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08. Migraine Variants and Mimics

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CHAPTER 8
MIGRAINE VARIANTS AND
MIMICS
EDWARD H. KOVNAR, MD
Ominous and dramatic, migraine variants may be confused with stroke, hemorrhage, central nervous system infection, acute
intoxication, seizures, or expanding intracranial mass lesions. A careful history and physical and neurologic examination, supplemented by the timely application of neurodiagnostic studies, will allow accurate diagnosis and appropriate management.
Historically, migraine variants have been understood as
subtypes of complex or complicated migraine. Recent classification schemes have attempted to characterize these
unusual headache syndromes as distinct clinical phenomena. In 1998, the International Headache Society established diagnostic criteria for some but not all migraine
variants (Table 8-1). Beyond empiric labeling, specific clinical syndromes have now come to be recognized as separate from classic and common migraines from a genetic
and pathophysiologic point of view. Familial hemiplegic
migraine is an example of a particular migraine syndrome
in which an ion channelopathy may play a critical role in
the pathogenesis of the disorder. As additional epidemiologic and molecular genetic data accumulate, other
migraine syndromes may be understood not merely in
descriptive terms but also with respect to pathophysiology.
Familial Hemiplegic Migraine
The occurrence of episodic attacks of reversible hemiparesis or hemiplegia followed by headache has long been
classified as a subtype of migraine with aura. Such a history in an individual with one or more similarly affected
first-degree family members is characteristic of familial
hemiplegic migraine. This striking clinical syndrome typically begins in childhood or adolescence, with a mean age
of onset of 12 years. Precipitating events may include emotional stress or minor head trauma. In most cases, ipsilateral sensory disturbances accompany the motor deficit.
Lethargy and confusion may further complicate the preCurrent Management in Child Neurology, Third Edition
В© 2005 Bernard L. Maria, All Rights Reserved
BC Decker Inc
TABLE 8-1. International Headache Society Classification
1.1 Migraine without aura (common migraine)
1.2 Migraine with aura (classic migraine)
1.2.1 Migraine with typical aura
1.2.2 Migraine with prolonged aura
1.2.3 Familial hemiplegic migraine
1.2.4 Basilar migraine
1.2.5 Migraine aura without headache
1.2.6 Migraine with acute onset aura
1.3 Ophthalmologic migraine
1.4 Retinal migraine
1.5 Childhood periodic syndromes
1.5.1 Benign paroxysmal vertigo
1.5.2 Alternating hemiplegia of childhood
sentation. Aphasia may accompany dominant hemisphere
involvement. The neurologic symptoms typically last
hours to days. Focal neurologic deficits are typically followed within 30 to 60 minutes by severe, pulsating
headache associated with nausea and vomiting. Although
complete resolution of neurologic signs and symptoms is
the rule, residual neurologic deficits have been reported.
Recurrent attacks of hemiparesis and headache with residual deficits must suggest the possibility of an underlying
vascular, hypercoagulable, metabolic, neoplastic, infectious, or inflammatory process.
To meet published diagnostic criteria for familial hemiplegic migraine, a positive history of at least one similarly
affected first-degree family member is required. The inheritance pattern is assumed to be autosomal dominant. An
Migraine Variants and Mimics
Pages 43–49
44 / The Office Visit: Headache
estimated 50% of affected pedigrees are linked to markers
on the short arm of chromosome 19 (19p13) (Joutel et al,
1993). In approximately 20% of families with familial
hemiplegic migraine, progressive cerebellar ataxia occurs
in addition to migraine. Magnetic resonance imaging
(MRI) in these individuals demonstrates cerebellar atrophy. All the families with familial hemiplegic migraine and
progressive ataxia have been linked to 19p13 markers. The
candidate region of the 19p13 locus for familial hemiplegic
migraine encompasses the gene CACNA1A, which codes
for the alpha 1A subunit of the P/Q-type voltage-gated
calcium channel. Other allelic mutations in this gene locus
are associated with episodic ataxia type 2 and spinocerebellar ataxia type 6. Individuals with episodic ataxia type
2 have been successfully treated with the carbonic anhydrase inhibitor acetazolamide. These observations provide
compelling evidence that familial hemiplegic migraine is
associated with an ion channelopathy that may be
amenable to specific treatment. Other families with familial hemiplegic migraine without ataxia have been linked to
markers on the long arm of chromosome 1 (1q23).
Mutations in the gene for the Na+,K+-adenosinetriphosphatase (ATPase) pump (ATP1A2) encoded on 1q23 have
been linked not only to familial hemiplegic migraine but
also to benign familial infantile convulsions.
The occurrence of acute focal neurologic deficits followed by headache necessitates a thorough investigation
for cardiac, cerebrovascular, prothrombotic, metabolic,
neoplastic, and inflammatory disorders (Table 8-2).
Among the less common but important etiologies on this
list is mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like attacks (MELAS). MELAS is characterized clinically by the following features: (1) stroke-like
episodes, typically before age 40 years; (2) encephalopathy,
manifested by seizures, dementia, or both; and (3) evidence of a mitochondrial myopathy with lactic acidosis,
ragged-red fibers, or both. In addition, at least two of the
following should be present: normal early development,
recurrent headache, or recurrent vomiting. Features
reported in most patients include exercise intolerance, limb
weakness, short stature, and hearing loss. The headaches of
MELAS are often most severe during the acute phase of the
strokes. The high frequency of migraine-like headaches in
patients with MELAS creates overlap with the clinical presentation of familial hemiplegic migraine. Fifteen different
mitochondrial DNA point mutations have been associated
with the MELAS clinical phenotype, the most prevalent of
which is an A-to-G transition mutation at nucleotide 3243
of the tRN-Leu-(UUR) (Goto et al, 1990). This mutation
has been found in about 80% of cases of MELAS.
The diagnostic approach to acute hemiparesis or hemiplegia in a previously unaffected individual must begin
promptly with appropriate neuroimaging. Although a norCurrent Management in Child Neurology, Third Edition
В© 2005 Bernard L. Maria, All Rights Reserved
BC Decker Inc
TABLE 8-2. Differential Diagnosis of Acute Hemiplegia in
Childhood
Cardiac disease
Bacterial endocarditis
Cyanotic congenital heart defects (right-to-left shunt)
Mural thrombus
Cerebrovascular malformations
Arteriovenous malformations
Sturge-Weber syndrome
Epilepsy (Todd’s paralysis)
Hemoglobinopathy (sickle cell disease)
Prothrombotic states
Migraine
Mitochondrial disease
MELAS
Neoplasia
Tumor
Leukemia (treatment-related)
Lymphoma
Trauma
Arterial dissection
Intracranial hemorrhage
Vasculitis
Systemic lupus
Takayasu’s arteritis
Vasculopathy
Moya moya syndrome
Other
Alternating hemiplegia of childhood
MELAS = mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike attacks.
mal cranial computed tomography scan can help allay
concern regarding an evolving neurosurgical emergency,
MRI with and without contrast is necessary to adequately
evaluate a possible neoplastic process, white matter lesion, or
cerebrovascular event. Exclusion of prothrombotic states
requires some if not all of the studies listed in Table 8-3. To
exclude endocarditis, mural thrombi, or passage of systemic
emboli via a patent foramen ovale, transthoracic echocardiography is required. The appropriate role of transesophageal
echocardiography in childhood stroke is the subject of
ongoing clinical investigation. The presence of fever,
meningeal signs, or suspicion of herpes simplex encephalitis
requires a lumbar puncture for gram stain, cell count, appropriate cultures, and polymerase chain reaction.A diagnosis of
MELAS is suggested by the presence of an elevated level of
protein in the cerebrospinal fluid (CSF) as well as elevated CSF
and serum lactic acid levels. The diagnosis may be confirmed
by mitochondrial DNA analysis or direct assay of mitochondrial enzymes from fresh muscle tissue.
After excluding structural, vascular, and infectious disorders, acute management of hemiplegic migraine is largely
Migraine Variants and Mimics
Pages 43–49
Migraine Variants and Mimics / 45
TABLE 8-3. Evaluation for a Suspected Prothrombotic
State
Activated protein C resistance
Anticardiolipin antibodies
Lupus anticoagulant
Antithrombin III
Protein C
Protein S
Factor V Leiden mutation
Prothrombin gene mutation
Serum homocysteine
symptomatic. The safety, tolerability, and efficacy of the
triptan drugs or dihydroergotamine have not been tested in
hemiplegic migraine. The triptan drugs would also be contraindicated in other classes of complicated migraine, such
as basilar migraine. Appropriate supportive care would,
however, include administration of analgesics, antiemetics, and intravenous fluids. Given the effectiveness of carbonic anhydrase inhibitors in the management of episodic
ataxia type 2, a trial of acetazolamide should be considered
in the child with confirmed familial hemiplegic migraine.
Other preventive treatment options might include a
ОІ-blocker, a calcium channel blocker, or an antiseizure
medication, such as divalproex sodium.
Basilar Artery Migraine
Basilar migraine, also known as Bickerstaff ’s migraine, is
the most common of the complicated migraine variants
and accounts for 3 to 19% of all cases of migraine. Although
the incidence of this syndrome reportedly peaks in adolescence, the syndrome has been known to occur in patients
as young as 12 to 18 months. Girls are more commonly
affected than boys. Affected children will have attacks of
intense dizziness and gait ataxia. Diagnostic criteria include
two or more of the following symptoms: bilateral visual
field deficits, dysarthria, vertigo, tinnitus, decreased hearing,
double vision, ataxia, bilateral paresthesias, bilateral paresis, and decreased level of consciousness. The associated
headache is typically throbbing, intense, and occipital in
location and often associated with nausea and vomiting.
The pathogenesis of basilar migraine is unknown.
The differential diagnosis includes tumors within the
posterior fossa (ie, medulloblastoma, ependymoma, cerebellar astrocytoma, or brainstem glioma), arteriovenous
malformations, congenital malformations (eg, Chiari type
I), and vertebral basilar insufficiency (eg, vertebral artery
dissection), acute intoxication, and inborn errors of
metabolism (eg, urea cycle defects, Hartnup disease, and
branched-chain aminoacidopathy). Initial evaluation
includes screening for an acute metabolic disorder or drug
ingestion. MRI and magnetic resonance angiography
Current Management in Child Neurology, Third Edition
В© 2005 Bernard L. Maria, All Rights Reserved
BC Decker Inc
(MRA) are often required to evaluate the possibility of a
posterior fossa mass or a vascular lesion involving the
vertebral-basilar arterial circulation. If visual disturbances
are accompanied by either loss of consciousness or
convulsive seizure activity, benign epilepsy of childhood
with occipital spikes should be considered and evaluated
with a sleep-deprived electroencephalogram (EEG).
Treatment for acute attacks is largely supportive. Triptan
drugs and dihydroergotamine are contraindicated in basilar migraine. Prophylaxis for recurrent attacks may include
a tricyclic antidepressant, ОІ-blocker, or antiseizure
medication (divalproex sodium).
Confusional Migraine
Confusional migraine comprises the clinical symptoms of
an acute confusional state, lasting from 4 to 24 hours,
accompanied by one or more of the following: blindness,
paresthesias, hemiparesis, or amnesia. Affected individuals
become restless, agitated, disoriented, unable to communicate, and, occasionally, combative. The typical age of
onset is between 8 and 17 years; boys are more commonly
affected than girls. Episodes may be precipitated by minor
head trauma. The term “football header’s migraine” is used
in Europe to describe the occurrence of an acute confusional state and headache in a soccer player after successfully “heading” the ball. Similar phenomenon may follow
other types of minor head trauma.
There appears to be a considerable degree of overlap
between confusional migraine, hemiplegic migraine, and
basilar migraine. Hence, no separate classification criteria
have been established for this syndrome. Therefore, it may
be more appropriate to include acute confusional migraine
under hemiplegic migraine if aphasia, hemiplegia, and
confusion predominate. Those with bilateral blindness,
vertigo, ataxia, and confusion would be best classified as
basilar migraine. The differential diagnosis for acute confusion with focal neurologic signs includes epilepsy with
postictal state, drug intoxication, metabolic encephalopathy, encephalitis, brain abscess, cerebrovascular disease,
and vasculitis. Evaluation should include cranial MRI and
MRA, drug screen, metabolic panel, CSF exam, and EEG.
Migraine Aura without Headache
Spatial distortions and other visual illusions may occur as
a migraine aura without headache. The similarity to Alice’s
metamorphosis in Lewis Carroll’s Alice’s Adventures in
Wonderland and Through the Looking Glass prompted the
term “Alice in Wonderland” syndrome. Affected children
experience alteration in visual perception, including
micropsia, where objects appear smaller than they actually
are; macropsia, where objects look larger; teleopsia, where
Migraine Variants and Mimics
Pages 43–49
46 / The Office Visit: Headache
objects appear far away; or metamorphopsia, where
objects, including faces, appear distorted. Other migrainous symptoms may include somatosensory disturbances,
impaired speech, motor weakness, and brainstem signs.
The differential diagnosis of visual auras without headache
includes benign epilepsy of childhood with occipital
spikes, acute metabolic disturbances, such as hypoglycemia, and adverse effects of medications taken either
as prescribed or by accidental ingestion.
Ophthalmoplegic Migraine
Ophthalmoplegic migraine is a rare but dramatic clinical
syndrome that may occur at any age. Characteristic symptoms and signs include the presence of periorbital or
retro-orbital eye pain and impairment of ocular motility.
Although this syndrome tends to appear in adolescence,
it may also occur in infants as young as 5 to 7 months of
age. Older children will describe blurred vision or
diplopia, whereas younger children may simply rub their
eyes. Symptoms referable to the oculomotor nerve occur
in 80% of cases. Ptosis often precedes the ophthalmoplegia. Pupillary involvement may be partial or complete.
Less commonly, involvement of the trochlear or abducens
nerve may occur. Symptoms may last for a few days or as
long as 4 weeks. The eye pain is usually mild and may initially be dismissed as local irritation. Episodes are usually
isolated or sporadic. Permanent sequelae may occur after
repeated attacks.
The mechanism of ophthalmoplegic migraine is
unknown but may involve ischemic, compressive, or inflammatory processes. Diagnostic criteria include the following:
(1) at least two attacks of migraine-type headache overlapping or followed by paresis of one or more of the cranial
nerves III, IV, or VI and (2) exclusion of a lesion of the
parasellar region, orbital fissure, or posterior fossa. The differential diagnosis includes Graves disease, ocular myasthenia, Kearns-Sayre syndrome, Miller Fisher variant of
Guillain-BarrГ© syndrome, cerebral aneurysms involving the
internal carotid artery or posterior communicating artery,
orbital tumor, abscess, or periorbital cellulitis. Initial evaluation should be directed toward exclusion of structural
lesions of the orbital apex, sphenoid rim, cavernous sinus,
and brainstem and includes MRI of the brain and orbits.
MRA will allow detection of an aneurysm 5 mm or larger.
Smaller aneurysms may require conventional angiography
and should be considered in patients with a third nerve
palsy who are 12 years and older.Younger children with selflimited symptoms need not undergo invasive neurodiagnostic studies. Methylprednisolone (Solu-MedrolВ®) 30 mg/kg
given daily for three successive days has been recommended
for acute attacks. The triptan agents and dihydroergotamine
have not been adequately tested in this clinical setting.
Current Management in Child Neurology, Third Edition
В© 2005 Bernard L. Maria, All Rights Reserved
BC Decker Inc
Retinal Migraine
Retinal migraine is relatively rare and is usually seen in
adolescents or young adults. Typical visual symptoms
include monocular “black-out” or “gray-out” with or without other visual disturbances, lasting from seconds to minutes or, rarely, over an hour. The descending, curtain-like
evolution of amaurosis fugax, more typical of adults with
atherosclerotic or embolic disease, is infrequent in retinal
migraine. Headaches associated with this syndrome are
usually mild, with a 30- to 60-minute interval between the
onset of visual changes and the onset of ipsilateral retroorbital head pain. Funduscopic examination during an
attack may reveal vascular constriction with retinal pallor.
Although resolution of all symptoms is usually complete,
rare cases of permanent visual deficits have been reported.
Evaluation for vascular disease, including carotid artery
dissection, cardiogenic emboli, and hypercoagulable disorders, must be considered. Once embolic disease and
other forms of cerebrovascular disease have been excluded,
management is largely supportive. No randomized,
prospective clinical trials have been reported that support
the use of amitriptyline, antiseizure medications, or
ОІ-blockers. In limited numbers of cases, treatment with
calcium channel blockers (nifedipine or verapamil) may
stop recurrent bouts of presumed retinal migraine.
Periodic Syndromes of Childhood
Two clinical syndromes, previously referred to as migraine
equivalents, are currently included by the International
Headache Society under the classification of childhood
periodic syndromes. These are benign paroxysmal vertigo
and alternating hemiplegia of childhood. Other periodic
syndromes that could be included under this heading
include paroxysmal torticollis, cyclic vomiting, and
abdominal migraine.
Benign Paroxysmal Vertigo
Benign paroxysmal vertigo is characterized by the occurrence of brief attacks of intense vertigo in an otherwise
healthy child. Typical attacks are so severe that the child
becomes unable to stand independently and grabs for the
nearest stationary object for support. Episodes usually last
several minutes, during which repeated vomiting is common and consciousness is preserved. Nystagmus may be
detected by a careful observer. Afterward, the child may
appear exhausted but returns to baseline after sleeping.
The typical age of onset of benign paroxysmal vertigo is
18 months. Episodes may occur one to four times per
month and recur over a 1- to 2-year period. A child with a
typical history whose neurologic examination is normal
between episodes may not require neurodiagnostic testing;
Migraine Variants and Mimics
Pages 43–49
Migraine Variants and Mimics / 47
instead, the practitioner may opt for simple observation.
In this setting, a family history of migraine is reassuring.
The persistence of symptoms or abnormal findings on
neurologic exam between acute episodes warrants metabolic and toxicologic screening and an evaluation of the
posterior fossa with cranial MRI.
Alternating Hemiplegia of Childhood
Alternating hemiplegia of childhood is an uncommon but
interesting disorder that typically appears before 18 months
of age. This syndrome is associated not only with attacks of
alternating hemiparesis but also with a variety of paroxysmal movements, including chorea, athetosis, and dystonia.
Bulbar signs, such as ophthalmoparesis, nystagmus, and
respiratory irregularities (hyperpnea), may be seen.
Episodes usually resolve after sleep. Intellectual decline may
occur. Proposed mechanisms have included mitochondrial
encephalopathy, ion channelopathy, epileptic syndrome, or
inborn error of metabolism. Although a specific diagnostic test for alternating hemiplegia is currently unavailable,
a positive response to empiric treatment with the calcium
channel blocker flunarizine is considered supportive evidence of this disorder. Unfortunately, this agent is currently
not approved by the U.S. Food and Drug Administration
and, therefore, not directly available in the United States.
Paroxysmal Torticollis
Paroxysmal torticollis is a rare disorder consisting of recurrent episodes of head tilt, which may occur with or without nausea, vomiting, and ataxia. Episodes may last for
hours or days. Affected children are normal between
attacks. Symptoms typically appear between 2 and
8 months of age. The etiology of these attacks has been
attributed to migraine or a variant of benign paroxysmal
vertigo. Alternatively, acute labyrinthitis may also explain
these events. The differential diagnosis includes gastroesophageal reflux associated with torticollis (Sandifer’s syndrome), idiopathic torsional dystonia, localization-related
epilepsy, and posterior fossa tumors.
Cyclic Vomiting Syndrome
The hallmark features of this poorly understood syndrome
include abrupt, unprovoked bouts of repeated vomiting,
often to the point of dehydration and collapse. Between
these episodes, the affected child appears entirely normal.
Clinical criteria include a high peak intensity of emesis
(more than four emeses per hour) and low frequency of
episodes (no more than two episodes per week). The
mechanism of cyclic vomiting syndrome is unknown.
Observations suggesting a relationship between cyclic
vomiting syndrome and migraine include a high incidence
of family members with migraine and a significant
response rate to antimigraine prophylaxis. Before a diagCurrent Management in Child Neurology, Third Edition
В© 2005 Bernard L. Maria, All Rights Reserved
BC Decker Inc
nosis of cyclic vomiting syndrome can be established, evaluation must exclude the possibility of a posterior fossa
tumor, gastrointestinal and renal disease, and intermittent
metabolic disorders. Treatment of acute episodes includes
antimigraine agents as well as antiemetics. Effective prophylactic therapy has been reported with cyproheptadine
as well as amitriptyline.
Abdominal Migraine
Although abdominal migraine almost always is included in
discussions of migraine variants, no entity is more controversial. The key clinical components usually required for
this diagnosis include recurrent stereotyped episodes of
severe abdominal pain between which the affected child is
well. The episodes are usually accompanied by prominent
autonomic symptoms. A family history of migraine is usually present. Supportive criteria include the following:
(1) negative screening tests to exclude gastrointestinal,
hepatic, biliary, and renal disease, (2) subsequent development of migraine headaches, and (3) a positive response to
abortive or prophylactic treatment for migraine. Although
considerable overlap exists between cyclic vomiting and
abdominal migraine, abdominal pain is more prevalent in
abdominal migraine.
Summary
In conclusion, migraine variants often present with ominous symptoms and can be alarming to the physician and
family as well as the patient. Diagnostic studies are often
required to exclude not only intracranial pathology but
also extracranial disease, including cardiac, hematologic,
metabolic, toxicologic, and gastrointestinal disorders.
Although significant advances have been made in understanding the pathophysiologic mechanism underlying specific migraine syndromes such as familial hemiplegic
migraine, the other conditions remain poorly understood.
With notable exceptions, treatment for these migraine variants remains largely supportive. Until our understanding
improves, management must include relief of symptoms
and exclusion of disorders with greater morbidity.
Suggested Readings
Bourgeois M, Aicardi J, Goutieres F. Alternating hemiplegia of
childhood. J Pediatr 1993;122:673–9.
Golden GS. The Alice in Wonderland syndrome in juvenile
migraine. Pediatrics 1979;63:517–9.
Goto YI, Nonaka I, Horai S. A mutation in the tRNALeu (UUR)
gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 1990;348:651–3.
Joutel A, Bousser M-G, Biousse V, et al.A gene for familial hemiplegic
migraine maps to chromosome 19. Nat Genet 1993;5:40-5.
Migraine Variants and Mimics
Pages 43–49
48 / The Office Visit: Headache
Li BU, Murray RD, Heitlinger LA, et al. Is cyclic vomiting syndrome related to migraine? J Pediatr 1999;134:567–72.
Marconi R, De Fusco M, Aridon P, et al. Familial hemiplegic
migraine type 2 is linked to 0.9 Mb region on chromosome
1q23. Ann Neurol 2003;53:376–81.
Mortimer MJ, Kay J, Jaron A. Clinical epidemiology of childhood abdominal migraine in an urban general practice. Dev
Med Child Neurol 1993;35:243–8.
Woody RC, Blaw ME. Ophthalmoplegic migraine in infancy. Clin
Pediatr 1986;25:82–4.
Practitioner and Patient Resources
National Headache Foundation
428 W. St. James Place, 2nd Floor
Chicago, IL 60614
Phone: (800) 843-2256
http://www.headaches.org
The National Headache Foundation is a nonprofit organization
dedicated to educating headache sufferers and health care professionals about headache causes and treatments.
American Headache Society
19 Mantua Road
Mt. Royal, NJ 08061
Phone: (856) 423-0043
Fax: (856) 423-0082
E-mail: [email protected]
Current Management in Child Neurology, Third Edition
В© 2005 Bernard L. Maria, All Rights Reserved
BC Decker Inc
http://www.ahsnet.org
The American Headache Society (AHS) is a professional society
of health care providers dedicated to the study and treatment of
headache and face pain. Founded in 1959, AHS brings together
physicians and other health providers from various fields and
specialties to share concepts and developments about headache
and related conditions.
American Council for Headache Education (ACHE)
http://www.achenet.org
ACHE is a nonprofit patient–health professional partnership
dedicated to advancing the treatment and management of
headache and to raising the public awareness of headache as a
valid, biologically based illness. ACHE was created in 1990
through an initiative of the American Headache Society.
MAGNUM: Migraine Awareness Group: A National Understanding
for Migraineurs
113 South Saint Asaph, Suite 300
Alexandria, VA 22314
Phone: (703) 739-9384
Fax: (703) 739-2432
http://www.migraines.org
MAGNUM was created to bring public awareness, utilizing the
electronic, print, and artistic mediums, to the fact that
migraine is a true biologic neurological disease, to assist
migraine sufferers, their families, and coworkers, and to help
improve the quality of life of migraine and head-pain sufferers
worldwide.
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