Clinical characteristics: Familial hemiplegic migraine (FHM) falls within the category of migraine with aura. In migraine with aura (including FHM) the neurologic symptoms of aura are unequivocally localizable to the cerebral cortex or brain stem and include visual disturbance (most common), sensory loss (e.g., numbness or paresthesias of the face or an extremity), and dysphasia (difficulty with speech). FHM must include motor involvement, such as hemiparesis (weakness of an extremity). Hemiparesis occurs with at least one other symptom during FHM aura. Neurologic deficits with FHM attacks can be prolonged for hours to days and may outlast the associated migrainous headache. FHM is often earlier in onset than typical migraine, frequently beginning in the first or second decade; the frequency of attacks tends to decrease with age. Approximately 40%-50% of families with CACNA1A-FHM have cerebellar signs ranging from nystagmus to progressive, usually late-onset mild ataxia.

Diagnosis/testing: The clinical diagnosis of FHM can be established in a proband: (1) who fulfills criteria for migraine with aura; (2) in whom the aura includes fully reversible motor weakness and visual, sensory, or language symptoms; and (3) who has at least one first- or second-degree relative with similar attacks that fulfill the diagnostic criteria for hemiplegic migraine. The molecular diagnosis can be established in a proband by identification of a heterozygous pathogenic variant in ATP1A2, CACNA1A, PRRT2, or SCN1A.

Management: Treatment of manifestations: A trial of acetazolamide for individuals with CACNA1A-FHM or a trial of prophylactic migraine medications (e.g., tricyclic antidepressants, beta-blockers, calcium channel blockers, anti-seizure medications) for all FHM types may be warranted for frequent attacks. Anti-seizure treatment may be necessary for seizures, which are prevalent in ATP1A2-FHM. Corticosteroids in children with cerebral edema to reduce life-threatening manifestations.

Surveillance: Neurologic evaluation to assess change in attack frequency and/or seizures, development of movement disorder, developmental delay, and/or learning disability annually or more frequently for worsening symptoms.

Agents/circumstances to avoid: Vasoconstricting agents because of the risk of stroke; cerebral angiography as it may precipitate a severe attack.

Genetic counseling: FHM and simplex hemiplegic migraine caused by a heterozygous ATP1A2, CACNA1A, PRRT2, or SCN1A pathogenic variant are inherited in an autosomal dominant manner. Because the diagnosis of FHM requires at least one affected first-degree relative, most individuals diagnosed with FHM have an affected parent. Individuals with simplex hemiplegic migraine (i.e., individuals with an FHM-causing pathogenic variant and an apparently negative family history) may have a de novo pathogenic variant or a pathogenic variant inherited from an asymptomatic parent. Each child of an individual with FHM has a 50% chance of inheriting the pathogenic variant. Once an FHM-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.