Headache Syndromes

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

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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

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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

12

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

vi

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

x

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

xi

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

12

4. Headache mechanisms 34 Andrew Charles

5. Headache in history 45 Mervyn J. Eadie

1

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

4

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).

5

6

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.

7

8

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.

9

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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.

e Headaches. 3rd ed. Philadelphia, PA: Lippincott Williams

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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.

(9) Lipton RB. Risk factors for an management of medication- overuse headache. Continuum 2015;21:1118–31.

(10) Bigal ME, Serrano D, Buse D, Scher A, Stewart WF, Lipton RB. Acute migraine medications and evolution from episodic to chronic migraine: a longitudinal population-based study. Headache 2008;48:1157–68.

(11) Tolner EA, Houben T, Terwindt GM, de Vries B, Ferrari MD, van den Maagdenberg AM. From migraine genes to mechan- isms. Pain 2015;156(Suppl. 1):S64–74.

(12) Eller M, Goadsby PJ. Trigeminal autonomic cephalalgias. Oral Dis 2016;22:1–8.

(13) Schwartz DP, Robbins MS, Grosberg BM. Nummular headache update. Curr Pain Headache Rep 2013;17:340.

(14) Yeh YC, Fuh JL, Chen SP, Wang SJ. Clinical features, imaging ndings and outcomes of headache associated with sexual ac- tivity. Cephalalgia 2010;30:1329–35.

(15) Frese A, Rahmann A, Gregor N, Biehl K, Husstedt IW, Evers S. Headache associated with sexual activity: prognosis and treat- ment options. Cephalalgia 2007;27:1265–70.

(16) Frese A, Eikermann A, Frese K, Schwaag S, Husstedt IW, Evers S, et al. Headache associated with sexual activity: Demography, clinical features, and comorbidity. Neurology 2003;61:796–800.

(17) Robbins MS, Grosberg BM, Napchan U, Crystal SC, Lipton RB. Clinical and prognostic subforms of new daily-persistent head- ache. Neurology 2010;74:1358–64.

(18) Peng KP, Fuh JL, Yuan HK, Shia BC, Wang SJ. New daily per- sistent headache: should migrainous features be incorporated? Cephalalgia 2011;31:1561–69.

(19) Fuh JL, Kuo KH, Wang SJ. Primary stabbing headache in a head- ache clinic. Cephalalgia 2007;27:1005–9.

(20) Ducros A. Reversible cerebral vasoconstriction syndrome. Lancet Neurol 2012;11:906–17.

(21) Lucas S, Ho man JM, Bell KR, Dikmen S. A prospective study of prevalence and characterization of headache following mild traumatic brain injury. Cephalalgia 2014;34:93–102.

(22) Singhal AB, Hajj-Ali RA, Topcuoglu MA, Fok J, Bena J, Yang D, Calabrese LH. Reversible cerebral vasoconstriction syn- dromes: analysis of 139 cases. Arch Neurol 2011;68:1005–12.

(23) Linn J, Fesl G, Ottomeyer C, Straube A, Dichgans M, Bruckmann H, et al. Intra-arterial application of nimodipine in

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(26) Schytz HW, Ashina M, Magyaari M, Larsen V, Olesen J, Iversen H. Acute headache and persistent headache attributed to cervical artery dissection: eld testing of ICHD-III beta. Cephalalgia 2014;34.

(27) Vieira DS, Masruha MR, Goncalves AL, Zukerman E, Senne Soares CA, Na ah-Mazzacoratti MG, et al. Idiopathic intracranial hyper- tension with and without papilloedema in a consecutive series of patients with chronic migraine. Cephalalgia 2008;28:609–13.

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(36) Edvardsson B, Persson S. Reversible cerebral vasoconstriction syndrome associated with autonomic dysre exia. J Headache Pain 2010;11:277–80.

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(39) Lal V, Sahota P, Singh P, Gupta A, Prabhakar S. Ophthalmoplegia with migraine in adults: is it ophthalmoplegic migraine? Headache 2009;49:838–50.

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11

2

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.

13

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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

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

15

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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.

3

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

18

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

19

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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 (%)

82

71

Cerebellum (%)

21

6

Multiple lesions (%)

41

Family history of migraine (%)

75

24

Patent foramen ovale (%)

40

65

* 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)

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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),

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(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.

Reproduced from Cephalalgia, 34, 11, Förster, A. et al, Perfusion patterns in migraine with aura, pp. 870–876. Copyright © 2014, © SAGE Publications. Doi: 10.1177/ 0333102414523339.

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

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(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

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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).

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(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

guidelines in the primary care setting: neuroimaging in patients with nonacute headache. Available at: http://tools.aan.com/pro- fessionals/practice/pdfs/gl0088.pdf (accessed 6 April 2014).

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33

4

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

35

36

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).

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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

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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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41

42

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CHaPTEr 4 Headache mechanisms

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(125) Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, Ashina M, et al. Safety and e cacy of ALD403, an anti- body to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol 2014;13:1100–7.

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5

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.

46

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).

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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

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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

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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

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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).

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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.

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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

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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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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

6

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.

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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.

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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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(31) Hare EH. Personal observations on the spectral march of mi-

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(32) Sacks O. Migraine. New York: Vintage Books, 1970 (revised

edition 1992).

(33) Plant GT. e forti cation spectra of migraine. Br Med J

1986;293:1613–17.

(34) Milner PM. Note on a possible correspondence between

the scotomas of migraine and spreading depression of Leao.

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(35) Leao AAP. Spreading depression of activity in the cerebral

cortex. J Neurophysiol 1944;7:359–90.

(36) Richards W. e forti cation illusions of migraine. Sci Am

1971;224/5:88–96.

(37) Charles AC, Baca SM. Cortical spreading depression and mi- graine. Nat Rev Neurol 2013;9:637–44.

(38) Iizuka T, Takahashi Y, Sato M, Yonekura J, Miyakawa S, Endo M, et al. Neurovascular changes in prolonged migraine aura in FHM with a novel ATP1A2 gene mutation. J Neurol Neurosurg Psychiatry 2012;83:205–12.

(39) Hodges JR, Warlow CP e aetiology of transient global am- nesia. A case-control study of 114 cases with prospective follow- up Brain 1990;113:639–57.

(40) Fuller GN, Marshall A, Flint J, Lewis S, Wise RJS. Migraine mad- ness: recurrent psychosis a er migraine. J Neurol Neurosurg Psychiatry 1993;56:416–18.

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7

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

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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

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

% Days with reported migraine

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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

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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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8

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

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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

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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

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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

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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)

(c) (d)

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.

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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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9

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

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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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(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.

(76) Winterkorn JS, Kupersmith MJ, Wirtscha er JD, Forman S. Brief report: treatment of vasospastic amaurosis fugax with calcium-channel blockers. N Engl J Med 1993;329:

396–9.

(77) Kupersmith MJ, Hass WK, Chase NE. Isoproterenol treatment of visual symptoms in migraine. Stroke 1979;10:299–305.

(78) Kupersmith MJ, Warren FA, Hass WK. e non-benign aspects

of migraine. Neuroophthalmology 1987;7:1–10.

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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

CHaPtEr 10 Migraine, stroke, and the heart

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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

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.

Copyright (2010) Wolters Kluwer Health, Inc.

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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11

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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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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(93) Rainero I, Limone P, Ferrero M, Valfre W, Pelissetto C, Rubino E, et al. Insulin sensitivity is impaired in patients with mi- graine. Cephalalgia 2005;25:593–7.

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12

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

D

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.

rEFErENCES

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13

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

(c) moderate or severe intensity

(d) aggravation by routine physical activity

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).

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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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(10) Dieterich M, Obermann M, Celebisoy N. Vestibular mi- graine: the most frequent entity of episodic vertigo. J Neurol 2016;263(Suppl. 1):S82–9.

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14

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

1g

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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15

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,

CHaPtEr 15 Treatment and management of migraine: preventive

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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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(111) Silberstein SD, Dodick DW, Bigal ME, Yeung PP, Goadsby PJ, Blankenbiller T, et al. Fremanezumab for the preventive treat- ment of chronic migraine. N Engl J Med 2017;377:2113–22.

(112) Stau er VL, Dodick DW, Zhang Q, Carter JN, Ailani J, Conley RR. Evaluation of galcanezumab for the prevention of episodic migraine: the EVOLVE-1 randomized clinical trial. JAMA Neurol 2018;75:1080–8.

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(117) Dodick DW, Silberstein SD, Reed KL, Deer TR, Slavin KV, Huh B, et al. Safety and e cacy of peripheral nerve stimula- tion of the occipital nerves for the management of chronic migraine: long-term results from a randomized, multicenter, double-blinded, controlled study. Cephalalgia 2015;35:344–58.

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16

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

17

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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Part 3 Trigeminal autonomic cephalgias

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 C