be a benign syndrome without demonstrable cause (4). Before this re- port, cough and exertional headaches were always considered om- inous symptoms, and there was no clear recognition that benign types of these headaches existed. e rst large series published on exertional headache or head pain related to exertion came from the Mayo Clinic. is work, however, still combined all exercise- induced headache, which contributed to the lack of di erentiation among these provoked subtypes and included the following state- ment: ‘in every patient with this complaint, an intracranial lesion of potentially serious nature, such as a brain tumour, aneurysm or vas- cular anomaly, has been suspected; and even when no such lesion could be identi ed, an uneasy uncertainty usually remained’ (5). It was not until modern neuroimaging techniques became available that these activity-related headaches were clinically di erentiated.

In the International Classi cation of Headache Disorders (ICHD), cough headache is included within ‘Other primary headaches’ and de ned as headache precipitated by coughing or straining in the ab- sence of an intracranial disorder. New ICHD-3 IHS diagnostic cri- teria are given in Box 24.1 (6).

Epidemiology

Cough headache has been classically considered a rare entity (7). However, Rasmussen and Olesen (8) have shown that the lifetime prevalence of cough headache is 1% (95% con dence interval 0–2).

Over 10 years, of the 6412 patients who attended a general neurology department, 68 (1.1%) consulted because of cough headache (9,10).

aetiology

Headache precipitated by cough can be either a primary benign condition or secondary to structural intracranial disease. From case series prior to computed tomography and magnetic res- onance imaging (MRI) it was concluded that about 20% of pa- tients with cough headache had structural lesions, most of them a Chiari type I malformation (3,5,11,12). However, with modern neuroimaging techniques it is clear that about 40% of patients with cough headache have secondary cough headache due to ton- sillar descent or, more rarely, to other space-occupying lesions in the posterior fossa/foramen magnum area (13). Up to one-third of patients with Chiari type I malformation experience headache ag- gravated by Valsalva manoeuvres, mainly cough (14). erefore, it can be concluded that about 60% of the patients with cough head- ache will show no demonstrable aetiology, while 40% will be sec- ondary to structural lesions, mostly at the foramen magnum level.

Pathophysiology

e pathophysiology of secondary cough headache is reasonably well understood. is headache seems to be secondary to a tem- porary impact of the cerebellar tonsils below the foramen magnum (15–18). In two patients with cough headache and tonsillar hernia- tion, Williams (15) demonstrated a pressure di erence between the ventricle and the lumbar subarachnoid space during coughing. is pressure di erence, called cranio-spinal pressure dissociation, dis- placed the cerebellar tonsils into the foramen magnum. Williams also observed that the headache disappeared a er decompressive craniectomy. Nightingale and Williams described four more pa- tients who had headache due to episodic impact of the cerebellar tonsils in the foramen magnum a er abrupt Valsalva maneuvers (17). Data from Pascual et al. (13,14) support the concept that ton- sillar descent is the actual cause of cough headache. Furthermore, it was also shown that the presence of cough headache in Chiari type

† It is with regret that we report that Peter van den Berg died on 26 January 2019.

I patients correlated with the degree of tonsillar descent (13,14), al- though this was not supported by ndings of Sansur et al. (18).

Alterations in posterior fossa cerebrospinal dynamics in symp- tomatic patients with Chiari type I with abnormal pulsatile motion of the cerebellar tonsils have been described (19,20). Such move- ment produced a selective obstruction of the cerebrospinal uid (CSF) ow from the cranial cavity to the spine. e amplitude of the tonsillar pulsation and the severity of the arachnoid space reduc- tion were associated with cough headache (20). ese data con rm that symptomatic cough headache is secondary to Chiari type I de- formity and that this pain is due to compression or traction of the causally displaced cerebellar tonsils on pain-sensitive dura and other anchoring structures around the foramen magnum innervated by the rst cervical roots.

In contrast to secondary cough headache, the pathophysiology of primary cough headache is not known. e possibility of a sudden increase in venous pressure being su cient itself to cause headache due to an increase in brain volume has been proposed (21). ere should be other contributing factors, however, such as a hypersensi- tivity of some receptors, sensitive to pressure, hypothetically local- ized on the venous vessels (22). One of the potential aetiologies for this transient receptor sensitization could be a hidden or previous infection. Interestingly, Chen et al. (23) have found that patients with primary cough headache are associated with a more crowded pos- terior cranial fossa, which may be a further contributing factor for the pathogenesis of this headache syndrome. A recent study using magnetic resonance venography showed a transverse or jugular vein stenosis in ve of the seven patients with primary cough headache. However, the question remains if and how is the stenosis related to primary cough headache (24).

Clinical manifestations

Primary cough headache is de ned as head pain precipitated by coughing or other Valsalva manoeuvres in the absence of any intra- cranial disorder. According to the ICHD-3 criteria (Table 24.1), primary cough headache is a sudden-onset headache lasting from 1 second to 30 minutes, brought on by and occurring only in asso- ciation with coughing, straining, and/or Valsalva manoeuvres (6).

e clinical picture of primary cough headache is somewhat characteristic, which should allow its di erentiation from sec- ondary cases (12,13,14,24–26). It usually a ects those over the age of 40 years, with a mean age in patient series above 60 years of age. ere is a slight male predominance. e pain begins immediately or within seconds of the precipitants. Such precipitants include coughing, sneezing, nose blowing, laughing, crying, singing, li ing a

weight, straining at stool, and stooping. Prolonged physical exercise is not a precipitating factor for primary cough headache. e pain is moderate to severe in intensity, with a sharp, stabbing, splitting, or even explosive quality. e headache is usually bilateral but can be unilateral. e pain is most o en in the occipital region, but may also be in the frontotemporal regions. According to the criteria the headache should last from 1 second to 30 minutes, but usually lasts seconds to several minutes. In some patients, a dull, aching pain fol- lows the paroxysm for several hours (27). Primary cough headache is not associated with other clinical manifestations, not even nausea or vomiting, photo- and phonophobia, and responds to indometh- acin (13,14). Primary cough headache is an episodic disease, ran- ging from 2 months to a maximum of 2 years in our experience.

Differential diagnosis

Cough headache can be either a primary benign condition or sec- ondary to structural intracranial disease (Figure 24.1). By de nition, primary cough headache can only be diagnosed if neuroimaging studies are normal. e presence of a Chiari type I malformation or any other lesion causing obstruction of CSF pathways or displacing cerebral structures must be excluded before cough headache is assumed to be benign (Figure 24.2). Around 30% of patients with Chiari type I mal- formation experience headache aggravated by Valsalva manoeuvres, mainly cough. Cough headache can be the only clinical manifestation of Chiari type I malformation for several years in about one- h of symptomatic patients (10,13). However, most if not all patients with symptomatic cough headache nally develop posterior fossa symp- toms or signs, mainly dizziness/vertigo, unsteadiness, and syncope.

Several clinical clues may be helpful in di erentiating between primary and secondary cough headache. Secondary cough headache usually begins earlier in life, is located more in the occipital region, is associated with fossa posterior symptoms, and does not respond to indomethacin. However, studies have showed a response to indo- methacin in some patients with secondary cough headache (28).

Di erential diagnosis with primary exertional headache is straightforward. Exertional headache is not brought on by Valsalva manoeuvres, but by prolonged physical exercise (see also Chapter 25). In addition, contrary to primary cough headache, pri- mary exertional headache is typical in young people (< 50 years of age) and contains a lot of migrainous characteristics. Primary sexual headache shares a lot of properties with exertional headache (see also chapter 25) (10,13). Sexual intercourse is a prolonged exercise with Valsalva manoeuvres; therefore, an orgasm can also be seen as precipitating factor for ‘exertional’ headache in some patients (29).

Migraine, cluster headache, post-lumbar puncture headache, and idiopathic intracranial hypertension can be aggravated, but not elicited, by cough. Cough headache can also be symptomatic of low CSF pressure (see Chapter 38) (30). ese patients complain of both orthostatic and cough headaches. ese are related to either a re- versible pseudo-Chiari due to brain sagging which can be seen on the MRI (Figure 24.3) (31), or cerebral venous sinus engorgement and cerebral venous hypertension. Given the di erential diagnosis outlined, every patient with cough headache should have an MRI of the brain to rule out a posterior fossa lesion, and MRI with gado- linium to rule out dural enhancement associated with CSF leak and intracranial hypotension. In spite of scattered reports, there is not enough scienti c background to support unruptured aneurysms

CHaPtEr24 Coughheadache

Box 24.1 Diagnostic criteria for primary cough headache

• At least two headache episodes ful lling criteria B–D

• Brought on by and occurring only in association with coughing,
straining and/or other Valsalva manoeuvre

• Sudden onset

• Lasting between 1 second and 2 hours

• Not better accounted for by another ICHD-3 diagnosis.
Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

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Patient consulting due to headache related with cough or other Valsalva manoeuvres

Headache precipitated by cough

Headache aggravated by cough

Elderly Normal exam Response to IDM

<50 years
Posterior fossa symptoms/signs No response to IDM

Young Normal exam

Migraine

Focal symptoms/signs

Neuroimaging

Headache due to SOL

Cranio-cervical MRI

Normal Primary CH

IDM

Abnormal Secondary CH

Posterior fossa decompresion

Figure 24.1 Differential diagnosis and management of patients consulting for headache related to cough. IDM, indomethacin; MRI, magnetic resonance imaging; CH, cough headache; SOL, space-occupying lesion.

(32) or carotid stenosis (33,34) as speci c causes for cough head- ache. erefore, a magnetic resonance angiography study is not mandatory in these patients.

treatment

Symptomatic treatment is not practical because of the short dur- ation and multiplicity of cough headaches. Potential precipitants,

(a)

for instance lung infections or cough-inducing medications, must be treated or withdrawn. Most patients with primary cough head- ache respond to indomethacin, given prophylactically at doses usu- ally ranging from 25 to 150 mg daily (25,35,36). e mechanism of action of this drug is unknown, but could include a decrease in intracranial pressure (37). is would explain the bene ts seen with lumbar puncture or acetazolamide in some patients with primary cough headache (21,22,38). ere is no consensus on treatment dur- ation with indomethacin. However, two studies show that a er good

(b)

Figure 24.2 (a) Cranial magnetic resonance imaging (MRI) of a patient consulting for cough headache showing slight tonsillar descent. (b) Cine-MRI con rms that this Chiari type I malformation makes the circulation of cerebrospinal uid dif cult, mainly posteriorly (arrows).

(a) (b)

CHaPtEr24 Coughheadache

Figure 24.3 (a) Cranial magnetic resonance imaging showing tonsillar descent (arrow) in a patient consulting for cough headache after a lumbar puncture. (b) Resolution of tonsillar descent (arrow) after a lumbar patch.

response to indomethacin the treatment should continue for about 6 months (10,25). Patients with symptomatic cough headache do not consistently respond to any known pharmacological treatment, including indomethacin, and need speci c surgical treatment. It has been shown that suboccipital craniectomy with posterior fossa re- construction relieves cough headache in patients with Chiari type I malformation (10,13).

prospective etiological and clinical study. J Headache Pain

2008;9:259–66.

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Hop Paris 1980;56:525–31.

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miscellaneous headaches. Med Clin North Am 1991;75:733–47.

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Cough, exertional, and sexual headaches. An analysis of 72 be-
nign and symptomatic cases. Neurology 1996;46:1520–24.

. (14) Pascual J, Oterino A, Berciano J. Headache in type I Chiari mal-
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. (15) Williams B. Cerebrospinal uid changes in response to
coughing. Brain 1976;99:331–46.

. (16) Williams B. Cough headache due to craniocerebrospinal pres-
sure dissociation. Arch Neurol 1980;37:226–30.

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. (19) Pujol A, Roig C, Capdevila A, Pou A, Marti-Vilalta JL, Kulisevsky J, et al. Motion of the cerebellar tonsils in Chiari type I malformation studied by cine-phase con trast MRI. Neurology 1995;45:1746–53.

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V. Cerebrospinal uid ow in foramen mágnum: te,poral and spatial pattersn at MR imaging in volunteers ad in patients with Chiari type I malformation. Radiology 2004;232;229–36.

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. (22) Raskin NH. e cough headache syndrome: treatment. Neurology 1995;45:1784.

. (23) Chen YY, Lirng JF, Fuh JL, Chang FC, Cheng HC, Wang SJ. Primary cough headache is associated with posterior fossa crowdedness: a morphometric MRI study. Cephalalgia 2004;24:694–9.

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. (1) Pascual J, González-Mandly A, Oterino A, Martín R. Primary cough headache, primary exertional headache, and primary headache associated with sexual activity. Handb Clin Neurol 2010;97:459–68.

. (2) Silbert P, Edis RH, Stewart-Wynne EG, Gubbay SS. Benign vas- cular sexual headaches and exertional headaches: interrelation- ship and long-term prognosis. J Neurol Neurosurg Psychiatry 1991;54:417–21.

. (3) Tinel J. La céphalée a l’e ort. Syndrome de distension douloureuse des veines intracraniennes. Médecine (Paris) 1932;13:113–18.

. (4) Symonds C. Cough headache. Brain 1956;79:557–68.

. (5) Rooke ED. Benign exertional headache. Med Clin North Am
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. (7) Ozge C, Atis S, Ozge A, Nass Ducce M, Saracoglu M, Saritias E.
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. (9) Pascual J, Combarros O, Leno C, Polo JM, Rebollo M,
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clinical and radiological study. Neuroradiology 2012;55:297–305.

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P. Cough headache secondary to spontaneous intracranial hypo- tension complicated by cerebral venous thrombosis. Neurol Sci 2012;33:429–33.

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2011;15:157–63.

. (32) Smith WS, Messing RO. Cerebral aneurysm presenting as cough
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. (34) Rivera M, del Real MA, Teruel JL, Gobernado JM, Ortuno J.
Carotid artery disease presenting as cough headache in a patient
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. (35) Diamond S, Medina JL. Benign exertional headache: successful
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. (37) Slavik RS, Rhoney DH. Indomethacin: a review of its cerebral
blood ow e ects and potential use for controlling intracra- nial pressure in traumatic brain injury patients. Neurol Res 1999;21:491–9.

. (38) Chalaupka FD. erapeutic e ectiveness of acetazolamide in hindbrain hernia headache. Neurol Sci 2000;21: 117–19.

Exertional and sex headache

Shih-Pin Chen, Julio Pascual, and Shuu-Jiun Wang

Introduction

Exertional headaches (or headaches provoked by prolonged phys- ical exercise) and sexual headaches have been recognized for dec- ades. ese two headache disorders share some pathophysiological and clinical characteristics, and might respond to similar pharma- cological treatments. ey can be either primary (benign) or sec- ondary to intracranial pathology (symptomatic). Investigation of secondary causes is mandatory for patients with these headaches.

De nitions of exertional headache and sexual headache have evolved with time. In 1932, the term ‘la céphalée à l’e ort’ was rst coined by Jules Tinel to describe four patients with intermittent par- oxysmal headache brought on by exertion or manoeuvres capable of increasing intrathoracic pressure (1). In 1968, E. Douglas Rooke (2) proposed the term ‘benign exertional headache’ for any head- ache precipitated by ‘exertion’, such as running, bending, coughing, sneezing, heavy li ing, or straining at stool. However, ‘exertion’ de- ned here actually included a mixture of physical activities with diverse mechanisms, such as Valsalva-like manoeuvres, general physical e orts, or mechanical factors related to the cervical spine. e in uence of Rooke remained prior to 1990s such that the term exertional headache actually encompassed cough headache, head- ache related to prolonged strenuous exercises, and headache attrib- uted to sexual activities. In 1991, Sands et al. (3) analysed a large group of cases with headaches provoked by cough or exertion. In this monograph, benign exertional headache was used to describe severe, short-lived pain a er coughing, sneezing, li ing a burden, sexual activity, or other similar brief e ort. Structural lesions of the brain or skull, especially posterior fossa mass lesions, were the most common organic aetiologies of these disorders.

Historically, primary sexual headache was also called benign or- gasmic cephalgia, benign coital headache, or benign vascular sexual headache, intercourse headache, and so on (4–6). James W. Lance (7) was one of the rst among his contemporaries to propose two dif- ferent subtypes of headaches related to sexual activities. Type 1 was a headache related to muscle contraction that developed as sexual ex- citement mounted in the pre-orgasmic phase, whereas type 2 was a severe, explosive headache occurring at orgasm, presumably of vas- cular origin. A third type—post-orgasmic postural headache—had been reported (5), which was recognized as a secondary headache due to low cerebrospinal uid (CSF) pressure. Lance proposed that

headaches related to sexual activities were analogous but distinct from headaches due to cough or exertions (7). However, in an ana- lysis by Silbert et al. (6), 40% of patients with sexual headache also experienced benign exertional headaches. e distinction and re- lationships of these headaches became clearer when Pascual et al. (8) reported 72 patients with cough, exertional, or sexual headaches in 1996. In this series, 42% of patients were symptomatic and dif- fered from benign ones in several clinical aspects. Benign exertional headaches speci cally referred to headaches that occurred during or a er strenuous physical exercise, while benign cough headaches were those triggered by cough or Valsalva-like manoeuvres. Similar to the observation of Silbert et al. (6), this study found that 31% of patients with sexual headaches could also ful l the diagnostic cri- teria of benign exertional headache proposed by International Headache Society in 1988 (9).

In subsequent prospective epidemiological studies (10–12), be- nign exertional headaches were used to refer speci cally to head- aches that occurred during or a er sustained strenuous physical exercise, while headaches that were precipitated mainly by Valsalva- like manoeuvres, with sudden mode of onset and short dur- ation, were classi ed as benign cough headaches. In fact, primary exertional headache (designated as primary exercise headache) and primary cough headache have been clearly de ned and separated in the third edition of the International Classi cation of Headache Disorders (ICHD-3) (see also Chapter 24). Primary headache asso- ciated with sexual activities is also coded separately in the ICHD-3, and a considerable association with reversible cerebral vasoconstric- tion syndrome (RCVS) is mentioned in the comments.

Epidemiology

Hospital-based studies suggested that exertional headache is not a common headache disorder, accounting for 1–2% of the consult- ations for headache in general neurological clinics (6,8,10) and 5.3% in a headache clinic (13). However, two large-scale epidemiological studies found that the prevalence of exertional headaches is much higher than previously thought (11,12). e prevalence of exertional headache in Norwegian adults is reportedly 12.3%, according to the Vågå study (11), while a report on Taiwanese adolescents found a prevalence of up to 30.4% (12). e discrepancy of prevalence

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between hospital-based studies and eld research might be due to the fact that most of the exertional headaches are not severe and the su erers do not usually seek medical help. Possible explanations for the lower prevalence in adults than adolescents might be recall bias of early-life experiences and being less physically active in adult- hood. Most of the hospital-based studies found that exertional head- aches are more prevalent in males (2,8,10), but these two large-scale eld studies, as well as one study performed in a headache clinic, found a female predominance (11–13).

By contrast, the prevalence and sex preponderance of sexual head- ache is more consistent between clinic-based studies (6,8,10,13–15) and eld research (16). e prevalence of headache associated with sexual activities is around 1%. ere is a 2–5-fold higher prevalence in males versus females (4,6,8,10,13–15,17). e mean age at onset is around the fourth and h decades (4,6,8,10,13–15,17). However, adolescent cases are being increasingly recognized (18,19).

Clinical features

Exertional headache is generally bilateral, pulsating, gradual onset, mild-to-moderate in intensity and short-lasting (8,10,11,20); how- ever, these characteristics are not invariable. For example, the head- aches are unilateral in 51% of adolescent patients and pulsating in 59% (12). Most adolescent patients have headaches lasting < 1 hour, but the headache duration tends to be longer in adults (8,10–12,20). Nearly half of patients with exertional headaches have comorbid mi- graine (6,12,13,20). Migrainous features such as nausea, vomiting, photophobia, or phonophobia are not common in exertional head- aches, but patients with comorbid migraine would have exertional headaches with more migrainous features (12,20). e most com- monly reported exercises that would lead to headaches include run- ning, various ball games, and swimming. However, some patients might also have headaches that could be elicited by short-lasting Valsalva-like manoeuvres (6,12). is might be owing to the fact that some exercises also involve isotonic or isometric activities simulating Valsalva manoeuvres, and activities that are Valsalva manoeuvres-like can also be strenuous. Another reason might be that Valsalva manoeuvres are actually aggravating factors rather than precipitating factors, but it is di cult for some patients to dif- ferentiate between these two.

Sexual headaches are mostly bilateral and predominantly oc- cipital or holocephalic in location (8,10,14,15,21). Most of the sexual headaches are explosive at onset (orgasmic type), but some are of gradual onset with increasing sexual excitement (pre-orgasmic type) (14,15). However, except for the mode of headache onset, these two subtypes do not have signi cant di erences in demographics, clinical features, comorbidities, or prognosis (14). erefore, in the ICHD-3, these two subtypes are no longer described (22). Sexual headaches are usually severe in intensity, lasting from minutes to hours, with a median duration of 30 minutes (14,15). Nausea, vomiting, and mood disturbance are occasionally noted (14,15). ese headaches usually occur during sexual intercourse or orgasm, but also can occur during masturbation and nocturnal emission (8,21,23). Comorbidity with other primary headaches, such as mi- graine, tension-type headache, or primary exertional headache, is common (6,14,15,21,24).

Diagnosis

Comprehensive investigations for these two headaches are mandatory. Detailed headache history, including the onset of headache (gradual or abrupt) and its temporal relationship with the precipitating factors (what kind of exercise or manoeuvre), headache duration, intensity, location, aggravating and relieving factors, accompanying symptoms (including migrainous features or any newly developed neurological symptoms), blood pressure change, and disease course, are very im- portant. Because secondary headaches might exhibit similar char- acteristics to these two headache disorders, a careful neurological examination, neuroimaging studies, or other appropriate diagnostic tests (e.g. CSF analysis) are also required.

According to the ICHD-3 criteria, primary exercise headache (code 4.2) was used to replace the term primary exertional head- ache, and the criteria were revised to cover these possible im- plicit characteristics of exertional headache in adolescents (Table 25.1). Probable primary exercise headache (code 4.2.1) was also proposed in the ICHD-3 for headaches that are believed to be primary exercise headache, but lacking one of the features re- quired to fulfil all the criteria (Table 25.1). The ICHD-3 stopped subclassifying primary headache associated with sexual activ- ities by means of a temporal relationship with orgasm (code 4.3; Table 25.1). For patients who experience only one attack of ‘4.3 Primary headache attributed to sexual activity’ during their life, or have headaches missing one of the all criteria, probable pri- mary headache attributed to sexual activity can be diagnosed (code 4.3.1; Table 25.1).

Of the primary headaches, migraine is the most important one to be di erentiated from primary exertional headache. Despite a high comorbidity of exertional headache and migraine, most head- aches induced by exercise were phenotypically di erent from mi- graine, even in migraineurs. For the minority of exercise-induced headaches that could ful l the diagnostic criteria of migraine, they should be coded as migraine and not as primary exertional headache.

Differential diagnosis

ese two entities are great diagnostic challenges to physicians be- cause the onset of both can be acute and whether the aetiology is primary or secondary cannot be judged based solely on clinical features.

In patients with exertional headaches, secondary causes including subarachnoid haemorrhage, metastatic tumour, sinusitis, ar- teriovenous malformation, Arnold-Chiari malformation, cardiac cephalalgia, fusiform aneurysms of the vertebral artery, elongated styloid process, and others have been reported (8,10,25–28). Hence, magnetic resonance imaging of the brain or appropriate diagnostic testing is indicated. Magnetic resonance angiography, venography, CSF studies, electrocardiogram, or otorhinolaryngology evalu- ations are sometimes required when vascular or other disorders are suspected.

e secondary causes of sexual headache include RCVS (see also Chapter 49), subarachnoid haemorrhage (see also Chapter 34), cer- vical or intracranial arterial dissection (see also Chapters 10 and

table 25.1 The ICHD-3 diagnostic criteria for primary exercise headache and primary headache associated with sexual activities.

4.2 Primary exercise headache

A. At least two headache episodes ful lling criteria B and C

B. Brought on by and occurring only during or after strenuous physical
exercise

C. Lasting < 48 hours

D. Not better accounted for by another ICHD-3 diagnosis

4.2.1 Probable primary exercise headache

A. Either of the following:
A single headache episode ful lling criteria B and C
At least two headache episodes ful lling criterion B but not criterion C

B. Brought on by and occurring only during or after strenuous physical exercise

C. Lasting < 48 hours

D. Not better accounted for by another ICHD-3 diagnosis

4.3 Primary headache associated with sexual activity

A. At least two episodes of pain in the head and/or neck ful lling criteria B–D

B. Brought on by and occurring only during sexual activity

C. Either or both of the following:
Increasing in intensity with increasing sexual excitement
Abrupt explosive intensity just before or with orgasm

D. Lasting from 1 minute to 24 hours with severe intensity and/or up to 72
hours with mild intensity

E. Not better accounted for by another ICHD-3 diagnosis

4.3.1 Probable primary headache associated with sexual activity

A. Either of the following:
A single headache episode ful lling criteria B–D
At least two headache episodes ful lling criterion B and either of criteria C and D

B. Brought on by and occurring only during sexual activity

C. Either or both of the following:
Increasing in intensity with increasing sexual excitement
Abrupt explosive intensity just before or with orgasm

D. Lasting from 1 minute to 24 hours with severe intensity and/or up to 72
hours with mild intensity

E. Not better accounted for by another ICHD-3 diagnosis

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

37), rupture of arteriovenous malformation, hypertensive crisis, and hydrocephalus (8,10,15). Considering the high proportion of vascular origin in secondary causes, comprehensive vascular imaging of head and neck is recommended in addition to structural brain imaging studies. When the patient experiences multiple ex- plosive headaches during sexual activities, RCVS should always be considered until proven otherwise. Because vasoconstrictions may not be observed at the early stage of RCVS, follow-up studies may be needed.

Pathophysiology

e pathophysiology of exertional headache remains unclear. It has been proposed that impaired myogenic cerebrovascular autoregulation might play a role, which leads to headaches caused by an aberrant vasodilatation during or following exercise (29). An incompetent internal jugular valve, which leads to transient

retrograde venous ow and increased intracranial pressure, was also proposed to be important in the pathogenesis (30). Similarly, sten- osis of intracranial venous sinuses has been reported in a few cases (31,32), indicating a potential role of dysfunctional venous system and transient intracranial hypertension. However, this seems to be more plausible in patients with headaches during or a er exercises involving components of Valsalva manoeuvres.

Sexual activities are, indeed, a special form of exercise, and thus many aspects of the speculated pathophysiology of sexual headaches are similar to exertional headaches. An impaired metabolic cere- brovascular autoregulation was demonstrated using transcranial Doppler sonography with the acetazolamide test (33). A high per- centage of comorbidity between sexual headache and RCVS sug- gests that an aberrant central sympathetic response and dysfunction regulation of cerebral vascular tone might play an important role (15). In a recent study, it was found that primary headache associ- ated with sexual activity is associated with high percentage (63%) of venous abnormalities, including either transverse sinus or jugular vein stenosis (31). It is mandatory to replicate these ndings in an- other independent cohort to validate the venous hypothesis.

treatment

ere has been no established treatment guideline for exertional headache. Conventional approaches include non-pharmacological and pharmacological interventions. Non-pharmacological interventions focus on preventive aspects, which include bio- behavioural strategies such as proper warm-up before exer- cise, hydration with a sports drinks, and regular sports training. Pharmacological interventions include preventive, pre-emptive, and acute abortive treatment. If the attacks are infrequent and predictable, pre-emptive treatment can be administered just be- fore exertion. Although anecdotal, indomethacin, taken 1–2 hours before exertion, might be the best choice. For attacks that are frequent or unpredictable, preventive therapy may be the best choice. Beta blockers (nadolol or propranolol) at 1–2 mg/kg daily for 2–6 months might be helpful (8,10). Acute pharmacological treatment may be tailored to clinical characteristics of exertional headache. Acetaminophen or non-steroidal anti-in ammatory drugs (NSAIDs), especially indomethacin, albeit based on only small case studies (34), could be considered in patients with mild-to-moderate attacks. For those whose attacks are more se- vere, especially if associated with migrainous features, speci c antimigraine therapy such as ergotamine or triptans might be ef- fective. In fact, most of the patients with exertional headache do not seek for medical treatment as the attacks are mostly infrequent and mild in intensity (11,12). In contrast, those who attend neuro- logical or headache clinics for exertional headaches are usually dis- abled, and are the target population to take care with. In cases with very high disability and known venous stenosis, direct retrograde cerebral venography with manometry and even stenting may be considered (32). However, these invasive procedures should only be performed by highly experienced specialists.

e treatment strategies for sexual headaches are quite similar to those for exertional headaches. Because there is highly vari- able clinical course, treatment should be tailored individually

CHaPtEr 25 Exertional and sex headache

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(14,15). Some patients can lessen the severity or abort the head- ache by stopping sexual activity when the headaches begin or by taking a more passive role (14,17). Weight loss and an exer- cise programme might also be helpful. In addition, it is suggested that patients should remain sexually inactive during the acute stage as recurrent attacks are frequent when they resume sexual activities early (14). Daily beta blockers, such as propranolol, metoprolol, and bisoprolol, or a calcium channel blocker, such as verapamil or diltiazem, may be e ective for prophylaxis in patients with frequent attacks (6,8,17,35). Indomethacin, 25–100 mg 1–2 hours before intercourse, is e ective as a pre-emptive treatment (17). Ergotamine tartrate, methysergide, or naratriptan have also shown positive results (6,8,17,35–37). Because there is substantial overlapping of sexual headache and RCVS, nimodipine, a calcium channel blocker, might also be considered (38). In contrast, vaso- constrictive drugs such as triptans, although possibly e ective in aborting the pain, might aggravate vasoconstriction and should not be used until RCVS or dissection has been excluded. Other NSAIDs (ibuprofen and diclofenac), aspirin or paracetamol, given a er the onset of headache, are generally ine ective. A recent case report showed that single greater occipital nerve injection with steroid and local anaesthetic e ectively aborted sexual headache (39). However, it is di cult to exclude the possibility that the head- ache remitted spontaneously.

Prognosis

In the Vågå study, it was found that patients with primary exertional headache usually experienced the condition during a circumscribed period in their early life (20). However, 15% of patients could have headaches for more than 30 years. Because this study is not a lon- gitudinal follow-up study, recall bias should be taken into consid- eration. About 33–50% of patients with sexual headaches could experience relapsing bouts or run a chronic course (≥ 1 year) (15,17). Nevertheless, most of these patients would nally obtain remission at a longer follow-up (4,6,17). Of note, when the sexual headaches are attributed to RCVS, devastating complications, including pos- terior reversible encephalopathy syndrome, ischaemic stroke, or intracranial haemorrhage, might ensue (40–42). Clinicians should be careful in treating these patients.

Conclusions

Exertional headache and sexual headache have many points in common, such as headache characteristics, high comorbidity with migraine, impaired cerebral autoregulation, or venous stenosis as possible pathophysiology, and good response to beta blocker and indomethacin treatment. ey account for a low proportion of headache consultations, but potentially devastating secondary causes such as subarachnoid haemorrhage should be considered. RCVS should be highly suspected in patients with these headache disorders, and their relationship deserves further study. Criteria for these headache disorders have been modi ed based on recent study ndings in the ICHD-3. Current evidence does not mandate us to provide any treatment guideline; randomized, placebo-controlled studies are required.

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229

Hypnic headache

Dagny Holle and David W. Dodick

Introduction

Hypnic headache (HH) is a rare primary headache that occurs only during sleep. It was rst described by Neil Raskin in 1988 (1). He re- ported ve men and one woman aged between 65 and 77 years that su ered from strictly nocturnal bilateral headache attacks, which lasted less than an hour. All patients responded favourably to a bed- time dose of lithium, with remission of attacks.

With the gradual introduction of more cases in the published lit- erature, operational diagnostic criteria were established and HH was included in the second edition of the International Classi cation of Headache Disorders (ICHD-2; subsection primary headaches: code 4.5) (2). HH was de ned as a dull headache that typically occurs a er the age of 50 years and awakens patients from sleep (Box 26.1). Headache attacks should occur more than 15 times a month without cranial autonomic symptoms and with no more than one migrainous feature (i.e. nausea, photophobia, and phonophobia) should accompany the headache. In 2018 new diagnostic criteria of HH were introduced (ICHD-3) (Box 26.1; and see Chapter 1). In contrast to the previous diagnostic criteria, headache attacks should occur on more than 10 days a month. e duration of headache attacks was limited up to 4 hours.

Currently, more than 200 cases have been reported in the litera- ture (3–8)ADD. ese cases have led to an expanded phenotype. Mild cranial autonomic features, such as lacrimation or rhinorrhoea have been described in a few patients (9,10). e pain is usually mild to moderate, but severe pain has been reported in up to 20% of patients (5). e pain may be unilateral in one-third of cases and attacks usually last from 15 minutes to 180 minutes. While most pa- tients have headache attacks daily or near daily, an episodic subtype (< 15 days per month) may occur.

Epidemiology

As a rare disorder, the prevalence of HH is di cult to determine. e frequency has only been estimated by its occurrence in large tertiary headache centres. At the Headache Clinic at Mayo Clinic in Rochester Minnesota, 1 in 1400 patients su ered from HH (11). In a German headache centre, HH was diagnosed in 0.1% of cases (12). In Spain, 1 in 100 patients with strictly unilateral headache

in a tertiary headache centre was found to su er from HH (13). Population-based estimates are not available. In addition, many pa- tients may remain undiagnosed for years as knowledge of this rare headache disorder is generally not known outside of the specialties of neurology and headache medicine. is hypothesis is supported by the observation that it takes, on average, 5 years for patients to be diagnosed with HH (5). Some case reports show that some pa- tients even su er from HH attacks for > 20 years until the diagnosis is made (10).

Clinical characteristics

HH is characterized by headache attacks that occur exclusively during sleep, including nocturnal sleep and daytime naps (9,14).

In contrast with the rst observation by Raskin (1), more women than men are a ected by HH (male-to-female ratio of 1:1.7) (Table 26.1) (5). One study compared the clinical features in male and female patients with HH, but it did not discover signi cant sex- associated di erences (15).

On average, HH starts at the age of 60 years, but younger patients and even children have been reported in the literature. Headache attacks usually last 162 ± 74.1 minutes a er awakening, which is not- ably longer than in the initial cases reports. Some patients even de- scribe HH attacks as lasting up to 10 hours (16,17). About two-thirds of patients describe the headache to be of mild or moderate intensity (65%); one-third (35%) reports severe pain. While the initial diag- nostic criteria characterized the pain as dull in character, approxi- mately 32% of patients describe other pain characteristics, such as a throbbing, pulsating, sharp, stabbing, or burning perception (5). In addition, HH was initially thought to be invariably bilateral (3), but about one-third of patients with HH have one-sided attacks (32%). e pain location is variable and located in fronto-temporal head region, or the pain may be di use and holocranial.

Most patients with HH report a high frequency of headache attacks (20.8 ± 9.9 per month). e majority of these headache attacks occur between 2.00 am and 4.00 am (58%). About one- quarter of HH attacks awaken patients between midnight and 2.00 am (24%), while 17% occur a er 4.00 am. Only a few patients report headache attacks before midnight, and some patients su er from HH attacks during daytime naps (9,14).

CHaPtEr 26 Hypnic headache table 26.1 Clinical characteristics in hypnic headache.

Box 26.1 Diagnostic criteria of hypnic headache according to the ICHD-3 classi cation

. A Recurrent headache attacks ful lling criteria B–E.

. B Developing only during sleep, and causing wakening.

. C Occurring on ≥ 10 days/month for > 3 months.

. D Lasting from 15 minutes up to 4 hours after waking.

. E No cranial autonomic symptoms or restlessness.

. F Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Sex(male/female)

37/63 1:1.7

Age at onset (y)

60.4 ± 10.4 (15–78)

Latency to diagnosis (y)

5.0 ± 4.7 (0.2–24)

Duration of attacks (min)

162 ± 74.1 (15–600)

Frequency of attacks/month

20.8 ± 9.9 (5–31)

Intensity of pain ∙ Mild/moderate ∙ Severe

65 35

Character of pain
∙ Dull
∙ Throbbing/pulsating
∙ Sharp/stabbing/burning

68 26 6

Side of headache ∙ Bilateral
∙ Unilateral

68 32

Migrainous features
∙ Nausea
∙ Phono-/photophobia

21 7

Trigeminoautonomic features
∙ Lacrimation
∙ Ptosis
∙ Rhinorrhoea/nasal congestion

6 2 7

Motor activity

In contrasts to patients with migraine, most patients with HH display some distinct motor activity (e.g. drinking, eating, reading, taking a shower), or at least prefer not to remain supine in bed. However, patients with HH never reach the degree of rest- lessness or agitation that is characteristically observed in patients with cluster headache. Mild migrainous features are reported by many patients with HH. Nausea is described by about 20% of patients, while 7% describe phonophobia and/or photophobia. Vomiting is not a typical clinical feature of HH and its presence should point to another diagnosis or a symptomatic subtype of HH (Table 26.2).

Until recently, cranial autonomic symptoms or signs were con- sidered rare or absent in patients with HH. However, a number of authors have described patients with HH with mild autonomic features (9,10). Respectively, lacrimation, ptosis, and rhinorrhoea/ nasal congestion are experienced by approximately 6%, 2%, and 7% of patients with HH.

Sleep and polysomnography

Initially, many case reports suggested that HH might be a rapid eye movement (REM) sleep-associated disorder. Some polysomnographic (PSG) studies showed headache attacks arising exclusively from REM sleep (12,18). is observation supported the postulated underlying pathophysiology of hypothalamus dys- function. Additionally, many patients reported vivid dreams be- fore awakening with a HH attack. However, recent data have not con rmed these early observations. Larger PSG studies showed REM and non-REM (NREM) sleep-associated HH attacks (19,20), interestingly, even in the same patient and during the same night (21). Currently, a total of 58 PSG-monitored HH attacks have been reported in 37 di erent patients (12,14,18–29). More than half of them occurred from NREM sleep stages (52%), and mainly from sleep stage 2 (38%). e high prevalence of attacks occurring during sleep stage 2 might be explained by the predominance of this sleep stage as a proportion of the total sleep time (21).

Macro- and microstructural analysis of sleep and actigraphy in a patient with HH showed a quantitative reduction in REM sleep (29). A er successful treatment with amitriptyline REM sleep increased again. Additionally, cyclic alternating patter that usually re ects disturbing factors, drug manipulations, and subjective sleep quality increased a er treatment. e authors concluded that nocturnal hypo-arousal might be involved in the pathophysiology of HH. Similar patterns had already been observed in migraineurs (30–32).

Data are % or mean ± SD (range)

Sleep disordered breathing, particularly obstructive sleep apnoea syndrome (OSAS), was previously thought be associated with HH. Many PSG studies in elderly patient with HH showed an increased apnoea/hypopnea index (AHI) > 5. However, the onset of the re- corded HH attacks was not temporally correlated with the observed drop of oxygen saturation (18,20,21). Only one report showed OSAS-triggered HH attacks that were treated e ectively with con- tinuous positive airway pressure treatment and nocturnal oxygen supplementation (18). e observed high OSAS rates in HH might be an artefact of the age of the patient population. is hypothesis is supported by data showing that about 80% of healthy persons over the age of 60 years have an AHI > 5 (33).

Headache comorbidities

As certain primary headache disorders are common, more than one-third of patients with HH report a history of migraine (5). It is still unclear if there is a causal or comorbid relationship between these two headache disorders or if their co-occurrence is from chance alone, given the prevalence of migraine and both disorders being more common in women. One patient with HH su ered from primary sexual headache (34). Both headache disorders were successfully treated with indomethacin. One patient was described as having short -lasting unilateral neuralgiform head- ache attacks with conjunctival injection and tearing (SUNCT) and HH (35).

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Part 4 Other primary short-lasting and rare headaches table 26.2 Clinical hints to discriminate between hypnic headache

and migraine.

Clinical feature

Hypnic headache

Migraine

Vomiting during headache attacks

–

Motor activity during headache attacks

–

Onset in elderly patients (< 50 years)

–

Triptan response

+/–

Lithium response

–

Caffeine response

+/–

Strict nocturnal headache attacks

–

+, typical clinical feature; +/– might occur in some cases, but is not a common observation; -, is usually not observed.

Disease course

e course of disease in HH is still unclear. Most studies do not re- port long-term follow-up of the reported cases. In a Taiwanese study, about half of patients present with an episodic subtype, with an at- tack period lasting between 7 and 365 days, with sustained remission a er treatment (20). Other studies described a relapsing–remitting or even chronic course of disease (20,23,36).

Pathophysiology

e pathophysiology of HH is still enigmatic (37). As distinct circa- dian rhythmicity with exclusive sleep-related headache attacks is the pathognomonic clinical feature of this disorder, hypothalamic dys- function was thought to be the source of the attacks. It is well known that descending projections from the hypothalamus terminate in the trigeminal nucleus caudalis and descending orexinergic projections modulate pain at this level. Additionally, the suprachiasmatic nucleus of the hypothalamus is known to play a major role in sleep regulation (38,39). Structural and functional alteration within the hypothal- amus has been demonstrated in other primary headache disorders with a circadian rhythmicity such as cluster headache (40–42), in addition to other disorders such as SUNCT (43,44) and paroxysmal hemicrania (45).

A Voxel-based morphometry study showed a signi cant decrease in grey matter volume within the posterior hypothalamus in pa- tients with HH compared with healthy controls (Figure 26.1) (46). Similar changes have been observed in narcoleptic patients (47). e posterior hypothalamus is known to be strongly connected to the periaqueductal grey, locus coeruleus, and median raphe nuclei, which are involved in descending control of pain perception, as well as in sleep regulation (38,39). Additionally, animal studies suggest that orexins are mainly localized in the posterolateral hypothalamus (48). ese neuropeptides are known to be involved in regulation of the sleep–wake cycle by activation of hypocertin type 2 receptors (48). Additionally, the antinociceptive e ects of orexins have been described (49). Despite alteration of the hypothalamic grey matter, further structural changes were observed in the so-called general pain network, including the bilateral operculum, frontal lobe, cin- gulate cortex, and cerebellum (46). ese changes seem not to be speci c for HH as they were also detected in other chronic pain

Figure 26.1 (see Colour Plate section) Voxel based morphometry shows decrease in grey matter volume within the posterior hypothalamus. The observed changes support the clinical suspicion
of hypothalamic involvement in hypnic headache (46).

conditions such as phantom limb pain (50,51), chronic back pain (52,53), bromyalgia (54,55), neuropathic pain (56), and chronic post-traumatic pain (57).

Only one electrophysiological study has been performed in HH investigating functional changes of trigeminal nociceptive pro- cessing using pain-related evoked potentials and nociceptive blink re ex. In contrast to cluster headache and migraine patients, pa- tients with HH did not show any alteration in terms of a facilitation or habituation de cit of evoked trigeminal responses (58).

Paediatric cases

HH in children is a very rare phenomenon and it is still questionable whether these cases should be considered as ‘true’ HH (59). None of the reported paediatric patients with HH entirely meet the ICHD-2 criteria, mainly owing to low attack frequency (60–62). However, the threshold for the frequency of attacks has been lowered in the revised ICHD-3 criteria. Based on the reported cases, more girls than boys are a ected (male-to-female ratio of 1:1.5), which is in line with the adult sex ratio. Mean age was 9 ± 1.6 years. Compared with the adult clinical presentation, HH attack duration was rather short (26.6 ± 11.3 minutes) and attack frequency rather low (9.6 ± 8.6 per month). Two additional adult patients have been reported in the literature who had a onset of their HH attacks during childhood (36,63).

Clinical work-up of HH

A diagnostic algorithm in patients presenting with HH symptoms is displayed in Figure 26.2. In all patients with HH cerebral brain imaging should be performed to rule out symptomatic cases of HH that might present exactly like idiopathic HH. ese symp- tomatic subtypes might include haemangioblastoma of the cere- bellum (64), non-functioning pituitary macroadenoma (65), growth hormone-secreting pituitary tumour (66), posterior

Patient presents with strict sleep related headache attacks

cMRI

24h-RR-measurement

Consider another idiopathic headache (e.g. cluster headache, migraine)

Figure 26.2 Diagnostic algorithm in hypnic headache. cMRI, cerebral magnetic resonance imaging; RR, blood pressure.

fossa meningioma (67), brain stem lesion (68), and basilar artery dolichoectasia (69).

Besides cerebral lesions, nocturnal arterial hypertension should be ruled out as symptomatic cause of HH. erefore, 24-hour blood pressure measurement is warranted and should be included in the diagnostic algorithm as it changes the therapeutic approach. In patients with secondary HH caused by nocturnal hypertension, headache might be relieved by antihypertensive medication (70). However, owing to the elderly patient population, up to two-thirds of patients with HH may also su er from arterial hypertension (20). Most do not report a therapeutic response to antihypertensive medication.

Differential diagnosis

A er ruling out underlying causes of the symptoms, the di eren- tial diagnosis mainly includes other primary headache disorders, especially migraine and trigeminal autonomic cephalalgias (TACs). Di erentiation may be challenging at times, but some clinical fea- tures might be helpful. HH is the only headache entity that only occurs during sleep. TACs might present predominantly during nocturnal sleep, but in most cases, attacks also occur during the day in awake patients. Age of onset of HH is usually later than in mi- graine or the TACs. Most patients with HH show some motor ac- tivity, or prefer to be up and out of bed, or at least sitting in bed, while patients with migraine prefer to be supine and still (Table 26.2), which is in strong contrast to the agitation and aggressive motor restlessness that is seen in more than 90% of patients with cluster headache (Table 26.3). Additionally, a therapeutic response to caf- feine and general lack of e cacy of triptans can help distinguish HH from migraine.

therapy

erapeutic recommendations are only based on case reports, small case series, and clinical experience. Randomized, placebo-controlled trials are not yet available.

CHaPtEr 26 Hypnic headache table 26.3 Clinical hints to discriminate between hypnic headache

and cluster headache.

Clinical feature

Hypnic headache

Cluster headache

Motor agitation during headache attacks

–

Headache attacks longer than 180 minutes

–

Excruciating pain intensity

–

Pronounced trigeminal autonomic symptoms

–

Onset in elderly patients (< 50 years)

–

Triptan response

+/–

Prednisone response

–

Caffeine response

–

Oxygen response

–

Strict nocturnal headache attacks

–

+, typical clinical feature; +/– might occur in some cases, but is not a common observation; –: is usually not observed.

acute therapy

Ca eine intake in form of a cup of co ee when awakening with head- ache seems the most e ective acute treatment option (Figure 26.2) (9,11,12,17,71–76). Many patients discover this treatment option by themselves before the diagnosis of HH is made. Ca eine-containing an- algesics might also be e ective in some patients, but the high frequency of HH attacks leads to an excessive consumption of analgesics with the resulting risk of systemic toxicity and medication overuse headache. Most of the other drugs that are commonly used in other primary headache disorders, including triptans (11,12,14,17,36,72,73,77), non- steroidal anti-in ammatory drugs (9,12,17,36,73,78–80), acetamino- phen (9,14,61,77,81), oxygen inhalation (9,13,82,83), metamizole (9), opioids (9), nimesulide (14,17,77,84), and ergotamine (81), have not demonstrated consistent e cacy in patients with HH.

Prophylactic therapy

Prophylactic intake of medication should prevent recurrent noc- turnal HH attacks. Adverse side e ects, particularly in the elderly given the changes in drug metabolism, elimination, and the risk of polypharmacy and drug interactions, should factor into the decision-making regarding preventive treatment for HH. Only three substances have been shown to be provide reasonably con- sistent e cacy—lithium carbonate, ca eine, and indomethacin.

Raskin described the e ectiveness of lithium in HH treatment in his initial report (1). Since then, lithium has been the most o en used preventive drug in HH. Lithium has shown high e cacy rates in up to two-thirds of patients with HH (10,14,17,20,24,27,71,77,78– 83,85–90), but bothersome side e ects o en lead to discontinu- ation. Additionally, many contraindications have to be considered before starting lithium therapy (e.g. heart and kidney failure, psoriasis, cardiovascular disease, tremor, electrolyte disturbances, hypothyroidism, and concomitant medications with the potential for drug interactions with lithium).

Ca eine appears to be an e ective alternative treatment option for some patients, with relatively few side e ects (9,11,12,17,71–76). For treatment, a cup of co ee should be consumed before going to bed.

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Part 4 Other primary short-lasting and rare headaches

Many patients are afraid of sleep disturbances due to ca eine intake, but this has only rarely been observed. erefore, patients should be encouraged at least to try this as a rst-line treatment option.

Many case reports also report indomethacin as e ective for the preventive treatment of HH (9,11,17,23,25,27,34,36,72,74– 76,80,89,91–92). Notably, in unilateral headache presentations, indomethacin should be considered as a treatment option (72). However, similar to lithium, indomethacin is associated with the potential for gastrointestinal and renal toxicity, especially in elderly patients, and is therefore o en stopped by many patients.

Topiramate (9,77,87), oxoterone (10), and melatonin (9,76,77) have been anecdotally reported to be e ective in individual pa- tients Many other drugs have been reported not to be e ective in preventing HH attacks or have shown only partial bene t in iso- lated patients—these include beta blockers (11,14,18,77), ver- apamil (12,14,17,72), unarizine (12,14,17,20,77,82,85,95,96), prednisone (11,17,18,71,84,87), benzodiazepines (14,18), gabapentin (17,27,76), antidepressants (18,36,73,75), valproic acid (14,36,77), acetazolamide (93), sodium ferulate (22), and botulinum toxin type A (73). In one patient occipital nerve stimulation was ef- fective (79), and in another one a greater occipital nerve block (97).

Conclusion

HH is a rare primary headache disorder characterized by strictly sleep-related headache attacks. Headaches usually start a er the age of 60 years, but onset could be as early as childhood. e underlying pathophysiology is still elusive. Voxel-based morphom- etry suggests involvement of the hypothalamus in the generation of attacks. Most attacks occur during stage 2 sleep. Cerebral imaging and 24-hour blood pressure measurement should be performed to rule out symptomatic subtypes. Other headache disorders such as cluster headache and migraine may also present with sleep-related headache attacks and should be considered rst in nocturnal head- ache. erapeutically, ca eine appears to be the rst-line acute and prophylactic treatment due to a combination of both e cacy and fa- vourable tolerability; indomethacin and lithium carbonate can also be used for preventive treatment in those resistant to or intolerant to ca eine.

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Cranial neuralgias and persistent idiopathic facial pain
Aydin Gozalov, Messoud Ashina, and Joanna M. Zakrzewska

trigeminal neuralgia

According to the recently published third edition of the International Classi cation of Headache Disorders (ICHD-3), trigeminal neur- algia (TN) is a recurrent unilateral paroxysmal pain and is divided into ‘classical’ and ‘‘secondary’ (1). Classical TN includes all cases with no de nitive aetiology identi ed apart from a vascular compres- sion of the trigeminal nerve. e new classi cation distinguishing classical TN (with demonstration of morphological changes in the trigeminal nerve root from vascular compression), secondary TN (due to an identi able underlying neurological disease), and idio- pathic TN (unknown aetiology) (1). ose with secondary TN have either a compression of the trigeminal nerve caused by tumours (benign and malignant) or other structural abnormalities such as arteriovenous malformations, or have multiple sclerosis (MS). In ICHD-3, TN is divided into a ‘purely paroxysmal’ form and a form ‘with concomitant persistent facial pain’ (1). ose patients who do not ful l all the diagnostic criteria identi ed by the International Headache Society Box 27.1 (2) have variously been termed atypical TN type II TN and, according to ICHD-3 criteria, classical TN with concomitant persistent facial pain (1,3–5). However, TN should be di erentiated from other facial pain disorders (Table 27.1).

Epidemiology

Katusic et al. (6) estimated the incidence rate of TN at 4.3 per 100,000. TN occurs more frequently in women than in men (female-to-male ratio of 3:2).Incidence rates increase with age and are highest in those aged 60 years and older (6,7). However, recent primary care surveys from both the UK (8) and the Netherlands (9) show much higher incidences of 26.8 and 28.9 per 100,000, respectively, but it was shown that misdiagnosis was common (10). A European study using a sample of 602 patients with neuropathic pain found that 14% had TN (11). e UK survey (8) showed a higher incidence in women of all age groups, and a peak incidence between 45 and 59 years of age, which is lower than reported previously. However, it is likely that some of the cases were potentially misdiagnosed as dental pain, sinusitis, or even temporomandibular disorders, as

these can present with symptoms similar to TN, especially when episodic and unilateral (12).

Pathophysiology

TN is a unique form of neuropathic pain and the true cause of TN is still unknown. It is believed that both peripheral and central dys- function play an important role. It has been suggested that vascular compression of the TN root entry zone causes focal demyelination and secondary ephaptic transmission. e prevailing hypothesis of the aetiology of TN is outlined by Devor et al. (13) as the ‘ignition hy- pothesis’. e hypothesis states that the trigger stimuli set o bursts of activity in the small cluster of trigeminal ganglion neurons that have been rendered hyperexcitable as a result of ganglion or trigem- inal root damage (13). Activity then spreads from this ganglion igni- tion focus to encompass more widespread portions of the ganglion. ese partially injured sensory neurons thus become hyperexcitable and exhibit a phenomenon known as ‘a er discharge’. ese a er- discharge bursts may be triggered by an external stimulus and ex- tend beyond the duration of the stimulus. ey can then also recruit additional neighbouring neurons, leading to a rapid build-up of electrical activity, which results in a paroxysmal explosion of pain. A er a brief period of autonomous ring, the activity is quenched by an intrinsic suppressive (hyperpolarizing) process, making the nerve refractory to further excitation (13). In addition, Obermann et al. (14) reported central facilitation of trigeminal nociceptive pro- cessing in patients with TN with concomitant chronic facial pain, suggesting overactivation of central sensory transmission.

Clinical features

e patient history is essential to diagnose TN and therefore all pa- tients must be carefully interviewed by a physician. Pain is described as brief, paroxysmal, lasting from a split second to 2 minutes, and described as super cial, intense, lancinating, stabbing, shooting, or like electric shocks or lightning. Pain can be evoked or spontaneous. Pain distribution is unilateral and follows the sensory distribution of the trigeminal divisions, typically radiating to the maxillary (V2) or mandibular (V3) territories. Ophthalmic (V1) on its own is less

238

Part 4 Other primary short-lasting and rare headaches

Box 27.1 Classi cation Committee of the International Headache Society: The International Classi cation
of Headache Disorders

13.1.1 Classical trigeminal neuralgia

Previously used term: tic douloureux.
Description: trigeminal neuralgia developing without apparent cause other than neurovascular compression.

Diagnostic criteria

A B

D E

At least three attacks of unilateral facial pain ful lling criteria B and C. Occurring in one or more divisions of the trigeminal nerve, with no radiation beyond the trigeminal distribution.
Pain has at least three of the following four characteristics:

. 1 Recurring in paroxysmal attacks lasting from a fraction of a second to 2 minutes

. 2 Severe intensity

. 3 Electric shock-like, shooting, stabbing or sharp in quality

. 4 Precipitated by innocuous stimuli to the affected side of the face.

No clinically evident neurological de cit.
Not better accounted for by another ICHD-3 diagnosis.

13.1.1.1 Classical trigeminal neuralgia, purely paroxysmal

Description: trigeminal neuralgia without persistent background facial pain.

Diagnostic criteria

. A Recurrent attacks of unilateral facial pain ful lling criteria for 13.1.1 Classical trigeminal neuralgia.

. B No persistent facial pain between attacks.

. C Not better accounted for by another ICHD-3 diagnosis.

Comment: 13.1.1.1 Classical trigeminal neuralgia, purely paroxysmal is usually responsive, at least initially, to pharmacotherapy (especially carbamazepine or oxcarbazepine).

13.1.1.2 Classical trigeminal neuralgia with concomitant persistent facial pain
Previously used terms: atypical trigeminal neuralgia; trigeminal neur- algia type 2.

Description: trigeminal neuralgia with persistent background facial pain.

Diagnostic criteria

. A Recurrent attacks of unilateral facial pain ful lling criteria for 13.1.1 Classical trigeminal neuralgia.

. B Persistent facial pain of moderate intensity in the affected area.

. C Not better accounted for by another ICHD-3 diagnosis.

Comments: 13.1.1.2 Classical trigeminal neuralgia with concomitant persistent facial pain has been referred to as atypical trigeminal neur- algia, or, recently, as trigeminal neuralgia type 2. Central sensitization may account for the persistent facial pain. Neurovascular compression on MRI is less likely to be demonstrated. Classical trigeminal neuralgia with concomitant persistent facial pain responds poorly to conservative treatment and to neurosurgical interventions. It is less likely to be trig- gered by innocuous stimuli.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

common and is considered indicative of symptomatic TN. e pain can be experienced extra-orally, intra-orally, or both. It is not felt in the teeth, but around them. e right side of the face is involved more frequently than the le . ere is no pain between paroxysms and a er an attack of pain there is a refractory period when the nerve cannot be stimulated. ere is o en an a er-pain, described as burning or dull, which slowly fades away. Paroxysms may occur several times a day. Especially in the early years of the condition there can be long periods of no pain, but these remission periods gradually become

shorter and shorter. e pain severity varies, but with time becomes worse and leads to reduced quality of life and depression.

Pain may be provoked by stimulating cutaneous or mucosal tri- geminal territories (trigger zones), regardless of the distribution of the perceived pain. Gently touching the face, washing or shaving, talking, brushing the teeth, chewing, swallowing, or even a slight breeze can trigger the paroxysms. Up to a third of patients will report the pain to a ect their sleep. Adjunctive signs may occur during paroxysms. Pain provokes brief muscle spasms of the facial muscles, thus producing the tic. Lacrimation, rhinorrhoea, or redness of the face is very rare, but is noted, and it can then be di cult to distinguish from short uni- lateral neuralgiform headache with autonomic features (SUNA) and these could be the same disorder (see also Chapter 20) (15).

ICHD-3 diagnostic criteria for 13.1.1 trigeminal neuralgia

Description

A disorder characterized by recurrent unilateral brief electric shock- like pains, abrupt in onset and termination, limited to the distribu- tion of one or more divisions of the trigeminal nerve and triggered by innocuous stimuli. It may develop without apparent cause or be a result of another diagnosed disorder. Additionally, there may be concomitant continuous pain of moderate intensity within the distribution(s) of the a ected nerve division(s).

Previously used terms

Tic douloureux, primary trigeminal neuralgia.

Diagnostic criteria

Recurrent paroxysms of unilateral facial pain in the distribution(s) of one or more divisions of the trigeminal nerve, with no radiation beyond,1 and ful lling criteria B and C.

a. Pain has all of the following characteristics:
1. Lasting from a fraction of a second to 2 minutes2
2. Severe intensity3
3. Electric shock-like, shooting, stabbing or sharp in quality.

B. Precipitated by innocuous stimuli within the a ected trigeminal distribution.4

C. Not better accounted for by another ICHD-3 diagnosis. Notes

1. In a few patients, pain may radiate to another division, but it re- mains within the trigeminal dermatomes.

2. Duration can change over time, with paroxysms becoming more prolonged. A minority of patients will report attacks predomin- antly lasting for > 2 minutes.

3. Pain may become more severe over time.

4. Someattacksmaybe,orappeartobe,spontaneous,buttheremustbe
a history or nding of pain provoked by innocuous stimuli to meet this criterion. Ideally, the examining clinician should attempt to con- rm the history by replicating the triggering phenomenon. However, this may not always be possible because of the patient’s refusal, awkward anatomical location of the trigger, and/or other factors.
Reproduced from Cephalalgia, 38, 1, e International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

CHaPtEr 27 Cranial neuralgias and persistent idiopathic facial pain table 27.1 Diagnostic criteria of trigeminal neuralgia (TN) and how these compare with other differential diagnoses

Symptom

Pulpitis

TMD

Neuropathic trigeminal pain

SUNA/SUNCT

Paroxysmal hemicrania

Character

Shooting, stabbing, electric

Sharp, aching, throbbing

Dull, aching, nagging

Aching, throbbing

Burning, stabbing, sharp

Throbbing, boring, stabbing

Site/radiation

Trigeminal distribution, intra/extra-oral

Around a tooth, intra-oral

Pre-auricular, radiates down mandible, temple area

Around tooth or area of past trauma/dental surgery

Peri-orbital but can affect maxillary division

Orbit, temple

Severity

Moderate to severe

Mild to moderate

Mild to severe

Moderate

Severe

Duration

1–60 s refractory period

Rapid but no refractory period

Not refractory, lasts for hours, mainly continuous can be episodic

Continuous soon after injury

Episodic 5–240 s

Episodic 2–30 min

Periodicity

Rapid onset and termination, complete periods of remission weeks to months

Unlikely to be > 6 months

Tends to build up slowly and diminish slowly, lasts for years

Continuous

Numerous, can be periods of complete remission

1–40 a day, can be periods of complete remission

Provoking factors

Light touch, non-nociceptive

Hot/cold applied to teeth

Clenching teeth, prolonged chewing, yawning

Light touch

Nil

Relieving factors

Keeping still, drugs

Avoid eating on that side

Rest, decrease month opening

Avoid touch

Nil

Indomethacin

Associated factors

Local anaesthetics placed in trigger area relives pain, severe depression and weight loss

Decayed tooth, exposed dentine

Muscle pain in other parts of the body, limited opening, clicking on wide opening

History of dental treatment or trauma in the area, may be loss of sensation, allodynia near pain, local anaesthetic relieves pain

Often restless, ipsilateral cranial autonomic symptoms

May have migrainous features, ipsilateral cranial autonomic symptoms

SUNA, short-lasting unilateral neuralgiform headache attacks with with cranial autonomic features; SUNCT, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing; TMD, temporomandibular disorder.

Reproduced from Postgraduate Medical Journal, 87, Zakrzewska JM, McMillan R, Trigeminal neuralgia: the diagnosis and management of this excruciating and poorly understood facial pain, pp. 410–416. Copyright (2011) with permission from BMJ Publishing Group Ltd. doi: 10.1136/pgmj.2009.080473.

Comments

e diagnosis of ‘13.1.1 Trigeminal neuralgia’ must be established clinically. Investigations are designed to identify a likely cause. Other than the triggering phenomenon, most patients with ‘13.1.1 Trigeminal neuralgia’ fail to show sensory abnormalities within the trigeminal distribution unless advanced methods are em- ployed (e.g. quantitative sensory testing). However, in some, clinical neurological examination may show sensory de cits, which should prompt neuroimaging investigations to explore possible cause.

Diagnosis of subforms, such as ‘13.1.1.1 Classical trigeminal neuralgia’, ‘13.1.1.2 Secondary trigeminal neuralgia’, or ‘13.1.1.3 Idiopathic trigeminal neuralgia’, is then possible.

When very severe, the pain o en evokes contraction of the muscles of the face on the a ected side (tic douloureux).

Mild autonomic symptoms such as lacrimation and/or redness of the ipsilateral eye may be present.

Following a painful paroxysm there is usually a refractory period during which pain cannot be triggered (reproduced from (1)).

About 15% of cases are secondary to major neurological disease such as tumours or MS (symptomatic TN) (16). A recent systematic review of pain in patients with MS shows a prevalence of 3.8% (95 con dence interval 2–6) and reviews of the literature on the char- acteristic of MS-related TN show that there is considerable overlap in symptoms between classical TN and that occurring in MS (17). De Santi and Annunziata conclude that there are no reliable clinical

predictors to di erentiate these (18). Many patients with symptom- atic TN have symptoms of typical TN (although both tumours and MS may also induce other types of facial pain without the charac- teristics of typical TN). In other words, the pain is indistinguish- able from ICHD-3 diagnostic criteria for classical TN but caused by a demonstrable structural lesion other than vascular compression. ere may be sensory impairment in the distribution of the appro- priate trigeminal division.

Traditionally, the clinical features that were considered indicators of probable symptomatic TN were:

• bilateral pain;
• sensory de cits;
• involvement of the ophthalmic division;
• unresponsiveness to medical treatment;
• onset age < 50 years;
• ipsilateral ear symptoms, such as hearing loss or a feeling of full-

ness, can indicate the presence of schwannomas or acoustic

neuromas;
• the nding of bedside sensory de cits may be an indicator of

symptomatic TN, but their absence does not indicate classical TN.

However, sensory abnormalities in TN have been debated (13,19) and reported (14,20) in previous studies. A prospective systematic study of clinical characteristics in 158 patients documented sen- sory abnormalities in TN (21), and the authors proposed modi ed

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ICHD-3 criteria with shown improved sensitivity (22). e involve- ment of the ophthalmic division is uncommon in TN. e absence of response to antiepileptic drugs, however, should also lead to very careful reconsideration of the diagnosis. e mean age at onset was signi cantly lower in symptomatic (48 years) compared with in classical (57 years) TN, but the histogram of onset age distribution showed that there was considerable overlap in the age ranges of the two populations (23). us, although younger age increases the risk of nding symptomatic TN, the diagnostic accuracy of age as a pre- dictor of symptomatic TN is too low to be clinically useful.

However, there are other patients that have many of the features of classical TN but who also have more prolonged pain. is has vari- ously been called TN type 2 (5), TN with concomitant pain (14), and now classical TN with concomitant persistent facial pain (ICHD-3).

Investigations

As it is impossible to exclude a symptomatic form on clinical grounds alone, performing neuroimaging at least once in all patients is re- commended (23,24). Recent advances in neuroimaging have proved the ability to diagnose symptomatic TN. Neuroimaging will identify the cause in patients with symptomatic TN—that is, MS plaques or compressive mass. e magnetic resonance imaging (MRI) protocol for TN assessment is used to both identify these cases and determine whether there is a vascular compression of trigeminal nerve. Recent guidelines from the American Academy of Neurology (AAN) and the European Federation of Neurological Societies (EFNS) have failed to nd su cient evidence to support or refute the fact that the presence of a neurocompression is the cause of TN (23,24). It is also

noted that neurovascular contact can be seen in 15–20% of people with no TN, but the authors did not grade the neurovascular contact (24). A recent study demonstrated that neurovascular contact was prevalent both on the symptomatic (89%) and asymptomatic side (78%), while severe neurovascular contact (causing displacement or atrophy of trigeminal nerve) was highly prevalent on the symp- tomatic (53%) compared with the asymptomatic side (13%) (25,26). is study concluded that severe neurovascular contact caused by arteries located in the root entry zone was involved in the aetiology of classical TN (26).

Medical management

ere are now several systematic reviews, including Cochrane re- views, detailing the evidence base and use of drugs in TN, in add- ition to guidelines for both general practitioners and specialists (23,24,27,28–34). Unfortunately, there have been few high-quality randomized controlled trials (RCTs), and many were conducted using small cohorts in single centres. e major drugs are summar- ized in Table 27.2.

All drugs will result in neurological side e ects such as drowsi- ness, ataxia, and diplopia at higher doses.

Carbamazepine (CBZ) is the drug of choice, as shown in Table 27.2. It is highly e ective and, in newly diagnosed patients, is likely to provide complete pain relief within a few days. It needs to be started at a low dose and increased slowly in order to minimize side e ects. However, this drug causes multiple adverse e ects, including drug interactions (35). erefore, this has led to the search for other similarly e ective drugs with potentially less problematic side e ect

table 27.2 Major drugs used in the medical management of trigeminal neuralgia

Drug

Daily dose range

Side effects

Use

Comments

Drugs used in RCTs

Carbamazepine (CBZ)

200–1000 mg

Drowsiness, ataxia, nausea, headaches, blurred vision

Begin with small doses, extended release version useful at night

Beware drug interactions (e.g. warfarin–CBZ, so dosages may need to be adjusted)

Oxcarbazepine

300–1200 mg

Better tolerated than CBZ, drowsiness, ataxia, hyponatremia at higher doses

Use on four-times-a-day basis

Hyponatraemia at higher doses

Baclofen

50–80 mg

Ataxia, lethargy, fatigue, nausea, loss of muscle tone

Begin very slowly, frequent dosage

Withdraw drug slowly to avoid side effects. Useful in patients with MS

Lamotrigine

200–400 mg

Dizziness, drowsiness, ataxia, diplopia, rapid dose escalation leads to rashes

Initially very slow escalation. Good when added to another AED

Rashes common if dose increased too quickly

Gabapentin with ropivacaine

1800–3600 mg gabapentin (RCT utilized up to 900 mg) with 4 mg ropivacaine injected into each trigger point

Sedation, ataxia, dizziness, oedema

Ropivacaine injected weekly into trigger areas

Use of ropivacaine reduced dose of gabapentin required

Drugs not evaluated in RCTs

Phenytoin

200–300 mg

Gum hyperplasia, depression, diplopia, ataxia

Can use with CBZ

> 300 mg can lead to severe side effects

Sodium valproate

600–1200 mg

Nausea, gastric irritation, diarrhoea, weight gain, hair loss

Often used by neurologists

May take weeks to see a response

Pregabalin

150–600 mg

Abnormal gait, balance or coordination problems, blurred vision, concentration problems

Effective used twice daily

Long-term cohort study shows promise

RCT, randomized controlled trial; MS, multiple sclerosis; AED, antiepileptic drug.

pro les. Recent guidelines have suggested that the second-line drug should be oxcarbazepine (OXC), which is, in fact, a prodrug of CBZ (23,24). is drug does not use the liver cytochrome system and therefore does not result in such widespread drug interactions and is generally better tolerated. It must, however, be remembered that, given the chemical similarity of these drugs, allergic cross-reactions between the two drugs can occur. According to recent guidelines (23,33), patients who reach e ective doses of CBZ or OXC but who do not experience enough pain relief become candidates for sur- gical interventions. ere is now evidence to suggest that females are more sensitive to both CBZ and OXC and lower dosages should be used in females (35). Patients who cannot reach e ective doses of CBZ and OXC because of contraindications or adverse events should try second-line drugs (36). Although there are cases series reporting the e cacy of several new drugs, there has only been one RCT, which demonstrated e cacy of lamotrigine as an add-on therapy (37). More recently, a RCT of gabapentin with regular ropivacaine injections into the trigger sites suggested that this combination was highly e ective. However, the patients in this trial were newly diag- nosed and may therefore have been likely to go into remission (34). e AAN/EFNS guidelines suggest that lamotrigine and baclofen are other second-line drugs that could be prescribed (23,24). ere is a RCT of Botox (38), which suggests that it can be e ective, but there are several methodological shortcomings (39). Linde et al. (40) suggest that Botox is not e ective. Pregabalin has been shown to be e ective in a long-term, well-conducted cohort study (41).

Oral phenytoin (historically, the rst antiepileptic drug used for the treatment of TN) is e ective in only 25% of patients and its chronic administration has potentially serious adverse e ects (24). However, phenytoin can be administrated intravenously and thus it is useful in emergency, when extremely frequent TN paroxysms pre- clude taking anything orally (42).

A new selective sodium channel blocker is currently being inves- tigated and is showing promising results (43).

ere are no placebo-controlled studies regarding the medical management of symptomatic TN. e existing studies all deal with TN associated with MS and are small, open-label trials. Lamotrigine, gabapentin, topiramate, misoprostol (a prostaglandin E1 analogue) and baclofen have been reported to be e cacious in patients with TN and MS (22,32,44). Figure 27.1 provides an algorithm for the treatment of TN.

Surgical therapy

ere is now increasing evidence to suggest that early surgical treatment may be appropriate, especially in patients with classical signs of TN and in whom MRI investigations show evidence of neurovascular compression of the trigeminal nerve. Candidates for surgical treatment for TN include patients who have failed medical therapy or patients who initially responded but later became in- tolerant to medical therapy and whose quality of life has markedly diminished. ere is a Cochrane review of surgical interventions with only three higher-quality studies (45) and no RCTs involving microvascular decompression.

ere is a wide variety of surgical treatments available and only one of these, microvascular decompression, aims to preserve tri- geminal nerve function. All of the other procedures can be termed destructive or ablative, as they aim to reduce sensory input and

MRI CBZ/OXC

No relief/intolerant

LTG, Gabapentin, Phenytoin, Pregabalin, Baclofen

CHaPtEr 27 Cranial neuralgias and persistent idiopathic facial pain

No relief/intolerant

Surgery

Reconsider diagnosis

Figure 27.1 Algorithm for the treatment of trigeminal neuralgia (TN). MRI, magnetic resonance imaging; CBZ, carbamazepine; OXC, oxcarbazepine; LTG,

lamotrigine.

hence give rise to a degree of nerve damage. e interventions are performed at three target areas:

• peripheral—that is, distal to the Gasserian ganglion at speci ed trigger points;

• Gasserian ganglion level;

• posterior fossa at the root entry zone;

• the data are based on the AAN/EFNS ndings (23,24).
Peripheral techniques
A wide variety of peripheral techniques have been described, including cryotherapy, neurectomies, peripheral acupuncture, per- ipheral radiofrequency thermocoagulations (RFTs), and a variety of injections, such as alcohol, phenol. and streptomycin. Only the latter has been reported in two RCTs, which demonstrated that it was inef- fective (46,47). Recent case study suggests that peripheral nerve eld stimulation can be an e ective treatment for refractory facial pain inclusive TN (four patients) (48).
ere is still insu cient evidence to support the use of peripheral treatments unless patients are medically un t and request an instant procedure. Pain relief is in the order of 10 months.
Percutaneous procedures at the level of the Gasserian ganglion
All percutaneous procedures involve the insertion of a cannula through the foramen ovale into the trigeminal ganglion under heavy sedation of short general anaesthetic. e ganglion can then be lesioned using heat (RFT), injection of glycerol, or mechanical compression by the use of a balloon. Usually, an overnight inpatient stay is required for these procedures. ere is limited evidence to support these treatments, with only two RCTs both comparing di erent techniques for RFT, with pain intensity being the primary outcome measure (49–51). ere is min- imal evidence from prospective case series that have used independent outcome measures (52). e major outcome measure has been pain

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Part 4 Other primary short-lasting and rare headaches

relief, and there are only a handful of studies that have measured quality of life. Up to 90% of patients are likely to obtain immediate pain relief, but this gradually reduces so that, by 5 years, about 50% of patients will have a recurrence of pain. Mortality is understandably low with regard to these procedures. Given that all these interventions are destructive, varying degrees of sensory loss are reported. is sensory loss can be very mild; however, up to 4% of patients may report severe anaesthesia dolorosa. When the treatments involve the rst division of the trigem- inal nerve, then eye problems such as corneal numbness and keratitis are possible. Pulsed peripheral RFT is a procedure whereby the RFT applied at the level of the Gasserian ganglion is a pulsed rather than a continuous current. e perceived bene t of pulsed over continuous is the reduction in postoperative sensory loss. However, current evidence suggests the pain relief outcome of pulsed RFT is inferior compared with traditional RFT (49).

Gamma knife surgery

is is an ablative procedure, which targets the trigeminal root entry zone on the posterior fossa and aims to focus a beam of ra- diation at this point. ere have been trials to determine both the optimum dose of radiation and its precise location (51). Initial reports suggested that this procedure was the most acceptable, as it was the least invasive and resulted in no side e ects. However, as data have now been accumulating, there is evidence to show that sensory loss also occurs in these patients, albeit o en with delay for some months a er the procedure. In those studies using independent outcome measures, it would appear that pain relief periods are similar to those procedures that are performed at the Gasserian ganglion level. Data using a non-validated question- naire suggest the quality of life is improved. Complete pain relief was achieved in 65.5% (13.8% with low-dose and 51.7% without medication). Pain improved partially in 17.2% of participants and another 17.2% had no bene t. e median time for complete pain relief was 3 months a er radiosurgery (range 1 week–17 months) and relapse occurred in 34.5%. Numbness or paraesthesia re- ported in 24% of patients. No severe adverse e ects were reported. Assessments took place at 6 months, 12 months, and then at yearly intervals (51).

ere are an increasing number of case series being reported but no systematic review, and the general consensus appears to be that pain relief can take up to 3 months to occur and that the long-term results are similar to other ablative procedures, with 50% being pain free at 5 years. Sensory loss can be delayed beyond the time of pain relief and varying sensory abnormalities can occur, including anaes- thesia dolorosa (53).

Microvascular decompression

Microvascular decompression is the only non-destructive pro- cedure, but it is the most invasive operation of all those done for TN. A craniotomy is performed in the postauricular area, which en- ables the trigeminal nerve to be exposed and vessels to be identi- ed and then moved out of direct contact with the trigeminal nerve. ere are no RCTs and only a handful of studies that have used in- dependent outcome measures (54). Given that this is a major neuro- surgical procedure, it follows that it will be associated with mortality, which varies from 0.2% to 0.5%. is is considerably lower than when the procedure was rst reported some 27 years ago. It has

been shown in the USA that high-volume units are likely to have lower mortalities and lower postoperative morbidity (55). Most of the complications tend to be in the early postoperative period and include cerebrospinal uid leaks, haematomas, aseptic meningitis, diplopia, and facial weakness. e major long-term complication is ipsilateral hearing loss, which can be as high as 10%.

Overall, when reporting practice guidelines, the AAN/EFNS could only state that the longest duration of pain relief could be obtained in patients undergoing microvascular decompression, 70% are pain free at 10 years, and that there is a lack of direct com- parative studies between the di erent surgical techniques (23,24). However, quality of life is likely to be better a er a microvascular decompression given there is no longer any need for medica- tions and the fear of pain return has gone. Moreover, the degree of neurovascular contact could be important when selecting patients for surgery (26).

A recent prospective systematic study showed that neurovascular contact with morphological changes and male sex are positive predictive factors for outcome of microvascular decompression. e ndings enable clinicians to better inform patients before surgery (56).

Recent reviews of patients seen in neurology units suggest that only a small percentage go on to have surgery (n = 13/178; 7%) (57). Patients need to make several decisions about treatment and this is di cult given the lack of evidence but marginally patients think surgical interventions are the better option (58). To help them fur- ther patients can be directed to patient support groups, which are a

good source of information (59).

Glossopharyngeal neuralgia

Glossopharyngeal neuralgia is a severe transient stabbing pain ex- perienced in the ear, base of the tongue, tonsillar fossa, or beneath the angle of the jaw. e pain is therefore felt in the distributions of the auricular and pharyngeal branches of the glossopharyngeal nerve. It is commonly provoked by swallowing, talking, or coughing and may remit and relapse in the fashion of TN. Stimulation of the vagus can result in syncope. In most cases, this condition is idiopathic, but some instances might be due to symptomatic causes, again compres- sion of the nerve by tumours or malformations. Patients will su er from episodes of pain lasting for weeks or months, and then have periods of remission. e attacks themselves also last for no more than 2 minutes. Again, the pain is unilateral.

ICHD-3 diagnostic criteria for 13.2.1 Classical glossopharyngeal neuralgia

Previously used term

Vagoglossopharyngeal neuralgia.

Description

A disorder characterized by unilateral brief stabbing pain, abrupt in onset and termination, in the distributions not only of the glosso- pharyngeal nerve, but also of the auricular and pharyngeal branches of the vagus nerve. Pain is experienced in the ear, base of the tongue, tonsillar fossa, and/or beneath the angle of the jaw. It is commonly provoked by swallowing, talking, or coughing, and may remit and relapse in the fashion of trigeminal neuralgia.

Diagnostic criteria

a. Recurring paroxysmal attacks of unilateral pain in the distribu- tion of the glossopharyngeal nerve1 and ful lling criterion B.

B. Pain has all of the following characteristics:
1. Lasting from a few seconds to 2 minutes
2. Severe intensity
3. Electric shock-like, shooting, stabbing, or sharp in quality 4. Precipitated by swallowing, coughing, talking, or yawning.

C. Not better accounted for by another ICHD-3 diagnosis.

Note

1. Within the posterior part of the tongue, tonsillar fossa, pharynx or angle of the lower jaw, and/or in the ear.

Reproduced from Cephalalgia, 38, 1, e International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Comments

‘13.2.1 Glossopharyngeal neuralgia’ can occur together with ‘13.1.1 Trigeminal neuralgia’. Reproduced from (1).

Epidemiology

Glossopharyngeal neuralgia is rare, with an incidence rate of 0.7 per 100,000, and it has been reported to co-exist with TN (60). It occurs in older age groups and seems to predominate in women. ere are no data on prognosis but, judging by the few reports of surgical treatment, it would appear that patients have a less severe history than those with TN. ere are no RCTs reporting the use of any drugs in glossopharyngeal neuralgia. e largest review of patients with TN, by Rushton et al. (61) in 1981, suggested the same drugs as for TN and half of the patients eventually under- went surgical management (61). Other drugs have been reported mainly as single-case reports: pregabalin, lamotrigine, OXC, CBZ, gabapentin (62–66).

Previously used term

Atypical facial pain.

Description

Persistent facial and/or oral pain, with varying presentations but re- curring daily for more than 2 hours/day over more than 3 months, in the absence of clinical neurological de cit.

Diagnostic criteria

a. Facial and/or oral pain ful lling criteria B and C.

B. Recurring daily for > 2 hours/day for > 3 months.

C. Pain has both of the following characteristics:
1. Poorly localized, and not following the distribution of a peripheral nerve
2. Dull, aching or nagging quality.

D. Clinical neurological examination is normal.

E. A dental cause has been excluded by appropriate investigations. F. Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, e International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Comments

A wide variety of words are used by patients to describe the char- acter of ‘13.12 Persistent idiopathic facial pain’, but it is most o en depicted as dull, nagging, or aching, either deep or super cial. It can have sharp exacerbations, and is aggravated by stress. With time, it may spread to a wider area of the craniocervical region.

Patients with ‘13.12 Persistent idiopathic facial pain’ are predom- inantly female.

‘13.12 Persistent idiopathic facial pain’ may be comorbid with other pain conditions such as chronic widespread pain and irritable bowel syndrome. In addition, it presents with high levels of psychi- atric comorbidity and psychosocial disability.

Persistent idiopathic facial pain (PIFP), previously termed ‘atypical facial pain’, is a persistent facial pain that does not have the characteristics of cranial neuralgias and cannot be attributed to a certain disorder. e facial pain occurs daily and persists throughout the day. Generally, it is limited to one particular area on one side of the face at disease onset, is deep and poorly local- ized, and is not associated with sensory loss or other neurological de cits (67). Investigations, including X-ray of the face and jaws or cranial computed tomography or MRI, do not demonstrate any relevant abnormality. e exact cause and pathophysiology of this syndrome is not known, and the syndrome may be a col- lection of di erent conditions. ese patients are o en found to also have di use musculoskeletal conditions such as bromyalgia, myofascial pain syndrome, and chronic fatigue syndrome (68). Antidepressant medications and cognitive behavioural therapy may play a bene cial role in treating PIFP (69).

Previously used term

Anaesthesia dolorosa.

Coded elsewhere

Here are described painful post-traumatic neuropathies; most tri- geminal nerve injuries do not result in pain and therefore have no place in ICHD-3.

Description

Unilateral facial or oral pain following trauma to the trigeminal nerve, with other symptoms and/or clinical signs of trigeminal nerve dysfunction.

Diagnostic criteria

a. Unilateral facial and/or oral pain ful lling criterion C.
B. History of an identi able traumatic event to the trigeminal nerve, with clinically evident positive (hyperalgesia, allodynia)

CHaPtEr 27 Cranial neuralgias and persistent idiopathic facial pain

ICHD-3 diagnostic criteria for 13.1.2.3 Painful post-traumatic trigeminal neuropathy

ICHD-3 diagnostic criteria for 13.12 Persistent idiopathic facial pain

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Part 4 Other primary short-lasting and rare headaches and/or negative (hypoaesthesia, hypoalgesia) signs of trigeminal

nerve dysfunction.
C. Evidence of causation demonstrated by both of the following:

1. Pain is located in the distribution of the same trigeminal nerve

2. Pain has developed within 3–6 months of the traumatic event. D. Not better accounted for by another ICHD-3 diagnosis.

Note

e traumatic event may be mechanical, chemical, thermal, or caused by radiation. Reproduced from (1).

Reproduced from Cephalalgia, 38, 1, e International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Comment

Pain duration ranges widely from paroxysmal to constant, and may be mixed. Speci cally following radiation-induced postganglionic injury, neuropathy may appear a er more than 3 months.

It is now increasingly recognized that trauma to the trigeminal nerve can result not just in neuropathy, but also in long-term neuro- pathic pain. Many patients previously diagnosed as having ‘atypical facial pain’ are probably patients that, in fact, belong to this group. e pain may be initiated by surgery or injury to the face, teeth, or gums, but it persists without any demonstrable local cause.

e use of speci c local analgesics (articaine in 4% solutions for mandibular blocks) is suspected to cause permanent nerve lesions resulting in persistent pain and sensory disturbance within the af- fected facial area (70,71). In addition, molar extractions in the lower jaw may also cause a permanent painful lesion within the man- dibular division of the trigeminal nerve. ere is also the highly speci c condition ‘atypical odontalgia’, which is de ned as pain in a tooth, or a tooth-bearing area, which is not related to any dental cause and again is o en mistaken as toothache and treated with mul- tiple dental treatments (66,72,73). e pain is continuous in a tooth socket, even a er tooth extraction. ese pains may, in fact, con- stitute a subset of trigeminal neuropathic pain and have been well characterized by Baad-Hansen (74) and List et al. (72). It has been suggested that it should be termed persistent dento-alveolar pain disorder (75), and studies show central changes (76).

Neurophysiological testing shows that these patients have per- ipheral and central sensitization changes, but there is also some evidence for nociceptive changes, which might therefore be im- portant in the choice of drugs (77). Currently, there are no data on the epidemiology of neuropathic pain, but it has been sug- gested that a risk factor for this could be inadequate anaesthesia during dental procedures, as this increases the risk for potential central sensitization. As with anywhere else in the body, trauma and compression of sensory nerves can result in long-term neuropathic pain.

e increasing recognition of this condition puts increasing chal- lenges on clinicians to manage this pain. A topical approach is the use of lidocaine or capsaicin patches, or even clonazepam. It may provide some bene t, especially if the pain is provoked by light touch activities and interferes with sleep. Some patients have found that the advantage of having a good night’s sleep enables them to cope better with their neuropathic pain throughout the day. However,

• Burning
• Aching, throbbing • Mild to moderate

• Continuous

• Years

• History of trauma

Character severity

Site

Timing periodicity

Provoking associated factors

• Neuro-anatomical

• Local/widespread

• Often tooth-bearing area

• Light touch evoked

• Allodynia

• Lidocaine topical
gives relief

Figure 27.2 Clinical features of trigeminal neuropathic pain. Reproduced from Orofacial Pain (ed) Joanna M. Zakrzewska. Copyright (2009) with

permission from Oxford University Press.

as trials have shown, it is highly likely that trigeminal neuropathic pain also results in central changes and therefore there is a require- ment for systemic drugs. Nortriptyline, o en in lower doses than re- commended in guidelines, seems to result in a 30% pain reduction. Pregabalin appears to be especially useful in patients who also show a high level of anxiety. Topical lidocaine may again be useful in those patients whose sleep is interrupted due to the allodynia.

e clinical features of trigeminal neuropathic pain are shown in Figure 27.2.

Previously used terms

Stomatodynia, or glossodynia when con ned to the tongue.

Description

An intra-oral burning or dysaesthetic sensation, recurring daily for more than 2 hours daily over more than 3 months, without clinically evident causative lesions.

Diagnostic criteria

a. Oral pain1 ful lling criteria B and C.
B. Recurring daily for > 2 hours daily for >3 months. C. Pain has both of the following characteristics:

1. Burning quality2

2. Felt super cially in the oral mucosa.
D. Oral mucosa is of normal appearance and clinical examination,

including sensory testing, is normal.
E. Not better accounted for by another ICHD-3 diagnosis.

Notes

1. e pain is usually bilateral; the most common site is the tip of the tongue.

ICHD-3 diagnostic criteria for 13.11 Burning mouth syndrome

2. Pain intensity uctuates.
Reproduced from Cephalalgia, 38, 1, e International

Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Comments

CHaPtEr 27 Cranial neuralgias and persistent idiopathic facial pain of high-quality studies and treatments are based on case series reports

or extrapolated from other conditions with similar mechanisms.

Update

Readers should refer to the updated 2019 guidelines for the latest information [83].

Subjective dryness of the mouth, dysaesthesia, and altered taste may be present.

ere is a high menopausal female prevalence, and some studies show comorbid psychosocial and psychiatric disorders. Laboratory investigations and brain imaging have indicated changes in central and peripheral nervous systems. Reproduced from (1).

Comment

Burning is usually bilateral and its intensity uctuates. e most common site is the tip of the tongue. Subjective dryness of the mouth, dysaesthesia, and altered taste may be present. ere is a high menopausal female prevalence, and some studies show comorbid psychosocial and psychiatric disorders. Recent laboratory and brain imaging investigations have indicated changes in central and per- ipheral nervous systems showing that this is probably a neuropathic pain (78).

Secondary burning mouth can be due to local (candidiasis, lichen planus, hyposalivation) or systemic causes (medication induced, anaemia, de ciencies of vitamin B12, folic acid, Sjögren syndrome, diabetes), or drugs.

associated factors

As with all pain conditions facial pain patients o en experience high levels of psychological distress and physical disability (79). A study by Taiminen (80) of 63 patients with burning mouth syndrome or atypical facial pain showed that over 50% of these patients had a life- time mental health disorder. Depression and personality disorders were common, and these o en were present prior to the facial pain. ese comorbidities may have a signi cant e ect on treatment out- comes and so a multidisciplinary approach to treatment is essential. Patient treatment goals must also be taken into consideration, as McCracken et al. (81) have shown that treatment satisfaction among chronic pain patients receiving standard pain clinic interventions (pharmacological treatment, nerve blocks, epidural steroid injec- tions, etc.) was only weakly related to the degree of pain relief they obtained. e strongest predictors of treatment satisfaction were a belief they had been given a full and complete assessment, and the provision of an explanation for the treatments that were being de- livered. A recent review of treatments for burning mouth syndrome suggest that cognitive behaviour therapy is likely to be bene cial and there is insu cient evidence to support the use of alpha lipoic acid, benzydamine, clonazepam, or any antidepressants (82).

Conclusion

Although some of the neuralgias are unique to the face, patients with these conditions will all have psychological responses that are similar to other patients with chronic pain and so are best managed by multi- disciplinary teams. For some of the conditions there are now some guidelines based on RCTs, but for many of them there remains a lack

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Some rare headache disorders, including Alice in Wonderland syndrome, blip syndrome, cardiac cephalalgia, epicrania fugax, exploding head syndrome, Harlequin syndrome, lacrimal neuralgia, neck–tongue syndrome, and red ear syndrome

Randolph W. Evans

Introduction

Alice in Wonderland syndrome, blip syndrome, cardiac cephalalgia, epicrania fugax, exploding head syndrome, Harlequin syndrome, lacrimal headache, neck–tongue syndrome, and red ear syndrome are among the fascinating array of rare headache disorders. James W. Lance, Juan A. Pareja, and colleagues have rst described or named six of them. Certainly, there are patients with additional rare headaches just waiting to be described by astute observers.

In case of a rare headache disorder, an appropriate diagnosis and treatment can be most reassuring to the patient.

alice in Wonderland syndrome

History

In 1952, Caro W. Lippman described seven migraineurs who had unusual distortions of body image (1). e descriptions are illustra- tive: ‘Occasionally the patient has an attack where she feels small, about 1 foot high.’ Another patient had the sensation of ‘her le ear ballooning out six inches or more’. A third patient described his sen- sations: ‘the body is as if someone had drawn a vertical line separ- ating the two halves. e right half seems to be twice the size of the le half.’ And a fourth noted, ‘I feel that my body is growing larger and larger until it seems to occupy the whole room.’ One of the pa- tients who felt short and wide while she walked referred to her ab- normal sensation as her Tweedledum or Tweedledee feeling (two

characters from Lewis Carroll’s 1871 book, rough the Looking- Glass, and What Alice Found ere (2)). Lippman concluded, ‘Alice in Wonderland [full title, Alice’s Adventures in Wonderland (3)] con- tains a record of these and many other similar hallucinations. Lewis Carroll (Charles Lutwidge Dodgson), who wrote “Alice,” was himself a su erer from classic migraine headaches.’

In 1955, Todd, in giving the syndrome its name, presented six new cases and described a syndrome of distortions of the size, mass, or shape of the patient’s own body or its position in space o en as- sociated with depersonalization and derealization (4). Distortions in the perceived passage of time were also described in some pa- tients. Todd discussed the many causes in addition to migraine. Since then, many authors have used Alice in Wonderland syndrome (AIWS) for the visual illusions and distortions of how others ap- pear rather than illusions of one’s own body as in Todd’s original description.

Alice’s Adventures in Wonderland was published in England in 1864 by Dodgson under the pseudonym of Lewis Carroll (the Latinization of Lutwidge Charles). Dodgson was a Professor of Mathematics at Oxford University and a migraineur. ere is specu- lation that he might have had the syndrome (5–7).

In the rst chapter of the book, Alice jumps down a rabbit hole and lands in a hallway where she nds a bottle, which she drinks from, causing her to shrink: ‘ “I must be shutting up like a telescope.” And so it was indeed: she was now only 10 in high.’ Later, she eats a piece of cake that makes her grow (Figure 28.1): ‘ “Curiouser and couriouser!” cried Alice.; “now I’m opening out like the largest tele- scope that ever was! Good-bye, feet!” (for when she looked down at

Figure28.1. Alicestretchedtall. Illustration by Sir John Tenniel, 1865.

her feet, they seemed to be almost out of sight, they were getting so far o .)’

Clinical features and aetiology

AIWS syndrome is a rare migraine aura usually where patients ex- perience distortion in body image characterized by enlargement, diminution, or distortion of part of or the whole body, which they know is not real (8–10). e syndrome can occur at any age but is more common in children. A 1-year prospective observational study of young people aged 8–18 years found that AIWS can occur be- fore the onset of headaches, may go unrecognized, and may be more common than previously realized (11). e symptoms are attributed to the non-dominant posterior parietal lobule.

In a review of 81 cases, the cases were categorized as somaesthetic (n = 7; 9%), visual (n = 61; 75%), or both (n = 13; 16%) (12). Epstein– Barr virus infection was commonly identi ed (n = 39; 48%) followed by migraine (n = 11; 14%). Other possible associations included other infectious disorders (varicella, H1N1 in uenza, coxsackievirusB1, scarlet fever, typhoid fever, and, not included in the review, an associ- ation with Lyme neuroborreliosis (13)), acute Zika virus infection (14), and mycoplasma infection (15), toxic encephalopathy, major depres- sion, epileptic seizures, medications (cough syrup with dihydrocodeine phosphate and DL-methylephedrine hydrochloride (16), topiramate, and aripiprazole (17)), a right medial temporal lobe stroke, and a right temporo-parietal cavernoma (18). Six of the migraine cases were som- aesthetic and two had somaesthetic and visual symptoms.

In a series of 20 paediatric cases, the average age was 9.5 ± 3.8 years (range 4–16 years) (19). Ninety per cent had micropsias and/or macropsias, 85% distortion of the form of the objects, 80% displacement of objects, 45% disturbances of body image, 45% ac- celeration of time, and 30% a sensation of unreality. Ninety- ve per cent of the children had many episodes a day; these episodes lasted less than 3 minutes in 90% of them. Neuroimaging was normal in all cases. Migraine was considered the cause in eight and Epstein– Barr virus infection in ve. e majority of cases had spontaneous resolution without recurrence. Another paediatric series of nine children followed-up for a mean of 4.6 years also showed only occa- sional recurrence, in two (20). ere is a case report of a 15-year-old female with AIWS following acute Zika virus infection (14).

ere is a single case report of a 17-year-old male with a history of abdominal migraine since the age of 10 years who developed AIWS (21). All of his symptoms improved a er treatment with valproate.

Topiramate has been reported as causing AIWS 1 week a er starting 25 mg daily (titrating up to 100 mg daily over 4 weeks) in a 31-year-old woman with chronic migraine (22,23). She described episodes of her entire body feeling either too big or too small and everything else either too small or too big (or two episodes of feeling too big and then too small) all lasting 5–10 minutes, followed by a mild headache behind the eyes lasting 30–45 minutes without medi- cation. e symptoms resolved 1 month a er stopping topiramate.

A 17-year-old female with episodic migraine developed distor- tions of body image where her head would grow bigger and the rest of her body would shrink or her hand would increase in size and become heavier while the rest of the arm would become smaller only when she did not directly fall asleep a er taking topiramate 75 mg at bedtime (24). e symptoms resolved on 50 mg at bedtime and reappeared on 75 mg at bedtime, and then ceased when she stopped the drug except for one episode 3 months later. An electroenceph- alogram and magnetic resonance imaging (MRI) of the brain were normal.

Routine neuroimaging studies in migraineurs with the syndrome are normal. Not surprisingly, there are no placebo-controlled studies on treatment of what appears to be a rare and self-limited migraine variant.

Prognosis

Of the 15 patients with follow-up with AIWS seen by a paediatric neuro-ophthalmologist over 20 years, 20% had a few more events, which eventually stopped a er the initial diagnosis, 40% had no more events, and 40% were still having symptoms at follow-up (25). Twenty-seven per cent developed migraines and 7% developed seiz- ures following the diagnosis of AIWS.

In a follow-up study over 30 years of 28 patients with paediatric migraine precursors, more than one-quarter still experienced distor- tions of time and nearly 20% still reported distortions of space (26).

Blip syndrome

History

Lance had unusual sensations himself for about 6 months, which he recognized were not associated with his cardiac extrasystoles, which he named ‘blip’ syndrome (27). He then reported 12 additional cases (including eight women; three physicians) ranging in age from 33 to

CHaPtEr 28 Some rare headache disorders

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75 years with symptoms present for periods of 2 months up to 5 years, with a typical frequency of episodes of 1–4 per month ( ve had two or more per day and one had 12–15 per day on some occasions) with each lasting a split second up to 2 seconds (28). Interestingly, four of 12 were migraineurs and none had seizure disorders.

Clinical features

Patients described sensations including ‘a short circuit in the brain’, their mind ‘going blank for a second’ with a pressure in the fore- head and a ‘feeling of losing balance’, ‘impending loss of conscious- ness’, and ‘a wave going through’. Testing on some of the patients, including electroencephalograms (EEGs), computed tom scans, electrocardiograms, and carotid ultrasounds were normal.

Case report

In 2013, I evaluated a 47-year-old man with a history of ‘little small short circuits’, which had been occurring for 7 months and which usually occurred 2–3 times per day up to 10 times per hour. He de- scribed a blip in his head that he did not see or feel but sensed for a half a second. e symptom could occur when sitting, standing, or walking but not when lying down. He had no alteration of con- sciousness, vertigo, paraesthesias, weakness, trouble speaking, asso- ciated headache, or other neurological symptom except for a brief feeling of slight imbalance.

ere was a history of episodic migraine without aura since child- hood and hyperlipidaemia. Neurological examination was normal.

He had seen another neurologist. MRI of the brain with and without contrast and magnetic resonance angiography of the brain were negative. Evaluation by an ear-nose-and-throat physician, including audiogram and electronystagmography, were normal. EEG was normal. Cardiac evaluation was normal.

aetiology

e aetiology of the episodes is not certain. Lance compared blip syndrome to other benign disorders such as déjà vu, night starts, and exploding head syndrome (see ‘Exploding head syndrome’).

Cardiac cephalalgia

Clinical features

Cardiac ischaemia may rarely cause a unilateral or bilateral head- ache brought on by exercise and relieved by rest. is is called ‘car- diac cephalalgia’, or ‘anginal headache’ (29–31). Headaches may occur alone or be accompanied by chest pain. In cases of unstable angina, headaches may also occur at rest (32). Even a thunderclap headache may accompany the chest pain (33).

irty-six well-documented cases of cardiac cephalalgia were re- ported in the literature up to 2013: 58.3% were males, usually over the age of 50 years (but 22% were younger than 50—the youngest 35) (34). Anti-anginal medications (nitrates) caused headaches in 56% of cases (35). irty per cent had associated symptoms such as photophobia, phonophobia, osmophobia, and nausea (36). Chest pain, pain in the le arm, sometimes radiating to the mandible or epigastric region, was present in 50% of cases. Cardiac cephalalgia was the only manifestation of angina in 27% of cases. Five more cases have been subsequently reported (37).

Cardiac cephalalgia should be distinguished from migraine as the use of triptans or dihydroergotamine, in general, is contraindicated in cardiac ischaemia and might even be harmful. Appropriate car- diac testing will make the diagnosis once suspected. e headaches resolve with revascularization or conservative treatment.

Migrainous thoracalgia, a diagnosis of exclusion, is a migraine ac- companied by an aura of chest pain and arm paraesthesias which can occur with or with headache (38).

Pathophysiology

Angina is generally believed to be the result of a erent impulses that traverse cervicothoracic sympathetic ganglia, enter the spinal cord via the rst and the h thoracic dorsal roots, and produce the characteristic pain in the chest or inner aspects of the arms. Cardiac vagal a erents, which mediate anginal pain in a minority of patients, join the tractus solitarius.

Although the cause is not known, a potential pathway for re- ferral of cardiac pain to the head would be convergence with craniovascular a erents (39). Two other possible mechanisms of headache have been suggested (25): (i) a reduction of cardiac output and an increase in right atrial pressure during myocardial ischaemia can be associated with reduction in venous return, which increases intracranial pressure producing headache; and (ii) release of chem- ical mediators resulting from myocardial ischaemia (serotonin, bradykinin, histamine, and substance P) may stimulate nociceptive intracranial receptors and produce headache.

Epicrania fugax

History

Pareja et al. (40) described 10 patients with a novel syndrome in 2008, which they named ‘epicrania fugax’, with over 100 cases reported (41–43). Eight cases are associated with nummular headache (44).

Clinical features

Epicrania fugax is characterized by paroxysmal pain through the surface of one side of the head in a linear or zig-zag trajectory, which may move forward or backward and is not in the distribution of one single nerve. So the pain may go between the posterior scalp and the ipsilateral forehead, eye, and nose. e pain, which typically has an electrical quality, is of moderate or severe intensity and lasts one to a few seconds. e frequency ranges from a few attacks per year or less to numerous attacks per day. ere may be associated ipsilateral cranial autonomic symptoms such as conjunctival injection, lacri- mation, or rhinorrhoea. e pain may shi sides. Between attacks, some patients have a persistent mild pain or tenderness in the area where the pain originates.

Neurological examination was normal in all patients except for local hypersensitivity at the area where the pain originates in a few patients. Diagnostic testing, including neuroimaging and erythro- cyte sedimentation rates, was normal.

Five patients have been reported with similar pain starting in the lower face (V2 or V3) and radiating upwards with a linear trajectory of moderate-to-severe intensity with a stabbing or electrical quality lasting one to a few seconds (45).

Management

Gabapentin and lamotrigine have been reported as providing partial or complete relief for some patients. A few patients have bene ted from pregabalin, levetiracetam, and carbamazepine. Amitriptyline, indomethacin, occipital nerve blocks, and trochlear injections have also been occasionally e ective (33,34,46).

Exploding head syndrome

History

Exploding head syndrome (EHS) was rst named by John M.S. Pearce in 1988 when he reported on 10 patients (47). Robert Armstrong-Jones provided the rst description as ‘snapping of the brain’ in 1920 (48), although Silas Weir Mitchell may have previ- ously described the disorder in 1890 (49).

Clinical features

CHaPtEr 28 Some rare headache disorders students, 18% had a lifetime prevalence and 16.6% had recurrent

cases, not more common in females (60).

Evaluation

e diagnosis is made by the clinical history. A sleep study does not assist in diagnosis and it is not certain whether the study changes management if the patient is found to have obstructive sleep apnoea (see ‘Management’) (51). e neurological exam is normal. Imaging studies are not necessary, although some patients may wish to be re- assured that they do not have a tumour or aneurysm.

Management

A er explanation and reassurance, most patients do not require medication. For those with frequent or disturbing symptoms, there are anecdotal reports of bene t of treatment with clomipramine (41), nifedipine (61), unarizine (45), topiramate (62), amitriptyline (58), and the use of an oral appliance for a patient with obstructive sleep apnoea (48).

Harlequin syndrome

History

Harlequin syndrome was rst described by Lance and colleagues in 1988 (63). e syndrome is named a er Arleccino (Harlequin) who was a character in the travelling improvisational theatre, which originated in Venice in the sixteenth century, Comedia Dell’Arte (64). Members wore Harlequin masks with blackening of one side (Figure 28.2), which was a similar appearance of the sweating half of the face that was demonstrated with application of alizarin powder (Figure 28.3).

Clinical features

Harlequin syndrome presents with unilateral erythema or redness and hyperhidrosis of the face and, less commonly, the ipsilateral arm and upper chest (65), and is believed to be due to a normal or ex- aggerated response to the contralateral interruption of the sympa- thetic nerve bres, resulting in a vasomotor de cit of the ipsilateral side and o en an exaggerated vasodilatory response on the contra- lateral side during thermal (exposure to heat or exercise) or emo- tional stimulation. ere is one case report where the leg was also involved (66).

aetiology

Abnormalities should be excluded at the level of the rst or sev- eral thoracic roots such as mediastinal and pulmonary masses (67). Harlequin syndrome has also been reported as a sequelae of internal jugular catheterization, peri-operative local anaesthesia, sympath- ectomy to treat severe hyperhidrosis (68), toxic goitre (69), spon- taneous cervical carotid artery dissection (70), and implantation of intrathecal pumps (71), obstetric epidural anaesthesia (72), upper lobectomy (73), excision of a neck schwannoma (74), and a neuro- blastoma (75). In most cases, no cause is found.

Management

Usually no treatment is required and patients are reassured by an ex- planation of a cause. A contralateral thoracic sympathectomy could

EHS is characterized by a momentary loud noise that patients usually experience during the early stages of sleep (50). Patients describe a sudden onset of ‘an explosion in the head’, enormous roar, bomb-like explosion, or lightning crack that awakens them from sleep. is is usually followed by a feeling of intense fear, terror and/or palpitations. However, there is no headache or pain associated with the noise.

Symptoms can arise from any stage of sleep, but primarily during stages 1 and 2 (51). One study of nine patients indicated that symptoms correlated with an alert state or awakening on polysomnographic recordings (52). Attacks can occasionally occur as patients are awakening following arousal and onset back to stage 1 sleep. e frequency is highly variable with a range of 2–4 attacks followed by prolonged or lifetime remission to seven attacks nightly for several nightly each week.

Fear, terror, palpitations, or a forceful heartbeat were reported as occurring a er the loud noise in 47/50 patients (38). Ten per cent of patients described an associated ash of light and 6% reported a curious sensation as if they had stopped breathing and had to make a deliberate e ort to breathe again—‘an uncomfortable gasp’ (38). Occasionally, brief myoclonic jerks of the extremities or the en- tire body may follow (53). Psychological stress and being tired may be triggers (38,41). ree patients of 50 reported a positive family history (38).

EHS may be a migraine aura. Kallweit et al. (54) reported a 54- year-old man with attacks of EHS followed by an exacerbation of his chronic migraine a er each attack. Evans (55) reported a 26-year- old woman with a history of migraine without aura with multiple episodes of EHS followed by brief sleep paralysis and then one of her typical migraine headaches. e exact cause of EHS, however, is un- known (56). Rossi et al. (57) reported a middle-aged man with EHS as an aura symptoms of migraine with brainstem aura.

Epidemiology

EHS can occur at any age, but is more common in patients older than 50 years of age, with a median age of 54 years (range 12– 84 years) and a female-to-male ratio of 3:2 (58,59). e prevalence is unknown as, anecdotally, patients may not report their symptoms. No large-scale prevalence studies have been performed and EHS has been believed to be rare. However, in a study of 211 US college

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Figure28.2 Harlequinmask.
Reproduced from Practical Neurology, 5, Lance JW, Harlequin syndrome,

pp. 176–177. Copyright (2005) BMJ Publishing Group Ltd.

Figure28.3 Harlequinsyndrome.

Sweating on the right half of the face delineated by the application of alizarin powder.

Reproduced from Journal of Neurology, Neurosurgery & Psychiatry, 51, Lance JW, Drummond PD, Gandevia SC, Morris JG, Harlequin syndrome: the sudden onset of unilateral ushing and sweating, pp. 635–642. Copyright (1988) by permission of BMJ Publishing Group Ltd. DOI: 10.1136/pgmj.2009.080473.

be performed to restore symmetry if desired by the patient (54), al- though most patients do not choose any treatment.

Lacrimal neuralgia

anatomy

e ophthalmic division of the trigeminal nerve divides into the frontal nerve (which divides into the supratrochlear and supraorbital nerves), the nasociliary nerve, and the lacrimal nerve. e lacrimal nerve runs along the upper border of the lateral rectus muscle in the orbit and splits into two branches, the lateral branch (which supplies the lacrimal gland) and the medial branch (sensory innervation to the lateral aspect of the upper eyelid and adjacent area of the temple) (Figure 28.4).

History

Pareja and Cuadrado reported the rst two cases of lacrimal neur- algia in 2013 (76).

Patient 1

A 66-year-old woman had a history of constant moderate-to- severe sore and burning pain, which was worse with lateral eye movements, in the lateral aspect of her le superior eyelid and ad- jacent area of the temple with onset at age 64 years, without prior trauma or other relevant disease. Neurological examination showed decreased sensation in the area supplied by the le lacrimal nerve and tenderness on palpation between the globe and the external edge of the le orbit. Ophthalmological examination was normal.

MRI of the brain and orbits and blood tests, including thy- roid tests, an erythrocyte sedimentation rate, and immunological screening, were normal. Her emotional state was not a ected on testing. A le lacrimal nerve block with 2% lidocaine produced com- plete improvement for around 4 hours. She had absolute relief with pregabalin 150 mg daily. A er 9 months, pregabalin was stopped.

Figure 28.4 Skin area supplied by the left lacrimal nerve (shaded area).

The lacrimal nerve gives sensory innervation to the lateral upper eyelid

and a small cutaneous area adjacent to the external canthus.

Reproduced from Cephalalgia, 33, Pareja JA, Cuadrado ML. Lacrimal neuralgia: So far, a missing cranial neuralgia, pp. 1998–1202. Copyright © 2013 by permission of SAGE. DOI: 10.1177/0333102413488000,

e same symptoms recurred a er 4 months, and she had the same absolute relief when pregabalin was resumed.

Patient 2

A 33-year-old woman had a history of constant moderate-to-severe pressure or stabbing pain in a small area adjacent to the lateral can- thus of her le eye since the age of 25 years, with an unremarkable medical history. e symptomatic area was tender to light touch. Combing her hair on the le side or chewing could occasionally trigger paroxysmal exacerbations.

Neurological examination showed super cial hypoaesthesia, hyperaesthesia, and allodynia in the le lacrimal nerve distribution. e supero-external angle of the le orbit was hypersensitive to pal- pation. Ophthalmological and psychiatric evaluations were normal.

A MRI of the brain and orbits was normal. Blood tests, including thyroid tests, an erythrocyte sedimentation rate, and immunological screening, were normal. A lumbar puncture was normal. Four lac- rimal nerve blocks with 2% lidocaine resulted in complete relief lasting up to 6 hours. Oral indomethacin, ibuprofen, gabapentin, unarizine, carbamazepine, oxcarbazepine, topiramate, amitrip- tyline, duloxetine, mirtazapine and tramadol did not help. Lidocaine patches and capsaicin cream in the symptomatic area were of no bene t. Pulsed radiofrequency of the lacrimal nerve, the Gasserian ganglion, the sphenopalatine ganglion and the ophthalmic nerve did not help. Pregabalin 400 mg daily provided partial but substantial relief.

ree additional cases with negative testing have responded to lacrimal nerve blocks (77).

A secondary case of lacrimal neuralgia has been reported in a woman who developed similar pain attacks lasting 1–2 minutes a er le cataract surgery, which was relieved by an anaesthetic block at the emergence of the lacrimal nerve (78), and another in a 53- year-old man with attacks triggered by argon laser photodynamic therapy and intravitreal injection of a ibercept relieved by lacrimal blocks (79).

Summary

Lacrimal neuralgia is a newly reported cause of orbital and peri- orbital pain which, so far, seems to only be partially or completely responsive to pregabalin or lacrimal nerve blocks. e features and response to treatment of future cases will be of interest.

Neck–tongue syndrome

History

James Cyriax reported two cases of neck–tongue syndrome in 1962 (80). Lance and Anthony named the syndrome when they reported four additional cases in 1980 (81). is is a rare disorder with a prevalence in the Vågå study of 0.2% (82) and over 50 cases reported in the literature. (80,83–85).

Clinical features

Neck–tongue syndrome is characterized by acute, unilateral oc- cipital pain lasting a few seconds to 1 minute and numbness of the ipsilateral tongue lasting seconds to 5 minutes precipitated by sudden movement, usually rotation, of the neck to either side. Less

frequently, dysarthria, dysphagia, tongue paralysis, or tongue move- ments may occur (86–90). Intermittent and then constant tongue paraesthesias have been reported (82). Rarely, symptoms may switch sides (78).

Pathophysiology

e symptoms are the result of transient subluxation of the atlantoaxial joint that stretches the joint capsule and the C2 ven- tral ramus, which contains proprioceptive bres from the tongue originating from the lingual nerve to the hypoglossal nerve to the C2 root (Figure 28.5) (76,91,92). Contraction of the accessory atlantoaxial ligament (Arnold’s ligament) during rotation might ir- ritate the second cervical nerve root, as well as the hypoglossal nerve at its exit from the foramen magnum in some cases (93).

aetiology

Neck–tongue syndrome can be idiopathic without obvious ab- normalities. A benign, familial form of neck–tongue syndrome is described without anatomical abnormality, which resolves spon- taneously during adolescence. About 25% of cases have pathology of the occipito-atlantoaxial joints. Secondary causes of neck–tongue syndrome include head and neck trauma, Chiari 1 malformation, congenital anomalies of the cervical spine, ankylosing spondyl- itis, degenerative spondylosis, rheumatoid arthritis, tuberculous atlantoaxial osteoarthritis, and cervical acute transverse myelopathy

CHaPtEr 28 Some rare headache disorders

Figure 28.5 Lateral view of the right atlantoaxial joint; the atlas has rotated to the right.

The small arrow shows the inferior articular process impinging the C2 spinal nerve and ventral ramus.

Reproduced from Headache, 40, Evans RW, Lance JW, Transient headache with numbness of half the tongue, pp. 692–693. Copyright (2000) with permission from John Wiley and Sons.

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Part 4 Other primary short-lasting and rare headaches (94–97). A prolonged slouching sitting posture has been proposed as

a cause (98).

Management

e most e ective treatment is not known (29). Non-steroidal anti-in ammatory drugs, muscle relaxants, medications for neuropathic pain (amitriptyline, gabapentin, and carbamazepine), and steroids have been reported to be helpful in single cases. Other treatments reported include cervical collars, analgesics, manipula- tion, injections of local anaesthetic, nerve resection, and cervical fusion.

red ear syndrome

History and clinical features

Since Lance rst described red ear syndrome in 1994 (99), more than 80 cases have been reported in children and adults (100–103). e disorder is characterized by episodic burning pain, usually in one ear lobe, associated with ushing or reddening of the ear with a duration of seconds to hours (constant in two cases). e average age for idiopathic cases is 35 years with 62% females and for secondary cases 50 years with 70% females.

In individuals, one ear, alternating ears, or occasionally both ears simultaneously can be involved in attacks that can occur rarely or up to 20 times daily. e redness can occur without pain. e pain may radiate to the cheek, forehead, a strip behind or below the mandible, behind the ear, occiput, and the ipsilateral upper posterior neck. Attacks may be spontaneous or precipitated (in 31% of idiopathic cases and 63% of secondary cases) by touching the ear, drinking, coughing, chewing, sneezing, neck movement, exercise, stress, or exposure to heat or cold.

anatomy

To understand secondary causes, it is helpful to recall the sensory supply of the ear, which includes C2 and C3, and cranial nerves V, VII, IX, and X. e anterosuperior ear lobe is supplied by the auriculotemporal nerve (from V3) and the inferoposterior ear lobe is supplied by the greater auricular nerve (C2 and C3). e blood supply to the ear comes from an anastomosis between branches of the middle temporal and posterior auricular arteries, part of the ex- ternal carotid circulation innervated by the trigeminal nerve.

aetiology

RES can be idiopathic or occur in association with migraine (during or between headache episodes), trigeminal autonomic cephalgias, thalamic syndrome, atypical glossopharyngeal and trigeminal neuralgia, upper cervical spine pathology (cervical arachnoiditis, cervical spondylosis, traction injury, Chiari malformation, or herpes zoster of the upper cervical roots), and dysfunction of the temporomandibular joint.

Pathophysiology

Lance postulates that the cause might be an antidromic discharge of nerve impulses in the third cervical root and greater auricular nerve in response to some local pain-producing lesion in the upper

neck or trigeminal areas of innervation. Al-Din et al. (104) suggest that primary and secondary cases may be due to activation of the trigeminal-autonomic re ex.

Management

A variety of treatments have been tried with variable success, including gabapentin, amitriptyline, indomethacin, unarizine, nimodipine, ibuprofen, and indomethacin (105). Local anaesthestic block or section of the third cervical root might be helpful. Some cases are resistant to treatment.

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PART 5

Tension-type and other chronic headache types

29. Tension-type headache: classi cation, clinical 32. features, and management 259
Stefan Evers

Frequent headaches with and without acute medication overuse: management and international differences 284
Christina Sun-Edelstein and Alan M. Rapoport

30. New daily persistent headache 267
Kuan-Po Peng, Matthew S. Robbins, and Shuu-Jiun Wang

31. Chronic migraine and medication overuse headache 275
David W. Dodick and Stephen D. Silberstein

33. Nummular headache 298
Juan A. Pareja and Carrie E. Robertson

Tension-type headache
Classification, clinical features, and management Stefan Evers

Introduction

Tension-type headache (TTH) is divided according to the headache classi cation of the International Headache Society (IHS) into three subtypes: infrequent episodic TTH (< 1 headache day per month), frequent episodic TTH (1–14 headache days per month), and chronic TTH (≥ 15 headache days per month) (Box 29.1) (1,2). is division may seem arti cial but is highly relevant for several reasons (3,4). Firstly, impact on quality of life di ers considerably between the three subtypes. Secondly, the pathophysiological mechanisms also di er signi cantly; peripheral mechanisms are probably more important in episodic TTH, whereas central pain mechanisms are pivotal in chronic TTH (5). irdly, treatment di ers between the subtypes, with symptomatic and prophylactic treatment being more appropriate for episodic and chronic TTH, respectively. erefore, a precise diagnosis is mandatory and should be established by means of a headache diary for at least 4 weeks.

In general, non-pharmacological management should always be part of the treatment. With respect to pharmacological manage- ment, the general rule is that patients with episodic TTH are treated with symptomatic (acute) drugs, while prophylactic drugs should be considered in patients with very frequent episodic or chronic TTH. Analgesics are o en ine ective in patients with chronic TTH. Furthermore, their frequent use increases risk of toxicity, as well as of medication overuse headache.

is chapter is based on treatment guidelines for TTH (6) and tries to summarize the knowledge of this very frequent but poorly studied headache disorder.

Epidemiology

e lifetime prevalence of TTH was about 78% in a population-based study in Denmark with the majority having episodic infrequent TTH without a speci c need of medical attention (7). Twenty-four to 37% had TTH several times a month, 10% had it weekly, and 2– 3% of the population had chronic TTH usually lasting for the greater part of a lifetime (8,9). In more recent studies, the prevalence gures

for chronic TTH are lower, for example 0.5% for Germany (10), which is the consequence of the introduction of chronic migraine in the IHS classi cation.

e female-to-male ratio of TTH is 5:4 indicating that, unlike mi- graine, women are only slightly more a ected than men (11,12). e average age of onset of TTH is higher than in migraine, namely 25– 30 years in cross-sectional epidemiological studies (9). e preva- lence peaks between the age of 30–39 years and decreases slightly with age. Poor self-rated health, inability to relax a er work, and sleeping few hours per night have been reported as risk factors for developing TTH (8).

A review of the global prevalence and burden of headaches (12) showed that disability caused by TTH as a burden of society is greater than that by migraine, which indicates that the overall costs of TTH are greater than those of migraine. Two Danish studies have shown that the number of workdays missed in the population was three times higher for TTH than for migraine (9,13), and a US study also found that absenteeism due to TTH is considerable (14). e burden is particularly high for the minority who have substantial and complicating comorbidities (15).

Clinical aspects

TTH is characterized by a bilateral, dull pain of mild-to-moderate intensity, occurring either in short episodes of variable duration or continuously. e headache is not associated with autonomic fea- tures. In the chronic form, however, only one out of photophobia and phonophobia or mild nausea is accepted (Box 29.1). Owing to the lack of accompanying symptoms and the relatively mild pain in- tensity, patients are rarely severely incapacitated by their pain. TTH is the most featureless of the primary headaches, and because many secondary headaches may mimic TTH, a diagnosis of TTH requires exclusion of symptomatic headache disorders (see Chapters 38, 39, 46, and 47).

e diagnosis of TTH is based on the patient’s history and a normal neurological examination. A correct diagnosis should be assured by a headache diary recorded over at least 4 weeks.

260

Part 5 Tension-type and other chronic headache types

Box 29.1 Diagnostic criteria of tension-type headache according to the International Headache Society classi cation

. 2.1 Infrequent episodic tension-type headache

. A At least 10 episodes occurring on < 1 day per month on average
(< 12 days per year) and ful lling criteria B–D.

. B Headache lasting from 30 minutes to 7 days.

. C At least two of the following four characteristics:

. 1 Bilateral location

. 2 Pressing/tightening(non-pulsating)quality

. 3 Mild or moderate pain intensity

. 4 Not aggravated by routine physical activity such as walking
or climbing stairs.

. D Both of the following:

. 1 No nausea or vomiting

. 2 No more than one of photophobia or phonophobia.

. E Not better accounted for by another ICHD-3 diagnosis.

. 2.2 Frequent episodic tension-type headache.

As 2.1 except for:
1 At least 10 episodes occurring on 1–14 days/month on average

for > 3 months (≥ 12 and < 180 days per year) and ful lling criteria B–D.

2.3 Chronic tension-type headache.

As 2.1 except for:

. 1 Headache occurring on ≥ 15 days per month on average for
> 3 months (≥ 180 days per year), ful lling criteria B–D.

. 2 Lasting hours to days, or unremitting.

. 3 Both of the following:

. 1 Nomorethanoneofphotophobia,phonophobia,ormild nausea.

. 2 Neither moderate or severe nausea or vomiting.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

e most relevant diagnostic problem is to di erentiate be- tween TTH and mild migraine. If the headache is strictly uni- lateral, cervicogenic headache should also be considered (16). e diary may also reveal triggers and medication overuse, and it will establish the baseline against which to measure the e cacy of treatment. Identi cation of a high intake of analgesics is es- sential because medication overuse requires speci c treatment. Diagnostic procedures, in particular brain imaging, is necessary if secondary headache is suspected (e.g. the headache character- istics are untypical), if the course of headache attacks changes, or if persistent neurological or psychopathological abnormalities are present.

Patients with chronic TTH have a high level of neuroticism and psychological distress. is can be either a primary or a secondary e ect related to the premorbid psyche or caused by the chronic pain (17). Signi cant comorbidity such as anxiety or depression should be identi ed and treated concomitantly. Poor compliance with prophylactic treatment might be a problem in chronic TTH. It should be explained to the patient that frequent TTH only seldom can be cured, but that a meaningful improvement can be obtained with the combination of drug and non-drug treatment. It should be noted that chronic TTH almost always evolves from episodic TTH and does not begin de novo.

Patients with TTH need more sleep than healthy controls and might be relatively sleep deprived. Inadequate sleep may also con- tribute to increased pain sensitivity and headache frequency in TTH

(18). However, no link between TTH and sleep apnoea syndrome could be detected (19).

If patients ful l the criteria of both episodic migraine and chronic TTH, chronic migraine should be diagnosed according to the IHS criteria (see Chapter 31). Another problem might be to di erentiate between chronic TTH and new daily persistent headache (NDPH) (see Chapter 30). If patients ful l the criteria for NDPH, this should be the default diagnosis.

Pathophysiology

e exact pathophysiology of TTH is still not clari ed. Despite sev- eral experimental studies, a precise explanation of pain processing in TTH is still missing. Meanwhile, it is obvious that episodic and chronic TTH do not share the same underlying pain processing (20). While chronic TTH seems to be a disturbance of the control of cen- tral pain processing, episodic TTH can be linked to increased per- ipheral pain perception and increased muscle tone, the latter being primary or secondary.

e tenderness of pericranial myofascial tissues and number of myofascial trigger points are considerably increased in patients with TTH. Mechanisms responsible for the increased myofascial pain sensitivity have been studied extensively. Peripheral activation or sensitization of myofascial nociceptors could play a role in causing increased pain sensitivity, but rm evidence for a peripheral ab- normality is still lacking. Peripheral mechanisms are most likely of major importance in episodic TTH. Sensitization of pain pathways in the central nervous system due to prolonged nociceptive stimuli from pericranial myofascial tissues seem to be responsible for the conversion of episodic to chronic TTH (21,22). In chronic TTH, a signi cant decrease of grey matter in pain processing brain areas has been reported (23).

acute drug treatment of tension-type headache

Acute drug therapy refers to the treatment of single headache attacks in patients with episodic or chronic TTH. Most headaches in pa- tients with episodic TTH are mild to moderate, and the patients can o en self-manage by using simple analgesics such as paracetamol or acetylsalicylic acid (ASA) or non-steroidal anti-in ammatory drugs (NSAIDs). e e cacy of simple analgesics tends to decrease with the increasing frequency of the headaches. In patients with chronic TTH, simple analgesics are usually ine ective and should be used with caution because of the risk of medication overuse headache at a regular intake of simple analgesics for more than 14 days a month, or triptans or combination analgesics for more than 9 days a month. Other interventions such as non-drug treatments and prophylactic pharmacotherapy should be considered.

e e ect of acute drugs in TTH has been examined in many studies, and these have used many di erent methods for meas- urement of e cacy. e IHS guideline for drug trials in TTH re- commends freedom from pain a er 2 hours as the primary e cacy measure (6). is has been used in some studies, while many older studies used other e cacy measures such as pain intensity di er- ence, time to meaningful relief, and so on. is makes comparison of results between studies di cult.

Simple analgesics and NSaID

Paracetamol 1000 mg was signi cantly more e ective than placebo in most (24–31), but not all (32,33), trials, while three trials found no signi cant e ect of paracetamol 500–650 mg compared with pla- cebo (30,32,34).

Aspirin has consistently been reported more e ective than pla- cebo in doses of 1000 mg (30,35,36), 500–650 mg (30,35,37,38), and 250 mg (35). One study found no di erence in e cacy between solid and e ervescent aspirin (38).

Ibuprofen 800 mg (37), 400 mg (26,28,32,37,39,40), and 200 mg (41) are more e ective than placebo, as are ketoprofen 50 mg (32,41), 25 mg (27,33,41), and 12.5 mg (33). One study could not demon- strate a signi cant e ect of ketoprofen 25 mg, possibly owing to a low number of patients (32). Diclofenac 25 mg and 12.5 mg have been reported to be e ective (40), while there have been no trials of the higher doses of 50–100 mg. Naproxen 375 mg (29) and 550 mg (34,42), and metamizole 500 mg and 1000 mg (36), have also been demonstrated e ective. e latter drug is not available in many coun- tries, because it carries a minimal (if at all) risk of agranulocytosis. Treatment with intramuscular injection of ketorolac 60 mg in an emergency department has also been reported to be e ective (43).

ere have only been a few studies investigating the optimal dose for drugs in the acute treatment of TTH. One study demon- strated a signi cant dose–response relationship of ASA, with 1000 mg being superior to 500 mg and 500 mg being superior to 250 mg (35). Ketoprofen 25 mg tended to be more e ective than 12.5 mg (33), while another study found very similar e ects of ketoprofen 25 mg and 50 mg (41). Paracetamol 1000 mg seems to be superior to 500 mg, as only the former dose has been demonstrated to be e ective. In the face of a lack of evidence, the most e ective dose of a drug well tolerated by a patient should be chosen. Suggested doses are pre- sented in Table 29.1.

Five studies reported an NSAID to be signi cantly more e ective than paracetamol (26,28,32–34), while three studies could not dem- onstrate a di erence (27,29,30). Five studies have compared the e – cacy of di erent NSAIDs without demonstrating a clear superiority of any particular drug (36,37,40,41,44).

With respect to parenteral acute treatment, metamizole, chlor- promazine, and metoclopramide showed evidence for e cacy in

table 29.1 Drugs for the acute treatment of tension-type headache (TTH).

TTH; the combination of metoclopramide anddiphenhydramine was superior to ketorolac; the following medications were not more e ective than placebo: mepivacaine, meperidine and promethazine, and sumatriptan (45).

A thorough review of the acute drug treatment of TTH could not detect any di erence in adverse events between paracetamol and NSAIDs, or between these drugs and placebo (46). However, it is well known that NSAIDs have more gastrointestinal side e ects than paracetamol, while the use of large amounts of paracetamol may cause liver damage. Of the NSAIDs, ibuprofen seems to have the most favourable side e ect pro le (46).

Combination analgesics

The efficacy of simple analgesics and NSAIDs is increased in combination with caffeine 64–200 mg (24,26,47–49). One com- parative study examined the efficacy of the combination of para- cetamol with codeine and showed a significantly better efficacy than placebo and a similar efficacy to ASA (50). Combinations of simple analgesics with codeine or barbiturates, however, are not recommended, because these drugs increase the risk of medica- tion overuse headache (51).

Miscellaneous drugs

Triptans have been reported to be e ective for the treatment of interval headaches (52), which are most likely mild migraine attacks (53). Triptans most likely do not have a clinically relevant e ect in patients with TTH (54,55) and cannot be recommended. Muscle relaxants have not been demonstrated to be e ective in episodic TTH. e use of opioids increases the risk of developing medication overuse headache (51). Opioids are not recommended for the treat- ment of TTH.

Conclusions

Simple analgesics and NSAIDs are drugs of rst choice in the acute treatment of TTH (Table 29.1). Paracetamol 1000 mg is probably less e ective than the NSAID but has a better gastric side e ect pro le (56). Ibuprofen 400 mg may be recommended as the drug of rst choice among the NSAIDs because of a favourable gastro- intestinal side e ect pro le compared with other NSAIDs (56). Combination analgesics containing ca eine are more e ective than simple analgesics or NSAIDs alone but are regarded by some experts to be more likely to induce medication overuse headache. Physicians should be aware of the risk of developing medication overuse headache as a result of frequent and excessive use of all types of analgesics in acute treatment. Triptans, muscle relaxants, and opioids do not play a role in the treatment of TTH.

Although simple analgesics and NSAIDs are e ective in episodic TTH, the degree of e cacy has to be put in perspective. For ex- ample, the proportion of patients being pain free 2 hours a er treat- ment with paracetamol 1000 mg, naproxen 375 mg, and placebo were 37%, 32%, and 26%, respectively (29). e corresponding rates for paracetamol 1000 mg, ketoprofen 25 mg, and placebo were 22%, 28%, and 16%, respectively, in another study with 61%, 70%, and 36% of patients reporting a worthwhile e ect (27). us, e cacy is modest, and there is clearly a need for better acute treatment options of episodic TTH.

CHaPtEr 29 Tension-type headache: classi cation, clinical features, and management

Substance

Dose

Comment

Ibuprofen

200–800 mg

Gastrointestinal side effects, risk of bleeding

Ketoprofen

25 mg

Side effects as for ibuprofen

Acetylsalicylic acid

500–1000 mg

Side effects as for ibuprofen

Naproxen

375–550 mg

Side effects as for ibuprofen

Diclofenac

12.5–100 mg

Side effects as for ibuprofen, only doses of 12.5–25 mg tested in TTH

Paracetamol

1000 mg

Less risk of gastrointestinal side effects than with NSAIDs

There is sparse evidence for optimal doses. The most effective dose of a drug well tolerated by a patient should be chosen. NSAID, non-steroidal anti-in ammatory drug.

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Part 5 Tension-type and other chronic headache types

Prophylactic drug treatment of tension-type headache

Prophylactic pharmacotherapy should be considered in patients with chronic or very frequent episodic TTH. Comorbid disorders such as obesity or depression should be taken into account. For many years, the tricyclic antidepressant amitriptyline has been used. More lately, other antidepressants, NSAIDs, muscle relaxants, anti- convulsants, and botulinum toxin have been tested in chronic TTH. e e ect of prophylactic drugs has been examined only in very few placebo-controlled studies, which have used di erent methods for measurement of e cacy. e IHS guidelines for drug trials in TTH recommend days with TTH or area-under-the-headache curve (AUC) as primary e cacy measure (6). ese parameters have been used in some studies, while other studies have used other e cacy measures such as pain reduction from baseline, headache inten- sity, and so on. is makes comparison of results between studies di cult.

amitriptyline

Lance and Curran (57) reported amitriptyline 10–25 mg q8h to be e ective, while Diamond and Baltes (58) found amitriptyline 10 mg daily but not 60 mg daily to be e ective. Amitriptyline 75 mg daily was reported to reduce headache duration in the last week of a 6-week study (59), while no di erence in e ect size between ami- triptyline 50–75 mg daily or amitriptylinoxide 60–90 mg daily and placebo was found in one study (60). Bendtsen et al. (61) showed that amitriptyline 75 mg daily reduced the AUC (calculated as head- ache duration times headache intensity) by 30% versus placebo, which was highly signi cant. Holroyd et al. (62) treated patients with antidepressants (83% took amitriptyline median dose 75 mg daily; 17% took nortriptyline median dose 50 mg daily) and com- pared this with stress management therapy and with a combination of stress management and antidepressant treatment. A er 6 months, all three treatments reduced the headache index by approximately 30% more than placebo, which was highly signi cant.

Other antidepressants

e tricyclic antidepressant clomipramine 75–150 mg daily (63) and the tetracyclic antidepressant mianserin 30–60 mg daily (63) have been reported more e ective than placebo. Interestingly, some of the newer, more selective antidepressants with action on sero- tonin and noradrenaline seem to be as e ective as amitriptyline with the advantage of better tolerability. e noradrenergic and speci c serotonergic antidepressant mirtazapine 30 mg daily reduced the headache index by 34% more than placebo in di cult-to-treat pa- tients without depression, including patients who had not responded to amitriptyline (64). e e cacy of mirtazapine was comparable to that of amitriptyline reported by the same group (61). A systematic review concluded that the two treatments may be equally e ective for the treatment of chronic TTH (65). e serotonin and noradren- aline reuptake inhibitor venlafaxine 150 mg daily (66) reduced head- ache days from 15 to 12 per month in a mixed group of patients with either frequent episodic or chronic TTH. Low-dose mirtazapine 4.5 mg daily alone or in combination with ibuprofen 400 mg daily was not e ective in chronic TTH. e selective serotonin reuptake in- hibitors (SSRI) citalopram (61) and sertraline (67) have not been

found more e ective than placebo. SSRIs have been compared with other antidepressants in six studies. ese studies were reviewed in a Cochrane analysis that concluded that SSRIs are less e cacious than tricyclic antidepressants for the treatment of chronic TTH (68).

Miscellaneous agents

ere have been con icting results for treatment of TTH with the muscle relaxant tizanidine (69,70). e N-methyl-d-aspartate an- tagonist memantine was not e ective (71). Botulinum toxin has been extensively studied in chronic TTH with negative results in all placebo-controlled trials (72). ere is some evidence from an open-label trial that topiramate is also e cacious in chronic TTH (73). e prophylactic e ect of daily intake of simple analgesics has not been studied in trials on chronic TTH, but explanatory analyses indicated that ibuprofen 400 mg daily was not e ective in one study (74). On the contrary, ibuprofen increased headache compared with placebo, indicating a possible early onset of medication overuse headache (74).

Conclusions

Amitriptyline has a clinically relevant prophylactic e ect in patients with chronic TTH and should be drug of rst choice (Table 29.2). Mirtazapine or venlafaxine are probably e ective, while the older tricyclic and tetracyclic antidepressants clomipramine, maprotiline, and mianserin may be e ective. A recent systematic review (65) con- cluded that amitriptyline and mirtazapine are the only drugs that can be considered proven bene cial for the treatment of chronic TTH. However, the last search was performed in 2007 before publi- cation of the study on venlafaxine (66).

Amitriptyline should be started at low dosages (10 mg daily) and titrated by 10 mg weekly until the patient has either good therapeutic e ect or side e ects. It is important that patients are informed about the independent action on pain by antidepressants. e mainten- ance dose is usually 30–75 mg daily administered 1–2 hours before bedtime to circumvent any sedative adverse e ects. e e ect is not related to the presence of depression (61). A signi cant e ect of ami- triptyline may be observed in the rst week on the therapeutic dose (61). It is therefore advisable to change to other prophylactic therapy if the patient does not respond a er 4 weeks on the maintenance dose. e side e ects of amitriptyline include dry mouth, drowsi- ness, dizziness, obstipation, and weight gain. Mirtazapine, of which

table 29.2 Drugs for the prophylactic treatment of tension-type headache (for side effects see text).

Substance

Daily dose (mg)

Drug of rst choice

Amitriptyline

30–75

Drugs of second choice

Mirtazapine

Venlafaxine

75–150

Drugs of third choice

Clomipramine

75–150

Maprotiline

Mianserin

30–60

the major side e ects are drowsiness and weight gain, or venlafaxine, of which the major side e ects are nausea, dizziness, and loss of li- bido, should be considered if amitriptyline is not e ective or not tolerated. Discontinuation should be attempted every 6–12 months. e physician should keep in mind that the e cacy of preventive drug therapy in TTH is o en modest, and that the e cacy should outweigh the side e ects.

Patient education

Non-drug management should be considered for all patients with TTH and is widely used. However, the scienti c evidence for the ef- cacy of most treatment modalities is sparse. e very fact that the physician takes the problem seriously may have a therapeutic e ect, particularly if the patient is concerned about serious disease, for ex- ample a brain tumour, and can be reassured by thorough examin- ation. A detailed analysis of trigger factors should be performed, as avoidance of trigger factors may have a long-lasting e ect. e most frequently reported triggers for TTH are stress (mental or physical), irregular or inappropriate meals, high intake or withdrawal of co ee and other ca eine-containing drinks, dehydration, sleep disorders, too much or too little sleep, reduced or inappropriate physical exer- cise, psycho-behavioural problems, as well as variations during the female menstrual cycle and hormonal substitution (75,76). Most of triggers are self-reported and so far none of the triggers has been systematically tested.

Information about the nature of the disease is important. It can be explained that muscle pain can lead to a disturbance of the brain’s pain-modulating mechanisms, so that normally innocuous stimuli are perceived as painful, with secondary perpetuation of muscle pain and risk of anxiety and depression. Moreover, the patient should be explained that the prognosis in the longer run is favourable, as ap- proximately half of all individuals with frequent or chronic TTH had remission of their headaches in a 12-year epidemiological follow-up study (13).

Psycho-behavioural treatments

A large number of psycho-behavioural treatment strategies have been used to treat chronic TTH. Electromyography (EMG) biofeed- back, cognitive–behavioural therapy (CBT), and relaxation training have been investigated the most. However, only a few trials have been performed with su cient power and clear outcome measures (77).

e aim of EMG biofeedback is to help the patient recognize and control muscle tension by providing continuous feedback about muscle activity. Sessions typically include an adaptation phase, a baseline phase, a training phase, where feedback is provided, and a self-control phase, where the patient practices controlling muscle tension without the aid of feedback. A recent review including 11 studies concluded that because of low power there is con icting evidence to support or refute the e ectiveness of EMG biofeedback versus placebo or any other treatments (77). However, a recent exten- sive and thorough meta-analysis including 53 studies concluded that biofeedback has a medium-to-large e ect. e e ect was found to be long-lasting and enhanced by combination with relaxation therapy (78). e majority of studies included employed EMG biofeedback.

It was not possible to draw reliable conclusions as to whether the ef- fect di ered between patients with episodic and chronic TTH.

e aim of CBT is to teach the patient to identify thoughts and beliefs that aggravate headache. ese thoughts are then challenged, and alternative adaptive coping self-instructions are considered. One study found CBT, treatment with tricyclic antidepressants, and a combination of the two treatments better than placebo with no signi cant di erence between treatments (62), while another study reported no di erence between CBT and amitriptyline (79). CBT may be e ective, but there is no convincing evidence (65).

e goal of relaxation training is to help the patient recognize and control tension as it arises in the course of daily activities. During the training, the patient sequentially tenses and then releases spe- ci c groups of muscles throughout the body. Later stages involve relaxation by recall, association of relaxation with a cue word, and maintaining relaxation in muscles not needed for current activities. Relaxation training has been compared with no treatment, waiting list control, or with other interventions. A recent review concluded that there is con icting evidence that relaxation is better than no treatment, waiting list, or placebo (77).

Mindfulness-based therapy was also studied in a randomized, controlled trial and showed a signi cant improvement of chronic TTH versus a waiting list (80).

EMG biofeedback has an e ect in TTH, while CBT and relax- ation training may have an e ect in TTH, but at this moment there is no convincing evidence to support this. ese treatments are rela- tively time-consuming, but, unfortunately, there are no guidelines regarding which psycho-behavioural treatment to choose for the individual patient. erefore, until scienti c evidence is provided, it is assumed that CBT will be most bene cial for patients in whom psycho-behavioural problems or a ective distress play a major role, while biofeedback or relaxation training may be preferable for tense patients.

Physical therapy

Physical therapy is widely used for the treatment of TTH and in- cludes improvement of posture, massage, spinal manipulation, oromandibular treatment, exercise programmes, hot and cold packs, ultrasound, and electrical stimulation, but the majority of these mo- dalities have not been properly evaluated. Active, but not passive, treatment strategies are generally recommended (81). Carlsson et al. (82) reported a better e ect of physiotherapy than acupunc- ture. A controlled study (83) combined various techniques such as massage, relaxation, and home-based exercises, and found a modest e ect. Adding craniocervical training to classical physiotherapy was found to be better than physiotherapy alone (84). A recent study found no signi cant long-lasting di erences in e cacy among re- laxation training, physical training, and acupuncture (85). Spinal manipulation had no e ect in episodic TTH (86) and no convin- cing e ect in chronic TTH (87–89), whereas manual therapy was re- ported to be better than standard care by a general practitioner (90). ere is no rm evidence for e cacy of therapeutic touch, cranial electrotherapy, or transcutaneous electrical nerve stimulation (91).

It can be concluded that there is a huge contrast between the widespread use of physical therapies and the lack of robust scienti c evidence for e cacy of these therapies, and that further studies of improved quality are necessary to either support or refute the e ect- iveness of physical modalities in TTH (91–93).

CHaPtEr 29 Tension-type headache: classi cation, clinical features, and management

Non-pharmacologic treatment of tension-type headache

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Part 5 Tension-type and other chronic headache types acupuncture and nerve blocks

e prophylactic e ect of acupuncture has been investigated in sev- eral trials in patients with frequent episodic or chronic TTH. Two trials reported better e ect of acupuncture than basic care or waiting list but no better e ect of Chinese acupuncture versus sham acupunc- ture (94,95), while a recent Cochrane analysis concluded that there was overall a slightly better e ect from acupuncture than from sham acupuncture based on the results of ve trials (96). Four trials com- pared acupuncture with physiotherapy (82,85,97), relaxation (85), or a combination of massage and relaxation (98); these trials suggest slightly better results for some outcomes with the latter therapies according to the recent Cochrane analysis (96,99). A meta-analysis using other criteria for inclusion of studies (100) and a review (65) concluded that there is no evidence for e cacy of acupuncture in TTH. Together, the available evidence suggests that acupuncture could be a valuable option for patients su ering from frequent TTH, but more research is needed before nal conclusions can be made.

A recent study reported no e ect of greater occipital nerve block in patients with chronic TTH (101).

recommendations

Non-drug management should always be considered in TTH treat- ment, although the scienti c background is limited. Information, reassurance, and identi cation of trigger factors may be rewarding. EMG biofeedback has documented e cacy in TTH, while CBT and relaxation training most likely are e ective, but there is no convin- cing evidence. Physical therapy and acupuncture may be valuable options for patients with frequent TTH, but there is no robust scien- ti c evidence for e cacy.

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New daily persistent headache

Kuan-Po Peng, Matthew S. Robbins, and Shuu-Jiun Wang

Introduction

History of new daily persistent headache

e term new daily persistent headache (NDPH) was rst used in an abstract by Vanast in 1986 (1). In this initial description, the head- ache was described as occurring daily since the rst day it began, and secondary causes, including psychological tension, trauma, or pre-existing headache disorders, had to be excluded before making a diagnosis of NDPH. Vanast reported 45 patients (26 females, 19 males), most in their twenties to forties. e headache features were heterogeneous, including steady headache (72%), pounding headache (28%), and unilateral headache (38%); associated symp- toms were rather common, including nausea (53% of females, 57% of males), photophobia (42% of females, 26% of males), and phonophobia (53% of females, 21% of males). e overall prognosis was good: more than 70% of the patients were free from headache by the 2-year follow-up. e positive outcome in Vanast’s series was quite di erent from the results of later series—NDPH was later con- sidered very resistant to treatment.

In early series, a diagnosis of NDPH was mostly made according to the clinical syndrome of a ‘new daily persistent’ headache, which therefore encompassed both idiopathic and secondary aetiologies (1–4). As both the clinical features and the aetiological diagnoses were varied, this led to a heterogeneous group of patients. In 1994, Silberstein and Lipton et al. (5) proposed the rst diagnostic cri- teria for NDPH, de ning it as a subtype of chronic daily headache (CDH), which is a headache exceeding 4 hours per day for > 15 days per month. In addition, the onset of NDPH is within ≤ 3 days, and secondary headaches and a previous history of tension-type head- ache (TTH) or migraine preclude the diagnosis of NDPH (5). e Silberstein and Lipton (S-L) criteria clearly de ned the onset and duration of the headache, but in this de nition NDPH is not ne- cessarily daily or persistent. In 2004, NDPH was listed as a primary headache disorder by the International Headache Society in the International Classi cation of Headache Disorders, 2nd edition

(ICHD-2) (6). In the ICHD-2 criteria, the headache features of NDPH were clearly de ned for the rst time as similar to TTH instead of being migrainous. In addition, the daily and persistent characteristics of NDPH were put back compared to the S-L criteria. However, many clinical series identi ed a certain proportion of pa- tients who otherwise ful lled the diagnostic criteria of NDPH, ex- cept for the TTH-like headache features (7–10). us, in the recently released third edition of the ICHD (ICHD-3), patients who have mi- grainous headache are no longer excluded. Moreover, patients with prior infrequent migraine or TTH are also allowed in the absence of increasing frequency of a pre-existing headache before the onset of NDPH, but a strict cut-o of baseline monthly headache days prior to NDPH onset remains absent (Box 30.1) (11).

Epidemiology

ere are few epidemiological studies of NDPH. Primary CDH a ects 4% of the general population (12,13), and up to 80% of patients in tertiary headache clinics (5,14,15). Four subtypes of CDH were ori- ginally proposed by Silberstein and Lipton et al. (5) and later adopted in ICHD-2 (6), including chronic migraine (CM), chronic tension- type headache (CTTH), hemicrania continua (HC), and NDPH. In patients with CDH from tertiary centres, NDPH might be more common in the paediatric (0.9–35%) (16–18) than in the adult popu- lation (2.5–10.8%) (10,14). However, in community-based studies, NDPH is rarely found. In Spain, the 1-year prevalence of NDPH is 0.1% in those aged > 14 years (13); in Norway, the 1-year prevalence is as low as 0.03% in those aged 30–44 years (19). In Taiwan, of 7900 ado- lescents aged 12–14 years, 122 patients with CDH were diagnosed, but none of them had NDPH (20). It must be noted that most of the afore- mentioned studies used ICHD-2 criteria, which are more restrictive. erefore, more studies are needed to re-evaluate the prevalence of NDPH using the newer and more permissive ICHD-3 criteria.

Reported triggers that are associated with NDPH onset are miscel- laneous and o en absent. In a large NDPH series (n = 97) by Rozen

Evolving diagnostic criteria for new daily persistent headache

triggers to the onset of new daily persistent headache and potential pathological links

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Part 5 Tension-type and other chronic headache types

Box 30.1 Criteria for new daily persistent headache

. A Persistent headache ful lling criteria B and C.

. B Distinct and clearly-remembered onset, with pain becoming con-
tinuous and unremitting within 24 hours.

. C Present for > 3 months.

. D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

(21), more than 50% of the patients recalled no speci c triggers. e various triggers that have been reported with NDPH may provide potential links to the underlying disease mechanism.

Infection or u-like episodes

An early case–control study indicated that viral infection might be a trigger to the onset of NDPH. Diaz-Mitoma et al. (2) reported that 27 of 32 (84%) patients with NDPH versus eight of 32 (25%) controls, have evidence of active Epstein–Barr virus (EBV) infec- tion, de ned by EBV secretion and/or early antigen titre > 1:32. is cohort of NDPH averaged 27.9 years in age, featured a ma- jority (84%) of women, and mostly presented with bilateral head- aches (81%) (2). In this study, NDPH was de ned as a new-onset headache that persisted for at least 1 month. Secondary causes of endocrine, autoimmune, or neoplastic disorders were excluded; however, other NDPH mimics, including high-/low-pressure head- aches, chronic meningitis, or vascular lesions, were not rigorously excluded. A subsequent large study reported 108 patients with sec- ondary NDPH, de ned as (i) bilateral daily headache lasting up to 8 weeks in the absence of a previous history of a primary head- ache disorder; (ii) laboratory evidence of active infection; and (iii) relief of headache a er proper antibiotic treatment. In this series, only four patients (3.7%) were positive for EBV, but other systemic infections were common, including Salmonella in 28 (25.9%), and Escherichia coli in 16 (14.8%). In a study by Rozen (21), who util- ized ICHD-3 diagnostic criteria, infection or u-like illness was the most common trigger (22%) in 97 patients with NDPH. e trig- gers did not di er between men and women (21). All these studies provided evidence that NDPH-like headaches might be a rather common symptom in those with an active systemic infection, re- gardless of the pathogen.

Two studies on the adult population showed peaks of NDPH onset in March/April and September (9,23). One recent study on the paediatric population showed peaks of NDPH onset in January and September (22), both at the start of a new semester. ese studies suggest a potential seasonal infectious or environmental link.

Stressful life events

Prior to the onset of NDPH, 9–26% of patients recall stressful life events (7,9,10,21,23). e direct mechanism by which stressful life events could lead to NDPH is unknown; however, the occurrence of a major life event is a known risk factor for CDH. Patients with CDH, versus controls, were more likely to report stressful life events in the year before the diagnosis of CDH (24). In animal models, chronic stress exposure produced hyperalgesia; central sensitization remains the most accepted mechanism how an episodic headache progresses to CDH (25). Nevertheless, stressful life events are easy

to be recalled, but the causality between the event and the headache onset is di cult to ascertain.

tumour necrosis factor-α and NDPH

Tumour necrosis factor (TNF)-α is a pro-in ammatory cytokine. Rozen and Swidan (26) examined the level of TNF-α in serum and cerebrospinal uid (CSF) in 20 patients with primary NDPH, 16 pa- tients with CM, and two patients with post-traumatic headache. e CSF TNF-α level was elevated in 19 of 20 patients with NDPH, 16 of 16 patients with CM, and two of two patients with post-traumatic headache; however, the serum TNF-α level was mostly normal (ele- vated in ve of 14 patients with NDPH patients, zero of 16 patients with CM, and one of two with post-traumatic headache) (26). e discrepancy between CSF and serum levels of TNF-α potentially suggested intrathecal rather than systemic in ammation. In animal models, both infection and stress activate glial cells and increase cytokine production, including TNF-α (27,28). TNF-α is known to increase the production of calcitonin gene-related peptide, a neuro- transmitter associated with headache and migraine (29). e role of TNF-α provides a link to how some triggers may result in NDPH or even other chronic headache disorders, including CM and post- traumatic headache, but its speci city for the individual forms of CDH is not clear.

Hypermobility syndrome

Rozen et al. (30) reported that 11 of 12 patients with NDPH had cervical spine joint hypermobility and 10 of 12 had widespread joint hypermobility, as evaluated by physical therapists using the Beighton score, but there was no control group in this study (30). In patients with hypermobility, a diagnosis of NDPH must be prudently made as a hypermobility syndrome can also be associated with spontan- eous intracranial hypotension (31), which possibly mimics NDPH in clinical presentation.

Other triggers

In some NDPH cohorts, several rare other triggers were reported. Li and Rozen (23) reported that 12% of their patients had undergone surgery before the onset of NDPH. In a later series by Rozen (21), he found that all of the patients who developed NDPH a er surgery had been intubated during surgery, and speculated a cervicogenic link. Robbins et al. (9) described others as triggers for NDPH in a series of 71 patients: menarche (n = 3), tapering of antidepressants (n = 2), and vaccination (n = 1). As all reported cohorts were retro- spective, these rare triggers might be life events easily recalled and thus causality to NDPH is questionable.

triggers in a paediatric population

Most of the aforementioned studies included adult patients only. Mack (32) reported on possible causes in a paediatric popula- tion, including both primary and secondary NDPH. He identi- ed 40 paediatric patients with NDPH. Seventeen (43%) of them reported a febrile disease at the onset of NDPH, and in nine of 17 an EBV infection was con rmed. Minor head trauma was re- ported in another nine patients, but this raised the concern of post- traumatic headache and not NDPH. Other causes in this study included idiopathic intracranial hypertension, surgery, and high- altitude climbing. Only ve patients (12.5%) recalled no speci c predisposing events.

Pathophysiological mechanisms of NDPH

ere is no consensus or solid evidence base to embrace any of the hypothesized pathophysiological mechanisms that have been pro- posed to date. Di erent studies used di erent diagnostic criteria for NDPH. Primary NDPH and secondary NDPH were both included in di erent studies. Moreover, primary NDPH might rather be a syndrome than a speci c disease, as Goadsby proposed (33); thus, multiple underlying mechanisms might co-exist. erefore, a con- sensus in clinical diagnostic criteria might be the rst step for fur- ther aetiological exploration.

Headache features

Despite the diverse headache features of NDPH in di erent clinical series, one key feature remains: most patients with NDPH present with an abrupt onset of a persistent or near-persistent headache on one speci c day. Although the ICHD-2 criteria allowed a 72-hour window of onset (6), patients with an onset of uctuating headache that becomes persistent within 72 hours might represent a minority of patients with NDPH, and the ICHD-3 criteria no longer allow for this variability in onset (11). For many clinicians, whether the pa- tient could recall the speci c day or circumstances of the headache onset remains crucial in the diagnosis of NDPH. In our experience, the circumstances of the headache onset might be usual: one pa- tient recalled the headache started when he was sitting on the couch watching television. Instead, speci c circumstances at the onset of headache should raise the concern of secondary headache diagnoses that mimic NDPH, i.e. an abrupt headache a er sneezing or weight li ing would raise the concern of low-pressure headache due to CSF leakage a er minor trauma.

A female predominance is reported in both adult (1.4–2.5:1) (1,9,10,23) and paediatric populations (1.8–2.9:1) (8,18), except for one Japanese study that reported a male predominance (1.3:1); this study used the more restrictive ICHD-2 criteria (7). e age at onset is wide, ranging from 6 to 76 years (8,9,23). Several earlier North American series reported a younger peak age at onset in women (10–35 years) (1,9,23) than in men (30–50 years) (1,23). On the contrary, two Asian studies reported a younger peak age at onset in men (10–30 years) (7,10) than in women (40–60 years) (10). A large-scale American study by Rozen (21) reported no obvious di erence in age at onset between the sexes (21). e location of pain was most frequently over occipital and temporal regions (1,23). e pain is usually moderate to severe (82–100%) (7,9,10,23), bi- lateral (53–89%) (7–10,23), and pulsating (41–90%) (7,9,10,23). In addition, the headache is o en associated with nausea (33–68%) (7–10,23), photophobia (45–69%) (8–10,23), and photophobia (41– 63%) (8–10,23).

Migrainous features in NDPH

Although TTH features are clearly de ned in the diagnostic criteria of NDPH in ICHD-2 (6), in most described cases, the headache could be very ‘migrainous’, even in those who follow the ICHD-2 criteria strictly (7,9,10). Owing to the frequent migrainous features

(moderate or severe headache, pulsating characteristics, nausea, photophobia, and phonophobia) in patients with NDPH, Kung et al. (8) proposed revised criteria that do not exclude those with prom- inent migrainous features. is concept was followed in subsequent studies despite slightly di ering details (9,10,34). us, in ICHD- 3, headache features, either migrainous or TTH-like, are no longer restricted (11).

Pre-existing headache disorders before the diagnosis of NDPH

A pre-existing headache disorder before the diagnosis of NPDH raises the concern of whether the new persistent headache is a de novo NDPH or deterioration of a pre-existing headache disorder. In the literature, pre-existing headache disorders (TTH or migraine) before the diagnosis of NDPH are rather common (7–38%) (7,9,10,23). In addition, the headache features of NDPH seem irrelevant to the pre- existing headache features; that is, patients with a previous migraine diagnosis were no more likely to develop NDPH with migrainous fea- tures (9,10,34). In the S-L criteria, a pre-existing headache disorder is not allowed; however, the ICHD-2 or the ICHD-3 do not exclude those with a pre-existing headache disorder. ere is no consensus of a maximum frequency of pre-existing headaches allowed before the diagnosis of NDPH. However, greater prudence should be taken before making a diagnosis of NDPH if a baseline headache increased in fre- quency before NDPH onset, or the baseline headache is not infrequent.

Giving the current diagnostic criteria, NDPH cannot be diagnosed unless other headache disorders have been excluded properly. One must keep in mind that none of the clinical spectrum of symp- toms is speci c to NDPH. us, NDPH must be di erentiated from any other headache disorder that occurs frequently or even persistently.

NDPH mimics: primary headaches

Of the primary headache disorders, CM and CTTH must be care- fully explored and a history of increased frequency of pre-existing headache disorder must be scrutinized. In addition, HC should be excluded, as up to 18% of patients with NDPH may present with side-locked unilateral headache (10). Furthermore, cranial auto- nomic symptoms are also common in 12.9–27.5% of patients with NDPH (9). us, a trial of indomethacin up to 150 mg daily (in cer- tain cases up to 225 mg daily) for up to 2 weeks should be admin- istered to exclude HC in those with unilateral NDPH (35). Primary thunderclap headache may also present with a subsequent persistent residual headache, even though the initial explosive headache o en lasts 1 hour to 10 days (6); however, with the better understanding of reversible cerebral vasoconstriction syndrome (RCVS), many of the patients, previously regarded as su ering from primary thun- derclap headache were later diagnosed with RCVS. RCVS will be discussed later in NDPH mimics of secondary headaches. Lastly, nummular headache (see also Chapter 33), which is newly proposed as a primary headache disorder in ICHD-3 (11), could also be per- sistent, but the de ning feature of pain over a xed region of 2–6 cm in diameter is rarely reported in NDPH series (11).

CHaPtEr 30 New daily persistent headache

Clinical presentation of new daily persistent headache

Diagnosis of new daily persistent headache: possible mimics

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Part 5 Tension-type and other chronic headache types NDPH mimics: secondary headaches

Any secondary headache disorder that can induce persistent head- aches could mimic NDPH. A neurological examination could reveal certain secondary causes, such as space-occupying lesions in the brain; however, several NDPH mimics can only be detected when a speci c examination and diagnostic work-ups have been performed (Figure 30.1).

active and previous meningitis

As previously mentioned in the pathophysiology, occult central ner- vous system infection poses an important di erential diagnosis of NDPH. Acute bacterial meningitis, presenting with neck sti ness,

fever, and changes of consciousness, is not o en confused with NDPH. However, the symptoms of certain chronic meningitides are less speci c and could consist of only headaches, i.e. mycobacterial meningitis, fungal meningitis, or Mollaret’s meningitis—commonly caused by herpes simplex virus type 2 (36). ese occult infections can only be excluded with the help of a CSF analysis. Except for active meningitis, post-meningitis headache is another di erential diag- nosis. Headache attributed to past bacterial meningitis is listed in the ICHD-3 (11); however, persistent headache attributed to past viral meningitis is not a valid diagnosis in ICHD-3 (11). Except for being younger, those who developed headaches a er resolution of menin- gitis did not di er from those without subsequent headache (37).

Secondary headache disorders

Viral meningitis

• Meningismus underrecognized • CSF analysis not performed

during acute period
• Post-viral meningitis headache

may be a discrete entity yet to be well defined

SIH

• Headache patterns and associated symptoms aside from the typical orthostatis nature not recognized

• MRI performed without gadolinium

Giant cell arteritis

• Erroneous presumption that pain is temporal in location

• ESR is not a perfect screening test

• Temporal artery biopsy not pursued

IIH

• Cases without overt papilledema easily missed

• Threshold for CSF analysis too high

RCVS

• Initial relapsing thunderclap headache pattern underrecognized

• Lack of focus of onset circumstances when presenting to a headache center several months or years after onset

Systemic illnesses

• Detailed review of systems or medical examination not performed

• HIV risk factors not routinely queried • Follow up not long enough

Primary headache disorders

• Antecedent escalating headache frequency underestimated

• Diagnosis or indomethacin trial not considered in cases of bilateral head pain

CTTH

• Antecedent escalating headache frequency underestimated

• Cranial palpation not routinely performed on clinical examination

• Circumscribed nature underrecognized

• Bifocal cases underrecognized

NDPH

Figure 30.1 Secondary and primary headache disorders that may be overlooked when new daily persistent headache (NDPH) is diagnosed.

CSF, cerebrospinal uid; ESR, erythrocyte sedimentation rate; RCVS, reversible cerebral vasoconstriction syndrome; SIH, spontaneous intracranial hypotension; MRI, magnetic resonance imaging; IIH, idiopathic intracranial hypertension; HIV, human immunode ciency virus; CM, chronic migraine; CTTH, chronic tension-type headache; HC, hemicrania continua; NH, nummular headache.

Reproduced from Headache, 52, 10, Robbins MS, Evans RW, The Heterogeneity of New Daily Persistent Headache, pp. 1579–1589. Copyright (2012) with permission from John Wiley and Sons.

Idiopathic intracranial hypertension

visualize CSF leakage without creating a secondary leakage during the process of injecting contrast into the intradural space when per- forming computed tomography myelography (51).

rCVS

e key features of RCVS are recurrent thunderclap headaches and reversible segmental vasoconstriction of arterial branches of the circle of Willis (see also Chapter 49). e headache is usually so severe as to raise the concern of aneurysmal subarachnoid haem- orrhage (SAH). Patients are mostly middle-aged women, but paedi- atric cases have also been reported (52). Recurrent thunderclap headaches remain for an average of 2 weeks; however, cerebral vaso- constriction may last up to 3–6 months, even a er the resolution of the clinical symptoms (53). Although the median duration of each thunderclap headache is 3 hours, up to 50% of the patients experi- ence a milder persistent headache at baseline during the interval of RCVS and sometimes mimicking or comorbid with migraine (54). In addition, 80% of the su erers have known triggers for the oc- currence of each thunderclap headache, including exertion, bathing, sex, and defaecation (55–57). Owing to the speci c triggers, most of the patients remembered the exact day of headache onset, as seen in patients with NDPH. To consolidate the diagnosis of RCVS, cere- bral magnetic resonance images including angiography and lumbar punctures—for the exclusion of occult SAH not detected on non- contrast computed tomography—remain the studies of choice.

Strictly speaking, RCVS rarely lasts for more than 3 months and thus seldom ful ls the diagnostic criteria of NDPH, despite similar clinical symptoms—a new-onset persistent headache (6). However, a study published in abstract form followed the long-term outcome of 16 patients with RCVS. Of the 14 patients successfully followed, CDH developed in six of the 14 (43%) patients a er an average of 99 weeks of follow-up (58). A second preliminary study also noted long-term persistent headache in a subset of patients (n = 11/20) with RCVS (59). us, NDPH might be extremely di cult to dif- ferentiate from RCVS in this subgroup of patients without early diagnostic evaluation at the onset of headache. Moreover, 9–63% patients may develop transient or permanent neurological de cits (56,57,60), including posterior reversible encephalopathy syndrome (9–14%), cerebral infarction (4–54%), cortical SAH (22–34%), or intracerebral haemorrhage (6–20%) (56,57,60,61). ese complica- tions may result in prolonged headache, even a er the resolution of RCVS.

Other secondary headache disorders

In patients > 50 years of age, giant cell arteritis (GCA) should al- ways be considered in the di erential diagnosis. More than half of patients with GCA complained of persistent and unremitting head- ache similar to NDPH (62). Moreover, the headache could be either unilateral or bilateral (62,63). An elevated erythrocyte sedimenta- tion rate (ESR) is generally observed; however, up to 22.5% of pa- tients present with a normal ESR at the beginning (64), although C-reactive protein may increase the diagnostic yield (65). us, temporal artery biopsy is recommended in patients suspected to have GCA (63). Other disorders, including various infection and neoplasms located in the head and neck, cervical artery dissections, vascular anomalies, or temporomandibular joint dysfunction, could also be considered if patients present with a compatible history of neurological ndings.

Idiopathic intracranial hypertension (IIH), also known as pseudotumour cerebri or benign intracranial hypertension, is an easily neglected cause of chronic daily headache (see also Chapter 39). It is usually seen in obese women of childbearing age. e most common symptoms are headache, papilloedema, and oc- casionally pulsatile tinnitus (38). Of note, around 5.3% of patients with IIH may present without papilloedema (39). ose without papilloedema are more likely to have photopsia, spontaneous venous pulsations, and a lower—albeit still elevated—CSF pres- sure than those with papilloedema. A detailed fundus and visual eld examination by a neuro-ophthalmologist is suggested (39). Regarding the headache features, IIH could either mimic CM (40) or CTTH (41). us, in patients without papilloedema or other focal neurological de cits, it is impossible to di erentiate IIH and NDPH according to clinical presentations. Moreover, both IIH and NDPH require a normal brain imaging study to exclude other diagnoses—although certain image ndings are rather common in patients with IIH, especially bilateral transverse sinus stenosis (42), as identi ed on magnetic resonance venography (MRV). us, a spinal puncture to measure the opening pressure is crucial, but a single normal spinal tap does not exclude the possibility of intra- cranial hypertension as a certain proportion of patients have inter- mittent, instead of persistent, intracranial hypertension (43). us, prolonged monitoring of CSF pressure for 30 minutes or more, or repetitive tapping with multiple measurements, is suggested (44) in those with common risk factors of IIH to completely exclude the diagnosis of IIH.

Spontaneous intracranial hypotension

Spontaneous intracranial hypotension (SIH) is a rare headache disorder—albeit generally believed to be under-diagnosed (see also Chapter 38). SIH most o en a ects young and middle-aged adults and is twice as common in women than in men (45). e headache features of SIH share certain similarities to those of NDPH. Firstly, the headache usually starts on a speci c day a er a trivial trauma such as sneezing or taking a rollercoaster ride (46), or no obvious triggers are identi ed. Secondly, the headache usually occurs daily from the onset (47). Although SIH features an orthostatic head- ache, which disappears completely or improves greatly a er lying supine and recurs within 15 minutes a er standing up (6), the head- ache may evolve to be persistent with minor uctuation a er pos- tural changes in time. us, taking a detailed history of the initial headache features at onset is important. Moreover, generalized con- nective tissue disease is a known predisposing factor to SIH (48–50), and one previous report identi ed that 11 of 12 patients with NDPH had cervical spine hypermobility syndrome—which is a feature of generalized connective tissue disorder (30). us, a relevant history of connective tissue disorder or hypermobility should raise concern for both diagnoses. Except for documentation of CSF hypotension through lumbar punctures, cranial MRI with and without contrast provides radiological evidence of CSF hypotension in a majority of patients of SIH, including (i) di use pachymeningeal enhancement; (ii) brain sagging; (iii) pituitary hyperaemia; and (iv) engorgement of venous structures (47). None of the above features should be seen in patients with NDPH. In addition, more evidence suggests magnetic resonance myelography might be a suitable alternative to

CHaPtEr 30 New daily persistent headache

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Part 5 Tension-type and other chronic headache types Suggested diagnostic tests

A great number of diseases could mimic NDPH; in order to make a proper diagnosis, a detailed headache history is crucial. As with diagnosing any headache disorder, it is important to let the patient express the symptoms in open questions rather than jumping into some criteria- tting closed questions. e physician should focus on how the headache started, although this might be rather di – cult as many patients visit the clinic years a er their headache onset. Further physical and neurological examinations follow the initial clues from the history taking. To properly exclude potential NDPH mimics, a brain image study, preferably MRI with and without con- trast, including magnetic resonance angiography and MRV is re- commended. In a study (n = 97) by Rozen (66), the majority (87%) of patients with primary NDPH had normal MRI studies, while the rest had white matter abnormalities. None in this cohort had infarct- like lesions. Among the patients with NDPH with white matter ab- normalities, all of them had co-existing cardiovascular risk factors (66). CSF studies should be considered to exclude a derangement in intracranial pressure, infection, or disseminated neoplasm if clinic- ally warranted. Systemic infection and in ammation should also be carefully ruled out.

treatment of new daily persistent headache

NDPH is o en treated with various abortive (i.e. non-steroid anti- in ammatory drugs, acetaminophen, or triptans) and preventative medications (i.e. tricyclic antidepressants, beta blockers, unarizine, serotonin–norepinephrine reuptake inhibitors, certain antiepileptic drugs (including valproic acid), topiramate, etc.) commonly used in migraine or TTH. However, there have been no double-blind ran- domized controlled trials to evaluate their e cacy. In one Japanese report, all patients (n = 30) were treated with muscle relaxants and 28 of them also received other medication concomitantly. Only eight of 30 responded to the muscle relaxants-based therapy (7). In one US series (n = 71), NDPH with TTH features were more likely to have pain reduction a er greater occipital, lesser occipital, auriculotemporal, supraorbital, or supratrochlear nerve blocks, but this did not reach statistical signi cance (9). A Taiwanese series (n = 92) reported that patients with early treatment (3–6 months a er NDPH onset) were more likely to have a better response at follow-up; however, no single medication seemed superior (10). In smaller series, responses to haloperidol (67), dihydroergotamine (68), and greater occipital nerve block were reported (69). In an- other report, nine patients with recent extracranial infection several weeks prior to the onset of NDPH-like headaches were treated with intravenous methylprednisolone pulse therapy (1 g daily for 5 days). All of the nine patients had nearly complete improvement by week 8 (70). However, only four of nine had a disease duration of more than 3 months and met the current criteria for NDPH (11). In the paediatric population, the more commonly prescribed medications were amitriptyline, topiramate, valproic acid, and gabapentin, but the responses were variable (17).

In general, NDPH is treated similarly to CM and CTTH, and the acute and prophylactic treatments of those disorders are ex- trapolated for use in NDPH according to the headache phenotype

(migrainous or tension-type). Although there is no consensus for optimal therapy, NDPH is commonly associated with medication overuse headache (MOH) in adult patients (34.8–75%) (9,10,14,19) and less commonly in paediatric patients (8.7%) (8). It is reasonable to treat NDPH associated with MOH with withdrawal therapy, ei- ther abrupt discontinuation or tapered withdrawal (71). Of note, the diagnosis of NDPH must be established before a subsequent diag- nosis of MOH.

Prognosis of new daily persistent headache

NDPH is generally considered very di cult to treat and the head- ache usually persists despite various therapeutic interventions. ere might be at least two subtypes of NDPH considering the disease courses: one type that remits within a certain period, usu- ally within 24 months, with or without further relapse (remitting NDPH); the other type lasts for years and is rather resistant to ther- apies (persistent NDPH). In the initial report by Vanast (1), presum- ably, most of the patients fell into the remitting NDPH category, as 86% of the male patients and 73% of the female patients became headache-free by 24 months. In the Japanese report, eight of 30 pa- tients had very good responses to treatment, including two patients who became headache-free. However, the remaining six responders still had daily headache, despite some improvement in the quality of life. us, 28 of 30 still had severe or daily headache (7). In the American series (n = 71), 54 (76.1%) had persistent headache, 11 (15.5%) had remission in a median duration of 21 months, and six (8.5%) had relapsing–remitting NDPH (9). In the Taiwanese series, among those successfully followed patients (n = 87), 57 (66%) had a good outcome (>50% reduction in frequency) including 23 (26.4%) headache-free a er an average of 2 years of follow-up. Of note, in this study, 56 (60.9%) had a headache duration between 3 and 6 months before the rst clinical visit, and these patients were more likely (hazard ratio 2.71) to be headache-free than those with a disease duration > 6 months (10). In an Indian study (n = 63), two-thirds of the patients had at least > 50% reduction in headache frequency (23). Another US study followed 28 of 51 paediatric patients with NDPH and 20 of these still had headache, but only eight had chronic daily headache (18). Owing to the discrepancy in the enrolment cri- teria among studies, interstudy comparisons are di cult. However, the headache remission in certain patients, including those with shorter disease durations, may re ect the fact that NDPH is a het- erogeneous syndrome of di erent aetiologies. For example, patients with secondary NDPH to infection might get better a er the infec- tion is successfully treated. Moreover, certain patients with ‘primary NDPH’ may indeed reach remission within a certain period, but, to date, there is no good predictor for the remitting NDPH subtype.

Conclusion

NDPH is a heterogeneous syndrome with di erent aetiologies. e update in the diagnostic criteria set forth in ICHD-3 re ects the di- verse clinical symptomatology and that migraine features should also be incorporated. Still, in order to make a diagnosis, the phys- ician must scrutinize each case for any possible alternative diagnoses before making the diagnosis of NDPH. e current treatment of

NDPH is not satisfactory. More studies are needed to provide better understanding and hopefully better treatment in the future.

CHaPtEr 30 New daily persistent headache

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Chronic migraine and medication overuse headache
David W. Dodick and Stephen D. Silberstein

Introduction

Chronic migraine (CM) is a subtype of migraine characterized by headache that occurs on ≥ 15 days per month for ≥ 3 months. e estimated global prevalence of CM varies from 1% to 3%, depending on the population, ethnicity, case de nition, and case ascertainment methodology (1–7). Persons with CM experience signi cantly more functional impairment and reduced quality of life compared with those with episodic migraine (EM) (6–8).

e case de nition for CM has evolved over the past three dec- ades. e observation that headache frequency can increase over time in some individuals with migraine is centuries old. However, in 1987, Mathew introduced the term transformed migraine (TM) to characterize a group of patients with migraine whose headache frequency and character gradually increased, or transformed, over time in a pattern or daily or near-daily headache (9). Among this group, most had migraine without aura and the majority overused acute headache medications. e discontinuation of the overused medication(s) o en resulted in clinical improvement. Saper et al. (10) made similar observations, noting that the vast majority of pa- tients in clinical practice with chronic headache (> 15 days/month) had a history of EM, overused acute medication, and improved and cessation of overuse.

Silberstein and Lipton, and colleagues (11), developed operational diagnostic criteria for TM that required a history of International Classi cation of Headache Disorders (ICHD)-1-de ned migraine, headache on at least 15 days per month lasting > 4 hours per day on average, a history of transformation, and subtypes based on the presence or absence of acute medication overuse (Box 31.1). ese criteria were revised in 1996 to include either a history of escalation over 3 months, a history of EM, or a headache at some time that meets ICHD criteria for migraine other than duration, as a remote history of transformation could not be recalled by up to 40% of pa- tients (Box 31.2) (11). No causal role of acute medication overuse was assigned and a hierarchical diagnostic rule was established to avoid a concurrent diagnosis of chronic tension-type headache (TTH) for those who met TM criteria. Prior to the development of operational diagnostic criteria by the ICHD, these criteria had been

used in clinic- and population-based studies, as well as in clinical trials around the world (12–14).

CM was added as a complication of migraine for the rst time in the ICHD-2 in 2004 (Table 31.1) (15). However, when acute medi- cation overuse was present, the diagnosis of CM could not be ap- plied concurrently. Instead, individuals could receive diagnoses of the preceding migraine subtype, probable CM, and probable medi- cation overuse headache (MOH). A diagnosis of CM would only be applied if the criteria for CM were still met 2 months a er the dis- continuation of overuse. Not only were these criteria cumbersome to apply in clinical practice, but they did not allow for the existence of MOH in the absence of chronic headache (i.e. headache < 15 days per month but overuse of medication). Moreover, the results of eld studies of ICHD-2 CM criteria revealed that the majority of indi- viduals who meet TM criteria do not meet CM criteria, and patients meeting the ICHD-2 diagnostic criteria for CM are rare in clinical practice (16,17).

Based on these shortcomings, the Classi cation Committee of the International Headache Society published a revised version of the criteria for CM in 2006 (Table 31.1) (18). e ICHD-2R criteria re- quired that patients have > 15 headache days per month for at least 3 months, with ≥ 8 migraine days (or ≥ 8 days on which headaches were treated and relieved by a triptan or an ergot). e ICHD-2R cri- teria have been eld-tested and validated in clinical practice (17,19). e ICHD-2R criteria have also been validated on the basis of data obtained through the pivotal phase III studies of onabotulinum toxin A for the treatment of CM (20–22). e ICHD-2R criteria were therefore included in the third edition of the ICHD (ICHD-3 Beta (ICHD-3B)) (23). ICHD-3B no longer considered CM a complica- tion of migraine, allows both migraine with and without aura, ex- cludes the diagnosis of TTH, and allows the concurrent diagnosis of CM and MOH (‘1.3 Chronic migraine’ and ‘8.2 Medication overuse headache’) (Table 31.1). ICHD-3B enabled a period of time for eld- testing and incorporation into the World Health Organization’s 11th edition of the International Classi cation of Diseases (ICD-11) prior to the nal published version of ICHD-3 in 2018 (see also Chapter 1).

Despite the advance, ICHD-3B criteria remained challenging to implement in clinical practice (24). e ability to recall the response

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Box 31.1 Original proposed criteria for transformed migraine

1.8 Transformed migraine (TM)

. A History of episodic migraine meeting any IHS criteria 1.1–1.6.

. B Dailyoralmostdaily(>15days/month)headpainfor>1month.

. C Average headache duration of 4 hours/day (if untreated).

. D History of increasing headache frequency with decreasing se-
verity of migrainous features over at least 3 months.

. E At least one of the following:

. 1 There is no suggestion of one of the disorders listed in groups 5–11

. 2 Such a disorder is suggested, but it is ruled out by appro- priate investigations

. 3 Such disorder is present, but rst migraine attacks do not occur in close temporal relation to the disorder.

. 1.8.1 Transformed migraine with medication overuse.

. 1.8.2 Transformed migraine without medication overuse.

IHS, International Headache Society.

Reproduced with permission from Silberstein SD et al. Classi cation of daily and near-daily headaches: eld trial of revised IHS criteria. Neurology 1996;47(4):871–5.

to migraine-speci c medication is o en not possible. is criterion also assumes that response to ‘migraine-speci c’ medication implies the attack is a migraine, but other primary headache disorders and even secondary headaches may respond to triptans. Furthermore, the term ‘relieved’ by triptan or ergot is not operationally de ned. is approach also makes diagnosis more di cult in those patients for whom triptans and ergots are contraindicated or not available. Furthermore, an accurate diagnosis would require very detailed headache diaries with all pain and associated symptoms recorded, rarely available at the time of an initial evaluation. Silberstein, Lipton, and Dodick have recommended, based on the evidence available and

extensive eld-testing already performed, that the ICHD-3B criteria for CM be modi ed by removing the criterion that speci es that CM must occur in a patient with at least ve prior migraine attacks, adding probable migraine to C1 and C2, removing the criterion (C3) that treatment and relief of headache by a triptan or ergot, adding the criterion that the headache does not meet criteria for new daily persistent headache or hemicrania continua, and de ning subtypes based on the continuous or remitting nature of the pain (Box 31.3) (24). ese revisions to the ICHD-3 criteria for CM (see Chapter 1) will facilitate large-scale international epidemiological, genetic, and treatment studies on each subtype, while maintaining the clinical and biological homogeneity of this patient population.

In addition to the overuse of acute headache medications, there are several other modi able risk factors that are associated with pro- gression from EM to CM, including high baseline attack frequency (one per week), ca eine consumption, snoring, female sex, obesity, and the inadequate acute treatment of migraine attacks (25–29). Female sex, allodynia, asthmatic bronchitis, head injury, low socio- economic status, depression, anxiety, and comorbid pain disorders are also risk factors for CM. e recognition and modi cation of these risk factors is important in clinical practice. Compared to EM, individuals with CM experience substantially reduced health- related quality of life and signi cantly higher impact on daily ac- tivities, direct medical costs, and rates of medical comorbidities (6–8,30). CM is also associated with greater rates of healthcare re- source utilization, including more frequent visits to primary care physicians, specialists, and emergency departments. Individuals with CM are also more frequently hospitalized and undergo more diagnostic tests.

Despite the availability of evidence-based guidelines intended to inform clinical decision-making and the care of patients with mi- graine, the management of migraineat a population level remains suboptimal. Obstacles to optimal migraine management include female sex, lack of health insurance, failure to present for medical attention, failure to receive an accurate diagnosis, and failure to re- ceive a minimally appropriate treatment regimen. Among those with CM, only 41% currently consult a healthcare provider and only 25% receive an accurate diagnosis (31). Even among those who receive an accurate diagnosis, over half are not prescribed an acute and pre- ventive treatment. e use of screening tools such as the Identify (ID)-Migraine and ID-Chronic Migraine (ID-CM) (32,33), and the implementation of evidence-based guidelines for the acute and pre- ventive treatment of migraine, should enhance the likelihood of pa- tients receiving an accurate diagnosis and optimal treatment (34–41).

Medication overuse headache

MOH is a prevalent condition. Epidemiological studies have dem- onstrated that 1–2% of the general population is a ected (42–45). However, as a causal mechanism is seldom obvious and the diagnosis is made simply on the basis of the arbitrary number of days an acute medication is used over the course of 3 months, the true prevalence remains unknown. In other words, medication overuse in epidemio- logical studies is a surrogate for a diagnosis of MOH. In addition, most studies reporting CM prevalence did not speci cally address whether MOH or medication overuse was also present. Natoli et al. (1) found that among adults with CM, the prevalence of medication

Box 31.2 Silberstein–Lipton (revised) criteria for chronic migraine

1.8 Chronicmigraine

. A Daily or almost daily (> 15 days/month) head pain for > 1 month.

. B Average headache duration of > 4 hours/day (if untreated).

. C At least one of the following:

. 1 History of episodic migraine meeting any IHS criteria 1.1–1.6

. 2 History of increasing headache frequency with decreasing
severity of migrainous features over at least 3 months

. 3 Headache at some time meets IHS criteria for migraine 1.1 to
1.6 other than duration.

. D Does not meet criteria for new daily persistent headache (4.7)
or hemicrania continua (4.8).

. E At least one of the following:

. 1 There is no suggestion of one of the disorders listed in groups 5–11

. 2 Such a disorder is suggested, but it is ruled out by appro- priate investigations

. 3 Such a disorder is present, but rst migraine attacks do not occur in close temporal relation to the disorder.

IHS, International Headache Society.

Reproduced from Neurology, 47, 4, Silberstein SD., Lipton RB, and Sliwinski M, Classi cation of daily and near-daily headaches: eld trial of revised IHS criteria, pp. 871–5. Copyright (1996) with permission from Wolters Kluwer Health.

CHaPtEr 31 Chronic migraine and medication overuse headache table 31.1 Diagnostic criteria for transformed migraine (TM) according to Silberstein–Lipton criteria and for chronic migraine (CM)

according to ICHD-2R and ICHD-3B (see also Chapter 1)

Silberstein-Lipton TM

ICHD-2R CM

ICHD-3 B

. A Daily or almost daily (> 15 days a month) head pain for > 1 month

. B Average headache duration of > 4 hours (if untreated)

. C At least one of the following:

. 1 History of episodic migraine meeting any
IHS criterion 1.1–1.6

. 2 History of increasing headache frequency
with decreasing severity of migrainous
features over at least 3 months

. 3 Headache at some time meets IHS criteria
for migraine 1.1–1.6 other than duration

. D Does not meet criteria for new daily persistent
headache (4.7) or hemicrania continua (4.8)

. A Headache on ≥ 15 days/month for 3 months

. B Occurring in a patient who has had at least
ve attacks ful lling criteria for ‘1.1 Migraine
without aura’

. C On ≥ 8 days per month, for at least 3 months,
headache ful ls criteria for migraine C1 and/or C2 below, that is, has ful lled criteria for pain and associated symptoms of migraine without aura
1 Criteria C and D for ‘1.1 Migraine without aura’ 2 Treated or relieved with triptans or ergotamine before the expected development of C1 above

. D No medication overuse and not attributable to other causative disorder

. A Headache on ≥ 15 days per month for at least 3 months

. B Occurring in a patient who has had at least ve attacks ful lling criteria for ‘1.1 Migraine without aura’ and/or ‘1.2 migraine with aura’

. C On ≥ 8 days per month for at least 3 months one or more of the following criteria were ful lled

. 1 Criteria C and D for ‘1.1 Migraine
without aura’

. 2 Criteria B and C for ‘1.2 Migraine with
aura’

. 3 Headache considered by patient to be
onset migraine and relieved by a triptan or
an ergotamine derivative

. D Not better accounted for by another ICHD-3
diagnosis

ICHD, International Classi cation of Headache Disorders; IHS, International Headache Society.

Source data from: Neurology, 47, 4, Silberstein SD., Lipton RB, and Sliwinski M, Classi cation of daily and near-daily headaches: eld trial of revised IHS criteria, pp. 871–5, 1996; Cephalalgia, 26, 6, Headache Classi cation Committee, Olesen J, Bousser MG et al., New appendix criteria open for a broader concept of chronic migraine, pp. 742–6, 2006; Cephalalgia, 33(9), The International Classi cation of Headache Disorders, 3rd edition (beta version), pp. 629–808. doi: 10.1177/0333102413485658. International Headache Society 2013.

overuse was 31–69%. In clinical populations, the prevalence also varies widely depending on the population. In European headache centres, 4–10% of patients have MOH, while in US specialty head- ache clinics, as many as 80% of patients who present with chronic headache use analgesics on a daily or near-daily basis (46–48).

e overuse of acute headache and pain medications is common among individuals with migraine who experience frequent attacks and poses a unique treatment challenge for clinicians. e threshold number of days that de nes medication overuse depends on the medication (> 10 days per month for opioids, butalbital-containing medications, triptans, ergots, combination analgesics; > 15 days for simple analgesics such as non-steroidal anti-in ammatory drugs (NSAIDs)) (Box 31.4). e greatest risk of progressing from EM to CM is associated with opioids (odds ratio (OR) 1.4) and butalbital- containing medications (OR 1.7), and can occur with as few as ve dosages per month (8,25). Individuals with CM and medica- tion overuse have even poorer quality of life, greater disability, and greater losses in productivity than people who have CM without medication overuse (8).

Diagnostic criteria for MOH were introduced in 2004 (15). However, the rst ICHD-2 classi cation of MOH stated that a diag- nosis of headache attributed to a substance becomes de nite only when the headache resolves or greatly improves a er the substance is discontinued for a period of 2 months. If improvement did not then occur within the 2-month period, the MOH diagnosis was dis- carded. erefore, MOH could only be diagnosed a er it resolved. Moreover, it excluded the possibility that medication-induced head- ache may not resolve even a er discontinuation. is criterion was therefore eliminated in ICHD-2R and, as noted earlier, a concur- rent diagnosis of MOH and CM could be assigned according to ICHD-3B.

MOH is currently de ned as headache occurring on ≥ 15 days per month together with the regular overuse, over a period of 3 months, of acute headache medication on ≥ 10, or ≥ 15 days per month, depending on the medication (23). e clinical features of CM and MOH appear to be very similar. In the Phase 3 REsearch Evaluating Migraine Prophylaxis erapy (PREEMPT) studies, patients kept daily diaries for almost 1 year. In this sample, patients with CM with or without overuse had a disease duration of approximately 20 years and an average of 20 headache days per month (21). While the previous literature suggested that most headache days assume the phenotype of TTH as migraine becomes more chronic or becomes associated with medication overuse, the PREEMPT studies demon- strated that the majority (n = 19/20) of the days with headache met the diagnostic criteria for migraine or probable migraine.

Box 31.3 ICHD-3 revised chronic migraine criteria

. A Headache (migraine- like or tension- type- like) on ≥15 days/ month for >3 months, and ful lling criteria B and C.

. B Occurring in a patient who has had at least ve attacks ful lling cri- teria B-D for 1.1 Migraine without aura and/ or criteria B and C for 1.2 Migraine with aura.

. C On ≥8 days/ month for >3 months, ful lling any of the following:
1 Criteria C and D for 1.1 Migraine without aura.
2 Criteria B and C for 1.2 Migraine with aura.
3 Believed by the patient to be migraine at onset and relieved by a
triptan or ergot derivative.

. D Not better accounted for by another ICHD- 3 diagnosis.

(See also Box 1.2).

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Box 31.4 ICDH-3 criteria for medication overuse headache

. A Headache occurring on ≥ 15 days/month in a patient with a pre- existing headache disorder.

. B Regular overuse for > 3 months of one or more drugs that can be taken for acute and/or symptomatic treatment of headache.

C Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1-211. © International Headache Society 2018.

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Pathophysiology of chronic migraine and medication overuse headache

e pathophysiology of CM is not completely understood. Central sensitization of trigeminal sensory pain pathways is thought to play a major role in the development of CM (49,50). Cutaneous allodynia, the clinical manifestation of central sensitization, is present in most individuals during migraine attacks and between attacks in those with frequent migraine (49,51–53). Cutaneous allodynia has been shown to be a risk factor for migraine progression in population- based studies (49,51–53). Severity of allodynia has been shown to be greater in individuals with CM than in those with EM (54). In addition, higher rates of persistent allodynia between attacks have been demonstrated in those with CM (with or without acute medi- cation overuse) versus EM, indicating the possibility of a progres- sive lowering of pain thresholds as a contributing factor in those with CM (55). Lower pain thresholds in patients with CM (56) and atypical cortical processing of cutaneous nociceptive input (57,58), support the hypothesis of disrupted central pain mechanisms as a pathophysiological process involved in the development of CM. In addition to functional changes in cortical sensory processing in patients with CM, imaging evidence of structural brain changes, including cortical thinning and regional brain volumes, has also been correlated with changes in pain thresholds and shown to dis- tinguish CM from EM (53,59).

Central sensitization might occur during repeated migraine attacks through impaired descending inhibition and/or enhanced descending facilitation of nociception. Functional imaging studies have demonstrated abnormal brainstem activation in EM and CM, suggesting that dysfunction of descending inhibitory pathways might facilitate migraine attacks. Functional imaging studies have also demonstrated interictal hypofunction of lateral descending pain modulatory circuits in patients with migraine (60). e role of descending pain modulatory circuits in CM was reinforced by a recent study (61), which demonstrated increased hypothalamic ac- tivation in response to painful trigeminal stimulation in CM com- pared to patients with EM and non-headache controls. In addition, the anterior hypothalamus was found to be associated with the ini- tiation of attacks in CM, while the posterior hypothalamus appears to be linked to the acute painful phase of the individual attack. e anterior hypothalamus has also been shown to be involved in the premonitory phase of migraine attacks and has long been implicated in the pathogenesis of migraine and other primary headache dis- orders. e hypothalamus is a part of the descending pain modu- lating network (62), and the increased activation patterns observed in CM may indicate a reduced threshold for the initiation of attacks in CM, which, in combination with other risk factors as described earlier, might lead to an enhanced susceptibility to frequent attacks.

Electrophysiological studies have also demonstrated functional changes that characterize the brain of those with CM versus EM. Persistent enhanced cortical excitability, exceeding that in patients with EM or in migraine-free controls, has also been demonstrated in individuals with CM (63–67). ese ndings suggest central in- hibitory dysfunction, increased cortical hyperexcitability, or both, in the development of CM.

Overuse of acute headache medications is a major risk factor for the development of CM, and recent studies have suggested potential

underlying mechanisms. Animal models have revealed persistent pronociceptive adaptations following exposure to opioids and triptans, resulting in enhanced sensitivity to stimuli that trigger mi- graine in humans (68,69). In this model, the sustained or repeated administration of triptans to rats elicited cutaneous tactile allodynia and increased labelling for calcitonin gene-related peptide (CGRP) in trigeminal dural a erents that persisted long a er discontinu- ation of triptan exposure. Even weeks a er drug exposure and sen- sory thresholds returned to baseline, enhanced cutaneous allodynia and increased blood levels of CGRP occurred a er challenge with a typical migraine trigger—nitric oxide. In a separate set of experi- ments using a similar animal model, prolonged sumatriptan ex- posure signi cantly decreased electrical stimulation threshold to generate cortical spreading depression (CSD) (70). In addition, CSD and environmental stress increased expression of early gene prod- ucts (c-Fos) in the trigeminal nucleus caudalis, and these e ects were blocked by topiramate. ese experiments demonstrated that overuse of acute headache pain medications induces neural adap- tations that result in a state of latent sensitization, and lower CSD threshold, both of which lead to increased trigeminal activation, and may represent potential biological mechanisms of CM related to overuse of acute headache medications.

treatment

e management of CM, especially when associated with medica- tion overuse, can be challenging (see also Chapter 32). ere is de- bate concerning whether patients should undergo discontinuation of the overused medication alone or with the addition of preventive treatment, or, whether withdrawal is necessary if preventive medi- cation is started. e European Federation of Neurological Sciences guideline recommends the abrupt discontinuation or taper of the overused medication and that preventive drug treatment be started before or simultaneously with discontinuation (46). However, to avoid exposure to other medications and the potential risk, some recommend discontinuation of overused medications and careful follow-up in 2–3 months to determine the need for preventive medication (71).

A recent systematic review evaluated the evidence to support dis- continuation alone, discontinuation plus preventive therapy, or pre- ventive therapy without discontinuation (72). Unfortunately, early discontinuation alone studies usually allowed preventive treatment before or a er discontinuation. For example, in one study involving 337 patients with probable MOH who underwent discontinuation of overused medications, a signi cant (46%; P < 0.0001) decrease in headache frequency occurred. However, only 64% of the patients completed the 2-month study and of those who did complete the study, 45% improved, 48% had no changes, and 7% experienced an increase in headache frequency (73). Patients with migraine had a signi cantly larger reduction in headache frequency than patients with TTH (67% and 0%; P < 0.001) or patients with both migraine and TTH (37%; P < 0.01). Triptan or ergot overusers improved the most (P < 0.0001). Two other prospective studies evaluated the e ect of intensive advice to discontinue the overused medication (74,75). Antiemetics and simple analgesics were allowed for rescue therapy, but preventive medication was not allowed. Both studies showed high discontinuation rates (79% and 76%, respectively), as well as

signi cant reductions (60–70%) in headache days and days with acute medication use. However, in one study the e ect was more prominent in patients with simple MOH than in those with com- plicated MOH (patients with medical or psychiatric comorbidity, psychosocial problems, and history of relapse). e discontinuation rate was 92.1% of 51 patients with simple MOH and 65.3% of 49 pa- tients with complicated MOH (P < 0.01).

Studies that combined discontinuation with the addition of pre- ventive medication also vary widely with regard to study setting (in- patient vs outpatient), the rescue medications allowed, and the type of preventive medications used. However, several studies report sig- ni cant improvements in quality of life and reductions from baseline in headache days, acute medication consumption, headache-related disability, and depression and anxiety within 1 year a er discon- tinuation combined with preventive medication (76). A recent international study involving headache centres from Europe and Latin America (COMOESTAS project (Continuous Monitoring of Medication Overuse Headache in Europe and Latin America: de- velopment and STAndardization of an Alert and decision support System)) established a protocol for the management of MOH (77). Patients were included for either inpatient or outpatient early dis- continuation. Preventive treatment was started simultaneous with discontinuation and the selection of therapy was made on the basis of the primary headache and comorbid conditions that were pre- sent. At the end of the study period, approximately two-thirds of the enrolled patients (n = 376) were no longer overusing acute medica- tions, nearly half had remitted to an episodic pattern of headache, and there was a notable reduction in disability and in the number of patients with depression and anxiety (78). e limitations of the COMOESTAS project were the exclusion of patients who had failed attempts at discontinuation in the past, who were using preventive medications, or who had signi cant psychiatric illness.

ere are several trials that suggest that the use of preventive medi- cation without withdrawal of overused medication(s) may be an ef- fective strategy. Hagen et al. (79) randomized 56 patients to receive preventive treatment without withdrawal, a standard outpatient withdrawal programme without preventive treatment, or no speci c treatment (79). e change in monthly headache days did not di er signi cantly between groups. However, the group started on pre- vention without withdrawal had the highest decrease in headache days compared with baseline, and a signi cantly greater reduction in total headache index ((headache days/month × headache inten- sity × headache hours)) at 3 (P = 0.003) and 12 (P = 0.017) months compared with the group who underwent withdrawal without pre- vention. A er 1 year, 53% of patients in the prevention group were responders (> 50% decrease in monthly headache days) versus 25% in the withdrawal group (P = 0.081). e responder rate was also signi cantly higher for the prevention group than controls (41% vs 5%; P < 0.01). is is the rst randomized study, despite the small sample size, that evaluated the e cacy of early introduction of pre- ventive medication compared with abrupt discontinuation therapy and a control group. is strategy was an e ective method to reduce headache days and headache burden and the improvement was sus- tained a er 4 years of follow-up (80).

Onabotulinum toxin A was also evaluated as a preventive treatment for CM in patients with and without medication overuse. In two phase III, 24-week, double-blind, parallel-group, placebo-controlled studies involving 66 global sites, 1384 patients

received either onabotulinum toxin A (155–195 units) or placebo. Medication overuse was present in 65.3% (n = 904) of the partici- pants (21,22,81). In the CM with medication overuse subgroup, a planned secondary analysis revealed a signi cant reduction in the group receiving onabotulinum toxin A for the primary end point of headache days (8.2 vs 6.2; P < 0.001). Signi cant reductions were also demonstrated in migraine days (P < 0.001), moderate/severe headache days (P < 0.001), cumulative headache hours on headache days (P < 0.001), headache episodes (P = 0.028), migraine episodes (P = 0.018), and the percentage of patients with severe headache- related disability (P < 0.001). However, while there was an overall re- duction in consumption of acute medications in both groups, there was no signi cant di erence between the groups. is indicated that the di erence between the treatment groups could not be accounted for by the reduction or discontinuation in acute medication con- sumption. e limitations of this study was that it was not a pure MOH population and the analysis was secondary and in a subgroup.

e e cacy of onabotulinum toxin A 100 units as a preventive treatment plus discontinuation of medication overuse was evaluated in a placebo-controlled study involving 68 patients (82). ere was no di erence in the reduction of headache days or headache-related disability between the two groups, but there was a signi cant reduc- tion in the acute medication consumption at 12 weeks in the active treatment group (secondary analysis). is study supports the use of onabotulinum toxin A along with early discontinuation in CM with medication overuse. e smaller sample size, lower dosage, shorter follow-up period, fewer injections, and fewer injection sites in this study may account for the di erences compared to the PREEMPT studies.

Diener et al. (83,84) reviewed the results from two similarly de- signed, randomized, placebo-controlled, multicentre studies of CM that were conducted in the USA and the European Union (EU) of the e cacy and safety of topiramate for the treatment of CM in patient populations both with and without medication overuse. Topiramate was e ective for the treatment of patients with CM. e intention- to-treat (ITT) population in the US study consisted of 306 partici- pants (topiramate, n = 153; placebo, n = 153); the ITT population in the EU study consisted of 59 participants (topiramate, n = 32; pla- cebo, n = 27) (80). A post-hoc analysis in the subset of patients with medication overuse in the US trial trended towards signi cance but did not reach a statistical di erence between topiramate and pla- cebo in the reduction in migraine/migrainous days (P = 0.059). In the EU trial, topiramate-treated patients with medication overuse experienced a signi cant reduction in the mean number of migraine days versus placebo treatment (P = 0.03). ere were several key di erences between the patient populations. In the US trial, 115 of 306 (37.6%) patients versus 46 of 59 (78.0%) patients in the EU trial reported using acute medications for migraine that met the de n- itions of medication overuse during the 28-day prospective base- line period. In the US, the most commonly overused medications were triptans and analgesics; 40% of patients overused NSAIDs and 6% overused opioids. In the EU trial, the vast majority of overused medications were triptans. Butalbital-containing analgesics were al- lowed in the US trial, but no butalbital-containing analgesics were available or prescribed in the EU trial.

e e cacy of nabilone, a synthetic cannabinoid CB1 receptor agonist, was evaluated in a 30-patient, randomized, double-blind, active-controlled (ibuprofen 400 mg), crossover study for the

CHaPtEr 31 Chronic migraine and medication overuse headache

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treatment of MOH (85). Nabilone 0.5 mg daily signi cantly reduced daily acute medication consumption and headache intensity at 20 weeks compared with ibuprofen. In a comparator study of preven- tion without discontinuation, both pregabalin 150 mg daily and topiramate 100 mg daily signi cantly improved disability while decreasing monthly headache frequency and days of acute medica- tion use (86). ere were no signi cant between-group di erences between the two drugs in this 16-week study.

Non-pharmacological treatment

Occipital nerve stimulation (ONS) has been evaluated for the treat- ment of CM with and without medication overuse. In a study of 34 patients with CM, of whom 85% had medication overuse, ONS was reported to signi cantly decrease headache frequency, intensity, and NSAID use from baseline a er acute medications were discontinued 2 months previously (87). In another ONS study, patients with medi- cation overuse had signi cantly less pain relief than those without medication overuse (mean 28% vs 78%; P = 0.0498) (88).

In a study designed to investigate the e cacy of acupuncture compared with topiramate treatment for the prevention of CM, 66 patients were randomly assigned to acupuncture administered in 24 sessions over 12 weeks or topiramate 100 mg daily (89). A sig- ni cantly larger decrease in the mean monthly number of mod- erate/severe headache days (primary end point) was observed in the acupuncture group compared the topiramate group (P < 0.01) Signi cant di erences favouring acupuncture were also observed for all secondary e cacy variables. Similar results were seen in the group with medication overuse. Adverse events occurred in 6% of the acupuncture group and 66% of the topiramate group

Emerging therapy

e important role of CGRP in the pathogenesis of EM and CM has led to the development of evaluation of monoclonal antibodies (mAbs) targeting GCRP and its receptor. ree mAbs targeting CGRP (fremanezumab, eptinezumab, galcanezumab) or its receptor (erenumab) have now been shown in phase II trials to be well toler- ated and e ective in the prevention of EM and CM (fremanezumab, erenumab) (90–95). Erenumab, galcanezumab, and fremanezumab have also recently reported positive results in phase III placebo- controlled trials in EM and CM, but these results await nal pub- lication. us far, the side e ect pro le appears very limited and there are as yet no serious safety concerns that have arisen in prelim- inary and pivotal trials. However, their safety in situations when the blood–brain barrier is compromised or on a developing fetus is still uncertain and long-term extension studies and postmarketing data will be needed to determine their overall safety pro le.

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Frequent headaches with and without acute medication overuse
Management and international differences
Christina Sun-Edelstein and Alan M. Rapoport

Introduction

In headache parlance, frequent headaches are those that occur on at least 15 days per month, for more than 3 months, and are grouped under the umbrella term ‘chronic daily headache’ (CDH). Although this is not an o cial International Headache Society (IHS) term, it was used for many years and it clearly suggests the types of head- ache that go on for years and occur on most days of the month. ese include the following headaches from various sections of the International Classi cation of Headache Disorders (ICHD)-3 classi- cation (1): chronic migraine (CM); chronic tension-type headache (CTTH); hemicrania continua (HC); new daily persistent headache (NDPH); chronic cluster headache (CCH); nummular headache; and medication-overuse headache (MOH) (see also Chapter 31). For migraine and tension-type headache, the word chronic denotes 15 or more headaches per month, not how long it is has lasted. For secondary headaches, chronic refers to duration, usually denoting more than 3 months.

CDH is a signi cant problem worldwide. In a study performed as part of the initiative, ‘Li ing the Burden: the Global Campaign to Reduce the Burden of Headache Worldwide’, the global preva- lence of CDH was found to be 3.4%. Although the data on CDH, as compared to migraine or tension-type headache (TTH), is relatively sparse, CDH seems to be most common in Central/South America (5%) and least common in Africa (1.7%) (2).

A summary of the approaches to CM, MOH, and CCH treatment is presented in this chapter, with an emphasis on international dif- ferences noted in the medical literature. In addition, we have asked a number of prominent headache specialists around the world to discuss their own management strategies for these disorders. eir comments are presented in the Appendices 32.1–32.3.

HC, now included in the trigeminal autonomic cephalgias (TAC) section of the ICHD-3 (1), is not discussed in detail as indomethacin is considered the standard of treatment. Likewise, CTTH is widely treated with non-steroidal anti-in ammatory drugs (NSAIDs) for acute treatment and with tricyclic antidepressants for preventive

treatment (3–5), and NDPH is generally treated empirically as there have been no randomized, placebo-controlled trials of acute or pre- ventive medications. ese headache disorders are reviewed else- where in this textbook.

Differences in healthcare systems

When evaluating international di erences in headache treatment, a major consideration is the di erences in healthcare systems between countries. e cost of care and the major cost drivers vary widely, thus a ecting the di erences in available headache therapies, de- livery of care, access to medications and specialist consultations, and cost of services (6). e following is a snapshot of several healthcare systems around the world, and how those systems a ect the delivery of headache care.

In Germany, a government-created reimbursement system for ‘integrated care’ of chronic diseases exists (7), which involves a multidisciplinary approach and care across the sectors of the healthcare system, integrating specialist clinics at large hospitals and physicians in private practice. is has allowed for the cre- ation of integrated headache centres sta ed by neurologists, be- havioural psychologists, physical and sports therapists, headache nurses, and consultants from psychosomatic medicine, psychiatry, and dentistry. In addition, the databases of insurance companies can be accessed, such that patients with chronic headache, medica- tion overuse, or risk factors for the development of chronic head- aches can be identi ed and invited for evaluation at the headache centre without a referral or co-payment. Another important aspect of this system is the higher reimbursement rates for these headache centres and participating private neurologists. In addition to im- proved patient outcomes, integrated headache care is cost-e ective, with an average yearly cost savings of 30%, attributed to decreased

Considerations in international comparisons of headache treatment

diagnostic testing, as well as reduced hospital admissions and visits to emergency departments (7).

In contrast to the European model of integrated headache care, which also encompasses collaboration between the government, insurance companies, and headache centres, headache care in the USA is ‘fragmented’ and somewhat dysfunctional (7). Patients are at the mercy of their private physician’s interest in and know- ledge of headache for their care, and many insurance systems discourage referrals to neurologists and to the limited number of available headache specialists. If a patient has no insurance or an inadequate policy, headache care can be di cult to access and inadequate. ere are very few academic headache centres, most of which su er from nancial di culties. Headache education in medical school and neurology training is limited, and headache sections are rare in academic neurology departments. Of these headache centres, very few have an inpatient programme for com- plicated patients. Furthermore, unlike in European countries such as Germany and Denmark, there is no increased reimbursement or compensation for complicated patients, and no funding for multidisciplinary care.

In Brazil, headache treatment by specialists is o ered in either of two ways. One is delivered by public services from public hospitals and is directed towards non-paying patients. e other is through private centres and centres of excellence, which are usually situated in the very few high-standard university hospitals (not available in Rio de Janeiro) and are directed to paying patients. e public system delivers a traditional, non-comprehensive approach, in which monotherapy is usually prescribed. e private centres o er a multidisciplinary approach and frequently use a combination of drugs and the latest techniques.

In some of the best headache centres in Brazil, patients are o en evaluated in long-duration initial consultations and undergo psy- chological screening. Most have refractory or intractable headaches and/or present with various comorbidities. ey have seen multiple previous physicians and have not usually had adequate care for their level of headache or other medical issues.

Canada comprises 10 provinces and three territories, each of which has a separate healthcare system with di erent aspects covered by each plan. In addition, there are private plans that sup- plement the costs of medications and certain forms of treatment. However, the training of doctors is fairly standard in each province, so the level of expertise should be fairly consistent. Doctor fees and the cost of laboratory testing and radiology are covered by Provincial Health plans. While most headache care in Canada is based on in- dividual physician–patient encounters, there are a number of head- ache clinics, such as the one in Women’s College Hospital in Toronto, the John Kree Migraine Clinic in London, and two in Montreal. Headache patients are also seen in pain clinics, which are generally run by anaesthetists or general practitioners with a special interest in pain and headache.

In Australia, health care is provided through a mix of public and private sector providers. e erapeutic Goods Administration, Australia’s regulatory authority for medications, approves drugs for various indications, while a separate committee determines which medications will be subsidized by the government through the Pharmaceutical Bene ts Scheme. Specialist headache care is usually provided through neurologists with an interest in headache as there are very few headache centres or clinics in the country.

Taiwan has a government-run, single-payer healthcare system with a low co-payment for outpatient and inpatient services. Over 99% of the population is covered by national health insurance. Physician referrals are not required for specialist care, unlike in the US, UK, or Canada, and patients are therefore able to access tertiary care institutions for primary care (8). As headache is an emerging subspecialty in Taiwan, headache specialists are rare (8).

regional and cultural factors

Regional factors also play an important role when considering inter- national di erences in headache treatment. In mainland China, until a few years ago there were no headache centres and most patients did not get much care in their local clinics. Today, China has many head- ache centres that have been developed along with guidelines set up in conjunction with the IHS. In low- and middle-income (LAMI) countries, life-threatening conditions are more prevalent than in higher-income countries, and headache care is thus relegated to a lower priority. In these regions, a large percentage of the popula- tion resides in rural areas and rates of illiteracy are high, further precluding access to medical care. In addition, headache research in LAMI countries in the developing world is limited, for a number of reasons, including lack of resources, lack of access to medical infor- mation and published literature, technical di culties in performing studies in rural areas, and language barriers. As research done at the local level helps to raise awareness, shape policy, and encourage the development of services, the paucity of research and publications impacts on the availability of headache treatment in these areas (9).

Cultural factors may a ect the experience and perception of pain and are also important when considering international di erences in headache treatment. For example, in Chinese culture, headache is considered an emotional problem or weakness, and men do not frequently admit to su ering from headaches (10). Likewise, head- ache is perceived as a psychological condition in India and, as of 2008, headache care was not covered by insurance in India for that reason. In Moldova, rates of medication overuse are relatively low, which has been attributed to phobias regarding medication side ef- fects and drug dependency. Furthermore, in Moldova, pain and pain tolerance have a religious signi cance in that the orthodox tradition considers the attitude to pain as something holy and connected with the spirit of Christianity, the dominant religion in the country (11).

Chronic migraine

CM is a common and disabling disorder that was initially classi ed in the second edition of the ICHD as a complication of migraine (12). In the ICHD-3 (1) it has its own category under migraine (sub- category 1.3). It is characterized by at least 15 headache days per month for at least 3 months, with at least eight headache days per month that meet criteria for migraine with or without aura, or would have if the patient had not taken an ergot or triptan. When compared to those with episodic migraine, patients with CM are more likely to be disabled, have a lower health-related quality of life, higher levels of anxiety and depression, and greater healthcare resource utiliza- tion (13,14).

A 2010 review of population-based based studies examining the prevalence and/or incidence of CM found a global prevalence of 0–5.1%, with estimates generally between 1.4% and 2.2% (15).

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Variations in regional prevalence were noted, although it was un- clear whether these di erences represented actual geographical variations, methodological di erences, or di erences in the CM de nition used in individual studies. CM was most prevalent in the Americas, at up to 5.1%, although there was a large variation be- tween studies (1.3–5.1%). Prevalence in Europe was generally lower (0–2.4%) and varied with the stringency of the CM de nition used.

As compared to Europe and the Americas, population-based data from Asia are sparse, and classi cation criteria vary between studies. A systematic review of CM and CDH in the Asia–Paci c region (16), which included two studies conducted in Taiwan and one study each in China, India, Korea, Malaysia, and Singapore, found a CM preva- lence ranging from 0.6% to 1.7%. ere were no eligible studies from Australia, New Zealand, or the Paci c Islands.

Management of CM

Few treatments for CM are evidence-based, owing, in part, to the relatively recent recognition of CM as its own diagnostic entity, and the evolution of its de nition (see also Chapter 31). e use of topiramate, sodium valproate, gabapentin, tizanidine, and ami- triptyline for the prevention of CM is supported by randomized placebo-controlled trials (17–23). In addition, beta blockers, cal- cium channel blockers, selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors (SNRIs), as well as other medications, are o en used on an empirical basis for CM treatment. In 2010, the US Food and Drug Administration (FDA) approved onabotulinum toxin A for the preventive treatment of CM in adults, a er publication of results from the PREEMPT (Phase 3 REsearch Evaluating Migraine Prophylaxis erapy) studies, two large, multicentre, double-blind, placebo-controlled trials (24).

Recently, anti-calcitonin gene-related peptide (CGRP) mono- clonal antibodies have emerged as e ective treatment for migraine prevention. ese disease-speci c, mechanism-based medications target the CGRP ligand or its receptor and have demonstrated positive results for episodic and chronic migraine in phase II and phase III studies, with only rare serious adverse events. In add- ition to their favourable tolerability pro le, other advantages over traditional oral preventive medications include an early onset of e ect, monthly or quarterly dosing schedule, and their potential for e cacy in patients with MOH (25). Erenumab, fremanezumab, and galcanezumab received FDA approval in 2018. At the time of publication, erenumab and galcanezumab have been ap- proved in Europe, and erenumab has received erapeutic Goods Administration approval in Australia.

Non-invasive neurostimulation has gained attention in recent years owing to its tolerability, safety, and relative ease of use. As such, various devices have been developed for the treatment of pri- mary headache disorders. Results from two randomized, controlled, double-blind studies assessing non-invasive vagal nerve stimulation (nVNS) for CM prevention have demonstrated safety and toler- ability (26,27). While ongoing treatment may reduce headache fre- quency, larger sham-controlled studies are needed to better assess its role in CM treatment. Open-label studies investigating transcuta- neous supraorbital nerve stimulation in CM prevention have shown signi cant reductions in headache days and use of analgesics, as well as a high percentage of satisfaction and intent to continue with treat- ment (28,29). However, there have been no randomized, double- blind, sham-controlled studies for this population.

In a 2004 study by Tepper et al. (30), patterns of practice for mi- graine prevention among headache specialists in Europe and North America were assessed by questionnaire. A high level of agree- ment was found in management strategies and prevention for pa- tients with three or more headaches per month, and more than 60% stated that acute medications should be used on no more than 8 days per month. In addition, the vast majority of physicians used beta blockers as a rst-line preventive treatment. Topiramate, ami- triptyline, and calcium-channel blockers were the most frequently used second-line agents, and valproate, newer antidepressants, and methysergide were third-line agents.

Despite an agreement among headache specialists regarding the use of acute and preventive medications, migraine remains undertreated around the world. e International Burden of Migraine Study (IBMS) (6) found that less than one-third of CM patients in ve European countries (UK, France, Germany, Italy, and Spain) reported the use of preventative medications. Similar rates of undertreatment have been reported in the USA (31,32) and Canada (32), although, overall, the use of preventive medications was higher in the USA than in Canada, with a signi cantly higher percentage of US patients with CM receiving an antiepileptic (32). More re- cent studies in the USA (33,34) indicate that migraine persists as an underdiagnosed and undertreated public health problem. Acute and preventive migraine treatments remain underused; those who received prevention discontinued it by the end of the rst year and were unlikely to switch to other preventive treatments.

Eurolight, an initiative supported by the European Commission Executive Agency for Health and Consumers and conducted by Li ing the Burden, utilized a cross-sectional survey in 10 countries (Austria, France, Germany, Ireland, Italy, Lithuania, Luxembourg, the Netherlands, Spain, and the UK) to compile data on headache disorders, headache-attributed burden, and the related use of medi- cations and medical services. Recently published evidence indi- cates that even in wealthy European countries, migraine remains undertreated, with too few migraineurs consulting physicians. Of those who do seek medical care, too many see specialists and migraine-speci c medications still remain underused (35).

In a Taiwanese clinic-based study (36), the rate of preventive medication usage for CM was notably higher (48.5%) than in most European countries, although this may be attributed to di erences in study design (i.e. clinic-based vs population-based samples). Nonetheless, fewer than half of the patients with CM in the study were on a preventive medication, once again underscoring the undertreatment of patients with CM.

European data from the IBMS also showed that the percentage of patients with CM reporting inpatient hospitalizations for migraine treatment was signi cantly higher in the UK (8.8%) compared with any other country (0% for France, 3.8% for Germany, 3.6% for Italy, and 3.6% for Spain). Although inpatient management is generally associated with higher costs, the authors suggested that the high percentage of patients with CM receiving inpatient migraine treat- ment in the UK might actually re ect better awareness and manage- ment of CM (6). ere are two inpatient scenarios in the USA. Non headache specialists sometimes admit patients with CM with an ex- acerbation for 3 days of an opiate. A limited number of headache specialists have excellent inpatient programs for CM, including de- toxi cation if needed, intravenous (IV) therapy, preventive therapy, and an interdisciplinary approach. is is a costly, but very helpful,

therapy from which many improve and it usually reduces the cost of care over time.

acute treatment

An assessment of medications used in the acute treatment of epi- sodic and chronic migraine in the USA (31,37) found that migraine- speci c treatments were used by only a minority (22%) of participants with CM. e vast majority (97%) of migraine-speci c medications were triptans, most of which were oral formulations (83%). Non- speci c medications included opiates (20.8%), butalbital-containing compounds (13.5%), and over-the-counter (OTC) medications, including paracetamol (35%), combination OTCs (62.8%), and NSAIDs (43.1%). Barbiturates and opioids were more commonly used in CM than in episodic migraine (EM), while NSAIDs and com- bination OTCs were used more frequently in EM than CM.

Similar patterns of acute medication usage in the treatment of mi- graine have been found in other countries. In a population-based study (38) of migraineurs in six Latin American countries (Mexico, Argentina, Ecuador, Venezuela, Brazil, and Colombia), of which 15% reported having > 15 migraine headache days per month, a widespread pattern of self-treatment with OTC medications was ob- served. Paracetamol and salicylates were the most frequently used medications, followed by NSAIDs and dipirone (metamizol, a non- narcotic analgesic). Ergot derivatives were used by fewer than one- third of migraineurs in Argentina and Ecuador, even though they are easily accessible, and triptan use overall was low (0–1.4%).

Studies evaluating patterns of triptan use in the Netherlands (39), Italy (40,41), and France (42) also indicated suboptimal acute treat- ment of migraine patients, with low rates of triptan and ergotamine utilization demonstrated in the studies. As in the Latin American study, the low rates of speci c treatment in the European studies were attributed to underdiagnosis and/or undertreatment of migraine.

Sumatriptan has also been shown to be underutilized in Taiwan, and many neurologists had never prescribed it to their migraine pa- tients (8). is may be attributed to the higher cost and strict regu- lations of the National Health Insurance, resulting in comparatively higher usage of NSAIDs or ergotamine for acute treatment.

Medication overuse headache

MOH is the generation, perpetuation, worsening, or maintenance of chronic headache resulting from frequent and excessive intake of medications used for acute headache treatment (see also Chapter 31) (1). MOH only occurs in patients with a prior headache history; the medication overuse itself does not cause the development of headache de novo. Migraineurs are particularly susceptible to the development of CDH associated with medication overuse (43), al- though patients with CTTH, HC, post-traumatic headache, NDPH, and others may also overuse symptomatic headache medications. Medication overuse is considered the most important aggravating factor in the progression from EM to CM (44).

MOH is one of the most common forms of CDH. e population- based 1-year prevalence of MOH in di erent countries ranges from 0.7% to 1.7%, with a female preponderance of 62–92% (45–50). Among patients aged > 65 years, the prevalence rates ranged be- tween 1.0% in Taiwan (10) and 1.7% in Italy (51). MOH a ects > 50% of patients in US headache clinics and up to 30% of patients in

European headache centres (52–54). By contrast, only 3.1% of pa- tients in a headache clinic in India were diagnosed with MOH (55). MOH can be caused by a number of medications used for acute

treatment, including ergotamine derivatives, barbiturates, triptans, simple and combined analgesics, opioids, benzodiazepines, and ca eine. Although the frequent use of NSAIDs is associated with progression to MOH in migraineurs with a high baseline migraine frequency, NSAIDs may actually be protective in patients with low baseline headache frequency (56). However, a causal role for NSAIDs in the chroni cation of headache has not been established (57).

Patterns of MOH in di erent countries depends on the availability and accessibility of acute care medications. Until the introduction of triptans, the drugs most commonly associated with MOH in the US were combination analgesics containing butalbital (a short-acting barbiturate), ca eine, and aspirin with or without codeine (58). In European countries combination analgesics with codeine or caf- feine, or ergots combined with codeine, were the most frequently used acute medications (59,60). e removal of ergotamine from some markets resulted in a period of high barbiturate use until barbiturate-containing medications for migraine were also removed from the market. Barbiturate-containing medications, such as com- bination analgesics with butalbital, continue to be available in the USA and, like opioids, are associated with an overall increased risk of transformed migraine, at any frequency of use (56).

e introduction of sumatriptan in the 1990s led to a shi in pat- terns of MOH, as demonstrated in a German prospective study in which triptans, despite their high cost, were found to cause MOH in many more cases than ergots. e study also showed that triptans caused MOH faster and at lower doses than other drugs such as ergots and analgesics (61). Similarly, in a chart review of 1200 patients at a large US headache centre between 1990 and 2005, a signi cant decrease in MOH attributed to ergotamine and com- bination analgesics was noted, while the frequency of MOH due to simple analgesics, combination of acute medications, and triptans increased signi cantly. e frequency of opioid overuse headache did not change signi cantly over the time period (54).

In countries where sumatriptan and other triptans were intro- duced more recently, MOH associated with triptans is less common. Triptans were rst introduced in Japan in 2000; in a 2007 retro- spective study of 47 patients with MOH (62), only one patient over- used triptans. Combination analgesics, none of which contained codeine or barbiturates, were most commonly associated with MOH. Similar results were seen in a larger, headache clinic-based study with 276 patients with MOH (63).

e cost of triptans also remains a prohibitive factor in some coun- tries such as India, where ergotamine remains the most common medication associated with MOH (55). Combination analgesics and opioids are limited in availability and short-acting barbiturates are not used for acute headache treatment in India. ose with head- aches are usually more inclined to try topical pain balms and alter- native therapies initially before resorting to painkillers, and this has been proposed as a reason for the lower incidence of MOH in India compared with Western countries (55).

Management of MOH

Treatment of MOH involves several steps: complete weaning of overused medications, initiation of preventive treatment and/or be- havioural or non-drug preventive strategies, establishing limits on

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future acute medication intake to prevent MOH relapse, and edu- cation of the patient and family (see also Chapter 31). Education is vital; if the patient is not convinced that the therapy is reason- able, the results will not be good. Treatment may be carried out in a number of di erent settings, depending on the individual patient’s clinical picture. When choosing a treatment plan, multiple factors are considered, including the duration and severity of headache attacks, the number of overused medications and their doses, and comorbid medical and psychiatric conditions. Outpatient treatment may be adequate for relatively uncomplicated patients, but infusion therapy (inpatient or outpatient) or integrated programmes (day hospital or inpatient programme) may be required for those with more severe headaches or those that use tranquilizers, opioids, or barbiturates, particularly in higher doses. All of the above may be necessary, with or without onabotulinum toxin A, for the most chal- lenging patients (64).

e weaning of o ending medications can be done slowly or rap- idly. Slow weaning is usually done over the course of 4–6 weeks, during which preventive treatment is established. A course of ster- oids may be helpful in refractory situations. Rapid weaning involves the abrupt discontinuation of the o ending medication, along with a 7–10-day oral or IV bridge to treat headaches and reduce with- drawal symptoms. Repetitive IV dihydroergotamine (DHE), based on the Raskin protocol, is typically used as a bridge in the USA (65). Other options such as NSAIDs, steroids, IV valproate, triptans, chlorpromazine, metoclopramide, and DHE nasal spray have been described, although none has been established in randomized, placebo-controlled trials. Patients who overuse high-dose opiates, barbiturates, and/or benzodiazepines require special, extended weaning protocols (64).

Although detoxi cation has traditionally been recommended before initiating preventive treatment in patients with CM and MOH, some have suggested that this is not necessary (66), on the basis of several studies showing the e ectiveness of topiramate and onabotulinum toxin A in patients with CM and MOH (24,67–70). is, however, remains a topic of active debate (66,71,72). e suc- cess of the monoclonal antibodies to CGRP or its receptor in treating MOH adds new data to the debate.

Withdrawal strategies are varied and no randomized studies have compared abrupt withdrawal treatment with tapered protocols. Treatment strategies may di er between countries, as well as be- tween centres in the same country. In the November 2008 issue of Cephalalgia, headache specialists from Moldova (11), Scandinavia (53), India (55), Japan (63), Germany (73), Spain (74), Taiwan (75), and Canada (76) discussed their experiences with MOH and its treatment. Despite the di erences in speci c protocols, some gen- eral themes emerged. Abrupt withdrawal of o ending medications in an outpatient setting is the most common initial strategy (53 55,63,73,74), although inpatient treatment is typically used for pa- tients who overuse opioids, fail outpatient withdrawal, or have sig- ni cant psychiatric comorbidity (53,63,73,74). Most specialists also recommended a multidisciplinary approach with an emphasis on patient education, behavioural treatment, and the identi cation of psychiatric issues (53,55,63,73,74,76). Many of these measures have also been incorporated into the guidelines for MOH treatment is- sued by the European Federation of Neurological Societies (77).

Country-speci c MOH protocols are described in further detail as follows.

Scandinavia

At the Danish Headache Center, abrupt discontinuation of all acute medications is recommended and patients are maintained in a medication-free state for 2 months (78,79). Outpatients attend a ‘headache school’ in which detailed, standardized information is o ered in a group of 6–8 patients, while inpatient treatment is o ered to severely a ected patients with comorbidities, high an- algesic intake, including opioids, and failed outpatient treatment. Levomepromazine or Phenergan are used as rescue treatment during withdrawal, and a 5-day course of phenobarbital or metha- done is used in patients with severe opioid overuse headache. Good outcomes have been described with this strict 8-week withdrawal programme (53).

India

Outpatient withdrawal is the most common strategy for MOH de- toxi cation in India. Inpatient withdrawal is undertaken relatively infrequently as patients in India are unwilling to be admitted for headache treatment, for various reasons. Although DHE is not avail- able in any form in India, some patients are able to procure it from elsewhere. Parenteral chlorpromazine, valproate, and steroids are used for inpatients who cannot obtain DHE. All inpatients and out- patients are started on amitriptyline 10 mg daily, and also undergo cognitive behavioural therapy. Treatment strategy is based on pa- tient preference rather than the overused medication (55).

Japan

In Japan, abrupt outpatient withdrawal is the recommended method of detoxi cation, although inpatient withdrawal is considered in dif- cult cases and tapering outpatient withdrawal is the least preferred option. Prevention aimed at the underlying headache disorder is o en initiated during withdrawal. Tricyclic antidepressants such as amitriptyline are used for both migraine and TTH, while lomerizine, a calcium channel blocker, is used for migraine. Anticonvulsants are also used. In addition, oriental herbal medicine, acupuncture, and headache exercise may be o ered in refractory cases (63).

Germany

In Germany, MOH is treated by a multidisciplinary team com- prising neurologists, psychologists, and physiotherapists. Abrupt drug withdrawal is the treatment of choice, which may be done through inpatient programmes or in an outpatient setting or day clinic. Outpatient withdrawal is recommended for highly motivated patients who do not overuse opioids or tranquilizers, while inpatient detoxi cation is undertaken in those who overuse opioids, fail out- patient withdrawal, or have signi cant psychiatric comorbidity. Most patients are treated with 100 mg oral prednisone for the rst 5 days a er medication withdrawal, and 500–1000 mg IV aspirin is usually given, if necessary, for rescue treatment (73).

Spain

In 2006 the Headache Group of the Spanish society of Neurology published local guidelines for the treatment of MOH. Detoxi cation is usually done abruptly, in an outpatient setting. Daily NSAIDs (e.g. sodium naproxen 550 mg q8h with gastric protection) are given for about 15–30 days, and triptans are used for moderate-to-severe head- aches for up to 2 days if they are not the overused drug. Preventive treatment is started early and is based on the underlying headache

disorder. Amitriptyline, 20–50 mg nightly, is used in patients with underlying TTH. Migraine patients are prescribed beta blockers with nocturnal amitriptyline, or an antiepileptic. Topiramate and valproic acid are both used, but topiramate is generally preferred. For patients who do not respond to the above regimen, a combin- ation of a beta blocker and an antiepileptic is prescribed, and botu- linum toxin type A may be added as well (74).

e pharmacological protocol for inpatient management is as follows: (i) IV methylprednisolone, at least 80 mg every 24 h, for 5–7 days; (ii) IV valproate 400–800 mg every 12 h for 3–5 days, then oral prevention with 500–1000 mg/daily; (iii) IV metoclopramide; (iv) short treatment with either benzodiazepines or neuroleptics (1– 2 weeks); and (v) NSAIDs (a er the steroids) and triptans as in the outpatient protocol. IV DHE is not available in Spain (74).

While the concept of MOH and recommendations for limitation of acute treatment have been widely accepted for some time, there is ongoing debate over whether MOH is truly a secondary headache disorder or whether the overuse of analgesics can be viewed as an epiphenomenon to a progressive primary headache disorder. As evidence from high-quality, large, well-designed randomized con- trolled clinical trials on MOH is lacking, some headache specialists have called for a critical appraisal of MOH in each individual patient, suggesting that frequent use of acute headache medications ‘should be viewed more neutrally, as an indicator of poorly controlled head- aches, and not invariably a cause’ (80,81).

Chronic cluster headache

Cluster headache is a TAC that presents with severe, unilateral pain accompanied by ipsilateral cranial autonomic features. Individual cluster attacks last 15–180 minutes and range in frequency from one attack every other day to eight attacks daily during cluster periods. Patients with CCH have attacks that occur for more than 1 year without remission or with remissions lasting less than 3 months (1).

Compared to migraine, the prevalence of cluster headache is very low and little is known about the population-based epidemiology of cluster headache. A meta-analysis of population-based studies of cluster headache published up to 2007 found that the 1-year preva- lence varied signi cantly between studies, ranging from 3 to 150 in 100,000. e pooled lifetime prevalence was 0.12% and the ratio of episodic versus chronic CH was 6.0. While regional di erences in cluster headache prevalence were di cult to establish owing to the small number of studies, trends suggested that in the more northern countries the prevalence rates were higher than in those countries closer to the equator (no studies from countries south of the equator were available) (82). Since then there have been only a few population-based studies, which showed a prevalence of 87 per 100,000 in the Republic of Georgia (83), 1.3% in rural Ethiopia (84), and 41.4 per 100,000 in Brazil (85).

e treatment of CCH requires acute, transitional, and preventive treatment (see also Chapter 18). Acute therapy includes oxygen in- halation, triptans (nasal spray or injectable), and DHE, while tran- sitional treatment generally involves steroids or an occipital nerve block. Patients with lengthy cluster periods or CCH require pre- ventive treatment that can be used on a long-term basis. Verapamil is usually used as a rst-line preventive treatment in CCH. Other

options include lithium, topiramate, divalproex sodium, gabapentin, and melatonin.

Surgical options, which include occipital nerve stimulation (ONS) and deep brain stimulation (DBS), may be considered in pa- tients with medically refractory CCH. A review of ONS in drug- resistant CCH (86) found that occipital nerve stimulation is e ective in about two-thirds of patients (> 50% frequency reduction). Hypothalamic DBS for CCH is generally reserved for patients with daily or near-daily attacks that are refractory to all pharmacology, including combination regimens. It was introduced by Leone et al. in 2001 (87), with a case report in which cluster attacks were elim- inated in a patient with CCH a er stereotactic positioning of an electrode followed by stimulation of the posterior inferior ipsilateral hypothalamic grey matter. Since then, DBS has been successful in reducing or preventing cluster attacks in approximately 50–60% of medication-refractory CCH patients treated at experienced centres (88–91). DBS for CCH is most well established in Italy, where the pioneering procedures were performed at the Istituto Neurologico Carlo Besta in Milan. Owing to potential serious adverse e ects, DBS should only be considered in the most severely disabled pa- tients a er all other medications and non-invasive therapies have been trialled. More recently, sphenopalatine ganglion stimulation has emerged as another potential surgical option for both acute and preventive treatment of medically refractory CCH (92–94).

nVNS, when used as acute or preventive CCH treatment, demon- strated a signi cant reduction in weekly attack frequency in a pro- spective, open-label randomized study in which nVNS combined with standard of care was compared with standard of care alone (95,96).

Conclusion

Among international headache specialists there appears to be broad agreement that treatment of CM generally begins by identifying whether MOH is present. If so, it is treated accordingly, and pre- ventive treatment is usually initiated early. International headache specialists use a number of preventive medications, most com- monly including tricyclic antidepressants, topiramate, valproate, and beta blockers. Botulinum toxin has been increasingly used, al- though its application is limited by cost and reimbursement issues in many countries. Most respondents use onabotulinum toxin A, and that is the toxin with the most evidence and the only one with FDA approval for CM treatment. e anti-CGRP receptor or ligand monoclonal antibodies have only recently been introduced in some countries. Given their e cacy and tolerability as shown in mul- tiple studies, their role in the management of episodic and chronic migraine as well as MOH in clinical practice is eagerly anticipated.

Abrupt withdrawal of overused medications in the outpatient setting is the preferred treatment of MOH, and inpatient treatment is reserved for those who fail outpatient treatment, su er from sig- ni cant psychiatric comorbidity, or overuse signi cant amounts of opioids, benzodiazepines, or tranquilizers. Speci c pharmaco- logical protocols vary, depending on the medications overused in a particular country, as well as the medications available for use in detoxi cation. Most headache specialists also agree that patient education and behavioural treatment are cornerstones of MOH management. Early clinical experience with the CGRP antibodies

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in treating all types of migraine and especially MOH shows promise. It appears that outpatient treatment with these new therapies may help patients to use fewer acute care medications as their headaches decrease.

CCH treatment around the world generally comprises preventive treatment with verapamil or lithium, and injectable sumatriptan, intranasal zolmitriptan, and oxygen therapy are typically used for acute treatment. Surgical options may be considered for medically refractory cases but are not widely available; experience with these procedures has been predominantly in Europe and began in Milan, Italy. We learned that CCH is very rare in Taiwan and other Asian countries.

CM and MOH are disabling conditions associated with signi – cant personal, societal, and economic burdens. However, both re- main under-recognized and undertreated worldwide. Increasing the awareness and treatment of CDH and its subtypes through research and public health policies will reduce the societal and economic costs associated with the disorder. In particular, promoting research in developing countries should be a priority as much of the world lives in LAMI countries where the burden of CDH may be high, but resources addressing the problem are scarce.

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HM, et al. Deep brain stimulation of the posterior hypothal- amic area in intractable short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT). Cephalalgia 2011;31:1405–8.

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appendix 32.1
Comments from international headache specialists on the treatment of chronic migraine

e prophylactic agents for episodic migraine most commonly prescribed by Australian general practitioners are pizotifen and propranolol (97). Most patients with chronic migraine would also be treated with these agents initially. Neurologists would o en move on to other agents, including topiramate, sodium valproate, and amitriptyline, as would be the case else- where. Methysergide is no longer available. Candesartan is popular with a number of neurologists; there is now a better-established evidence base to support its use. It is e ective in a proportion of cases and is well tolerated in most patients (98). Onabotulinum toxin A has become increasingly widely used, especially since being subsidized by the Pharmaceutical Bene ts Scheme, which makes it a ordable.

Dr Richard Stark, Australia

My rst step is to ensure there are no obvious precipitating factors such as analgesic overuse or the contraceptive pill, and to manage depression with tricyclic antidepressants. Many patients respond to topiramate, which is o en reasonably well tolerated if the dose is built up slowly from 12.5 mg daily towards 100 mg daily or more. ere are occasional patients who are referred to my colleague for botulinum toxin A injections.

Dr Richard Peat eld, England

e general approach comprises clear and emphatic patient education, with handing out of written material, especially in tertiary centres, aggressive withdrawal of overused symptomatic medications, sometimes with a bridge treatment using steroids as Brazil doesn’t have dihydroergotamine in in- jectable preparations, initiation of preventive therapies usually with rational combination of drugs, rescue treatment, and enforcing adherence to a pro- gramme of exercise and sleep hygiene (99).

Speci cally for chronic migraine or migraine and medication overuse headache, in addition to prevention with a combination of pharmacological agents, acute treatment is prescribed with a maximum frequency of twice a week. Two classes of drugs are simultaneously prescribed and even for severe attacks a written prescription for injectable triptan + rectal non- steroidal anti-in ammatory agents is provided with orientation of seeking emergency departments willing to administer the right medications (chlor- promazine, steroids, and not only simple analgesics and opioids). We en- force the prohibition of using opioids despite the stubbornness of some centres in giving tramadol to patients. Botulinum toxin is not used in our centre as most of our patients present with unsuccessful previous attempts and we don’t think it has been used other than with commercially driven approaches by most health professionals. Additionally, we push the patients to adhere to a 4-day per week 1-hour-long fast walking programme and follow-up the patients every 1–2 months and ask them to keep a detailed headache calendar. We are con dent in the success of our approach as a re- cent Masters’ degree study carried out in our centre demonstrated a higher than 80% compliance rate (100).

Dr Abouch Krymchantowski, Brazil

Twenty to 37% of chronic daily headache (CDH) patients in Taiwan were found to have medication overuse in population-based studies (10,45,101), while a clinic-based study found that medication overuse headache could be diagnosed in up to 48% of CDH patients (102). Most of the patients with medication over use headache (MOH) are actually chronic migraine patients. Detoxi cation is undertaken either in the hospital or in the out- patient setting, depending on patient characteristics [see ‘Medication overuse headache’]. Like the practices in many countries, migraine prophy- lactic agents are always prescribed simultaneously with acute abortive treat- ment and maintained for months.

Dr Shuu-Jiun Wang, Taiwan

Chronic migraine is most commonly treated by topiramate or by botulinum toxin. is depends on the preference of the doctor and the patient. Both are reimbursed by all health insurances. Many doctors also give amitriptyline, duloxetine, or mirtazapine, either alone or in combination with topiramate and botulinum toxin. If medication overuse is present, withdrawal treat- ment is also always considered. In only very few centres, vagal nerve stimu- lation is o ered. At the time of writing this comment, the monoclonal antibody erenumab has been approved also for the treatment of migraine, including chronic migraine, and is being prescribed more and more. e monoclonal antibodies galcanezumab and fremanezumab will also be ap- proved for migraine, including chronic migraine, in short time. e anti- bodies are fully reimbursed by all health insurances if at least four oral drugs and botulinum toxin were not e cacious.

Dr Stefan Evers, Germany

e rst choice for treating chronic migraine in Estonia is generally ei- ther tricyclic antidepressants, topiramate, or non-cardioselective beta blockers. In case of intolerability or lack of e cacy, candesartan or SNRIs (venlafaxine, duloxetine) are in use. Failure to achieve substantial e ect leads to consideration of an injectable treatment with onabotulinum toxin A or erenumab; however, the high price and absence of reimbursement of these treatment options limit their usage considerably.

Dr Mark Braschinsky, Estonia

In our practices we follow the 2012 Italian Guidelines for Primary Headaches (103), which we helped to write. Di erent from the US, unarizine is avail- able in Italy and it is considered among the rst-line drugs for the prophy- laxis of migraine. Subcutaneous sumatriptan is di cult to nd and pizotifen has recently become unavailable.

Dr Giorgio Zanchin, Federico Mainardi, Italy

e Canadian Headache Society Guidelines for Migraine Prophylaxis pro- vide a detailed approach to the management of many scenarios. ey can be accessed at http://www.headachesociety.ca (104). e acute guidelines will take a similar approach. Whether the guidelines will have any impact on practice

remains to be seen. Previous guidelines from 1997 (105) had a measured 2% impact on practice patterns.

Although onabotulinum toxin A has been approved by Health Canada for the indication of chronic migraine, the fee for the injection is not covered

When I do see a patient for onabotulinum toxin A therapy, I tend to incorporate both PREEMPT data and my own experience as an injector for nearly 30 years. is entails assessment of possible dystonic features, myofascial features such as head forward posture, or possible temporo- mandibular disorder components. us, I assess whether there are areas of pain that are prominent on one side compared to the other, bruxism, or clenching, or whether one side of the neck or shoulder is more sore or tender. is is followed by physical examination, looking for features that would guide dosing in an asymmetric fashion. My average dose for Botox treatment is about 180 units. I typically have the patient follow-up with my physician assistant in a month or so for reassessment, and the assistant will take care of any interval prescriptions. e patient schedules their 12-week re-injection visit at the time they leave from their injection.

Now, with the advent of monoclonal antibodies indicated for migraine prevention, with evidence for bene t including patients with CM, I have started to incorporate them into our treatment algorithm. Trial results have generally shown e ectiveness comparable to that with onabotulinum toxin A, with side e ects that thus far have been comparable to placebo. e long- term e ects of chronic CGRP blockade are, of course, being closely watched.

Dr Jack Schim, USA

Patients with medication overuse headache (MOH) are either hospitalized for detoxi cation or treated in the outpatient clinic, depending on their severity, medical comorbidities, and preference. In outpatient treatment, oral DHE, prochlorperazine, and non-steroidal anti-in ammatory drugs are commonly prescribed for detoxi cation. For inpatient treatment, intra- venous prochlorperazine has been commonly used as there is no available injection form of dihydroergotamine in Taiwan. In our experience, repeti- tive intravenous prochlorperazine treatment is highly e ective in aborting withdrawal headaches (109). Intravenous magnesium sulfate, ketorolac, methylprednisolone, sodium valproate, lidocaine, or olanzapine are the other alternatives.

In Taiwan, prophylactic agents, including propranolol, unarizine, ami- triptyline, valproic acid, or topiramate, are given to MOH patients a er de- toxi cation for a period of at least several months and are tapered if their headache symptoms improve substantially (75).

Dr Shuu-Jiun Wang, Taiwan

In Australia, unfortunately, combination analgesics containing up to 15 mg codeine per tablet have been available without prescription (until February 2018 when they became prescription-only) and combinations of up to 30 mg per tablet are prescribed regrettably o en for frequent headaches by general practitioners. us, we have to deal with many patients overusing codeine in substantial amounts. Withdrawal in such patients is associated with a great increase in headache severity, so that outpatient protocols are o en unsuccessful. On this background, the use of intravenous lignocaine (lido- caine) has become popular as a means of managing medication withdrawal (110,111). In our experience, lignocaine provides better relief in some pa- tients than dihydroergotamine and in our department it is the rst-line ap- proach in patients requiring inpatient detoxi cation. Cardiac complications have not been an issue, but neuropsychiatric symptoms may occur if the dose is pushed too high (112). We have generally used a conservative dose of 2 mg per minute and rarely see such problems, but occasionally the dose must be increased to obtain a better response. Alternatively, if serum ligno- caine levels can be obtained promptly, the dose can be adjusted accordingly.

Dr Richard Stark, Australia

for this indication, except in Quebec.

Dr Marek Gawel, Canada

In the headache centre of the Leiden University Medical Center, we rarely see patients with chronic migraine (CM) who are not overusing acute anti- headache medications. It was shown that patients with medication overuse and underlying migraine bene t greatly from withdrawal therapy, especially when combined with guidance by a specialized headache nurse. Current treatment of CM in our centre consists of withdrawal of overused medica- tion [as described under ‘Medication overuse headache’]. is means acute withdrawal of all acute headache medication and phasing out of prophy- lactic treatment with no escape medication during the withdrawal period. During this period a headache diary is lled out by the patient. A er two or three months of the withdrawal phase (two for triptans, three for anal- gesics or combination of analgesics and triptans), treatment for remaining migraine attacks is started. Patients are strongly advised not to treat more than two migraine attacks per month, each during a maximum of 2 days, using a maximum of two triptans per day (2 × 2 rule). is way, recurrence of triptan overuse is prevented. Patients with two or more attacks per month are also advised to start prophylactic treatment, to reduce the number, se- verity, and duration of attacks. is will make it possible for the patient to ful l the rule of maximum of 2 × 2 acute treatments per month.

e question remains, however, whether prophylactic treatment should be started during withdrawal. Recently, trials using onabotulinum toxin A have been shown to elicit a small but signi cant response in chronic mi- graineurs, who were not withdrawn from medication overuse (106,107). As our current treatment of CM (withdrawal with support of a headache nurse) is inexpensive and seems adequate, treatment with onabotulinum toxin A only seems unwise. However, there might be a role for it as a prophylactic treatment during the withdrawal period, using it to bridge the worst part of the withdrawal e ects, and it may further reduce the number of headache days a er the withdrawal. We have recently nished a trial to investigate this further (CHARM (CHroni cation And Reversibility of Migraine) trial). In this trial, we show that onabotulinum toxin A does not a ord any additional bene t over acute withdrawal alone (108). We thus strongly recommend that withdrawal of acute medication should be tried rst before initiating more expensive treatment with onabotulinum toxin A.

A new treatment class that also will become available for CM are the CGRP antibodies. However, also for trials with this new type of preventive medication, CM patients with medication overuse headache (MOH) were included. We strongly recommend a trial showing that anti-CGRP-R anti- bodies have an additional e ect on withdrawal in CM + MOH patients.

Drs Judith Pijpers, Dennis Kies, and Gisela Terwindt, e Netherlands

In my practice, chronic migraine (CM) is the most frequently seen pri- mary headache disorder. It is very common to have comorbid medication overuse. Causality can be quite di cult to ascertain; therefore, I educate the patient regarding the issues, advise on the limits of acute medication, and add e ective preventives.

Onabotulinum toxin A was the only Food and Drugs Administration (FDA)-indicated treatment for CM until the new CGRP antibodies be- came available; many patients are speci cally referred for consideration of onabotulinum toxin A therapy. It is frequent that the insurer will require that ‘medical necessity’ be shown by not only having a diagnosis of CM, but also that the patient has been tried on several ‘standard’ preventives. Of course, none of these is FDA-indicated for CM. Of the various medicines that are frequently advised, only topiramate has clinical data supporting its e cacy for CM. Antidepressants, beta blockers, and calcium channel blockers have no substantial evidence in their favour for the preventive management of CM.

CHaPtEr 32

Frequent headaches with and without acute medication overuse

appendix 32.2
Comments from international headache specialists on the treatment of medication overuse headache

295

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Part 5 Tension-type and other chronic headache types

One of the problems with the UK’s National Health Service is a dire shortage of beds for inpatient analgesia withdrawal and we have to try to persuade the patient to stop taking medication while still at home. In the UK, opiates and particularly codeine, dihydrocodeine, and, until recently, dextropropoxyphene were on sale to the public in small doses and most abusing patients take paracetamol/codeine combinations of some type. Barbiturates have always been prescription drugs and are not a problem; there are a few patients who take excessive quantities of triptans, although there are usually nancial restraints on general practitioners that keeps the number of prescription per month down. I nd there are a number of ‘ad- dictive personalities’ who reappear 2 or 3 years a er withdrawing one drug taking another; we have no easy answers!

Dr Richard Peat eld, England

Medication overuse headache is always treated rst by withdrawal therapy. About 50% of the patients still undergo inpatient withdrawal therapy, but this rate is decreasing. Most doctors start prophylactic treatment early in the withdrawal period. During withdrawal therapy, steroids are given in most clinics. Also, naproxen, aspirin, and metoclopramide are given as acute medication. Patients are followed up regularly a er withdrawal. We do not use dihydroergotamine infusion.

Dr Stefan Evers, Germany

Despite some advances in healthcare professionals’ awareness in the eld of medication overuse headache, it is still largely under-recognized, underdiagnosed, and undertreated in Estonia. e vast majority of pa- tients are managed in Tartu University Headache Clinic, where treating this group of patients is complex, starting with patient education by a headache specialist and headache nurse, and includes detoxi cation, initiation of prophylactic medication, and cognitive–behavioural treatment. If the out- patient approach fails, patients are admitted to the neurology department, where steroids are used.

Dr Mark Braschinsky, Estonia

Medication overuse headache (MOH) is a condition o en seen in Leiden Univesity Medical Center. e patients receive two diagnoses: (i) MOH (following ICHD criteria); and (ii) the presumed underlying primary head- ache syndrome. Substances most o en overused are simple analgesics, non- steroidal anti-in ammatory drugs, triptans, or combination analgesics, such as paracetamol with ca eine. Overuse of opioids, barbiturates, or er- gotamine is rarely seen in the Netherlands.

Regular treatment for MOH is acute cessation of all oral anti-headache medication and ca eine, as well as the phasing out of any prophylactic medication. e duration of this withdrawal period is determined by the type of substance overused. For analgesics, combination analgesics and combinations of analgesics and triptans, or ca eine, withdrawal is 3 months. For triptans the withdrawal period is 2 months. During this period, no escape medication is allowed. No prednisone is given. During the withdrawal period, patients are regularly counselled by a trained head- ache nurse, who is available for support and gives tips and advice on how to get through the withdrawal period. Patients are not hospitalized during the withdrawal phase.

A recent (unpublished) study conducted in our centre showed that guid- ance by our headache nurse signi cantly increased the chance of success- fully withdrawing from overused medications from 61% to 73%. Patients with migraine and medication overuse had a larger reduction in headache days than patients with underlying tension-type headache (mean relative reduction in headache days: 56.1% vs 26.0%) (unpublished data).

Drs Dennis Kies and Gisela Terwindt, e Netherlands

For medication overuse headaches, I classify patients into ve categories: (i) daily acute medication intake without harm; (ii) toxic/side e ects from daily acute medication intake; (iii) excessive acute medication intake due to or as- sociated with psychiatric comorbidity; (iv) rebound headache due to anal- gesics causing allodynia or increase in pain sensitivity; (v) acute medication

abuse ( tting Diagnostic and Statistical Manual of Mental Disorders, 5th Edition diagnostic criteria for substance abuse disorder).

In patients in the rst group, daily analgesic intake is just a consequence of having daily headaches; there is no rebound e ect. A preventive medi- cation is started and the patient withdraws analgesics naturally. Usually no signi cant comorbidity is diagnosed and washout is not necessary. In group 2, patients are taking an excessive amount of daily medication and having side e ects from the medication, so the analgesic should be abruptly discon- tinued and an inpatient programme may be needed. In group 3, screening for mood disorders (bipolar expected to be common), high anxiety levels (generalized anxiety disorder, panic, phobias, post-traumatic stress disorder may occur), compulsivity with or without obsessive–compulsive disorder, or attention-de cit hyperactivity disorder, is carried out. Cephalalgiaphobia is common in those patients. Psychiatric comorbidity should be addressed, and treated with medication and non-pharmachological approaches. In group 4, acute medication class should be changed or its use avoided; pre- vention should be started currently with washout strategies. In group 5, a substance abuse behaviour is found, and other substances are commonly abused too; the patient should be managed in line with substance abuse guidelines.

Dr Mario Peres, Brazil

I am performing more magnetic resonance imaging scans to exclude pi- tuitary and other comparable diseases in patients without a very long history of episodic cluster headache. I always emphasize prophylaxis and would try verapamil rst (building up from 120 mg q8h towards 240 mg q8h, or perhaps even slightly more), monitoring the QT interval on the electrocardiogram. If that does not work, I am fairly liberal with lithium carbonate in chronic cluster patients, using the proprietary long-acting preparation Priadel 400 mg q12h in the rst instance and increasing it weekly to a maximum of 800 mg q12h in patients who do not respond, trying to get the level to just above 1 mmol/l. ere is a good domicil- iary oxygen delivery service in England, and I try to arrange for cluster headache patients to have oxygen cylinders, 9 l/minute regulators and 100% masks to use at home, with the zolmitriptan nasal spray (it tastes better than sumatriptan and there is good evidence for its e ectiveness) for attacks away from home. In my experience, there is no place for oral triptans or other analgesics.

Dr Richard Peat eld, England

For chronic cluster headache we use the combination of verapamil, lithium, and ergotamine in over 90% of our cases. Because we believe that long- acting verapamil formulations (120 mg and 240 mg) are not as e ective as the usual 80 mg presentation, we may prescribe up to three 80-mg tablets every 8 hours, which has shown e ectiveness among once-refractory verap- amil users. Very rarely other drugs are prescribed. Injectable sumatriptan and/or oxygen inhalation is our most common approach for the acute treat- ment. Despite current phytotherapy and hormonal suggestions of therapies, we don’t believe they may be e ective. Neuromodulation with electronic devices are recently arriving in Brazil and robust personal experiences are still not available.

Dr Abouch Krymchantowski, Brazil

Dissimilar to the high prevalence in Western countries, there are very rare patients with chronic cluster headache in Taiwan (113) as in other Asian countries, such as Japan (114) and China (115). Hence, our experience in this subset of patients is limited.

Dr Shuu-Jiun Wang, Taiwan

appendix 32.3
Comments from international headache specialists on chronic cluster headache

Chronic cluster headache is treated by verapamil in a dose as high as needed or as tolerated.

Many patients receive steroid treatment from time to time (over 2 weeks, on average). In frustrating cases, topiramate (dose as high as needed or tolerated) and botulinum toxin (dosing as in chronic migraine) are used. In clinical trials, occipital nerve stimulation, sphenopalatine ganglion stimulation, and vagal nerve stimulation are o ered in a few centres.

Dr Stefan Evers, Germany

e rst choice for cluster headache prophylactic treatment is verapamil. In case of intolerability or lack of e cacy second choice medications in- clude amitriptyline, topiramate, and sometimes other anticonvulsants, like lamotrigine and alpha-2-deltas. Lithium is not available in Estonia. Despite the technical availability of neuromodulation, it is not used owing to the absence of reimbursement and national guidelines for treating cluster headache.

Dr Mark Braschinsky, Estonia

High doses of verapamil and corticosteroids have been e ective in a few cases of chronic cluster headace, one of which was described in a case report presented in abstract form (116). e patient was administered methylprednisolone 500 mg intravenously daily for 2 days, then 250 mg for 3 days, followed by prednisone 25 mg orally for 2 days, and then tapered over 8 days. Verapamil was increased gradually up to 680 mg daily with a

subsequent disappearance of attacks. A er several months, verapamil was reduced to 320 mg daily without a recurrence of attacks. e same results were achieved in a cohort of 25 patients.

Drs Giorgio Zanchin and Federico Mainardi, Italy

Hypothalamic stimulation for drug-refractory chronic cluster headache (dr-CCH) was started a er increased blood ow in the posterior hypothal- amus was shown in positron emission tomography studies during cluster headache attacks (117). e rst hypothalamic implantation was success- fully performed in 2000 in a severe dr-CCH patient (87). So far, more than 90 patients with dr-CCH have been reported in the literature (118–132), including other types of trigeminal autonomic cephalalgia (133–137) with long-term follow-up and good results: pain-free patients or those with ≥ 50% improvement are > 70%. ese results are sustained over years (138). More recently, occipital nerve stimulation has been tried. In addition to having less safety concerns, the e cacy gures are similar to deep brain stimulation (139).

In order to improve the e cacy rate and because of the invasiveness of the procedures, the patients must be highly selected by expert headache specialists and thoroughly evaluated by an experienced multidisciplinary team (140).

Dr Massimo Leone, Dr Giovanni Broggi, Dr Gennaro Bussone, Dr Proietti Cecchini Alberto, Dr Giuseppe Messina, Dr Angelo Franzini, Italy

CHaPtEr 32

Frequent headaches with and without acute medication overuse

297

Nummular headache

Juan A. Pareja and Carrie E. Robertson

Introduction

Nummular headache (NH) is a well-de ned clinical picture char- acterized by focal head pain exclusively felt in one small, well- circumscribed, area of the surface of the head, in the absence of an underlying lesion.

e term ‘nummular’ was inspired by the Latin word nummus, which means coin (i.e. ‘coin-shaped cephalalgia’). NH was described by Pareja et al. in 2002 (1), and in 2018 it was included in the third edition of the International Classi cation of Headache disorders (ICHD-3) (2).

Since the early description, many other cases have—in a cres- cendo fashion—increasingly been reported from several countries in Europe, America, and Asia. e worldwide experience with NH is rather impressive, with almost 300 patients with NH reported thus far. It should therefore be possible at this stage to accurately delineate NH clinically.

Epidemiology

Epidemiological data on NH are still lacking. In two hospital-based series, incidences of 6.4/100,000 (3) and 9/100,000 (4) were esti- mated. In an outpatient neurological service NH represented 0.25% of all consultations, and 1.25% of the consultations for headache (5). In a recent prospective study of patients with unilateral headache, 6% were found to have NH (6).

NH slightly prevails in females (female-to-male ratio 1.5:1), and the mean age of onset is about 44 years (range 4–79 years). e duration of symptoms before diagnosis ranges from < 1 month to 50 years (7,8).

Clinical picture

e most distinctive feature of NH is the topography of the symp- toms. e pain is exclusively felt in one small, rounded (80%) or elliptical (20%) area of the surface of the head, with well-de ned borders, typically 1–6 cm in diameter (mean 3.5 cm; total range 0.6–10 cm) (7,8).

In most cases of NH the pain is strictly unilateral, with the right side being slightly more a ected than the le (7,8). Although any region of the head may be involved, the parietal area, particularly the most convex part (tuber parietale), is the common location of NH. Other symptomatic areas include occipital, temporal, frontal, vertex, or crossover regions. Some patients may report a sagittal lo- cation (in vertex or occiput) with the symptomatic area divided in half by the midline (3,7–16). Rarely, the disorder may be bifocal or multifocal, with each symptomatic area retaining all the character- istics of NH (7,17–21). e various symptomatic areas may appear simultaneously or dyssynchronously.

e pain is commonly described as oppressive or stabbing, and less frequently as throbbing, sharp, burning, or pulsatile. Pain in- tensity is generally mild to moderate, but occasionally severe (3,4,13,15,18,22–28). Superimposed on the background pain, spontaneous or triggered exacerbations (lasting from seconds to hours) may occur (1,3,7,9,13–17,25–34). Mechanical stimuli (such as touching or combing hair) on the symptomatic area commonly trigger or exacerbate the pain. Exceptional cases have been reported with the pain possibly precipitated by intercourse (n = 1), coughing and Valsalva manoeuvres (n = 2) (35), menstruation, or sleep de- privation (n = 1) (36).

e a ected area frequently shows variable combinations of hypoaesthesia, paraesthesia, dysaesthesia, allodynia, and/or tender- ness (1,3). In addition, a minority of patients may develop trophic changes such as a patch of skin depression, hair loss, reddish colour, and local increased temperature (19,25,37). Development of NH in a congenital patch of hair heterochromia has been reported in a 4- year-old child (38). We have also observed emergence of NH in a small area of aplasia cutis.

Autonomic accompaniments are virtually always lacking. Nevertheless, one patient reported bilateral lacrimation and rhinorrhoea during exacerbations (13), and phonophobia has been described in two patients (23,38).

e pain predominates during the daytime and hardly ever awakens patients (3,23,29). e temporal pattern is highly vari- able: in up to two-thirds of published cases, the disorder has been chronic (present for > 3 months), whereas one-third displayed an episodic pattern with durations of seconds, minutes, hours, or days. During symptomatic days the pain may be continuous, uctuating,

or intermittent. Rarely, the chronic course evolves from an episodic pattern (3). Spontaneous remissions—with/without recurrence— can ensue (3,39). Persistent remissions a er successful treatment have also been described (22,34,40). Pseudo-remissions may be ob- served when the pain reaches a very low grade or only discomfort (not pain) is reported (39).

Physical examination is normal in the vast majority of cases. Physical examination should include a careful inspection and pal- pation of the scalp, assessment of tenderness on the emergence and trajectory of all pericranial nerves, and palpation of occipital, temporal, and frontal arteries. Supplementary examinations with analytical (routine blood work, erythrocyte sedimentation rate, standard biochemical determinations, thyroid function) and con- ventional immunological scrutiny generally render normal results. Neuroimaging studies (such as skull X-ray, computed tomography scan, or magnetic resonance imaging of the head) are commonly normal. Skin biopsies were performed in three patients with trophic changes, and were not speci c for any particular dermatological disease (25).

Past history (and temporally related illnesses)

ere does not seem to be any tendency towards systematic appear- ance of any particular antecedents. So far, none of the patients with NH reported has had a family history of circumscribed headache identi able as NH.

e onset of symptoms is generally spontaneous. Some type of
head trauma has been reported in 4–12.8% of patients (8,41,42); however, most of the traumatic incidences were remote, and it is dif-
cult to know whether there was any relationship with the onset of
NH (1,3,5,13,16,22,25,40). Only a minority of patients have reported
a link between the trauma site and the area where the pain was ex- perienced (3). One patient, for instance, related onset of symptoms
a er an insect bite in the a ected region (25). Another patient devel-
oped NH a er surgical treatment of a hypophyseal adenoma but in (c) the opposite hemicranium (32).

NH may rarely co-exist with other primary headaches, such as migraine, tension-type headache, medication overuse headache, chronic daily headache, orgasmic headache, primary stabbing head- ache, epicrania fugax, and trigeminal neuralgia. e onset and course of concurrent headaches have proven to be independent (1,3,7,8,16).

Pathophysiology

Experiments designed to determine the extent and distribution of pain-sensitive structures within the cranium (43,44) have shown that stimulation of the scalp produces sharply localized pain at the site of the stimulus, whereas stimulation of other intracranial struc- tures results in referred pain in a rather wide area.

Clinically, super cial pain is o en reported as well localized in a small area. is is consistent with the NH patient’s accurate de- scription of their symptoms (Figure 33.1), even outlining the symp- tomatic area or drawing it in a 1:1 scale. ere is generally a good concordance between patient’s description and physician’s mapping of the symptomatic area (3).

e natural inference from experimental and clinical data is that NH stems from peripheral tissues. e con nement of pain and sensory symptoms to a small cranial area apparently re ects

(a)

(b)

CHaPtEr33 Nummularheadache

Figure 33.1 Topography of nummular headache (NH).
Patients with NH outlining the symptomatic area: (a) ‘Here’, (b) ‘precisely

here’, and (c) ‘nowhere else but here’.

a non-generalized and rather limited disorder. In fact, tenderness and mechanical pain sensitivity (lower pressure pain thresholds) are also restricted to the symptomatic area (Figure 33.2) (45–47). On the contrary, central pain generates symptoms in wider areas, with

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Pressure Pain Thereshold (kg/cm2)

2 1.9 1.8 1.7 1.6 1.5 1.4 1.3

LR
Figure 33.2 (see Colour Plate section) Pressure pain threshold (PPT) topographical map of a patient with nummular headache.

The PPT map shows local hypersensitivity just in the symptomatic area. L, left; R, right.

Reproduced from Cephalalgia, 30, Cuadrado ML, Valle B, Fernández de las Peñas C et al., Pressure pain sensitivity of the head in patients with nummular headache: a cartographic study, pp. 200-206. Copyright © 2010, © SAGE Publications.

blurred borders, and tends to spread over time (48). NH can be con- ceived as an in situ headache. e peripheral hypothesis seems to be substantiated by a report (8) of a patient with NH who experienced complete relief a er surgical removal of the symptomatic area, al- though the patient had recurrent NH in a nearby location later.

e size and shape of the symptomatic area, along with signs and symptoms of local sensory dysfunction, suggest neuralgia of a ter- minal branch of a pericranial nerve. Moreover, trophic changes to- gether with pain and sensory disturbances strongly suggest a lesion or dysfunction of the peripheral nervous system. Speci cally, NH with trophic changes (25) might be considered a restricted form of complex regional pain syndrome, which would probably be related to nerve injury. However, two features militate against the neuralgia/ neuropathy pathogenesis: (i) anaesthetic block of the symptom- atic area is usually ine ective; (ii) the extension of the painful area across the midline (with the symptomatic area divided in half by the midline).

Admittedly, a peripheral pain mechanism is non-existent for headaches attributed to psychiatric disorders as psychogenic head- aches should materialize clinically from a central drive. However, some patients with NH may have been dismissed as having neurotic or psychogenic symptoms (12). Neither the clinical features nor psy- chiatric examinations have pointed to psychological disturbances in NH (1,3,9). It has been documented that NH is not associated with depression or anxiety (49).

As the source of NH is unclear, we prefer to provisionally con- sider NH as an epicrania, i.e. a headache probably stemming from epicranial tissues—i.e.internal and external layers of the skull, and all the layers of the scalp, including epicranial nerves and arteries (50). is proposal takes into account the possible anatomical source of the pain and may provide interesting clues for research.

aetiology: primary and secondary cases

e aetiology and pathogenesis of NH are largely unknown, so NH is considered a primary headache (2).

e vast majority of patients with NH have had normal immuno- logical screening. However, one study (51) shows a high prevalence of abnormal autoimmune markers and comorbid disorders in pa- tients with NH. is suggests a possible relationship between NH and autoimmunity, possibly as an autoimmune neuropathy.

Secondary cases have also been described, most typically as- sociated with super cial structural lesions, i.e. arising from the meninges, the skull, or the scalp, and so substantiating the con- cept of an epicranial pathogenesis (50). Various headaches with a nummular pattern have been related to local lesions of the scalp (fusiform aneurysm of a branch of the super cial tem- poral artery) (52,53), the skull ( brous dysplasia) (32), a local- ized calci c haematoma of the scalp (54), linear scleroderma (55), craniosynostosis (56), or the adjacent intracranial structures (meningiomas, arachnoid cysts) (15,35,57). Such ndings make neuroimaging examination of the head a mandatory part of the diagnostic work-up. Concurrency of NH with any other disorder may likely occur just by chance. Additional data, such as com- plete resolution of the symptoms a er surgical/medical treatment of any structural lesion/disturbance, may be needed to fortify the presumption of a symptomatic case.

e periosteum is the pain-sensitive structure of the diploe. e internal periosteum of the diploe is replaced by the endosteal layer of the dura mater. So, we postulate that intracranial processes irritating the endosteal dura may still t with the concept of epicrania and might theoretically produce a circumscribed pain referred super cially.

Diagnosis

A er ruling out secondary aetiologies, diagnosis of NH is based on the clinical features and distinction from other similar headaches (Box 33.1). NH should be considered when encountering other pri- mary headaches and cranial neuralgias with focal symptoms. Within such a clinical frame the possibilities are limited and mainly consist of epicrania fugax, primary stabbing headache, and cranial neuralgias.

Epicrania fugax is a paroxysmal head pain lasting 1–10 seconds, felt in motion from the onset to end, described as a linear or zig- zag trajectory across the surface of one hemicranium, starting and ending in territories of di erent nerves (58). e stemming area may remain tender in between attacks and this may pose some di culty in its di erentiation from NH. Nevertheless, NH pain is typically continuous and locked in a small cranial area. Superimposed par- oxysms do exist in NH, but they always conclude in situ (1,3,58,59). Concurrency of NH and epicrania fugax has been observed (60).

Unlike NH, primary stabbing headache paroxysms are ultra-short (typically 1–3 seconds), multilocalized, and multidirectional (61,62), the attacks changing from one area to another, in either the same or the opposite hemicranium (see also Chapter 23). Occasionally, a short series of primary stabbing headache is side-locked, but then may change side or locations with the next series. In those cases, duration of pain is a helpful distinguishing characteristic.

Neuralgias are de ned according to the topography of the pain, which should be perceived within the territory supplied by a given nerve, and can be temporarily inhibited by anaesthetic block of the nerve. None of the acknowledged neuralgias of the head ( rst branch trigeminal, supraorbital, auriculotemporal, and occipital) had the spatial characteristics of NH (see also Chapter 27) (2,63–65).

treatment

Owing to the typically moderate severity of the symptoms and be- nign course, reassurance is adequate in many cases. In patients with low-to-moderate pain, regular analgesics, and non-steroidal anti-in ammatory drugs (NSAIDs) may su ce. In cases with per- sistent, moderate-to-intense pain, and lack of response to analgesics and NSAIDs, a preventive therapy with neuromodulators may be indicated. In such instances, gabapentin proved to be e ective in a substantial number of patients (10,22,40). Alternatively, tricyclic antidepressants rendered satisfactory results in a small series of patients with NH (30). Individual cases have also been reported

to respond to topiramate (16,18), carbamazepine (16,66), and indomethacin (34).

Twenty- ve units of botulinum toxin type A injected in several points distributed in both the symptomatic and surrounding areas (31), or 10 units injected in the symptomatic area (67), has been tried in 24 cases (18,28,31,68), with a generally good response.

Treatment with transcutaneous electrical nerve stimulation has been reported as e ective in one patient with NH (27).

Neurotropin® (a non-protein extract from the in amed skin of rabbits inoculated with Vaccinia virus) has been reported as a useful treatment in three patients with NH (69).

It is worth mentioning that anaesthetic block of the symptomatic area has been tried extensively and was generally of no avail.

Prognosis

NH is a benign condition that may spontaneously remit a er a variable duration of symptoms. However, the disorder may last for decades. e few cases in which a clinical picture similar to NH was attributed to a cranial structural lesion proved to have benign underlying condi- tions with favourable outcome a er surgical treatment.

Conclusions

NH is a primary disorder with a clear-cut clinical picture and a dis- tinctive topography. e inherent attribute of NH is that pain and other signs and symptoms of sensory dysfunction always remain in situ—within a small, sharply contoured, symptomatic area that re- mains immutable over time.

e particular topography and features suggest a peripheral mechanism, particularly a neuralgia of a terminal branch of cuta- neous nerves of the scalp, although it has not yet been demonstrated. A provisional concept of epicrania has been proposed to group NH and other headaches with a probable source in the epicranial tissues.

CHaPtEr33 Nummularheadache

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Box 33.1 International Headache Society diagnostic criteria for nummular headache

. A Continuous or intermittent head pain ful lling criterion B.

. B Felt exclusively in an area of the scalp, with all of the following four
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1 Sharply contoured
2 Fixed in size and shape 3 Round or elliptical
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303

PART 6

Secondary headaches Diagnosis and treatment

34. Thunderclap headache 307 Hille Koppen, Agnes van Sonderen,
and Sebastiaan F. T. M. de Bruijn

35. Headache associated with head trauma Sylvia Lucas

36. Cervicogenic headache 322 Nikolai Bogduk

37. Headache and neurovascular disorders Marieke J.H. Wermer, Hendrikus J. A. van Os,
and David W. Dodick

38. Headache attributed to spontaneous intracranial hypotension 346
Farnaz Amoozegar, Esma Dilli, Rashmi B. Halker, and Amaal J. Starling

314

334

42. Remote causes of ocular pain 392 Deborah I. Friedman

43. Orofacial pain: dental head pains, temporomandibular disorders, and headache 399
Steven B. Graff-Radford† and Alan C. Newman

44. Headache with neurological de cits and cerebrospinal uid lymphocytosis (HaNDL) syndrome 403
Germán Morís and Julio Pascual

45. Nasal and sinus headaches 409 Vincent T. Martin and Maurice Vincent

46. Giant cell arteritis and primary central nervous system vasculitis as causes of headache 418 Mamoru Shibata, Norihiro Suzuki, and Gene Hunder

47. Headache related to an intracranial neoplasm 428
Elizabeth Leroux and Catherine Maurice

48. Headache and Chiari malformation 442 Dagny Holle and Julio Pascual

49. Reversible cerebral vasoconstriction syndromes 447
Aneesh B. Singhal

39. Headache associated with high cerebrospinal uid pressure 356
Ore-ofe O. Adesina, Sudama Reddi, Deborah I. Friedman, and Kathleen Digre

40. Headache associated with systemic infection, intoxication, or metabolic derangement 367 Ana Marissa Lagman-Bartolome and Jonathan P. Gladstone

41. Headache associated with intracranial infection 384
Matthijs C. Brouwer and Jonathan P. Gladstone

Thunderclap headache

Hille Koppen, Agnes van Sonderen, and Sebastiaan F.T.M. de Bruijn

Introduction

underclap headache refers to the abrupt onset of a severe head- ache (1–3). e characteristics of the pain are not strictly de- ned, but intensity is considered to peak within 1 minute. e International Classi cation of Headache Disorders (ICHD) gives criteria for primary thunderclap headache: namely, maximal in- tensity within 1 minute and a duration of at least 5 minutes (4). Some studies include patients with headache reaching maximum intensity in up to 1 hour. Patients o en describe ‘the worst head- ache ever’, which refers to the intensity of the pain, and not its abrupt onset. e di erential diagnosis of thunderclap headache is extensive, and the diagnosis of primary thunderclap headache can only be made once secondary causes have been excluded. e initial work-up is focused on detecting or excluding a subarach- noid haemorrhage (SAH), a er which other secondary causes of thunderclap headache should be considered, such as reversible cerebral vasoconstriction syndrome (RCVS), cervical artery dis- section, cerebral venous sinus thrombosis (CVST), and stroke (see Table 34.1). is chapter focuses on the work-up of alert neurologically intact patients presenting with an acute and severe headache, not related to trauma. Work-up to detect or exclude a SAH is described rst, followed by an overview of investigations to detect a cerebral aneurysm (see Figure 34.1). erea er, other secondary causes of thunderclap headache and their suitable ana- lysis will be discussed, followed by a brief overview of primary thunderclap headaches.

Subarachnoid haemorrhage

Epidemiology

e prevalence of SAH among alert and neurologically intact pa- tients with thunderclap headache probably is around 10% (6). e incidence of SAH is estimated at nine cases per 100,000 person- years, accounting for approximately 5% of all strokes (7). Half of the SAHs occur in patients younger than 55 years of age. An aneurysm is found in approximately 85% of the SAHs (8). About 10% of the SAHs is non-aneurysmal, mostly showing a perimesencephalic blood con guration. However, a posterior circulation aneurysm is

found in approximately 9% of the patients with a perimesencephalic blood distribution on head computed tomography (CT) (9). Another 5% of SAHs are due to rare causes such as spinal arterio- venous malformations or arteritis (8).

Clinical features

ere are no clinical features to distinguish headache due to a SAH from other causes of thunderclap headache. In a series of 42 patients with aneurysmal SAH headache evolved within a minute in 75% of patients. Headache usually lasts for 1–2 weeks, but the exact limits of duration are unknown, including the shortest duration. Besides abrupt onset of severe pain in the head, patients may experience nausea, vomiting, photophobia, neck sti ness, seizures, and brief loss of consciousness. (6,10).

Only some of the patients with an aneurysmal SAH retrospect- ively report a sudden and severe headache in the 4 weeks prior to the SAH. is can be due to either enlargement of the aneurysm causing ‘sentinel headache’, or due to an undiagnosed minor SAH (some- times referred to as a ‘warning leak’, but this is a true SAH) (6). e signi cance of these phenomena is unknown, mainly owing to the retrospective nature of the obtained information.

Diagnostic work-up: detecting or excluding a SAH

Timely detection of an aneurysmal SAH is essential because of the high risk of a re-bleed (8,11). Early treatment to prevent a re-bleed is related to better outcome, which underlines the need for immediate diagnosis (12).

Head CT

e initial investigation in all patients suspected of having a SAH is a head CT. Accuracy is in uenced by the amount of subarach- noid blood and the interval between the onset of symptoms and the time of scanning. As time passes, blood will spread away from the bleeding site, and haemolysis will impede the detection of blood on CT within hours. Blood in the subarachnoid space is visible on CT as an increased attenuation of the basal cisterns and subarachnoid spaces. In perimesencephalic SAHs, blood is con ned to the cisterns around the midbrain, with possibly limited extension of blood to the interhemispheric and Sylvian ssure.

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Table 34.1 Causes of thunderclap headache.

scan was 92.9% (95% con dence interval (CI) 89.0–95.5). In the subgroup of 669 patients with head CT performed within 6 hours a er ictus, 67 patients showed a SAH on CT. In the CT-negative patients, no SAH was diagnosed by lumbar puncture or during follow-up, resulting in a sensitivity of 100% for head CT within 6 hours a er ictus. e sensitivity for head CT performed more than 6 hours a er ictus was 85.7% (95% CI 78.3–90.9). e study has some methodological limitations. e number of patients who did not have a lumbar puncture a er a negative CT was not reported. In these patients, a SAH could have be missed if no re-bleed had oc- curred within the next 6 months. Besides, if a lumbar puncture was performed, cerebrospinal uid (CSF) analysis consisted of visual xanthochromia or red blood cells (RBCs) in the nal tube, which might not be the most accurate methods in detecting subarachnoid blood, as stated later on (13). A second study was published in 2012 and had a retrospective design. Two hundred and y patients were included, all suspected of having a SAH, with a maximum Glasgow Coma Scale score and no focal neurological de cits. Of the 137 pa- tients who had a CT performed within 6 hours a er ictus, a SAH was visible in 68. e remaining 69 patients had a lumbar punc- ture. CSF was analysed using absorption spectrophotometry. CSF analysis was positive for bilirubin in only one patient. is patient had presented with neck pain and sti ness without headache, and appeared to have bled from a cervical arteriovenous malformation. e sensitivity of CT cerebrum within 1 hour was 98.5% (95% CI 92.1–100), including this patient. If only patients presenting with acute headache were included in the analysis, the sensitivity in- creased to 100% (95% CI 94.6–100). is study showed a sensitivity of 92.3% (95% CI 79.1–98.4) for CT performed a er 6 hours (but within 10 days a er ictus) (14).

Thunderclap headache in secondary headaches (4)

Thunderclap headache in primary headaches

More common causes

• Subarachnoid haemorrhage (8) • Reversible cerebral vasoconstriction

syndrome (39,41)
• Cervical artery dissection (45–47) • Cerebral venous sinus thrombosis

(48–51)
• Spontaneous intracranial hypotension

(52–54)
• Stroke (ischaemic, haemorrhagic)

(56–60)
• Pituitary apoplexy (61–63)

• Primary cough headache (4) • Primary headache associated

with sexual activity (4) • Primary thunderclap

headache (4)
• Primary exercise headache (4)

Miscellaneous causes

• Retroclival haematoma (64,65) • Meningitis or vasculitis (59) • Acute hydrocephalus (aqueduct

stenosis (67)/colloid cyst (68) • Sinusitis (66)
• Cardiac cephalalgia (70,71) • Phaeochromocytoma (69)

In the past, the sensitivity of unenhanced head CT for the detec- tion of a SAH was reported to be between 90% and 98%. Two studies report a sensitivity of 100% if CT is performed within 6 hours a er headache onset. e rst report is a prospective study from 2011, which investigated 3132 alert patients without focal neuro- logical de cits, with headache peaking in intensity within 1 hour. In patients with a negative head CT, a SAH was ruled out by either lumbar puncture or a 6-month follow-up. Overall sensitivity of CT

Thunderclap headache in neurologically intact patient

Figure 34.1 Diagnostic evaluation of neurologically intact patients with thunderclap headache.
CT, computed tomography; CT-A, computed tomographic angiography; SAH, subarachnoid haemorrhage; CSF, cerebrospinal uid; DSA, digital substraction angiography.

SAH hours

Positive Negative

CT-A

Aneurysmal SAH

Head CT

CT > 6 hours

CT < 6

SAH without confirmed aneurysm

Lumbar puncture > 12 hours after onset

No SAH

Positive

Perimesencephalic blood distribution on head CT

No typical perimesencephalic blood distribution on head CT

SAH confirmed

Positive for blood breakdown products

Negative for blood breakdown products

Consider other causes of thunderclap headache

Evaluate CSF opening pressure and cell count

Perimesencephalic SAH

DSA

Negative

Consider repeat DSA

In conclusion, in patients presenting with acute headache with a normal level of consciousness and no focal neurological de cit, a normal head CT performed within 6 hours is su cient to exclude a SAH. Evidence is based on studies in which CT scans were in- terpreted by a quali ed (neuro-)radiologist. In patients presenting more than 6 hours a er ictus, a negative CT is insu cient to rule out a SAH. In these cases, CSF analysis in indicated, preferably by means of spectrophotometry.

False-positive CT results can be seen as a result of radiological SAH mimics, also called pseudo-SAHs. is mostly applies to pa- tients with raised intracranial pressure, such as cases of cerebral oe- dema or bacterial meningitis. e increased intracranial pressure forces CSF out of the subarachnoid space. Meanwhile, engorgement of venous structures causes increased attenuation of the subarach- noid space on CT, mimicking a SAH. Additionally, the attenuation of the brain parenchyma decreases as a result of brain swelling. Leakage of intravenous contrast into the subarachnoid space is an- other potential SAH mimic on CT (15,16). False-positive CT results can be harmful to the patient due to redundant invasive examin- ations, and because it moves the focus away from other secondary causes of thunderclap headache.

Lumbar puncture and CSF analysis

Blood in the subarachnoid space can be detected by CSF ana- lysis. erefore, a lumbar puncture is the next step in excluding or identifying a SAH, unless a SAH is su ciently excluded by head CT within 6 hours. In patients with a negative head CT done 6 hours or more a er ictus, approximately 5% turn out to have a SAH, fol- lowing positive CSF analysis (14). It is also recommended that CSF opening pressure is measured as well. Although not contributing to identifying a SAH, CSF pressure can be helpful in analysing other secondary causes of thunderclap headache such as cerebral venous thrombosis, once a SAH is excluded.

Methods for CSF analysis

ree methods of CSF analysis for the diagnosis of a SAH are in use, namely RBC count and the detection of breakdown products by xanthochromia and spectrophotometry. In our opinion, the latter is thought to be most reliable, but there are no studies available com- paring these three methods, and local preferences di er. e main- stay of CSF analysis in the UK is spectrophotometry, whereas visual inspection and RBC count is more widely used in the USA (17). In all three methods, the distinction between a SAH and a traumatic puncture can be challenging. Waiting to perform lumbar puncture at least 12 hours a er ictus may be of great value. False-positive re- sults can be harmful to the patient because of subsequent unneces- sary cerebral angiography, while a false-negative outcome results in the risk of a re-bleed in an untreated aneurysm.

e reported method of analysing CSF within 30–60 minutes a er ictus is RBC count in the CSF but should be avoided. RBCs also emerge into the CSF in the case of a traumatic tap. A decrease in the number of RBCs in successive tubes is said to indicate a traumatic puncture, but if a patients does, indeed, have a SAH and a traumatic puncture is performed, the number of RBCs will decrease in succes- sive tubes anyway. e conclusion that a SAH is ruled out would be incorrect. Additionally, there is no de ned threshold for the number of RBCs in the CSF indicating a SAH.

Analysis of blood breakdown products is considered most reli- able in making a distinction between a SAH and a traumatic punc- ture. Breakdown products can be detected within 12 hours a er ictus and remain detectable for at least 2 weeks (18). Haemolysis of erythrocytes a er a SAH leads to the release of oxyhaemoglobin in the CSF. rough enzymatic reactions, oxyhaemoglobin is further degraded to bilirubin by macrophages, which occurs in vivo only. In CSF tapped a er 12 hours of the ictus, oxyhaemoglobin can still be the result of a traumatic puncture, but bilirubin indicates an earlier haemorrhage (17,19). ere are two exceptions: bilirubin is also de- tectable in the CSF in case of serum hyperbilirubinaemia, or when CSF bilirubin is raised as a result of a high CSF albumin, to which bilirubin binds. e combination of pre-existing CSF bilirubin and oxyhaemoglobin due to a traumatic puncture can be misleading. erefore, to rule out a false-positive result, serum bilirubin con- centration and CSF protein level should be measured if CSF analysis is positive (20). Tapped CSF should not be exposed to light because light increases the rate of bilirubin degradation.

Once a puncture is performed 12 hours a er the ictus, there are two methods with which to detect bilirubin in the CSF. e most basic method is visual evaluation of CSF, based on the yellowish discolouration of CSF containing bilirubin, called xanthochromia. e sensitivity of this procedure is limited because human colour vision is insu cient to detect small amounts of bilirubin and it is di cult to di erentiate the colours of haemoglobin and bilirubin (17,21,22). CSF pigments can be analysed more reliably with spec- trophotometry, in which the absorption spectrum is measured for several haeme pigments in the CSF (17,23). is requires special equipment and understanding of the time course of development of haeme pigments.

A lumbar puncture is frequently complicated by post-lumbar puncture headache. More hazardous complications, such as infec- tions and subdural haematoma, are rare.

Negative head CT and negative CSF analysis

ere are a few case reports of patients with a negative head CT and lumbar puncture who appeared to have an aneurysm (24). However, asymptomatic aneurysms are reported in about 2–3% of the popu- lation (25,26). e yield of searching for, and possibly treating of, an unruptured aneurysm is unclear. Besides, prospective studies do not support the need for angiography in patients with negative head CT and negative CSF analysis (27). e chance of detecting an asymp- tomatic aneurysm, the potential risks related to invasive examin- ations, patient discomfort, and the cost of further examination and extended hospital admission should be balanced against the slight risk of missing a SAH if analysis is terminated as this point.

SAH con rmed: aneurysm detection

Once a SAH is diagnosed, further investigation is focused on the detection of an aneurysm, which is found in approximately 85% of cases (8). Although intra-arterial digital subtraction angiography (DSA) is the gold standard, CT angiography (CTA) is currently the most feasible investigation to start with. CTA is non-invasive, readily available in the emergency setting, and it can be performed immedi- ately a er blood is detected on unenhanced CT. In most cases, CTA is also accurate in determining feasibility for coiling. erefore, the decision between open neurosurgical clipping and endovascular

CHAPTER34 Thunderclapheadache

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management can be made within a short time. e sensitivity of CTA in detecting cerebral aneurysms was investigated in a meta-analysis. Forty- ve studies were included, comprising 3643 patients, of whom 86% were investigated because of a non-traumatic SAH. e sensi- tivity of CTA in detecting an aneurysm in a patient was 97.2% (95% CI 95.8–98.2), speci city was calculated to be 97.9% (95% CI 95.7– 99.0), with DSA as the reference standard. Higher-class CT con- taining 16 or 64 detector rows is more sensitive, which is especially meaningful in the detection of smaller-sized aneurysms (< 4 mm) (28). DSA is currently not the examination of rst choice because it is a time-consuming and invasive procedure, with potential risks of complications: groin haematomas occur in 4.2% of patients, stroke with permanent de cit is seen in 0.14% of cases, and death occurs in 0.06%. An increased risk of neurological complications is seen in patients investigated because of a SAH (29). e advantage of DSA is the opportunity to perform endovascular coiling at once, when- ever this seems feasible. An alternative for CTA or DSA is magnetic resonance angiography (MRA). MRA is non-invasive and radiation- and contrast-free. Accuracy is good, but feasibility is poor in the set- ting of a SAH, owing to limited availability in the emergency setting, longer scan time, and patient-speci c contraindications to undergo magnetic resonance imaging (MRI) (30,31).

In conclusion, the search for an aneurysm in patients with a con- rmed SAH starts with a CTA. If no aneurysm is seen on CTA, and blood distribution is typical for a perimesencephalic haemorrhage, it is reasonable to end the work-up (8,32). In all other cases, a negative CTA should be followed by DSA. e yield of repeat DSA a er initial negative CTA and DSA is under debate. ere should not be an in- nite search for an aneurysm, knowning the signi cant rate of non- aneurysmal SAHs. However, several cases of aneurysms detected on a second DSA are reported, even a er a negative CTA (33–35). In the situation of a lack of consensus, clinician preference and patient characteristics in uence to which extent patients are analysed.

Prognosis

e mortality rate of SAHs is high. Ten to een per cent of pa- tients die before reaching the hospital. Additionally, the 30-day case fatality rate is 28.7–36.5% in hospitalized patients (36,37). In untreated aneurysmatic SAHs, the risk of a re-bleed is estimated to be up to 12% in the rst 24 hours (11). In patients who survive the rst day, the risk of a re-bleed in an untreated aneurysm is approxi- mately 40% in the next 4 weeks. Eighty per cent of the patients who experience a re-bleed die or remain disabled (8). To prevent a re- bleed in aneurysmatic SAHs, the aneurysms can be treated by either endovascular coiling or open neurosurgical clipping. About 10% of SAHs are due to a non-aneurysmal perimesencephalic haemor- rhage. Treatment in these patients is supportive, with analgesics and control of blood pressure, and outcomes are excellent (8,38).

Other secondary causes of thunderclap headache

e primary focus in thunderclap headache is directed on detecting or excluding a SAH. Once a SAH is excluded, it is mandatory to exclude a range of conditions, as stated in the ICHD (4). ese sec- ondary causes of thunderclap headache are discussed in the fol- lowing subsections and in Table 34.1.

Reversible cerebral vasoconstriction syndrome

Recurrent attacks of thunderclap headache over a few days are the most common presenting symptom of RCVS (see also Chapter 49). e headache is of severe intensity with a peak within 1 minute (4). Headache can last for minutes up to days, but usually resolves a er 1–3 hours. Patients may report nausea, vomiting, photophobia, and phonophobia. Focal neurological de cits are seen in 8–43% of the cases. Patients experience an average of four attacks in 1–4 weeks. A moderate headache can persist between these attacks (39). RCVS can be complicated by focal or generalized seizures. Haemorrhages and ischaemia may cause transient or permanent impairment. Several conditions are known to trigger an attack in RCVS, among which are sexual activity (before of just at orgasm), exer- tion, Valsalva-like manoeuvres, emotions, bending, bathing, and showering (4). e pathophysiology of RCVS and its time course are not yet fully established. Ducros et al. (40) suggested that alternating vasoconstriction and vasodilatation starts in smaller vessels and progresses towards medium- and large-sized vessels. underclap headache may be triggered by stretching of vessel walls. Early in the course of disease, haemorrhages may be seen as a result of small- vessel rupture or reperfusion injury. A er disease progresses to larger vessels, secondary vasoconstriction in these vessels may cause watershed infarction. RCVS is slightly more common in women than in men, with a mean age of onset of 42 years. Several clinical conditions are associated with RCVS. e most common are preg- nancy, the postpartum period, exposure to vasoactive medications such as selective serotonin reuptake inhibitors, triptans, and recre- ational drugs, such as cocaine and cannabis. Any of these conditions is seen in at least half of the cases (4). Other associated conditions are the exposure to blood products, catecholamine-secreting tu- mours and vascular disorders as unruptured aneurysm and cervical artery dissection (39,41). RCVS seems to occur more frequently in patients having migraine, and migraine patients are prone to evolve the haemorrhagic complications of RCVS.

Fi y- ve per cent of patients with RCVS have normal head CT or MRI at initial presentation. Vasoconstrictions may not be observed in the early stages of RCVS. However, most patients evolve abnor- malities in the course of the disease (42). Convexity SAH is not only suggestive of RCVS, but can also be seen in amyloid angiopathy, most o en seen in the elderly. CT may show parenchymal haemor- rhage early in the course of the disease. Cerebral infarction is seen in a minority of patients, mostly occurring in the second week. Brain oedema can be seen as well, with a similar distribution as in pos- terior reversible encephalopathy syndrome (43). e gold standard for diagnosing the alternating pattern of vasodilation and vasocon- striction seen in RCVS is cerebral angiography. Indirect methods such as CTA and MRA are non-invasive and seem to be a good al- ternative to show the strings-of-beads pattern. Comparative studies are not available. Because the disease is suspected to a ect smaller arteries rst, and disease in these arteries is di cult to see, negative vascular examination should be repeated a er 1–2 weeks. At that time, vasoconstriction and vasodilatation of middle-sized and large arteries may be seen. Vasculitis may also cause vessel irregularity, but thunderclap headache is less likely in vasculitis. Transcranial Doppler may show vasospasm in RCVS. Abnormalities in blood ow are usually not as severe as seen in patients with an aneurysmal SAH (44). CSF abnormalities occur in a minority of patients with

RCVS and may include a raised protein concentration or raised white blood cell count.

RCVS is a self-limiting condition. Vasoconstriction resolves ei- ther partially or completely within 12 weeks. Management of RCVS is based on expert opinion. Patients are recommended to rest for several weeks. Triggers of thunderclap headache such as physical exertion and vasoactive drugs should be avoided. Pain should be controlled by analgesics. Empirical therapies to control vasospasm include nimodipine, verapamil, and magnesium sulfate. Blood pressure should be monitored carefully, aiming for normotension. Hypertension should be treated with caution, considering the risk of watershed infarction related to hypotension.

Cervical artery dissection

underclap headache can be the presenting symptom of a cervical artery dissection. Pain in the head and neck are common features of cervical dissection, o en accompanied by other symptoms such as Horner’s syndrome, cranial nerve palsies and retinal and cere- bral ischemia. It is a major cause of strokes in young adults. Pain in the head is thought to be referred pain. It usually occurs ipsilat- eral to the dissection, but bilateral pain is reported as well. In ver- tebral arterial dissection, cervical and occipital pain are frequent. Temporal and frontal pain is reported in cervical artery dissections more o en (45,46). An analysis of 1027 patients with a spontaneous cervical artery dissection showed headache in 71.1%. Pain was more intense in vertebral artery dissection than in carotid artery dissec- tion. underclap headache, which was not further speci ed in this study, was seen more o en in vertebral artery dissection. e overall incidence of thunderclap headache was 5.4%. However, a signi cant number of patients also had a SAH related to the dissection (47).

Cerebral venous sinus thrombosis

CVST presents with headache in 80–90% of cases (see also Chapter 37). Headache is usually accompanied by other symp- toms such as focal neurological deficits, altered mental state, or seizures. However, CVST can be seen in patients presenting with a headache as the sole manifestation, even if head CT and CSF pressure are unremarkable (48,49). There is no identifiable uni- form pattern of headache in CVST (50). Patient series of CVST have shown thunderclap headache in 2.4–14% of cases (48–51). Some patients are more susceptible to developing a CVST. This applies, in particular, to patients in a hypercoagulability state, such as genetic coagulability disorders, sepsis, and hormone- related hypercoagulability, such as pregnancy, the postpartum period, and the use of oral contraceptives. Structural damage to the sinuses after head trauma is a risk factor as well. MRI is the imaging method of choice to visualize a thrombus, and may also show complications such as oedema, intracerebral haemorrhage, or venous infarction. Imaging of the venous sinuses by MR ven- ography or CT venography is useful to demonstrate the absence of flow in the occluded venous sinuses. In all patients with thun- derclap headache analysed with lumbar puncture, opening pres- sure should be measured. A raised opening pressure (> 250 mm CSF) raises the suspicion on a underlying cause of thunderclap headache, such as CVST. Relief of the headache after CSF tap sup- ports this. However, a raised CSF opening pressure is neither sen- sitive nor specific for CVST.

CHAPTER34 Thunderclapheadache Spontaneous intracranial hypotension

In case of spontaneous intracranial hypotension patients experience orthostatic headache, which may be accompanied by neck sti ness, tinnitus, and diplopia (see also Chapter 38). An acute severe head- ache is reported in 14–16% of patients, although a recent small series showed a higher incidence (52–54). Intracranial hypotension is due to a spinal CSF leak. Characteristic features on head MRI are down- ward displacement of the brain, di use pachymeningeal enhance- ment, and subdural uid collections (55). Lumbar puncture is not recommended to diagnose intracranial hypotension, but low CSF pressure can be an incidental nding in the analysis of a patient with headache. Liquor hypotension is de ned as a CSF pressure < 60 mm CSF (4).

Stroke

underclap headache as isolated symptom may rarely be the pre- senting feature of an ischaemic stroke, as described in a few case reports (see also Chapters 10 and 37). Patients had experienced a thunderclap headache, a er which neurological examination, head CT, and CSF analysis were normal, but di usion-weighted MRI showed acute cerebral ischaemia. One of these case reports de- scribed normal MRA as well, but in the other reports speci c causes of stroke, such as cervical dissection or RCVS, were not excluded (56–58). Patient series of thunderclap headache report cases of par- enchymal and intraventricular haemorrhages as well; however, these series do not report whether patients had de cits on neurological examination, suggesting a stroke at presentation (59,60).

Pituitary apoplexy

Pituitary apoplexy was the cause of thunderclap headache in some case reports. Patients present with sudden onset of severe head- ache, which is followed by nausea, vomiting, visual disturbance, and diplopia in the next few hours to days. e initial presentation can mimic a SAH. Pituitary apoplexy is most o en caused by haemor- rhage into a macroadenoma of the pituitary gland. Diagnosis can be challenging because pituitary apoplexy is easily missed on head CT (61–63).

Miscellaneous causes of thunderclap headache

A few cases of thunderclap headache are reported in patients with a retroclival haematoma (64,65), meningitis (6,59), sinusitis (66), and aqueduct stenosis (67). Colloid cysts of the third ventricle may pre- sent with attacks of abrupt severe headache, resolving abruptly a er change of position (68). Recurrent episodes of thunderclap headache are reported in phaeochromocytoma (69). Headache during an epi- sode of cardiac ischaemia, knows as cardiac cephalalgia, rarely pre- sents with a thunderclap headache as the sole manifestation (70,71). Acute glaucoma may present with thunderclap headache as well.

Primary headaches

Primary thunderclap headache refers to high-intensity headache of abrupt onset in the absence of intracranial pathology. e max- imum pain intensity should be reached within 1 minute, whereas the pain should last at least 5 minutes. As thunderclap headache is o en

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caused by serious intracranial disorders, particularly SAH, extensive examination of an underlying cause should be negative (this means normal brain imaging, including the brain vessels, and normal CSF) to make the diagnosis of primary thunderclap headache (4). Cervical vascular imaging should also be considered.

underclap headache can also be related to cough, exercise, or sexual activity (see also Chapters 24 and 25). Primary cough head- ache arises moments a er the cough and reaches maximum intensity immediately. Primary headache associated with sexual activity usu- ally starts as a dull ache as sexual excitement increases and suddenly exacerbates at orgasm. ese two types of primary headache may recur with the recurrence of respectively coughing or sexual activity (4). Distinction should be made with RCVS, in which sexual activity is one of the possible triggers for an attack (see also Chapter 49). Some cases of sudden severe headache during weightli ing are re- ported, ful lling criteria for primary exercise headache (72).

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Headache associated with head trauma

Sylvia Lucas

Introduction

Traumatic brain injury (TBI) has become an extremely important global health issue in the past several years. Considerable atten- tion and interest has focused on several populations susceptible to TBI: soldiers deployed in war zones, professional athletes and young people involved in school sports activity, and civilians engaged in usual activities of daily living who may be involved in motor vehicle accidents, falls, or assaults, among other injuries.

In the USA, approximately 2.5 million civilian TBIs occurring each year present for medical attention. In 2010, e Centers for Disease Control estimated that 87% of those were treated and re- leased from emergency departments (ED), 10% were hospitalized and discharged, and 2% died (1). ese numbers do not account for persons with TBI who never receive medical attention or have o ce- based outpatient visits, or for those receiving care at federal facilities such as in military or Veterans Administration hospital systems. In the USA there is limited information on TBI-related disability, with estimates ranging from 3.2 to 5.3 million persons living with dis- ability 1 year a er injury (2).

In the USA, 75% of TBI is classi ed as mild TBI (mTBI), whereas in a New Zealand cohort, 95% of brain injuries were mTBI (2). e aetiology of mTBI is di erent in di erent age groups. For example, falls are the most common cause of mTBI in children aged 0–4 years and in adults over the age of 75 years (1,3). Rates of TBI-related ED visits increased the most for those younger than 4 years of age, who have the highest rate of injury of any age group, with almost twice the rate of those in the next highest age group (15–24 year olds). Although rates of TBI have increased, particularly in men, civilian deaths have declined in the past decade, likely from industry im- provements in air bag technology for vehicle occupants and seat belt requirements in motor vehicles, protective helmet design for use in sports activities and two or three-wheeled vehicle use, and other public health-driven protective measures.

Sports-related head injuries, almost always resulting from mTBI, may be underestimated for reasons other than not seeking care by medical professionals or others who could report injury rates. Many athletes, especially younger players, may not recognize symp- toms of concussion or head injury; others may minimize their in- jury or will not report an injury because of a strong desire to remain in the game. e incidence of sports-related concussion has been

estimated at 3.8 million events per year in a population of 44 mil- lion children and 170 million adults in organized sports activity participation (4).

e most common aetiology of the additional TBI burden in mili- tary or civilian personnel in active military missions in Iraq, Syria, or Afghanistan is exposure to combat-related explosions with approxi- mately 80% of mTBI secondary to blast exposure (5,6). Injury to military personnel reported by the Congressional Research Service show a total of 327,299 TBI cases between 1 January 2000 and 5 June 2015 with 269,580 mild, 27,728 moderate, 8,287 penetrating or se- vere, and 21,704 not classi able (7).

Post-concussive symptoms

Concussion is a symptom manifestation of a TBI, but the term ‘concussion’ and mTBI are not synonymous. Headache is the most common physical symptom following TBI; however, it may not occur in isolation. Headache may be part of a symptom complex known as the post-concussion syndrome (PCS) comprising physical or somatic, psychological, and cognitive symptoms (8,9). One pro- spective, longitudinal study of symptoms following 1 month a er TBI reported the most common symptoms as fatigue, headache, dizziness, memory trouble, trouble sleeping, trouble concentrating, irritability, blurred vision, anxiety, increased light, and sound sen- sitivity (10). Severity of brain injury was correlated with number of symptoms and more severe injuries tended to be associated with a greater proportion of cognitive and psychological symptoms in add- ition to physical symptoms. Studies of sports concussions report that females have higher rates of concussion and have greater post- concussion cognitive changes (4,11). When comparing the same sports, such as so ball/baseball, girls have almost twice the rate of concussion than boys (12,13), which may be from biomechanical (e.g. smaller head/neck mass or head-to-ball mass ratios, or weaker neck muscles) (11), or sociological factors, or both.

Post-traumatic headache

Posttraumatic headache (PTH) has no de ning clinical features, and is classi ed as a secondary headache disorder in the International

Classi cation of Headache Disorders, third edition (ICHD-3) (Box 35.1) (14). A secondary headache is a headache that occurs in close temporal relation to another disorder that is presumed to cause the headache, or ful ls other criteria for causation by that disorder; the new headache is coded as a secondary headache attributed to the causative disorder. Secondary headaches may have characteristics of primary headaches (migraine, tension-type headache, cluster head- ache, or one of the other primary headaches). is may be problem- atic in persons who have pre-existing primary headache disorders. If the headaches are worsened in frequency or intensity in close tem- poral relationship to the presumptive causative injury, then the new or worse headaches are de ned as PTH.

Primary headache disorders are described and classi ed on the basis of clinical symptoms and are thought to be genetically ac- quired syndromes that involve trigeminovascular pathway dysfunc- tion. Although the physiology of the primary headache disorders is not clear, animal models of neurogenic in ammation and cortical spreading depression (CSD), limited human imaging studies, and the response of migraine to a class of drugs known as ‘triptans’ (e.g. sumatriptan), which act as agonists at serotonin (5-HT) 1B/1D re- ceptors, give us potential physiological pathways of head pain (15). PTH, as a secondary headache, is thought to have a structural or functional causation that, if corrected, would result in the resolution of the secondary headache. To support a temporal relationship be- tween injury and onset of headache, the ICHD requirement that

PTH occur within 7 days a er an injury does not necessarily ensure causation. Many reports of PTH occurring more than 7 days a er an injury have been published. In a prospective study of civilians with moderate-to-severe TBI, approximately 28% of new headaches were reported 3 months a er the injury (16). Following mTBI, 32% of hospitalized paediatric patients reported headache 2–3 weeks a er the injury (17). In a study of active duty US soldiers, only 27% of headaches were reported to develop within a week of mild head in- jury (18). If the ICHD classi cation of PTH is strictly adhered to, up to one-third of PTH could be underdiagnosed on the basis of la- tency constraints and therefore clinical judgement may be required to make causation.

Post-traumatic headache epidemiology

Despite headache being the most common symptom a er TBI, the prevalence has ranged from 30% o 90% in retrospective studies (19–22). Comparison of brain injury studies is di cult because of variability in subject selection, case ascertainment, TBI severity, in- clusion and exclusion criteria, and study length. Select epidemio- logical civilian adult and paediatric, as well as military studies are shown in Table 35.1 (10,16,23–33).

In one civilian prospective study of 452 people admitted to inpatient rehabilitation units a er a moderate-to-severe TBI, the majority

CHAPTER 35 Headache associated with head trauma

Box 35.1 International Classi cation of Headache Disorders criteria for post-traumatic headache

5.2.1 Acute headache attributed to moderate or severe traumatic injury to the head
Diagnostic criteria:

Associated with none of the following:

. (a) Loss of consciousness for > 30 minutes

. (b) GCS score < 13

. (c) Post-traumatic amnesia lasting > 24 hours

. (d) Altered level of awareness for > 24 hours

. (e) Imaging evidence of traumatic head injury, such as intracranial
haemorrhage and/or brain contusion

Associated immediately following the head injury with one or more of the following symptoms and/or signs:

. (a) Transient confusion, disorientation, or impaired consciousness

. (b) Loss of memory for events immediately before or after the head injury.

. (c) Two or more other symptoms suggestive of mild traumatic brain injury: nausea, vomiting, visual disturbances, dizziness, and/or vertigo, impaired memory and/or concentration

A B

Any headache ful lling criteria C and D.
Traumatic injury to the head associated with at least one of the following:

. 1 Loss of consciousness for > 30 minutes

. 2 Glasgow Coma Scale (GCS) score < 13

. 3 Post-traumatic amnesia lasting > 24 hours

. 4 Altered level of awareness for > 24 hours

. 5 Imaging evidence of traumatic head injury such as intracranial
haemorrhage and/or brain contusion.

Headache is reported to have developed within 7 days after one of the following:

. 1 The injury to the head.

. 2 Regaining consciousness following the injury to the head.

. 3 Discontinuation of medication(s) that impair ability to sense or
report headache following the injury to the head.

Either of the following:

. 1 Headache has resolved within 3 months after the injury to
the head

. 2 Headache has not yet resolved, but 3 months have not yet
passed since the injury to the head.

Not better accounted for by another ICHD-3 diagnosis.

Headache is reported to have developed within 7 days after one of the following:

. 1 The injury to the head

. 2 Regaining consciousness following the injury to the head

. 3 Discontinuation of medication(s) that impair ability to sense or report headache following the injury to the head.

Either of the following:

. 1 Headache has resolved within 3 months after the injury to
the head

. 2 Headache has not yet resolved, but 3 months have not yet
passed since the injury to the head.

Not better accounted for by another ICHD-3 diagnosis.

5.2.1.1 Persistent headache attributed to moderate or severe traumatic injury to the head
Diagnostic criteria: as for 5.2.1 except for D.

D Headache persists for > 3 months after the injury to the head

5.2.1.2 Acute post-traumatic headache attributed to mild traumatic injury to the head
Diagnostic criteria:

. A Any headache ful lling criteria C and D.

. B Injury to the head ful lling both of the following:

5.2.2 Persistent headache attributed to mild traumatic injury to the head
Diagnostic criteria: as for 5.2.1.2 except for D.

D Headache persists for 3 months after the injury to the head.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

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Table 35.1 Recent civilian and US active duty service member post-traumatic headache (PTH) studies.

Authors

Year/location

Number

Study design

Population

Key results

Blume et al. (23)

2012/US

462

Prospective cohort

Age 5–17 y;
mTBI = 402; moderate–

severe TBI = 60; controls = 122 (arm

injury)

mTBI HA prevalence: after 3 mo = 43%; after 1 y = 41%

Moderate–severe TBI prevalence: after 3 mo = 37%; after 1 y = 35%

Control 3 mo = 26%; after 1 y = 34%

Dikmen et al. (10)

2010/US

732

Prospective case–control

Age > 16y; any TBI

TBI after 1 mo = 55%; after 1 y = 26% (if HA the week before)

Erickson (24)

2011/US

100

Retrospective cohort

Headache clinic; 100 consecutive soldiers with chronic PTH

77% had blast-related PTH; > 95% met migraine criteria

Faux and Sheedy (25)

2008/Australia

100

Prospective ED; case–control

Age>16y; moderate–severe TBI

Prevalence at time of evaluation = 100% At 1 mo = 30%; at 3 mo = 15%

Hoffman et al. (16)

2011/US

452

Prospective in-person enrolment; telephone interview at 3,6, and 12 mo

Moderate–severe TBI

Cumulative incidence 1 y = 71%; baseline prevalence = 47%; at 1 y = 44%

Hoge et al (26)

2008/US

2525

Cross-sectional survey

Soldiers after 1 y Iraq deployment

HA the only symptom associated with concussion adjusting for mood disorder

Kuczynski et al. (27)

2013/Canada

670

Prospective ED cohort Retrospective chart

review of treatment cohort from brain injury clinic; telephone interview 7–10 d after injury and monthly until resolution

Age 0–18 y; mTBI

Prevalence of PTH at 16 days = 11%; at 3 mo=8%

ED cohort migraine = 54%
Clinic cohort migraine = 39% (mixed

HA, MOH, mood disorders with HA excluded)

Lieba-Samal et al. (28)

2011/Austria

100

Prospective telephone interview

Age 18–65 y (exclusions: whiplash;

medication overuse, pre-existing chronic PTH)

Prevalence of acute PTH 7–10 d = 66% All resolved by 3 mo; migraine/probable

migraine = 35%

Lucas et al. (29, 30)

2012/US 2014/US

452 212

Prospective in-person enrolment; 3, 6, and 12 mo telephone interview

Age>16y; 2012: moderate–

severe TBI; 2014 mTBI

Moderate–severe TBI study: migraine/ probable migraine = 52%; at 1 y = 54% mTBI study: cumulative incidence = 92%

Migraine/probable migraine = 49%; 1 y=49%

Stovner et al. (31)

2009/Lithuania

217

Prospective ED cohort; case–control; questionnaire at 3 mo and 1 y

Age 18–60; LOC < 15 min

Prevalence of HA at 3 mo = 65% Migraine at 3 mo = 19% and at 1 y = 21%

Theeler et al. (33,61)

2012/US 2012/US

1033

Cross-sectional, survey-based

Soldiers with concussion in post-deployment evaluation over 5 mo in 2008

HA in 98% of soldiers (PTH criteria in 37%). Migraine type = 89%; CDH = 20% (PTH criteria in 55%)

mTBI, mild traumatic brain injury; HA, headache; TBI, traumatic brain injury; ED, emergency department; MOH, medication overuse headache; LOC, loss of consciousness; CDH, chronic daily headache, mo, month; y, year.

Adapted from: Lucas, S. Post Traumatic Headache. In Headache and Migraine Biology and Management. Diamond S, ed. Elsevier, 2015; Headache, 53, 6, Theeler B, Lucas S, RIechers RG, Ruff RL, Posttraumatic headache in civilians and military personnel: a comparative clinical review, pp. 881–900, 2013.

were men injured in vehicle-related accidents, with an average age of 44 years. Seventy-one per cent reported headache during the rst year. Prevalence was 46% at the initial inpatient interview and remained high, with 44% reporting headache 1 year a er TBI. Headache consist- ency in this study (whether headache was reported at initial inpatient interview or at 3, 6, and 12 months a er the injury) showed that al- though 34% of this head-injured population never had a headache following the injury, 23% had headache at every time point at which they were interviewed (16). In a follow-up study by the same group, using a similar headache assessment, a cohort of 212 individuals ad- mitted to the hospital with mTBI and evaluated within 1 week a er TBI, 91% reported new or worse headache (compared with before the

injury) over the rst year. e prevalence of new or worse headache was 54% within the rst week of the injury and also remained high (58%) at 1 year a er injury. In this cohort, 18% had headache at no time a er injury and 41% had headache at all time-points a er in- jury (30). Other studies have also reported a higher prevalence of PTH a er mild versus more severe brain injury (3,20,21,34).

Post-traumatic headache risk factors

A prior history of headache was signi cantly related to PTH in sev- eral studies (16,27,28,30,31). Age appears to be inversely correlated

to PTH. Older age (> 60 years) had a lower prevalence of headache in a study of mTBI (30), as well as in a study of all severity levels of TBI (10). More controversial is whether females are more likely to have PTH than males. In the large, prospective studies discussed earlier, female sex was not a risk factor for new or worse PTH versus pre- injury in those following mild or moderate-to-severe brain injury (16,30). In a telephone interview of 168 patients 9–12 months a er concussion or suspected concussion, a Danish study reported an ad- justed odds ratio of 2.6 of women versus men for PTH (35). No sex di erence was found between girls and boys with persistent PTH in a paediatric study a er mild TBI either in an ED cohort or a clinic treat- ment cohort (27). Using a Veterans Administration 2011 database of over 470,000 Iraq and Afghanistan war veterans, headache diagnoses were found to be higher in women (18%) than in men (11%), with most of the di erence due to higher prevalence of migraine. When adjusted for prior history of primary headache disorder, PTH was found to be less prevalent in women than in men (36).

Although PTH is one of the most prevalent secondary headaches clas- si ed in ICHD-3 (14), there are no de ning clinical characteristics that would di erentiate a PTH from another primary or secondary headache disorder (37). Following a TBI of any severity, a variety of headache symptoms may develop without speci c location, severity, frequency, duration, or associated features, such as nausea, vomiting, photophobia, phonophobia, or presence of aura. In addition, the head- ache may change features from headache to headache or over time a er injury. Most PTH has clinical characteristics that are similar to the primary headache disorders, although some are not classi able ac- cording to ICHD-3 criteria. Whether phenotypic classi cation will be important as a diagnostic marker, guide successful treatment of PTH, or only be of epidemiological interest remains unknown. However, in an e ort to describe PTH and to target treatment according to clinical characteristics, many studies have used the classi cation criteria for primary headache disorders to characterize PTH (18–33) (Table 35.1).

Recent studies using classi cation criteria support migraine or probable migraine as the most common type of PTH. An early re- view suggested that the headaches meeting tension-type headache (TTH) criteria were the most prevalent PTH; however, ICHD diag- nostic criteria were not consistently utilized (19). In a large, longi- tudinal study of PTH following moderate-to-severe brain injury, migraine or probable migraine was the most common PTH pheno- type. Migraine or probable migraine was found in > 52% of those reporting headache at initial evaluation, and in 54% of those with headache at 1 year. In those with no prior history of headache, mi- graine or probable migraine was found in 62% reporting headache initially and in 53% at 1 year (29).

Migraine or probable migraine was also the most common head- ache phenotype in a large study of headache a er mTBI in civilians (30). ese two headache types were found in 49% of patients, up to a year a er injury, with TTH never > 40% of the total PTH types over that year. Importantly, these study populations are primarily males (> 71%) injured in vehicle accidents. e migraine or probable migraine headache type seen a er TBI appears to be much more fre- quent in males than would be seen in primary migraine or probable

migraine in the general population (38). Cervicogenic headache, a secondary headache with de ning clinical features, made up 10% or fewer of classi able headaches in these studies in which the major mechanism of injury was vehicle accidents (29,30).

Other studies of adult civilians in whom headache classi cation a er mTBI was reported state that migraine (or probable migraine) followed by TTH (or probable TTH) were the most common headache types found (28,39). In a large cohort of children evaluated in an ED, mi- graine was found to be the most common headache type, reported in 55% of those children who had headache a er mTBI (27). In studies reporting TTH as the most common PTH type a er mTBI (31,40,41), some potential factors underlying di erences in results might be selec- tion of subjects, inpatient or outpatient specialty clinics, a long interval between injury to evaluation, and retrospective chart review. Some studies will report more than one headache type and others will take a hierarchical view of headache, only reporting migraine type, while others may present the PTH as mixed headache types.

PTH frequency is higher in those who have more severe PTH such as the migraine type. Civilians who had migraine or probable mi- graine PTH types were most likely to describe headaches occurring several days a week or daily when compared to those with TTH or cervicogenic headache type (29). Whereas in the general population, 4–5% of those with headache have chronic daily headache (CDH) (42,43), 23% of patients a er moderate-to-severe TBI with migraine or probable migraine headache type reported a headache frequency of 15 days of headache per month or more over the year a er TBI (29). A er mTBI, of those who experienced headache several times a week or daily, 62% of the headache types were migraine or probable migraine (30). In another civilian population-based study, head and neck injury accounted for about 15% of CDH cases (44).

Although uncommon, some PTH phenotypes can present with clinical features of hemicrania continua (45), chronic paroxysmal hemicrania (46), short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) syndrome (47), and cluster headache (48). Although no signi cant relationship has been found between acute neuroimaging abnormalities and the presence or absence of PTH in a study of moderate-to-severe brain injury (49), secondary headache patterns associated with speci c craniocerebral injuries are reported. For example, leakage of cerebrospinal uid (CSF) can produce low CSF pressure headaches, or post-craniotomy head- ache can occur following surgical treatment of a TBI (50).

Sports-related post-traumatic headache

Approximately 20% of all civilian TBIs in the USA occurs in amateur athletic events through college level and is primarily mTBI (1,2,51). Approximately 90% of athletes are symptom-free within 1 month, but 10–20% may continue to have symptoms of PCS, including headache (52). Multiple episodes of TBI are more likely to have PTH that persists for longer than 1 month (53). One of the sports activ- ities with the highest risk of concussion is American football (4,54). ere have been several studies examining the relative playing pos- ition of athletes and intensity and frequency of contact, using both clinical evaluations, and visual and helmet-sensor information. Not surprisingly, o ensive and defensive linemen, for example, may have frequent, short distance, lower-magnitude impacts, whereas run- ning backs, wide receivers, linebackers, and even quarterbacks, may

CHAPTER 35 Headache associated with head trauma

Clinical characteristics of post-traumatic headache

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experience fewer, but greater magnitude, head impacts due to high- speed tackling (55). In a study of 730 National Collegiate Athletic Association Division I football championship series athletes using a self-report questionnaire, there were no signi cant di erences be- tween diagnosed concussions and player position; however, there were signi cant di erences in undiagnosed concussions based on reported post-concussive symptom frequency, the most being ‘bell rung’, dizziness, and headache. O ensive linemen returned to play or practice while experiencing symptoms more o en than other pos- ition groups (56). ose who sustain more frequent, but lower inten- sity, head impacts, such as the linemen in this study, may see these symptoms as routine as they are experienced so o en; the clinical relevance to brain function and long-term risk of neurodegeneration may not be appreciated until years in the future (57).

Military combat-related TBI is complicated by extreme physical and psychological conditions of war (58). Many combat-related PTHs develop following blast exposure, although rarely is this an isolated causative mechanism and may include blast exposure followed by blunt trauma when hitting a vehicle or the ground (32,59,60). In one report, > 80% of 978 US Army soldiers reporting headaches a er re- turn from deployment were exposed to ve or more blasts occurring within 60 feet (61). Similarly to the civilian population discussed earlier, PTH in this setting also may have a delayed onset beyond the 1-week latency requirements of the ICHD. In recently deployed soldiers, almost 40% of PTHs began within the rst week a er the mTBI, but 20% were reported within the rst month and approxi- mately 40% a er the rst month (32).

Also similar to studies in a civilian population, is the high preva- lence of the migraine phenotype in PTH, as well as a high prevalence of chronic headache syndromes in the military. Recent studies in military and Veteran populations found occurrence of the migraine phenotype in 60–97% of cases, depending on the study population and methodology (18,32,62,63). Migraine was 5.4 times more likely in those who sustained a concussion than in those who did not (58). While migraine is also the predominant headache phenotype in this population, other headache types such as tension type, continuous headache, and cluster type did occur (18,64). CDH (> 15 days of headaches per month, > 4 hours per day) was common. Of 978 US Army soldiers with deployment-related concussion, 20% reported headaches on 15 or more days per month in the preceding 3 months, with a median of 27 headache days per month (65). Similarly, of 100 US Army soldiers with chronic PTH seen in a headache clinic, the average headache frequency was 17 days per month (62). Migraine features are present in 70% or more of the chronic PTH disorders in the military studies (58).

Post-traumatic headache mechanisms

Although there are animal models of PTH, the relevance of ndings using these models to human headache mechanisms is di cult to determine.

As headache is the most common symptom a er TBI, the ini- tiation, as well as the persistence, of PTH may be linked to the physiological changes with TBI. e clinical similarities between the primary headache disorders and the PTH phenotypes may indicate shared physiological changes that develop a er TBI and those seen in the primary headaches. Despite the mechanism of the initial injury and the magnitude of brain dysfunction, longer- term consequences of the initial injury, for example following subarachnoid haemorrhage, may initiate di erent and unique physiological changes, depending on the damage from initial injury.

Although the brain injury itself can cause extensive changes in all brain tissues, a reactive TBI response is also important and may have positive or negative long-term consequences. Changes associ- ated with in ammation, including cytokine up- or downregulation, cerebral metabolic and haemodynamic alterations, axonal and glial injury, and neuropeptide and neurotransmitter activity abnormal- ities, have been reported a er TBI.

Increased cytokine concentrations in the central nervous system (CNS), primarily driven by activated glia a er injury are seen al- most immediately. Post-mortem studies have shown elevated mes- senger RNA levels of interleukin 1, 6, and 10, and tumour necrosis factor- α (66). Elevated cytokine concentrations may have both pro- and anti-in ammatory functions in the postinjury response, and, in turn, a ect permeability of the blood–brain barrier (BBB) (67) and the initiation of pain (68). Repetitive or prolonged micro- glial activation may be an important mechanism occurring with repetitive head trauma, as continual release of potentially pro- in ammatory cytotoxins could contribute to progressive symp- toms (69,70). Direct BBB injury or a transient response to the injury exposes the brain to in ammatory and other components of peripheral blood into the CNS, which in itself can result in neur- onal and glial changes that are indirect consequences of the injury. is can result in chemokine tra cking into the CNS, change in regulation of matrix metalloproteinases and Toll-like receptors among other mediators of in ammatory responses, which can af- fect neuronal-to-glial signalling, and even sensitization and main- tenance of pain (71).

e mechanism that links TBI to postinjury headache is the subject of intense current research. Several likely important physio- logical processes may result from changes in meningeal, neuronal, glial, and vascular structural or functional changes that can lead to CSD (72) and trigeminovascular activation (73) following TBI.

Either CSD or trigeminovascular activation can increase calci- tonin gene-related peptide levels, which may be involved in vaso- dilatation, neuroin ammation, and pain (74). Current research e orts are also focused on nding diagnostic markers for TBI, and common data elements have been de ned by the Biospecimens and Biomarkers Working Group (75).

New imaging techniques, although not in clinical use, have con- tributed to ndings in those with PTH a er injury. Di usion tensor imaging techniques showed decreases in fractional anisotropy in white matter tracts of patients developing chronic pain a er TBI (76), and functional magnetic resonance imaging a er TBI showed a disruption in the default mode network (77). No de nitive rela- tionships between structural or functional imaging as biomarkers a er TBI and PTH have been found to date.

Post-traumatic headache in US soldiers and Veterans

PTH management

e treatment of PTH is empirical, and for many practitioners, typing the headache according to primary headache clinical char- acteristics may serve as a guideline for management, but no de ni- tive studies regarding medical management or the validation of this approach have been done. O en, TBI may be accompanied by other, severe injuries which may be addressed acutely with headache evaluated much later a er injury. ose with PTH may seek care only if the headache becomes disabling, interfering with work or social function. ere are many practitioners who may be involved with the care of a patient with PTH. If other injuries are still clinic- ally important, a TBI clinic or rehabilitation clinic may be assessing PTH. Less o en, a patient with PTH may seek a headache specialist or neurology clinic. Most PTH, however, is managed by a primary care practitioner or sports medicine specialist, if the injury is sports related.

Self-treatment of headache a er TBI with over-the-counter (OTC) medication is the most likely treatment. In a study of 212 patients a er mTBI, with a prevalence of headache not less than 58% of patients within 1 year a er injury, > 75% of those with headache used acetaminophen or a non-steroidal anti-in ammatory drug (NSAID). Less than 5% of this group used a triptan, despite a mi- graine or probable migraine-type headache being the most common headache type (30,78).

In a review of PTH interventions, including pharmacological and non-pharmacological treatment, there were no class I studies and one class II study of a non-pharmacological intervention (79). Several class III studies have been published (80–83), and the Defense and Brain Injury Center has recommended PTH treatment for deployed and non-deployed soldiers based on class IV evidence (84).

To date, expert opinion suggests treatment of PTH according to its clinical characteristics using primary headache classi cation criteria (85,86). Based on similar clinical characteristics of PTH to primary migraine, probable migraine, and TTH, as well as other primary headache disorders, it is reasonable to provide acute head- ache care using a strati ed approach. e goal of treatment of a PTH should be similar to the goal of treating a primary headache disorder: education regarding treating early with an e ective acute therapy such as a triptan for a migraine-type headache, avoidance of medication overuse, and maintenance of a headache diary or other means of evaluation of PTH and e ectiveness of treatment. Two treatment approaches are used for primary headaches such as mi- graine. Acute or abortive therapy treats a headache as it occurs and preventive therapy is used daily for high attack frequency, inability to use e ective, acute therapy, or when response is suboptimal (87). Acute and preventive therapies are discussed in detail elsewhere in this book.

Medication overuse in a PTH population can be problematic and result in persistent headache. Potential adverse e ects of overuse of any analgesic, such as gastritis or acute renal failure with prolonged high NSAID, is also of concern. is is likely because of high OTC use and self-treatment for headache (78), as well as treatment for other injuries such as musculoskeletal or joint injuries that can co- occur. Self-medication management may be a potential problem in those who have sustained a head injury. Assessment of cognitive limitations at the time of medication evaluation may necessitate the

CHAPTER 35 Headache associated with head trauma involvement of family members or caregivers when management

with any therapy is discussed.

Conclusion

Headache is the most common physical symptom following TBI of any severity. It is highly prevalent in both adult and paediatric ci- vilian, as well as military, populations. PTH has been classi ed in these populations using primary headache disorder classi cation criteria with the most frequent headache type meeting criteria for migraine or probable migraine. Currently, PTH management is em- pirical, with many providers using management strategies based on principles of strati ed care and clinical similarity to primary head- aches. is approach has not been validated, and whether or not similar phenotypes of primary headaches and PTH respond simi- larly to treatment is not known. Given the high incidence of TBI and prevalence of PTH, controlled, blinded clinical trials are needed to determine the most e ective management of PTH.

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321

Cervicogenic headache

Nikolai Bogduk

Introduction

Other forms of secondary headache share the feature that the source of pain lies within the head (1). Cervicogenic headache has the dis- tinction that, although the pain is perceived in the head, its source lies in the cervical spine. For these reasons, cervicogenic headache is less a form of headache and more a form of spinal referred pain. Consequently, the entity is more widely recognized by health pro- fessionals who treat spinal pain than it is by headache specialists or neurologists.

Historical background

e earliest reference to headaches and the neck can be traced back to 1860–1862 (2,3). e earliest, easily accessible publication is that of Holmes (4), who, in 1913, stated that headache could arise from the neck. Since that time, various theories as to its causes have been advanced but subsequently refuted (5–8).

No evidence has ever been provided for ‘ brositis’ (4), ‘rheum- atic headache’ (9–11), trigger points (12,13), or weakened bro- osseous insertions (14,15) as a cause of headache. ese conditions were diagnosed only on the basis of tenderness in the upper cervical muscles, but tender points in the neck occur in many forms of head- ache, including migraine (16–19), and are not indicative speci cally of a cervical source of pain.

In 1926, Barré proposed that vascular headaches of the vertebral artery could be caused by irritation of the vertebral nerve by arth- ritis of the cervical spine (20), but studies in laboratory animals have shown that electrical stimulation of the vertebral nerve does not in- uence vertebral blood ow (21), and the vertebrobasilar system is remarkably resistant even to intra-arterial injections of vasoactive agents (21).

Some authors have attributed headaches to cervical spondylosis (22–28), but no study has shown that cervical spondylosis is signi – cantly more common in patients with headache than in asymptom- atic subjects.

Neuroanatomy

e neuroanatomical basis for cervicogenic headache is well under- stood (6–8). e structure of the trigeminocervical nucleus provides the anatomical substrate for referral of pain from the cervical spine to the head. e grey matter of the pars caudalis of the spinal nucleus of the trigeminal nerve is continuous with the apical grey column of the spinal cord (29–34). Nociceptive a erents of the trigeminal nerve descend in the spinal tract of the trigeminal nerve, and send collat- eral terminals not only into the pars caudalis of the spinal nucleus, but also into the dorsal horns of the upper three segments of the cer- vical spinal cord (30). Within these segments, nociceptive a erents of trigeminal origin converge onto second-order neurons that also receive a erents from the upper three cervical spinal nerves. Also, cervical a erents converge on neurons subtended by other cervical a erents. is convergence allows for upper cervical pain to be re- ferred to regions of the head innervated either by cervical nerves (occiput and peri-auricular regions) or by the rst division of the trigeminal nerve (parietal and frontal regions, and orbits).

is neuroanatomy dictates that the principal catchment area for possible sources of cervicogenic headache lies among those structures innervated by the upper three cervical nerves. ese en- compass intracranial sources and spinal sources. Of the intracra- nial sources, the inferior surface of the tentorium cerebelli, and the dura mater of the posterior cranial fossa are innervated by cervical nerves found in the meningeal branches of the hypoglossal and vagus nerves (35); the dura mater of the clivus is innervated by the upper cervical sinuvertebral nerves; and the vertebral artery is innervated by the vertebral nerve, which is formed by sympathetic e erents and cervical a erents (21,36). Of the spinal sources, the ventral rami of the rst three cervical spinal nerves innervate the sternocleidomastoid muscle and trapezius (35); the C1 and C2 ven- tral rami innervate the atlanto-occipital and lateral atlanto-axial joints (37–39); the C1 dorsal ramus innervates the suboccipital muscles (35); the C2 and C3 dorsal rami innervate the larger pos- terior neck muscles and the C2–3 zygapophysial joint (40); and the C1–C3 sinuvertebral nerves innervate the C2–3 intervertebral disc

(41,42), and the transverse ligament and the alar ligament (43). e sensory innervation of the extracranial portions of the internal carotid artery has not been explicitly demonstrated, but is presum- ably also cervical in origin. To various extents, each of these struc- tures has been incriminated as a source of cervicogenic headache.

Physiology

Frederick Kerr (44) provided the rst physiological evidence of trigemino-cervical convergence. He mapped the sites in the C1–2 seg- ment of the spinal cord that responded to electrical stimulation of both the trigeminal nerve and the sensory roots of the C1 or C2 spinal nerves.

Modern studies have demonstrated neurons in the lateral cer- vical nucleus of the cat that respond to electrical stimulation of both the superior sagittal sinus and the greater occipital nerve (45), and neurons in the C2 spinal cord segment of the rat that receive input from both trigeminal and cervical a erents (46,47). e latter in- cluded wide dynamic-range neurons and nociceptive-speci c neurons, located in laminae V and V, and laminae I and II of the dorsal horn, which receive convergent input from Aδ and C bres.

Electrical or chemical stimulation of trigeminal a erents sen- sitizes central neurons and increases their responses to cervical stimulation (46,47). Reciprocally, stimulation of cervical a erents sensitizes the responses of central neurons to trigeminal stimula- tion. Stimulation of C bres in cervical a erents produce greater and more enduring increases in central sensitization than does stimu- lation of Aδ bres (46), and cervical input from muscle produces a greater and longer-lasting increase in neural excitability than does cutaneous input (47).

C1–2

95–100% 70–94% 45–69%

20–45%

C3–4

95–100% 70–94% 45–69%

20–45%

Adapted from Pain Medicine, 8, Cooper G, Bailey B, Bogduk N., Cervical zygapophysial joint pain maps, pp. 344–353. Copyright (2007) by permission of Oxford University Press.

CHAPTER36 Cervicogenicheadache

Studies in humans

Studies in human volunteers have demonstrated the patterns of referred pain that can occur from cervical structures to the head. Electrical stimulation of the dorsal rootlets of C1 produces frontal headache (48). Noxious stimulation of the greater occipital nerve produces headache in the ipsilateral, frontal, and parietal regions (49). Noxious stimulation of the suboccipital muscles of the neck produces pain in the forehead (50–53). Distending the C2–3 inter- vertebral disc, but not lower discs, produces pain in the occipital region (54,55). Distending the C2–3 zygapophysial joint with in- jections of contrast medium produces pain in the occipital region (56), as does distending the lateral atlanto-axial joint or the atlanto- occipital joint (57). In normal volunteers, all segments from the oc- ciput to C4–5 are capable of producing referred pain to the occiput. Referral to the forehead and orbital regions more commonly occurs from segments C1 and C2 (51).

Complementary studies in patients with headache have shown that some headaches can be relieved by anaesthetizing structures in- nervated by the C1, C2, or C3 nerves, such as the C2–3 zygapophysial joint (58–60), the lateral atlanto-axial joint (61–66), or the C3–4 zygapophysial joint (65,67). Of these, the C2–3 zygapophysial joint is the most common source, followed by the lateral atlanto-axial joint, and occasionally the joint at C3–4 (65–67).

Pain from particular structures or particular spinal segments does not consistently refer to speci c sites, but certain tendencies have been observed (Figure 36.1) (65). Pain from C2–3 tends to be per- ceived across the lateral occipital region and into the forehead and orbital region. Pain from C1–2 also tends to gravitate to the orbital region, but otherwise more o en occurs in the vertex or around the

C2–3

95–100% 70–94% 45–69%

20–45%

Figure 36.1

Maps of the distribution of pain in patients who were relieved of their headaches by controlled diagnostic blocks of the joints indicated. The shading re ects the proportion of patients who reported pain in the region indicated.

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ear. Pain from C3–4 tends to focus in the suboccipital region and upper cervical spine; when it does spread to the head, it is largely restricted to the posterior regions, sparing the forehead and orbit.

Contemporary con icts

e cardinal issue concerning cervicogenic headache pertains to the mode of its diagnosis. Neurologists are accustomed to diagnosing headache on the basis of clinical features, perhaps coupled with medical imaging. erefore, some neurologists sought to de ne and diagnose cervicogenic headache in this manner.

e clinical criteria, proposed in 1990 and revised in 1998 de- ned cervicogenic headache as a unilateral headache associated with evidence of cervical involvement, in the form of provocation of pain by movement of the neck or by pressing the neck, concur- rent pain in the neck, shoulder, and arm, and reduced range of mo- tion of the neck (68,69). Subsequent studies, however, showed that unilaterality was not unique to cervicogenic headache (70–72), nor was triggering of headache by neck movement or by pressure on the neck (73). Patients said to have cervicogenic headache have re- duced pressure-pain thresholds (74) and impaired muscle function (75), but their scores in these features overlap considerably those of normal subjects, so that a valid diagnostic criterion cannot be sup- ported. Similarly, radiographic abnormalities are either lacking in patients said to have cervicogenic headache (76,77), or have a distri- bution that overlaps that of normal subjects (78).

When tested for agreement between observers, the proposed clinical features of cervicogenic headache di er in their reliability. Whereas some were reliable, others lacked reliability (79,80). However, none has been shown to be a valid sign of a cervical source of pain.

Some authorities have developed a less dogmatic, clinical approach to diagnosis. Using a list of seven criteria, a diagnosis of cervicogenic headache could be o ered quali ed by two grades of certainty (Box 36.1) (81). A diagnosis of ‘possible’ cervicogenic headache could be o ered if patients had ‘unilateral headache’ and ‘pain starting in the neck’. Satisfying any three additional criteria promotes the diag- nosis to ‘probable’ cervicogenic headache. e clinical features most

strongly indicative of cervicogenic headache are ‘pain radiating to the shoulder and arm’, ‘varying duration or uctuating continuous pain’, ‘moderate, non-throbbing pain’, and ‘history of neck trauma’.

e de nitive diagnosis of cervicogenic headache, however, re- quires demonstration of a cervical source of pain. Currently, the only means of doing so is by the application of controlled diagnostic blocks. Diagnostic blocks circumvent the di culties of reliability and validity of clinical examination, and provide direct evidence of a cervical source of pain.

e revised criteria of the International Headache Society (IHS) re ect the tension between clinical diagnosis and diagnostic blocks

Box 36.2 Diagnostic criteria for cervicogenic headache

Description

Headache caused by a disorder of the cervical spine and its component bony, disc and/or soft tissue elements, usually but not invariably accom- panied by neck pain.

Diagnostic criteria

. A Any headache ful lling criterion C.

. B Clinical and/or imaging evidence1 of a disorder or lesion within the
cervical spine or soft tissues of the neck, known to be able to cause
headache.2

. C Evidence of causation demonstrated by at least two of the following:

. 1 Headache has developed in temporal relation to the onset of the cervical disorder or appearance of the lesion

. 2 Headache has signi cantly improved or resolved in parallel with improvement in or resolution of the cervical disorder or lesion

. 3 Cervical range of motion is reduced and headache is made sig- ni cantly worse by provocative manoeuvres

. 4 Headache is abolished following diagnostic blockade of a cer- vical structure or its nerve supply.

. D Not better accounted for by another ICHD-3 diagnosis.3,4,5

Notes

. 1 Imaging ndingsintheuppercervicalspinearecommoninpatients without headache; they are suggestive but not rm evidence of causation.

. 2 Tumours, fractures, infections, and rheumatoid arthritis of the upper cervical spine have not been formally validated as causes of headache, but are accepted to ful l criterion B in individual cases. Cervical spondylosis and osteochondritis may or may not be valid causes ful lling criterion B, again depending on the individual case.

. 3 When cervical myofascial pain is the cause, the headache should prob- ably be coded under ‘2. Tension-type headache’; however, awaiting further evidence, an alternative diagnosis of ‘A11.2.5 Headache attrib- uted to cervical myofascial pain’ is in the Appendix.

. 4 Headache caused by upper cervical radiculopathy has been postu- lated and, considering the now well-understood convergence between upper cervical and trigeminal nociception, this is a logical cause of headache. Pending further evidence, this diagnosis is in the Appendix as ‘A11.2.4 Headache attributed to upper cervical radiculopathy’.

. 5 Features that tend to distinguish 11.2.1 ‘Cervicogenic headache’ from ‘1. Migraine’ and ‘2. Tension-type headache’ include side-locked pain, provocation of typical headache by digital pressure on neck muscles and by head movement, and posterior-to-anterior radiation of pain. However, while these may be features of ‘11.2.1 Cervicogenic head- ache’, they are not unique to it and they do not necessarily de ne causal relationships. Migrainous features such as nausea, vomiting, and photo/phonophobia may be present with ‘11.2.1 Cervicogenic headache’, although to a generally lesser degree than in ‘1. Migraine’, and may differentiate some cases from ‘2. Tension-type headache’.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Box 36.1 The collapsed criteria for cervicogenic headache

. 1 Unilateral headache without side shift.

. 2 Symptoms and signs of neck involvement: pain triggered by neck
movement or sustained awkward posture and/or external pressure of the posterior neck or occipital region, ipsilateral neck, shoulder, and arm pain, and reduced range of motion.

. 3 Pain episodes of varying duration or uctuating continuous pain.

. 4 Moderate, non-excruciating pain, usually of a non-throbbing nature.

. 5 Pain starting in the neck, spreading to oculo-fronto-temporal areas.

. 6 Anaesthetic blockades abolish the pain transiently provided com-
plete aanesthesia is obtained

Or sustained neck trauma a relatively short time prior to the onset:
7 Various attack-related phenomena: autonomic symptoms and signs,

nausea, vomiting, ispilateral oedema and ushing in the periocular area, dizziness, photophobia, phonophobia, and blurred vision in the ipsilateral eye.

Reproduced from Cephalalgia, 21, Antonaci F, Ghirmai S, Bono S, Sandrini G, Nappi G. Cervicogenic headache: evaluation of the original diagnostic criteria, pp. 573–583. Copyright © 2001, © SAGE Publications.

for cervicogenic headache (Box 36.2) (82). ey require evidence of a cervical source of pain, but the explanatory notes declare that clin- ical features that lack reliability or validity are not acceptable. In the absence of other evidence, controlled diagnostic blocks become the only means of establishing the diagnosis.

Refuted or contentious causes

Although various entities have been advanced as causes of cervicogenic headache, few have satis ed the IHS criteria. Congenital abnormalities are only incidental ndings in some pa- tients with headache, and have not been shown to cause pain. No evidence shows that the diagnosis of ‘trigger points’ as a cause of headache is either reliable or valid. Patients with rheumatoid arth- ritis can develop headache when their atlanto-axial joints become involved, but the diagnosis is evident from the systemic distribution of the disease. e evidence for osteoarthritis of the median atlanto- axial joint being a cause of headache is barely circumstantial (83,84).

A particular vexatious entity is occipital neuralgia. e IHS de- nes occipital neuralgia as ‘paroxysmal jabbing pain in the distri- bution of the greater or lesser occipital nerves’ (82). Paroxysmal lancinating pain is the hallmark of neuralgia and is the essential diagnostic criterion for occipital neuralgia. Explicitly, this de nition does not apply to deep, aching pain in the occiput. is can arise from diseases of the posterior cranial fossa and base of skull (85) and the upper cervical joints (58–60). Indeed, the IHS comments that occipital neuralgia must be distinguished from occipital referral of pain from the atlanto-axial or upper zygapophysial joints (82).

Traditionally, it has been believed that occipital neuralgia is caused by irritation of the greater occipital nerve where it enters the scalp. However, there is no compelling evidence of such irrita- tion. Lancinating occipital neuralgia has been recorded as a feature of temporal arteritis (86), in which case in ammation of occipital artery could a ect the companion nerve. However, in the majority of cases of so-called occipital neuralgia no such pathology is evi- dent. Also, anatomical studies have denied that occipital neuralgia is caused by entrapment of the greater occipital nerve where it pierces thetrapezius (40). e greater occipital nerve emerges from under an aponeurosis between the trapezius and the sternocleidomastoid. At surgery, this aponeurosis could be mistaken for ‘scar’ tissue.

Although Curwood Hunter and Frank May eld proposed that occipital neuralgia could be caused by compression of the occipital nerve between the posterior arch of the atlas and the lamina of C2 (87), and recommended treatment by greater occipital neurectomy, it has since been shown that the greater occipital nerve cannot be injured in this way (88,89). Indeed, in a later publication, May eld was more reserved about his earlier enthusiasm for greater occipital neurectomy and its success rate (90).

Entities with evidence

C2 neuralgia

e C2 spinal nerve runs behind the lateral atlanto-axial joint, resting on its capsule (38,39). In ammatory or other disorders of the joint may result in the nerve becoming incorporated in the brotic

changes of chronic in ammation (91,92). Release of the nerve re- lieves the symptoms. Otherwise, the C2 spinal nerve and its roots are surrounded by a sleeve of dura mater and a plexus of epiradicular veins, lesions of which can compromise the nerve. ese include meningioma (93), neurinoma (94), anomalous vertebral arteries (95), and venous abnormalities, ranging from single to densely interwoven dilated veins surrounding the C2 spinal nerve and its roots (96) to U-shaped arterial loops or angiomas compressing the C2 dorsal root ganglion (91,95,96). Nerves a ected by vascular ab- normalities exhibit a variety of features indicative of neuropathy, such as myelin breakdown, chronic haemorrhage, axon degener- ation and regeneration, and increased endoneurial and pericapsular connective tissue (95).

e pain associated with these pathological changes is intermit- tent, lancinating pain in the occipital region associated with lacrima- tion and ciliary injection. is pain satis es the criteria for occipital neuralgia, but the pathology lies in the C2 spinal nerve, not in the greater occipital nerve. Consequently, the diagnostic criterion is complete relief of pain following local anaesthetic blockade of the C2 spinal nerve, or sometimes the C3 nerve (91). ese blocks are performed under radiological control and employ discrete amounts (0.6–0.8 ml) of long-acting local anaesthetic to block the target nerve selectively (91).

In order to distinguish this condition from occipital neuralgia, as commonly understood—or misunderstood—it has been referred to as ‘C2 neuralgia’ (97). is term serves to draw attention away from the greater occipital nerve to the C2 spinal nerve, while still recog- nizing the occipital location of the pain.

Neck–tongue syndrome

Neck–tongue syndrome is characterized by acute, unilateral, oc- cipital pain precipitated by sudden movement of the head, usu- ally rotation, and accompanied by a sensation of numbness in the ipsilateral half of the tongue (98) (see also Chapter 28). e pain appears to be caused by temporary subluxation of a lateral atlanto- axial joint, whereas the numbness of the tongue arises because of impingement, or stretching, of the C2 ventral ramus against the edge of the subluxated articular process (39). e numbness occurs be- cause proprioceptive a erents from the tongue pass from the ansa hypoglossi into the C2 ventral ramus (98). Neck–tongue syndrome can occur in patients with rheumatoid arthritis or with congenital joint laxity (99). Hypomobility in the contralateral lateral atlanto- axial joint may predispose to the condition (100).

Lateral atlanto-axial joint pain

Diagnostic blocks of the lateral atlanto-axial joint require injection of a small volume of local anaesthetic into the joint, under uoro- scopic guidance (Figure 36.2) (101). Certain patients can be relieved of their headache by such blocks (61–66). One study attributed the pain to radiographically evident osteoarthritis (61), but such arth- ritis is not always evident. In post-traumatic cases, the responsible lesions might include capsular rupture, intra-articular haemor- rhage, and bruising of intra-articular meniscoids, or small fractures through the superior articular process of the axis (102). In one study, the source of pain could be traced to the lateral atlanto-axial joints in 16% of patients presenting with headache (64), while in another study the prevalence was 13% (103).

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(a) (b)

Figure 36.2 Fluoroscopy images of a needle in place for an intra-articular block of the right lateral atlanto-axial joint. (A) Antero-posterior view. (B) Lateral view.

Discogenic pain

ere is some evidence to implicate the C2–3 intervertebral disc as a source of cervicogenic headache. Stimulation of this disc repro- duces the pain su ered by some patients with headache (54,55). Arthrodesis of that disc has been reported to relieve headache (104). e nature of the causative pathology remains unknown.

Third occipital headache

e C2–3 zygapophysial joint is innervated by the third occipital nerve (40). e joint can be anaesthetized by blocking the third occipital nerve under uoroscopic guidance (Figure 36.3) (105). Headache stemming from the C2–3 zygapophysial joint, therefore, can be relieved by third occipital nerve blocks, and, accordingly, has been named third occipital headache.

In the past, the pathology that causes pain from cervical zygapophysial joints was elusive. Experimental studies in laboratory

Figure 36.3 Lateral uoroscopy view of a needle in place for a right third occipital nerve block.

animals have now shown that these joints can become a source of per- sistent nociception when their capsules are subjected to submaximal strain injuries (106,107). is provides the pathophysiological basis for neck pain and headache a er injury to these joints, and com- plements the clinical studies concerning the prevalence of cervical zygapophysial joint pain (107).

A study using controlled diagnostic blocks established that, in pa- tients with neck pain a er whiplash, the prevalence of third occipital headache was 27% (60). Among patients in whom headache was the dominant complaint, the prevalence was 53% (95% con dence interval 37–68%).

A signi cant feature of patients in whom third occipital nerve blocks have been positive is that all had a history of trauma. is reinforces ‘history of trauma’ as a cardinal clinical feature for ‘prob- able’ cervicogenic (Table 36.1). No studies have shown that third oc- cipital headache occurs without a history of trauma.

Differential diagnosis

Two groups of conditions constitute the important di erential diagnosis of cervicogenic headache. Each is distinguished from cervicogenic headache by features other than pain. ey are dis- orders of the posterior cranial fossa, and aneurysms of the vertebral or internal carotid arteries.

As they are innervated by cervical nerves, disorders of the pos- terior cranial fossa can have a distribution of referred pain similar to that of cervicogenic headache. ese disorders include tumours, which distend the dura mater of the posterior cranial fossa, and haemorrhage or meningitis, which irritate the dura chemically. ese conditions are distinguished from cervicogenic headache by their mode of onset and by their associated features, such as neuro- logical signs, systemic illness, and meningismus.

Less distinctive, at onset, is headache due to aneurysm of either the vertebral artery or the internal carotid artery. Headache is the

most common presenting feature of internal carotid artery dis- section (108,109), and may occur together with neck pain (109). Headache is also the cardinal presenting feature of vertebral artery dissection. In both instances, some 60–70% of patients present with headache, typically in the occipital region, although not exclusively so (109–111). However, following the onset of headache, cerebro- vascular symptoms and signs rapidly evolve, and declare the nature of the condition.

A case has been reported of cervicogenic headache caused by a lymph node metastasis in ltrating the cervical plexus (112). is case illustrates that cervical causes of headache need not be re- stricted to musculoskeletal structures.

Investigations

Imaging

ere is no evidence that medical imaging is diagnostic of any cause of cervicogenic headache. Imaging is indicated only in patients who exhibit neurological signs. In that context, however, imaging is used is to determine the cause of the neurological abnormality, not neces- sarily the cause of pain.

In patients with cardiovascular risk factors or a history of neck distortion or cervical manipulation, aneurysm needs to be con- sidered. For this entity, magnetic resonance angiography is the ap- propriate investigation.

Manual examination

Manual therapists contend that they can diagnose symptomatic joints by examining the cervical spine. Previously, this belief was based on one small study (113), but that study has now been refuted by a larger study, using more rigorous diagnostic criteria and more rigorous statistical analysis (114). Manual examination, therefore, lacks a foundation as a diagnostic test for cervicogenic headache.

Diagnostic blocks

Diagnostic blocks are the mainstay of diagnosis for cervicogenic headache (7,8,105). Only by these means can a cervical source of pain be established in a valid manner. However, in order for blocks to be valid, they must be conducted under controlled conditions (115–117).

In many studies that have used diagnostic blocks in the investi- gation of cervicogenic headache, controls were not implemented (5,115). erefore, the results are uninterpretable. Of particular con- cern, is the common use of blocks of the greater occipital nerve. is nerve supplies no structure that is known to be a source of chronic pain. It supplies only the skin of the scalp and the occipitalis muscle. Consequently, a response to a greater occipital nerve block is not evidence of a cervical source of pain. Nor can blocks be considered to be target-speci c for the nerve when they involve volumes such as 5 ml (74) or 10 ml (118,119) of local anaesthetic (115).

Given that stimulation of the greater occipital nerve facilitates responses in the trigeminocervical nucleus to noxious stimu- lation of the dura mater (46), it may be that greater occipital nerve blocks downregulate non-speci c headache mechanisms or dysnociception, and do not imply a cervical source of pain. Circumstantial evidence favours this contention. Greater occipital

nerve blocks relieve pain, temporarily, in substantial proportions of patients with migraine, cluster headache, and hemicrania continua (120). A positive, greater occipital nerve block, therefore, cannot be a speci c test for cervicogenic headache.

To date, in the diagnosis of cervicogenic headache, third oc- cipital nerve blocks are the only blocks that have been subjected to controls. Consequently, C2–3 zygapophysial joint pain is the only cause of cervicogenic headache for which there are valid diagnostic data. ird occipital nerve blocks are performed under uoroscopic guidance, using aliquots of 0.3 ml of local anaesthetic (Figure 36.3) (105). ey are controlled by using local anaesthetic agents with dif- ferent durations of action, on two separate occasions (60,115–117).

Lateral atlanto-axial joint blocks are a complement to third oc- cipital nerve blocks. ey involve injecting local anaesthetic into the cavity of the joint (Figure 36.2), and serve either to pinpoint or to exclude a source of pain in that joint (101). ey can be performed in a controlled fashion by rst establishing that blocks of the C2–3 joint do not relieve pain, or by testing the joint with intra-articular injections of normal saline.

For patients with lancinating, occipital pain, C2 spinal nerve blocks are required to con rm the diagnosis of C2 neuralgia. e nerve can readily be blocked, under uoroscopic guidance where it lies behind the lateral atlanto-axial joint (38).

Treatment

A variety of treatments have been used and advocated for cervicogenic headache (121,122). ey can be grouped according to whether a speci c source of pain is targeted or not, and whether the source has been presumed or diagnosed using a valid procedure. Intriguingly, success—in terms of degree of relief and duration of relief—is conspicuously greater when treatments target a diagnosed source of pain.

No source

Into this category fall conservative therapies, few of which have been vindicated by evidence. No drug has been claimed to be e ective for cervicogenic headache, let alone shown to be so. Transcutaneous electrical nerve stimulation is partially e ective in some patients, but only for a short time (123). Onabotulinum toxin is no more ef- fective than placebo (124). Manual therapy is commonly used, but most of the literature consists of case reports or case series (3). e few randomized controlled studies provided follow-up of only 1 or 3 weeks, and provided con icting results (3).

e largest and most recent study of conservative therapy showed that treatment with manual therapy, speci c exercises, or manual therapy plus exercises was signi cantly more e ective at reducing headache frequency and intensity than was no spe- ci c care by a general practitioner (125). Manual therapy alone, however, was not more e ective than exercises alone, and com- bining the two interventions did not achieve better outcomes. Some 76% of patients achieved a > 50% reduction in headache frequency at the 7-week follow-up, and 35% achieved complete relief. At 12 months, 72% had > 50% reduction in headache fre- quency, but the proportion that had complete relief was not re- ported. Corresponding gures for reduction in pain intensity were not reported.

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For most treatments in this category the greater occipital nerve has been targeted, for a presumed diagnosis of greater occipital neur- algia. Injection of depot methylprednisolone onto the greater oc- cipital nerve can produce temporary relief (126), but no studies have explored the bene t of repeat injections in providing lasting relief. Surgical ‘liberation’ of the nerve (127), or excision of the greater oc- cipital nerve, also provide temporary relief in some 70–80% of pa- tients (128), but pain typically recurs, and the procedure cannot be repeated to reinstate relief.

Pulsed radiofrequency applied to the greater occipital nerve is no more e ective than injection of methylprednisolone and bupivacaine onto the nerve, with about 50% of patients reporting 50% relief of pain at 9 months (129). Pulsed radiofrequency has also been applied to the C2 ganglion but described only in case reports (130,131).

A novel intervention has been the injection of processed, autolo- gous, adipose tissue onto the greater occipital nerve. Nineteen of 24 patients were said to have had a good clinical response (not other- wise de ned) at 3 months (132).

In other studies the lateral atlanto-axial joint has been targeted, but without evidence that prior diagnostic blocks had relieved the head- ache. In one study, 32 patients were treated with an intra-articular injection of a 1-ml mixture of triamcinolone and bupivacaine; and 25% reported at least 50% relief at 3 months (103). In another study, 86 patients were treated with intra-articular pulsed radiofrequency, and 43 reported 50% relief at 6 months, with 38 continuing to have relief at 12 months (133).

Diagnosed source

In one study, patients were selected for surgery if they satis ed the clinical criteria for ‘cervicogenic headache’ and obtained relief of headache from diagnostic blockade of the C2 spinal nerve (134). ey underwent decompression and microsurgical neurolysis of the C2 spinal nerve, with excision of scar, and ligamentous and vascular elements that compressed the nerve. Fourteen of 31 patients were rendered pain-free. Details on the remaining patients are incom- plete, but, ostensibly, 51% gained what was called ‘adequate’ relief, and 11% su ered a recurrence.

For patients whose headache can be relieved by lateral atlanto-axial joint blocks, an option for treatment is arthrodesis of the joint. e surgical literature attests to complete relief of pain being achieved, albeit in small numbers of patients, for over 2 years (135–137).

In those patients in whom the source of headache can be traced to the C2–3 intervertebral disc, disc excision and anterior cervical fusion reportedly can be e ective (104). For pain from the C2–3 zygapophysial joint, intra-articular injection of steroids might pro- vide relief for a small proportion of patients (138).

A minimally invasive treatment for a diagnosed and targeted source of pain is thermal radiofrequency neurotomy. In this treat- ment, an electrode is introduced percutaneously in order to co- agulate the nerve or nerves shown to be responsible for mediating the headache, on the basis of controlled diagnostic blocks of those nerves (Figure 36.4). e available evidence shows that the e ect- iveness of radiofrequency neurotomy is contingent on the rigour of diagnosis and the rigour of treatment.

ree controlled trials have provided salutary evidence on prac- tices that are not e ective (139–141). Radiofrequency neurotomy is

Black needle

Electrolyte

Figure 36.4 Lateral uoroscopy view of an electrode in place for third occipital thermal radiofrequency neurotomy.

A block needle lies nearby for administration of local anesthetic if required.

not e ective: when patients are selected for treatment simply on the basis of clinical criteria; when nerves are indiscriminately targeted, without having been subjected previously to controlled diagnostic blocks; or when techniques for radiofrequency neurotomy are used that have not been validated (8,142,143).

Radiofrequency neurotomy becomes e ective when patients are selected whose headache has been completely relieved by con- trolled diagnostic blocks of the target nerve (or nerves), and when meticulous surgical technique is used. For headaches stemming from the C2–3 zygapophysial joint, the diagnostic requirement is complete relief of pain from controlled third occipital nerve blocks (105), and standards for the execution of third occipital neurotomy have been de ned (143). For headaches stemming from the C3–4 zygapophysial joint the diagnostic requirement is complete relief of headache from controlled C3, C4 medial branch blocks (144), and the treatment requires C3, C4 medial branch neurotomy (143).

If these diagnostic criteria are satis ed, and the correct technique is used, complete relief of pain can be achieved in 88% of patients, for a median duration of some 297 days (145). Such results have been corroborated by second (146) and third (147) independent studies.

Similar outcomes have been reported in patients whose headache could be relieved by controlled blocks of the C3, C4 medial branches (148). A er thermal radiofrequency neurotomy of these nerves, > 70% of patients maintained at least 75% relief of their headache at 6 and 12 months.

For patients in whom headaches recurs, relief can be reinstated by repeating the neurotomy. By repeating neurotomy as required, some patients have been able to maintain relief of their headache for > 2 years (145), for up to 5 years (147), and beyond (149).

A study that has escaped attention in the literature explored the e ectiveness of arthrodesis in the treatment of proven cervicogenic headache (150). Patients presenting with chronic headache were investigated using diagnostic blocks of the C2 and C3 nerve roots, and diagnostic blocks of the C2–3 and C3–4 zygapophysial joints conducted on separate occasions. Based on complete, or near com- plete, relief of headache following nerve root blocks and likewise

following zygapophysial joint blocks, 34 patients underwent pos- terior fusion of C1–2–3 using Brook’s triple-wire fusion. Another 10 patients underwent fusion variously at C1–2, C2–3, or C1–2–3 based on positive responses to nerve root blocks but no response to zygapophysial joint blocks.

Before treatment, all 44 patients had severe or excruciating head- ache, rated as 8/10, 9/10, or 10/10 on a visual analogue scale. No evidence of injuries to the upper cervical joints was evident on pre- operative imaging, using exion–extension radiographs, computed tomography, and magnetic resonance imaging (MRI). During sur- gery, the capsule of the C2–3 zygapophysial joint was judged to be disrupted in 36 patients. Deeper joints, such as the lateral atlanto- axial joints could not be inspected.

At 1 year a er surgery, three patients had no pain, 22 had only mild pain, and 16 had moderate pain, in all cases rated as less than 5/10. ese outcomes were sustained at 4 years, when seven patients had no pain, 22 had mild pain, and 10 had moderate pain. During this period of follow-up, in only two patients did pain scores deteri- orate to pre-operative levels.

is study provides corroborating evidence that in patients with se- vere headaches, injuries to the upper cervical joints can escape detec- tion using conventional imaging, but can be detected using diagnostic blocks and veri ed at surgery. Furthermore, the outcomes achieved invite consideration of posterior cervical fusion as an option for the treatment of severe, otherwise intractable, cervicogenic headache.

Clinical pathway

A clinical pathway has been recommended for the e cient manage- ment of cervicogenic headache (142). e pathway involves a discip- lined approach to diagnosis, and uses treatments for which there is reasonable evidence of e ectiveness but abjures those treatments for which evidence of lasting and worthwhile e ect is lacking.

e primary indicator that a patient might have cervicogenic headache is pain in the occipital region or pain starting in the neck. However, even so, other forms of headache need to be considered, and excluded, before proceeding. If other conditions have been ex- cluded, a diagnosis of ‘possible’ cervicogenic headache can be made.

e di erential diagnosis includes posterior fossa lesions and an- eurysms of either the vertebral artery or internal carotid artery. If these are possible or suspected, investigations with MRI or magnetic resonance angiography are indicated. In that event, cervicogenic headache is no longer a consideration, and the patient exits the clin- ical pathway.

If the patient has lancinating pain a diagnosis of occipital neur- algia can be pursued. is will entail performing C2 spinal nerve blocks, in order to con rm the diagnosis.

A diagnosis of ‘probable’ cervicogenic headache can be formulated if the patient has dull, aching pain that is continuous or uctuating in intensity, associated with pain radiation into the shoulder, or a history of trauma. Such a level of certainty in the diagnosis can be adequate if conservative therapy is pursued.

e only conservative therapy for which there is any strong evi- dence of e cacy is manual therapy coupled with exercises. Most pa- tients in primary care should bene t from this intervention.

Patients who do not bene t can be investigated more intensively. Since the pretest probability is highest for C2–3 zygapophysial joint pain, investigations should start with third occipital nerve blocks. If controlled blocks are positive, the patient can be treated with third occipital radiofrequency neurotomy. Intra-articular injection of steroids is a plausible, less destructive option, but lacks a de nitive evidence base. If radiofrequency neurotomy is not available, pos- terior arthrodesis of C2–3 can be entertained.

If C2–3 blocks are negative, the next step is to test for lateral atlanto-axial joint pain with C1–2 blocks. If these are positive, treat- ment by arthrodesis can be considered.

If C1–2 blocks are negative, the C3–4 zygapophysial joint should be tested. If blocks are positive, treatment is possible with C3,4 medial branch radiofrequency neurotomy.

If C3–4 blocks are negative, the only remaining option is to test for C2–3 disc pain by discography. If discography is positive, treatment by arthrodesis can be considered.

In patients with sources of pain at multiple levels, such as C2–3 and C1–2, posterior fusion of both segments can be considered.

If discography and blocks of the joints of the upper three cervical segments all prove negative, there are no further, established inves- tigations to pursue. e patient and their management should be revaluated. Either the diagnosis is not cervicogenic headache, or the patient has a cervical cause of pain that cannot be pinpointed using currently available technology.

e options may be to treat the patient palliatively, by providing non-speci c pain-relief, or to enrol them in whatever ethics- approved study is available of procedures that have experimental or investigational status. Such procedures might include, but are not limited to, atlanto-occipital joint blocks, pulsed radiofrequency, implanted greater occipital nerve stimulation, or procedures dir- ected at suboccipital muscles as the sources of pain. Ethics-approved studies guarantee patient safety, and protect them from unwittingly being subjects to practitioners who are no more than experimenting with untested and unproven procedures, without disclosing to the patient that they are doing so.

CHAPTER36 Cervicogenicheadache

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Headache and neurovascular disorders

Marieke J.H. Wermer, Hendrikus J. A. van Os, and David W. Dodick

Headache as a risk factor for neurovascular disorders

e relationship between migraine, ischaemic stroke, and ele- vated cardiovascular Framingham risk factors has been a well- documented association in case–control, cohort, observational studies, and population-based studies. Individuals with migraine have a twofold increased risk of ischaemic stroke (1–3). e risk of stroke appears to be independent of typical vascular risk factors and is best established in those with migraine with aura (MA), especially in women younger than 45 years of age (4,5). Smoking and the use of oral contraceptive agents appear to magnify the risk substantially (6,7). e risk also appears to increase with increasing migraine at- tack frequency (4). e risk of stroke in women with migraine has also been demonstrated in those older than 45 years of age. In the Women’s Health Study, MA was associated with incident ischaemic stroke (hazard ratio (HR) 1.70, 95% con dence interval (CI) 1.1– 2.6) and most evident for those < 55 years of age at baseline (HR 2.25, 95% CI 1.3–3.9) (6). MA was also found to be a risk factor for myocardial infarction (MI), coronary revascularization, and death due to cardiovascular disease. Similar results suggest that the risk of adverse cardiovascular events in patients with migraine may also be seen in men over the age of 45 years (8).

Several population-based studies have also linked migraine and asymptomatic brain infarctions. In a prospective longitudinal population based study (Cerebral Abnormalities in Migraine, an Epidemiological Risk Analysis (CAMERA)) in the Netherlands, mi- graine was associated with an increased likelihood of asymptomatic cerebellar infarct-like lesions (see also Chapter 10) (9,10). Although the risk was similar in women with and without aura, the risk was highest in those with MA and a frequency of more than one attack per month (odds ratio (OR) 15.8, 95% CI 1.8–140). ese ndings were independent of traditional cardiovascular risk factors (11). e association between MA and late-life infarct-like lesions in the cerebellum was also demonstrated (OR 1.4, 95% CI 1.1–1.8) in a population-based prospective study in Iceland. is study evalu- ated older adults (mean age 51 years) with migraine and also dem- onstrated that the risk of these asymptomatic infarcts was stronger in women (OR 1.9, 95% CI 1.4–2.6) (12). Finally, the presence of infarct-like lesions was con rmed (OR 12.4, 95% CI 1.6–99.4; p for trend = 0.005) by another population-based study, but the lesions

were not con ned to the cerebellum or the brain tissue supplied by the posterior cerebral circulation (13).

Migraine has also been shown to be a risk factor for adverse cere- brovascular and cardiovascular outcomes during pregnancy. In a re- cent systematic review, an increased risk of gestational hypertension (OR 1.23–1.68), pre-eclampsia (OR 1.08–3.5) and ischaemic stroke during pregnancy (OR 7.9–30.7) was demonstrated in those with migraine compared to those without. An association between mi- graine and increased risk of acute MI and heart disease (OR 4.9, 95% CI 1.7–14.2), and thromboembolic events during pregnancy (deep venous thrombosis OR 2.4, 95% CI 1.3–4.2; pulmonary embolus OR 3.1, 95% CI 1.7–5.6) was also demonstrated (14).

Headache as symptom of neurovascular disorders

Headache is a frequently encountered symptom in neurovascular disorders. It can occur at di erent stages such as at stroke onset, during the rst days a er stroke or as delayed headache in the chronic phase. Although headache is more frequent in certain sub- types of neurovascular diseases, it is o en not useful in clinical prac- tice to discriminate between di erent stroke subtypes. e start of the headache, however, can sometimes point towards a particular diagnosis, especially in case of a thunderclap onset (see Chapter 34). In certain vascular diseases, such as subarachnoid haemorrhage (SAH), reversible cerebral vasoconstriction syndrome (RCVS), cer- vical artery dissection (CAD), and cerebral venous sinus throm- bosis (CVST), headache can be the only presenting symptom, which makes the diagnosis of these o en serious diseases challenging. e frequency and nature of headache symptoms di er between dif- ferent neurovascular diseases (Table 37.1).

Ischaemic stroke and transient ischaemic attack

An ischaemic stroke occurs as a result of an obstruction within a blood vessel supplying blood to the brain. is obstruction can be persistent, causing permanent damage, or it can be transient, without leaving any clinical or radiological de cit (transient ischaemic attack (TIA)). Most physicians associate headache primarily with a haem- orrhagic cause of stroke, but this is incorrect as headache is also a frequently reported symptom in patients with cerebral ischaemia.

CHAPTER 37 Headache and neurovascular disorders Table 37.1 Overview headache characteristics per subtype of neurovascular disease.

Neurovascular disease

Headache frequency (%)

Headache nature*

Associated factors†

Ischaemic stroke and TIA

14–38

Pressure like, throbbing

Young age, female sex, history of migraine

Intracerebral haemorrhage

34–57

Tension type, migraine type

Cerebellar or lobar location, transtentorial herniation

Subarachnoid haemorrhage

Thunderclap headache

Sentinel headache, preceding 1–3 days

Cerebral venous sinus thrombosis

70–90

Band-like, throbbing, thunderclap headache

Focal neurological de cits, seizures, papilloedema

Reversible cerebral vasoconstrictor syndrome

Thunderclap headache, recurrent attacks

Anxiety and depression are aggravated by chronic headache

Cervical artery dissection

Throbbing, constrictive

Neck pain, history of migraine

Arteriovenous malformation

25–56

Migraine (especially migraine with aura)

History of migraine (with aura), larger nidus volume, tortuosity of the feeding artery

Unruptured aneurysm

Unknown

Headache symptoms may decrease or increase after endovascular treatment

Cavernoma

31–65

Tension type, migraine type

History of migraine

Cerebral angiitis

57–90

Divers

Jaw claudication in case of giant cell angiitis

TIA, transient ischaemic attack. *Headache nature that is most frequently described in patients. †Predictors of headache prevalence or concomitant factors.

e prevalence of headache at presentation of ischaemic stroke varies between 7% and 38% (15–22). e di erences in prevalence are possibly explained by study design and method of headache re- trieval. Recent prospective series report frequencies varying from 14% to 38% (20–22). Rarely, headache is the most prominent or even sole symptom of ischaemic stroke (23,24).

Headache associated with ischaemic stroke is related to certain clinical and stroke characteristics. It appears to occur more o en in women and patients with a history of migraine (15,16,18,19,22). In contrast, patients with a history of hypertension and older patients seem to have a lower headache prevalence (18,19,21,22,25). In pa- tients with lacunar infarctions, leukoaraiosis was less frequent and less severe in patients without headache (26). Headache has been associated with relatively low (< 120 mmHg systolic and < 70 mmHg diastolic) or very high blood pressure (systolic blood pressure >200 mmHg) on admission (18,27). Other less frequently reported and therefore more controversial risk factors are not smoking and use of warfarin (25,28).

Headache at symptom onset is relatively more common in infarc- tions located in the posterior circulation than in the anterior circu- lation (22,25,29). One study found a relation with cerebellar stroke and not with other brainstem locations (18). Although headache is o en associated with cortical located lesions, several studies re- ported headache in lacunar infarctions, with a prevalence ranging from 10% to 23% (20,25,30). e size of the lesions was found to increase headache prevalence, but not headache severity, in two studies (21,28). e large scale of the Stroke in Young Fabry Patients (SIFAP1) study, which included 4431 young stroke patients, enabled multivariable analyses and revealed lower age, female sex, size of the largest lesion, and localization in the vertebrobasilar territory as independent predictors for headache during the ischaemic event (21). Until now, no clear association between headache and stroke aetiology has been demonstrated, although some studies found headache to be more common with cardioembolic stroke and large artery atherosclerosis and less common with small-vessel disease (15,18,25). Interestingly, another study found that headache was

more common in patients without atherosclerosis in the anterior circulation (22).

Concomitant headache most o en starts at onset or within the rst one day a er onset of ischaemic stroke and lasts, according to a study including both patients with ischaemic stroke and intracerebral haemorrhage (ICH), on average 4 days (31). Headache associated with ischaemia is found to be bilateral in 55% of cases. When unilat- eral, the headache appears to be more o en ipsi-lesional than contra- lesional (16,31). is suggests that the presence of headache may be associated with pathophysiological mechanisms in and around the ischaemic area and not just a general sign of stress, raised blood pressure, or intracranial hypertension. If the headache has an acute onset and is located in the neck, behind the eye or the ear, a CAD as the cause of the infarction should be considered (see ‘Cervical ar- tery dissection’). In ischaemic stroke, headache symptoms are gen- erally reported to be mild to moderate, but in cases of ischaemia in locations around the putamen or thalamus and in the posterior circulation severe pain has been described (17,21,28). Concomitant headache o en has no speci c features and is usually described as continuous, pressure-like, throbbing or non-throbbing (32).

In the long term, ischaemic stroke patients can develop chronic headache. A er 6 months, 13% of patients reported newly devel- oped headache in a prospective study of 299 patients (33). In a population-based study, 10% of 608 post-stroke patients reported headache 2 years a er the event (34). In contrast, some patients with a history of migraine report improvement of their migraine symp- toms a er stroke (35–38).

Headache can also be one of the presenting symptoms of a TIA with a prevalence similar to cerebral infarction in some studies. In the SIPFAP1 study, headache was as frequent in TIAs (30%) as in ischaemic stroke (21). Because TIA symptoms can mimic a mi- graine aura, di erentiation from a migraine attack can sometimes be challenging, especially in younger patients with visual or sensory symptoms. Generally, the progression of symptoms over time is con- sidered to be the most important distinctive feature of migraine aura versus the sudden symptom onset in patients with true TIAs.

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PART 6 Secondary headaches Migrainous infarction

Rarely, an ischaemic stroke starts as migraine aura that subsequently transfers into a cerebral infarction (see also Chapter 10). If a mi- graine aura persists longer than 60 minutes a migrainous infarct should be suspected and immediate imaging is indicated. Around 0.2% of ischaemic stroke cases seem to be caused by a migrainous in- farction (39). In younger patients, migrainous infarction is reported to be more prevalent than in adults (40). In addition, migrainous infarction is 2–3 times more prevalent in women, which may very well be explained by the fact that MA is around three times more prevalent in women as well (41,42). e incidence of migrainous in- farction may be overestimated, as other possible disorders leading to stroke should be ruled out so the diagnosis is dependent on the ex- tent of radiological and cardiac work-up. Also, in younger patients, where migrainous infarction incidence is highest, the prevalence of MA and cryptogenic stroke are also relatively high (43).

Migrainous stroke is predominantly located in the posterior cir- culation (70–82%) (39,44). In a study of 18 patients in whom mag- netic resonance imaging (MRI) was performed, 71% had lesions in the posterior circulation and 29% in the territory of the middle cere- bral artery. Small lesions were present in 65% and multiple lesions were found in 41% of patients (39). e prognosis a er migrainous infarction is reported to be more benign than a er an infarct of an- other cause. Patients are likely to have a relatively favourable out- come with o en only minor remaining de cits and no residual symptoms in 65% of patients (39).

Sometimes a migraine aura is mistaken for ischaemic stroke and patients are admitted to the hospital and treated with thrombolysis. Studies report migraine as the likely aetiology in 8–38% of stroke mimic cases. In total, around 40 such patients have been reported in the literature and in none of them has haemorrhagic complica- tions occurred (45–48). Computed tomography (CT) perfusion ab- normalities showing either hyperperfusion or hypoperfusion not reaching penumbra limits have been found in small series of such patients (49).

Intracerebral haemorrhage

An ICH is bleeding that occurs within the brain tissue (see also Chapter 10). When no large-vessel malformation is found it is o en called primary or spontaneous ICH. Deep ICH is o en due to small vessel disease caused by hypertension and/or diabetes, whereas lobar ICH is thought to be more o en related to amyloid angiopathy. Headache is one of the main presenting symptoms of ICH and is re- ported in 34–57% of cases (20,50–52).

Analogous with ischaemic stroke, headache at ICH onset is more common in cerebellar and lobar haemorrhages than in deep haem- orrhages. In multivariable analyses in 165 patients, female sex (OR 1.6), presence of meningeal signs (OR 2.3), cerebellar or lobar lo- cation of the ICH (OR 2.1), and transtentorial herniation (OR 1.8) were statistically signi cant predictors of headache at ICH onset (52). Surprisingly, these factors were more predictive of headache presence than haematoma location and the authors suggest that headache is more o en related to activation of an anatomically dis- tributed system in susceptible persons and to the presence of sub- arachnoid blood than to intracranial hypertension (52). Another study that included 189 patients with supratentorial ICH admitted within the rst 12 hours of symptom onset found a relationship with

several in ammatory markers. Patients with headache had a signi – cantly higher frequency of history of infection, in ammation, and higher body temperature than patients presenting without headache (51). In addition, leukocyte count, erythrocyte sedimentation rate, mass e ect on admission, and plasma concentrations of interleukin- 6 and tumour necrosis factor-α were signi cantly higher in patients with headache. Headache was also associated with the residual cavity volume of the haemorrhage (51).

Headache in ICH has most o en been described as tension-type headache, followed by a migraine phenotype (31). Compared to headache in ischaemic stroke, headache in ICH has approximately the same duration with a mean of 4 days but is signi cantly more incapacitating (30,31).

In the chronic stage a er ICH, headache is also a frequently en- countered problem. ICH survivors, who were asked in the second year a er ICH for headaches before and a er ICH by a headache questionnaire reported new headaches in 11% and ongoing head- aches in 43%. Twenty-four patients (27%) never had headaches and in 17 (19%) previous headaches remitted a er the haemorrhage (53). Remission of headaches seemed to be related to removal of headache precipitants such as alcohol use or possibly to structural or functional changes of the trigeminovascular system. Chronic post- ICH headaches were usually tension-type in phenotype and were signi cantly associated with depression (53).

Subarachnoid haemorrhage

A SAH is a bleeding in the subarachnoid space of the brain caused in 90% of cases by a ruptured aneurysm (aSAH). In approximately 10% of patients no aneurysm is found. When the blood is primarily located around the brainstem, a perimesencephalic SAH (PMH) is diagnosed, which most likely has a venous cause.

Patients with aSAH typically present with sudden thunderclap headache (see Chapter 34) and/or loss of consciousness combined with nausea, vomiting, and sometimes neurological symptoms. In approximately one-third of patients, headache is the single clin- ical symptom, whereas in < 1% of the patients, no headache occurs (54,55). Most of patients with aSAH without headache present with an acute confusional state (55). Headache in patients with aSAH usually starts instantaneously in 50% of patients and within 5 min- utes in another 19% (56). In patients with PMH, headache devel- oped almost instantaneously in 35%, and within 1–5 minutes in 35% (56). How long the headache generally lasts is less clear and therefore there is no clear cut-o point to rule out aSAH by headache duration. A headache duration of 1–2 weeks has been described, but some pa- tients report disappearance of their headache the rst hours a er the start of the haemorrhage (57). Headache caused by aSAH is in general di use and extremely severe (57). It is unknown if the char- acter of the headache di ers between aSAH and PMH. Continuing headache in patients with aSAH during admission requires medical attention as it can be a sign of a developing hydrocephalus or treat- ment (drain)-related infection.

ere is debate in the literature whether in some patients a warning leak occurs. A warning leak is assumed to be an episode of acute headache in the days or weeks just before rupture of an an- eurysm caused by a sudden distention of the aneurysm or subintimal haemorrhage in the aneurysm wall (58). When a warning leak exists, it would give an opportunity to prevent aSAH by urgent treatment

of the aneurysm. However, it is likely that its association is at least partly based on recall bias (56).

In the chronic stage a er SAH headache is also o en encountered. In a long-term follow-up study of 610 patients with a clipped aneur- ysms a er aSAH, 12% of patients reported chronic headaches a er a mean follow-up period of 9 years (59).

Cerebral venous sinus thrombosis

CVST occurs when a blood clot forms in the brain’s venous sinuses that prevents blood from draining out of the brain. CVST is a rare but serious cause of headache. Headache is the most common presenting symptom and is present in 70–90% patients (60–62). Headache seems to be less common in paediatric patients, where it was reported in only one-third of cases (63). In CVST patients presenting with headache, around 20% already had a previous his- tory of headache, including migraine, tension headache, and cluster headache (63). Headache in patients with CVST is associated with other clinical symptoms as focal neurological de cits (36%), seizures (32%), and papilloedema (32%) (61). However, in 32% of patients with headache neurological examination was normal and 12–15% had headache as sole symptom (61). Diagnosis of CSVT is especially challenging in these cases and only imaging can reveal the cause for the headache (61,64). When CVST is suspected, contrast-enhanced MRI or CT venography is required to establish the diagnosis (65).

e presentation of headache in CVST is diverse and can mimic thunderclap headache (see Chapter 34), migraine, orthostatic head- ache, cluster headache, headache related to increased intracra- nial pressure, and di use tension-type headache. e duration of headache is 1–3 days in almost two-thirds of patients, 4–14 days in a quarter, and > 14 days in one-tenth of patients (63). e quality of headache most o en is band-like (20%), followed by throbbing (9%), thunderclap (5%), or other (pounding, exploding, stabbing (20%)). e location of headache is reported to be unilateral in 37%, localized in 19%, and di use in 20%. ere seems to be no asso- ciation between headache and the presence of hydrocephalus or venous haemorrhages on imaging. Most patients had di use head- ache without any significant association to the presence of haemor- rhage and location of thrombosis. One exception might be sigmoid sinus thrombosis, where 17 of 28 (61%) patients reported pain in the occipital and neck region (63).

e mechanism underlying headache occurrence in CVST is not well understood. Mechanisms that are proposed to play a role in headache pathogenesis are the stretching of sensory a erent nerve bres in the dural venous sinuses, inflammation of sinus walls, raised intracranial pressure, and presence of SAH. e significant correlation between sigmoid sinus thrombosis and occipital pain is possibly related to inflammation and stretching of sigmoid sinus walls due to the thrombus (63). Chronicity of headache a er CVST has been reported by a 1-year follow-up study, where 14% of the 624 patients reported severe headache (66).

Reversible cerebral vasoconstriction syndrome

RVCS is a condition characterized by one or more episodes of thun- derclap headache (see Chapter 49). Patients were found to experience an average of 4–5 attacks occurring in a mean period of 1 week; attack duration varied from 5 minutes to 36 hours (67,68). While there can be other concomitant symptoms such as stroke or epileptic seizures,

around three-quarters of patients experience headache as the only symptom. On imaging segmental constriction of vessels can be found, sometimes combined with cortical subarachnoid blood, cere- bral ischaemia or ICH (67,69). Moderate headache persists between exacerbations. In a series of 191 patients with RCVS followed for a median of 78 months, 53% reported chronic/persistent headache of mild-to-moderate intensity that are distinct from the ‘thunderclap’ headaches at RCVS onset. e majority (88%) reported improvement in the severity of headache over time. e majority (97%) regain com- plete functional ability, but anxiety/depression are frequent, o en ag- gravated by concomitant chronic headaches, and may be associated with lower quality of life (70). e underlying pathophysiology is still poorly understood, but it is probable that a transient disturbance of regulation of cerebrovascular tone plays a role (71).

Cervical artery dissection

Spontaneous CAD is a separation of the layers of the cervical ar- tery wall and a frequently encountered cause of cerebral infarction, especially in young stroke patients (see also Chapter 10). Besides dizziness/vertigo and stroke, headache and neck pain are o en en- countered in patients with CAD and present in approximately 50% of patients (72). In around 10% of the patients headache is the only symptom (73). Other presentations include local manifestations such as Horner syndrome, cranial nerve palsies, tinnitus, or, more rarely, cranial root pathology. Patients with internal carotid artery (ICA) dissection more o en present with headache but less o en present with cervical pain. In addition, patients with dissections of the ICA have cerebral ischaemia less o en than patients with vertebral artery disease (74). Of 20 patients with pain as the only symptom (12 with vertebral, three with ICA, and ve with multiple dissections), six patients presented with headache, two with neck pain, and 12 with both. e onset of headache was progressive in six, acute in eight, and of a thunderclap nature in four. Headache was de- scribed as throbbing in 13 and constrictive in ve patients. Pain was unilateral in 11 and bilateral in nine patients (73).

Migraine is more common among patients with CAD than pa- tients without CAD. In a large series of 635 patients with CAD with stroke and 653 controls (patients with non-CAD stroke), migraine was found in 36% of patients with CAD versus in 27% of the controls (75). is di erence was statistically signi cant. In particular, mi- graine without aura (MO) was more prevalent in patients with CAD (20% vs 11%) (75). In a meta-analysis including ve case–control studies, MO almost doubled the risk of CAD (OR 2.06, 95%CI 1.21– 3.10). e association with MA was less strong (OR 1.50, 95% CI 0.76–2.96) (76). e pathophysiology and the causality of the associ- ation between migraine and CAD remains to be elucidated. A recent genome-wide association study of CAD identi ed a signi cant as- sociation at the same index single nucleotide polymorphism (SNP) (rs9349379 in the PHACTR1 locus) as is associated with migraine, indicating the potential for a shared genetic relationship between migraine and CAD (77). A positive migraine history did not a ect the chance of ischaemia, the distribution of strokes, or the prognosis in patients with CAD (75).

Arteriovenous malformations

Arteriovenous malformations (AVMs) of the brain are abnormal direct connections between arteries and veins within the brain

CHAPTER 37 Headache and neurovascular disorders

337

338

PART 6 Secondary headaches

parenchyma leading to shunting without a true capillary bed re- sulting in a nidus of tangled vessels. ey are mostly detected in patients around the age of 30–40 years. eir exact prevalence in the general population is uncertain but is estimated to be around 0.1% (78). e relationship between AVMs and headache has been reported for a long time but remains controversial. Headache as symptom at detection of unruptured AVMs has been described in 25–56% of patients with occipital AVMs, but prospective data are lacking (79,80). In a large combined database of 1289 patients with AVM from three hospitals, chronic headache at the time of diagnosis was reported in 14% of cases (78). In a retrospective series of 37 pa- tients with small occipital AVMs treated with radiosurgery, peri- odic headaches were found in 17 (46%) of the patients and seemed to occur more o en with a larger nidus volume, tortuosity of the feeding artery, and cortical drainage with re ux in the superior sa- gittal sinus (81).

e most o en described primary headache syndrome associ- ated with AMVs is migraine, especially MA. In several series of pa- tients with AVM, migraine was present in 19–23% of cases (80,81). Whether the relationship between migraine and AVMs is causal re- mains unclear, as migraine has a high prevalence in young, other- wise healthy adults, and especially in women. However, one study reported 58% of women with cerebral AVMs to have migraine (32% MA and 26% MO) (82). e number of women with MA in this study seems to be higher than expected in the general population.

In older studies, migraine is reported particularly in occipital, parietal, and temporal AVMs, and less in frontal and only rarely in central AVMs (83). In favour of a causal relationship are the ndings of an observational study of 40 patients, where in all patients with occipital AVM the migraine symptoms occurred ipsilateral to the AVM lesion (80). In addition, a er AVM treatment, migraine symp- toms sometimes seem to improve (84,85). In a small series of 17 radiosurgically treated patients headaches resolved or improved in 12 (71%) of cases, including six of seven patients with migraine (81).

Where some report classic migraine histories according to the International Classi cation of Headache Disorders (ICHD)-2 cri- teria (80), others state that a er careful review of the patient his- tory most spells diagnosed as aura were atypical for migraine and some could rather be epileptic phenomenon (86). In most patients with AVM with migraine no family history for migraine is present (81). Other types of primary headache syndromes that have been described in patients with AVMs are cluster headache, chronic par- oxysmal hemicranias, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) (87–90). For cluster headache improvement of symptoms a er AVM treatment have been described in one case report (91).

e exact yield of screening for AVMs in patients with MA in general or in case of atypical symptoms is unknown. Imaging of the brain should be strongly considered in patients with strictly unilat- eral symptoms of migraine, late onset of migraine, change in attack frequency, or neurological symptoms, including epileptic seizures.

e pathophysiology behind the association between headache and AVMs is not clear. It has been suggested that the high frequency of headache and migrainous symptoms in AVMs supplied by the posterior cerebral artery suggests a particular sensitivity in this ar- terial system. For AVMs in the occipital lobe, a link with spreading depolarization (SD) has been described, as this area of the brain is more susceptible to this phenomenon, which is the presumed

underlying mechanism of migraine aura (80). e headaches may be related to involvement of the dural arterial system to the AVM. Dural supply to the AVM was found to be present more frequently in patients with headache than in those without headache. However, headache also occurred in the majority of patients without an iden- ti able dural arterial supply to the AVM (79).

Unruptured aneurysms

Whether unruptured aneurysms can be a cause of headache is un- known. Most unruptured intracranial aneurysms are thought to be asymptomatic lesions. However, several case reports associate unruptured aneurysms with headaches sometimes in combination with cerebrospinal uid lymphocytosis (92,93). In addition, a posi- tive e ect of aneurysm treatment on headache symptoms has been suggested in single cases and small-size studies. In one study that included 72 elderly patients, of whom 72% reported headache be- fore treatment, three-quarters reported improvement of headache a er endovascular treatment (94). A prospective study of 44 patients (38 coiled, ve clipped, and three treated with liquid embolic infu- sion) also found a decrease in 90-day headache frequency. Headache frequency was reduced in 68% of patients, but 9% of patients had new or worsening headaches following treatment. Pretreatment mi- graine, more severe pretreatment headaches, higher pretreatment anxiety and stent-assisted aneurysm coiling were associated with absence headache improvement (95). Two other studies reported headache improvement in > 90% of cases (96). No di erences were found between the surgical and endovascular group (97).

Headache in the rst days a er aneurysm treatment and exacer- bation of existing headache have been found in other studies (98,99). More than half of 90 patients treated with coiling experienced head- ache in the rst hours a er the procedure. All headaches resolved within an average of 3 days. No hypertension history and a coil packing attenuation of > 25% were suggested risk factors of head- ache development. A er certain special endovascular treatments, such as ow-diverting stents and bioactive coils, peri-aneurysmal brain in ammation and oedema have been found (100,101). It is un- clear if these ndings are related to the occurrence of postprocedural headache.

Cavernomas

Cavernous hemangiomas or cavernomas are blood-filled, enlarged, immature capillaries lined with a single layer of endothelial cells without intervening neural tissue, ranging in size from a few milli- metres to several centimetres (102). e prevalence is around 1 in 100,000 in children and around 18 in 1,000,000 in adults (103).

ere are few clinical and demographic studies on cavernomas with large sample sizes. Headache as initial presentation is reported in 31–65% of patients (104,105). Other frequent symptoms are epi- leptic seizures or intracranial haemorrhage. Clinical presentation in children is di erent, where headache at presentation is reported less o en (3–18%) and presentation with ICH is more prevalent (102,106). In a prospective follow-up study of 35 patients, 11 had headache at initial presentation. During follow-up chronic head- ache developed in 19 of 35 patients, and all patients developed seizures (104).

A number of case studies link cavernomas with the occurrence of migraine (107–109). In one study the disappearance of new-onset

migraine was described a er the removal of a cavernoma in the le temporo-occipital lobe (107). In other case studies, chronic mi- graine and chronic occipital neuralgia was linked to cavernomas in the brainstem, suggesting a role for the trigeminocervical system and the contralateral midbrain periaqueductal grey matter (108).

Cerebral angiitis

Headache is a common manifestation of primary angiitis of the central nervous system (PACNS) or secondary forms of vasculitis, caused by systemic vasculitides. PACNS is a rare disease a ecting both medium- and small-sized vessels, with an estimated annual in- cidence of 2:1,000,000 (110). e mean age of onset is 50 years, and men are a ected twice as o en as women (111). ere is no precise test or marker that is speci c to the disease, and high clinical sus- picion coupled with thorough investigations are needed to exclude mimics. One important mimic of PACNS is RVCS, as this disorder has the same radiological features and in both diseases headache is the main symptom of clinical presentation. In contrast with RVCS, where headache is reported in all cases and characterized by thun- derclap onset, in PACNS headache occurs in 57–63% of cases and is described as insidious-onset subacute headache. underclap head- ache was not present in any of the patients (110,112). Prompt recog- nition of primary or secondary vasculitis is needed to not only treat headache symptoms, but also to prevent secondary symptoms such as stroke, seizures, and encephalopathy.

e nature of headache in vasculitis is not well described. A stab- bing nature of the headache has been reported to be related with autoimmune disorders via neuroin ammation (113). Presentation as migraine has been reported in a paediatric case (114). In the case of temporal located pain, giant cell arthritis (GCA) should be sus- pected. GCA is the most frequent form of vasculitis in patients older than 50 years of age, with a prevalence of 15–30/10,000 (115). In 50% of patients with GCA headache is the initial symptom, and eventu- ally it occurs in 90% of patients (116). e headache in GCA can be accompanied by jaw claudication. Other neurological symptoms include visual problems, such as diplopia, icker scotoma, and am- aurosis fugax, with blindness or stroke as a dreaded complication (110). Headache in GCA can take many forms, and can present as migraine, cluster headache, tension headache, and even thunderclap headache (116,117).

Genetic cerebral angiopathies

e close relationship between migraine and stroke becomes clear in several monogenetic disorders were migraine and cerebrovascular symptoms occur together (see also Chapter 8). Investigation of these monogenetic diseases such as familial hemiplegic migraine (FHM), cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL), retinal vasculopathy with cerebral leukodystrophy and systemic manifestations (RVCL-S), and mito- chondrial myopathy with encephalopathy, lactate acidosis, and stroke (MELAS) o ers a unique opportunity to increase understanding of the pathophysiology behind the connection between migraine and stroke. FHM is an autosomal dominant disease in which MA is the key symptom. e migraine symptoms are typically accompanied by the gradual onset of neurological de cits, mostly hemiparesis, which can last for hours to weeks. An attack resembles a stroke, but, unlike a stroke, it resolves in time. Other associated symptoms are ataxia

and coma. FHM is caused by mutations in several genes: CACNA1A (FHM1), ATP1A2 (FHM2), and SCN1A (FHM3).

CADASIL is a disease caused by a mutation in NOTCH3 that is characterized by dementia, white matter lesions, and lacunar in- farcts. Migraine, most o en with aura, is present in 20–40% of the cases and is o en the presenting event. Migraine auras are o en prolonged, atypical, or associated with confusional episodes (118). However, in a study of 55 patients with CADASIL with a R544C mutation and an overall headache prevalence of 45%, the majority (88%) of patients had tension-type headache (119).

In contrast to FHM and CADASIL, RVCL-S is mostly associated with MO. RVCL is caused by a mutation in TREX1. MELAS is a disease that a ects many parts of the body but mainly the central nervous system and the muscles. It is caused by mutations in the genes in mitochondrial DNA. In MELAS, migraine-like headache episodes can be followed by acute neurological symptoms.

Headache at stroke onset may not be just innocent bystander but could, because of an associated di erent underlying pathophysi- ology, in uence short- and long-term outcome a er stroke. In this section the studies on headache and prognosis in ischaemic and haemorrhagic stroke are described. Less is known about the prog- nostic role of headache in sinus thrombosis, SAH, vascular malfor- mations, RVCS, and angiitis.

Short-term outcome

Five studies that investigated headache and short-term outcome found contrasting results regarding the relationship between con- comitant headache and stroke outcome. (15,16,20,22,26). In the rst prospective, community-based cohort of both haemorrhagic and is- chaemic stroke patients, 241 of 867 (28%) patients had headache in relation to stroke onset. ere was no correlation between headache and mortality and stroke outcome at time of discharge, as measured with the Scandinavian Stroke Scale (16,120). In the second study, data on headache were available for 1391 patients, of whom 1185 had an ischaemic stroke and 201 had an ICH. Headache was found in 18.2% of patients (46.3% of ICH and 13.5% of ischaemic stroke patients) and was associated with a higher 30-day mortality in ICH (HR 2.09, 95% CI 1.18–3.71) but not in ischaemic stroke (HR 1.01, 95% CI 0.53–1.92) (20). In the third study, no di erences in neurological or functional outcome 6 months a er discharge were detected between 145 lacunar ischaemic stroke patients with and without headache within the rst 72 hours a er symptom onset (26). In the fourth study, including 11,523 participants in the Taiwan Stroke Registry, patients with onset headache (7.4% of the population) had a lower frequency of stroke evolution, a greater improvement in National Institutes of Health Stroke Scale score on discharge, a higher mean Barthel index, and a lower frequency of a modi ed Rankin Scale (mRS) score > 2 (15). ere was also a trend for better functional outcome at 3 and 6 months in this follow-up (15). e h study, which included 284 ischaemic stroke patients, found no di erence in mRS score > 2 at the 3-month follow-up in patients with onset headache (38% of the population) versus patients without (22).

CHAPTER 37 Headache and neurovascular disorders

Headache as a prognostic factor for vascular disorders

339

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PART 6 Secondary headaches Long-term outcome

In a long-term follow-up study of ischaemic stroke patients, con- comitant headache appeared to result in a better outcome with fewer recurrent vascular events and a lower overall death rate. In this study, 2473 participants of the Dutch TIA trial with a TIA or minor stroke of non-cardioembolic origin, were followed over a me- dian time of 14.1 years (29). Onset headache was present in 17% of this population, was more prevalent in women, and more o en associated with lesions involving the cortical and posterior circula- tion. Patients with headache at stroke onset had an adjusted HR of 0.83 (95% CI 0.71–0.97) for new vascular events during follow-up. For cardiac events the adjusted HR was 0.88 (95% CI 0.67–1.14), and for cerebral events the HR was 0.97 (95% CI 0.76–1.24). Participants with headache were at lower risk of vascular death (adjusted HR 0.73, 95% CI 0.61–0.87).

Migraine, spreading depolarizations, and outcome after stroke

SDs are presumed to be the underlying mechanism of a migraine aura and are characterized by slowly spreading waves of depolariza- tion (temporary loss of function) of brain cells (121). In healthy brain this mechanism is relatively benign, but SDs can be harmful in dam- aged brain tissue (121). Migraineurs with aura are probably more susceptible to SDs. As SDs are thought to have a detrimental e ect on recovery of cerebral ischaemia one could expect patients with MA to be at risk for a poorer outcome a er stroke. FHM type 1 mice har- bouring the CACNA1 mutation are more susceptible to SDs and were shown to have larger strokes and a higher mortality a er middle cere- bral artery occlusion than wild-type mice (122). However, in a large prospective cohort of 27,852 women enrolled in the Women’s Health Study a relatively good functional outcome was found in female mi- graineurs (123). During a mean follow-up of 13.5 years, 398 TIAs and 345 ischaemic strokes occurred in this cohort of women without a history of cardiovascular disease, cancer, or other major illnesses and an age of ≤ 45 years at baseline. Compared with women without a his- tory of migraine and who did not experience a TIA or stroke, women who reported active MA had an adjusted relative risk of 1.56 (95% CI 1.03–2.36) for TIA, 2.33 (95% CI 1.37–3.97) for stroke with a good outcome (mRS 124 0–1) (124), 0.82 (95% CI 0.30–2.24) for stroke with a moderate outcome (mRS 2–3), and 1.18 (95% CI 0.28–4.97) for stroke with a poor outcome (mRS 4–6). e risk of any of these outcomes was not signi cantly higher in women who experienced MO or who had a past history of migraine (123).

e underlying pathophysiological mechanisms behind headache in vascular diseases are, in general, poorly understood. In this section the pathophysiology of headache as risk factor, symptom, and prog- nostic factor is summarized.

Pathophysiology of headache as risk factor

A number of factors may underlie the occurrence of ischaemic stroke in migraineurs. It is important to distinguish the timing of stroke in

those with migraine, as the underlying pathophysiology may di er. Stroke may occur during or completely separately from a migraine attack. e occurrence of stroke during a migraine attack is known as migrainous infarction. is is a very rare syndrome. Even in those cases that meet the ICHD-3 criteria for migrainous infarction, cere- bral ischaemia can precipitate cortical spreading depression (CSD) and aura symptoms, and, in some cases, the migraine aura is likely symptomatic of cerebral ischaemia rather than the ischaemia and infarction being secondary to events that occur during the migraine attack. Nevertheless, several physiological events during a migraine attack, particularly with aura, may increase the risk of ischaemic stroke in a vulnerable individual. CSD is associated with a profound metabolic derangement characterized by a signi cant increase in the consumption of high-energy phosphates, glucose, and oxygen, while nutrient substrate delivery is compromised by metabolic ow uncoupling and a reduction in cerebral blood ow (125–128). While not usually su cient in humans to result in irreversible cerebral injury, the combination of these physiological changes and other factors shown to be present in those with MA, such endothelial dysfunction, elevated circulating procoagulants, and in ammatory cytokines, especially in the setting of oral contraceptive use or envir- onmental factors such as dehydration and elevated blood viscosity, may be su cient to result in cerebral infarction (129,130).

e underlying mechanism(s) by which migraine increases the risk of ischaemic stroke independently of migraine attacks (mi- grainous infarction) is likely multifactorial. Migraine is associated with well-established and emerging cardiovascular and cerebrovas- cular risk factors, including obesity (131,132), patent foramen ovale (133), increased tobacco and exogenous hormone use (13,134), cer- vical carotid artery dissection (76), and elevated Framingham risk scores, versus non-migraineurs (5,135).

Endothelial dysfunction has also been considered to be a poten- tially important pathogenetic factor underlying the increased risk of ischaemic stroke in those with MA (129).

MA has been associated with Sneddon syndrome, a disorder characterized by endothelial dysfunction. Migraine is also associ- ated with elevated levels of biomarkers of endothelial dysfunction, including tissue plasminogen activator, high-sensitivity C-reactive protein, von Willebrand factor, vascular endothelial growth factor and nitric oxide metabolites, lower levels of endothelial repair (pro- genitor) cells, and elevated levels of procoagulants, including pro- thrombin fragment 1.2 (136–139).

An emerging body of evidence also supports an association be- tween migraine and inherited risk factors for venous thrombo- embolism and vascular disease. ere is an increased risk of MA in carriers of factor V Leiden or factor II G2021 mutations (140). Individuals with methylenetetrahydrofolate reductase 677 TT geno- type appears to increase the risk of MA and this combination has been shown to increase the risk of ischaemic stroke (OR 1.81, 95% CI 1.02–3.22; HR 4.19, 95% CI 1.38–12.74) (141,142). A recent meta- analysis of 22 genome-wide association studies that included data from 59,674 patients with migraine and 316,078 controls collected from six tertiary headache clinics and 27 population-based cohorts identi ed 44 independent SNPs signi cantly associated with mi- graine risk that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus identi ed on chromosome X—a nding not previously reported. Several of the identi ed genes (PHACTR1, TGFBR2, LRP1, PRDM16, RNF213, JAG1, HEY2, GJA1,

Pathophysiology of headache related to neurovascular disorders

and ARMS2) have previously been associated with vascular disease or are involved in smooth muscle contractility and regulation of vas- cular tone (MRVI1, GJA1, SLC24A3, and NRP1). is seminal work provides evidence that migraine-associated genes are involved in both arterial and smooth muscle function and represents both the potential for the vasculature to be a trigger for migraine, as well as underscoring a potential genetic predisposition to ischaemic stroke in migraineurs (143).

Pathophysiology of headache as symptom

Headache as a symptom of stroke is generally thought to be due to stimulation of cerebral pain regulation systems. Intracranial noci- ceptive structures are the meninges and blood vessels. ese struc- tures are innervated by the ophthalmic branch of the trigeminal nerve; a erent bres pass through the trigeminal ganglion and syn- apse on second-order neurons in the trigeminocervical complex. ese neurons, in turn, project through the quintothalamic tract (144). Stimulation of sensory a erents of the trigeminovascular system is increasingly recognized as a very important pain- regulating mechanism. e trigeminovascular system can be trig- gered in several ways. As described previously in this chapter, one detrimental mechanism that is indirectly able to stimulate the system is CSD (145,146). e posterior circulation is more densely innervated by the trigeminovascular system than the anterior circu- lation. is might explain, in part, why headache more o en occurs in vertebrobasilar strokes. Other pain-regulating centres may also be involved. Stroke-related pain has been linked to lesions in the thalamus (147,148). Interestingly, stroke-associated headache oc- curs more o en in patients with a history of headache. is seems to be the case for di erent types of headache, such as migraine and tension-type headache. It has been suggested that in these patients pain-sensitive mechanisms are reactivated, triggered by their stroke. For migraineurs, a higher susceptibility for SD might play a role in reactivation of prestroke headache.

In addition to the pain-regulation systems, more generalized mechanisms are activated in the brain during and a er stroke. Raised intracranial pressure is a known cause of headache. e rela- tion that was found in headache and lesion size in ischaemic stroke patients with size of haematoma cavity and signs of herniation in patients with ICH point in this direction. In one study headache was more severe with movement and coughing (31). e role of lesion- related oedema is not clear. Headache at ICH onset was associated with cerebral in ammation (51). For ischaemic stroke, evidence for an association between in ammation and headache is lacking. Some studies have found a higher frequency of headache in patients with high blood pressure on admission (18). is may suggest a role for a disturbance in autoregulation. e dysfunction of autoregulation especially a ects the posterior regions of the brain. is is empha- sized by the fact that headache is also frequently encountered in hypertension-related vasculopathies like posterior reversible en- cephalopathy syndrome and cerebral hyperperfusion syndrome a er carotid endarterectomy (149,150).

Local vascular structures and vascular drainage patterns are also linked to headache occurrence, especially in patients with AVM and CVST. In patients with AVM, headache was associated with a larger nidus volume, tortuous change of feeding artery, cortical drainage with re ux in the superior saggital sinus, and dural arterial supply to

the AVM (79,81). In one small CVST study, the majority of patients with sigmoid sinus thrombosis reported pain in the occipital and neck region (63). However, large studies on local vascular structures and stroke headache are limited and therefore these data should be interpreted with caution. e advent of new non-invasive imaging techniques such as CT angiography and MR angiography and per- fusion o er an opportunity to gain more insight in the relation be- tween local vascular structures and stroke-related headache.

Pathophysiology of headache as prognostic factor

As described herein, there are con icting results on the association between headache and short-term outcome in ischaemic stroke. For haemorrhagic stroke this relationship seems to be more robust. As headache in ICH is related to haemorrhage size, posterior location, and in ammation, these factors might contribute to a relatively poor outcome. SDs are supposed to have a detrimental e ect on recovery of cerebral ischaemia in stroke patients in general (not only patients with a history of migraine) (121). In animal experiments, SDs in in- jured brain resulted in hypoperfusion and aggravation of ischaemia (122). Recently, it was shown that SDs occur and play a detrimental role in the penumbra of patients with large middle cerebral artery infarctions (145). In addition, in a small series of patients with SAH, SDs were found to be related to the occurrence of delayed cerebral ischaemia (DCI) (151). Future research should further determine the exact role of SD in outcome a er stroke in humans.

e more benign long-term vascular prognosis in patients with headache at presentation of ischaemic stroke might point to a dif- ferent pathophysiology behind the stroke or might be caused by a di erence in associated vascular risk factors in stroke patients with and without headache. Certain subtypes of stroke present more o en with headache than others. ese stroke subtypes might have more benign vascular prognoses, possibly because they are not directly re- lated to atherosclerosis. Arterial dissections and RCVS are examples of diseases associated with headache and a better long-term outcome (152,153). ere might also be a relation between headache at presen- tation and cardiovascular risk factors. Headache at ischaemic stroke onset is more o en found in relatively young patients without cardio- vascular risk factors such as hypertension. is better cardiovascular risk pro le in patients with headache might explain the more benign long-term prognosis, but further research on this topic is needed.

CHAPTER 37 Headache and neurovascular disorders

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Headache attributed to spontaneous intracranial hypotension
Farnaz Amoozegar, Esma Dilli, Rashmi B. Halker, and Amaal J. Starling

Introduction

Cerebrospinal uid (CSF) leaks can occur spontaneously or a er a dural puncture. While both types of CSF leak lead to a reduction in CSF volume, spontaneous leaks can di er from dural puncture leaks in terms of clinical presentation, location of the leak, response to blood patch, and overall prognosis. Spontaneous intracranial hypo- tension (SIH) was de ned in 1997 as a triad of postural headache, low CSF pressure, and imaging abnormalities. However, since then, it has become apparent that not all patients display an orthostatic headache, especially as time goes on, not all patients have low CSF opening pressures on testing, and not all patients clearly show signs of CSF leak on routine imaging. erefore, the de nition has be- come broader over time but still lacks high sensitivity. e latest version of the International Classi cation of Headache Disorders (ICHD-3), de nes SIH as headache which has developed in tem- poral relation to the CSF leakage, or has led to its discovery, with either low CSF pressure (< 60 mm water) and/or evidence of CSF leakage on imaging (1).

Almost all cases of SIH occur at the level of the spine rather than the cribiform plate or skull base (2). With the advent of magnetic resonance imaging (MRI) and other advanced imaging studies, it has become much easier to detect SIH and this has led to the dis- covery that symptoms can vary considerably. In this chapter, we will review the epidemiology, clinical features, pathophysiology, investi- gations, treatment options, and prognosis of SIH.

Epidemiology

e true incidence and prevalence of CSF leaks are unknown. Although some report an incidence of 2–5 cases per 100,000 people per year, CSF leaks are considered to be underdiagnosed (3,4). Women appear to be a ected more than men, with a female-to-male ratio of 2:1 (5). SIH has been reported in 2-year-old to 86-year-old patients, with a peak incidence occurring between 35 and 42 years of age (4–8).

Pathophysiology

In the vast majority of cases, SIH results from spontaneous CSF leaks. Most of these leaks occur at the level of the spine, commonly at the cervico-thoracic junction or the thoracic region (9–11). Rarely, a leak can occur at the skull base. ese leaks can occur as a result of defects in the cribiform plate, the sphenoid and frontal sinuses, the ethmoid roof, the sella, or the temporal bone (9).

Although there is much variability with regard to clinical pres- entation and ndings on imaging in patients with SIH, the key pathogenetic factor is loss of CSF volume (11,12). In many cases of SIH, the exact underlying cause for the leak remains unknown, but the aetiology and pathogenesis of this condition are felt to be multifactorial (10).

e presence of a connective tissue disorder is a risk factor for the development of SIH. Among these, Ehlers–Danlos syndrome type II, Marfan syndrome, and autosomal dominant polycystic kidney disease are the conditions most likely to be associated with CSF leaks (10). ese patients appear to have a weakness of the con- nective tissue matrix within the dural sac. In these cases, CSF leaks can occur spontaneously, or a trivial trauma, such as coughing or li ing, may be su cient to cause a dural tear leading to a CSF leak (10,11). Some patients with connective tissue disorders also have ectatic dural sacs, meningeal diverticula, and dilated nerve root sleeves (10,12). Familial cases of SIH have been described, mainly in patients with underlying connective tissue disorders (10).

Spondolytic spurs and herniated discs can also be a causative factor in the creation of CSF leaks (10,11). Occasionally, congenital bony spurs can also be found. At the time of surgery, many other ab- normalities of the dura can be found, such as dural holes or rents, or even complete absence of the dura (10).

e symptoms of SIH can be explained by the loss of CSF volume and the Monro–Kellie hypothesis (11,12). is hypothesis states that with an intact skull, the sum of the volume of brain, CSF, and blood is constant (11,12). erefore, if there is loss of CSF, other components in this equation must compensate for that loss. As a result, the blood component tends to increase, resulting in venous engorgement and

pituitary hyperaemia. e meningeal venous hyperaemia leads to pachymeningeal enhancement. Subdural uid collections are also compensatory (11,12).

e headache is felt to be as a result of sagging of the brain and traction of the pain-sensitive structures (9,11). Engorgement of venous structures may also contribute to the pain experienced by patients (9,12). e postural nature of the headache may be related to worsening of CSF hypotension due to gravitational pull and from an increase in the sagging of the brain and traction of the pain- sensitive structures when upright (9).

Cranial nerve de cits, including vestibulocochlear dysfunction, are felt to be related to traction and compression of the corres- ponding nerves at the level of the brainstem (9,11). Alterations in the pressure of the perilymph in the inner ear may also be respon- sible for altered hearing and tinnitus (9). Other clinical features also seem to relate to traction of other structures in the brain, such as the pituitary stalk or mesencephalon (11). However, one must keep in mind that these explanations have not been proven.

Another postulation for the headache is that there may be an al- tered distribution of craniospinal elasticity. is may occur as a re- sult of spinal loss of CSF leading to spinal dural sac collapse and increased compliance of the lower spinal CSF space (10).

In 2010, an Italian group proposed a novel speculative pathophysio- logical hypothesis for the cause of SIH (13). ey proposed that the underlying pathology in SIH is not a primary loss of CSF from a dural tear, but a loss of CSF into the epidural space as compensation for negative pressure within the inferior vena cava (IVC). ey believe that negative pressure within the IVC will result in over-drainage of venous blood from the spinal epidural venous plexus, resulting in a modi cation of epidural gradients (13). Franzini et al. (13) suggested that it is this modi cation that results in CSF leakage into the epidural space. However, it is unclear how the negative pressure in the IVC be- comes signi cantly low enough to cause such a phenomenon. e au- thors do not provide a clear explanation for this. eir proposal has not been substantiated by other groups and remains entirely speculative.

Most recently, the current understanding of SIH pathogenesis holds that the symptoms are related to loss of intracranial CSF volume, ra- ther than strictly a reduction in pressure (14). Many patients with SIH exhibit normal opening pressures. Perhaps this is related to the compensatory mechanisms described earlier. Hence, this compen- sation may, in turn, normalize the CSF opening pressure. What may lead to loss of CSF volume? is is felt to occur by three major aeti- ologies in the spine: (i) leaks secondary to dural weakness in the area of the nerve root sleeves/meningeal diverticula; (ii) ventral dural tears associated with degenerative disc disease/osteophytes/disc her- niations; and (iii) CSF venous stulas (14). e CSF venous stula has recently been described and represents a direct connection between a paraspinal vein and CSF within the subarachnoid space.

Clinical manifestations

ICHD-3 de nes SIH as a headache that has developed in temporal re- lation to low CSF pressure or CSF leakage, or has led to its discovery, along with the presence of low CSF pressure (< 60 mm CSF) and/or evi- dence of CSF leakage on imaging (Box 38.1) (1). Prior to the publica- tion of the ICHD-3 criteria, in 2011 Schievink et al. (15) also proposed similar diagnostic criteria for headache due to SIH (Box 38.2) (15).

e most common clinical manifestation of SIH is an orthostatic headache, or a headache that is present when upright and improves when supine (11,12,16,17), and this feature is experienced by > 95% of patients (18). Because SIH can have a sudden onset in 15% of cases, it also re- mains in the di erential diagnosis of thunderclap headache (19–21). e pain is o en described as throbbing, dull, or a pressure sensation, which can be severe and varied in location. Some patients feel the headache is holocephalic, and others cite speci c regions, most o en the occiput or subocciput region, as experiencing the most intense pain. Classically, the headache is expected to improve within 15–30 minutes of being supine, but, in reality, this can vary considerably (22,23). If SIH is le untreated, the positional component can diminish over time and it can simply be reported as a chronic daily headache and o en mimic chronic migraine, chronic tension-type headache, or cervicogenic headache.

In some cases, the diagnosis can be challenging because the head- ache may lack the characteristic orthostatic component from the start. ere are reports of patients presenting with Valsalva-induced or exercise-related headache, paradoxical headaches in which the pain is present when supine and improved when upright, headaches that lack obvious orthostatic features but instead the pain comes on later in the day (suggesting a subtle orthostatic component, as it comes on a er an individual has been upright for a prolonged period of time), a new daily persistent headache phenotype, or even inter- mittent headaches that can be associated with intermittent CSF leaks (24–26). e presentation of a non-orthostatic headache with CSF leak may be due to a compensatory response with a normal physio- logical reaction to the CSF leak (27).

CHAPTER 38 Headache attributed to spontaneous intracranial hypotension

Box 38.1 ICHD-3 criteria for headache attributed to spontaneous intracranial hypotension

. A Any headache ful lling criterion C.

. B Low cerebrospinal uid (CSF) pressure (< 60 mm CSF) and/or evi-
dence of CSF leakage on imaging.

. C Headache has developed in temporal relation to the low CSF pres-
sure or CSF leakage, or has led to its discovery.

. D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Box 38.2 Diagnostic criteria for headache due to spontaneous intracranial hypotension

. A Orthostatic headache.

. B The presence of at least one of the following:

. 1 Low opening pressure (≤60 mm H2O)

. 2 Sustained improvement of symptoms after epidural blood
patching

. 3 Demonstration of an active spinal cerebrospinal uid leak

. 4 Cranialmagneticresonanceimagingchangesofintracranialhypo-
tension (e.g. brain sagging or pachymeningeal enhancement)

. C No recent history of dural puncture.

. D Not attributable to another disorder.

Reproduced from Headache, 51, Schievink WI, Dodick DW, Mokri B, Silberstein S, Bousser MG, Goadsby PJ. Diagnostic criteria for headache due to spontaneous intra- cranial hypotension: a perspective, pp. 1442–1444. Copyright (2011) with permission from John Wiley and Sons.

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PART 6 Secondary headaches

A minority of patients lack headache altogether, and it is the other symptoms that lead to the discovery of the CSF leak. Owing to menin- geal irritation, > 50% of patients experience posterior neck pain and sti – ness with nausea, photophobia, and phonophobia. Vestibulocochlear symptoms, such as changes in hearing (echoing, under water sensa- tion), tinnitus, ear fullness, and dizziness/vertigo, may be orthostatic and are the most common cranial nerve symptoms (28,29). Stretching of the vestibulocochlear nerve or abnormal CSF pressure to that of perilymph uid are possible reasons for these symptoms (30).

Visual blurring; visual eld defects; diplopia; facial numbness or facial pain; facial weakness or spasm; parkinsonism, including tremor and chorea; ataxia; and dementia have been rarely reported (31–34). Interestingly, the presence of diplopia with headache had a positive predictive value of 91%, while the presence of diplopia to- gether with the absence of limb numbness had a positive predictive value of diagnosing a CSF leak in 95% (35).

In some patients, distortion of the pituitary stalk may lead to hyperprolactinaemia and galactorrhoea (36). Rarely, severe brain displacement may result in diencephalic herniation with decreased level of consciousness, encephalopathy, and even coma (37–39).

Spinal manifestations are uncommon; however, 6% of patients experience spinal symptoms/signs such as interscapular pain, local back pain at leak site, quadriparesis, and radicular symptoms (40). Spinal venous plexus engorgement may be the mechanism of the radiculopathy and myelopathy (41). e spinal manifestations are usually not positional, but instead thought be to related to mass ef- fect from an extradural CSF collection (40).

It is important to keep in mind that features of SIH can be found incidentally on MRI without symptoms (42). Furthermore, ortho- static headaches may also occur in orthostatic hypotension, postural orthostatic tachycardia syndrome with excessive increase in heart rate when standing, vasovagal syncope, or even migraine, and this di erential should be considered in patients with orthostatic head- ache and normal MRI of the brain (43,44). Cervicogenic headache can at times present with an orthostatic component as well (14,45). Other less common headaches that may be positional in nature include headaches associated with diabetes insipidus and post- decompression surgery for Chiari malformations (45,46).

Investigations

Over the years, many di erent diagnostic investigations have been used in patients with SIH. is section will review the pros, cons, and results of the various investigations, and then recommend an investigative algorithm based on the currently available evidence.

Lumbar puncture

A lumbar puncture and CSF analysis can be performed, but the results may be normal and the dural puncture itself may worsen the leak and subsequent intracranial hypotension (Table 38.1) (47). Although the opening pressure is sometimes low, it is in many cases within normal limits. Even in the same patient, variable opening pressures may be recorded at di erent time points, depending on the rate of ow of the leak (47). A retrospective case series that reviewed 106 patients with SIH showed that 61% of the patients had a CSF opening pres- sure between 6 and 20 cm water, and only 34% had a pressure ≤ 6 cm

Table 38.1 Lumbar puncture and cerebrospinal uid analysis in spontaneous intracranial hypotension.

Opening pressure

Typically low, but may be normal or may vary depending on the ow rate of the leak (44)

Colour

Typically clear, but may be xanthochromic or blood- tinged in the setting of a traumatic tap

White blood cells

May be normal or elevated (typically ~ 50 cells/mm2) (45,46).

Red blood cells

May be normal or slightly elevated in the setting of a traumatic tap

Protein

May be normal or high (typically < 100 mg/dl)

Glucose

Normal

Gram stain

Negative

Cytology

Normal

water (48). A few factors associated with increased pressure included abdominal circumference, symptom duration, and a normal MRI of the brain. is paper, in addition to others, indicates that a normal CSF opening pressure can occur o en, and therefore the absence of a low CSF opening pressure should not exclude the diagnosis of SIH.

e CSF is typically clear, but may be xanthochromic or blood- tinged in the setting of a traumatic tap (12). Traumatic taps are common in SIH, most likely due to the low opening pressure and/ or engorgement of the epidural venous plexus (12). e erythrocyte count is typically normal, but can be elevated, usually in the setting of a traumatic tap (12). e leukocyte count is typically normal. However, a lymphocytic pleocytosis, ranging from 50 to 200 cells/ mm2, has been reported in the literature (49,50). e protein con- centration can be normal or high; values > 100 mg/dl, have been reported but are rare (47). e glucose concentration, Gram stain, and cytology are always normal (12).

Radioisotope cisternography

Radioisotope cisternography may identify the presence of a CSF leak, but it rarely identi es the exact site of the leak. Radioisotope cisternography involves the intrathecal injection of a radioisotope, indium-111, followed by sequential scanning at intervals up to 24 or even 48 hours. Typically, at the 24-hour mark, radioactivity should be detected over the cerebral convexities (51–53). A CSF leak is sus- pected in the absence of radioactivity over the cerebral convexities at 24 hours. is is the most common abnormality that is seen on radioisotope cisternography in SIH (12). In addition, the early ap- pearance of radioactivity in the kidneys and urinary bladder sug- gests that the intrathecally introduced radioisotope has leaked out of intrathecal space, entered the systemic circulation, been ltered by the kidneys, and appeared prematurely in the urinary bladder. However, false positives can occur via the extravasation of the radio- isotope through the dural puncture, which would lead to early ac- tivity present in the urinary bladder. A CSF venous stula can also contribute to the early appearance of the radioisotope within the urinary bladder. It is possible, but less common, that paradural ac- tivity may point to the level or approximate site of the leak. However, the accumulation of the radioisotope within meningeal diverticula or dilated nerve root sleeves may appear as paradural activity (12). In addition, inadvertent injection of the radioisotope extradurally

may appear as a collection of paradural activity. Myelography can di erentiate between these possibilities. In suspected SIH, radioiso- tope cisternography may indicate the likelihood that a CSF leak is present; however, it is unlikely to indicate the site of the leak and it involves a dural puncture. Typically, in cases where radioiso- tope cisternography results suggest the presence of a CSF leak, a myelographic study is needed to con rm the presence of the leak and location prior to treatment.

Computed tomography of the head

A non-contrast computed tomography (CT) scan of the head is typ- ically of limited value; however, it may show the presence of sub- dural uid collections (12).

MRI of the brain and spine

MRI of the brain and spine can be very useful for the diagnosis of SIH and a spinal CSF leak. For the evaluation of SIH, an MRI of the brain with and without gadolinium contrast including T1-weighted midline sagittal views, as well as gadolinium enhanced T1-weighted coronal views through the sella and pituitary, are necessary (12). Common abnormalities on MRI of the brain with and without con- trast in the setting of SIH include di use pachymeningeal enhance- ment without abnormal leptomeningeal enhancement, sagging of the brain with descent of the brainstem, engorgement of the venous structures, pituitary hyperaemia, and subdural uid collections (11,12). A mnemonic has been proposed to remember the major MRI brain abnormalities present in SIH—SEEPS (Box 38.3) (4). Di use pachymeningeal enhancement is the most common MRI brain abnormality seen in SIH; however, it can be absent in some patients (54,55).

Other signs on MRI brain in SIH include the venous distension sign, which assesses the inferior margin of the midportion of the dominant transverse sinus. Normally, on T1-weighted sagittal views, this margin shows a concave or straight con guration, while in SIH it usually assumes a distended convex con guration (the venous dis- tension sign). In one study, the sensitivity of the venous distension sign for the diagnosis of SIH was found to be 94%; speci city was also 94% (56). e ‘venous hinge’ sign: reduction of the angle between the vein of Galen and internal cerebral vein, which returns to baseline a er treatment, has also been reported (57). e mamillopontine distance and the pontomesencephalic angle have recently been de- scribed as additional quantitative methods to aid in the diagnosis of

SIH (58). e sensitivity and speci city of these measures is lower than that of the venous distension sign. Dural thickening of the in- ternal auditory canal has also been described (59).

Novel orbital ndings have also been described recently on rou- tine brain MRI scans. Compared to controls, one study found that patients with SIH demonstrated signi cantly reduced CSF in the optic nerve sheath and a more straightened optic nerve angle (60). Some research has also looked at the use of transorbital ultrasound in cases of SIH. One study found that patients with SIH who had orthostatic headache had a signi cant decrease in optic nerve sheath diameter, as measured by ultrasound, when shi ing from the supine to the upright position (61). is group was compared to patients with SIH who had no orthostatic headache and with control pa- tients (61). As a nal note about MRI, it is important to remember that about 15–20% of patients with SIH can have normal MRI of the brain (45).

MRI spine abnormalities seen in SIH include extradural uid collections that may be focal or extend along several vertebral seg- ments, spinal dural enhancement, meningeal diverticula and dilated nerve root sleeves, and engorgement of epidural venous plexus (12). Although it is possible, especially with highly T2-weighted images, to approximate the site of the CSF leak, the MRI of the spine does not appear to be a substitute for myelography in identifying the site of the leak for more targeted treatment approaches (62). However, both MRI brain and MRI spine are sensitive diagnostic techniques for suspected cases of SIH and are not invasive, meaning they do not involve a dural puncture, and do not involve radiation.

Myelography

CT myelography (CTM) involves the intradural injection of contrast to identify the presence and location of a spinal CSF leak. Extradural uid collections, meningeal diverticula, and extradural extrava- sation of contrast into the paraspinal so tissues are common ab- normalities that are seen in the setting of SIH (12). Although the extradural uid collections can be quite focal, it is also possible that they may extend several spinal levels. With the invasive forms of myelography, about 10% of patients can have retrospinal uid col- lections of contrast at the C1–2 level (45). is does not correlate with the site of a CSF leak and is felt to be a false localizing sign (45).

CTM is conventionally a static diagnostic study, not dynamic. It is important to note that the rate of a CSF leak may vary from very slow to intermittent to very fast. us, the results of CTM are in uenced by the rate of CSF leakage, which can be a challenge at both extremes, when the CSF leak ow is very slow or very fast. In the setting of slow- ow CSF leak, delayed CT scanning or MRI myelography with intrathecal injection of gadolinium may be helpful (63). Digital sub- traction myelography (DSM) (64,65) and ultrafast dynamic CTM (66,67) are techniques that have excellent temporal resolution versus a standard CTM. ese techniques are useful for CSF leaks with a rapid ow rate. Although, CTM has been the gold standard for diag- nosis of spinal CSF leaks, a diagnostic technique that does not in- volve a dural puncture or radiation, and is not in uenced by the rate of CSF leak ow is needed.

MRI myelography, which involves intrathecal injection of gado- linium, can be helpful in the identi cation of the site of a slow CSF leak. However, intrathecal use of gadolinium is o -label and this technique should be considered only when the diagnosis of the CSF

CHAPTER 38

Headache attributed to spontaneous intracranial hypotension

Box 38.3 SEEPS: a mnemonic for common magnetic resonance imaging head abnormalities seen in spontaneous intracranial hypotension (4)

S Sagging of the brain

E Enhancement of pachymeningeal

E Engorgement of venous structures

P Pituitary hyperaemia

S Subdural uid collections

Source data from JAMA, 295, Schievink WI. Spontaneous spinal cerebrospinal uid leaks and intracranial hypotension, pp. 2286–2296, 2006.

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leak is highly suspected and when the site of the CSF leak has not been detected by other diagnostic techniques such as CTM (63).

A group of researchers at the Mayo Clinic in Rochester, New York, employ spinal MRI to plan subsequent investigations (68). ey use spinal MRI rst and then determine if CTM is needed and, if so, what type of CTM to do (conventional vs dynamic). If the spinal MRI does not localize the leak, but extradural uid is present, then a dynamic CTM is performed. If extradural uid is not present, a conventional CTM is performed. is algorithm has resulted in a reduction of CTMs in general and has also minimized unnecessary dynamic CTM. is is bene cial as it results in reduced radiation ex- posure and fewer invasive procedures for patients, and cost savings for the healthcare system.

As previously indicated, a more recently recognized cause of CSF leaks is a CSF venous stula. A CSF venous stula is a direct commu- nication between CSF in the subarachnoid space and a paraspinal vein, with usually negative ndings on myelography. Kranz’s group at Duke University Medical Center (Durham, NC, USA) have de- scribed a recent nding on CTM that may help aid the recognition of a CSF venous stula as the underlying cause of the CSF leak (48). e ‘hyperdense paraspinal vein’ sign is a hyper-attenuated paraspinal vein that is seen in close proximity to the area of the CSF venous s- tula. is is felt to occur as a result of rapid passage of myelographic contrast into the venous system via the stula (48).

DSM involves digital subtraction X-rays acquired during intra- thecal injection of contrast via lumbar puncture. is specialized technique may be useful as an adjunct to more commonly used mo- dalities, particularly for (i) high ow or fast leaks, without precise localization of the leak; (ii) when a CSF leak occurs as a result of a CSF venous stula; and (iii) for localizing leaks ventral to the spinal cord (45,64,65,69).

It is important to note that there are di erent types of CSF leaks and imaging ndings can vary based on the type of leak suspected (69). Dr Schievink’s group at Cedars-Sinai (Los Angeles, CA, USA) reviewed 568 patients for the type of CSF leak (at surgery) and com- pared this to spinal MRI or myelography ndings (69). ey identi- ed four major groups of CSF leaks at the time of surgery: dural tears, meningeal diverticula, CSF venous stulas, and an indeterminate/ unknown group. ey found that extradural uid collections com- monly occur with dural tears (in nearly 100% of patients), but occur in only about one- h of patients with meningeal diverticula, and in none of the patients with CSF venous stulas. So, this may explain why certain patients show few or no ndings on routine testing.

Based on the currently available evidence and clinical experience, an MRI of the brain with gadolinium contrast is the most sensitive and least invasive investigation to detect the presence or absence of SIH. An MRI of the spine without contrast may de nitively dem- onstrate the presence of an extradural uid collection and a spinal CSF leak; however, myelography is still the gold standard for CSF leak localization. Depending on the speed of the leak or extradural uid collections, standard CTM, dynamic CTM, DSM, or MRI myelography may be pursued.

Treatment

e treatment of SIH begins with conservative measures, usually for a few days to a few weeks, depending on the severity of symptoms,

to see if the CSF leak will seal itself over (11,12,70,71). In some cases, these conservative measures are su cient and no other interven- tions are required.

Conservative measures for treatment include lifestyle modi ca- tions, such as bed rest, ca eine, and hydration, as well as medica- tions (11,12). Ca eine does provide symptomatic bene t for many patients, but the e ect is short-lived. Several cases using various analgesics, theophylline, and corticosteroids have been reported in the literature (72,73). Success with these medications is highly variable and inconsistent (10–12). With regard to corticoster- oids, various doses and forms have been used, such as prednisone, methylprednisolone, udrocortisone, and dexamethasone (73). It is not clear how steroids improve symptoms related to SIH. It is pro- posed that they work via four possible mechanisms. ese include improving brain oedema and reducing in ammation, encouraging uid retention, reducing CSF hyperabsorption, and increasing re- absorption of extradural uid (73). However, among those who have improvement of their symptoms, the bene ts are usually temporary. Given the signi cant side e ects of steroids, long-term use is also not appropriate (11). No randomized controlled trials have been per- formed in SIH with any medications.

In rare cases where the patient is decompensating quickly from a neurological point of view, such as a coma, urgent volume replace- ment may be needed to stabilize the patient. Intravenous saline in- fusions, as well as intrathecal uid injections, such as dextran, have been reported as providing limited and temporary improvement in patient symptoms (11,12). e underlying cause, i.e. the CSF leak, must, however, be managed as quickly as possible.

When conservative measures have failed a er an appropriate trial, the mainstay of treatment is a large-volume epidural blood patch (EBP) (10–12). e EBP entails the injection of autologous blood into the epidural space. If the site of the CSF leak is not known, a blind or non-directed blood patch is o en done in the lumbar re- gion. When the site of the leak is known, a directed or targeted blood patch can be performed in the region of the leak (11,12).

It is not known exactly how the EBP works, but it is felt to act in two ways. Firstly, volume replacement, which is felt to lead to the immediate e ects of the EBP. Secondly, sealing of the dural defect, which is likely a delayed e ect of the EBP (11,12). Sealing of the leak is proposed to occur from dural tamponade. It may also restrict CSF ow, restrict CSF absorption, and potentially change dural resist- ance or sti ness (74).

Response to the EBP is quite variable with regard to the onset of bene t (instant to hours), degree of bene t (none to full resolution of symptoms), and duration of e ect (hours to long term) (11,12). Overall, it appears that in those receiving a rst non-directed EBP, about one-third have good and long-lasting response. Many patients will require a second or third EBP before any bene t is noted. With a second EBP, another 20–33% of patients experience relief and an additional 50% have bene t with subsequent EBPs (74). A min- imum of 5 days between EBPs is recommended.

It is important to note that SIH is a di erent condition than post- dural puncture headache (PDPH). In PDPH, given a relatively clean puncture of the dura at a known site and no associated complex anatomy, the response to an EBP is excellent. About 90% of patients have full and lasting bene t from a rst EBP and essentially all re- spond fully to a second EBP (11,12). e CSF leak(s) from SIH are complex in anatomy and location, and may be multiple, leading to

a lower success rate with EBPs (11,74). As a result, many experts advocate a high-volume EBP when possible and as tolerated by the patient. Typical EBP volumes for PDPH are in the range of 10–20 ml. In SIH, a volume of 20–50 ml is generally recommended (11,74). e patient symptoms, such as radicular pain or intense back pain, are the limiting factors for the volume injected (74).

Ferrante et al. (75) have recommended the use of acetazolamide 18 hours and 6 hours pre-EBP procedure, and have shown higher success rates in their group of patients (75). ey suggest that acetazolamide may decrease CSF ow or pressure across the leak and provide a higher chance of success for the EBP. eir work re- mains to be reproduced by others and more studies are required to determine if acetazolamide does, indeed, help.

Some centres use uoroscopy and contrast material while per- forming EBPs. is can be helpful to demonstrate the epidural lo- cation of injection, the level, and the spread. However, it does not appear to improve the chances of success (74).

Wu et al. (76) performed a retrospective analysis of 150 patient cases who had targeted EBP for SIH (76). Factors predicting re- sponse to the rst EBP were (i) volume of injected blood; (ii) length of the anterior epidural CSF collection; and (iii) midbrain–pons angle. When the EBP volume was ≥ 22.5 ml response rate was 67.9% versus a response rate of 47% when the EBP volume was < 22.5 ml (P = 0.01). When the anterior epidural CSF collection length was < 8 segments, the response rate was 72.5% versus 37.3% when the anterior epidural CSF collection was > 8 segments (odds ratio 4.4; P < 0.001). Patients with anterior epidural CSF collection involving < 8 segments and an injected EBP volume of > 22.5 ml had an 80.0% response rate, while patients with anterior epidural CSF collection involving > 8 segments and a midbrain-pons angle < 40o had a 21.2% response rate (76).

Complications a er EBPs are generally uncommon. Some neck and back pain for hours to a few days a er the EBP may occur. is is likely as a result of blood tracking back into the subcutaneous and muscular tissues of the neck and back (74). In rare cases, a dural puncture may occur and lead to worsening of headache. Other rarer complications include persistent haematoma or abscess, delayed neurological de cits, chronic back pain, arachnoiditis, intracranial hypertension, acute meningeal irritation, and post-procedure visual changes (74). Contraindications to EBP include local infection at the proposed site of injection, sepsis, coagulopathy, and inability to cooperate (74).

ere are no speci c guidelines or protocols in determining how many EBPs should be done in a patient. Many authors advocate for doing up to three non-directed EBPs before proceeding to more costly tests to localize the CSF leak. Once the leak is found, directed EBPs can then be performed (74).

Studies indicate that targeted EBPs have a higher chance of suc- cess (62,77–80). A Korean study assessed the e cacy of directed EBPs versus non-directed EBPs (79). is study had several limita- tions and should be interpreted with caution. For example, it was not blinded or randomized, and was retrospective in design. e volume of blood injected was 9–20 ml in the non-directed EBP group, and 10–15 ml autologous blood mixed with contrast medium (1–2 ml iopamidol) under uoroscopic guidance in the directed EBP group (79). e authors de ned a good outcome as complete recovery or minimal symptoms, and a poor outcome as persistent symptoms re- quiring a repeat EBP (79). irty-one patients received a targeted

EBP; 27 (87%) had a good outcome (79). e other four patients had a repeat directed EBP and went on to have a good outcome. Of 25 patients with a non-directed EBP, 13 (52%) had a good outcome (79). In this study, no EBP-related complications were reported (79). Several subsequent case series have also demonstrated higher suc- cess rates with directed blood patches (vs non-directed) and gen- erally better results with higher-volume EBPs (vs lower-volume patches) (81).

It is important to note, however, that targeted EBPs that are done at higher levels, such as thoracic or cervical, may be associated with slightly higher complication risks, including compression of the spinal cord and nerve roots, intrathecal blood injection, and chem- ical meningitis (74).

In cases where the site of the CSF leak is known and repeated directed EBPs are not successful, CT-guided percutaneous brin glue injections can be performed (82). Fibrin glue ( brin sealant) is a bovine product that allows the blood to coagulate by forming a stable brin clot that can assist haemostasis and wound healing (82). ere are possible side e ects, including infection or bleeding at the site, arachnoiditis, and brous scar formation (82). In rare cases, sensitization and anaphylaxis can occur (74,82). For this reason, 3–6 months is recommended between brin glue injections (74). Pretreatment with diphenhydramine may help reduce sensitization and anaphylaxis rates. Variable success rates have been reported with these injections (74,82).

Neurosurgery is reserved as the nal intervention if everything else fails and the patient continues to have disabling symptoms. e site of the leak should be known before surgery is undertaken (10–12). e surgery is o en intricate and complex. Sometimes the anatomy or pathology di ers at the time of surgery than expected from the imaging ndings (11,12,83). Various techniques can be used to repair the leak. For example, leaking meningeal diverticula can be ligated with metal aneurysm clips or the leak can be sealed with a muscle pledget. In some cases, gel foam and brin sealant can be used at the leak site. In other cases, the dural rent can be repaired with sutures (10,83). Most patients appear to have some improve- ment of symptoms a er surgery, but large studies are lacking (83).

SIH has been associated with connective tissue disorders. A 2013 study from Cedars-Sinai Medical Center (84) enrolled a consecu- tive group of 50 patients diagnosed with SIH and found that nine patients had heritable connective tissue disorders, which included Marfan syndrome, Ehlers–Danlos syndrome, and others. In seven of these patients, SIH was the rst manifestation of their illness. e authors suggest that patients with SIH should be screened for connective tissue disorders and vascular abnormalities. Our recom- mendation would be to use a clinical questionnaire to screen pa- tients. If there are concerns based on this, the patient can then be referred to a medical geneticist for further assessment and genetic testing if warranted.

An echocardiogram is also suggested to assess for valvular disease (e.g. mitral valve prolapse) and dilatation of the aortic root (85). In

CHAPTER 38

Headache attributed to spontaneous intracranial hypotension

Screening patients with spontaneous intracranial hypotension for connective tissue disorders, cardiac abnormalities, and vascular pathology

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this 2014 study, the rate of cardiovascular abnormalities detected for the same cohort of 50 patients with SIH seen at Cedars-Sinai was quite high (85). Six patients had aortic root dilatation and three had valvular heart disease (n = 9/50 (18%)) (85). Only two of the nine pa- tients had an underlying connective tissue disorder, indicating that cardiovascular pathology can occur even in patients with no known connective tissue disorders.

In addition, vascular abnormalities occur with higher frequency in patients with SIH than in controls. One study showed intracranial aneurysms in 9% of patients versus 1% of controls (45). So, patients with SIH should have intracranial vascular imaging at one point during their assessment, either with CT angiogram or magnetic res- onance angiogram (MRA). ose with an established connective tissue disorder, such as Marfan syndrome, should be screened fur- ther with MRA of the neck, chest, abdomen, and pelvis, because they are at risk of large arterial aneurysms (45).

Complications

Subdural haematomas can occur alone or in conjunction with sub- dural hygromas, which are more common (11,12). If the haematoma is large and exerting mass e ect, it may need to be surgically evacu- ated. However, it must be kept in mind that it can reaccumulate if the underlying cause—i.e. the CSF leak—is not addressed. erefore, the CSF leak must be treated as soon as the patient is stable (11,12).

A er treatment of a CSF leak, rebound intracranial hypertension is occasionally encountered (11). O en the headache phenotype changes and patients headaches become frontal or retro-orbital in location. Other features of increased intracranial pressure, such as blurred vision, nausea, and vomiting, may occur. Many patients will have mild symptoms, but a few may have more severe symptoms. Acetazolamide, a carbonic anhydrase inhibitor that decreases pro- duction of CSF, and time may help. e patient should be monitored carefully and reassessed at regular intervals to ensure resolution over time.

Rarely, cerebral venous sinus thrombosis or bi-brachial amyot- rophy are seen (11,12,86–88). Cerebral venous sinus thrombosis should be on the di erential diagnosis when there is a sudden change in the headache character and/or there are new neurological symptoms or signs. Bi-brachial amyotrophy can be seen in the context of extra-arachnoid uid collections, usually in the ventral cervical spine (11,88). In very rare cases, super cial siderosis may occur, as a remote complication of prior CSF leaks (89,90). Fluid col- lections are typically seen in a similar distribution as in bi-brachial amyotrophy (11). Other more recently recognized complications in- clude frontotemporal dementia (behavioural variant), di use non- aneurysmal subarachnoid haemorrhage, spinal cord herniation, and brainstem infarction (91,92).

Prognosis

e majority of patients with SIH have a good prognosis, recovering fully with conservative measures or EBPs. Some require brin glue injections or neurosurgery, and improve with these measures. Unfortunately, a portion of patients will not respond to any treat- ment modality and remain symptomatic and disabled for years

(11,12). It is important to ensure that there are no other headache diagnoses contributing to their symptomatology, and to ask about change in headache character during follow-up visits.

CSF leaks that have been successfully treated may recur in the fu- ture or patients can develop new sites of leak down the road (11). ere is a great deal of variability in the frequency of recurrence and time a er the rst presentation. Large studies in this area are lacking and it is unknown what percentage of patients have recurrence. Patients should be vigilant in returning to see the physician if they have recurrence of symptoms or a new headache.

Conclusion

SIH is a disorder classically presenting with orthostatic headache and MRI ndings of pachymeningeal enhancement and sagging of the brain. However, the clinical presentation and imaging ndings can be broad and quite variable. e headache is not always ortho- static, there are many other neurological symptoms that can accom- pany the headache, and imaging can sometimes be normal. A high degree of suspicion must be exercised to diagnose the atypical forms of SIH.

Over the years, we have come a long way in the imaging modal- ities used to diagnose SIH and CSF leaks. Non-invasive techniques such as MRI scans of the spine are now favoured over invasive and radiation-intensive techniques such as CTMs. However, each tech- nique has its advantages and disadvantages, and some patients will need several tests to identify the leak. Still, the leak may not be found in every case.

Treatment with an EBP is recommended when conservative measures have failed. High-volume non-targeted or blind patches can be done initially, as a certain portion of patients will respond to these. However, if there is no sustained bene t, e orts should be expended in nding the leak site and doing a targeted blood patch if possible. ere is some evidence that high-volume targeted blood patches provide a higher chance of success than non-targeted blood patches. If several high-volume blood patches fail, then brin glue injections and neurosurgery are other options in patients with known leak sites.

Although the prognosis is generally felt to be good in patients with SIH, those presenting to headache centres are usually patients that are more severely a ected and disabled. As a result, prognosis is good in some cases but not others. Patients can have disabling headaches for years, despite multiple blood patches and other inter- ventions. Some can have success with brin glue and neurosurgery, but others do not have long-term bene t from these measures. In such cases, it is always important to reassess the patient and ensure that there are no other contributing factors or other possible head- ache diagnoses.

As further advances are made in neuroimaging and we gain further knowledge of this fascinating and complex condition, we hope that finding the site of the CSF leak will become easier and treatments will become more refined. Future studies should focus on prospective and systematic data collection from these unique patients to allow us to gain a better understanding of the natural history of this condition, to determine what imaging modalities would be best, and to determine the best course of management.

CHAPTER 38 Headache attributed to spontaneous intracranial hypotension

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CHAPTER 38 Headache attributed to spontaneous intracranial hypotension

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355

Headache associated with high cerebrospinal fluid pressure
Ore-ofe O. Adesina, Sudama Reddi, Deborah I. Friedman, and Kathleen Digre

History of idiopathic intracranial hypertension

Idiopathic intracranial hypertension (IIH) is a disorder of raised intracranial pressure (ICP), almost always associated with papilloedema, in the absence of underlying central nervous system (CNS) pathology. Although several authors had documented fea- tures of IIH in the preceding decades, it was rst described in 1893 by the German physician Heinrich Quincke (1842–1922), the inventor of the lumbar puncture (LP) needle. In 1902 he published a mono- graph, ‘Die Technik der Lumbalpunktion’, in which he reported 10 cases of raised ICP where two women conformed to current criteria for IIH. Both su ered headaches and had papilloedema and raised cerebrospinal uid (CSF) pressure, with normal CSF composition. Quincke called the syndrome ‘meningitis serosa’ and postulated that an increase in CSF secretion was mediated by the autonomic ner- vous system, with possible underlying causes of head injury, stress, excessive alcohol, pregnancy, in uenza, and otitis media (1).

e term ‘pseudotumor cerebri’ was introduced in 1904 by Quincke’s countryman, Max Nonne (1861–1959), when he re- ported 18 patients with raised ICP and no underlying intracranial mass lesion. Several of these patients were found to have underlying dural venous sinus thrombosis (1), and, although they did not con- form precisely to the modern de nition of IIH, this moniker has remained in use since then. Over the years, the syndrome has also been called hypertensive meningeal hydrops, toxic hydrocephalus, pseudo-abscess, otitic hydrocephalus, and many other terms, ex- posing the poor understanding of the underlying pathophysiology of the disease.

In 1937, Walter Dandy (1886—1946), an American neurosur- geon, described 22 patients with increased ICP without brain tu- mours. All of these patients presented with headache, and most also complained of blurred vision, dizziness, vomiting, and drowsiness. Dandy also documented many other signs and symptoms that were experienced by these patients, including buzzing in the ears, fundus abnormalities, stumbling gait, episodic numbness, and drowsiness. He summarized the ndings of increased CSF opening pressure (250–500 mm CSF), normal CSF contents, and small ventricles on ventriculography (2).

Joseph Foley coined the term ‘benign intracranial hypertension’ in 1955 in an attempt to simplify the nomenclature and contrast the syndrome with elevated ICP secondary to brain tumours and other compressive processes (3). Although not associated with intracranial mass lesions, work by Corbett and Wall in the 1980s and 1990s dem- onstrated the signi cant loss of vision associated with IIH through the e ects of severe or chronic papilloedema (4). e adjective ‘be- nign’ was subsequently dropped and replaced by ‘idiopathic’ to denote both the unknown aetiology of the syndrome, as well as the less-than- benign visual outcomes that can result from progressive or poorly managed disease. Advances in neuroimaging technology and recog- nition of additional secondary causes of intracranial hypertension fur- ther advanced the understanding of IIH. e Dandy criteria (2) were modi ed in 1985 by Smith, revised again in 2004 by Friedman and Jacobson (5), and updated most recently by Friedman, Liu, and Digre to incorporate our understanding of these factors and to further ex- clude other underlying causes of raised ICP (see Box 39.1) (6).

Epidemiology

IIH is considered a rare disease, with an annual incidence of around 1 in 100,000 people and an onset between 11 and 58 years of age, with an overall mean age of onset of 31 years (7). e incidence among women aged 15–44 years is 3.5 in 100,000, rising to 19 in 100,000 in obese women aged 20–44 years who are at least 20% heavier than ideal weight (4). However, most epidemiological studies were published prior to 2000, and the incidence has increased in corres- pondence with the rise in obesity seen in society (8). e female-to- male ratio is 4–8:1, with > 90% of patients being obese women of childbearing age (9). One study showed that men were, on average, 9 years older than their female counterparts, and there was no dif- ference in rates of obesity based on sex (9). Men are more likely to develop vision loss than women with IIH (9,10).

IIH may occur at any age in children; however, epidemiological studies show that it is more likely to occur in older children and ado- lescents (12–15 years) than in younger children (2–12 years) (11–13). It is exceedingly rare in infancy. IIH appears to be a di erent disease

CHAPTER 39 Headache associated with high cerebrospinal uid pressure

of headache in IIH, it is rst important to review the mechanics of CSF ow and the theories underlying the pathophysiology of raised ICP in this disease process. ICP is a function of the volume of the contents of the cranial cavity (CSF, brain parenchyma, vasculature and its contents, dura). Any imbalance in one or more of these com- partments can lead to a rise in ICP and compression of structures, as there is little room for expansion in this xed, enclosed space. e expansion of CSF volume is of particular interest, as elevated ICP is a diagnostic criterion for the diagnosis of IIH. CSF is produced in the choroid plexus of the lateral and fourth ventricles at a rate of 0.36 ml/ minute or 400–500 ml/day. A er secretion into the ventricles, it ows throughout the ventricular system and enters the subarachnoid space via the foramina of Luschka and Magendie. Here the CSF bathes the cerebrum, cerebellum, and spinal cord before being absorbed through the arachnoid villi into the dural venous sinuses. ere is also evidence that a portion of the CSF cycles through the brain interstitial space, enters the parenchyma along perivascular spaces that surround penetrating arteries, and is cleared along paravenous drainage pathways (16). e entire volume of CSF is 125–150 ml and is replaced every 6–8 hours. Normal CSF pressure ranges from 70 to 200 mm CSF in adults and up to 280 mm CSF in children (17,18).

e exact mechanism of the rise in CSF pressure in IIH is still un- known at this time. ere is no evidence for either increased CSF pro- duction or cerebral oedema in IIH; thus, proposed theories include reduced CSF absorption and increased cerebral venous pressure. e site of impaired absorption may be at the level of the arachnoid granulations, paravenous drainage pathways, peri-olfactory lymph- atics, or in the dural venous sinuses. Some other possible causes of IIH include intracranial venous hypertension and abnormal vitamin A metabolism (19).

ere are a multitude of conditions and drugs that have also been associated with raised ICP; the best substantiated are listed in Box 39.2, and the reader is referred to Digre and Corbett’s comprehensive

Box 39.1 Diagnostic criteria for pseudotumor cerebri syndrome

A diagnosis of pseudotumour cerebri syndrome (PTCS) is ‘de nite’ if the patient ful ls criteria A–E. The diagnosis is considered ‘probable’ if cri- teria A–D are met, but the measured cerebrospinal uid (CSF) pressure is lower than speci ed for a ‘de nite’ diagnosis. Idiopathic intracranial hypertension is diagnosed if no secondary cause is found.

. 1 Required for diagnosis of PTCS:

. A Papilloedema

. B Normal neurological examination except for cranial nerve
abnormalities

. C Neuroimaging: normal brain parenchyma without evidence of
hydrocephalus, mass, or structural lesion, and no abnormal men- ingeal enhancement on magnetic resonance imaging (MRI), with and without gadolinium, for typical patients (female and obese), and MRI, with and without gadolinium, and MR venography
for others. If MRI is unavailable or contraindicated, contrast-
enhanced computed tomography may be used

. D Normal CSF composition

. E Elevated lumbar puncture (LP) opening pressure (> 250 mm CSF
in adults and > 280 mm CSF in children (250 mm CSF if the child
is not sedated and not obese)) in a properly performed LP.

. 2 Diagnosis of PTCS without papilloedema:

• In the absence of papilloedema, a diagnosis of PTCS can be made if B–E above are satis ed, and, in addition, the patient has a unilat- eral or bilateral abducens nerve palsy

• In the absence of papilloedema or sixth nerve palsy, a diagnosis of PTCS can be ‘suggested’ but not made if B–-E from above are sat- is ed, and in addition at least three of the following neuroimaging criteria are satis ed:
(i) Empty sella
(ii) Flattening of the posterior aspect of the globe
(iii) Distention of the peri-optic subarachnoid space with or without a tortuous optic nerve
(iv) Transverse venous sinus stenosis.
Reproduced from Neurology, 81, 13, Friedman DI, Liu G, Digre KB. Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children, pp. 1159–65. © 2013 American Academy of Neurology.

Box 39.2 Conditions and medications associated with intracranial hypertension

Medications

• Tetracycline and related antibiotics.

• Corticosteroid withdrawal.

• Vitamin A and related tretinoin compounds.

• All-trans retinoic acid.

• Lithium.

• Levonorgestrel.

• Nalidixicacid.

• Thyroid hormone replacement in children.
Medical conditions

• Obesity.

• Renal failure.

• Severe anaemia

• Turner syndrome.

• Hypoparathyroidism.

• Polycystic ovarian syndrome.

• Circulatory conditions.

• Right heart failure.

• Impaired cerebral venous drainage (i.e. jugular vein, cerebral

venous sinuses).

process in prepubertal children than in postpubertal adolescents and adults, as evidenced by an almost equal male-to-female ratio, as well as a less de nitive association with obesity (11). A study examining trends in obesity in 40 paediatric patients with IIH found that 43% of patients aged 3–11 years were obese, whereas 81% of those in the 12–14-year age group and 91% of those in the 15–17-year age group met the criteria for obesity (11). In a recent large study of paediatric IIH, three subgroups were identi ed: a young group that was not overweight, an early adolescent group that was either overweight or obese, and a late adolescent group that was mostly obese (14).

e cost of IIH has not been truly established, but hospitalization costs are four times more than for an average individual without IIH and estimated at $444 million dollars per year for direct and indirect costs (15).

Pathophysiology

Since the earliest accounts, obesity, female sex, menstrual irregu- larities, and endocrine disorders have been described as common associations of IIH; however, in order to understand the aetiology

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review for a more extensive list (7). ese should be adequately ruled out in order to make the diagnosis of IIH, as it is a diagnosis of exclu- sion. e mechanism of elevated ICP in the majority of these causes, as well as in the idiopathic form, is still poorly understood at this time. A detailed discussion of all of the theories underlying the aeti- ology of elevated ICP is outside of the scope of this text; however, the reader is directed to other excellent reviews of the subject (20,21).

As the brain parenchyma is insensate, how then does raised ICP lead to headache in IIH? eoretically, it is felt to be related to com- pression of and traction on pain-sensitive structures within the intracranial vault. ese include blood vessels (both arterial and venous), dural venous sinuses, meninges, cranial nerves, and cer- vical nerves. A erent projections from these structures are trans- mitted via the trigeminal system and nerves C1 and C2 to the nucleus caudalis of the spinal trigeminal nucleus (STN), which runs from the level of the pons to the upper cervical spinal cord. e STN re- ceives information regarding pain and temperature sensation from face and orofacial structures, as well as the intracranial structures mentioned earlier. Ascending bres from the STN then decussate as they travel up through the brainstem as the trigeminal lemniscus or the ventral trigeminothalamic tract to terminate in the ventral posteromedial nucleus of the thalamus. is nucleus then sends the signals to higher cortical structures where pain sensation is brought to consciousness (22). e distribution of a erents to the trigeminal nucleus caudalis helps to explain the o en holocranial distribution of IIH-related pain, as well as referred pain to the eyes and cervical regions.

Despite our understanding of the complex innervation of the head and intracranial cavity, the exact mechanism underlying IIH-related headache pain is still unknown. A de nitive causal relationship be- tween ICP and headaches has not been made, as low ICP can also result in headache (both are likely due to mechanical deformation of the meninges). Fay and Kunkle, in 1925 and 1942, respectively, arti- cially elevated ICP in patients, as high as 680 mm CSF in Kunkle’s investigation (23,24). Some of Fay’s patients reported frontal and temporal headaches; however, many had no headaches (23), and neither of Kunkle’s patients experienced headaches in the setting of arti cially elevated ICP (24). In 1974, Johnston and Paterson per- formed ICP monitoring in 20 patients with idiopathic elevated ICP using intraventricular catheters. Patients reported pain without pressure spikes and no pain with signi cantly elevated ICP. Some patients also continued to experience headache a er normalization of ICP, documented by repeat LP, indicating that there is not a 1:1 correlation between ICP and headache (25). Headache in IIH there- fore appears to be multifactorial, with elevated ICP being one factor that can trigger pain. e ongoing IIHTT (Idiopathic Intracranial Hypertension Treatment Trial) will hopefully be able to shed some light on the relationship between ICP and headache and possible therapies to help treat this potentially debilitating symptom (26).

Presentation

Symptoms

headache phenotype of IIH is not speci c. It is o en described as daily, bilateral, frontal, or retro-ocular; hence, IIH is in the di eren- tial diagnosis of new daily persistent headache (see also Chapter 30) (28,30). However, it may also occur intermittently and is sometimes hemicranial. It is usually moderate to severe in intensity, and some patients describe increased severity upon awakening. e headache may also be throbbing, with nausea, vomiting, and photophobia, resembling migraine (31). In one study, headache as a presenting symptom was less common in men (55%) than in women (75%) (9). ere is no correlation between the presence or severity of head- aches, and the LP opening pressure or papilloedema grade (28). Young children may not present with headache, either due to in- ability to articulate their symptoms or from lack of head pain. Neck and upper back pain are o en prominent features, and cervical or radicular pain may occur (28,31).

Transient obscurations of vision (TOV) are the second most common symptom, occurring in 50–70% of patients (26,31). TOV are described as dimming, greying-out, or complete vision loss in one or both eyes, usually lasting seconds to a minute. Vision re- turns to baseline between episodes. ey may be provoked by eye movements (particularly upward gaze) and changes in posture, as in arising from a seated or stooped position. ey indicate the presence of papilloedema and likely arise as a result of transient ischaemia to the optic nerve. TOV may also occur with optic disc drusen but are rarely reported in patients with papilloedema from other causes. ey do not predict vision outcome in IIH.

Pulsatile tinnitus is present in about half of patients and is likely under-reported by patients unless speci cally inquired for. Patients report hearing their own heartbeat or a whooshing noise in their ears or head, which may sometimes be loud enough to prevent sleep. Other, less common non-visual symptoms include mu ed or de- creased hearing, neck sti ness, arthralgias, ataxia, and low back pain (31).

Visual symptoms range from non-speci c blurred vision to severe vision loss and o en re ect the pattern of visual eld abnormality. Patients may see their physiological blind spot, which is normally not noticeable. Descriptions of this symptom are a dark spot to the side with temporal blind spot enlargement or as di culty seeing words or parts of words on the printed page with nasal enlargement of the blind spot. Others report dim or dark vision or loss of per- ipheral (‘tunnel’) vision. Central vision loss early in the course, with impaired ability to see, read, or distinguish colours, is generally a bad prognostic sign.

Diplopia is present in one-third to two-thirds of patients and is generally binocular, resolving when either eye is occluded (28,31). It is usually horizontal and worse at distance than at near. Monocular diplopia may occur if macular oedema is present.

Signs

e most important ndings are related to the neuro-ophthalmic examination, particularly visual acuity, perimetry, ocular motility, and the fundus examination. e visual acuity, measured with best correction, is most o en normal. Decreased central acuity at the time of presentation indicates either macular oedema or optic nerve compromise and o en portends a poor prognosis. Optic neuropathy occurs from direct compression of the nerve from elevated CSF pressure in the peri-optic subarachnoid space or ischaemic optic

Overall, the most common presenting symptom of IIH is head- ache, occurring as the initial manifestation in 70–80% of adults and children and ultimately a ecting > 90% of patients (26–29). e

Figure 39.1 Humphrey visual elds demonstrate bilateral enlarged blind spots and early nasal depression bilaterally.

neuropathy. Vision loss from the former cause is o en reversible in the early stages with treatment, while vision loss from ischaemia is permanent.

Evaluation of the visual eld is of paramount importance, as most visual morbidity of IIH is a consequence of visual eld loss. Automated or kinetic perimetry is necessary for adequate assess- ment. Confrontation visual elds are not sensitive enough to detect most visual eld abnormalities in IIH; thus, a defect detected using confrontation testing is generally serious. Enlargement of the physio- logical blind spot is the most common and earliest sign, representing the oedematous and expanded optic nerve head. Visual eld loss in IIH arises from impairment of the retinal nerve bre layer, producing characteristic arcuate defects, nasal step, and peripheral constric- tion of the eld (see Figure 39.1). Perimetric assessment is utilized throughout the course of the disease to monitor the patient’s progress.

Unilateral or bilateral abducens nerve palsies are the most fre- quent ocular motility abnormalities in adults and children, a non- localizing indication of increased ICP producing an esotropia on examination. Other ocular motor nerve involvement (III, IV) is less common, and generalized ophthalmoparesis rarely occurs (32). Abnormalities of cranial nerves III, IV, VII, IX, and XII have been documented and usually resolve with adequate treatment of elevated ICP (33,34).

e hallmark of IIH is papilloedema, which is required in the acute phase for diagnosis. e timing of the onset of papilloedema likely varies among patients and is occasionally not present if the clinical evaluation occurs very early. Previous optic atrophy also precludes the development of papilloedema, a major consideration when evaluating the patient for recurrence, and it may be challen- ging to discern papilloedema if optic disc drusen are present. Early papilloedema is di cult to detect using a direct ophthalmoscope, and other methods, such as biomicroscopy, indirect ophthalmos- copy, orbital ultrasound, and uorescein angiography, are useful techniques in such cases. Documentation of the optic nerve appear- ance using fundus photography is invaluable for both diagnosis and subsequent follow-up.

e Frisén system is used to grade papilloedema. Early (grade 1) papilloedema is characterized by disruption of the normal ra- dial nerve bre layer arrangement with greyish opacity accentuating the nerve bre bundles. A subtle grey peripapillary halo is apparent with the indirect ophthalmoscope. ere may be concentric or retinochoroidal folds. With progression of papilloedema grade, the borders of the optic disc become indistinct, with elevation of the disc margins (grade 2). e nerve head diameter increases, and the oe- dematous nerve bre layer obscures one or more segments of major blood vessels leaving the disc (grade 3) (see Figure 39.2). With se- vere papilloedema (grades 4 and 5), the optic nerve protrudes, the peripapillary halo becomes more demarcated, and the optic cup is obliterated (35). Hyperaemia, vessel tortuosity, haemorrhages, ex- udates, nerve bre layer infarcts (cotton wool spots), and optic nerve pallor are o en observed but are too variable to use for staging pur- poses. Papilloedema will not develop in the setting of optic atrophy, which is an important consideration when considering recurrence.

Spontaneous venous pulsations are o en relied upon to diagnose early papilloedema. ey are best observed at the optic nerve head using direct ophthalmoscopy. Loss of spontaneous venous pulsa- tions occurs when the CSF pressure is approximately 190 mm CSF (36). Spontaneous venous pulsations are only present in about 75% of normal individuals. eir absence does not con rm intracranial hypertension, but their presence is reassuring.

Laboratory testing

e diagnosis of IIH is predicated on the exclusion of other CNS disorders producing intracranial hypertension, such as a mass le- sion, infection, malignancy, or in ammation. Magnetic resonance imaging (MRI) is the recommended imaging study for diagnosis. e brain parenchyma and ventricular size should be normal for age (37). Subtle signs of increased ICP include an empty sella, cerebellar tonsillar descent, expansion of the optic nerve sheath complex, attening of the posterior sclerae, tortuosity of the optic nerve, and protrusion of the optic nerve papilla into the vitreous (38–40) (see Figure 39.3). If an MRI is unavailable, contrast-enhanced computed

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Figure 39.2 Stage 3 papilloedema with 360-degree blurring of the disc margin and obscuration of vessels as they leave the disc.

tomography may be used to exclude a brain tumour or hydroceph- alus, but it will not visualize the more nuanced ndings mentioned. Magnetic resonance venography may show transverse sinus stenosis (see Figure 39.4) and is recommended in atypical patients (e.g. men, children, individuals > 45 years of age) and in patients at risk (e.g. known thrombophilia, oral contraceptive use), or in those not re- sponding to therapy to assess for a venous sinus thrombosis. e presence of transverse sinus stenosis does not correlate with disease severity in IIH (41).

A LP is required for diagnosis. e diagnostic opening pressure in a properly performed LP (patient in the lateral decubitus position, not anaesthetized) is at least 250 mm CSF in adults and 280 mm CSF in children (17). ere are many factors a ecting CSF pressure, which uctuates over a wide range during the course of a day and is in uenced by activity and Valsalva manoeuvres (42). e LP rep- resents a ‘snapshot in time’ and should be repeated if there is any question about an erroneously high or low pressure measurement in the appropriate clinical context. CSF analysis at the time of diagnosis

Figure 39.3 Signs of increased intracranial pressure include an empty sella, expansion of the optic nerve sheath complex, attening of the posterior sclerae, tortuosity of the optic nerve, and protrusion of the optic nerve papilla into the vitreous.

includes determination of glucose, protein, cell count with di eren- tial, microbiology studies, and cytology.

Comorbid conditions

e most common comorbidity in adults is obesity. Menstrual ir- regularities reported in the older literature are likely related to obesity, rather than IIH. As the co-occurrence of sleep apnoea and intracranial hypertension in men is so frequent, sleep studies are re- commended in all men and in women with symptoms suggestive of obstructive sleep apnoea to rule out this treatable cause (43–45). Anxiety and depression occur more commonly in women with IIH, who have poorer quality-of-life assessment scores than age-, sex-, and weight-matched control subjects (46). No studies to date have con rmed an association between migraine or any other primary headache disorders and the subsequent development of IIH. IIH may begin or recur during pregnancy but with no increased fre- quency compared to non-pregnant women in a similar age cohort (47). e incidence of polycystic ovarian syndrome has been found to be higher in IIH (48), and, similarly, metabolic syndrome may be a risk factor for development of IIH given its association with obesity. Orthostatic oedema, characterized by dependent oedema in

Figure 39.4 Magnetic resonance venogram demonstrating partial narrowing of the left transverse sinus.

the absence of cardiac or renal abnormalities, is associated with IIH in women (49).

Treatment

e goal of treatment in IIH is to e ectively reduce ICP to minimize the e ects of the major morbidities associated with the disease: vi- sion loss from chronic or severe papilloedema and headache. It can also help to alleviate symptoms from cranial nerve palsies. ere are reports of cerebral venous sinus thrombosis and subarachnoid haemorrhage occurring as a result of chronically elevated ICP in IIH (50). Secondary causes of intracranial hypertension should be treated if discovered. is includes anticoagulation for venous sinus thrombosis, discontinuation of medications associated with intra- cranial hypertension, treatment of metabolic and haematological disorders, and treatment of dysparathyroid and dysthyroid states. However, treating the secondary cause may not be adequate to pre- vent vision loss, and other medical and surgical therapies used to treat IIH are frequently necessary. Immediate management is pri- marily based on the duration of symptoms, evaluation of visual function, and patient characteristics. In 2015, a Cochrane Database review concluded that two randomized controlled trials showed modest bene ts for acetazolamide for some outcomes but with in- su cient evidence to recommend or reject the e cacy of this inter- vention for treating people with IIH, which was also true for any other treatments currently available (51). Since then, several results of the large IIHTT have been published (52). e commonly used medical and surgical treatment options available are discussed in the following sections. Although the IIHTT did not involve paediatric patients, treatment strategies are similar in children and adults.

Medical management

Weight loss

While the exact causal mechanism remains unknown, the relation- ship between weight gain, obesity, and the development of IIH is well established clinically and in the literature (12). Even non-obese pa- tients with a body mass index < 30 are at greater risk for developing IIH if they experience a recent moderate weight gain of as little as 5–15% of their body weight. It has also been documented that loss of as little as 5–10% of total body weight can reduce symptoms of headache ,as well as ICP and papilloedema, and their attendant risk of vision loss (53,54). Subsequent weight gain is associated with re- currence of symptoms and papilloedema (12,20).

Weight loss through reduction of calorie, uid, and sodium intake has been shown to be e ective in treating IIH. In 1974, Newborg reported remission of papilloedema in all nine patients placed on a low-calorie adaptation of the Kempner rice diet of 400–1000 calories per day. Fluids and sodium intake were also restricted (55). While this is a somewhat restrictive diet, it does support the concept that weight loss is an e ective treatment for IIH. Reduction in dietary intake of tyramine has also been shown to improve headache asso- ciated with IIH (56). is concept was reinforced by the ndings of the IIHTT in which patients randomized to medical treatment plus weight loss and weight loss alone saw improvements in papilloedema grade and quality of life (52). More detailed ndings of the IIHTT are summarized in the next section. In general, patients without

vision loss (visual eld defects and preserved acuity) that have grade 1 or 2 papilloedema may be managed with diet alone. ey should be followed closely, and if their acuity or elds worsen, acetazolamide should be added. Weight loss alone is not an e ective short-term therapy and must be combined with medical therapy in the initial management of the disease when vision loss is present (52). Weight loss and prevention of uctuations in weight for the long-term man- agement of obese patients with IIH cannot be understated.

Diuretics

Acetazolamide is an oral carbonic anhydrase inhibitor (CAI), which has been the mainstay of treatment of IIH for decades. It decreases CSF ow once 99.5% of choroid plexus carbonic anhydrase is in- hibited, which may require up to 4 g daily (8,52). It may also promote weight loss through an anorexic e ect by changing the taste of foods. Patients nearly always experience paraesthesias in the ngers, toes, and peri-oral region and less commonly have malaise. Renal stones occur in a small percentage of patients. Metabolic acidosis, indicated by lowered serum bicarbonate, indicates adherence to treatment and rarely requires treatment. A rare, but serious, idiosyncratic side ef- fect is aplastic anaemia, which occurs in 1 in 15,000 patient-years of treatment (8). e sulfa moiety in acetazolamide di ers from sulfa antibiotics, and little evidence exists to support a self-reported sulfa allergy will produce a life-threatening cross-reaction with the drug (57). Acetazolamide is generally started at 1 g daily in divided doses and increased to a maximum tolerated dose of 4 g daily as needed. Typically, 1–2 g per day is well tolerated and is su cient to adequately lower ICP and reduce signs and symptoms.

e IIHTT was a multicentre randomized, double-masked, placebo- controlled trial investigating the e ect of acetazolamide at reducing or reversing visual eld loss a er 6 months of treatment when added to a supervised, low sodium weight reduction programme versus the programme plus placebo. e primary outcome variable was the change in perimetric mean deviation (PMD) from baseline to month 6 in the most a ected eye, as measured by Humphrey visual elds (Carl Zeiss Meditec, Dublin, CA, USA). PMD is a measure of global visual eld loss, as a mean deviation from age-corrected normal values, with a range of 2 to –32 dB. Secondary outcome vari- ables included changes in papilloedema grade, quality of life (Visual Function Questionnaire 25 and 36-Item Short Form Health Survey), headache disability, and weight at month 6. e study showed that in patients with mild visual loss (a PMD of –2 to –7 dB), acetazolamide plus diet had better visual outcomes than those taking placebo plus diet. Patients taking acetazolamide also had signi cantly improved papilloedema and visual quality-of-life measures, although no sig- ni cant di erence was found in visual acuity in the study or fellow eye. ere was also no statistically signi cant di erence between the groups with respect to headache or headache disability. e bene ts of acetazolamide and diet were independent, and patients tolerated up to 4 g acetazolamide per day (52).

Seven participants (six on diet plus placebo) met criteria for treat- ment failure. Male patients, those with high-grade papilloedema, and those with decreased visual acuity at baseline were more likely to experience treatment failure. All but one of these patients was treated with diet alone (52). To assess the e ect on papilloedema ret- inal nerve bre layer (RNFL) thickness, total retinal thickness (TRT), optic nerve volume, and retinal ganglion cell layer, measurements

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were derived using spectral-domain optical coherence tomography (OCT). Acetazolamide and weight loss e ectively improved RNFL thickness, TRT, and optic nerve volume swelling measurements re- sulting from papilloedema. In contrast to the strong correlation at baseline, OCT measures at 6 months showed only moderate correl- ations with Frisén papilloedema grade (58).

Topiramate

Topiramate is a sulfamate-substituted derivative of fructose. It was rst developed as an antiepileptic drug (AED). It is e ective in treating refractory chronic partial seizures and has been used as monotherapy in adolescents and adults. It is a polypharmic AED with e ects on carbonic anhydrase activity, and α-amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid (AMPA) and γ-aminobutyric acid (GABA) receptors, as well as Ca2+ and Na+ channels (59). e use of topiramate in IIH was rst reported in a prospective open- label study using both topiramate (daily dose range 100–150 mg) and acetazolamide daily (dose range 1000–1500 mg). No placebo group was included. A statistically signi cant improvement in visual eld was found with both drugs, and no statistically signi cant dif- ference was found when compared with each other. Weight loss was prominent in the topiramate group (48). e side e ect pro le is similar to acetazolamide; however, adverse cognitive e ects can occur, and the drug is not recommended for use in patients with a history of severe depression. As a frontline drug in the treatment of migraines, topiramate is o en used as a substitute or adjunct for acetazolamide in patients with IIH with predominantly migraine- like headache symptoms (48).

e loop diuretic furosemide has also been used to lower ICP in IIH. It appears to work by diuresis and reducing sodium transport into the brain. Treatment is initiated a dosage of 20 mg by mouth twice daily and gradually increased, if necessary, to a maximum of 40 mg by mouth three times daily. Potassium supplementation is given as needed. Other diuretics used in the treatment of IIH in- clude methazolamide (in patients with renal disease), another CAI, as well as spironolactone for patients who are allergic to CAIs and thiazide diuretics.

Headache treatment

Headache associated with IIH can be debilitating and signi cantly a ect quality of life, mood, and psychosocial status. As headache does not correlate with CSF pressure, it is o en necessary to treat the headache separately in these patients. Treatment of headache should proceed with prophylactic and symptomatic therapies as tolerated with medications found to be e cacious in individual patients. Topiramate is o en e ective with the additional poten- tial bene ts of weight loss and mild carbonic anhydrase inhibition. Tricyclic antidepressants, such as amitriptyline and nortripyline, are useful and o en not associated with weight gain at low doses. Other preventative medications associated with weight gain, such as divalproex sodium and cyproheptadine, should not be used. Corticosteroids are not recommended because of their numerous undesirable side e ects (including weight gain and uid retention) and potential rebound intracranial hypertension as they are with- drawn. For symptomatic headache treatment, acetaminophen, para- cetamol, and non-steroidal anti-in ammatory drugs (NSAIDs), such as ibuprofen, should be limited to no more than 3 days per

week, to prevent the development of medication overuse headaches. Naproxen is less likely to cause medication overuse headache, and indomethacin may lower CSF pressure. Triptans may be employed if the headache phenotype is similar to migraine. Headaches may per- sist even a er the ICP is controlled (60). We have successfully em- ployed onabotulinum toxin A treatment in patients with persisting headaches having characteristics of chronic migraine. Mathew et al. (61) found that a combination of a diuretic and migraine pre- ventative appeared to be the best treatment for headache associated with IIH.

Drugs used in treatment of headache in IIH are summarized in Table 39.1.

Therapeutic lumbar puncture

LP can be both a diagnostic and therapeutic procedure in the manage- ment of IIH. LP may relieve headache, diplopia, and papilloedema, and can reverse and/or prevent vision loss, especially in acute ful- minant cases. It is not uncommon to see a lasting clinical remission following a single LP in some patients with IIH that obviates the need for further medical or surgical treatment. Some patients may also bene t from a transient lumbar drain while awaiting a more def- inite surgical procedure, especially in acute fulminant cases. While some patients may be managed with episodic LPs to remain asymp- tomatic, routine LPs for long-term management are generally not advocated as the procedure is technically di cult in obese patients, and there is a rare risk of infection associated with the procedure. e vast majority of patients will also require medical therapy and weight loss in the long-term to manage their disease. erapeutic LPs are useful for intermittent exacerbations of symptoms and for management of IIH during pregnancy. ere is no evidence to sup- port the e ectiveness of a ‘large volume’ LP (i.e. removal of ≥ 20 ml CSF), and post-LP headache may occur. We recommend removing enough CSF to achieve a closing pressure within the normal range (approximately 150–170 mm CSF).

Surgical management

Surgical management of IIH is indicated for patients with progressive vision loss despite maximal medical therapy and severe vision loss in the case of fulminant IIH. Surgery is not recommended as a primary treatment of headaches. e most commonly employed surgical op- tions include optic nerve sheath fenestration (ONSF) and various CSF diversion procedures. e decision to use one or the other is o en based on local preferences and the availability of surgeons versed in either procedure; some centres always perform ONSF as a rst-line treatment, while some use both procedures based on the patient’s symptoms and signs (e.g. ONSF for vision loss and shunt for vision loss and headaches). ere are no randomized clinical trials comparing the two procedures, and outcomes are greatly dependent upon the experience of the surgeons performing the procedures.

Recently, endovascular venous stenting of the dural venous sinuses has been shown to reduce cerebral venous pressure, reduce ICP, and improve symptoms and signs in selected patients with IIH (20,62). It is still unclear, however, if primary treatment of the observed stenosis bene ts patients with IIH, as it is still not certain whether stenosis is the cause or the result of raised ICP. Given the known complications of the procedure (stent migration, venous sinus per- foration, re-stenosis, in-stent thrombosis, cerebral haemorrhage,

CHAPTER 39 Headache associated with high cerebrospinal uid pressure Table 39.1 Treatment of headache in idiopathic intracranial hypertension: the best treatment for the headache is usually a diuretic and a

headache preventative.

Medication types

Examples

Other uses

Side effects

FDA pregnancy category

Diuretics

Acetazolamide 250–4000 mg Methazolamide 25–50 mg Furosemide 2–80 mg Chlorthalidone 100 mg

Carbonic anhydrase inhibitor; loop diuretic

Kidney stones; rash; dehydration

C CC B

Beta blockers 30 mg daily

Propranolol 20–120 mg daily Nadolol 10–80 mg daily Timolol 10–30 mg daily

Blood pressure; migraine prevention; tremor

Hypotension; reduced heart rate

Calcium channel blockers

Verapamil 80–240 mg daily Amlodipine 2.5–10 mg daily

Blood pressure; migraine; circulation

Hypotension; constipation; fatigue

Seizure medications

Topiramate 25–200 mg daily

Migraine and cluster headache

Kidney stones; anaemia; acute-angle closure glaucoma; rash

Valproate 250–2000 mg/day

Migraine

Weight gain; nausea; tremor

Gabapentin 100–1000 mg/day

Face pain; bromyalgia; seizure

Drowsiness; water retention; weight gain

Tricyclic antidepressants

Amitriptyline 10–150 mg at night Nortriptyline 10–100 mg at night Imipramine 10–100 mg at night Desipramine 10–100 mg at night

Migraine; depression; insomnia; nerve pain

Constipation; drowsiness; dry mouth; weight gain

Antidepressants: SSRIs

Fluoxetine 10–60 mg daily Sertraline 25–200 mg daily Paroxetine 10–40 mg daily Citalopram 10–40 mg daily

Depression; anxiety; post-traumatic stress disorder

Dry mouth; diarrhoea;
sexual side effects

Others

Botulinum toxin

Chronic migraine

FDA, US Food and Drug Administration; SSRI, selective serotonin reuptake inhibitor.

death) and the paucity of data on the safety and long-term outcomes of venous stenting, its use at this time should be limited to selected refractory patients who cannot undergo or have failed more conven- tional surgical treatment.

Gastric bypass surgery has been used with some success in pa- tients with IIH; however, is it is felt that this procedure should be re- served for morbidly obese patients who have failed other weight-loss approaches, as well as medical treatment of their IIH (63).

ONSF

ONSF is performed in cases of fulminant IIH where patients are rap- idly losing vision from signi cantly elevated ICP or in cases of pro- gressive vision loss in patients who are not responding to medical therapy or are non-adherent with therapy. ere are a number of sur- gical approaches to fenestrating the optic nerves; however, the nal goal is to create a window or a series of slits in the optic nerve sheath just behind the globe to release CSF under pressure causing compres- sion of the nerve. ere is large amount of literature supporting the e cacy of the procedure in protecting or improving vision in both

the fenestrated and non-fenestrated eye. e mechanism of action is felt to be due to both decompression of the peri-optic subarachnoid space, as well as scarring of the surgical site, preventing further accu- mulation of CSF. Although not employed solely for the treatment of headaches, ONSF may reduce headache in over half of patients with IIH undergoing the procedure (64–66). e mechanism for the im- provement of headaches a er ONSF is unclear.

Although generally safe when performed by an experienced sur- geon, ONSF is not without complications, including progressive vision loss, permanent vision loss, postoperative nerve sheath haem- orrhage, and diplopia that is generally transient (67–69). Long-term failure may occur a er ONSF and may require CSF diversion sur- gery. Overall, ONSF is felt to be a good and safe option for many pa- tients with predominant symptoms of vision loss in IIH, especially in acute fulminant cases.

CSF diversion procedures

CSF diversion procedures include lumboperitoneal (LPS), ventriculoatrial, ventriculojugular, and ventriculoperitoneal

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shunts (VPS). LPS is more commonly performed than VPS be- cause insertion and maintenance of patency may be more di cult in the latter procedure. However, the failure rate of LPS exceeds that of VPS, and more neurosurgeons are employing VPS for the treatment of IIH. e immediate e cacy treating vision loss is well-documented (70–72). Although shunting usually reduces headache in IIH immediately a er the procedure is performed, at least 50% of patients have recurrent headaches within 3 years, and most patients require a shunt revision within the rst year (72). Sinclair et al. (73) reported an overall improvement in visual symptoms a er shunting, but headaches remained in a majority of patients (79%) (73). Shunting is also not without complications. More than half (56%) of patients in the series of Eggenberger et al. (71) required shunt revision, and 10 of 25 patients in the series of Abubaker et al. (70) also required revisions. Other documented complications were radicular pain, abdominal pain, low-pressure headaches, and shunt infection (70–72). In-hospital mortality for new shunts is 0.5%, with 0.9% for ventricular shunts and 0.2% for lumbar shunts (74). Major causes of shunt failure include catheter or valve obstruction, low ICP, catheter migration, and lumbar radiculopathy. Over-shunting with LPS can lead to an ac- quired Chiari malformation or chronic intracranial hypotension. Most patients experience a postural headache, but there may be symptoms that are similar to those of elevated ICP, such as neck pain, vomiting, photosensitivity, blurred vision, transient visual obscurations, peripheral visual eld loss, and sixth nerve paresis (75). Headache is less frequent in VPS than in LPS, and a program- mable shunt valve with VPS can o en prevent low-pressure head- aches, obviating the need for re-operation (5).

Despite the apparent high rate of complications, and failure, CSF shunting procedures remain the most widely performed surgical treatment for IIH (74). ey can be very useful acutely to prevent or treat devastating vision loss in selected patients.

As IIH occurs in young women of childbearing years, IIH will be seen in pregnant women. Diagnosis, evaluation, and treatment should follow the same general guidelines as in non-pregnant women, with a few caveats. While weight loss is o en promoted in non-pregnant women, women who are obese should be counselled to limit weight gain in pregnancy (47). Acetazolamide has been studied in pregnant women, and teratogenicity in their children was not greater than ex- pected in the general population. erefore, acetazolamide should be used when indicated in pregnant women (76).

While surgical procedures are o en avoided in pregnancy, when vision loss occurs, surgery may be required. No guidelines exist for surgical treatment of IIH in pregnancy. Shunting into the abdomen of a pregnant woman is technically challenging but possible, and ONSF may be the preferred procedure (77). Delivery for women should be based on obstetric indications. If there is concern for vi- sion loss during the second stage of labour (pushing or Valsalva man- oeuvre), low-outlet forceps may be indicated. Caesarean section or operative delivery is not indicated for IIH alone and should be based on obstetric indications. Treatment of the headache in pregnancy is di cult, as medication exposures are limited. In early pregnancy,

NSAIDs can be used safely (Food and Drug Administration category B in early pregnancy); later in pregnancy, because of problems of premature ductus arteriosus closure and decreases in amniotic uid production, NSAIDs are avoided. Medications that are used to treat other headaches in pregnancy include tricyclic antidepressants and, when comorbid depression is present, serotonin reuptake inhibitors. In general, anticonvulsants (e.g. topiramate, sodium valproate) are not recommended in early pregnancy because of the risks of fetal malformations.

Prognosis

Medical treatment of IIH is seldom lifelong, and ICP-lowering agents are generally tapered and discontinued when the patient’s vi- sion status and optic nerve appearance have stabilized or when the disease has been in remission for at least 6 months (7). Clinical ex- perience, however, indicates that it is common for patients to have headaches or chronic papilloedema while being otherwise asymp- tomatic with stable visual function. ey may also continue to have symptoms that require medical agents to lower ICP. is suggests that intracranial hypertension, symptomatic or not, persists in many patients with IIH. In a series by Corbett et al. (78), 10 of 12 (83%) patients in long-term follow-up who underwent repeated LPs showed persistently elevated ICPs, ranging from 220 to 550 mm CSF. Recurrent symptoms and papilloedema have been reported in 8– 37% of patients, o en years a er the initial diagnosis (7). Recurrence of symptoms may warrant reinstitution of medications, but head- aches can typically be managed without diuretics or CAIs, unless there is evidence of elevated ICP documented by LP or recurrence of papilloedema.

Poor visual prognosis seems to be associated with severe acuity loss at presentation, and secondary causes such as anaemia, renal failure, and venous sinus thrombosis.

Treatment of idiopathic intracranial hypertension in special populations: pregnancy

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Headache associated with systemic infection, intoxication, or metabolic derangement
Ana Marissa Lagman-Bartolome and Jonathan P. Gladstone

Headaches attributed to exposure to a substance

Headache attributed to exposure to a substance (previously referred to as ‘toxic headaches’) is a secondary type of headache disorder that occurs for the rst time in close temporal relation to exposure to or withdrawal from a substance. Over the years, many substances known to induce headaches in susceptible individuals have been identi ed, including alcohol, prescription and illicit drugs, chemical products, food additives, and others (1–4).

It is important to recognize that it is not uncommon for primary headache disorders to be precipitated or exacerbated by exposure to certain substances. For example, cluster headache patients are o en very susceptible to alcohol, and migraineurs can be particu- larly hypersensitive or susceptible to a wide range of exposures. It is therefore crucial when evaluating patients with headaches re- lated to substance exposures to distinguish whether the headaches are primary or secondary. According to the third edition of the International Classi cation of Headache Disorders (ICHD-3), when a pre-existing headache disorder occurs in temporal relation to sub- stance exposure, both the initial headache diagnosis and a diagnosis of ‘headache attributed to a substance’ should be given. e factors in favour of secondary causation or toxic headaches include close temporal association, marked worsening of pre-existing headache, evidence that the substance can aggravate the primary headache, and improvement or resolution of headache on discontinuation of the substance (5). is chapter will highlight the primary recognized headaches attributed to intoxication (see Box 40.1).

Toxic headaches can be subdivided into three subgroups: (i) head- aches that are caused by an unwanted e ect of a toxic substance (a substance that is considered toxic); (ii) headaches that happen as an unwanted e ect of a normal exposure; (iii) headaches that occur as an unwanted e ect of an exposure to an experimental substance (e.g. phase I-phase III studies of new medications) (6).

Headache as a side e ect has been recorded with most drugs, usu- ally merely re ecting the high prevalence of headache in the general population (rather than a speci c medication-related side e ect).

Only when headache occurs more o en a er an active drug than a er placebo in double-blind controlled trials can headache truly be regarded as a legitimate side e ect. ere is a minimum dose of exposure that is required wherein the headache follows at least half of the exposures (and at least three times), and the headache resolves when the substance is eliminated. ese headaches can be induced with onset immediately or within hours a er acute and occasionally with chronic exposures, which may re ect the chemical sensitivity of the headache-prone brain. e characteristics of headaches due to intoxication are generally non-speci c. e headaches are o en generalized, persistent, and at times throbbing, and increase in in- tensity with increased dosage of substances. Box 40.2 describes the diagnostic criteria for headache attributed to substance use using the ICHD-3 (5).

Epidemiology

Published literature regarding the relative incidence of headache re- lated to di erent drugs is lacking. ere are also no population-based prospective epidemiological data on the incidence of substance- induced headaches (1). In 1989, Askmark et al. (7) carried out a survey of 10,506 reports of drug-induced headaches from 1972 to 1989 from the World Health Organization Collaborating Centre for International Drug Monitoring of ve countries, including the USA, Australia, New Zealand, Sweden, and the UK. Of the headaches re- ported from these ve countries and the other 27 member countries during this period, the most common headache type was migraine followed by headaches associated with intracranial hypertension and then headaches that were unclassi able (7). Substance-induced headaches were found to be more common in older patients, espe- cially with psychoactive drugs (8). Migraineurs, tension-type and cluster headache patients were found to have greater risk for drug- induced headache (5,9).

e common drugs that are implicated in producing headaches in- clude non-steroidal anti-in ammatory drugs (NSAIDs: indometh- acin, diclofenac), calcium channel blockers (nifedipine), histamine receptor blockers (cimetidine, ranitidine), steroids (beclomethasone,

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Box 40.1 ICHD-3 categorization of headaches attributed to a substance

8.1 Headache attributed to use of or exposure to a substance

. 8.1.1 Nitric oxide (NO) donor-induced headache:

. 8.1.1.1 Immediate NO donor-induced headache

. 8.1.1.2 Delayed NO donor-induced headache.

. 8.1.2 Phosphodiesterase inhibitor-induced headache.

. 8.1.3 Carbon monoxide-induced headache.

. 8.1.4 Alcohol-induced headache:
8.1.4.1 Immediatealcohol-inducedheadache
8.1.4.2 Delayedalcohol-inducedheadache.

. 8.1.5 Cocaine-induced headache.

. 8.1.6 Histamine-induced headache:
8.1.6.1 Immediatehistamine-inducedheadache
8.1.6.2 Delayedhistamine-inducedheadache.

. 8.1.7 Calcitonin gene-related peptide (CGRP)-induced headache:
8.1.7.1 ImmediateCGRP-inducedheadache
8.1.7.2 Delayedhistamine-inducedheadache.

. 8.1.8 Headache attributed to exogenous acute pressor agent.

. 8.1.9 Headache attributed to occasional use of non-headache
medication.
8.1.10 Headache attributed to long-term use of non-
headache medication.
8.1.11 Headache attributed to use of or exposure to other
substance.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

methylprednisolone) and antibiotics (monocyclines, tetracyc- lines, trimethoprim-sulfamethoxazole), and oral contraceptives (ethinylestradiol). Other drugs reported include isotretinoin, danazol, tamoxifen, and isosorbide dinitrate (1,7).

Pathophysiology

e precise mechanisms underlying the development of headache associated with substance use are not well understood. Various pathophysiological abnormalities have been reported: intracranial

vasodilation (10), vasoconstrictive e ects from noradrenergic al- teration in vessel tone due to cocaine (11), altered serotoninergic signal transmission in the brain with abnormal serotonin levels within synapses (12) and frequency of the allelic variant of alcohol dehydrogenase enzyme polymorphism (13) seen in alcohol use, N– methyl-d-aspartate receptor dysfunction in analgesic abuse (14), persistent orbitofrontal hypometabolism, and metabolic changes in pain processing structures (15). Headaches can also occur in situ- ations potentially associated with cerebral oedema and intracra- nial hypertension observed in drugs such as lithium, tamoxifen, cimetidine, indomethacin, antibiotics (tetracycline, monocycline, doxycycline, nalidixic acid, nitrofurantoin, trimethoprim- sulfamethoxazole), vitamin A and retinoids (isotretinoin, all-trans retinoic acid), hormones (thyroxine, human growth hormone, levo- norgestrel), and steroids (beclomethasone, methylprednisolone, prednisolone) (7,16). However, these mechanisms do not explain how other drugs that do not penetrate the blood–brain barrier but are frequently implicated in case reports cause headaches. Reviews of the published literature on this are quite limited. Several hypoth- eses include direct chemically mediated irritative e ects on tri- geminal a erents, the role of altered neurotransmitter sensitivity in peripheral and central sensitization, as well as a primary cerebral neuronal action, possibly triggering a vascular reaction and subse- quent headache (1,9).

Toxic headaches can be induced by acute or delayed exposure to a substance. e immediate headache is closely temporally related to the exposure with onset immediately or within hours, while the delayed headache occurs many hours to days a er the immediate headache has resolved. Box 40.1 list the di erent headaches attrib- uted to use of or exposure to a substance. In this section, we discuss some of the more common headaches attributed to a substance or its withdrawal.

Nitric oxide donor-induced headache

Nitric oxide (NO) donor-induced headache includes those as- sociated with the contact or use of nitroglycerin (NTG), (nitro- glycerin headache or dynamite headache) and nitrates or nitrites (hot-dog headache), which may be due to cyclic guanine monophosphate (cGMP) activation (1). NO donors, including amyl nitrate, erythrityl tetranitrate, pentaerythrityl tetranitrate, NTG, isosorbide mono- or dinitrate, sodium nitroprusside, and mannitol hexanitrate, are known to induce both an immediate and delayed type of toxic headache. is type of headache is typically bilateral, frontotemporal, and pulsating. NTG induces immediate headache in most people, but can also cause a delayed headache in patients with migraine or chronic tension-type headache (5,17). ese delayed headaches occur, on average, 5–6 hours a er ex- posure. Patients with cluster headache are known to be more susceptible to developing delayed headache only during cluster periods: NTG usually induces a cluster headache attack 1–2 hours a er intake (18).

Some susceptible individuals report variable intensity headaches minutes or hours a er ingestion of nitrate or nitrites containing food like sausages, other cured meats, and sh (i.e. frankfurters, bacon, ham, salami, pepperoni, corned beef, and pastrami) hence the name ‘hot-dog headache’ (19). Other nitrite-containing drugs that may trigger headaches include dipyridamole, nimodipine, pa- paverine hydrochloride, and tolazoline hydrochloride (1).

Box 40.2 ICHD-3 general criteria for headache attributed to a substance

8 Headache attributed to a substance or its withdrawal. A Headache ful lling criterion C.

B Use of, exposure to or withdrawal from a substance known to be able to cause headache has occurred.

C Evidenceofcausationdemonstratedbyatleasttwoofthefollowing:

1 2

3 4

Headache has developed in temporal relation to use of, ex- posure to, or withdrawal from the substance
Either of the following:

. (a) Headache has signi cantly improved or resolved in close
temporal relation to cessation of use of or exposure to the
substance

. (b) headache has signi cantly improved or resolved within a
de ned period after withdrawal from the substance

Headache has characteristics typical for use of, exposure to, or withdrawal from the substance
Other evidence exists of causation.

D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

CHAPTER 40 Headache associated with systemic infection, intoxication, or metabolic derangement

Phosphodiesterase inhibitor-induced headache

Phosphodiesterase (PDE) inhibitor-induced headache develops within 5 hours of intake of a single dose of PDE inhibitor (i.e. sildena l, vardena l, tadala l, dipyridamole) and resolves spontan- eously within 72 hours of onset. PDE-5 inhibitors increase levels of cGMP and/or cyclic adenosine monophosphate. is type of head- ache has the characteristics of either tension-type headache (bilat- eral and mild-to-moderate in intensity) or migraine (pulsating and aggravated by physical activity) (1,5).

Carbon monoxide-induced headache

Carbon monoxide (CO)-induced headache is a secondary type of headache, also called warehouse workers’ headache, occurring in > 90% (20) of individuals a er CO exposure, resolving spontan- eously within 72 hours a er its elimination. It is usually bilateral, frontal, dull, and continuously discomforting, developing within 12 hours of exposure to CO (20,21). Di erent levels of exposure to CO, an odourless and colourless gas, cause di erent clinical symp- toms. Carboxyhaemoglobin levels of 10–20% cause a mild headache without gastrointestinal or neurological symptoms; levels of 20–30% cause a moderate pounding headache and irritability; and levels of 30–40% cause a severe headache with nausea, vomiting, and blurred vision. At levels > 40%, headache is usually not a complaint because of the alternation in consciousness (i.e. confusion at 40–50%, coma at 50–60%, and death at 80%) (1,5). One study did suggest that peak intensity of pain did not correlate with the carboxyhaemoglobin levels (20). Common sources of CO poisoning include faulty oil burners or gas cooking appliances in poorly ventilated spaces.

Alcohol-induced headache

Alcohol-induced headache (also referred to as cocktail headache) can begin immediately (within 3 hours), or a er a delay (within 5– 12 hours; ‘hangover headache’) following the ingestion of alcohol (usually in the form of alcoholic beverages) (3,22,23). e head- ache typically resolves within 72 hours a er alcohol ingestion (5). Alcohol-induced headache is usually bilateral, pulsating, and aggra- vated by physical activity. Alcohol-containing beverages can induce headaches within 30–45 minutes a er ingestion in susceptible indi- viduals. e e ective dose of alcohol to cause alcohol-induced head- ache is variable, and can be very small in migraineurs. Alcohol is also a well-known trigger of migraine and cluster headaches.

Delayed alcohol-induced headache is one of the commonest types of secondary headache; however, the mechanism of how ethanol causes ‘hangover headache’ pain remains unclear (24). e alcohol hangover (also termed veisalgia cephalgia) is characterized by headache with or without tremulousness, dryness, pallor, nausea, dizziness, diarrhoea, fatigue, and hyperexcitability combined with decreased occupational, cognitive, or visual–spatial skill perform- ance, which occur several hours a er the interruption of the inges- tion of alcohol, when the tissue level of the alcohol is low or nil (25). Migraine su erers are found to experience more severe hangover headaches with less alcohol consumption (5). More than 75% of men and women who have consumed alcohol report that they have experienced hangover at least once, and 15% experience hangovers at least monthly (26). Headaches are a common feature of the syn- drome with migraine features including a throbbing quality and ag- gravated by body movements. So-called vesalgia cephalgia usually

lasts 5–10 hours a er the alcohol has been metabolized, with an immediate reduction in symptoms with a fresh ingestion of alcohol indicative of possible withdrawal syndrome (1). is syndrome de- velops when blood alcohol concentration returns to zero and is char- acterized by a feeling of general misery that may last > 24 hours (27).

e possible mechanisms by which alcohol induces headache in- clude disruption of cerebral autoregulation and decreased cerebral turnover of serotonin, rather than vasodilation (12,28). Alcohol has little or no e ect on vascular smooth muscle or cerebral blood ow (1), so that the headache mechanism is likely not related to intra- or extracranial vasodilation. It was also thought that hypomagnes- aemia or alcohol additives may participate in inducing the headache. Combining alcohol with other substances such as monoamine oxi- dase inhibitors, tyramine, disul ram, metronidazole, furazolidone, chloramphenicol and moxalactam disodium, tolbutamide, or chlorpropamide may cause headache (1).

Maxwell et al. (24) found that direct administration of acetate in- creased nociceptive behaviours, suggesting that acetate, not acetal- dehyde, accumulation results in hangover-like hypersensitivity in a rat model of alcohol hangover. Inhalation of oxygen provides relief of hangover syndrome, which is consistent with the hypothesis that the hangover syndrome is due to a delay in the metabolic recovery of the redox state modi ed by ingestion of alcohol (1).

Symptoms of hangover may be caused by dehydration, hormonal alterations, dysregulated cytokine pathways, and toxic e ects of alcohol. Physiological characteristics include increased cardiac work with normal peripheral resistance, di use slowing on elec- troencephalography, and increased levels of antidiuretic hormone. E ective interventions for hangover headache may include rehydra- tion, prostaglandin inhibitors, and vitamin B6 (25). e section on headache induced by food and/or additives was deleted from the new ICHD-3.

Cocaine-induced headache

Headaches can be provoked by a variety of psychoactive sub- stances, but the exact mechanism is still unknown. Beckmann et al. (8) found that of the 1055 psychoactive substance abusers 27% of patients reported having headache. Eighteen per cent of patients reported having headache attributed to a substance or its withdrawal, and 1.4% had unclassi ed headache. e most com- monly used substances were cannabis (80.5%), alcohol (74.6%), methylamphetamine (18.7%), benzodiazepine (10.4%), volatile solvent (5.8%), cocaine (4.4%), heroin (2.1%), opioids (0.5%), and other substances (1.7%).

e adverse e ects of cocaine have been described in the med- ical literature for over 100 years. Neurological complications related to cocaine use can be classi ed as neurovascular events (cerebral or spinal, mainly stroke), seizures (generalized or partial), ab- normal movements (extrapyramidal symptoms like tics, dystonia), hyperpyrexia, and rhabdomyolysis, as well as miscellaneous compli- cations, including visual loss caused by retinal artery occlusion or optic neuropathy, cardiac events (myocardial infarction, dysrhyth- mias, aortic dissection,), pregnancy disturbances (pre-eclampsia or eclampsia), psychiatric disturbances (agitation, anxiety, depres- sion, psychosis, paranoia, and suicidal ideation), and headaches (1,29). Cocaine-induced headache is a secondary type of headache occurring within 1 hour of administration of cocaine by any route (oral (‘chewing’), intranasal (‘snorting’), intravenous (‘mainlining’),

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and inhalation (smoking)) and resolves within 72 hours. Cocaine- related headaches were reported to be as high as 60–75% in pre- vious studies (11,29). It is typically a moderate-to-severe, bilateral (61–87%), temporal, and pulsating headache that is aggravated by physical activity and associated with phonophobia (73–87%) (5,8). Dhuna et al. (11) identi ed three patterns of headaches following cocaine use: acute onset of headaches within minutes of cocaine use, increasing headache during a binge, and headaches during abstin- ence. Migraines were more pronounced in patients using cocaine than in those taking cannabis and alcohol (8). Cocaine-induced headaches begin immediately a er drug ingestion, and are usually not associated with nervous system pathology; however, if pro- longed and accompanied by focal neurological signs, haemorrhagic or ischaemic stroke or vasculitis should be considered (29,30).

e precise mechanisms underlying the development of headache associated with cocaine are not understood but may be related to the sympathomimetic or vasoconstrictive e ects caused by a sudden cocaine surge produced by alkaloidal form of cocaine known as ‘crack cocaine’ or by the intravenous route by rapidly blocking pre- synaptic norepinephrine reuptake causing calcium-dependent acute constriction of vascular smooth muscle producing a migraine-like headache, usually with a benign course (1,11,31). Other patho- physiological abnormalities include presynaptic depletion of sero- tonin, dopamine, and norepinephrine (11).

Histamine-induced headache

Histamine-induced headache is caused immediately (onset at 1 hour and resolves within 1 hour), or a er a delay (onset at 2–12 hours and resolves within 72 hours), by acute exposure to histamine admin- istered subcutaneously, by inhalation, or intravenously. is type of headache is usually a bilateral, mild-to-moderate, and pulsating headache that is aggravated by physical activity. Histamine causes an immediate headache in most people, but can also cause a delayed headache in susceptible migraineurs and patients with tension-type headache. ese delayed headaches occur, on average, 5–6 hours a er exposure. Cluster headache patients develop delayed headache usually 1–2 hours a er exposure that is unilateral with associated autonomic features only during cluster periods. e mechanism is primarily mediated via the H1 receptor, and is almost completely blocked by mepyramine (5).

Calcitonin gene-related peptide-induced headache

Calcitonin gene-related peptide (CGRP) is the most potent vaso- dilator naturally occurring in the central nervous system, and has long been implicated in the pathophysiology of migraine. Headache induced by CGRP can occur immediately (within 1 hour) a er administration by infusion, or a er a delay (within 2–12 hours), following acute exposure to CGRP. e headache triggered by CGRP is usually bilateral and mild to moderate in intensity with migraine features (pulsating quality and aggravated by physical activity).

CGRP is a neuropeptide released from activated trigeminal sen- sory nerves that dilates intracranial blood vessels and transmits vascular nociception. Several studies described this mechanism of CGRP as the rationale for its role in pathophysiology of migraine and using CGRP inhibitors or antibodies in preventing or aborting migraine by showing elevation of CGRP in human external jugular blood during migraine and a drop post-migraine or a er treatment

with subcutaneous sumatriptan by inhibition of trigeminal CGRP release or CGRP-induced cranial vasodilatation (32,33).

Headache attributed to exogenous acute pressor agent

is is a type of secondary headache disorder occurring during, and caused by, an acute rise in blood pressure induced by an exogenous pressor agent occurring within 1 hour of administration of pressor agent and resolves within 72 hours (5).

Headache attributed to occasional use of non-headache medication

Headache attributed to occasional use of non-headache medication develops as an acute adverse event a er occasional use of a medi- cation (onset within minutes to hours of intake and resolves within 72 hours) taken for purposes other than the treatment of headache. ese headaches in most cases are dull, continuous, and di use with a moderate-to-severe intensity. Headache attributed to occasional use of non-headache medication has been reported as an adverse event a er use of many drugs. e following are the most commonly reported drugs: atropine, digitalis, disul ram, hydralazine, imipra- mine, nicotine, nifedipine, and nimodipine (5).

Headache attributed to long-term use of non-headache medication

Headache attributed to long-term use of non-headache medication develops as an adverse event during long-term use of a medication taken for purposes other than the treatment of headache. e head- ache is not necessarily reversible. is type of headache is present on ≥ 15 days per month a er long-term use of a medication taken and develops in temporal relation to the commencement of medication intake, or has signi cantly worsened a er an increase in dosage of the medication, or signi cantly improved or resolved a er a reduc- tion in dosage or a er stopping the medication that is recognized to cause headache during long-term use (5). e dosage and duration of exposure that may result in headache during long-term use varies for di erent medications. is headache can be a result of direct pharmacological e ect of the medication, such as vasoconstriction producing malignant hypertension, or to a secondary e ect such as drug-induced intracranial hypertension. Long-term use of drugs such as anabolic steroids, amiodarone, lithium carbonate, nali- dixic acid, thyroid hormone replacement therapy, tetracycline, and minocycline has been reported to potentially, in some users, lead to the development of intracranial hypertension (5).

Headache attributed to use of or exposure to other substance

Headache attributed to use of or exposure to other substance is a secondary type of headache disorder occurring during or soon a er, and caused by, use of or exposure to a substance other than those described earlier, including herbal, animal, or other organic or inorganic substances given by physicians or non-physicians with medicinal intent although not licensed as medicinal products. is type of headache develops within 12 hours of exposure and resolves within 72 hours. In most cases this type of headache is dull, di use, continuous, and of moderate-to-severe intensity. Headache attrib- uted to use of or exposure to other substance has been reported a er exposure to a number of other organic and inorganic substances. e ICHD-3 notes that the most commonly reported agents include inorganic compounds (arsenic, borate, bromate, chlorate, copper,

CHAPTER 40 Headache associated with systemic infection, intoxication, or metabolic derangement

iodine, lead, lithium, mercury, tolazoline hydrochloride) and or- ganic compounds (aniline, balsam, camphor, carbon disul de, carbon tetrachloride, chlordecone, ethylenediaminetetraacetic acid, heptachlor, hydrogen sul de, kerosene, long-chain alcohols, methyl alcohol, methyl bromide, methyl chloride, methyl iodine, naphtha- lene, organophosphorous compounds (parathion, pyrethrum)) (5).

Management

Ideally, the approach to the management of headaches attributed to substance use are as follows: (i) identify the clinical syndrome; (ii) stop further exposure to the substance immediately; and (iii) advise the pa- tient to avoid contact with the substance or substances in the future. Realistically, this is not always possible as the medication in question may be required; however, typically, alternate options can be substituted.

Speci c treatments may be available depending on the impugned substance in question. Pure or hyperbaric oxygen is given to treat CO intoxication. Ergotamine has been shown to have the potential abort headaches induced by NTG in many individuals. Injectable sumatriptan can terminate the delayed headache induced by an NO donor (1).

e prognosis of headaches associated with acute use of sub- stances, in general, is good with the spontaneous resolution of symp- toms a er exposure stops; however, excessive exposure to some substances (i.e. CO) can be lethal as can excessive use of illicit drugs (particularly those containing contaminants or combinations with other substances such as crack or amphetamine analogues) (1).

Headaches attributed to disorders of homeostasis

Headaches attributed to disorders of homeostasis were referred to as ‘headaches associated with metabolic or systemic diseases’ in the rst edition of the ICHD (34). e most recent version (ICHD-3) states that if a headache occurs for the rst time in close temporal relation to a disorder of homoeostasis, it is coded as a secondary headache at- tributed to that disorder speci cally (even when the new headache has the characteristics of any of the primary headache disorders) (5). e headaches attributed to disorders of homeostasis include headaches attributed to (i) hypoxia and/or hypercapnia (high altitude, diving, sleep apnoea); (ii) dialysis; (iii) arterial hypertension (phaeochromo- cytoma, hypertensive crisis without hypertensive encephalopathy, hypertensive encephalopathy, pre-eclampsia or eclampsia, autonomic dysre exia); (iv) hypothyroidism; (v) fasting; (vi) cardiac cephalalgia; and (vii) other disorder of homoeostasis. Although there are varied mechanisms behind causation of these di erent subtypes of headache attributed to disorder of homoeostasis (10.0), there are general diag- nostic criteria applicable in most cases as seen in Box 40.3 (5,35).

Headache attributed to hypoxia or hypercapnia

is is a group of headache disorders caused by hypoxia and/or hypercapnia and occurring in conditions of exposure to one or both. It is di cult to separate the e ects of hypoxia and hypercapnia (Box 40.4). e ICHD-2 criteria for headache secondary to hypoxia state that headache begins within 24 hours a er acute onset of hypoxia with a partial pressure of oxygen (PaO2) < 70 mmHg or in chron- ically hypoxic patients with a PaO2 persistently at or below these levels; the ICHD-3 does not specify the parameters for the hypoxia/ hypercapnia. Diseases that are related to acute or chronic hypoxia/

hypercapnia may be associated with headache. Any disease that in- duces a hypoxic state, such as pulmonary diseases (asthma, chronic obstructive pulmonary disease), cardiac disease (congestive heart failure), or haematological disorders (with signi cant anaemia), may be associated with headache.

ere are four unique situations associated with headaches attrib- uted to hypoxia that are common, potentially manageable, and cited in the ICHD-3. ese entities include headaches attributed to high altitude, airplane travel, diving, and sleep apnoea, and each will be discussed in detail in this section.

High altitude headache

ICHD-3 de nes high-altitude headache as typically a bilateral head- ache, aggravated by exertion, and caused by ascent above 2500 metres, which resolves spontaneously within 24 hours a er descent (Box 40.5). Although the criteria suggest that the headaches are more o en bilateral, unilateral headaches can occur, and this is seen more o en in migraineurs (36).

Headache is the most frequent symptom of acute exposure to high altitude, with an incidence as high as 73.3–86.7% (37–39). High- altitude headache is o en associated with nausea, photophobia, ver- tigo, and poor concentration. In severe cases, impaired judgement and symptoms or signs suggestive of brain oedema can occur. Risk

Box 40.3 Headache attributed to a disorder of homoeostasis

. A Headache ful lling criterion C.

. B A disorder of homoeostasis known to be able to cause headache
has been diagnosed.

. C Evidence of causation demonstrated by at least two of the following:

. 1 Headache has developed in temporal relation to the onset of the disorder of homoeostasis

. 2 Either or both of the following:
(a) Headache has signi cantly worsened in parallel with
worsening of the disorder of homoeostasis
(b) Headache has signi cantly improved after resolution of the
disorder of homoeostasis

. 3 Headache has characteristics typical for the disorder of
homoeostasis.

. D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Box 40.4 Headache attributed to hypoxia or hypercapnia

. A Any headache ful lling criterion C.

. B Exposure to conditions of hypoxia and/or hypercapnia.

. C Evidence of causation demonstrated by either or both of the
following:

1 2

Headache has developed in temporal relation to the exposure Either or both of the following:
(a) Headache has signi cantly worsened in parallel with

increasing exposure to hypoxia and/or hypercapnia
(b) Headache has signi cantly improved in parallel with im-

provement in hypoxia and/or hypercapnia.
D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

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PART 6 Secondary headaches

Box 40.5 Headache attributed to high altitude

. A Headache ful lling criterion C.

. B Ascent to altitude above 2500 metres has occurred.

. C Evidence of causation demonstrated by at least two of the following:

1 2

Headache has developed in temporal relation to the ascent Either or both of the following:

. (a) Headache has signi cantly worsened in parallel with
continuing ascent

. (b) Headache has resolved within 24 hours after descent to
below 2500 metres

Headache has at least two of the following three characteristics:

. (a) Bilateral location

. (b) Mild or moderate intensity

. (c) Aggravated by exertion, movement, straining, coughing, and/

or bending.
D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1-211. © International Headache Society 2018.

factors for high-altitude headache include a history of migraine, low arterial oxygen saturation, high perceived degree of exertion, uid intake < 2 L within 24 hours, insomnia, high heart rate and high Self-Rating Anxiety Scale score (36,37).

Like many headaches associated with disorders of homeostasis, the precise pathophysiological process that causes high-altitude headache remains unknown. Hypoxia elicits neurohumoral and haemodynamic responses that result in over-perfusion of micro- vascular beds, increased hydrostatic capillary pressure, capillary leakage, and consequent oedema (40). Several neuroimaging studies have demonstrated a mild increase in brain volume associated with an increased T2 relaxation time and apparent di usion coe cient that were consistently associated with the severity of neurological symptoms. e authors suggested that the brain oedema is predom- inantly vasogenic (with movement of uid and proteins out of the vascular compartment into extracellular brain areas) rather than a cytotoxic oedema (due to cellular swelling). Mild extracellular vasogenic oedema contributes to the generalized brain swelling ob- served at high altitude, and may be of signi cance in headache at- tributed to altitude (41). is was supported by ndings that elderly people have fewer headaches than younger people a er exposure to high altitude, probably due to a certain degree of brain atrophy (42).

A recent study examined indices of brain white matter water mobility a er 2 and 10 hours in normoxia (21% O2) and hypoxia (12% O2) using magnetic resonance imaging (MRI) whole-brain analysis (tract-based spatial statistics). e results of this study indicate that acute periods of hypoxaemia cause a shi of water into the intracellular space within the cerebral white matter, which were found to be related to the inten- sity of high-altitude headache, whereas no evidence of brain oedema (a volumetric enlargement) is identi able (43). Furthermore, e orts to demonstrate a speci c genotype associated with a predisposition to develop this headache led to the suggestion that low mRNA expression of the ATP1A1 subunit of the ATPase gene may be of importance (44).

Medical treatment of headaches attributed to high altitude involves simple analgesics such as paracetamol (acetaminophen) or ibuprofen, antiemetic agents, as well as acetazolamide, at 125–250 mg twice daily ± dexamethasone (45–47). Randomized, placebo-controlled trials also showed a signi cant reduction in the risk of headache with the use of acetylsalicylic acid at a dose of 320 mg taken three times at 4-hour

intervals, starting 1 hour before ascent (28), or ibuprofen at a dose of 600 mg three times daily (48,49), starting a few hours before ascent to altitudes between 3480 and 4920 metres. In a recent systematic review and meta-analysis of three randomized controlled trials showed that ibuprofen seems e cacious (with absolute risk reduction of 15% and number needed to treat of seven for the prevention of high-altitude headache (47). Important non-pharmacological strategies include 2 days of acclimatization prior to engaging in strenuous exercise at high altitudes, slow ascent, liberal uid intake, and avoidance of alcohol (46).

Headache attributed to airplane travel

Headache attributed to airplane travel (Box 40.6), also called ‘airplane headache’ (AH), is a new addition to the ICHD classi cation criteria, rst introduced in ICHD-3 (see also Chapter 56). is headache is o en severe, usually unilateral and periocular, and without autonomic symptoms, occurring during and caused by airplane travel and it re- mits a er landing (5). e largest case series of AH reported a rather stereotyped nature of the attacks, which include the short duration of pain (lasting < 30 minutes in up to 95% of cases), a clear relationship with the landing phase, a male preponderance, and the absence of ac- companying signs and/or symptoms (50). AH occurs in up to 8.3% of Scandinavian air travellers, according to a recent study (51), and during landing in > 85–90% of patients (51,52). Although the patho- physiology of AH remains unclear, speculation exists that the in- ammation squeeze e ect on the frontal sinus wall, when air trapped inside it contracts, producing a negative pressure leading to mucosal oedema, transudation, and intense pain (53). Another proposed theory is that this type of headache generally results from the tem- porary local in ammation caused by hypoxia or dryness in the sinus mucosa or sinus barotraumas (54). e most recent systematic review on AH showed that the most common theoretical mechanism in the development of AH include changes in cabin pressure during take-o and landing, which lead to sinus barotrauma and local in ammation (prostaglandin E2 (PGE-2) is found to be a potential biomarker for AH), as well as possibly vasodilation in the cerebral arteries (55,56).

ere are no speci c guidelines for the treatment of AH because this type of headache is considered short-lasting and aborted a er the ight travel is over. Prophylactic therapy for AH may include trials of simple analgesics, NSAIDs, antihistamines, triptans, and

Box 40.6 Headache attributed to airplane travel

. A At least two episodes of headache ful lling criterion C.

. B The patient is travelling by airplane.

. C Evidence of causation demonstrated by at least two of the following:

1 2

Headache has developed during the aeroplane ight

Either or both of the following:

. (a) Headachehasworsenedintemporalrelationtoascentfollowing
take-off and/or descent prior to landing of the aeroplane

. (b) Headache has spontaneously improved within 30 minutes
after the ascent or descent of the aeroplane is completed

Headache is severe, with at least two of the following three characteristics:

(a) Unilateral location
(b) Orbitofrontal location
(c) Jabbing or stabbing quality.

D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

CHAPTER 40 Headache associated with systemic infection, intoxication, or metabolic derangement

Box 40.7 Diving headache

. A Any headache ful lling criterion C.

. B Both of the following:

. 1 The patient is diving at a depth > 10 metres

. 2 No evidence of decompression illness.

. C Evidence of causation demonstrated by at least one of the following:

1 2

Headache has developed during the dive
Either or both of the following:
(a) Headache has worsened as the dive is continued

(b) Either of the following:

. (i) Headache has spontaneously resolved within 3 days of
completion of the dive

. (ii) Headache has remitted within 1 hour after treatment with
100% oxygen

At least one of the following symptoms of CO2 intoxication: (a) Mental confusion

(b) Light-headedness
(c) Motor incoordination (d) Dyspnoea
(e) Facial ushing.

D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

nasal decongestants administered 30 minutes up to 1 hour prior to travel (52,53,55,56). Among these medications, ibuprofen, na- proxen, and triptans (sumatriptan, naratriptan, zolmitriptan, and eletriptan have been found the most e ective (55); however, there is a need to perform randomized controlled trials in pharmaco- logical treatments for AH. Performing speci c active spontaneous manoeuvres (i.e. pressure on the pain area, Valsalva manoeuvres, relaxation methods, chewing, and extension of the earlobe) has been shown to decrease the pain intensity (52,57).

e most common symptoms of AH include severe, short lasting (< 30 minutes in most cases) unilateral, throbbing, or stabbing head- ache over the fronto-orbital area with parietal spread, which can side-shi between di erent ights in 10% of cases, autonomic fea- tures like restlessness and unilateral tearing, and migraine features like nausea, photophobia, and phonophobia (51,55,56).

Diving headache

Diving headache (Box 40.7)is a headache caused by diving below 10 metres, occurring during the dive and o en intensi ed on resur- facing, in the absence of decompression illness. It is usually accom- panied by symptoms of carbon dioxide (CO2) intoxication. It remits quickly with oxygen or, if this is not given, spontaneously within 3 days a er the dive has ended (5). e best clinical example of head- ache attributed to hypercapnia is diving headache. ere is some evi- dence that hypercapnia (arterial partial pressure of CO2 (pCO2) > 50 mmHg) is known to cause relaxation of cerebrovascular smooth muscle, leading to intracranial vasodilatation and increased intra- cranial pressure leading to headache (57,58). CO2 may accumulate in a diver who intentionally holds his or her breath intermittently (skip breathing) in a mistaken attempt to conserve air, or takes shallow breaths to minimize buoyancy variations in the narrow pas- sages of a wreck or cave. Divers may also hypoventilate unintention- ally when a tight wetsuit or buoyancy compensator jacket restricts chest wall expansion, or when ventilation is inadequate in response to physical exertion. Notably, strenuous exercise increases the rate of

CO2 production more than 10-fold, resulting in a transient elevation of pCO2 to > 60 mmHg. Inadequate ventilation of compressed gases can lead to CO2 accumulation, cerebral vasodilation, and headache (57,58). Diving headache usually intensi es during the decompres- sion phase of the dive or on resurfacing.

Notably, a study by Di Fabio et al. (59) suggested that the preva- lence of headache among male divers and matched controls was not signi cant (16% vs 22%) and concluded that scuba diving is not as- sociated with headache.

It is well established that headache in divers, although uncommon (4.5–23%) and relatively benign, can occasionally signify serious consequences of hyperbaric exposure, such as arterial gas embolism, decompression sickness, and otic or paranasal sinus barotrauma (60– 62). For patients in whom the headache is not obviously benign, the diagnostic evaluation should consider otic and paranasal sinus baro- trauma, arterial gas embolism, decompression sickness, CO2 retention, CO toxicity, hyperbaric-triggered migraine, cervical and temporo- mandibular joint strain, supraorbital neuralgia, carotid artery dissec- tion, and exertional and cold stimulus headache syndromes (57). Focal neurological symptoms, even in the migraineur, should not be ignored, but rather treated with 100% oxygen acutely, and the patient should be referred without delay to a facility with a hyperbaric chamber (35). Interestingly, a relationship between patent foramen ovale and mi- graine with aura was rst observed in scuba divers (63). In 2015, the South Paci c Underwater Medicine Society (SPUMS) and the United Kingdome Sports Diving Medical Committee (UKSDMC) published joint guidelines recommending that screening for PFO using a bubble contrast transthoracic echocardiography with provocative man- oeuvres should be considered in divers with high risk factors, including a history of migraine with aura, cerebral, spinal, inner ear or cutaneous decompression illness, a family history of PFO or atrial septal defect or those with other forms of congenital heart disease (58,64).

Sleep apnoea headache

Sleep apnoea headache (Box 40.8) is a recurrent morning headache, usually bilateral and typically with a duration of less than 4 hours,

Box 40.8 Headache attributed to sleep apnoea

A Headache present on awakening after sleep and ful lling criterion C. B Sleepapnoeawithapnoea–hypopnoeaindex≥5hasbeendiagnosed. C Evidence of causation demonstrated by at least two of the following:

1 2

Headache has developed in temporal relation to the onset of sleep apnoea
Either or both of the following:

. (a) Headache has worsened in parallel with worsening of
sleep apnoea

. (b) Headache has signi cantly improved or remitted in parallel
with improvement in or resolution of sleep apnoea

Headache has at least one of the following three characteristics:

. (a) Recurring on ≥ 15 days/month

. (b) All of the following: (i) Bilateral location
(ii) Pressing quality
(iii) Not accompanied by nausea, photophobia or
phonophobia.

. (c) Resolving within 4 hours.

D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

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PART 6 Secondary headaches

caused by sleep apnoea diagnosed using polysomnography with an apnoea–hypopnoea index (AHI) ≥ 5. AHI is calculated by dividing the number of apnoeic events by the number of hours of sleep (5). Importantly, this headache disorder resolves with successful treat- ment of the sleep apnoea (65,66).

e relationship between headache and sleep disorders is com- plex and incompletely understood (see also Chapter 57). Firstly, sleep disturbances may trigger migraine (67). Secondly, snoring and other sleep disorders are risk factors for migraine progression (68) irdly, sleep apnoea is a risk factor for cluster headache and morning headaches (69,70). Although morning headache is sig- ni cantly more frequent in patients with obstructive sleep apnoea (OSA) (11.8% vs 4.6%) than those without OSA, headache present on awakening is a non-speci c symptom that occurs in a variety of primary and secondary headache disorders, in sleep-related respira- tory disorders other than sleep apnoea (e.g. Pickwickian syndrome, chronic obstructive pulmonary disease), and in other primary sleep disorders such as periodic leg movements of sleep (71).

Studies have demonstrated higher prevalence (27.2–74%) of morning headaches in patients with OSA (66,72–74), habitual snoring (23.5%) (72), and insomnia (48%). Other predictors for sleep apnoea headache include female sex, history of migraine, psy- chological distress, and obesity (72,74).

e exact pathophysiology of sleep apnoea headache remains de- batable. Several possible mechanisms include hypoxia or oxygen desaturation, hypercapnia, or disturbance in sleep architecture (i.e. shorter rapid eye movement sleep), as well as increase in intracranial pressure (66,72–74).

Dialysis headache

Dialysis headache (Box 40.9) is a type of secondary headache dis- order with no speci c characteristics occurring during or a er (most o en a er the second hour) haemodialysis (35,75,76). It re- solves spontaneously within 72 hours a er the haemodialysis ses- sion has ended or headache episodes may also stop altogether a er a successful kidney transplant and termination of haemodialysis (5). Dialysis headache occurs in 27–73% of patients receiving haemo- dialysis (76–79. However, in a prospective study, around one- third of patients with otherwise typical dialysis headache also had similar headache in between their dialysis sessions and the head- aches occurred mainly in the second half of the haemodialysis (86%) (77). is type of headache is described as a mild to moderate

(73%), bifronto-temporal (50%) ache, which can escalate to severe throbbing (87%) pain lasting for < 4 hours (63%), that worsens in the reclined position and is accompanied by nausea and vomiting (76).

ere is no consensus on pathophysiology of dialysis headache; how- ever, it thought to commonly occur in association with hypotension and dialysis disequilibrium syndrome. Dialysis disequilibrium syn- drome may begin as a headache and then progress to obtundation and coma, with or without seizures. e most consistent triggers for dialysis headache found in several studies include arterial hypertension (38%), arterial hypotension (12%), and changes in weight during the haemo- dialysis sessions (79,80). Reduced serum osmolality, low magnesium, and high sodium levels may also be risk factors for developing dialysis headache (78). Variations in NO, CGRP, and substance P levels related to dialysis pose another potential contributor to dialysis headache (76).

Dialysis headache may be prevented by changing dialysis para- meters. ere is no speci c treatment for dialysis headache. Acute treatment is mainly symptomatic and complicated by the chronic renal insu ciency status. Analgesics and NSAIDs are o en used during dialysis sessions. e use of preventative medication may be necessary to improve headache burden; however, evidence for this is very limited. Angiotensin-converting enzyme inhibitors were given in one case, with a good response reported (81).

Headache attributed to hypertension

Headache attributed to hypertension (Box 40.10) is caused by arterial hypertension, usually during an acute rise in systolic (to ≥ 180 mmHg) and/or diastolic (to ≥ 120 mmHg) blood pressure. e headache is o en bilateral and pulsating. e headache remits a er normalization of blood pressure. Mild (140–159/90–99 mmHg) or moderate (160– 179/100–109 mmHg) chronic arterial hypertension does not appear to cause headache. Some studies have suggested that ambulatory blood pressure monitoring in patients with mild and moderate hypertension has demonstrated no convincing relationship between blood pres- sure uctuations over a 24-hour period and the presence or absence of headache (82,83). Others report a signi cant correlation between blood pressure levels and headache, as well as reduced headache fre- quency with treatment of hypertension (84–86). Whether moderate hypertension predisposes to headache at all remains unclear.

Several studies have documented association of headache with phaeochromocytoma (87–90), hypertensive encephalopathy (91,92), pre-eclampsia and eclampsia (93,94), as well as autonomic

Box 40.10 Headache attributed to hypertension

1 Any headache ful lling criterion C
2 Hypertension, with systolic pressure ≥180 mm Hg and/or diastolic

pressure ≥120 mm Hg, has been demonstrated
3 Evidenceofcausationdemonstratedbyeitherorbothofthefollowing:

1 2

Headache has developed in temporal relation to the onset of hypertension
Either or both of the following:
(a) Headache has signi cantly worsened in parallel with

worsening hypertension
(b) Headache has signi cantly improved in parallel with im-

provement in hypertension
Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1-211. © International Headache Society 2018.

Box 40.9 Dialysis headache

. A At least three episodes of acute headache ful lling criterion C.

. B The patient is on haemodialysis.

. C Evidence of causation demonstrated by at least two of the following:

1 2

Each headache has developed during a session of haemodialysis Either or both of the following:
(a) Each headache has worsened during the dialysis session

(b) Each headache has resolved within 72 hours after the end of the dialysis session

3
D Not better accounted for by another ICHD-3 diagnosis.

Headache episodes cease altogether after successful kidney transplantation and termination of haemodialysis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

CHAPTER 40 Headache associated with systemic infection, intoxication, or metabolic derangement dysre exia (95). e proposed mechanism for this type of headache

Box 40.12 Headache attributed to hypertensive crisis without hypertensive encephalopathy

. A Headache ful lling criterion C.

. B Both of the following:

. 1 A hypertensive crisis is occurring

. 2 No clinical features or other evidence of hypertensive
encephalopathy.

. C Evidence of causation demonstrated by at least two of the following:

1 2

Headache has developed during the hypertensive crisis Either or both of the following:

. (a) Headache has signi cantly worsened in parallel with
increasing hypertension

. (b) Headache has signi cantly improved or resolved in parallel
with improvement in or resolution of the hypertensive crisis

Headache has at least one of the following three characteristics: (a) Bilateral location

(b) Pulsating quality

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

is failure of the normal baroreceptor re ex (85).

Headache attributed to phaeochromocytoma

Headaches attributed to phaeochromocytoma (Box 40.11) are usu- ally severe and of short duration (< 1 hour) with attacks accom- panied by sweating, palpitations, pallor, and/or anxiety (5). is type of headache occurs as a paroxysmal headache in 51–80% of patients with phaeochromocytoma (87,88). e headache is o en severe, frontal or occipital, and usually described as either pulsating or constant in quality. A notable feature of the headache is its short duration: < 15 minutes in 50% and < 1 hour in 70% of patients (87). Associated features include apprehension and/or anxiety, o en with a sense of impending death, tremor, visual disturbances, abdominal or chest pain, nausea, vomiting, facial ushing, and, occasionally, paraesthesia (87,89). e diagnosis of phaeochromocytoma is es- tablished by the demonstration of increased excretion of catechol- amines or catecholamine metabolites, and can usually be secured by analysis of a single 24-hour urine sample collected when the patient is hypertensive or symptomatic (87,89,90). e variable duration and intensity of the headache correlates with the pressor and cranial vasoconstrictor e ects of the secreted amines (89).

Headache attributed to hypertensive crisis without hypertensive encephalopathy

Headache attributed to hypertensive crisis (Box 40.12) without hypertensive encephalopathy is usually a bilateral and pulsating headache, caused by a paroxysmal rise of arterial hypertension (sys- tolic ≥ 180 mmHg and/or diastolic ≥ 120 mmHg). It remits a er normalization of blood pressure (5). Paroxysmal hypertension may occur in association with failure of baroreceptor re exes (a er ca- rotid endarterectomy or subsequent to irradiation of the neck) or in patients with enterochroma n cell tumours.

Headache attributed to hypertensive encephalopathy

Headache attributed to hypertensive encephalopathy (Box 40.13) consists of a headache (usually bilateral and pulsating), caused by persistent blood pressure elevation to 180/120 mmHg or above and accompanied by symptoms of encephalopathy such as confusion, lethargy, visual disturbances, or seizures. It improves a er normal- ization of blood pressure (5). Hypertensive encephalopathy presents with persistent elevation of blood pressure to ≥ 180/120 mmHg and at least two of confusion, reduced level of consciousness, visual disturbances including blindness, and seizures (91,92). Headache is one of the most frequent signs (22%) at presentation in hyper- tensive urgencies (92). It is thought to occur when compensatory cerebrovascular vasoconstriction can no longer prevent cerebral

Box 40.11 Headache attributed to phaeochromocytoma

. A Recurrent discrete short-lasting headache episodes ful lling criterion C.

. B Phaeochromocytoma has been demonstrated.

. C Evidence of causation demonstrated by at least two of the following:

. 1 Headache episodes have commenced in temporal relation to development of the phaeochromocytoma, or led to its discovery

. 2 Either or both of the following:

. (a) Individual headache episodes develop in temporal relation
to abrupt rises in blood pressure

. (b) Individual headache episodes remit in temporal relation to
normalization of blood pressure

. 3 Headache is accompanied by at least one of the following:
(a) Sweating (b) Palpitations (c) Anxiety
(d) Pallor

. 4 Headache episodes remit entirely after removal of the phaeochromocytoma.

. D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Box40.13 Headacheattributedtohypertensive encephalopathy

. A Headache ful lling criterion C.

. B Hypertensive encephalopathy has been diagnosed.

. C Evidence of causation demonstrated by at least two of the following:

1 2

Headache has developed in temporal relation to the onset of the hypertensive encephalopathy
Either or both of the following:

. (a) Headache has signi cantly worsened in parallel with
worsening of the hypertensive encephalopathy

. (b) Headache has signi cantly improved or resolved in par-
allel with improvement in or resolution of the hypertensive
encephalopathy.

Headache has at least two of the following three characteristics: (a) Diffuse pain

(b) Pulsating quality

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

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Box 40.14 Headache attributed to pre-eclampsia or eclampsia

. A Headache, in a woman who is pregnant or in the puerperium (up to 4 weeks postpartum), ful lling criterion C.

. B Pre-eclampsia or eclampsia has been diagnosed.

. C Evidence of causation demonstrated by at least two of the following:

1 2

Headache has developed in temporal relation to the onset of the pre-eclampsia or eclampsia
Either or both of the following:

. (a) Headache has signi cantly worsened in parallel with
worsening of the pre-eclampsia or eclampsia

. (b) Headache has signi cantly improved or resolved in parallel with improvement in or resolution of the pre-eclampsia or
eclampsia

Headache has at least two of the following three characteristics: (a) Bilateral location

(b) Pulsating quality
(c) Aggravated by physical activity.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Box 40.15 Headache attributed to autonomic dysre exia

. A Headache of sudden onset, ful lling criterion C.

. B Presence of spinal cord injury and autonomic dysre exia docu-
mented by a paroxysmal rise above baseline in systolic pressure of
≥30 mm Hg and/or diastolic pressure of ≥ 20 mm Hg.

. C Evidence of causation demonstrated by at least two of the following:

1 2

Headache has developed in temporal relation to the rise in blood pressure
Either or both of the following:

. (a) Headache has signi cantly worsened in parallel with increase
in blood pressure

. (b) Headache has signi cantly improved in parallel with decrease
in blood pressure

Headache has at least two of the following four characteristics:

. (a) Severe intensity

. (b) Pounding or throbbing (pulsating) quality

. (c) Accompanied by diaphoresis cranial to the level of the spinal
cord injury

. (d) Triggered by bladder or bowel re exes.

D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

hyperperfusion as blood pressure rises (96). As normal cerebral autoregulation of blood ow is overwhelmed, endothelial perme- ability increases and cerebral oedema occurs (91). On MRI, this is o en most prominent in the parieto-occipital white matter (97). Although hypertensive encephalopathy in patients with chronic ar- terial hypertension is usually accompanied by a diastolic blood pres- sure of > 120 mmHg, and by grade III or IV hypertensive retinopathy (Keith–Wagener–Barker classi cation), previously normotensive individuals can, occasionally, develop signs of encephalopathy with blood pressures as low as 160/100 mmHg (98).

Headache attributed to pre-eclampsia or eclampsia

Headache attributed to pre-eclampsia or eclampsia (Box 40.14) is usually a bilateral and pulsating headache, occurring in women with pre-eclampsia or eclampsia during pregnancy or the immediate puerperium (99). It remits a er resolution of the pre-eclampsia or eclampsia (5). Pre-eclampsia and eclampsia appear to involve a strong maternal in ammatory response, with broad immunological systemic activity (93). e diagnosis of pre-eclampsia and eclampsia require hypertension (> 140/90 mmHg) documented on two blood pressure readings at least 4 hours apart, or a rise in diastolic pressure of ≥ 15 mmHg or in systolic pressure of ≥ 30 mmHg, coupled with urinary protein excretion > 0.3 g/24 hours for diagnosis. ey are considered as multisytemic disorders that may present with tissue oedema, thrombocytopenia, and abnormalities in liver function (93), as well as seizures in patients with eclampsia. A case–control study found that headache was signi cantly more frequent in pa- tients with pre-eclampsia (63%) than in controls (25%) (odds ratio 4.95, 95% con dence interval 2.47–9.92) (100).

Headache attributed to autonomic dysre exia

Headache attributed to autonomic dysre exia (Box 40.15) is a throbbing, severe headache, in patients with spinal cord injury (SCI) and autonomic dysre exia (5). It is a sudden-onset type of se- vere headache associated with sudden increase in blood pressure, altered heart rate, and diaphoresis cranial to the level of SCI (95). Severe headaches occur in 56–85% of the patients with autonomic

dysre exia (101,102). Triggers include noxious or non-noxious stimuli, usually of visceral origin (bladder distension, urinary tract infection, bowel distension or impaction, urological procedures, gastric ulcer, and others), but also of somatic origin (pressure ulcers, ingrown toenail, burns, trauma, or surgical or invasive diagnostic procedures) (102). e time to onset of autonomic dysre exia a er SCI is variable and has been reported to be from 4 days to 15 years (101). e most important predictors of autonomic dysre exia are the level and severity of SCI. Patients with complete SCI are at greater risk of development of autonomic dysre exia and, consequently, more susceptible to develop headaches (95). Little is known about the mechanism of headache attributed to autonomic dysre exia; however, it has been postulated that this type of headache has a vasomotor nature and may result from passive dilation of cerebral vessels or increased circulating PGE-2 (95). Given that autonomic dysre exia can be a life-threatening condition, its prompt recogni- tion and appropriate management are critical. e primary treat- ment of this type of autonomic headache involves management of actual episode of autonomic dysre exia, which includes close monitoring of blood pressure and heart rate as the following steps are followed: (i) patient is placed in a sitting position; (ii) removal/ loosening of clothing or constrictive devices; (iii) scrutinize for po- tential triggers (i.e. bladder distension and bowel impaction); (iv) pharmacological treatment with a rapid-onset and short-duration antihypertensive agent (i.e. nifedipine or nitrates) for elevated sys- tolic blood pressure (≥ 150 mmHg) (95).

Headache attributed to hypothyroidism

Headache attributed to hypothyroidism (Box 40.16) is usually bilat- eral and non-pulsatile, occurring in patients with hypothyroidism and remitting a er normalization of thyroid hormone levels (5,103) occurring in approximately 30% of patients with hypothyroidism with female preponderance (103,104). In migraineurs with sub- clinical hypothyroidism, treatment of borderline hypothyroidism is

CHAPTER 40 Headache associated with systemic infection, intoxication, or metabolic derangement

Box 40.16 Headache attributed to hypothyroidism

. A Headache ful lling criterion C.

. B Hypothyroidism has been demonstrated.

. C Evidence of causation demonstrated by at least two of the following:

1 2

Headache has developed in temporal relation to the onset of the hypothyroidism, or led to its discovery
Either or both of the following:

. (a) Headache has signi cantly worsened in parallel with
worsening of the hypothyroidism

. (b) Headache has signi cantly improved or resolved in parallel

with improvement in or resolution of the hypothyroidism Headache has either or both of the following characteristics: (a) Bilateral location

3
D Not better accounted for by another ICHD-3 diagnosis.

(b) Constant over time.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Box 40.18 Cardiac cephalalgia

. A Any headache ful lling criterion C.

. B Acute myocardial ischaemia has been demonstrated.

. C Evidence of causation demonstrated by at least two of the following:

1 2

Headache has developed in temporal relation to the onset of acute myocardial ischaemia
Either or both of the following:

. (a) Headache has signi cantly worsened in parallel with
worsening of the myocardial ischaemia

. (b) Headache has signi cantly improved or resolved in par-
allel with improvement in or resolution of the myocardial
ischaemia.

Headache has at least two of the following four characteristics: (a) Moderate-to-severe intensity

(b) Accompanied by nausea
(c) Not accompanied by photophobia or phonophobia (d) Aggravated by exertion
Headache is relieved by nitroglycerin or its derivatives.

4
D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

sometimes followed by dramatic improvement in the control of the headache (105). is type of headache is described as intermittent, unilateral, throbbing pain associated with nausea and/or vomiting, which begins within 2 months of the onset of hypothyroidism and lasts < 3 months a er its e ective treatment (106). e mechanism of headache attributed to thyroid disease is unclear. ere is a female preponderance and o en a history of migraine in childhood.

Hypothyroidism has also been identi ed as a potential risk factor for new daily persistent headache in a clinic-based case–control study, when the control group was migraine (105). In the presence of hypothyroidism, it is important to remember that headache can also be a manifestation of pituitary adenoma (107).

Headache attributed to fasting

Headache attributed to fasting (Box 40.17) is typically a di use non- pulsating headache, usually mild to moderate, occurring during and caused by fasting for at least 8 hours that is relieved a er eating (see also Chapter 7) (5). Even though the typical headache attributed to fasting is di use, non-pulsating, and mild to moderate in intensity, in those with a prior history of migraine the headache may resemble migraine without aura (108).

e aetiology of fasting induced headaches is uncertain (109). A commonly reported migraine triggers is hypoglycaemia. Headache attributed to fasting is signi cantly more common in people who have a prior history of headache, particularly migraine. However, in individuals without a well-de ned history of headache, prolonged fasting may also be associated with the development of headaches.

is is o en seen in prolonged religious fasting and has been docu- mented as ‘Yom Kippur headache’ (110) and ‘ rst of Ramadan head- ache’ (49). e likelihood of headache developing as a result of a fast increases with the duration of the fast. Fasting headache can occur in the absence of hypoglycaemia, suggesting that other factors play an important role (e.g. ca eine withdrawal, duration of sleep, and circadian factors).

In terms of treatment, a recent study suggested that pre-emptive cyclooxygenase 2 (COX-2) inhibitor treatment (rofecoxib, 50 mg just before the onset of fasting) is e ective in reducing these forms of head- ache, similar to its e ect in menstrual migraine (108). Because COX-2 inhibitors are not available in many countries, pre-emptive treatment with NSAIDs or long-acting triptans may be a reasonable option (110).

Cardiac cephalalgia

Cardiac cephalalgia (Box 40.18) is a headache with migraine features, usually but not always aggravated by exercise, occurring during an episode of myocardial ischaemia that is relieved by NTG (see also Chapter 28) (5). Lipton et al. (111) proposed that this type of head- ache is a rare and treatable form of exertional headache. During a stress test in two subjects, typical headaches correlated with electro- cardiography changes indicative of myocardial ischaemia. In both patients, coronary angiography revealed three-vessel disease, and myocardial revascularization procedures were followed by complete resolution of headaches.

ICHD-3 states that the diagnosis must include careful and detailed headache history and simultaneous cardiac ischaemia during tread- mill or nuclear cardiac stress testing. However, cardiac cephalalgia occurring at rest has been described (112). Several authors reported that this type of headache may be the sole manifestation of myo- cardial ischaemia (112–115). A recent literature review of cardiac cephalalgia showed that in more than half of the 35 reviewed cases, the headache was triggered by high myocardial oxygen consump- tion (i.e. exertion, sexual activity, and emotional uctuation); how- ever, in six cases the headache occurred during rest. Appropriate and timely diagnosis of cardiac cephalalgia is necessary to avoid serious

Box 40.17 Headache attributed to fasting

. A Diffuse headache not ful lling the criteria for ‘1. Migraine’ or any of its types but ful lling criterion C below.

. B The patient has fasted for ≥ 8 hours.

. C Evidence of causation demonstrated by both of the following:

. 1 Headache has developed during fasting

. 2 Headache has signi cantly improved after eating.

. D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

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consequences (115). Cardiac cephalalgia, like migraine, can present with severe headaches associated with photophobia, phonophobia, osmophobia, nausea, or vomiting, and triggered by exertion (116). It is therefore crucial to distinguish this disorder from migraine without aura, particularly as vasoconstrictor medications (e.g. triptans, ergots) are indicated in the treatment of migraine but contraindicated in patients with ischaemic heart disease.

e mechanisms involved in cardiac cephalalgia remain un- clear as this diagnosis was introduced in 1997. However, possible mechanisms reported are related to neural convergence, including somatic and sympathetic impulses converging in the posterior horn of the spinal cord, mixing neural supply to cervical area and cra- nial vessels; transient increases of intracardiac pressure that cause intracranial pressure elevation and severe headache; and a func- tioning ventricular pacemaker producing the headache (35,113). A recent case report of cardiac cephalalgia con rmed evidence of cerebral hypoperfusion, which is the new proposed mechanism for this type of headache, including reversible cerebral vasoconstric- tion and possible sympathetic hyperfunction through activation of cardiac sympathetic a erents during myocardial ischaemia, which can increase the sympathetic out ow through cardiac sympa- thetic nerve re exes, as well as abnormal hypothalamic functional connectivity (116).

Headache attributed to other disorder of homoeostasis

Headache attributed to another disorder of homoeostasis (Box 40.19) is caused by any disorder of homoeostasis not described thus far. Although relationships between headache and a variety of systemic and metabolic diseases have been proposed, systematic evaluation of these relationships has not been performed and there is insu cient evidence on which to build operational diagnostic criteria (5).

Headache attributed to systemic infection

Headache attributed to systemic infection is a secondary type of headache disorder, which occurs for the rst time in close temporal relation to an infection (11). Other terms used include fever-related headache, headache caused by microorganisms, toxaemic headache,

septicaemic headache, or headache as part of the infectious dis- ease syndrome (117). It is usually the consequence of active infec- tion, resolving within 3 months of eradication of the infection (11). Depending on the pathogenic agent, the infection may not be able to be e ectively eradicated and as long as the infection remains ac- tive the headache may not resolve. Rarely, the infection resolves or is eradicated, but the headache may last longer than 3 months, which is termed persistent or chronic headache attributed to the infection (11).

Headache of variable duration caused by systemic infection, is re- ported without speci c descriptive features and is usually accom- panied by other symptoms and/or clinical signs of the infection as part of the ‘infectious disease syndrome’ that includes fever, chills, malaise, myalgia, arthralgia, and asthenia (118).

Box 40.20 describes the diagnostic criteria for headaches attrib- uted to systemic infection based on the ICHD-3. ese headaches must have an appropriate temporal association with the non- cephalic infection. Headaches associated with systemic infections have a varied presentation: (i) mild headache accompanied by mal- aise, fever, and other systemic infections, (ii) prominent headache, or (iii) headache due to intracranial infection like meningitis or en- cephalitis (119). According to ICHD-3, if a headache occurs with systemic infection in the presence of meningitis or encephalitis it is coded as a subtype of ‘9.1 Headache attributed to intracranial infec- tion’ (see also Chapter 41) (5).

Headaches attributed to systemic infection generally have non- speci c characteristics and are o en described as bilateral and di use, but occipital, fronto-temporal, or distinctive retro-ocular pain in cer- tain cases can occur with variable intensity (118). Headaches related to infection can be throbbing or steady, and can be worsened by head movement or any Valsalva manoeuvre. e headaches may be asso- ciated with symptoms such as photophobia, phonophobia, conjunc- tival injection, neck guarding, nausea, and vomiting. e pain may be acute (< 3 months duration) or chronic/persistent (> 3 months’ dur- ation), occurring beyond the active infection. ere are a number of studies, which reported that non-cephalitic infections can trigger or worsen primary headache disorders such as migraine, tension-type (120), and cluster headache (121) in susceptible individuals.

Box 40.20 Headache attributed to systemic infection

. A Headache of any duration ful lling criterion C.

. B Both of the following:

. 1 Systemic bacterial infection has been diagnosed

. 2 No evidence of meningitic or meningoencephalitic involvement.

. C Evidence of causation demonstrated by at least two of the following:

. 1 Headache has developed in temporal relation to onset of the systemic bacterial infection

. 2 Headache has signi cantly worsened in parallel with worsening of the systemic bacterial infection

. 3 Headache has signi cantly improved or resolved in parallel with improvement in or resolution of the systemic bacterial infection

. 4 Headache has either or both of the following characteristics: (a) Diffuse pain
(b) Moderate or severe intensity.

. D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Box 40.19 Headache attributed to other disorder of homoeostasis

. A Any headache ful lling criterion C.

. B A disorder of homoeostasis other than those described above, and
known to be able to cause headache, has been diagnosed.

. C Evidence of causation demonstrated by at least one of the following:

. 1 Headache has developed in temporal relation to the onset of the
disorder of homoeostasis

. 2 Headache has signi cantly worsened in parallel with worsening
of the disorder of homoeostasis

. 3 Headache has signi cantly improved or resolved in parallel with
improvement in or resolution of the disorder of homoeostasis.

. D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

CHAPTER 40 Headache associated with systemic infection, intoxication, or metabolic derangement

When other neurological symptoms develop, direct involvement of cerebral structures (e.g. meningitis, encephalitis, brain abscess) should be suspected. In these cases, it is crucial to distinguish be- tween headache attributed to a systemic infection and headache as- sociated with intracranial infection. It is therefore necessary to do a cerebrospinal uid examination to exclude intracranial infection in cases with high index of suspicion or particularly ill patients, particularly in the presence of neurological symptoms, including meningismus, focal neurological de cits, seizures, and altered level of consciousness (117).

Epidemiology

e incidence of headache associated with any one infectious dis- ease is generally unpredictable with wide variation in reported rates. Little is known of the exact prevalence of this type of headache as the epidemiology of systemic infections that cause this type of headache vary widely, depending on the season, geographical location, and individual patterns of the disease. In addition, there is signi cant variability, as well in the propensity, of systemic infections to cause headache.

Aetiology

Headache is a common symptom in systemic infections, including bacterial infections (‘9.2.1 Brucellosis, leptospirosis, rickettsia, le- gionella, and mycoplasma’) or viral infections (‘9.2.2 In uenza, adenovirus, dengue virus, West Nile virus) in the absence of menin- gitis or meningoencephalitis.

Headache may accompany sepsis as a part of septic encephalop- athy (122). In bacterial infections due to Rickettsiae, Ehrlichia canis, Mediterranean spotted fever, Rocky Mountain spotted fever, and Q fever, headache occurs in a high percentage (up to 90%) of pa- tients and closely parallels fever, with severe headache occurring with high temperature (123–125). In Legionella pneumophila and Mycoplasma pneumoniae infection, headache co-exists with fever, fatigue, arthralgia, myalgia, cough, and breathlessness (48,126). In leptospirosis, which also presents with severe kidney and liver dis- ease, and occasionally meningeal involvement, headache occurs in 97% of cases (127). ere are a number of diseases in which head- ache is less common than fever. In brucellosis, headache (128) is pre- sent in 23% of cases, much lower than the incidence of fever (91%) (129). Similarly, headache incidence is reported at < 10% in typhoid fever (130).

Systemic viral infections like in uenza are accompanied by head- ache co-existing with fever, with an incidence ranging from 68% to 100% (131). A distinctive retro-orbital pain has been described in 26% of patients (132). In a case series of epidemic adenovirus in- fection, headache had an incidence of 83% with associated con- junctival injection of 51% (133). Retro-orbital pain, photophobia, nausea, abdominal pain, vomiting, skin rash, and severe headache (76–97%) have been reported in dengue fever (134–136). Among the viral illnesses, herpes simplex virus (HSV) and Epstein–Barr virus (EBV) seem particularly related to the occurrence of delayed or recurrent headaches. For example, chronic headache is the prom- inent symptom of HSV-induced chronic fatigue syndrome (137). Moreover, an increased frequency of EBV excretion has been found in patients with daily persistent headache (138) so that some authors

recommended searching for EBV infection in patients with what new daily persistent headache (138).

Headaches attributed to infections may accompany a hetero- geneous group of other systemic infections (9.2.3 in ICHD-3) frequently seen in immunosuppressed patients or in speci c geo- graphical areas, including systemic fungal infection, or infestation by protozoa or other parasites. e most common fungal infec- tions associated with headache are due to pathogenic fungi like Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis, as well as the opportunistic fungi like Candida species, Aspergillus species, and others. Among protozoa, infestations due to Pneumocystis carinii and Toxoplasma gondii were found to be as- sociated with headache. Headache has also been reported with the nematode Strongyloides stercoralis (5). In the acute stage of malaria, fever has been found in 94% of patients and in 33.5% severe head- ache (139). During the acute stages of borreliosis, headache associ- ated with erythema and fever has been reported in 88% of patients (140). Chronic headache (3 months) was found in 73–75% of pa- tients with trypanosomiasis without any co-existing fever (141).

Pathophysiology

ere is limited literature about the pathogenesis of headache due to systemic infection and the exact nature of these mechanisms remains unclear. However, several mechanisms causing headache associated with non-cephalic infection have been postulated, including direct (dependent on intrinsic characteristics of microorganisms) or indirect (depends on mechanisms induced by fever), or a combination of both.

In the direct mechanism, several cells are likely to be involved (ac- tivated microglia and monocytic macrophages, activated astrocytes, and blood–brain barrier and endothelial cells), as well as several immunoin ammatory mediators (cytokines, glutamate, COX-2/ PGE-2 system, NO–inducible nitric oxide synthase system and re- active oxygen species system) (5,118). Some infective agents may invade brainstem nuclei such as locus coeruleus, trigeminal nuclei, and raphe nuclei to release substances that cause headache or endo- toxins, which may activate in ammatory and nociceptive mediators (i.e. NO, prostaglandins, and cytokines), which play a role in gen- eration of headache where the release of toxins or the toxic proper- ties of cellular fragments activate headache mechanisms (142,143). Some studies reported that microorganism infected cells, particu- larly activated macrophages, release interleukin (IL), and interferon (IFN)-γ, which act as pyrogens, mediate in ammatory responses, and directly induce headache (118,144).

Indirect theory, however, postulates that the headache occurring due to systemic infection may be secondary to fever. In systemic infections, headache commonly co-exists with fever; however, headache can also occur in the absence of fever. Fever can be stimulated exogenously by pyrogens, such as in ammatory medi- ators and toxins, or directly, by microorganisms or fragments of microorganisms. Endogenous pyrogens release additional pyro- gens from stimulated leukocytes or induce IL-1 and IFN-γ, which also induce headache. Pyrogens also induce increased arachi- donic acid metabolites such as the COX-derived prostaglandins, prostacyclin, and thromboxane. PGE-2 has vasoactive properties and could be indirectly implicated in any vascular component of headache (145). Headache can be secondary to either increase or decrease in cerebral blood ow, most commonly the former

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produced by high pCO2. Hypotension due to shock can induce a decrease in cerebral blood ow and sometimes account for head- ache (118). However, the great variability in their propensity for causing headache indicates that systemic infections do not have this e ect simply through fever and exogenous or endogenous pyrogens, which indicates that under di erent circumstances the pain may have di erent mechanisms (5).

Treatment

Management of this type of headache includes speci c treatment directed to the underlying infection (if possible). Other recom- mendations include treatment of fever with antipyretics and treat- ment of associated in ammation with NSAIDs. Headache-speci c therapy is also recommended for those patients who are predisposed to primary headache disorders and who develop systemic infection- induced migraine or cluster headaches (117).

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CHAPTER 40 Headache associated with systemic infection, intoxication, or metabolic derangement

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383

Headache associated with intracranial infection Matthijs C. Brouwer and Jonathan P. Gladstone

Introduction

Headache is a common presenting symptom in patients with intra- cranial infections and may be the only symptom (1–3). A wide range of neurological infections, both acute and chronic, can be included in the di erential diagnosis of headache, although only a minority of headache patients will eventually be diagnosed with a neuro- logical infection (4). In patients that have experienced an intracra- nial infection, persisting headache occurs, although the incidence of headache in these patients may not exceed that of the general popu- lation (5,6). Within the International Classi cation of Headache Disorders, third edition (2018; ICHD-3), headache due to intra- cranial infections is described in Part 2 (Secondary Headaches), Chapter 9.1 (7). In the classi cation, a distinction is made between acute, chronic, and persisting headache associated with intracranial infections (7). In clinical practice, when patients suspected of having an acute intracranial infection present, the focus of attention will be on diagnosing the neurological infection and subsequent treat- ment (8). is also holds true for patients with chronic meningitis, which o en poses a diagnostic challenge and not only includes in- fection due to viruses, bacteria, fungi, yeast, and parasites, but also autoimmune and in ammatory conditions such as sarcoidosis (9). Classi cation and treatment of headache in these patients will o en not be the primary concern of the physician. In contrast, in patients with persisting headache following intracranial infection the di er- ential diagnosis may include other headache syndromes, such as mi- graine or tension-type headache (5). In this chapter we will discuss the epidemiology, diagnosis, and treatment of headache associated with intracranial infections.

Bacterial meningitis

Epidemiology

e incidence of acute bacterial meningitis is 1.4–2.6 per 100,000 persons per year in high-income countries, and may be 100-fold higher in poor-resource settings with high rates of human immuno- de ciency virus (HIV) infection and meningitis epidemics (10–12).

e epidemiology of bacterial meningitis varies with geographical region, age, HIV infection rate, and other causes of immunosup- pression, and with the availability of vaccines (13).

e introduction of conjugate vaccines against Haemophilus in uenzae type B, Streptococcus pneumoniae and Neisseria meningitidis has changed the epidemiology of bacterial menin- gitis over the past two decades (13). e rst widely used conju- gate vaccine against H. in uenzae type b (Hib) has led to a virtual elimination of Hib meningitis in higher-income countries (11,13). Currently, the Hib vaccine had been introduced in 184 countries, but only reaches 50% of children worldwide (14). e introduc- tion of conjugate vaccines against seven serotypes of S. pneumoniae that are among the most prevalent in children aged 6 months– 2 years has reduced the rate of invasive pneumococcal infections in young children and in older persons by 25% (13,15). However, a 61% increase in pneumococcal serotypes not included in this vaccine was shown, suggesting serotype replacement and empha- sizing the need for continuing surveillance and the development of new vaccines with wider coverage (10). In recent years, 10- and 13-valent pneumococcal vaccines have been introduced, providing higher coverage (13,16). e incidence of meningococcal menin- gitis varies over time, per serogroup and geographical location, even in the absence of vaccination programmes (13). Major epi- demics of meningococcal meningitis with incidence rates of 1% of the population occurred in the so-called ‘meningitis belt’, a region of sub-Saharan African countries (17,18). Serogroups B, C, and Y predominantly cause sporadic meningitis in high-income countries (19,20). Introduction of the conjugate meningococcal group C vac- cine has led to a decrease in meningococcal meningitis serogroup C incidence by more than 90% (13). Owing to the implementation of these vaccine strategies, the incidence of bacterial meningitis in chil- dren has sharply decreased, and bacterial meningitis has become a disease primarily occurring in adults, caused by S. pneumoniae and N. meningitidis in 85% of cases (1,21). Less common causes of bac- terial meningitis such as Listeria monocytogenes or Staphylococcus aureus are o en related to speci c comorbid conditions, such as cancer, immunocompromised state, old age, or endocarditis (Table 41.1) (22,23).

CHAPTER 41 Headache associated with intracranial infection Table 41.1 Causative microorganisms of adult bacterial meningitis and clinical characteristics.

Microorganism

Frequency (%)

Mean age (years)

Risk factors

Headache on presentation (%)

Mortality (%)

Streptococcus pneumoniae (50)

Otitis, sinusitis, pneumonia

Neisseria meningitides (19)

–

Listeria monocytogenes (23)

Age > 50 years, cancer, immunocompromised

Haemophilus in uenza (70)

Otitis

100

Staphylococcus aureus (22,71)

Endocarditis, pneumonia

Clinical characteristics and headache prevalence

e classic symptoms and signs of bacterial meningitis are neck sti ness, fever, and impaired consciousness (1). e presence of this classic triad is, however, low and identi ed in less than half of children and adults with proven bacterial meningitis (1,24). Headache is a common symptom of bacterial meningitis, which is found in approximately 90% of adults and 75% of children over 5 years of age with bacterial meningitis (1,24). In a retrospective study analysing the sequence and development of signs and symp- toms before hospital admission in meningococcal disease in 448 children and adolescents, it was found that headache was the ini- tial symptom in 94% of patients over 5 years of age old (25). In this study, characteristic symptoms of meningococcal meningitis of rash, neck sti ness, and impaired consciousness did not develop until late in the prehospital illness. Owing to the low speci city of headache for the diagnosis of bacterial meningitis, it is, however, of little use in the diagnostic work-up. When headache was added to the classic triad of symptoms, 95% of patient had a least two out of four symptoms of headache, neck sti ness, fever, and an altered mental status (1). e speci city of these ndings is probably also low, and especially in childhood bacterial meningitis and in elderly patients the typical ndings on the clinical history and physical examination may be absent (26). Studies have been performed to

assess whether a sudden increase in headache provoked by hori- zontal rotation of the head 2–3 times per second, described as ‘jolt accentuation’, could be used detect cerebrospinal uid (CSF) pleo- cytosis (27). Although the initial study showed a high sensitivity, subsequent studies showed that the test performed very poorly (28,29). Other symptoms and clinical tests, such as neck sti ness, and Kernig and Brudzinski signs also have poor diagnostic ac- curacy (8). erefore, in patients with suspected bacterial menin- gitis, a lumbar puncture should always be performed to con rm or rule out the diagnosis.

Headache characteristics

In patients with bacterial meningitis headache may have a sudden onset (30), but in most patients it develops gradually and may ini- tially be localized at a co-existing ear or sinus infection. Because of the sudden onset in some patients, the patient may initially be suspected as having a subarachnoid haemorrhage (SAH), espe- cially if fever is absent (30). Initial cranial imaging in bacterial meningitis may also put the physician on the wrong track, as pus in the CSF may show up as a so-called ‘pseudo-SAH’ on CT (Figure 41.1) (31,32).

Qualitative studies have not been performed that address characteristics of headache in patients with bacterial meningitis

Figure 41.1 Cranial computed tomography showing a hyperdense aspect of the subarachnoid space caused by a high protein and leukocyte content of the cerebrospinal uid, mimicking the radiological image of a subarachnoid haemorrhage (SAH), which is referred to pseudo-SAH.

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Box 41.1 Diagnostic criteria for headache attributed to bacterial meningitis or meningoencephalitis

. A Headache of any duration ful lling criterion C.

. B Bacterial meningitis or meningoencephalitis has been diagnosed.

. C Evidence of causation demonstrated by at least two of the following:

. 1 Headache has developed in temporal relation to the onset of the bacterial meningitis or meningoencephalitis

. 2 Headache has signi cantly worsened in parallel with worsening of the bacterial meningitis or meningoencephalitis

. 3 Headache has signi cantly improved in parallel with improve- ment in the bacterial meningitis or meningoencephalitis

. 4 Headache is either or both of the following:
(a) Holocranial
(b) Located in the nuchal area and associated with neck stiffness.

. D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

during the acute phase. e characteristics attributed to headache in bacterial meningitis are that it is generalized, severe, and unre- mitting (33). Following the diagnostic criteria for headache attrib- uted to bacterial meningitis according to the ICHD-3 (Box 41.1), the diagnosis of headache in bacterial meningitis can be made when there is a diagnosis of bacterial meningitis and a clear tem- poral relationship between development and resolution of bac- terial meningitis and headache (7). Furthermore, the headache should be generalized or located in the neck and associated with neck sti ness. In general, these criteria are not likely to be used to establish the diagnosis of headache in patients with bacterial meningitis, given the obviousness of the diagnosis of headache in bacterial meningitis patients. Furthermore, the criteria only fa- cilitate a retrospective diagnosis as a temporal relation must be present when the diagnosis is made (Box 41.1). It is unclear why the holocranial or nuchal area location of the headache (Box 41.1) is included as a criterion, given the lack of studies on headache quality in patients with bacterial meningitis.

Several factors can contribute to the development of headache in patients with bacterial meningitis. Firstly, the majority of pa- tients with bacterial meningitis have an elevated intracranial pres- sure. In a large prospective cohort study the mean intracranial pressure in patients with bacterial meningitis was 370 mm H2O (normal upper limit 200 mm) (1). Controversies exist about the clinical e cacy of lowering intracranial pressure, either by place- ment of CSF catheters, or the use of osmotherapy by means of gly- cerol or mannitol (34–37). So far, no clear bene t has been shown on mortality or the development of neurological sequelae (37). In these studies, duration or severity of headache has not been evaluated as outcome parameter. A second cause of headache in patients with bacterial meningitis may be the direct stimula- tion of meningeal nociceptors by bacterial products, mediators of in ammation, and reactive oxygen species (33). Furthermore, a range of complications of bacterial meningitis may cause or ag- gravate headache, including hydrocephalus, subdural empyema, cerebral abscess, cerebral infarctions, and cerebral haemorrhages, which have been described to occur in 2–25% of patients (38– 42). Some of these complications require urgent neurosurgical intervention and therefore a sudden increase in headache during

treatment for bacterial meningitis should prompt cranial imaging to detect these conditions.

Diagnosis and treatment

Rapid diagnosis and treatment of bacterial meningitis reduces mortality and neurological sequelae (8). When bacterial menin- gitis is suspected, CSF examination is of the utmost importance to confirm the diagnosis and rationalize antibiotic treatment. In selected patients with risk factors for space-occupying le- sions cranial imaging is indicated before the lumbar puncture is performed to assess whether this can be done safely (8,43). Cranial imaging, however, has been identified as an import source of delay in administration of antibiotics, resulting in in- creased mortality and morbidity (44,45). Therefore, treatment with antibiotics and adjunctive dexamethasone should be initi- ated before the patients goes to the scanner when cranial imaging is indicated. Characteristic CSF findings in acute community- acquired bacterial meningitis are polymorphonuclear pleocy- tosis, hypoglycorrhachia, and raised CSF protein concentrations (1). CSF culture is the gold standard for diagnosis of bacterial meningitis and is positive in 80–90% of cases before treatment has started (8). Polymerase chain reaction (PCR) may be useful to identify the causative bacteria in culture negative cases, es- pecially in patients that received antibiotic treatment before the lumbar puncture was performed (8,11).

Empirical antimicrobial treatment for bacterial meningitis de- pends on local epidemiology, patient’s age, and resistance rates (46). If resistance rates are low, a third-generation cephalosporin combined with amoxicillin/ampicillin su ces, otherwise vanco- mycin has to be added to this regimen (46). Adjunctive dexa- methasone was shown to be bene cial in children and adults in high-income countries in the most recent Cochrane systematic review and meta-analysis including 25 trials involving 4121 par- ticipants (47). erefore, adjunctive dexamethasone is currently advised in all adults and children with suspected bacterial menin- gitis in high-income countries. In resource-poor settings no bene t of dexamethasone was observed (47). Other adjunctive treatments such as therapeutic hypothermia, acetaminophen, and glycerol have been tested in randomized clinical trials but either showed no e ect (acetaminophen) or caused excess mortality (hypothermia, glycerol) (48,49).

Speci c treatment of headache in patients with bacterial men- ingitis has not been studied. In general, treatment with analgesics and antipyretics will be started upon admission to relieve headache symptoms.

Outcome and postbacterial meningitis headache

Individual predictors of outcome in patients with bacterial menin- gitis are the patient’s age, level of consciousness on admission, the causative microorganism, CSF white blood cell count, and signs of septic shock (1). Mortality rates vary per causative microorganism and are approximately 20% in pneumococcal meningitis, 5% in meningococcal meningitis, and 35% in L. monocytogenes men- ingitis (19,23,50). Up to half of patients experience neurological sequelae, especially in pneumococcal meningitis, which may consist of focal neurological abnormalities, neuropsychological defects, and hearing loss (1,51,52).

Box 41.2 Diagnostic criteria for chronic headache attributed to bacterial meningitis or meningoencephalitis

. A Headache ful lling criteria for ‘9.1.1 Headache attributed to bacterial meningitis or meningoencephalitis’, and criterion C below.

. B Bacterial meningitis or meningoencephalitis remains active or has resolved within the last 3 months.

. C Headache has been present for > 3 months.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1-211. © International Headache Society 2018.

Headache a er bacterial meningitis is classi ed by the ICHD-3 in two separate categories, which di er in whether the bacterial men- ingitis needs to be resolved or do not ful l the criteria (Boxes 41.2 and 41.3) (7).

e frequency of headache a er experiencing bacterial menin- gitis has been studied in one retrospective and one longitudinal study (5,6). In the retrospective study, 70 of 141 (50%) identi ed patients (17 bacterial meningitis, 53 viral meningitis) lled out questionnaires concerning headache following the disease episode (5). Controls were hospital visitors without neurological disease. e frequency of headache in this population was 26% prior to meningitis and 43% a er meningitis versus 28% in the control group. However, the retrospective design, choice of controls, and probable selection bias limit the interpretation of these results. e second study presented incidence data from the Nord-Trøndelag Health Survey (HUNT 3), a large, longitudinal, population-based study on headache inci- dence (6). In this study 43 patients with prior intracranial infections, mostly bacterial and viral meningitis, were interviewed an average of 11.2 years a er the infection. Any type of headache was present in 18 of 43 patients (42%) versus 14,202 of 39,647 (36%) controls, which was not signi cantly di erent (odds ratio 1.10, 95% con dence interval 0.58–2.07) (6). When speci ed for migraine or tension-type headache, no di erence was identi ed. Interestingly, the frequency of headache in this population was similar to that in the retrospective study. Treatment of persistent or chronic headache following bac- terial meningitis has not been studied, but it is reasonable to base the treatment on headache characteristics: if the headache has a tension- type headache quality, it should be treated accordingly.

Viral meningitis

Viruses are thought to be the major cause of the aseptic meningitis syndrome, a term that is used to de ne any meningitis for which

a cause is not apparent a er initial evaluation. Aseptic meningitis is been characterized as a self-limiting disease with u-like symp- toms, including headache, fever, and general malaise. e majority of patients (70%) presenting with a CSF pleocytosis (> 5 cells/mm3) were eventually diagnosed as having aseptic meningitis, and in only a small proportion of these patients was a virus detected (4). Enteroviruses are the most commonly identi ed cause of viral men- ingitis, found in 3% of this population.

e diagnosis of viral meningitis is made in the presence of CSF pleocytosis, with no indication of bacterial, mycobacterial, fungal, or other speci c cause of meningitis. Several clinical prediction rules have been designed to rule out bacterial meningitis by use of clinical characteristics, serum markers of in ammation (C-reactive protein and procalcitonin), and CSF parameters of in ammation (4,8). Although most of these rules have good test characteristics, they are o en not validated in independent cohorts and include low numbers of patients with bacterial meningitis, limiting the clinical usefulness. erefore, most of the patients who eventually are diag- nosed with viral meningitis will be admitted for observation until clinical recovery has set in and CSF cultures are negative (8). An im- portant di erential diagnosis in patients with viral meningitis and headache is the syndrome of transient headache and neurological de cits with CSF lymphocytosis (HaNDL—see also Chapter 44). Both are diagnoses of exclusion and will present with lymphocytic meningitis (53). As HaNDL may also be accompanied by fever, the distinction may be impossible.

No studies have been performed that assess the quality of head- ache in viral meningitis, but, in general, it is considered to be similar to that in bacterial meningitis (54). ICHD-3 criteria for diagnosing headache in patients with viral meningitis are similar to those in bacterial meningitis and the diagnosis requires a clear temporal rela- tionship between established viral meningitis and headache, which should be holocranial or located in the nuchal area and associated with neck sti ness (Box 41.4) (7).

To speci cally allocate the headache to viral meningitis neuroimaging is required to show enhancement of leptomeninges (Box 41.5) (7). In clinical practice, the diagnosis of viral meningitis is not based on neuroimaging and leptomeningeal enhancement may be absent.

CHAPTER 41 Headache associated with intracranial infection

Box 41.4 Diagnostic criteria for headache attributed to viral meningitis or encephalitis

. A Any headache ful lling criterion C.

. B Viral meningitis or encephalitis has been diagnosed.

. C Evidence of causation demonstrated by at least two of the following:

. 1 Headache has developed in temporal relation to the onset of the viral meningitis or encephalitis

. 2 Headache has signi cantly worsened in parallel with worsening of the viral meningitis or encephalitis

. 3 Headache has signi cantly improved in parallel with improve- ment in the viral meningitis or encephalitis

. 4 Headache is either or both of the following:
(a) Holocranial
(b) Located in the nuchal area and associated with neck stiffness.

. D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Box 41.3 Diagnostic criteria for persistent headache attributed to past bacterial meningitis or meningoencephalitis

. A Headache ful lling criteria for ‘9.1.1 Headache attributed to bacterial meningitis or meningoencephalitis’, and criterion C below.

. B Bacterial meningitis or meningoencephalitis has resolved.

. C Headache has persisted for > 3 months after resolution of the bac-
terial meningitis or meningoencephalitis.

. D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

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Box 41.5 Diagnostic criteria for headache attributed to viral meningitis

. A Headache ful lling criteria for ‘9.1.2 Headache’ attributed to viral meningitis or encephalitis’.

. B Neuroimaging shows enhancement of the leptomeninges exclusively.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Box 41.7 Headache attributed to localized brain infection

. A Any headache ful lling criterion C.

. B A localized brain infection has been demonstrated by neuroimaging
and/or specimen analysis.

. C Evidence of causation demonstrated by at least two of the following:

. 1 Headache has developed in temporal relation to development of the localized brain infection, or led to its discovery

. 2 Headachehassigni cantlyworsenedinparallelwithdeterioration of the localized brain infection shown by either of the following:

. (a) Worsening of other symptoms and/or clinical signs arising
from the localized brain infection

. (b) Evidence of enlargement (or rupture, in the case of brain ab-
scess) of the localized brain infection

. 3 Headache has signi cantly improved in parallel with improve-
ment in the localized brain infection

. 4 Headache has at least one of the following characteristics:

. (a) Intensity increasing gradually, over several hours or days, to moderate or severe

. (b) Aggravated by straining or other Valsalva manoeuvre

. (c) Accompanied by fever, nausea, and/or vomiting

. (d) Unilateral, and ipsilateral to the localized brain infection.

. D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Treatment of headache attributed to viral meningitis is symptom- atic with analgesics and antipyretics, and symptoms are expected to wane in a matter of days. Chronic and residual headache due to viral meningitis has not been systematically described, but is not ex- pected to be above that of the normal population.

Viral encephalitis

In contrast to viral meningitis, viral encephalitis is a severe infection with high mortality (2,55). Key symptoms of viral encephalitis are fever, headache, and altered mental status. Furthermore, seizures and focal neurological de cits are commonly present. Headache has been reported on admission in 50–75% of patients with viral meningitis (2), but the quality and severity of the headache has not been studied. In patients with suspected viral encephalitis, the di erential diagnosis is o en broad, including other infectious diseases such as tuberculous meningitis or bacterial meningitis, and several autoimmune diseases (e.g. acute disseminated encephalomyelitis, paraneoplastic meningitis) (2,55). e most common causes of viral encephalitis include herpes simplex virus, Japanese encephalitis virus, varicella zoster virus, tick- borne encephalitis virus, and West Nile virus, although the epidemi- ology is highly variable, depending on the region. Diagnostic work-up for patients with suspected meningitis include cranial magnetic reson- ance imaging (MRI), CSF examination, including PCR for neurotropic viruses, and sometimes electroencephalography (56). Whenever viral encephalitis is suspected, immediate treatment with antiviral therapy is warranted (Box 41.6).

Cerebral abscess

Brain abscess is a focal intracerebral infection consisting of an en- capsulated collection of pus cause by bacteria, mycobacteria, fungi,

protozoa, or helminths (57,58). e incidence of bacterial brain abscess is 0.4–0.9 per 100,000 per year, and is thought to be con- siderably higher in patients with speci c risk factors, such as HIV infection, or recipients of a solid organ transplant (59–61). A meta- analysis of clinical characteristics, treatment, and outcomes of brain abscess patients, including 9699 patients from 123 studies, showed that the most common presenting symptom was headache, which was present in 69% of patients (62). Headache in patients with brain abscess is thought to be caused by the raised intracra- nial pressure, which is accompanied by nausea and/or vomiting in 47% of cases and 35% of patients have papilloedema (62). Nausea and/or vomiting are also included as a criterion contributing to the ICHD-3 diagnosis of headache attributed to cerebral abscesses (Box 41.7). Furthermore, a temporal relationship between the documented abscess and the headache is an important criterion for the diagnosis. Headache may suddenly worsen in patients with rup- ture of the abscess into a ventricle, leading to ventriculitis and acute hydrocephalus (62). is requires immediate cranial imaging and o en necessitates placement of an external CSF catheter to treat the hydrocephalus and, when indicated, facilitate intraventricular anti- biotic treatment (63).

In patients with cerebral abscess it is important to identify and treat any underlying focus of infectious, which is continuous with the abscess in ~50% of patients (e.g. sinus, mastoid, trauma, neurosur- gery) and haematogenous in 35% (heart, lung) (62). Identi cation of a primary focus of infection may also reveal the causative bacterium. However, in a substantial number of patients with brain abscess, ab- scess aspiration is required to acquire the pathogen, and will simul- taneously reduce the size of the abscess (62). Treatment consists of intravenous antibiotic therapy for 6 weeks or more, depending on clinical condition of the patients and radiological characteristics of the abscess.

Box 41.6 Diagnostic criteria for headache attributed to viral encephalitis

. A Headache ful lling criteria for ‘9.1.2 Headache attributed to viral meningitis or encephalitis’.

. B Either or both of the following:
1 Neuroimaging shows diffuse or multifocal brain oedema 2 At least one of the following:
(a) Altered mental status
(b) Focal neurological de cits (c) Seizures.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Subdural empyema

Subdural empyema is a collection of pus in the subarachnoidal space (between the dura mater and arachnoidea), which is o en associated with ear, mastoid, or sinus infection (39,64). Clinical characteris- tics consist of headache, fever, and altered mental status (64). It is important to realize that cerebral venous thrombosis may co-exist in patients with mastoiditis and empyema, and provide an alternate explanation for the headache.

Headache attributed to subdural empyema has similar ICHD- 3 criteria as headache in patients with brain abscess consisting of a diagnosis of subdural empyema, and evidence of a causal rela- tion between the development of the empyema and the headache. Treatment of subdural empyema consists of antibiotic therapy for 6 weeks or more and neurosurgical removal of the empyema depending on the size of the empyema, clinical condition of the pa- tient, and degree of midline shi .

Tuberculous meningitis

Meningitis due to tuberculosis is an important problem world- wide, with the heaviest burden of disease in Africa and South East Asia. Between 50% and 80% of patients have headache on presen- tation, with fever, anorexia, and vomiting being the other key clin- ical characteristics (65). e headache is caused by a combination of factors: patients not only o en have raised intracranial pressure, but also the in ammatory response leading to meningeal irritation contributes to the headache. Complications of tuberculous men- ingitis consist of hydrocephalus, cerebral infarctions, and cerebral tuberculomas, which can all result in headache. A de nite diagnosis of tuberculous meningitis is made by positive CSF Ziehl–Neelsen staining, Mycobacterium tuberculosis PCR, or culture, while a prob- able diagnosis can be made based on the pattern of CSF abnormalities in combination with pulmonary or extrapulmonary tuberculosis (66). Treatment consists of a combination of antituberculosis drugs and dexamethasone, and must be continued for at least 6 months. Despite adequate treatment, mortality is still high (~50%) (67).

Headache in HIV-positive patients

Headache is a common symptom in HIV-positive patients (33,70). A 2012 cross-sectional study from the USA showed that 107 of 200 HIV-positive patients (54%) experienced headache, of which most met the ICHD-2 criteria for migraine (n = 88; 85%) and tension- type headache (n = 15; 15%) (68). Only a minority (n = 4; 2%) had secondary headache. In this study and others the prevalence of headache was proportional to the degree of immunocompromise (33,68). Newly developed headache related to the HIV infection can be caused by the primary HIV infection, or can be secondary to op- portunistic infection. Headache in patients with a recent HIV sero- conversion can be due to HIV meningitis, which occurs in 1–2% of patients (33). e most common secondary causes of headache in HIV-positive patients are cerebral toxoplasmosis, cryptococcal meningitis, central nervous system lymphoma, tuberculous menin- gitis, and progressive multifocal encephalopathy. In most of these

disorders headache is one of the symptoms, and focal neurological de cits, cognitive slowing, or altered mental status will also occur. e exception to this is cryptococcal meningitis, in which headache is a prominent symptom, present in 99% of patients, and can be ac- companied by vomiting, papilloedema and loss of vision (69). e ICHD-3 criteria for headache in cryptococcal meningitis and men- ingitis due to other fungi and parasites are presented in Box 41.8.

ere is considerable variability in the location, quality, severity, and presence of associated symptoms in headache attributable to primary HIV-1 infection and headaches secondary to opportun- istic infections, making the diagnosis of headache in HIV-infected patients di cult (33). e work-up for HIV-positive patients with headache depends on their immune status: if the CD4 count is > 200 cells/μl, the patient can be considered to have a low risk for op- portunistic infections and primary headache may be the more likely diagnosis. In patients with a low CD4 count, a cranial MRI is indi- cated to identify opportunistic infections, followed by CSF examin- ation when no abnormalities are shown on MRI.

CHAPTER 41 Headache associated with intracranial infection

Box 41.8 Headache attributed to intracranial fungal or other parasitic infection

. A Any headache ful lling criterion C.

. B Intracranial fungal or other parasitic infection has been diagnosed.

. C Evidence of causation demonstrated by at least two of the following:

. 1 Headache has developed in temporal relation to the onset the intracranial fungal or other parasitic infection

. 2 Headache has signi cantly worsened in parallel with worsening of the intracranial fungal or other parasitic infection

. 3 Headache has signi cantly improved in parallel with improve- ment in the intracranial fungal or other parasitic infection

. 4 Headache develops progressively, and is either or both of the following:
(a) Holocranial
(b) Located in the nuchal area and associated with neck stiffness.

. D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

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391

Remote causes of ocular pain

Deborah I. Friedman

Introduction

Ocular and periocular pain may occur with processes originating remotely from the eye, including primary headache disorders, pain originating in branches of the trigeminal nerve, and, occasionally, disorders of the upper cervical spine. e primary headaches pro- ducing periocular pain include migraine, tension-type headache, cluster headache and other trigeminal autonomic cephalgias, par- oxysmal hemicrania, and other miscellaneous headaches not as- sociated with a structural lesion. is chapter focuses on unusual primary headache disorders that manifest as eye pain, as well as secondary causes of ocular pain, including ophthalmic and or- bital conditions, in ammatory and infectious processes, cranial neuralgias, and vascular disorders.

Primary stabbing headache

Previously known as ice pick headache, jabs and jolts syndrome, ophthalmodynia periodica, and idiopathic stabbing headache, primary stabbing headache commonly a ects the ocular area and produces a sense of fear in its su erers (Box 42.1) (see also Chapter 23). ere are sudden, unprovoked paroxysms of severe pain that occur as a stab or series of stabs. Many patients have other co-existing primary headache disorders. e ophthalmic division of the trigeminal nerve is most fre- quently a ected, followed by the face or other regions of the head; the site of pain varies in individual patients, who may experience up to 50 attacks daily. ere are no autonomic or other accompanying features.

Laboratory testing

A secondary cause is uncommon, especially if the pain migrates. Giant cell arteritis (GCA) is a consideration in older adults. Imaging may be considered if the pain does not improve with treatment.

Treatment

Indomethacin is usually e ective for preventing attacks. Melatonin, gabapentin, and amitriptyline may also be helpful.

Hemicrania continua

Hemicrania continua (HC) is uncommon and the diagnosis is frequently missed, particularly if the pain is periocular (see also Chapter 21). e pain is strictly unilateral, located in the orbital or retro-orbital area in 77–83% of patients (1). Rare cases of bilateral pain have been reported. e pain may be throbbing, non-throbbing, or a combination of both. It is constantly present, with punctuated exacerbations lasting 5–60 minutes, and associated with the auto- nomic symptoms seen in HC, most frequently tearing and conjunc- tival injection (1). Migrainous features, such as nausea, vomiting, photophobia, and phonophobia may also be present during exacer- bations. Aura is rare.

Laboratory testing

In addition to neuroimaging to exclude a secondary cause, evalu- ations for GCA may be warranted in patients over 60 years of age, particularly if other manifestations of GCA are seen in the patient’s history. Responsiveness to indomethacin (150 mg daily or more, if tolerated) is required for the diagnosis.

Treatment

If indomethacin is not tolerated, topiramate, Boswellia (a genus of trees), greater occipital nerve blocks, and occipital nerve stimulation may be helpful (2).

Migraine ‘variants’: benign episodic pupillary mydriasis

A separate entity, benign episodic pupillary mydriasis, produces anisocoria that may be associated with blurred vision, head pain, photophobia, conjunctival injection or transient visual obscurations (3). e attacks last from minutes to a week, with a median duration of 12 hours. e anisocoria is generally ≤ 3 mm, and the pupil may or may not react to light. e mechanism is uncertain, but most re- ported patients are women with a history of migraine. Physiological anisocoria and benign episodic pupillary mydriasis may co-exist in the same patient.

Diagnostic testing

Unilateral mydriasis is very uncommonly a manifestation of an an- eurysm and appropriate imaging studies may be warranted for the rst event.

Primary headache disorders manifesting as eye pain

Treatment

Benign episodic pupillary mydriasis resolves spontaneously. Associated headaches are treated with migraine symptomatic therapies.

Recurrent painful ophthalmoplegic neuropathy

Cranial nerve palsies are reported in migraine, although the syn- drome known as ‘ophthalmoplegic migraine’ is no longer considered a type of migraine by the International Classi cation of Headache Disorders (ICHD) (Box 42.2). It is now termed ‘recurrent painful ophthalmoplegic neuropathy’ (RPON) and classi ed as a painful neuropathy rather than a migraine subtype (4). e aetiology and classi cation of the syndrome remain controversial. e source of debate in classi cation arises because some patients have recurrent attacks with no identi able structural abnormality, a phenotype suggesting a true migraine variant that recurs and resolves without corticosteroid treatment. Others have a structural cause or episodes that resolve only with corticosteroid treatment, suggesting that the primary process is not migraine (5).

e syndrome was originally described in children with epi- sodes of headache followed by an ocular motor palsy, o en lasting

weeks a er resolution of the headache. e oculomotor nerve is most commonly involved, although trochlear and abducens paresis may occur. e diagnostic criteria for RPON specify at least two attacks of a migraine-like headache accompanied or followed within 4 hours by paresis of one or more of the ocular motor nerves (III, IV, VI). Parasellar, orbital ssure, or posterior fossa pathology must be excluded. e headache is usually ipsilat- eral to the ocular motor cranial neuropathy, and may persist for a week or more. e ipsilateral pupil is commonly dilated in cases of oculomotor RPON.

Ophthalmoplegia may be permanent and is rarely accompanied by aberrant regeneration. e condition is rare, with an estimated incidence of 0.7 per 1,000,000 (6). Neuroimaging studies (magnetic resonance imaging (MRI) with gadolinium) frequently demonstrate thickening and enhancement of the oculomotor nerve fascicle, sug- gesting an in ammatory process (6). e enhancement may persist for months to years. Acute treatment with corticosteroids provides prompt resolution of headaches and may prevent a permanent neurological de cit. e pathophysiology of RPON is uncertain. Trigeminovascular activation with sterile in ammation and demye- lination of the oculomotor nerve at its entry from the brainstem is postulated. Other secondary causes of the RPON syndrome include an oculomotor nerve schwannoma, midbrain vascular anomaly, and carotid stenosis.

Laboratory testing

Neuroimaging in RPON rarely demonstrates a secondary cause in patients with a typical history of recurrent episodes and a normal neurological examination. Patients with new-onset headaches, headaches with a progressive course, headaches with a signi cant change in pattern, headaches that never alternate sides, and head- aches associated with ophthalmoparesis, any other neurological ndings, or seizures have a substantially higher likelihood of a sec- ondary cause such as tumour, arteriovenous malformation, or other structural lesion (7).

Treatment

RPON is generally treated with prednisone, which relieves the pain and may hasten recovery of the cranial mononeuropathy.

Trigeminal neuralgia and herpes zoster-related neuralgia

e most common of the cranial neuralgias, trigeminal neuralgia (TN) is one of the most painful conditions a ecting humans (see also Chapter 27). It may begin at any age, with 90% of patients over the age of 40 years (peak age 50–60 years) (8). Multiple sclerosis (MS) should be considered in patients under 50 years of age. e pain is in the maxillary and mandibular divisions of the face, with only 5% of cases involving the ophthalmic nerve. us, TN is an uncommon cause of periorbital or ocular pain. Typical TN pro- duces sharp, sudden, stabbing pain lasting less than a second to a few seconds, sometimes with clusters lasting up to 2 minutes (Box 42.2). Patients o en wince coincident with the excruciating pain, hence the term tic douloureux (painful spasm). ere is usually a brief refractory period and most patients identify triggers, such as tactile stimuli, eating, jaw, or tongue movement, or a thermal stimulus.

CHAPTER 42 Remote causes of ocular pain

Box 42.1 Other primary headache disorders causing ocular or periocular pain

Primary stabbing headache

. A Head pain occurring spontaneously as a single stab or series of stabs
and ful lling criteria B–D.

. B Each stab lasts for up to a few seconds.

. C Stabs recur with irregular frequency, from one to many per day.

. D No cranial autonomic symptoms.

. E Not better accounted for by another ICHD-3 disorder.

Hemicrania continua

. A Unilateral headache ful lling criteria B–D.

. B Present for > 3 months, with exacerbations or moderate or greater
intensity.

. C Either or both of the following:

At least one of the following symptoms or signs, ipsilateral to the headache:
(a) Conjunctival injection and/or lacrimation

(b) Nasal congestion and/or rhinorrhoea (c) Eyelid oedema
(d) Forehead and facial sweating
(e) Forehead and facial ushing

(f) Sensation of fullness in the ear
(g) Miosis and/or ptosis
A sense of restlessness or agitation, or aggravation of the pain by movement .

. D Responds absolutely to a therapeutic dose of indomethacin (150–225 mg PO daily in adults).

. E Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Secondary headache disorders producing ocular and periocular pain

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Box 42.2 Secondary headache disorders causing ocular or periocular pain

Recurrent painful ophthalmoplegic neuropathy

. A At least two attacks ful lling criterion B.

. B Unilateral headache accompanied by ipsilateral paresis of one, two, or
all three ocular motor nerves.

. C Orbital, parasellar, or posterior fossa lesion has been excluded by ap-
propriate investigation.

. D Not better accounted for by another ICHD-3 diagnosis.

Classical trigeminal neuralgia

. A At least three attacks of unilateral facial pain ful lling criteria B and C.

. B Occurring in one or more divisions of the trigeminal nerve, with no
radiation beyond the trigeminal distribution.

. C Pain has at least three of the following four characteristics:

. 1 Recurring in paroxysmal attacks lasting from a fraction of a second to 2 minutes

. 2 Severe intensity

. 3 Electric shock-like, shooting, stabbing, or sharp in quality

. 4 Precipitated by innocuous stimuli to the affected side of the face.

. D No clinically evident neurological de cit.

. E Not better accounted for by another ICHD-3 disorder.

Painful trigeminal neuropathy attributed to acute herpes zoster

. A Unilateral continuous or near-continuous pain in the distribution of
nervus intermedius and ful lling criterion C.

. B One or more of the following:

. 1 Herpetic eruption has occurred in the territory of nervus intermedius

. 2 Varicella zoster virus (VZV) has been detected in cerebrospinal uid by polymerase chain reaction (PCR).

. 3 Direct immuno uorescence assay for VZV antigen or PCR assay for VZV DNA is positive in cells obtained from the base of the lesions.

. C Pain developed in temporal relationship to the herpes zoster.

. D Not better accounted for by another ICHD-3 disorder.

Postherpetic trigeminal neuropathy

A Unilateral head and/or facial pain persisting or recurring for ≥ 3 months and ful lling criterion C.

B History of acute herpes zoster affecting a trigeminal nerve branch or branches.

C Evidence of causation demonstrated by both of the following:

. 1 Pain developed in temporal relationship to the acute
herpes zoster

. 2 Pain is located in the distribution of the same trigeminal branch or
branches.

D Not better accounted for by another ICHD-3 disorder.

Cervicogenic headache

. A Any headache ful lling criterion C.

. B Clinical, laboratory, and/or imaging evidence of a disorder or lesion
within the cervical spine or soft tissues of the neck, known to be able
to cause headache.

. C Evidence of causation demonstrated by at least two of the following:

. 1 Headache has developed in temporal relation to the onset of the cervical disorder or appearance of the lesion

. 2 Headache has signi cantly improved or resolved in parallel with improvement in or resolution of the cervical disorder or lesion

. 3 Cervical range of motion is reduced and headache is made signi – cantly worse by provocative manoeuvres

. 4 Headache is abolished following diagnostic blockade of a cervical structure or its nerve supply.

Trochleitis

. A Periorbital and/or frontal headache ful lling criterion C.

. B Clinical and/or imaging evidence of trochlear in ammation.

. C Evidence of causation demonstrated by at least two of the following:

. 1 Unilateral ocular pain

. 2 Headache is exacerbated by movement of the eye, particularly
downward in adduction

. 3 Headache is signi cantly improved by injection of local anaesthetic
or steroid agent into the peritrochlear region

. 4 In the case of a unilateral trochleitis, headache is ipsilateral to it.

. D Not better accounted for by another ICHD-3 disorder.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Herpes zoster is much more likely than TN to involve the oph- thalmic division. With acute infection, the pain precedes the rash by a few days in most patients, with intervals of up to 100 days being reported (9). us, the diagnosis may be delayed for some time before the rash develops. Paraesthesias and dysaesthesias in the a ected dermatome may also occur. Spontaneous pain in the acute period (within 30 days of rash onset) is described as con- stant or nearly constant shooting, stabbing, burning, or electric shock-like (Box 42.2). Similarly to TN, stimulus-evoked pain is common. Postherpetic neuralgia (PHN) persists for 120 days or more a er rash onset; remission is unlikely a er 180 days. It is the most common complication following acute zoster infection and the incidence increases with age. e pain may be dysaesthetic (spontaneous, constant, deep burning, throbbing, and aching), hyperpathic (intermittent sharp, stabbing, shooting, lancinating pain in response to a stimulus or spontaneous), or allodynic (painful response to an ordinarily non-painful stimulus that per- sists beyond the duration of the stimulus) (Box 42.2) (8). PHN pain may occur in areas where sensation is lost or impaired (an- aesthesia dolorosa).

Laboratory testing

Neuroimaging is performed to exclude a secondary cause of TN (e.g. a lesion in the posterior fossa), identify a compressive vascular loop, and look for evidence of MS in younger patients or those with bilateral TN. Zoster-related neuralgia is diagnosed by history and examination.

Treatment

Carbamazepine is the rst-line medical treatment of TN and produces pain relief in 80% of individuals immediately and in the short term. However, relief may not be sustained and many patients do not tolerate the medication. Other agents include baclofen, lamotrigine, pimozide, oxcarbazepine, topiramate, and sodium valproate. Onabotulinum toxin injections targeted at the site of pain are a safe and e cacious emerging treatment (10), with microvascular decompression, gamma knife radiosurgery, and other procedures employed in refractory cases.

Cervicogenic headache as a cause of ocular or periocular pain

Disorders of the upper cervical spine are frequently implicated as the cause of headache, although the relationship of cervical spine

disease and headache is not well validated (see also Chapter 36). ere is a physiological basis for this phenomenon, as the upper cervical neurons receive convergent inputs from trigeminal and cervical a erents, and stimulation of cervical a erents sensitizes neurons to trigeminal input in experimental animals. Cervicogenic headache is de ned as a headache caused by a disorder of the cer- vical spine and its component disc and/or so tissue elements, usually but not invariably accompanied by neck pain. It is o en pro- voked by digital pressure on the neck muscles or by head movement with posterior-to-anterior radiation of pain, sometimes a ecting the oculo-fronto-temporal regions. e pain is usually moderate in severity and non-throbbing (11). Headache attributed to upper cervical radiculopathy (C2 and C3) is usually posterior but may radiate more anteriorly (4). It is generally lancinating and may be unilateral or bilateral. e pain of occipital neuralgia may reach the fronto-orbital area.

Some investigators have emphasized suboccipital tenderness as a diagnostic hallmark for these pain syndromes (12) and others have emphasized the importance of unilateral pain that begins as neck pain for the diagnosis of cervicogenic headache (11). One of the de ning characteristics of these entities is resolution of the pain with anaesthetic blockade, which may be a confounding feature, as many di erent types of headaches improve with greater occipital nerve blocks; a potentially causative cervical lesion is o en not demon- strated. HC may have similar features.

Laboratory testing

Cervical imaging is speci ed as per ICHD-3.

Treatment

ere are no controlled trials upon which to base treatment recom- mendations. A trial of indomethacin is warranted if the symptoms suggest HC. Success has been reported with greater occipital nerve blocks, spinal blocks, and manual therapy. Percutaneous rhizotomy and ‘liberation’ surgery of the nerves provide only temporary relief.

Carotid artery dissection

Dissection of the carotid artery produces pain in the ipsilateral head, neck, face, or jaw. (see also Chapter 37). e pain is frequently lo- cated in the forehead or periocular region. e character of the pain varies, and is o en described as a constant, non-throbbing pain of gradual onset. However, some patients experience severe, throbbing pain or a thunderclap onset (13). e pain may precede the neuro- logical symptoms by hours, days, or, rarely, weeks. Manifestations include an ipsilateral Horner syndrome, transient monocular visual loss, central or branch retinal artery occlusion, ocular ischaemic syndrome and positive visual phenomena, cranial nerve palsies (III, V, VI), contralateral limb numbness or weakness, or stroke; headache with an ipsilateral Horner syndrome is considered a ca- rotid dissection until proven otherwise (13, 14). Involvement of the nerves emerging from the jugular and hypoglossal foramen pro- duce sternocleidomastoid weakness, hoarseness, dysgeusia, and hemilingual paralysis. Pulsatile tinnitus occurs in < 25% of patients and may be the only presenting symptom.

Carotid dissection may occur at any age, most frequently af- fecting individuals between 35 and 50 years of age (13). Minor direct trauma or a twisting injury to the neck may precipitate

dissection. Abnormalities of the arterial media and elastic tissue, such as Ehlers–Danlos syndrome and bromuscular dysplasia, pre- dispose to dissection but are seldom found. e major confounding diagnosis of patients with carotid artery dissection is cluster head- ache, as both conditions may present with a unilateral headache and an ipsilateral Horner syndrome. Any patient with a new onset of cluster headache symptoms lasting longer than the typical dur- ation of cluster headache (2 hours) should be evaluated for a carotid dissection.

Laboratory testing

Preferred imaging techniques are computed tomography (CT) angi- ography, magnetic resonance angiography, conventional angiog- raphy, and axial MRI with fat saturation, which demonstrates the lack of ow void, intramural blood, and mural expansion of the dis- section. Doppler imaging may also be helpful.

Treatment

Various treatments are used, although no controlled trials of med- ical or surgical therapy have been performed. Anticoagulants, antiplatelet treatment, and thrombolytic agents have been employed. Endovascular and surgical treatment are rarely indicated.

Ophthalmic and orbital causes of pain

Trochleitis and primary trochlear headache

e superior oblique tendon and its surrounding brovascular sheath pass through the trochlea, a ring-like cartilaginous structure that is innervated by the ophthalmic nerve (15). In ammation of the superior oblique tendon within the trochlea, or trochleitis, is char- acterized by local pain, swelling, and tenderness, which worsen with upward gaze in adduction. Palpation of the superiomedial aspect of the orbit provokes exquisite tenderness, and localized troch- lear swelling may be felt. e aetiology is most o en primary, al- though trochleitis may accompany rheumatoid arthritis, systemic lupus erythematosus (SLE), sarcoidosis, and other in ammatory disorders. Most o en, it is akin to a tendonitis and has been called ‘tennis elbow of the eye’.

Primary trochlear headache is distinguished from trochleitis by the absence of in ammation and its common association with other headache disorders, particularly migraine (16,17). It a ects women 90% of the time, producing pressure-like or dull pain in the troch- lear and temporoparietal regions that worsens with supraduction of the a ected eye. ere may be nocturnal awakening, but autonomic features are absent (15). Of 25 patients with trochlear headache evaluated at the Mayo Clinic, 22 had a new daily persistent headache (17), characterized as periorbital pain associated with photophobia and aggravated by reading. Five of 12 patients with trochleitis had a secondary cause.

Treatment

e treatment of both conditions is a single injection of corticoster- oids (3 mg betamethasone acetate or 0.5 ml methylprednisolone 80 mg/ml, which may be given in combination with 0.3–0.5 ml of 2% lidocaine). Relief occurs rapidly and the patient may be rendered pain-free for months or years. Forty per cent of patients in the Mayo

CHAPTER 42 Remote causes of ocular pain

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PART 6 Secondary headaches
Clinic series had complete remission a er trochlear blocks. e in-

jection may also provide relief of associated migraine pain (16).

Idiopathic orbital in ammation

Idiopathic orbital in ammation (IOI), previously termed ‘in am- matory orbital pseudotumour’, may occur at any age, presenting with acute, chronic, or recurrent symptoms and signs. Di use in amma- tory disease typically produces exophthalmos, external swelling, and conjunctival hyperaemia, whereas individuals with speci c involve- ment of the extraocular muscles may present with diplopia and limi- tation of eye movements (18). e di erential diagnosis includes infectious orbital cellulitis, neoplasms with in ammatory signs, and vascular lesions, which may produce similar manifestations. ere are granulomatous and non-granulomatous forms of IOI, which may be idiopathic or a component may be part of a systemic dis- ease such as sarcoidosis, tuberculosis, antineutrophil cytoplasmic antibodies-associated orbital granulomatosis with polyangitis, in- ammatory bowel disease, IgG4-related disease, dermatomyositis or SLE (19,20).

Orbital pain is a variable symptom, occurring in at least half of a ected individuals, and is typically associated with other signs and symptoms depending on the involved orbital structures (18). e pain is o en severe and may worsen with eye movement or retropulsion of the globe. Headache or severe eye pain may be pre- sent without external in ammatory signs. Orbital ultrasonography is helpful to demonstrate involvement of the posterior sclera, a less common but important form of IOI.

Laboratory testing

Diagnosis requires an ocular and orbital evaluation followed by tar- geted laboratory studies and radiological imaging, such as CT and fat-saturated and gadolinium-enhanced MRI (21). As lymphoma and other malignancies may have similar manifestations, a biopsy may be required to rule out neoplasia.

Treatment

Treatment includes systemic corticosteroids, other immunosup- pressant agents, and radiation therapy (22,23).

Angle closure glaucoma

Acute angle closure glaucoma occurs when the intraocular pres- sure rapidly rises as a result of closure or blockage of the drainage angle of the eye, the site of aqueous out ow. It may occur in any situation associated with pupillary dilation, which causes the iris to move anteriorly and come into contact with the lens (e.g. emerging from a darkened movie theatre). Risk factors include advancing age, a strong family history of glaucoma, a history of ocular trauma, hyperopia (far-sightedness) and pseudoexfoliation (24). ere is a heritable component, as individuals with narrow angles are predis- posed, particularly elderly Chinese women. Systemic medications, such as topiramate and medications with anticholinergic properties, are associated with angle closure glaucoma (25).

Typical symptoms are ocular pain, headache, nausea, and vomiting. e attack is o en accompanied by blurred vision and patients o en complain of seeing halos around lights. Incomplete or mild attacks may abort spontaneously. erefore, these attacks may be mistaken for migraine. However, unlike migraine patients,

patients with acute angle closure will typically demonstrate the fol- lowing ocular signs:

• Elevated intraocular pressures (typically > 30 mmHg). When tonometry is unavailable, the a ected eye may be palpated under closed lids using the thumb pad. A hard, unyielding globe indi- cates an elevated pressure.

• Conjunctival injection. e eye is typically red and there is o en a ring of vascular congestion surrounding the corneal–scleral junction.

• Shallow anterior chamber. e iris is commonly rotated forward towards the back side of the cornea, making the anterior chamber shallower. e angle may be visualized using gonioscopy or op- tical coherence tomography (24).

• Mid-dilated pupil. e pupil is usually dilated, and either xed or sluggishly reactive. e combination of pain and dilated pupil angle closure may be mistaken for a third cranial nerve palsy, but the elevated pressure and the lack of ptosis or ocular motor palsy excludes that diagnosis.

• Corneal oedema. e cornea may appear oedematous or cloudy. Laboratory tests
e diagnosis is made clinically. Ophthalmological evaluation re- veals markedly elevated intraocular pressure and angle closure on gonioscopy.
Treatment
While the pain associated with angle closure may improve using analgesics, it quickly subsides once the intraocular pressure is controlled. Intraocular pressure control is usually achieved using cholinergic agents, such as pilocarpine, to constrict the pupil and open the angle. When the intraocular pressure is very elevated (> 45 mmHg), topical medications such as beta blockers and alpha-2 adrenergic agonists, as well as intravenous mannitol and carbonic anhydrase inhibitors, may be needed. Laser peripheral iridotomy is a de nitive therapy in nearly all cases.
Ocular surface disease (dry eye)
e cornea contains the highest density of pain receptors in the body with representation in the ventral part of the caudal end of the trigeminocervial complex in the medulla (26). Pain is a common symptom of ocular surface disease that may result from a primary tear lm de ciency or abnormality, corneal epithelial disease, con- tact lens use, and exposure to topical medication, or it may be sec- ondary to systemic in ammatory diseases, including rheumatoid arthritis, Sjögren syndrome, SLE, and psoriasis. It is a common and underdiagnosed cause of ocular pain. Dry eye and pain or redness is a source of dissatisfaction following laser in situ keratomileusis (LASIK). Other common causes of ocular pain are a corneal foreign body, abrasion, or infectious keratitis. Dry eye also occurs with con- ditions that interfere with normal blinking, such as thyroid eye dis- ease, Parkinson disease, progressive supranuclear palsy, and facial paresis. An underlying cause is not identi ed in many cases.
Symptoms of ocular surface disease or dry eye may range from a mild discomfort to severe, debilitating symptoms that interfere with activities of daily life. Patients may experience ocular pain, a burning or foreign body sensation, pruritis, redness, re ex tearing, blurred

vision, photophobia, monocular diplopia, or visual distortion. e symptoms o en uctuate and characteristically worsen during ac- tivities requiring visual concentration, such as reading, driving, using the computer or smartphone, or watching television.

Examination of the eye using uorescein dye with a blue light and magni cation will quickly identify corneal foreign bodies, abrasions, or keratitis. Abnormalities in the Schirmer sterile test strip evaluation of tear production, vital staining of the corneal surface, and the tear break- up time as viewed with slit-lamp bi-microscopy are helpful in making the diagnosis of dry eye. erapy for dry eye symptoms in- cludes topical lubricants, anti-in ammatory medications, and punc- tual occlusion or surgical intervention to prolong ocular tear contact.

Chronic neuropathic corneal pain

e symptoms of corneal neuropathy cause pain that is similar to that of dry eyes, with unremitting burning pain associated with photo- phobia and, in some cases, re ex blepharospasm (27). is recently recognized entity is characterized by decreased corneal sensitivity as measured by aesthesiometry and a reduced tear lake with normal cor- neal epithelium on slit-lamp examination. Morphometric analysis of the cornea using in vivo laser scanning confocal microscopy reveals abnormal corneal nerve morphology. e condition is suspected when patients have symptoms of dry eyes but do not respond to standard treatment. It may follow corneal gra ing or LASIK procedures. Topical anaesthetics temporarily relieve the pain in some cases (27).

Laboratory testing

In vivo confocal corneal microscopy shows tortuosity, branching, or loss of density of corneal nerves.

Treatment

A uid-based gas-permeable contact lens that rests entirely on the sclera is the rst line of treatment a er conventional dry eye treat- ments fail. Topical lacosamide 1% may be used in the reservoir of the scleral lens if hydration alone is unsuccessful. Scrambler therapy, which synthesizes 16 di erent types of nerve action potentials to de- termine a patient-speci c cutaneous electrostimulation, works in some refractory patients.

Thyroid eye disease

yroid eye disease (TED) is the most common extra-thyroid manifestation of Graves’ disease. Approximately 2% of patients with Graves’ disease have mild and inactive TED, 6% have moderate- to-severe active TED, and 1% have sight-threatening TED associ- ated with optic neuropathy (28). TED may precede or accompany the thyroid disease and likely represents an expression of the same autoimmune process a ecting the thyroid and ocular tissues. It is characterized by oedema and in ammation a ecting the lacrimal gland, extraocular muscles, and orbital fat, with a secondary de- crease in venous and lymphatic drainage from the orbit (29). TED is much more common in women than in men, and cigarette smoking negatively impacts the course and response to treatment.

Pain commonly occurs in TED, resulting from dry eye and orbital in ammation. Lacrimal gland dysfunction leads to decreased tear production and inadequate corneal lubrication, which may be com- pounded by proptosis, which increases corneal exposure to air. With severe proptosis and eyelid retraction, there is incomplete blinking

and eye closure, causing further corneal dryness. In ammatory in l- tration of ocular tissues may produce constant, aching orbital pain.

e diagnosis is made clinically and the eyes are usually asymmet- rically a ected. Signs of external involvement include conjunctival in- jection and oedema, and corneal dryness. e upper and lower eyelids become oedematous and retracted, producing a staring appearance and exaggerating the impression of proptosis. Extraocular muscle involvement, generally a ecting the inferior and medical recti rst, produces diplopia from restrictive ocular myopathy. Exophthalmos results when the ocular muscle enlargement causes anterior displace- ment of the globe. While cosmetically distressing and worsening the ocular surface disease, exophthalmos sometimes protects the optic nerve. In patients with ‘tight’ orbits, there may be limited proptosis and a compressive optic neuropathy results from marked ocular muscle enlargement within the con nes of the bony orbit.

Laboratory testing

CT of the orbits reveals increased density of the orbital fat, enlarge- ment of the rectus muscles sparing their tendons, proptosis, slight bowing of the medial orbital wall, and optic nerve compression when present (30). MRI of the orbits provides better tissue di er- entiation and demonstrates oedema within the orbital structures. Serum markers include thyroid-stimulating hormone receptor anti- bodies, thyroid stimulating immunoglobulin, and thyroid function tests; euthyroidism does not exclude the diagnosis of TED.

Treatment

Vigorous ocular lubrication (particularly if eyelid retraction or ex- ophthalmos prevents complete blinking or eye closure during sleep), smoking cessation, monocular occlusion to prevent diplopia, and selenium supplementation are rst-line therapies. More severe cases with orbital congestion are treated with fractionated radiotherapy (20 Gy total). Corticosteroids may be used, although there is no consensus regarding the optimal dose, route of administration or duration of treatment. Biologics targeting the IGF1R receptor, tocilizumab and rituximab, are being explored (31). Orbital decompression is indi- cated for patients with optic neuropathy. e active disease runs a course of about 18 months. A erwards, various surgical procedures, such as orbital decompression, strabismus surgery, and eyelid surgery, are employed to restore a more normal appearance to the eyes, de- crease the risk of corneal exposure, and treat the diplopia.

Orbital tumours

Depending on the location in the orbit, orbital tumours may pro- duce pain, proptosis, displacement of the globe, diplopia, optic neuropathy, chemosis, ptosis, leukocoria (in infants), or progressive visual loss. e pain may be ocular, retro-ocular, periocular, or fa- cial, if the trigeminal nerve is a ected. Metastatic disease accounts for a small percentage of all orbital tumours, the orbital mass may develop before the primary tumour is diagnosed, and the presen- tation is usually unilateral. In a large series of 2480 orbital tumours 68% were benign and 32% malignant (32). e frequency of malig- nancy increased in patients over 60 years of age. Common sources of metastasis are cancer of the breast, lung, thyroid, and prostate. Lymphoma and basal cell carcinoma frequently a ect the orbit. e most common orbital tumours of childhood and adolescence are capillary haemangioma, rhabdomyosarcoma, neuroblastoma, optic

CHAPTER 42 Remote causes of ocular pain

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nerve glioma, histiocytosis, and cystic lesions. Many tumours in children have an osseous origin, such as brous dysplasia, juvenile ossifying broma, and osteosarcoma (33). Optic nerve meningioma, adenoid cystic carcinoma, and tumours of the lacrimal gland, and cavernous haemangioma are the most common tumours in patients over 21 years of age. e di erential diagnosis includes orbital in- ammatory disorders, infections, and thyroid eye disease.

Laboratory testing

Patients suspected of having an orbital tumour should have a com- plete ophthalmological examination. Imaging is performed using orbital MRI (better for showing detail and so tissue) and CT (dem- onstrates bony changes). Orbital echography may be useful in some cases. Fine-needle aspiration of the tumour is sometimes possible to obtain a tissue diagnosis prior to treatment.

Treatment

e treatment is dependent on the tumour type and may include ob- servation, surgical excision, exenteration, corticosteroids, radiation, and chemotherapy.

. (15) Pareja JA, Sánchez del Río M. Primary trochlear headache and other trochlear painful disorders. Curr Pain Headache Rep 2006;10:316–20.

. (16) Yangüela J, Sanclez-del-Rio M, Bueno A, Espinosa A, Gili P, Lopez-Ferrando N, et al. Primary trochlear headache: a new cephalgia generated and modulated in the trochlear region. Neurology 2004;62:1134–40.

. (17) Smith JH, Garrity JA, Boes CJ. Clinical features and long-term prognosis of trochlear headaches. Eur J Neurol. 2014;21:577–85.

. (18) Mombaerts I, Bilyk J, Rose GE, et al. for the Expert Panel of the Orbital Society. Consensus of the diagnostic approach of idio- pathic orbital in ammation using a modi ed Delphi approach. JAMA Ophthamol 2017;135(7):769–76.

. (19) Shields JA, Shields CL. Orbital pseudotumor versus idio- pathic nongranulomatous orbital in ammation. Ophthal Plast Reconstr Surg 2013;29:349.

. (20) Origuchi T, Yano H, Nakamura H, Hirano A, Kawakami A. ree cases of IgG4-related orbital in ammation presented as unilateral pseudotumor and a review of the literature. Rheumatol Int 2013;33:2931–6.

. (21) Ferreira TA, Saraiva P, Genders SW, Buchem MV, Luyten GPM, Beenakker JW. CT and MR imaging of orbital in ammation. Neuroradiology 2018;60(12):1253–66.

. (22) Carruth BP, Wladis EJ. In ammatory modulators and biologic agents in the treatment of idiopathic orbital in ammation. Curr Opin Ophthalmol 2012;23:420–6.

. (23) Prabhu RS, Kandula S, Liebman L, Wojno TH, Hayek B, Hall WA, Crocker I. Association of clinical response and long-term outcome among patients with biopsied orbital pseudotumor. Int J Radiat Oncol Biol Phys 2013;85:643–9.

. (24) Razeghinejad MR, Myers JS. Contemporary approach to the diagnosis and management of primary angle-closure disease. Surv Ophthalmol 2018;63(6):754–68.

. (25) Wu A, Khawaja AP, Pasquale LR, Stein JD. A review of systemic medications that may modulate the risk of glaucoma. Eye (Lond) 2019 Oct 8: doi:10.1038/s41433-019-0603-z (Epub ahead of print).

. (26) Panneton WM, Hsu H, Gan Q. Distinct central representations for sensory bers innervating either the conjunctiva or cornea of the rat. Exp Eye Res 2010;90:388–96.

. (27) Borsook D, Rosenthal P. Chronic (neuropathic) corneal pain and blepharospasm: ve case reports. Pain 2011;152:2427–31.

. (28) Tanda ML, Piantanida E, Liparulo L, Veronesi G, Lai A, Sassi L, et al. Prevalence and natural history of Graves’ orbitopathy in a large series of patients with newly diagnosed Graves’ hyperthyroidism seen at a single center. J Endocrinol Metabl 2013;98:1443–9.

. (29) Melcescu E, Horton WB, Kim D, Vijayakumar V, Corbett JJ, Crowder C, et al. Graves orbitopathy: update on diagnosis and therapy. So Med J 2014;107:34–43.

. (30) Müller-Forell W, Kahaly GJ. Neuroimaging of Graves’ orbitopathy. Best Pract Res Clin Endocrinol metabol 2012;26:259–71.

. (31) Roos JCP, Murthy R. Update on the clinical assessment and management of thyroid eye disease. Curr Opin Ophthalmol 2019;30:401–6.

. (32) Bonabolontà G, Strianese D, Grassi P, Comune C, Tranfa F, Uccello G, Iuliano A. An analysis of 2,4780 space-occupying le- sions of the orbit from 1976–2011. Ophthal Plast Reconstr Surgy 2013;29:79–86

. (33) Chung EM, Murphey MD, Cube R, Smirniotopoulos JG. From the Archives of the AFIP. Pediatric orbit tumors and tumorlike lesions: osseous lesions of the orbit. Radiographics 2008;28:1192–214.

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Orofacial pain

Dental head pains, temporomandibular disorders, and headache

Steven B. Graff-Radford† and Alan C. Newman

Introduction

Orofacial pain involves pain conditions associated with the hard and so tissues of the head, face, neck, and all the intraoral structures (1,2). e eld of orofacial pain encompasses diagnosis and treat- ment of primary headaches, temporomandibular disorders, neuro- pathic pain, cervical pain, and myofascial pain (see also Chapter 27) (3). e evaluation and treatment of orofacial pain has evolved into a shared responsibility between the dentist and physician, with con- siderable overlap, distinguished only by the practitioner’s knowledge and training (1,4).

In the International Classi cation of Headache Disorders published by the Headache Classi cation Subcommittee of the International Headache Society, orofacial pains are included in the section titled ‘Headache or facial pain attributed to disorders of cra- nium, neck, eyes, ears, nose, sinuses, teeth, mouth or other facial or cranial structures’. is section includes the following subsec- tions: ‘Headache or facial pain attributed to temporomandibular joint (TMJ) disorder’, and ‘Headache attributed to other disorders of cranium, neck, eyes, ears, nose, sinuses, teeth, mouth or other facial or cranial structures’ (5).

Headache is not exclusively located in the ophthalmic (V1) tri- geminal distribution. Rather, headache can present in any part of the head, face, or even the neck (6), which is important diagnostically and therapeutically. Facial pain in the perioral region is o en diag- nosed as a dental problem without considering referral from a pri- mary headache disorder. e patient may receive dental treatment, without a conclusive diagnosis, resulting in unnecessary treatment and poor outcome. Similarly, primary headache in the face may not be treated by the physician because the pain location is in a ‘dental area’ and it is assumed it must be odontogenic.

Accurate diagnosis requires a very thorough history, which in- cludes identifying the pain location, quality, intensity, and time

course throughout the day, week, and month. We also want to under- stand alleviating or aggravating factors, whether the pain is spontan- eous or triggered, and if there are changes in the pain with posture. Assessment of accompanying symptoms is also important. Once this information is gathered, together with careful examination of the cranial nerves, temporomandibular joints, cervical spine, and dental structures, a diagnosis can be made (7).

e purpose of this chapter is to raise physicians’ awareness of orofacial pains so that they can expand their di erential diagnosis to include these non-primary headache conditions. We focus on dental pains and temporomandibular pains.

Tooth pains

Tooth pathology pain can present as headache (in the V1 distribu- tion), especially when the a ected tooth is located in the maxilla (8,9). Initial pain from tooth pathology can present as headache, al- though this is unusual. Typically, pain begins in the tooth and then headache may occur secondarily. ere can also be simultaneous localized tooth area pain and headache. Painful dental pathology includes tooth decay, tooth cracks, endodontic (nerve) infections, and periodontal disease, although any one of these pathologies can also be non-painful. In the absence of local dental pain a headache diagnosis may be di cult. e physician may be focused on non- dental causes and not look for dental aetiologies. Until there is local dental pain, a reason for the pain may not be elucidated. e pa- tient may be treated with all the usual preventive or abortive medi- cations for headache with limited response. Referral to an orofacial pain specialist may then prompt an evaluation for dental pathology. Physicians should consider the possibility that head pain may be a dental problem, especially when other causes have been ruled out and treatment is unsuccessful or of limited success.

† It is with regret that we report the death of Steven B. Gra -Radford in October 2017.

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Dental pathology presenting as headache is explained through tri- geminal and central mechanisms with referred pain. A patient with primary headache such as migraine or tension type may see an ex- acerbation in headache frequency and intensity in the presence of dental pathology. Also, if the patient has a primary headache dis- order, tooth pain from dental pathology may worsen. e trigeminal nerves are the common pathway for all head pains (dental, head- ache, temporomandibular, etc.), and central connections allow for referred pain between the three trigeminal divisions, as well as the upper cervical levels (10,11).

It is more likely that a non-tooth pain presents as toothache rather than vice versa. Medical conditions such as primary headache, sinus disease, and trigeminal neuralgia (TN) can present at toothache (12,13). A erent nociceptor sensitization can lead to allodynia (pain from non-painful stimuli). is pain starts in the anatomical region where the headache is felt, typically the rst division of the trigem- inal nerve, and can spread to other parts of the body. Likewise, this can lead to pain in the dental area that is not dental in origin. An example would be an increased sensitivity to tooth pulp testing in a normal healthy tooth (14).

A phenomenon of ‘pain remapping’ has been described in some patients with migraine, a er an insult to the trigeminal system. e insult could be a simple dental lling or major facial trauma. For example, prior to the dental lling the patient may have had bilat- eral temporal pain, but a er the lling a shi of pain to the tooth site occurs. e associated migraine features may also change. is remapping of pain may lead to unnecessary dental treatment and other procedures, as the pain practitioner may not recognize the pain as migraine. Remapping may occur from peripheral a erent input to the second order neurons in the trigeminal nucleus from the location of the injury leading to a central change in processing of the nociceptor signals, leading to a change in pain location of future migraine attacks (15).

Dental caries, or tooth decay, starts in the enamel and the dentin of the tooth but can progress to the neurovascularized pulp of the tooth. At any stage of the decay process there can be pain. is pain can be aching, burning, sharp, pulsatile, or throbbing, and can wake people from sleep. It can be intermittent or continuous. ere is o en hot and/or cold sensitivity of the tooth or teeth. e duration of pain typically outlasts the time of stimulus. Dental radiographs will usually show the decay, but early stages may not be shown. Some patients have di culty localizing the pain, which can make the diag- nostic process more di cult. Applying heat or ice to the teeth, the use of an electric pulp tester, percussing the teeth with a metal in- strument, or palpating the gums around the teeth can help to locate the problematic tooth (16). Dental therapy, such as a lling or a root canal procedure, can then usually be e ective.

Once decay has spread to the pulp of the tooth, the infection can travel though the entire neurovascular root canal system. is can result in extravasation of the infection out of the apex of the root or roots and appear as a periapical endodontic lesion, which presents as a radiolucency on radiographs. is infection can be painful or non-painful. Pain upon chewing or percussion is a classic sign of periapical pathology. Eventually, the pulp can become necrotic and become painless. Treatment is with endodontic root canal therapy where the pulp is removed and replaced with an inert material called gutta-percha. Dependent on the level of pulp pathology, the diag- nosis may be reversible or irreversible pulpitis.

A cracked tooth can present like TN with brief, sharp shooting pain when pressure is applied, which opens the crack. e pain is usually triggered with chewing food or teeth grinding. It is usually not spontaneous, as in TN. Using a tooth sleuth (a specialized plastic bite stick) can help nd cracks. When the patient bites on the tooth sleuth and gets pain upon releasing a crack may be present. Standard dental radiographs, such as periapical lms, which are two dimen- sional, can show large cracks or cracks that are in the plane of the X-ray beam but o en do not show many cracks (17). e use of a three-dimensional cone beam computed tomography (CBCT) scan is more likely to show cracks then conventional lms (17). A cracked tooth may be repairable with restorative treatment or may need to be extracted (18).

One way to help di erentiate between a dental problem and a pri- mary headache syndrome is by local anaesthetic blockade. If dental pathology is suspected, a local in ltration of anaesthetic at the tooth site should block the pain. If the pain does not resolve with anaes- thetic blockade, another pathology should be suspected.

Neuropathic pain can also be confused with dental pathology. TN presents as brief electric shocks of pain typically in the second or third trigeminal nerve distributions and o en around the teeth. TN is almost always one sided, and is o en triggered by stimuli such as brushing the teeth, washing the face, shaving, or having a breeze blow across the skin of the face. It is typically quiescent at night. Pain caused by dental pathology di ers in that it can occur during the night, and as described , can be triggered by hot or cold foods. With TN, the temperature of food usually is not a provoking factor. Pain when chewing can also be seen with TN (19).

Periodontal disease involves in ammation and infection of the gingiva, alveolar bone, periodontal ligament, and cementum. If un- treated, periodontal disease can lead to bone loss, tooth mobility, and, eventually, tooth loss. Pain is usually associated with later stages of the disease, although there can be pain earlier on. e cause of periodontal disease is from plaque deposits on the teeth. Such a plaque is made up of bacteria, mucus, and food debris, leading to in- ammation and irritation of the gums. Treatment includes debride- ment, antibiotics, and sometimes surgery.

Temporomandibular disorders

Temporomandibular dysfunction refers to disorders of the temporo- mandibular joint (TMJ) and associated structures. is includes painful and non-painful conditions. Painful temporomandibular disorders may be associated with headache and pain in the distribu- tion of the trigeminal, upper cervical, and glossopharyngeal nerves (20,21).

Temporomandibular dysfunctions (TMDs) include TMJ arthritis, TMJ capsulitis, TMJ internal derangement, TMJ trauma, TMJ dis- location, myalgia, myofascial pain, spasm, and trismus.

TMJ pain is reported in 10% of the population (22). TMD may occur in up to 46% of the population (23). ese statistics show how TMDs can be a major contributor to the number of people with head or face pain. Physicians and dentists need to be aware of this and examine the TMJ system as part of their pain evaluation. e measure to which headaches and TMDs have a causal role with each other, however, is not known. It is possible that treating TMD’s can help to relieve headaches and vice versa.

e subjective complaint of headache may be the only presenta- tion for patients with TMDs. Muscle or joint pain can present as headache and/or exacerbate headache. Headache and TMDs are o en comorbid (24).

Myalgia and myofascial pain are muscular TMDs if the pain af- fects the muscles around the TMJs. e muscles most commonly involved are the masseters, temporalis, and pterygoids ere may be no joint-speci c subjective or objective ndings, but a TMD can be considered if the muscles are involved with movement of the jaw. Myalgia is muscle pain that can arise from trauma such as a blow to the face or from overuse such as from ngernail biting, or gum chewing or overstretching of the jaw. Other aetiological factors can be bruxism and emotional and behavioural stressors. Treatment may include rest, a so diet, moist heat applications, massage, phys- ical therapy, muscle relaxants, topical non-steroidal drugs or an- algesics, a bite guard, and trigger point injections (25). If the pain persists and becomes chronic it may be harder to treat. If the cause is ongoing parafunction (clenching or grinding teeth, gum chewing) the pain may not improve until the parafunction ceases.

Myofascial pain is regional muscle pain, the hallmark of which is muscle pain points at pressure with referral to areas of di erent dermatomal distribution from the original pain site (26). ese pain points, also known as trigger points, are localized areas in the muscle, tendon, or fascia that are felt as taught bands. When active, palpation of trigger points can refer to other areas (27). For example, palpating the trapezius can cause pain in the temporalis muscle area. e mechanisms for the pain referral of myofascial pain are thought to be through central sensitization. In addition to remote pain re- ferrals, myofascial pain can be accompanied by disturbed sleep, diz- ziness, tinnitus, memory issues, sweating, numbness, stu y nose, runny nose, and blurry vision, associated features that can confuse the diagnosis. Myofascial pain is described as a deep ache, burning or sore, but may also be shooting or throbbing. Management of myofascial pain is best achieved with physical medicine techniques, exercises, injections, and medications (25). Typically, muscle re- laxant, non-steroidal anti-in ammatory drugs, and tricyclic anti- depressant medications are used (25). e usefulness of these medications is through their central actions. Injecting the trigger point with local anaesthetic will reduce the pain and can be helpful diagnostically and therapeutically (25).

When examining a headache patient it is imperative to do a muscular examination that includes palpation of the muscles of the head and neck. If muscles are painful on palpation, the patient should be asked if that pain is the same as the chief complaint or not. If there is a muscular component, treatment should be as listed earlier. In patients that have headaches and muscle pain, treatment of the muscle component can reduce headache frequency and intensity.

e TMJ is a ginglymoarthrodial synovial joint, thus having a dual function joint, as it both hinges and glides. It has both an upper and lower compartment separated by an articular disc. Its innerv- ation is mainly from the auriculotemporal branch of the mandibular nerve (28). e joint is also made up of the condyle of the mandible and the temporal bone fossa.

In ammation causes joint pain, the potential aetiologies of which are a trauma, bruxism, emotional and behavioural stressors, low serum oestradiol levels, and autoimmune diseases (29). e cause can also be idiopathic.

Macro-trauma would be injury from a single application of force such as being struck on the face. e injury can be acute and re- solve quickly, or can become chronic. Micro-trauma results from re- petitive overuse such as from frequent chewing of gum, nail biting, and clenching and grinding the teeth. Micro-traumas are o en re- ferred to as ‘habits’. Repetitive movements can cause joint in am- mation leading to pain and eventually the breakdown of the joint components. ey also cause micro-tearing of muscle bres, the sheath around the muscles, and the connective tissue. Over time, the trauma causes damage to the orofacial structures and pain and/ or dysfunction.

TMJ arthritides include osteoarthritis (OA), rheumatoid arthritis (RA), traumatic arthritis, and infectious arthritis (30).

OA or wear-and-tear arthritis is the most common type of arth- ritis of the TMJ. Complaints of pain with function and crepitation sounds are common. Imaging shows attening of the articular surfaces. Cyst formation of the condyle(s) and/or temporal bone can occur.

RA of the TMJ occurs in around 17% of adults and children with RA. e most common ndings are pain, swelling, and restricted range of motion. Ankylosis is a possible sequalae of RA of the TMJ (24). Imaging may show irregular articular surfaces, although early stages may look similar to OA.

TMJ internal derangements are disc condyle complex incoord- ination and disc displacement, with or without reduction. In ei- ther case, noise in the joint is the hallmark. There may or may not be pain. In disc displacements, the disc that normally accounts for stability in the TMJ becomes displaced, resulting in an in- coordination. Alteration in the disc morphology and changes to the retrodiscal ligament can lead to the displacement and tissue breakdown.

In disc displacement with reduction, the disc assumes its normal position during mouth opening, which results in a click type of noise. It may also lose its normal position upon closing and then a ‘reciprocal’ click may be heard. In disc displacement without reduc- tion, the disc does not go back to its normal physiological position and stays displaced. en, no noise is heard.

e quality of TMD pain varies from the dull, aching sensation of muscular pains to the potentially sharp, shooting pain of arthritides and disc derangements. In some instances there is no pain, only noises in the joint or locking.

Diagnostic imaging may be necessary to detect fractures, arthritides, and derangements (31). A computed tomography scan (ideally a CBCT) will show fractures and arthritis if present. MRI shows disc position quality and function, joint e usion, arthritic changes, and fractures. A CBCT scan is better at viewing the bony structures, whereas MRI is better for viewing so tissues. Sometimes both are needed. A panoramic X-ray can give a quick overall idea of the condition of the bony surfaces.

Treatments for TMDs should follow a medical and not a dental model of care, including habit avoidance, rest, heat, ice, physical therapy, medications, injections, cognitive behavioural therapy, occlusal guards, and acupuncture. Dental treatments such as oc- clusal adjustments or tooth restorations are irreversible and not warranted. Conservative treatment o en signi cantly improves or resolves TMDs.

In summary, there are relationships between headaches and dental disease, and headaches and TMDs. It is imperative that the

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headache: principles of diagnosis and management. Curr Pain
Headache Rep 2001;5:376–81.

. (26) Bron C, Dommerholt JD. Etiology of myofascial trigger point.
Curr Pain Headache Rep 2012;16:439–44.

. (27) Gerwin RD. Classi cation, epidemiology, and natural his-
tory of myofascial pain syndrome. Curr Pain Headache Rep
2001;5:412–20.

. (28) Fernandez PR, de Vasconsellos HA, Okenson JP, Bastos RL,
Maia ML. e anatomical relationship between the position of the auriculoemporal nerve and mandibular condyle. Cranio 2003;21:165–71.

. (29) Gunsen MJ, Arnett GW, Formby B, Falzone C, Mathur R, Alexander C. Oral contraceptive pill use and abnormal menstrual cycles in women with severe condylar resorption: a case for low serum 17beta-estradiol as a major factor in progressive condylar resorption. Am J Orthod Dentofacial Orthop 2009;136:772–9.

. (30) Mehta NR. e Merck Manual Home Health Handbook. Temporomandibular Disorders. Available at: https://www. msdmanuals.com/en-gb/home/mouth-and-dental-disorders/ temporomandibular-disorders/temporomandibular-disorders (accessed 15 July 2019).

. (31) Hunter A, Kalathingal S. Diagnostic imaging for temporo- mandibular disorders and orofacial pain. Dent Clin North Am 2013;57:405–18.

clinician is aware of these relationships, and takes the history and examines the patient with these in mind. If the clinician is unsure of the pain diagnosis the patient should be referred to an orofacial pain dentist who can help make the diagnosis and treat the pain, whether it is dentally based or not.

REFERENCES

. (1) De Leeuw R. Orofacial Pain, Guidelines for Assessment, Diagnosis, and Management. 4th ed. Oceanville, NJ: e American Academy of Orofacial Pain.

. (2) Schi man E, Ohrbach R, Truelove E, Look J, Anderson
G, Goulet JP. Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) for Clinical and Research
Applications: recommendations of the International RDC/TMD Consortium Network and Orofacial Pain Special Interest Group. J Oral Facial Pain Headache 2014;28:6–27.

. (3) Shephard MK, Macgregor EA, Zakrzewska JM. Orofacial pain: a guide for the headache physician. Headache 2014;54:22–39.

. (4) Kumar A, Brennan MT. Di erential diagnosis of orofacial pain and temporomandibular disorder. Dent Clin North Am 2013;57:419–28.

. (5) Headache Classi cation Subcommittee of the International Headache Society. e International Classi cation of Headache Disorders, 3rd edition. Cephalalgia 2018;38:1–211.

. (6) Debruyne F, Herroelen L. Migraine presenting as chronic facial pain. Acta Neurol Belg 2009;109:235–7.

. (7) Stern I, Greenberg MS. Clinical assessment of patients with orofacial pain and temporomandibular disorders. Dent Clin North Am 2013;57:393–404.

. (8) Palla S. Headache and teeth. er Umsch 1997;54:87–93.

. (9) Roberts HW, Wright EF. Atypical presentation of odontogenic
pain. Gen Dent 1999;47:46–7.

. (10) Laibovitz BM. Temporomandibular disorders and headache: a
review of the literature. Oral Health 2006;96:12–19.

. (11) Bartsch T, Goadsby PJ. Increased responses in trigeminocervical
nociceptor neurons to cervical a er stimulation of the dura
mater. Brain 2003;126:1801–13.

. (12) Moncada E, Gra -Radford SB. Cough headache presenting as a
toothache: a case report. Headache 1993;33:240–3.

. (13) Alonso AA, Nixdorf DR. Case series of four di erent headache
types presenting as tooth pain. J Endodont 2006;32:
1110–13.

. (14) Burstein R, Cutrer MF, Yarnitsky D. e development of cuta-
neous allodynia during migraine attack clinical evidence for sequential recruitment of spinal and supraspinal nociceptive neurons in migraine. Brain 2000;123:1703–9.

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Headache with neurological deficits and cerebrospinal fluid lymphocytosis (HaNDL) syndrome
Germán Morís and Julio Pascual

Introduction

In 1951, Symonds described a man who had stereotyped spells of visual loss and unilateral weakness, followed by headache, drowsi- ness, and vomiting (1). Associated with these symptoms were in- creased cerebrospinal uid (CSF) pressure and pleocytosis. Each attack lasted several days and resolved without sequelae. Similar cases were subsequently reported, but it was not until 1981 that Bartelson and colleagues coined the term ‘migrainous syndrome with CSF pleocytosis’ (2). ese authors described a series of patients who had migraine-like attacks accompanied by sensory, motor, speech, and visual disturbances in addition to CSF abnormalities, and they provided a literature review of similar cases. In 1984, Martí-Massó published a series of cases in a Spanish journal (3). A er reviewing available cases and adding seven patients with a similar presentation, in 1995 Berg and Williams proposed the term ‘headache with neuro- logic de cits and CSF lymphocytosis’ (HaNDL) (4). Subsequently, Gomez-Aranda and colleagues described a series of 50 patients with this syndrome and called it ‘pseudomigraine with temporary neuro- logical symptoms’ (5). Some reviews include the early descriptions of Spanish cases (6,7).

Epidemiology

Approximately 100 HaNDL cases have been reported in the litera- ture, which suggests that the syndrome is rare. Its exact incidence is unknown as no epidemiological studies have been reported. However, HaNDL is probably underdiagnosed because of the un- familiarity with the disorder (8). In our experience in Spain, and a er actively looking for these cases for more than 10 years, the in- cidence of HaNDL is estimated to be approximately 0.2 cases per 100,000 inhabitants per year. Even though this syndrome has been mainly described in the south of Europe and in the USA, we are aware of HaNDL cases in many other countries. For instance, a Japanese case was reported in 2003 (9).

HaNDL is more frequent in men (3:1) (5,10). Reported ages at onset ranged from 7 to 50 years, but most patients are around 30 years of age at onset (5,10), although some authors have recently suggested that HaNDL is underdiagnosed in children (11).

Clinical presentation

By de nition, HaNDL syndrome is a self-limited syndrome that is characterized by a sudden onset of headache with temporary neurological de cits and CSF lymphocytosis (4,5,9). e diag- nostic criteria of HaNDL, according to the new International Classi cation of Headache Disorders, third edition (ICHD-3), classi cation of the International Headache Society, are presented in Box 44.1 (12).

Up to 3 weeks prior to the onset of headache, about one-third of patients report cough, rhinitis, diarrhoea, and/or general- ized malaise. The majority of patients describe their headache as severe, throbbing, oppressive, or of a type not previously ex- perienced (5). However, some patients experience episodes with only mild or no headache (5,13). The pain may be bilateral or hemicranial, lasting from 1 hour to 1 week (mean 19 hours), and may be accompanied by nausea, vomiting, photophobia, or phonophobia. Most patients with HaNDL do not report a history of migraine headaches.

e temporary neurological de cits of this syndrome are char- acteristic and di er from those seen in migraine auras (14). Eighty per cent of patients with HaNDL have transient neurological de cits restricted to one hemisphere. e remaining 20% have either epi- sodes a ecting di erent brain regions (5). ree-quarters experi- ence de cits in the dominant hemisphere. In our opinion, this phenomenon is due to a higher clinical awareness of dysfunction in this hemisphere. Right hemisphere spells may pass unnoticed. In patients with multiple episodes in one hemisphere, the neuro- logical de cits were not always the same in di erent episodes (5). Transient neurological de cits last between 5 minutes and 1 week

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Box 44.1 Diagnostic criteria of HaNDL

. A Episodes of migraine-like headache ful lling criteria B and C.

. B Both of the following:

Accompanied or shortly preceded by the onset of at least one of the following neurological symptoms lasting > 4 hours:
(a) Hemiparaesthesia

(b) Dysphasia
(c) Hemiparesis
Associated with CSF lymphocytic pleocytosis (> 15 white cells per μl), with negative aetiological studies.

C Evidence of causation demonstrated by either or both of the following:

. 1 Headache and transient neurological de cits have developed or signi cantly worsened in temporal relation to the CSF lympho- cytic pleocytosis, or led to its discovery

. 2 Headache and transient neurological de cits have signi cantly improved in parallel with improvement in the CSF lymphocytic pleocytosis.

D Not better accounted for by another ICDH-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

(mean 5 hours); only one patient had aphasia that lasted longer than 1 week. Sensory symptoms (78% of episodes), language disorders (60%), and hemiparesis (56%) are the more frequent focal de cits. Sensory symptoms are described as numbness that frequently starts in the hand, progresses through the arm, and then a ects the face and tongue, with the legs rarely involved. Pure motor aphasia is the most frequent speech disorder (36% of episodes), followed by global aphasia (22%) and pure sensory aphasia (2%). Di use manifest- ations in the form of confusion may be part of the clinical expres- sion (15,16). Visual symptoms occur in a lower percentage (10%) than in migraine aura. Seizures are infrequent. e most common combinations of focal symptoms are motor aphasia plus sensory and motor right hemibody symptoms, motor aphasia plus right sen- sory symptoms, and isolated sensory symptoms in one hemibody. Approximately 50% of patients also have nausea and vomiting: some of them also experience phonophobia and photophobia. Fever oc- curs in 25% of patients and coincides with the episodes. Meningeal signs have not been reported (5).

Patients are asymptomatic between episodes. e described number of episodes per patient ranges from 1 to 12 (median 2) and the duration is always shorter than 3 months. All patients with HaNDL reported recovered completely within 1 to 84 days. e only reported complications were related to the diagnostic work-up, es- pecially cerebral angiography, and not to the syndrome itself. All reported patients with HaNDL have recovered completely. e syn- drome is self-limiting and thus far recurrence has not been reported (2,4,5,10).

Aetiology and pathophysiology

e aetiology of HaNDL is unknown. A viral aetiology, such as an Epstein–Barr virus (EBV) infection, aseptic vasculitis, and migraine, have been proposed, although none is proven to date.

Although the age of patients with HaNDL syndrome coin- cides with that of the maximum incidence of migraine, there are a number of differences between migraine and this monophasic syndrome. Some of the headache characteristics differ from those seen in migraine. The duration of temporary deficits (5 hours on average) in HaNDL is longer than the typical aura dur- ation in migraine (< 1 hour). In migraine with aura visual symp- toms are the most frequent, followed by sensory, aphasic, and motor symptoms, which is exactly the opposite in HaNDL (14). A constant feature of HaNDL is (by definition) CSF lymphocytic pleocytosis. CSF pleocytosis of more than 10–15 mononuclear cells/mm3 does not occur in migraine with aura, or even in the most severe forms of stuporous migraine or hemiplegic migraine (17–20).

ere are many infectious conditions that may present with tem- porary neurological de cits, headache, and CSF lymphocytic pleo- cytosis. Clinical and complementary data must rule out conditions such as Lyme disease, neurosyphilis, neurobrucellosis, mycoplasma infections, human immunode ciency virus (HIV) meningitis, and granulomatous and neoplastic arachnoiditis, that could the- oretically account for clinical symptoms such as those observed in HaNDL. However, despite extensive viral serological evaluation, vir- uses have been very rarely detected. ese data, together with the absence of meningeal irritation during and between episodes, seem to rule out conventional viral meningoencephalitis as its aetiology, although it still appears reasonable to search for neurotropic viruses in selected cases.

If migraine and infectious meningoencephalitis do not explain HaNDL, what else could be its cause? We have proposed that HaNDL could be an autoimmune disorder, conceptually similar to (for in- stance) Guillain-Barré syndrome (Figure 44.1). Approximately one-third of patients with HaNDL have symptoms of a ‘viral’ illness in the preceding 3 weeks. It is possible that such an infection could trigger the immune system, producing antibodies to neuronal or cranial vessel antigens. is may induce the transient neurological symptoms throughout a spreading depression-like mechanism and then aseptic vasculitis, which would account for the ‘vascular’ headache and CSF pleocytosis (21,22). It has been shown that intra- venous administration of high-dose immunoglobulins induces aseptic meningitis, manifested as headache and sometimes accom- panied by transient focal symptoms, in approximately 10% of pa- tients. Interaction between immunoglobulin G (IgG) alloantibodies and endothelial antigens in cranial vessels has been proposed to be the cause for this complication (23). Supporting this hypothesis, antibodies to a subunit of the T-type voltage-gated calcium channel CACNA1H have been described in the sera of two of four patients with HaNDL (24).

Differential diagnosis

e diagnosis of HaNDL is made a er excluding more common conditions that present with headache and transient neurological signs and symptoms. HaNDL can be confused with migraine, particularly hemiplegic and basilar migraine, but migraine nor- mally is not associated with CSF lymphocytosis (25). Patients with

CHAPTER 44 Headache with neurological de cits and cerebrospinal uid lymphocytosis (HaNDL) syndrome

‘Viral’ trigger

Autoimmune attack directed to neuronal or vascular antigens

Spreading depression-like mechanism

Activation of the trigeminovascular system

Sterile leptomeningeal vasculitis

Resolution

Figure 44.1 Putative pathophysiology of headache with neurologic de cits and cerebrospinal uid lymphocytosis (HaNDL).

hemiplegic aura usually have a positive family history (familial hemiplegic migraine) (see Chapter 8), and a study of mutations in the CACNA1A gene in HaNDL cases was negative (26). Patients with basilar migraine may have a similar presentation (2), but re- current symptoms topographically consistent with the basilar ar- tery territory, a history of other types of headaches, and a good response to antimigraine therapy will usually help in di erentiating basilar migraine from HaNDL. e syndrome described as ‘mi- graine associated with focal cerebral oedema, CSF pleocytosis, and progressive cerebellar ataxia’ usually recurs over many years and is associated with cerebral oedema, which can be documented on magnetic resonance imaging (MRI) and is di erent from HaNDL (27). e rst episode of HaNDL can mimic an acute ischaemic stroke (see Chapters 10 and 37), leading to the consideration of systemic thrombolytic therapy (28–31). Normality of di usion- weighted MRI images in the acute phase is an important clue for diagnosis in these cases (32).

Other conditions that present with headache, CSF lymphocytosis, and transient neurological symptoms, and signs include viral meningitis, Mollaret meningitis, neuroborreliosis, neurosyphilis, neurobrucellosis, mycoplasma infection, neoplastic meningitis, granulomatous meningitis, autoimmune disease (33), and HIV in- fection (see Chapter 41). Appropriate laboratory studies and brain imaging help to exclude these conditions and should be performed before making a diagnosis of HaNDL.

Multiple sclerosis can be confused with HaNDL, particularly when a rst episode manifests as focal neurological symptoms with headache. e clinical course, presence of oligoclonal bands, and ab- normal immunoglobulin synthesis in the CSF will distinguish this disease from HaNDL.

Occasionally, seizures and status epilepticus present with focal signs (Todd’s paralysis) and CSF lymphocytosis (see Chapter 12) (34,35). When the seizures are witnessed, distinguishing them from HaNDL is not di cult, but in the event of unwitnessed spells, an electroencephalography (EEG) may be helpful (36).

Diagnostic work-up

e diagnostic work-up of HaNDL should be focused on excluding other, more common, and less benign disorders. Routine laboratory determinations, including immunological studies, are within normal limits in most cases. In very few cases, a slight leucocytosis, increased levels (<100 U/L) of transaminases, or positive antinuclear anti- bodies (< 1/80) have been reported. Serologies or cultures for virus, Brucella, Borrelia, Mycoplasma, Treponema, and tuberculosis are negative, but HaNDL-like syndromes have been described as a result of cytomegalovirus, EBV, and herpervirus 6 infections (19,36,37).

CSF opening pressure is elevated in more than 50% of HaNDL cases. CSF glucose is always normal. Reported CSF pleocytosis ranges from 10 to 760 cells/mm3 (mean 200 cells/mm3), with a clear lymphocytic predominance. Protein levels are elevated in more than 90% of cases (mean 94 mg/dl; maximum 250 mg/dl). IgG and adeno- sine deaminase levels are within normal limits and oligoclonal bands are absent. If performed, other CSF studies, including bacterial, viral fungal, and immunological studies, are invariably normal (4,5).

A good-quality imaging study to rule out a space-occupying le- sion (computed tomography (CT) or preferably MRI) should be the rst step in the diagnostic work-up of HaNDL. e only abnor- mality sometimes observed on MRI in patients with HaNDL is non- speci c T2 hyperintensity, which can also be seen in patients with migraine (4,5). Magnetic resonance di usion-weighted imaging during temporary focal symptoms was initially reported to be normal (38), but recent reports have shown a complete hemispheric perfusion/di usion mismatch (39,40). is nding, together with a normal MRI angiogram, should therefore raise the suspicion of HaNDL. Changes in blood ow accompanied by changes in vessel pulsatility, which are liable to be interpreted as a traumatic brain injury pattern consistent with occlusion and embolism, have been described with transcranial Doppler (39,41,42). Conventional cere- bral angiograms do not help in the diagnosis as they are usually normal or show non-speci c abnormalities, even in the symptom- atic phase. Occasionally, irregularities suggestive of vessel wall in- ammation have been described in opercular arteries. Angiograms must, however, be avoided as they can trigger new episodes (4,5).

During the episodes, more than two-thirds of patients with HaNDL show unilateral EEG slowing over the symptomatic side (43,44). Up to 1 day a er the episodes, a brain single-photon emission CT (SPECT) usually detects focal areas of decreased radionuclide activity, which is coincident with the neurological symptoms. SPECT becomes normal within 2 days a er the transient neurological symptoms (Figures 44.2 and 44.3) (5,45).

Treatment

It is important to recognize this benign syndrome in order to avoid unnecessary testing, such as cerebral angiography. Its self-limiting character, including a complete resolution of all symptoms and la- boratory abnormalities and a lack of recurrence indicate that only symptomatic and supportive treatment may be needed. No treat- ment options have been reported either to abort the acute episodes or to prevent its recurrence.

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Figure 44.2 Electroencephalogram of the same patient as in Figure 44.3 showing slow waves over the left hemisphere. A further study 3 days later was unremarkable.

Figure 44.3 (see Colour Plate section) Single photon emission computed tomography (SPECT) image in a typical patient with headache with neurologic de cits and cerebrospinal uid lymphocytosis (HaNDL) 16 hours after an episode of headache accompanied by right motor and sensory symptoms and global aphasia showing decreased tracer uptake in the left hemisphere (arrow). A SPECT study carried out 3 days later was normal.

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Nasal and sinus headaches

Vincent T. Martin and Maurice Vincent

Introduction

Very few topics in the headache eld engender more controversy than nasal and sinus headache. Patients o en believe that their head- aches are attributed to these disorders because they experience rhin- itis symptoms (e.g. rhinorrhoea, nasal congestion, and postnasal drip) during their attacks. Primary care physicians, otolaryngol- ogists, and allergists o en diagnose nasal and sinus headaches and treat them with rhinitis medications, antibiotics, allergy shots, and surgical interventions, with varying levels of success. In contrast, most neurologists and headache specialists believe that many pa- tients with a diagnosis of sinus headache are su ering from migraine or another primary headache disorder.

History

In 1908 Sluder described patients with severe rhinosinusitis of the ethmoid or sphenoid sinus that later developed a pain in the upper jaw, teeth, orbit, ear, and mastoid region accompanied by ipsilat- eral parasympathetic symptoms (e.g. nasal obstruction, lacrima- tion, conjunctival injection) (1,2). In addition, some of the patients experienced nausea, forti cation spectra, and vertigo with these headaches. He postulated that that the sphenopalatine ganglion was damaged by toxins from the rhinosinusitis. Furthermore, he attempted to destroy the sphenopalatine ganglion by injecting it with phenol to treat this condition (3). is syndrome was later termed ‘Sluder’s neuralgia’ or ‘sphenopalatine ganglion neuralgia’ (3,4). Considering the non-uniform location of the headaches, the presence of autonomic and migrainous symptoms, and the clus- tering of attacks it is quite probable that many of the patients with ‘Sluder’s neuralgia’ may have been su ering from migraine or cluster headache.

In 1943 McAuli e and Wolfe performed experiments in which they applied an electrical stimulus to various structures of the nose and paranasal sinuses and asked patients to record the locations of pain a er these stimuli (5). ey found that pain was referred to very speci c areas depending upon which locations were stimulated (Table 45.1). e most common regions of referred pain included

the frontal, temporal, orbital, nasal, and medical canthal regions of the head. e results from this study have been used by otolaryn- gologists to bolster their contention that disorders of the nose and paranasal sinuses can cause facial pain and headache. However, a more recent study could not corroborate these results and found that application of a pressure stimulus or substance P to the nasal mucosa only produced local discomfort and did not produce the referred pain, as noted in McAuli e’s study (6).

What are sinus headaches?

ere are no formal diagnostic criteria for ‘sinus headache’, as pro- posed by the International Classi cation of Headache Disorders, third edition (ICHD-I3). Most of the past epidemiological studies have based a diagnosis of sinus headache on the belief by the pa- tient or his/her treating physician that abnormalities of their sinuses were causing their headaches. Not surprisingly, these studies have included a high percentage of patients with symptoms of rhinitis. In fact, one study (7) found sinus pressure, nasal congestion, and rhinorrhoea in 84%, 63%, and 40%, respectively, of 2396 patients with a concomitant diagnosis of sinus headaches and migraine.

ere are several reasons to support the contention that so- called ‘sinus headaches’ simply represent variants of migraine. Firstly, attacks of migraine are commonly located in the frontal, orbital, glabellar, and temporal regions of the head, which are locations overlying or adjacent to the paranasal sinuses. Secondly, cranial parasympathetic symptoms (e.g. lacrimation, rhinorrhoea, nasal congestion) occur in up to 40–45% of mi- graine attacks and their presence could cause physicians and pa- tients to incorrectly assume that their headaches originate in their sinuses (8,9). irdly, studies have demonstrated a prevalence of migraine headache ranging from 68% to 88% in patients with self- reported sinus headache, and these headaches tend to respond to migraine-speci c abortive medications (7,10–15). However, these data do not preclude the possibility that disorders of the nose and paranasal sinuses could, indeed, produce headache/facial pain or modulate the frequency and disability of existing primary head- ache disorders.

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PART 6 Secondary headaches
Table 45.1 Summary of McAuliffe’s study of electrical stimulation

of the nose and paranasal sinuses.

Box 45.2 ICHD-3 diagnostic criteria for headache attributed to chronic or recurring rhinosinusitis

. A Any headache ful lling criterion C.

. B Clinical, nasal endoscopic, and/or imaging evidence of current or
past infection or other in ammatory process within the paranasal
sinuses.

. C Evidence of causation demonstrated by at least two of the following:

. 1 Headache has developed in temporal relation to the onset of chronic rhinosinusitis

. 2 Headache waxes and wanes in parallel with the degree of sinus congestion and other symptoms of the chronic rhinosinusitis

. 3 Headache is exacerbated by pressure applied over the paranasal
sinuses

. 4 In the case of a unilateral rhinosinusitis, headache is localized
and ipsilateral to it.

. D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Site of stimulation

Pain intensity

Location of pain

Nasal septum

1–2+

Zygoma, pre-auricular, inner canthus

Superior turbinate

–

Medical canthus, forehead, lateral nose

Inferior turbinate

4–6+

Upper teeth, zygoma, ear, under eye

Middle turbinate

4–6+

Zygoma, ear, temple

Maxillary ostium

6–9+

Nasopharynx, molars, temple

Frontal sinus

1–2+

Forehead

Ethmoidal sinus

5–6+

Over eye, medial canthus, upper jaw, deep in eye, upper teeth, lateral nose

Maxillary sinus

–

Eye, jaw, molars

Sphenoid sinus

5–6+

Deep in head, over eye, upper teeth, vertex

Adapted from Research publications – Association for Research in Nervous and Mental Disease, 23, McAuliffe G, Goodell H, and Wolff H. Experimental studies on headache: pain from the nasal and paranasal sinuses, pp. 185–208. 1943.

Headache attributed to disorders of the nose and paranasal sinuses

Headaches attributed to disorders of the nose and paranasal sinuses have recently been recognized within the diagnostic criteria of ICHD-3 as causes of facial pain and headache. e ICHD-3 criteria for headaches associated with rhinosinusitis (acute and chronic/ recurring types) and disorders of the nasal mucosa, turbinates, or septum are shown in Boxes 45.1 and 45.2. Note that there must be clinical, nasal endoscopic, or imaging evidence of the disorder, as well as proof that the disorder is causing the headaches.

Innervation of the nose and paranasal sinuses

e nose and maxillary sinuses are richly innervated by branches of the ophthalmic (V1) and maxillary (V2) divisions of the trigeminal

nerve, which could provide an anatomical basis to explain the pain and headache encountered with disorders of the nose and sinuses (16). e anterior ethmoidal nerve is a branch of V1 and innerv- ates the anterior septum and anterior part of the lateral nasal wall. Branches of V2 traverse the sphenopalatine foramen and form the nasopalatine nerve that innervates the inferior part of the nasal septum. e infraorbital nerve arises from V2 and is encased in a bony canal in the roof of the maxillary sinuses. e superior, middle, and inferior alveolar nerves are branches of the infraorbital nerve and innervate the maxillary sinus.

Speci c disorders

ere are a number of speci c disorders of the nose and sinuses that have been associated with headaches in the literature (Table 45.2) (17). Examples of sinus disorders that are associated with headache include rhinosinusitis, dehiscence of the infraorbital nerve, vacuum

Box 45.1 ICHD-3 diagnostic criteria for headache attributed to acute rhinosinusitis

. A Any headache ful lling criterion C.

. B Clinical, nasal endoscopic, and/or imaging evidence of acute
rhinosinusitis.

. C Evidence of causation demonstrated by at least two of the following:

1 2

Headache has developed in temporal relation to the onset of rhinosinusitis
Either or both of the following:
(a) headache has signi cantly worsened in parallel with

worsening of the rhinosinusitis
(b) headache has signi cantly improved or resolved in parallel

with improvement in or resolution of the rhinosinusitis Headache is exacerbated by pressure applied over the paranasal

sinuses
In the case of a unilateral rhinosinusitis, headache is localized and ipsilateral to it.

4
D Not better accounted for by another ICHD-3 diagnosis.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Box 45.3 ICHD-3 diagnostic criteria for headache attributed to the nasal mucosa, turbinates or septum

. A Any headache ful lling criterion C.

. B Clinical, nasal endoscopic, and/or imaging evidence of a hyper-
trophic or in ammatory process within the nasal cavity.1

. C Evidence of causation demonstrated by at least two of the following:

. 1 Headache has developed in temporal relation to the onset of the
intranasal lesion, or led to its discovery

. 2 Headache has signi cantly improved or signi cantly worsened
in parallel with improvement in (with or without treatment) or
worsening of the nasal lesion

. 3 Headache has signi cantly improved following local anaesthesia
of the mucosa in the region of the lesion

. 4 Headache is ipsilateral to the site of the lesion.

. D Not better accounted for by another ICHD-3 diagnosis.

Note

1Examples are concha bullosa and nasal septal spur.

Reproduced from Cephalalgia, 38, 1, The International Classi cation of Headache Disorders, 3rd edition, pp. 1–211. © International Headache Society 2018.

Table 45.2 Speci c disorders of the nose and sinuses that are associated with headache.

the prevalence is higher in women, in smokers, and in those with a lower socio- economic status (23,24).

A diagnosis of ARS is primary based on history and physical examination. Purulent nasal drainage and nasal obstruction are o en self-reported by the patient, but can also be observed on direct examination of the nares with an otoscope. Facial pain, pressure, and fullness are generally located in the anterior face and periorbital regions, but could be generalized throughout the head. Persistence of these symptoms for > 10 days or an improvement in symptoms followed by a worsening increases the likelihood of a bacterial rhinosinusitis as opposed to a viral rhinosinusitis (21). Sinus radi- ography is not generally indicated for diagnostic purposes as viral rhinosinusitis cannot be distinguished from bacterial rhinosinusitis in the early stages of an upper respiratory infection.

A diagnosis of CRS is more challenging and o en requires the pre- viously mentioned clinical symptoms, as well as radiological studies and/or direct visualization of the nares, to establish a diagnosis (19). A computed tomography (CT) scan of the sinuses would be the radiographic procedure of choice and typically shows opaci cation, air uid levels, or moderate-to-severe mucosal thickening of the sinuses. Purulent drainage, oedema of the middle meatus or ethmoid region, and nasal polyps could be visualized by nasal endoscopy.

e pathophysiology of rhinosinusitis is complex and probably involves anatomical, in ammatory, and infectious mechanisms (25). Anatomical variations of the nose, such as enlarged middle and inferior turbinates, concha bullosa, and septal deviation, could block drainage of the sinuses and predispose to bacterial over- growth. Co-existing allergic rhinitis could lead to an in ammatory reaction within the nasal mucosa that could obstruct the sinus ostia and produce mucosal thickening, which is commonly encountered with rhinosinusitis. However, the hallmark of rhinosinusitis is a bac- terial infection of the sinuses. e most common bacteria involved in ARS are Streptococcus pneumoniae, Haemophilus in uenzae, and Moraxella catarrhalis, while Staphylococcus aureus, coagulase- negative staphylococci, and anaerobes predominate in CRS (25,26).

e mainstay of treatment for ARS is antibiotics for 10 days, but a 3– 5-day course has been shown to be as e ective in some studies (27,28). Most guideline statements recommend amoxicillin as the rst-line antibiotic, followed by a macrolide antibiotic (e.g. clarithromycin, azithromycin) or trimethoprim-sulfamethoxazole (19). Treatment with intranasal steroids, oral/topical decongestants, and nasal saline irrigation may also reduce symptom scores in those with ARS (29–32).

Recent guideline statements recommend that antibiotics only be used in patients with CRS that have purulent nasal drainage (19). Several studies have demonstrated that 2–6-week courses of anti- biotics are e ective in the treatment of CRS (33,34). Fluoroquinolones (e.g. cipro oxacin), macrolides, and amoxicillin/clavulanic acid are the antibiotics of choice to treat CRS. If patients have nasal polyps or co-existing atopy then intranasal corticosteroids and leukotriene antagonists (e.g. montelukast) may also improve symptomatology (35). Endoscopic sinus surgery is reserved for patients that are re- fractory to medical therapy and have continued endoscopic and/or radiographic evidence of obstruction of the sinus ostia that predis- poses them to recurrent bouts of rhinosinusitis.

Headache and facial pain are common complaints in patients diagnosed with CRS. Ling and Kountakis (36) interviewed 210 consecutive patients with CRS undergoing endoscopic sinus sur- gery and reported that 78% experienced facial pain/pressure and

CHAPTER 45 Nasal and sinus headaches

Types of disorders

Examples

Sinuses

Acute and chronic sinusitis
Vacuum headache
Dehiscence of the infraorbital nerve Airplane headache

Nasal, turbinates and septum

Chronic rhinitis
Impacting nasal spurs
Middle and superior turbinate syndrome Other anatomic abnormalities

Other

Mid-segment facial pain

headaches, and airplane headaches. Nasal disorders include chronic rhinitis, mucosal contact points, and other anatomical abnormal- ities of the nose and sinuses. In the following sections, we will dis- cuss the diagnosis, epidemiology, pathophysiology, and treatment of these disorders, as well as the scienti c evidence linking these dis- orders to headache and facial pain.

Acute and chronic rhinosinusitis

Acute and chronic rhinosinusitis are de ned as in ammatory condi- tions of the paranasal sinuses. In the past, rhinosinusitis was simply thought to represent an infection of the paranasal sinuses, but recent work has also implicated in ammatory mechanisms in its patho- genesis, as atopy occurs in 25–70% patients with this disorder (18). Nasal polyps are thought to arise from mucosal in ammation in the nares and therefore rhinosinusitis may exist both with and without nasal polyps.

e de nitions of acute and chronic rhinosinusitis as developed by the American Academy of Otolaryngology are listed in Table 45.3 (19). Note that the cardinal symptoms of rhinosinusitis include purulent nasal drainage, facial pain/pressure, and nasal obstruction. Acute rhinosinusitis (ARS) lasts for less than 4 weeks, while chronic rhinosinusitis (CRS) lasts for longer than 3 months (20).

ARS is one of the most common conditions encountered by pri- mary care physicians, accounting for 20 million o ce visits per year in the USA (22). CRS occurs in 2 – 5% in the general population and

Table 45.3 De nitions of acute and chronic rhinosinusitis.

Type of sinusitis

De nition

Acute

Up to 4 weeks of purulent nasal drainage accompanied by nasal obstruction, facial pain/pressure/fullness, or both

Chronic

Twelve weeks or longer of two or more of the following signs or symptoms:
• mucopurulent drainage
• nasal obstruction

• facial pain-pressure-fullness or • decreased sense of smell

AND one or more of the following:
• purulent mucous or oedema in the middle meatus or

the ethmoid regions
• polyps in the nasal cavity or middle meatus
• radiological evidence showing in ammation of the

paranasal sinuses

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PART 6 Secondary headaches

71% had headaches. Banerji et al. (37) compared the prevalence of CRS symptoms in those with and without nasal polyps and found that headache/facial pain was more common in those without nasal polyps (95% vs 83%; P = 0.02), but nasal obstruction and anosmia were more common in those with nasal polyps. Another study (38) demonstrated that 29% of patients with purulent drainage on nasal endoscopy experienced facial pain. e di erences in the prevalence rates noted in these studies might be partially explained by use of di erent outcome measures to de ne facial pain (e.g. sinus pressure vs sinus/facial pain vs headache). For example, some patients may not perceive ‘sinus pressure’ or ‘sinus/facial pain’ as headache as the pain is localized to the face.

Other studies have reported the locations of rhinosinusitis and facial pain may not always be congruent. Cli on and Jones (38) de- ned rhinosinusitis as the presence of purulent drainage on nasal endoscopy and found that only 65% of the time did the location of the sinusitis correspond to that of the facial pain. Another study (39) reported no correlation between the site of sinus pain and the radiographic location of sinusitis, but they included a number of ab- normalities on imaging that would be unlikely to produce pain (e.g. mucosal thickening and mucus retention cysts).

A recent study (40) showed that CRS may also be associated with the prevalence of chronic daily headache (≥ 15 days per month with headache). It was reported that the risk of chronic daily headache was increased ninefold in those with CRS versus the general popu- lation (40). e characteristics of the headaches associated with CRS included a bilateral location, mild-to-moderate intensity, and an absence of migraine-associated symptoms. ese results suggest that CRS may be associated with frequent headaches that resemble chronic tension-type headache.

Evidence suggests that medical and surgical treatments of CRS may improve headache and/or facial pain. Zeng et al. (41) random- ized patients with CRS to either an antibiotic (clarithromycin) or nasal steroid (mometasone furoate) and found that both therapies reduced scores of headache versus baseline a er 12 weeks of treat- ment. Lal et al. (42) studied 211 patients referred to an otolaryn- gology clinic for complaints of sinus pressure, pain, or headache and reported that medical and/or surgical otolaryngic therapies im- proved pain in 52% of referred patients. A recent meta-analysis (43) included the results of 21 studies of endoscopic sinus surgery in the treatment of CRS. e pooled analyses showed that both headache and facial pain were signi cantly reduced postoperatively compared with their pre-operative values, but the e ect sizes were considered moderate for facial pain and small for headache. It should be noted that the outcome measures used in these studies were visual ana- logue scales and symptoms scores were obtained from question- naires administered pre- and postoperatively. None of the studies used headache diaries to document the frequency of headache that was experienced both prior to and a er the surgical intervention.

Chronic rhinitis

Chronic rhinitis is a disorder of the nose associated with rhinorrhoea, nasal congestion, postnasal drip, nasal itchiness, and sneezing. Symptoms of rhinitis can be perennial, seasonal, or both. Chronic rhinitis can be further categorized into allergic (AR), nonallergic (NAR), and mixed rhinitis (MR) subtypes. A diagnosis of AR re- quires the presence of rhinitis symptoms upon exposure to an al- lergen, positive allergy testing to that allergen, and a lack of rhinitis

symptoms upon exposure to non-allergic rhinitis triggers (e.g. cigar- ette smoking, perfumes, gasoline, etc.). Patients with NAR experience rhinitis symptoms to non-allergic triggers and have negative allergy testing to allergens that are indigenous to their area. Patients with MR have rhinitis symptoms to both allergic and non-allergic triggers.

e prevalence of chronic rhinitis in the general population ranges from 24% to 54% (44–47). Of those with chronic rhinitis, AR accounts for 43%, while NAR and MR occur in 23% and 34%, re- spectively (48). Immunological mechanisms are important in those with allergic rhinitis subtypes (e.g. AR, MR) and involve the binding of allergens to IgE antibodies that are bound to the surface of mast cells, which results in their degranulation (49). Neurological mech- anisms predominate in those with non-allergic subtypes (e.g. NAR, MR) and include an upregulation of nerve growth factor, substance P, and voltage-gated sodium channels within neurons found in nasal turbinate biopsies of patients with rhinitis patients (50–52).

e treatment of chronic rhinitis depends upon the rhinitis subtype that is diagnosed in the patient. Patients with AR or MR may bene t from oral and nasal antihistamines, nasal steroids, anticholinergics, or antileukotriene drugs (53,54). Oral or subcutaneous immuno- therapy (e.g. allergy shots) can also be used if pharmacotherapy fails to control symptoms (53). Patients with NAR are generally treated with intranasal steroids and intranasal antihistamines (53,55–57).

AR and hay fever (a term used to designate AR) have been asso- ciated with an increased prevalence of migraine headache in past studies. Ku et al. (58) found that the prevalence of migraine was 34% in patients with AR and 2% in controls (P < 0.05). Meltzer et al. (59) conducted a telephone survey of patients with AR in Latin America and reported that 41% experienced migraine headache. Several other studies demonstrated that migraine was 1.5–2.9 times more common in those with hay fever (60–62).

More recent studies suggest that patients with chronic rhinitis may have a more severe clinical phenotype of migraine than those without rhinitis. Martin et al. (63) found that migraine headache frequency and headache-related disability were increased by 34% and 33%, respectively, in migraineurs as compared to those without chronic rhinitis. A second clinic-based study (64) also demonstrated similar increases in headache frequency and headache-related dis- ability in patients with chronic rhinitis, but also reported that those with the MR and NAR subtypes had greater e ect sizes for these outcomes measures than patients with the AR subtype. erefore, it appears that patients with non-allergic rhinitis triggers may have the highest migraine frequency and disability.

Medical treatments for rhinitis have been associated with a de- creased frequency and severity of headache and sinus pain/pressure in selected studies. e administration of subcutaneous immuno- therapy was associated with a 52% decrease in migraine frequency and 45% reduction in headache-related disability in younger mi- graineurs with allergic rhinitis (65). Intranasal uticasone, which is a corticosteroid, led to signi cantly greater relief from sinus pain and pressure than placebo in patients with AR (66). Another study found a 65% decrease in headache severity in patients with non-allergic rhinitis treated with capsaicin nasal spray versus placebo (67).

Vacuum headaches, infraorbital nerve dehiscence, and airplane headache

‘Vacuum headaches’ were popularized by Sluder (68) and described as frontal or maxillary headaches that occurred as a consequence of

negative pressure changes within the sinuses due to air ow obstruc- tion at the ostia of the sinuses. In fact, studies have demonstrated that negative pressures develop when the size of the ostia is reduced below a certain threshold (69). ese negative pressures are thought to occur as a result of gas absorption in a closed sinus and ciliary function that propels mucous out of the sinus creating a piston ef- fect (70,71). e exact mechanisms through which negative pressure might produce pain are unknown, but one investigator found that hyperaemia was associated with the positional discomfort that re- sulted a er occlusion of the maxillary sinus (72).

Dehiscence of the infraorbital nerve has been implicated as a possible cause of vacuum headaches of the maxillary sinus (73). Normally, the infraorbital nerve is surrounded by a bony canal in the roof of the maxillary sinus prior to its exit from the infraorbital foramen. Autopsy series suggest that 12–16% of cadavers have complete dehiscence of the infraorbital nerve. Whittet (73) re- ported that six of 12 patients with infraorbital nerve dehiscence presented with atypical facial pain. He further postulated that the pain was caused by exposure of the infraorbital nerve to the nega- tive pressures encountered within the maxillary sinus as a result of small ostia.

Airplane headache is a type of the headache that occurs with air travel that is thought to be caused by pressure changes within the sinuses (see also Chapter 56) (74). Most of the cases occur upon des- cent of the aircra , but some may be precipitated by ascent. It is the- orized that expansion of gases during ascent and negative pressures created during descent produce barotrauma to the sinuses (75). e headaches are generally unilateral, severe, and located in the fronto- orbital location in 76% (74). eir duration is less than 30 minutes. Treatment with topical/oral decongestants and triptans has been re- ported to prevent these headaches (76).

Mucosal contact points

Mucosal contact points can occur between various structures in the nares. ey generally develop in patients with anatomical vari- ations such as a deviated nasal septum, pneumatized or paradoxic- ally bent turbinates, or enlargements of the bony structures within the nose (e.g. concha bullosa, uncinate process, or halar nasal cells). ese contact points are theorized to activate the trigeminal a erents within the nasal cavity, producing headache and facial pain. Although anatomical variations within the nose/sinuses have been associated with headache and facial pain, these variations occur in similar proportions in symptomatic and asymptomatic people (77). erefore, the presence of head pain and any anatom- ical abnormality of the nose/sinuses does not establish a causal relationship.

Several case series have reported that surgical correction of mu- cosal contact points can ameliorate headache disorders (78–83). Yazici et al. (83) studied 73 patients with primary headache dis- orders that had anatomical variants of the nasal septum and turbin- ates. Seventy-three per cent (n = 53) of this group did not respond to medical treatment of their headache disorder and were later o ered surgical correction of their anatomical variant. Compared to base- line, those receiving surgery (n = 38) had a signi cant reduction in their visual analogue scale score for headache at 3–6 months a er surgery, while those refusing surgery showed no change from base- line. Behin et al. (84) reported their results of patients with refractory

migraine (n = 12; 57.2%) or transformed migraine (n = 9; –42.8%) that had radiographic evidence of contact points in the sinonasal area and who underwent endoscopic sinus surgery and septoplasty. Headache frequency and headache-related disability decreased by 57% and 68%, respectively, in these patients 6–62 months a er the surgical procedure. Welge-Luessen et al. (81) reported on 20 patients with headache and endonasal mucosal contact points. e diagnoses in these patients included migraine and cluster headache. Following septoplasty, with or without sinus surgery or middle turbinectomy, 65% experienced headache relief a er a 10-year follow-up.

Application of topical lidocaine to the nasal mucosa has been used to determine the functional signi cance of mucosal contact points. Mokbel et al. (80) studied 120 patients undergoing endoscopic sur- gery and classi ed them as responders or non-responders based on the relief of facial pain by application of topical lidocaine. Ninety- nine per cent of responders improved from surgery versus 40% in the non-responder group. e authors suggested that a lidocaine test may be used as a diagnostic tool to predict success of endoscopic surgery.

Evidence contrary to the ‘mucosal contact theory’ is the fact that the prevalence of nasal mucosal contact points is similar in those with and without facial pain (4% in both groups) (85). One has to also consider that there is a tendency for regression to the mean in clinical studies involving headache and that the aforementioned studies were not placebo controlled. Other factors, such as an- algesic overuse and psychological issues, were not adjusted for in these studies, which could signi cantly a ect headache outcome measures.

e possibility exists that mucosal contact points may only cause facial pain or headache in patients with primary headache disorders. Such patients may have hyperactivity of the trigeminal system and further activation of trigeminal a erents by a mucosal contact point might be enough to trigger a headache.

Taken together, data indicate that selected patients with headache may be due to nasal/sinus anatomical non-in ammatory abnor- malities. e attending physician should consider a possible nasal origin in the case of nasal, frontal, and/or periorbital headaches that are refractory to usual care and probably atypical, as compared to usual primary headaches. Under these circumstances, appropriate CT scans and direct endoscopic examinations are advisable. Surgical procedures may be planned if anatomical changes are found and local anaesthesia proves to be positive, but decisions will always have to be taken based on careful individual analyses, including a head- ache diary, as this relationship remains highly controversial.

Mid-segment facial pain

Mid-segment facial pain, considered the most frequent pain syn- drome in a rhinology clinic (85,86), has been described as a sensation of pressure or tightness over the middle third of the face that would resemble tension-type headache in all aspects except for its location. ere is no nausea, vomiting, photophobia, or phonophobia. As no abnormalities are detected with nasal endoscopy and on a CT scan of the paranasal sinuses, mid-segment facial pain most likely has the same underlying mechanisms as tension-type headache, which is postulated to involve a central dysmodulation of pain transmission (87). So far, there is not enough evidence to support this entity as an independent disorder.

CHAPTER 45 Nasal and sinus headaches

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PART 6 Secondary headaches Potential mechanisms

ere are several potential mechanisms through which sinus and nasal disorders could be associated with headache, sinus pres- sure/discomfort, and facial pain (Figure 45.1). Firstly, these dis- orders could directly activate V1 and V2 a erents in the nose and paranasal sinuses to produce head pain. is could occur as a result of mucosal contact points in the nares, negative pressure phenom- enon in the sinuses, release of in ammatory mediators from mast cells (if atopy is present), or cytokine release from in ammatory cells (if sinusitis is present). Secondly, disorders of the nares cause nasal congestion and/or obstruction that might disrupt sleep or lead to obstructive sleep apnoea, which could precipitate headaches (88–90). In addition, they can produce snoring, which has been as- sociated with chronic daily headache (91). irdly, they might not directly trigger headache or facial pain, but could be associated with other disorders that may cause or modulate headache disorders. For example, chronic rhinitis is more common in those with depres- sion, obstructive sleep apnoea, and asthma, which are associated with the prevalence and attack frequency of migraine (62,92–94). Fourthly, there could be shared environmental or genetic factors that might explain the association. For example, rhinitis is more prevalent in those that smoke and smoking is associated with a greater attack frequency of migraine (95,96). Finally, it is possible that this is a spurious association and all of the ‘sinus symptoms’ represent cranial autonomic symptoms that occur as part of a mi- graine attack (8).

Differential diagnosis

ere are a number of headache disorders that might be confused with headaches attributed to the nasal mucosa, septum, turbinates, and rhinosinusitis (97). Firstly, migraine, the trigeminal autonomic cephalalgias (cluster, episodic/chronic paroxysmal hemicranias, short-lasting, unilateral, neuralgiform headaches with conjunc- tival injection and tearing (SUNCT/SUNA), hemicrania con- tinua) o en have cranial autonomic symptoms and thus could mimic many of the symptoms encountered with rhinological headaches (see also Chapter 17). However, each of these headache

types have characteristic features that can di erentiate them from rhinological headaches (98). ese include stereotyped cir- cadian rhythms, such as in cluster headache, short-lasting epi- sodes, such as in SUNCT or absolute indomethacin e ect, such as in hemicrania continua. Secondly, mid-segment facial pain and headaches attributed to chronic rhinosinusitis have been reported to have characteristics of chronic TTH (see also Chapter 29). It is interesting to postulate that subgroups of patients with a TTH-like pain could have a rhinologic aetiology for their headaches. irdly, trigeminal neuralgia is characterized by short-lived bursts of facial pain lasting from seconds to minutes that are located mostly in the maxillary and mandibular regions and is distinguished from rhinogenic headaches by its short duration (see also Chapter 27). Finally, the headaches in the so-called ‘salt and pepper in the face syndrome’ are located in the orbital region and may indicate an evolving brainstem stroke (99,100). ese headaches are di eren- tiated from disorders of the nose and sinuses by their associated neurological signs and symptoms.

Clinical approach

One must develop a clinical approach to the management of nasal and sinus disorders in headache patients to avoid unnecessary diagnostic testing, medical treatments, and surgeries. Rhinitis, rhinosinusitis, and anatomical abnormalities of the nose/sinuses are common disorders and clearly will be encountered in patients with primary headache disorders. e question remains as to whether they play a causative role for headaches or are simply innocent bystanders. Given that the data are inconclusive, the authors rec- ommend medical treatment of rhinitis and rhinosinusitis in head- ache patients. e medical therapies are listed in Table 45.4, and

Table 45.4 Medical therapies used to treat speci c nasal and sinus disorders.

Nasal and sinus disorders

Medical therapies

Acute rhinosinusitis

• First-line antibiotics: amoxicillin

• Second-line antibiotics: macrolide or
trimethoprim-sulfamethoxazole

• Use of nasal steroids may shorten the duration of
symptoms

• Oral/intranasal decongestants may improve
congestion (short-term use advised)

Chronic rhinosinusitis

• Antibiotics: uroquinolone, macrolide, or amoxicillin/clavulanic acid

• Intranasal steroids indicated • Saline lavage helpful

Nasal polyps

• Intranasal/oral steroid
• Antileukotriene medications

Allergic and mixed rhinitis

• First-line: oral antihistamine, intranasal steroid • Second-line: antileukotriene medications
• Moderate-to-severe disease: immunotherapy

(allergy shots)

Nonallergic rhinitis

• Intranasal steroids, intranasal antihistamine • Oral antihistamines do not work

Deviated septum/ obstruction of maxillary ostia

• Oral/intranasal decongestants
• Nasal steroids if allergies present

Mast cell activaon and release of inflammatory mediators

Nasal obstrucon leading to obstructive sleep apnoea or insomnia

Mucosal contact

points activating trigeminal afferents

Headache, facial pain or sinus pressure

Associaon with other comorbid disorders

Obstruction of ostia of sinuses producing negative pressures within the sinuses

Shared genetic and environmental factors

Figure 45.1 Potential mechanisms through which nasal and sinus disorders could produce headache, facial pain, or sinus pressure.

di er depending upon which nasal and sinus disorder that is being treated. ese therapies generally have a low side e ect pro le and their use will improve symptoms related to the nasal and sinus dis- orders, and could improve headache and sinus pressure/discomfort in some instances. e authors would discourage the use of surgical interventions for the sole purpose of treating headache, as the data do not currently support such an approach.

Conclusion

‘Sinus headaches’ encompass a variety of nasal and sinus disorders that have been associated with an increased prevalence of headache disorders. Emerging data suggest that treatment of these disorders might reduce sinus pain/pressure, as well as headache in some in- stances. It is unknown if the nasal or sinus disorders cause headache or if their symptoms are simply a result of an underlying primary headache secondary to activation of cranial parasympathetics. Clearly, further research is indicated to elucidate the complex rela- tionship between these disorders and headache.

CHAPTER 45 Nasal and sinus headaches

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417

Giant cell arteritis and primary central nervous system vasculitis as causes
of headache
Mamoru Shibata, Norihiro Suzuki, and Gene Hunder

Giant cell arteritis

Introduction

Giant cell arteritis (GCA) is a granulomatous vasculitis a ecting large- and medium-sized blood vessels, especially the proximal aorta and its branches. ere is a predilection for extracranial branches of the carotid arteries, including the super cial tem- poral artery. As such, this disorder is also referred to as temporal arteritis. Clinical manifestations are caused by in ammation and ischaemia. When a new headache has developed in a patient over the age of 50 years physicians should always be alert to the possi- bility of GCA. e headache is o en unilateral but may be more generalized. Inspection and palpation of the scalp arteries, par- ticularly the temporal artery ipsilateral to the headache is essen- tial when evaluating suspected cases. Ultrasonography over the a ected temporal artery should be performed, which is helpful in determining the appropriate site of biopsy. High-dose cortico- steroids are the mainstay of treatment. Steroid administration does not have to wait until the temporal artery is biopsied. e aim of early therapy is to prevent visual loss and other vascular complications.

Epidemiology

e disease primarily a ects people over 50 years of age (1). e female-to-male ratio is approximately 2–3:1 (1). e incidence is higher in certain ethnic groups. Most patients with GCA are white. Scandinavians and North Americans of Scandinavian origin have the highest incidence rates (> 17 per 100,000 individuals aged > 50 years), whereas Southern Europeans have incidence rates of < 12 per 100,000 individuals aged > 50 years. In one study the incidence of GCA in black individuals was one-seventh that of white persons (2). Similarly, a review of US patients with biopsy-proven GCA found a lower prevalence in Asian than in white patients (3). e incidence in Japanese people is even lower. A Japanese government-supported

survey revealed that the prevalence in patients aged > 50 years was 1.47 per 100,000 population in Japan (4).

It is well-known that GCA is o en found in patients with polymyalgia rheumatica (PMR). e association with PMR is ap- parently in uenced by ethnicity, as shown by a lower rate (30.3%) in Japanese patients with GCA (4).

Pathology and pathogenesis

In ammatory changes chie y involve the large- and medium-sized muscular arteries, especially the proximal aorta and its branches (5,6), which have a prominent internal elastic membrane and vasa vasora. Because these structures are less developed in intracra- nial arteries, they are rarely a ected by GCA (7). e nal patho- logical picture of GCA is panarteritis, which involves all vascular layers. e classic pathological hallmarks consist of a granuloma- tous in ammatory in ltrate with lymphocytes, macrophages, and multinucleated giant cells, which are usually observed at the intima–media junction (Figure 46.1). Such in ammatory changes within the arterial walls are o en seen in a segmental fashion, which necessitates sampling of long segments in the diagnostic biopsy. Jaw claudication and diplopia are the symptoms with signi cant pre- dictive value for positive biopsy, with likelihood ratios of 4.2 and 3.4, respectively (8).

e cause of GCA remains elusive. Non-genetic factors also seem to be concerned with the aetiology. Several studies have explored the involvement of infectious agents with inconsistent results (9). With regard to cardiovascular risk factors, an increased risk of GCA in heavy smokers, and in individuals with previous atherosclerotic disease has been reported (10). In patients with GCA, the most com- monly identi ed genetic association is with the HLA-DRB1*0401 allele (11). Scores of susceptible genetic foci, most of which are re- lated to immune response and in ammation, have been reported. ese ndings strongly raise the possibility that immunogenicity determined by a genetic factor(s) plays a role in the development of disease.

(a)

CHAPTER 46 Giant cell arteritis and primary central nervous system vasculitis as causes of headache (b)