No Longer a Headache: Accessing Continuum on the Go
This issue of Continuum is devoted to the diagnosis and management of headache and facial pain, symptoms that are common in our clinical practices and have profound effects on patients’ quality of life. To achieve this goal, I am indebted to Dr Matthew S. Robbins for accepting my invitation to serve as guest editor of this issue and
for enlisting outstanding and prominent experts in the field to guide us in the diagnosis and management of primary or secondary headache disorders.
The issue begins with two articles that serve as important introductions to the articles that follow. First, Dr David W. Dodick provides a very practical overview of his clinical approach to the diagnosis of patients with secondary and primary headache disorders. Next, Dr Ana Recober reviews the current thinking regarding the underlying pathophysiology of migraine and its various phases from prodrome to postdrome.
Dr Jessica Ailani reviews the many agents and approaches currently available in our armamentarium for the management of acute migraine attacks. Dr Rebecca Burch then discusses the many therapeutic strategies and options available for the prevention of migraine. Dr Stephanie J. Nahas next describes the diagnosis of and current management options for cluster headache and
other trigeminal autonomic cephalalgias, stressing the severity of these syndromes and the great impact these painful disorders can have on our patients’ lives.
Dr Jonathan H. Smith reviews the diagnosis and management of the variety of other primary headache disorders; recognition of the unique clinical characteristics of these disorders can lead the clinician to the most appropriate counseling and treatment options. Dr Carrie Robertson
then discusses the diagnosis and current
management strategies of the cranial neuralgias, including trigeminal and glossopharyngeal neuralgia and other neuralgias of the head and neck.
Dr Jelena M. Pavlović provides us with an extensive overview of the diagnosis and treatment of headache in women, with emphasis on the relation of headache to hormonal changes during the menstrual cycle, in pregnancy, and throughout life. Next,
Dr Christina Szperka provides an approach to the unique aspects of history taking, diagnosis, management, and counseling of the most common headache disorders presenting in children and adolescents.
Dr Robbins then reviews the indications, evidence base, technical aspects, and safety considerations of various procedural therapies for headache disorders, particularly migraine and cluster headache. In the final review article of the issue, Dr Shuu-Jiun Wang discusses the variable clinical presentations (including headache and nonheadache symptoms), diagnostic testing, and current therapeutic strategies for patients who present with spontaneous intracranial hypotension.
In this issue’s Medicolegal Issues article, Ms Rachel V. Rose and Dr Joseph S. Kass provide several real-life examples relevant to neurology to discuss the False Claims Act and its implications for neurologists.
570
JUNE 2021
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Downloaded from http://journals.lww.com/continuum by juGL3SikQGgPeJhlsy5S2tR2Je1+DSLxXM5+5U0pNQ/o8Sr9B6vmzj4RAT1RqJBz5vmQ6bjYts4rZHominWNXy0H3U65GuTdNee3fZ5dQ+6XNmvYCGaBTods9Wqj4Xuj38PhBKDAOyxDHbtzda8GcRokJZqQbumdttFhFmAeKsA= on 06/12/2021

After reading the issue and taking the Postreading Self-Assessment and CME Test written by Drs Adam G. Kelly and Allison L. Weathers, readers may earn up to 20 AMA PRA Category 1 CreditsTM toward self-assessment CME or, for Canadian participants, a maximum of 20 hours toward the Self-Assessment Program (Section 3) of the Maintenance of Certification Program of the Royal College of Physicians and Surgeons of Canada. Additional credit can be obtained by listening to Continuum Audio interviews associated with this and other Continuum issues, available to all subscribers, and completing tests on the Continuum Audio web platform or mobile app. Continuum Audio is also accredited by the Royal College of Physicians and Surgeons of Canada.
This issue is part of a pilot program of Continuum issues read aloud. Different from Continuum Audio, these are recordings read verbatim from the print articles by Dr Michael Kentris, a neurologist at Bon
…I am indebted to Dr Matthew S. Robbins…for enlisting outstanding and prominent experts in the field to guide us in the diagnosis and management of primary or secondary headache disorders.
Secours Mercy Health in Youngstown, Ohio. The audio files are available to all Continuum subscribers in the AAN’s Online Learning Center at continpub. com/CME. I encourage you to listen and submit the survey with your feedback on this pilot, which has been extended to include this issue and the
August 2021 issue.
We are also pleased to introduce the rollout of the new Continuum mobile experience at ContinuumJournal.com. Just follow the directions on the inside front cover in the “Beyond the Page” section of this issue to save Continuum to your phone’s home screen. You will then be able to simply and easily navigate content from any Continuum issue on your mobile phone as well as read full-text articles and access tables and figures wherever you are and whenever you need it, including at the point of care.
My sincere thanks to Dr Robbins for his skillful and dedicated guest editorship and to all of the experienced and thoughtful experts who joined him in this issue. This issue so thoroughly covers so many practical aspects of the diagnosis and management of both the common and uncommon disorders that may present as headaches and whose effective treatment can have such an important impact on improving our patients’ quality of life.
—STEVEN L. LEWIS, MD, FAAN EDITOR-IN-CHIEF
© 2021 AMERICAN ACADEMY OF NEUROLOGY.
CONTINUUMJOURNAL.COM
571
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

REVIEW ARTICLE
Diagnosing Secondary
and Primary Headache
Disorders
By David W. Dodick, MD, FAAN, FAHS
ABSTRACT
PURPOSE OF REVIEW: This article provides a systematic diagnostic approach to the patient with headache.
RECENT FINDINGS: The vast majority of patients presenting with headache in clinical practice have a primary headache disorder. The most common primary headache disorder in clinical practice is overwhelmingly migraine. Unfortunately, a substantial proportion of patients with migraine do not receive an accurate diagnosis. In addition, the clinical features of migraine overlap with secondary causes of headache, making a careful history and deliberative evaluation for warning symptoms or signs of a secondary headache disorder of paramount importance.
SUMMARY: The approach to the patient with headache requires knowledge of the diagnostic criteria for primary headache disorders, recognition
of the importance of a systematic evaluation for red flags associated with secondary headache disorders, and awareness of the pearls and pitfalls encountered in the diagnostic evaluation of a patient with headache.
INTRODUCTION
Headache is the most common symptom neurologists are asked to evaluate. Because headache is a ubiquitous symptom in the general population, is a common and often cardinal manifestation of a myriad of diseases, and may be a disease unto itself, a disciplined and systematic diagnostic approach is required. The challenge is
made more difficult because primary headache disorders are highly prevalent;
therefore, it is common for patients with a secondary cause of headache to also
have a long-standing history of a primary headache disorder. Worldwide, almost
3 billion people have a headache disorder; of those, approximately 1.89 billion
have tension-type headache and 1.04 billion have migraine. For tension-type
headache, the global age-standardized prevalence is 30.8% for women and 21%
for men, whereas the prevalence rates for migraine are 19% for women and 10%
1
for men. In addition, serious secondary causes of headache invariably present
with clinical features that are consistent with or indistinguishable from the most common primary headache disorders. Therefore, a standardized approach to identifying warning signals in all patients is necessary, whether evaluating a

CONTINUUM AUDIO INTERVIEW AVAILABLE ONLINE
CITE AS:
CONTINUUM (MINNEAP MINN) 2021;27(3, HEADACHE):572–585.
Address correspondence to
Dr David W. Dodick, Mayo Clinic, 13400 E Shea Blvd, Scottsdale AZ 85259, dodick.david@mayo. edu.
RELATIONSHIP DISCLOSURE:
Dr Dodick has served as a consultant for AEON Biopharma; Alder Biopharmaceuticals Inc; Allergan; Amgen Inc; Atria BPH; Biohaven Pharmaceuticals; Cerecin Inc; Clexio Biosciences; Cooltech Medical; Ctrl M Health; eNeura Inc; Equinox Pharma Limited; GlaxoSmithKline plc; Impel NeuroPharma, Inc; Lilly; Linpharma, Inc; Lundbeck; Nocira; Novartis AG; Pieris Pharmaceuticals; Praxis Pharmaceutical; Promius Pharma, LLC; Revance; Satsuma Pharmaceuticals, Inc; Theranica Bio-Electronics Ltd; Upjohn (Division of Pfizer Inc); W. L. Gore & Associates, Inc; Xoc Pharmaceuticals, Inc; and Zosano Pharma Corporation, as chair of the American Brain Foundation, and on the board of directors of the American Migraine Foundation; EPIEN Medical, Inc; King-Devick Technologies, Inc; Matterhorn Medical Ltd; Ontologics, Inc; and Precon Health Inc. Dr Dodick has received personal compensation for speaking engagements from Continued on page 585
UNLABELED USE OF PRODUCTS/INVESTIGATIONAL USE DISCLOSURE:
Dr Dodick reports no disclosure.
© 2021 American Academy of Neurology.
572
JUNE 2021
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Downloaded from http://journals.lww.com/continuum by juGL3SikQGgPeJhlsy5S2tR2Je1+DSLxXM5+5U0pNQ/o8Sr9B6vmzj4RAT1RqJBz5vmQ6bjYts4rZHominWNXy0H3U65GuTdNee3fZ5dQ+6XNmvYCGaBTods9Wqj4Xuj38PhBKDAOyxDHbtzda8GcRLfvcU004nnnb8ZkysxmKc= on 06/12/2021

patient with headache for the first time or assessing a change in headache pattern in an established patient with a primary headache disorder.
SECONDARY HEADACHE DISORDERS
A plethora of systemic, neurologic, and vascular disorders may present with headache as a prominent or predominant feature. Although about 2% of those with headache may have a secondary cause for headache, up to 18% of patients presenting with headache to tertiary care centers may harbor an underlying secondary cause.2 The index of suspicion for a secondary cause of headache can be effectively raised by identifying historical and examination red flags. The acronym SNOOP4 (“snoop for” red flags) may be useful as a memory aid to ensure that warning signals for sinister causes of headache that are associated with serious morbidity and mortality are not overlooked (TABLE 1-1).3 Recently, this acronym was expanded (to SNOOP10) to include other non– life-threatening conditions, such as medication-overuse headache and posttraumatic headache.2
Warning Signals to Raise Suspicion of Secondary Causes of Headache Using the Mnemonic SNOOP4a
TABLE 1-1
Letter Warning signal
S Systemic symptoms
Secondary diseases
O Onset
P1 Positional
P3 Pregnancy/ postpartum
Features
Fever, night sweats, chills, weight loss, jaw claudication
Cancer, immunosuppression, chronic infection (human immunodeficiency virus [HIV], tuberculosis)
Thunderclap
Orthostatic, recumbent, or worsens with change in position
New onset during pregnancy
Differential diagnosis
Metastases, giant cell arteritis, infection (central nervous system, systemic)
Reversible cerebral vasoconstriction syndrome (RCVS), stroke, subarachnoid hemorrhage, cerebral venous sinus thrombosis, arterial dissection, pituitary apoplexy, idiopathic intracranial hypertension
Low intracranial pressure (CSF leak), mass lesion, cerebral venous sinus thrombosis, sinus pathology
Cerebral venous sinus thrombosis, preeclampsia, RCVS, pituitary lesion, stroke
N Neurologic Confusion, focal neurologic symptoms/signs, Mass lesion, structural lesion, stroke, symptoms/signs diplopia, transient visual obscurations, hydrocephalus
pulsatile tinnitus
O Older (age New onset, persistent/progressive Mass lesion, giant cell arteritis >50 years) headache
P2 Prior history New onset or change to persistent/daily Mass lesion, infection (central nervous system/ headache systemic)
P4 Precipitated by Cough, sneeze, bending, straining Intracranial/posterior fossa mass, Chiari Valsalva malformation
CSF = cerebrospinal fluid.
a Data from Dodick DW, Semin Neurol.3
CONTINUUMJOURNAL.COM 573 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

DIAGNOSING SECONDARY AND PRIMARY HEADACHE DISORDERS
CASE 1-1
A 38-year-old man presented to the emergency department for evaluation of headache. The headache began suddenly during intercourse and was throbbing in quality. It began in the occipital region, but then quickly generalized to envelop his entire head. He vomited twice and reported continued nausea and sensitivity to light, and the headache was made worse with movement.
His examination was notable for elevated blood pressure
(160/98 mm Hg), but all other vital signs and neurologic examination were normal. Unenhanced head CT was normal, and a lumbar puncture was acellular with normal protein and glucose. The patient was diagnosed with migraine by the emergency department physician, reassured, and discharged with a prescription for 10 tablets of oxycodone.
The patient returned to the emergency department 2 days later with a recurrent headache that occurred while straining on the toilet. It was explosive and generalized, and again he vomited several times. Examination again revealed elevated blood pressure (170/100 mm Hg), and repeat head CT was again negative. MRI brain with gadolinium was ordered and revealed increased signal intensity in the posterior white matter of the occipital lobes on fluid-attenuated inversion recovery (FLAIR) sequences and gadolinium leakage through a breeched blood-brain barrier on contrast-enhanced FLAIR sequences. Magnetic resonance angiography (MRA) was ordered and showed multiple segmental areas of vasoconstriction in the basilar and middle cerebral arteries.
This patient has reversible cerebral vasoconstriction syndrome (RCVS). He was misdiagnosed with migraine because the headache and associated symptoms met International Classification of Headache Disorders, Third Edition (ICHD-3) criteria for migraine.4 However, he presented with a thunderclap headache and had no prior history of migraine or recurrent headache, and at least five attacks are required for the diagnosis of migraine. In addition, he had a negative CT and lumbar puncture, effectively ruling out subarachnoid hemorrhage. However, the most common cause of thunderclap headache is RCVS, which requires parenchymal brain imaging and noninvasive vascular imaging to make the diagnosis. Recurrent thunderclap headache is the hallmark of RCVS. The most common triggers are activities that induce a Valsalva maneuver, such as sexual intercourse and straining during defecation. Hypertension is present in 50% of patients with RCVS. The gadolinium-enhanced MRI revealed changes consistent with posterior reversible encephalopathy syndrome (PRES), which is present in at least 15% of patients, and gadolinium extravasation indicating endothelial dysfunction, which is present in about 70% of patients with definite RCVS. MRA demonstrated multifocal vasoconstriction. RCVS can present with intracerebral hemorrhage and ischemic stroke, the latter usually occurring in the second or third week after onset when vasoconstriction becomes most severe. This case illustrates the importance of imaging the brain and the cerebral vasculature with MRI in patients with thunderclap headache, especially after ruling out subarachnoid hemorrhage with a negative head CT and lumbar puncture.
COMMENT
574
JUNE 2021
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

In addition to the red flag features within the SNOOP4 acronym, a patient presenting for a single episode of headache as opposed to recurrent or persistent headache should always raise suspicion of a secondary cause. A particular headache that raised the patient’s or a family member’s concern may alert the clinician to a thunderclap headache or headache that was substantially different from previous headaches. Asking about whether a headache was sudden in onset is often not sufficient to determine whether a headache was thunderclap in onset. Being more specific by asking whether the headache went from zero to 10 in intensity within seconds or 1 minute or using a hand gesture, such as a clap, is prudent to make it clear that sudden means absent to severe within 1 minute and not over the course of many minutes to hours. It is also helpful to ask what the patient was doing when the headache began. Sometimes patients will then respond with information that they otherwise might not volunteer spontaneously and that may signify a truly thunderclap onset (eg, during sexual intercourse, during defecation) (CASE 1-1).
One pitfall that may be encountered in practice is to overlook a secondary cause for headache because the headache phenotype is consistent with migraine, tension-type headache, or a trigeminal autonomic cephalalgia, such as cluster headache. Although the number of primary headache disorders is substantial, the clinical features are usually restricted to one of these three phenotypes. In other words, the clinical features that are often associated with migraine
(eg, unilateral headache, throbbing headache, photophobia, nausea), cluster headache (eg, unilateral lacrimation, nasal congestion, rhinorrhea), or tension-type headache (featureless dull pressure without accompanying symptoms) may be seen in a wide variety of neurologic and systemic diseases. The clinician should therefore be alert to the overlapping features of primary and secondary headaches and be vigilant about investigating for red flag features and assessing the temporal profile (sudden onset of a single headache or loss of pain-free periods between recurrent headaches) regardless of the clinical “phenotype” of the headache. This principle is the reason the International Classification of Headache Disorders, Third Edition (ICHD-3) diagnostic criteria for each headache disorder include an absolute criterion that must be met: “Not better accounted for by another ICHD-3 diagnosis.”4
NEUROIMAGING FOR HEADACHE
CT of the head has a very limited role in the evaluation of secondary headache disorders. Head CT without contrast is useful to exclude intracranial blood in patients suspected of having a subarachnoid hemorrhage, epidural or subdural hematoma, or intraparenchymal hemorrhage. It is also useful in identifying skull fractures in patients who have experienced trauma. An estimated 80 million CT scans are performed annually in the United States, and an estimated 50% of these imaging studies are believed to be medically unnecessary. Moreover, of particular concern is the overuse of CT in children, in whom the vulnerability to radiation exposure is higher and cumulative.5 Indeed, epidemiologic studies have demonstrated an increased cancer risk associated with CT scans performed during childhood, and the National Cancer Institute has recently demonstrated that compared with the general population, the incidence of brain tumors was higher in a cohort of children who had undergone CT.
When evaluating a head CT for possible subarachnoid hemorrhage, it is important to identify the locations where subarachnoid blood may be less conspicuous and thus overlooked. The acronym PITS (parenchymal, intraventricular,
KEY POINTS
● The SNOOP4 acronym is a useful guide to assist clinicians in systematically evaluating for warning symptoms and signs of a secondary cause of headache.
● Since secondary causes of headache often have features that resemble migraine, tension-type headache, or a trigeminal autonomic cephalalgia, caution must be exercised and warning signs and symptoms of secondary headache must be evaluated.
● A headache history is the most important aspect of the evaluation of a patient presenting with headache, and eliciting worrisome features with directed questioning is necessary. The history must be taken without assuming that key features will be volunteered by the patient.
● Brain MRI is the imaging procedure of choice when evaluating for intracranial or neurovascular causes of headache. Other than the detection of skull fracture or acute intracranial blood, the use of CT in the evaluation of secondary headaches should be restricted, especially in children.
CONTINUUMJOURNAL.COM 575 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

DIAGNOSING SECONDARY AND PRIMARY HEADACHE DISORDERS
TABLE 1-2
truncal, sulci) may be useful in making certain these locations are systematically evaluated:
u Parenchymalblood,especiallywhenthesylvianfissureiscompressed,mayobscurethe subarachnoid blood and a middle cerebral artery aneurysm that ruptured
u Intraventricularblood,especiallyasmallamountofbloodlayeringthedependentand posterior portion of the lateral ventricle, can also easily be overlooked when the focus is on the parenchyma
u Truncal(pons,sometimesreferredtoasthetrunk)subarachnoidhemorrhagemaybe present in the prepontine, perimesencephalic, or interpeduncular cisterns
u Subarachnoidbloodmaybelimitedtothesulciinsomepatients,particularlyaftertrauma or in those with reversible cerebral vasoconstriction syndrome (RCVS)
For the majority of secondary intracranial causes of headache, MRI is the imaging study of choice if not contraindicated. For parenchymal, dural, leptomeningeal, posterior fossa, and intraventricular pathology, brain MRI increases the yield and resolution for identifying secondary causes. The acronym PIN (“pin” the diagnosis) can be helpful when considering the diagnoses that are best visualized by brain MRI:
u Pressureabnormalities:intracranialhypertension(idiopathicintracranialhypertension and secondary), intracranial hypotension (CSF leaks)
u Infection:meningitis,encephalitis,cerebritis,sphenoidsinusitis
u Neoplasticdisease:parenchymalandextraaxialneoplasms(especiallyposteriorfossa),
meningeal carcinomatosis, pituitary tumor, brain metastases
When the index of suspicion for cerebrovascular pathology as a cause of headache is high, especially in context of a thunderclap headache, MRI or CT of the extracranial and intracranial arteries and the intracranial venous system is essential.6 The vascular disorders that should be considered in the evaluation of thunderclap headache are outlined in TABLE 1-2.
MRI, when available, may be superior to CT imaging of the cerebrovasculature to avoid radiation and to enable comparison with follow-up scans, for which MRI
Disorders Associated With Thunderclap Headache
Vascular (vascular imaging required)
◆ Subarachnoid hemorrhage
◆ Arterial (vertebral, carotid, intracranial artery) dissection ◆ Cerebral venous sinus/cortical vein thrombosis
◆ Reversible cerebral vasoconstriction syndrome Nonvascular
◆ Spontaneous intracranial hypotension
◆ Pituitary apoplexy
◆ Colloid cyst of the third ventricle
◆ Acute hypertensive crisis
576
JUNE 2021
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

may be more suitable. Imaging of the brain parenchyma with MRI is also necessary to rule out some early changes that may be consistent with certain secondary disorders, such as posterior reversible encephalopathy syndrome (PRES), or subclinical infarction in patients with arterial dissection. Even when appropriate diagnostic imaging has been obtained, distinguishing between certain secondary headaches can be challenging. For example, the diffuse multifocal vasoconstriction associated with RCVS may be difficult to distinguish from other arteriopathies, such as central nervous system vasculitis. Recently, a scoring algorithm was developed (the RCVS2 score), which demonstrated that a score or 5 or more had 99% specificity and 90% sensitivity for diagnosing RCVS, whereas a score of 2 or less had 100% specificity and 85% sensitivity for excluding RCVS.7 Recurrent thunderclap headache over a period of days to weeks is the sine que non of RCVS, makes up half the total RCVS2 score, and will reliably distinguish RCVS from central nervous system vasculitis, especially when associated with a trigger (eg, sexual intercourse, straining, bathing) and normal parenchymal brain imaging on MRI.
When ordering an MRI for a presumed secondary cause for headache, it is important to know the correct sequences to request, when gadolinium is helpful, and the characteristic/diagnostic findings of the disease/disorder for which imaging is being done. Disorders of intracranial pressure are important causes of secondary headache that may be assessed with imaging. When examining a brain MRI for idiopathic intracranial hypertension and spontaneous intracranial hypotension secondary to a CSF leak, awareness of and a keen eye for the abnormalities that may be seen in both of these disorders is important
(TABLE 1-38 and TABLE 1-49).
Although several of the features of spontaneous intracranial hypotension listed in TABLE 1-4, including subdural fluid collections and pachymeningeal enhancement, are qualitatively distinctive and often easily recognizable on brain MRI, other features require a more objective and quantitative assessment. For example, with regard to venous sinus congestion, the venous distention sign is best seen on T1-weighted sagittal imaging of the transverse sinus.10 Although not easily quantified, when the transverse sinus is visualized in its midportion on sagittal images of the brain, the contour of the dominant (larger) transverse sinus normally has a concave or straight inferior border, but in patients with intracranial hypotension, the inferior border takes on a distended appearance with a convex bulging of its inferior border. The sensitivity and specificity of the venous
Imaging Features of Idiopathic Intracranial Hypertensiona
TABLE 1-3
Imaging feature
Reduced pituitary gland height (empty sella syndrome)
Increased optic nerve sheath diameter
Flattening of posterior globe
Transverse venous sinus stenosis
Any three out of four features
a Data from Mallery RM, et al, J Neuroophthalmol.8
Sensitivity/specificity
80%/64%
51%/83%
97%/53%
78%/unknown
64%/100%
CONTINUUMJOURNAL.COM 577 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

DIAGNOSING SECONDARY AND PRIMARY HEADACHE DISORDERS
TABLE 1-4
distention sign for the diagnosis of intracranial hypotension is approximately 94%. Brain sagging occurs in 18% to 61% of individuals with intracranial hypotension, and both qualitative signs and quantitative measures can be helpful and important in radiologically confirming its presence. Ventricular effacement, narrowing of the chiasmatic cistern and the prepontine cistern, and cerebellar tonsillar descent are qualitative MRI features of a sagging brain.11 Recently, a nine-point predictive scoring system based on the six most discriminating imaging features of spontaneous intracranial hypotension was developed and validated (TABLE 1-5).12 The score is based on three qualitative and three quantitative signs and identifies a patient with a high (score ≥5), intermediate (score 3 to 4), or low (score ≤2) probability of having a CSF leak. This may guide the clinician’s diagnostic and treatment decision making regarding myelographic procedures and targeted percutaneous or surgical dural sealing treatments.
Gadolinium may be helpful in characterizing parenchymal brain lesions and for diseases that are associated with pachymeningeal pathology (eg, CSF leak/intracranial hypotension, granulomatous pathology such as sarcoidosis and granulomatosis with polyangiitis) or leptomeningeal pathology (eg, leptomeningeal carcinomatosis). Gadolinium is also useful for characterizing intracranial tumors, infections, or other mass lesions and when evaluating for breakdown of the blood-brain barrier that may be seen in posttraumatic headache (postconcussion)13 or in patients with RCVS.14 The recommended MRI sequences when evaluating for thunderclap headache are outlined in TABLE 1-6.15
PRIMARY HEADACHE DISORDERS
Like secondary headache disorders, primary headache disorders are defined by a set of operational diagnostic criteria. The ICHD-3 criteria define three major categories of disorders: primary headaches, secondary headaches, and cranial neuralgias and facial pain.4 The three major and most common primary headache disorders are migraine, tension-type headache, and trigeminal autonomic cephalalgias. Although tension-type headache is the most common primary headache disorder in the general population, migraine is overwhelmingly the most common primary headache disorder presenting to clinicians, especially neurologists. In the Landmark Study involving 1203 male and female patients
Imaging Features of Intracranial Hypotension Using the Mnemonic SEEPSa,b
Imaging feature
Subdural fluid collection
Enhancement of pachymeninges
Engorgement of venous sinuses
Pituitary enlargement/hyperemia
Sagging of brain
a Data from Schievink WI, JAMA.9
b Invariably secondary to spinal CSF leak.
Prevalence range
36-50%
56-83%
48-93%
5-63%
18-61%
578
JUNE 2021
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Scoring System Using Six Imaging Signs Most Discriminative for Spontaneous Intracranial Hypotensiona
Imaging characteristic
Engorgement of venous sinus
Pachymeningeal enhancement
Subdural fluid collection
Suprasellar cistern (≤4 mm) Prepontine cistern (≤5 mm) Mamillopontine distance (≤6.5 mm)
a Data from Dobrocky T, et al, JAMA Neurol.12
TABLE 1-5
Point score
2
2
1
2
1
1
Recommended MRI Sequences When Evaluating for Thunderclap Headachea
TABLE 1-6
MRI sequences
T1, T2
Gradient recalled echo (GRE) (T2*) or susceptibility-weighted imaging (SWI)
Magnetic resonance angiography (MRA)
Magnetic resonance venography (MRV)
T1 with contrast (axial, sagittal, coronal)
Cervical T1 fat saturation with contrast
CSF = cerebrospinal fluid; MRI = magnetic resonance imaging. a Data from Chen SP et. al, J Headache Pain.15
Imaging features
Exclude structural lesions or blood products (eg, pituitary apoplexy)
Hemosiderin deposition from subtle SAH or parenchymal microbleeds
Exclude vasoconstriction, aneurysm, dissection
Exclude cerebral venous sinus/cortical vein thrombosis
CSF leak/spontaneous intracranial hypotension
Exclude cervical carotid artery dissection
Fluid-attenuated inversion recovery (FLAIR)/ contrast-enhanced FLAIR/dynamic contrast-enhanced MRI
White matter lesions and distal hyperintense vessels (RCVS), subtle (sulcal) subarachnoid hemorrhage (SAH), posterior reversible encephalopathy syndrome (PRES) (with/without RCVS)
Diffusion-weighted imaging/apparent Vasogenic and cytotoxic edema (eg, PRES versus ischemic diffusion coefficient stroke)
CONTINUUMJOURNAL.COM 579 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

DIAGNOSING SECONDARY AND PRIMARY HEADACHE DISORDERS
TABLE 1-7
between 18 and 65 years of age who consulted their primary care physician with headache as a primary or secondary concern, 94% of patients with either a physician diagnosis of migraine or nonmigraine primary headache actually had either migraine (76%) or probable migraine (18%).16 Only 3% had episodic tension-type headache. The study concluded that the vast majority of patients consulting their physicians with episodic headache as a primary or secondary concern have migraine, regardless of whether or not the patients consider their headaches to be migraine.
Therefore, it is important for the clinician to have a working knowledge of the ICHD-3 classification criteria for migraine (TABLE 1-7). A few caveats should be considered when applying the criteria that can help avoid pitfalls. First, at least five attacks meeting the criteria are required for the diagnosis. This avoids misdiagnosing a sinister secondary headache (eg, subarachnoid hemorrhage) that could otherwise meet the headache and associated symptom criteria for migraine. Second, no single feature is either necessary or sufficient to make the diagnosis; the diagnosis requires only two of the pain criteria and one associated symptom criterion. Third, in patients who meet either the pain criteria or the associated symptom criteria, the diagnosis is probable migraine. In other words, a bilateral and generalized squeezing headache of moderate intensity that causes avoidance of routine physical activity and is not associated with photophobia or nausea meets criteria for probable migraine. This type
ICHD-3 Diagnostic Criteria for Migraine Without Auraa Migraine without aura
A B C
D
E
At least five attacksb fulfilling criteria B-D Headacheattackslasting4-72hours(untreatedorunsuccessfullytreated)c,d Headachehasatleasttwoofthefollowingfourcharacteristics:
1 Unilateral location
2 Pulsatingquality
3 Moderateorseverepainintensity
4 Aggravationbyorcausingavoidanceofroutinephysicalactivity(eg,walkingorclimbing stairs)
Duringheadacheatleastoneofthefollowing:
1 Nauseaand/orvomiting
2 Photophobiaandphonophobia
Not better accounted for by another ICHD-3 diagnosis
580
JUNE 2021
ICHD-3 = International Classification of Headache Disorders, Third Edition.
a Reprinted with permission from Headache Classification Committee of the International Headache Society, Cephalalgia.4 © 2018 International Headache Society.
b One or a few migraine attacks may be difficult to distinguish from symptomatic migrainelike attacks. Furthermore, the nature of a single or a few attacks may be difficult to understand. Therefore, at least five attacks are required. Individuals who otherwise meet criteria for migraine without aura but have had fewer than five attacks should be coded probable migraine without aura.
c When the patient falls asleep during migraine and wakes up without it, duration of the attack is reckoned until the time of awakening.
d In children and adolescents (aged under 18 years), attacks may last 2-72 hours (the evidence for untreated durations of less than two hours in children has not been substantiated).
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

of presentation, especially in patients with a history of anxiety or depression (a common comorbidity in patients with migraine) and especially if neck pain accompanies the headache (present in at least 70% of patients with migraine) often receives a misdiagnosis of tension-type headache.
Migraine is also associated with a variety of symptoms that occur commonly but are not part of the diagnostic criteria. Premonitory symptoms such as fatigue, impaired concentration, neck stiffness, yawning, photophobia, nausea, increased urination, irritability, and changes in mood occur hours or days before the onset of pain and are seen in about 70% of patients.17 The presence of neck pain (75%), sinus pain/pressure (40%), and cranial parasympathetic
ICHD-3 Diagnostic Criteria for Migraine With Aura and Migraine With Typical Auraa
Migraine with aura
A AtleasttwoattacksfulfillingcriteriaBandC
B Oneormoreofthefollowingfullyreversibleaurasymptoms:
1 Visual
2 Sensory
3 Speechand/orlanguage 4 Motor
5 Brainstem
6 Retinal
C Atleastthreeofthefollowingsixcharacteristics:
1 Atleastoneaurasymptomspreadsgraduallyover≥5minutes
2 Twoormoreaurasymptomsoccurinsuccession
3 Eachindividualaurasymptomlasts5-60minutesb
4 Atleastoneaurasymptomisunilateralc
5 Atleastoneaurasymptomispositived
6 Theauraisaccompanied,orfollowedwithin60minutes,byheadache
D Not better accounted for by another ICHD-3 diagnosis
Migraine with typical aura
A AttacksfulfillingcriteriaformigrainewithauraandcriterionBbelow B Aura with both of the following:
1 Fullyreversiblevisual,sensory,and/orspeech/languagesymptoms 2 Nomotor,brainstem,orretinalsymptoms
ICHD-3 = International Classification of Headache Disorders, Third Edition.
a Reprinted with permission from Headache Classification Committee of the International Headache
Society, Cephalalgia.4 © 2018 International Headache Society.
b When, for example, three symptoms occur during an aura, the acceptable maximal duration is 3 60 minutes. Motor symptoms may last up to 72 hours.
c Aphasia is always regarded as a unilateral symptom; dysarthria may or may not be.
d Scintillations and pins and needles are positive symptoms of aura.
TABLE 1-8
CONTINUUMJOURNAL.COM 581 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

DIAGNOSING SECONDARY AND PRIMARY HEADACHE DISORDERS
TABLE 1-9
symptoms such as lacrimation and nasal congestion (50%) is, in part, responsible for the frequent misdiagnosis of migraine as tension-type headache or sinus headache.
The most frequent subtypes of migraine seen in clinical practice are migraine without and with aura (TABLE 1-8) and chronic migraine
(TABLE 1-9). Chronic migraine is often associated with the overuse of acute medications (TABLE 1-10). Both chronic migraine and medication-overuse headache may be overlooked in practice because patients with migraine may disregard and underreport days with headaches that are not severe, do not cause functional impairment, or that they do not believe to be consistent with migraine. Once a diagnosis of migraine is made, the following questions will ensure that the actual number of days with headache each month is accurately captured and that the diagnosis of chronic migraine or
ICHD-3 Diagnostic Criteria for Chronic Migrainea Chronic migraine
A Headache(migrainelikeortension-type–likeb)on≥15days/monthfor>3months,and fulfilling criteria B and C
B OccurringinapatientwhohashadatleastfiveattacksfulfillingcriteriaB-Dformigraine without aura and/or criteria B and C for migraine with aura
C On≥8days/monthfor>3months,fulfillinganyofthefollowingc:
1 Criteria C and D for migraine without aura
2 CriteriaBandCformigrainewithaura
3 Believedbythepatienttobemigraineatonsetandrelievedbyatriptanorergot derivative
D NotbetteraccountedforbyanotherICHD-3diagnosisd,e,f ICHD-3 = International Classification of Headache Disorders, Third Edition.
a Reprinted with permission from Headache Classification Committee of the International Headache Society, Cephalalgia.4 © 2018 International Headache Society.
b The reason for singling out chronic migraine from types of episodic 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 patients are extremely difficult 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 migrainelike and tension-type–like headaches (but not secondary headaches).
c Characterization of frequently recurring headache generally requires a headache diary to record information on pain and associated symptoms day-by-day for at least 1 month.
d Because tension-type–like headache is within the diagnostic criteria for chronic migraine, this diagnosis excludes the diagnosis of tension-type headache or its types.
e New daily persistent headache may have features suggestive of chronic migraine. The latter disorder
evolves over time from migraine without aura and/or migraine with aura; therefore, when these criteria A-C are fulfilled by headache that, unambiguously, is daily and unremitting from <24 hours after its first onset, code as new daily persistent headache. When the manner of onset is not remembered or is otherwise uncertain, code as chronic migraine.
f The most common cause of symptoms suggestive of chronic migraine is medication overuse, as defined under medication-overuse headache. Around 50% of patients apparently with chronic migraine revert to an episodic migraine type after drug withdrawal; such patients are in a sense wrongly diagnosed as chronic migraine. Equally, many patients apparently overusing medication do not improve after drug withdrawal; the diagnosis of medication-overuse headache may be inappropriate 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 chronic migraine and for medication-overuse headache should be coded for both. After drug withdrawal, migraine will either revert to an episodic type or remain chronic, and should be rediagnosed accordingly; in the latter case, the diagnosis of medication-overuse headache may be rescinded.
582
JUNE 2021
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

medication-overuse headache (also known as rebound headache) is not overlooked (CASE 1-2):
u Howmanydayspermonthdoyouhaveaheadacheofanytypeorhowmanydaysper month are you completely free of headache (crystal clear) from morning until night?
u Howmanydayspermonthdoyoutakesomething,includingprescriptionand over-the-counter medications, to alleviate a headache?
CONCLUSION
Although headache is a ubiquitous symptom and a feature of many diseases and primary headache disorders, an accurate diagnosis of the underlying cause
of headache can be accomplished by clinicians using a simplified and standardized approach. First, a history of features that raise the suspicion for a secondary cause must be actively elicited by the clinician when taking a history. Using the SNOOP4 mnemonic can assist in identifying these worrisome features and guiding appropriate diagnostic investigations. Imaging is invariably an essential investigation in excluding most secondary causes, but it is important to select the most appropriate imaging study and be aware of the pitfalls and pearls in the interpretation of these imaging studies, especially for the most common secondary causes of headache. MRI of the brain parenchyma, dura, and cerebral blood vessels is the most appropriate imaging modality in the majority of cases. Special attention must be paid to patients with thunderclap headache as the cause is often vascular, treatment varies according to the cause, and the morbidity can be serious if these disorders are missed. Cardinal imaging features and novel scoring systems have
ICHD-3 Diagnostic Criteria for Medication-Overuse Headachea,b
Medication-overuse headache
A Headacheoccurringon≥15days/monthinapatientwithapreexistingheadachedisorder
B Regularoverusefor>3monthsofoneormoredrugsthatcanbetakenforacuteand/or symptomatic treatment of headachec,d,e
C NotbetteraccountedforbyanotherICHD-3diagnosis
ICHD-3 = International Classification of Headache Disorders, Third Edition.
a Reprinted with permission from Headache Classification Committee of the International Headache Society, Cephalalgia.4 © 2018 International Headache Society.
b Overuse is defined by the use of all acute medication on >10 days per month except for simple analgesics (eg, acetaminophen, nonsteroidal anti-inflammatory drugs), for which overuse is defined as use on >15 days per month.
c Patients should be coded for one or more subtypes of medication-overuse headache according to the specific medication(s) overused and the criteria for each below. For example, a patient who fulfils the criteria for triptan-overuse headache and the criteria for one of the subforms of nonopioid analgesic– overuse headache should receive both these codes. The exception occurs when patients overuse combination-analgesic medications, who are coded combination-analgesic-overuse headache and not according to each constituent of the combination-analgesic medication.
d Patients who use multiple drugs for acute or symptomatic treatment of headache may do so in a manner that constitutes overuse even though no individual drug or class of drug is overused; such patients should be coded medication-overuse headache attributed to multiple drug classes not individually overused.
e Patients who are clearly overusing multiple drugs for acute or symptomatic treatment of headache but cannot give an adequate account of their names and/or quantities are coded medication-overuse headache attributed to unspecified or unverified overuse of multiple drug classes until better information is available. In almost all cases, this necessitates diary follow-up.
TABLE 1-10
CONTINUUMJOURNAL.COM 583 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

DIAGNOSING SECONDARY AND PRIMARY HEADACHE DISORDERS
recently emerged for some of the most common, serious, and disabling secondary headache disorders. Awareness of these features is important as they can guide clinical decision making regarding treatment or subsequent investigations. If a secondary headache disorder is excluded, a primary headache disorder diagnosis should be made. “Headache not otherwise specified” is not an acceptable diagnosis. Since the vast majority of patients presenting to clinical attention with a primary headache disorder will have a subtype of migraine, a working familiarity with the diagnostic criteria for migraine is essential. However, it must always be kept in mind that if worrisome features are present, regardless of the phenotype of the headache or prior history of a primary headache disorder, further diagnostic investigations are inevitably appropriate and essential.
CASE 1-2
A 32-year-old woman presented for evaluation of headaches. The headaches had begun after the birth of her first child 2 years ago. They were preceded by yawning, fatigue, and irritability about 2 hours before the onset of headache. The headaches occurred about twice per week and reached a peak intensity of at least moderate pain within 30 minutes, typically beginning in the frontal and temporal head regions but spreading to involve the occiput and cervical and trapezius muscles. The headaches were throbbing in quality and were associated with tearing of both eyes, nausea, and a sensation of dizziness (disequilibrium). She had difficulty concentrating and processing information during the headaches. The headaches lasted about 12 hours, but the patient felt lethargic, nauseated, and in a “cognitive fog” for about 24 hours. When questioned further, she said she also had milder headaches that were throbbing and limited her activity to some extent, but they lasted only about 4 hours and were relieved with simple analgesics. These occurred about twice per week. The patient was taking an over-the-counter combination analgesic to treat or preempt the headaches at least 5 days per week. This pattern had been present for the past 18 months. The patient’s general physical and neurologic examination was normal.
This patient has migraine without aura, chronic migraine, and medication- overuse headache. The occurrence in the postpartum period is not uncommon. Her headaches meet International Classification of Headache Disorders, Third Edition (ICHD-3) criteria for chronic migraine and medication-overuse headache as migraine headaches occur at least 8 days per month, and she has at least 15 days of headache each month and uses an analgesic about 20 days per month. She has a premonitory phase and a postdromal phase that impair her ability to function for longer than the duration of the headache itself. Only when questioned about days of the month without any headache and days of the month when she took something to relieve the pain did it become evident that she has chronic migraine and medication-overuse headache.
COMMENT
584
JUNE 2021
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

REFERENCES
KEY POINTS
1 GBD 2016 Headache Collaborators. Global, regional, and national burden of migraine and tension-type headache, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2018;17(11):954-976. doi:10.1016/S1474-4422(18)30322-3
2 Do TP, Remmers A, Schytz HW, et al. Red and orange flags for secondary headaches in clinical practice: SNNOOP10 list. Neurology 2019;92(3): 134-144. doi:10.1212/WNL.0000000000006697
3 Dodick DW. Pearls: headache. Semin Neurol 2010; 30(1):74-81. doi:10.1055/s-0029-1245000
4 Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018; 38(1):1-211. doi:10.1177/0333102417738202
5 Meulepas JM, Ronckers CM, Smets A, et al. Radiation exposure from pediatric CT scans and subsequent cancer risk in the Netherlands. J Natl Cancer Inst 2019;111(3):256-263. doi:10.1093/ jnci/djy104
6 Yang CW, Fuh JL. Thunderclap headache: an update. Expert Rev Neurother 2018;18(12):915-924. doi:10.1080/14737175.2018.1537782
7 Rocha EA, Akif Topcuoglu M, Silva GS, Singhal AB. RCVS2 score and diagnostic approach for reversible cerebral vasoconstriction syndrome. Neurology 2019;92(7):e639-e647. doi:10.1212/ WNL.0000000000006917
8 Mallery RM, Rehmani OF, Woo JH, et al. Utility of magnetic resonance imaging features for improving the diagnosis of idiopathic intracranial hypertension without papilledema.
J Neuroophthalmol 2019;39(3):299-307 doi: 10.1097/WNO.0000000000000767]
9 Schievink WI. Spontaneous spinal cerebrospinal fluid leaks and intracranial hypotension. JAMA 2006;295(19):2286-2296. doi:10.1001/ jama.295.19.2286
DISCLOSURE
Continued from page 572
Academy for Continued Healthcare Learning; Cambridge University Press; Clinical Care Solutions; CME Outfitters; Curry Rockefeller Group; DeepBench; Global Access Meetings, Inc; KLJ Associates; Majallin LLC; MedLogix Communications; MJH Life Sciences; Miller Medical Communications, LLC; Oxford University Press; Southern Headache Society (Mountain Area Health Education Center); WebMD LLC/Medscape; and Wolters Kluwer, NV. Dr Dodick holds stock or stock options in Aural Analytics; Ctrl M Health; EPIEN Medical, Inc; ExSano
10 Farb RI, Forghani R, Lee SK, et al. The venous distension sign: a diagnostic sign of intracranial hypotension at MR imaging of the brain. AJNR Am J Neuroradiol 2007;28(8):1489-1493. doi:10.3174/ ajnr.A0621
11 Aslan K, Gunbey HP, Tomak L, et al. Magnetic resonance imaging of intracranial hypotension: diagnostic value of combined qualitative signs and quantitative metrics. J Comput Assist Tomogr 2018;42(1):92-99. doi:10.1097/ RCT.0000000000000646
12 Dobrocky T, Grunder L, Breiding PS, et al. Assessing spinal cerebrospinal fluid leaks in spontaneous intracranial hypotension with a scoring system based on brain magnetic resonance imaging findings. JAMA Neurol 2019; 76(5):580-587. doi:10.1001/jamaneurol.2018.4921
13 O’Keeffe E, Kelly E, Liu Y, et al. Dynamic blood-brain barrier regulation in mild traumatic brain injury. J Neurotrauma 2020;37(2):347-356. doi:10.1089/neu.2019.6483
14 Lee MJ, Cha J, Choi HA, et al. Blood-brain barrier breakdown in reversible cerebral vasoconstriction syndrome: implications for pathophysiology and diagnosis. Ann Neurol 2017; 81(3):454-466. doi:10.1002/ana.24891
15 Chen CY, Chen SP, Fuh JL, et al. Vascular wall imaging in reversible cerebral vasoconstriction syndrome—a 3-T contrast-enhanced MRI study. J Headache Pain 2018;19(1):74. doi:10.1186/ s10194-018-0906-7
16 Tepper SJ, Dahlof CG, Dowson A, et al. Prevalence and diagnosis of migraine in patients consulting their physician with a complaint of headache: data from the Landmark Study. Headache 2004;44(9):856-864. doi:10.1111/ j.1526-4610.2004.04167.x
17 Dodick DW. Migraine. Lancet 2018;391(10127): 1315-1330. doi:10.1016/S0140-6736(18)30478-1
Inc; Healint Pte Ltd; King-Devick Technologies, Inc; Matterhorn Medical Ltd; Nocira; Ontologics, Inc; Palion Medical; Precon Health Inc; Second Opinion/ Mobile Health, and Theranica Bio-Electronics Ltd. Dr Dodick receives research/grant support from the American Migraine Foundation, the Henry M. Jackson Foundation for the Advancement of Military Medicine, the National Institutes of
Health (R21 HD089035, U01 NS093334), the Patient- Centered Outcomes Research Institute, the Sperling Foundation, and the US Department of Defense (FP00114103) and patent royalties for a botulinum toxin dosage regimen for chronic migraine p

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

%d bloggers like this: