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 © 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 © 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 β-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 © 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, β-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-Barré 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-Medrol®) 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 © 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 β-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 © 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: ahshq@talley.com Current Management in Child Neurology, Third Edition © 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. Migraine Variants and Mimics Pages 43–49
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