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FHM is a rare phenotype of migraine with aura with a characteristic presentation of motor aura. Motor aura presents as unilateral muscle weakness that tends to be felt first in the hands or arm and may spread to the face. To date, three distinct types have been identified by mutations in one of three genes. Type 1 is the most common and is associated with mutations in the gene CACNA1A. Mutations in ATP1A2 underlie type 2 FHM, and mutations in SCN1A underlie type 3 FHM.
FHM is distinguished from other hemiplegic migraine by family history of one or more affected first- or second-degree relatives. Genetic studies have shown FHM to have autosomal dominant inheritance. From half to three quarters of patients with FHM will have one of the more than 30 identified mutations on CACNA1A that diagnose type 1 FHM. These mutations affect transmission of glutamate in the neurons and neuronal reactions, increasing the susceptibility to cortical spreading depression associated with migraine. Mutations in ATP1A2 are found in about 20% of patients with FHM (type 2). More than 80 individual mutations have been identified, which alter sodium-potassium metabolism in neurons. About 5% of patients have type 3 FHM, associated with mutations in SCN1A that create gain of function or loss of function in neuronal voltage-gated sodium channels. Studies of other possible genes and mutations in relation to FHM, including PRRT2, are ongoing, but to date the associations are not clearly established.
Patients with FHM may also report sensory symptoms, visual disturbances, or aphasia. FHM generally affects people in their teens and twenties (women more than men) and has an estimated prevalence of 0.003% of the population. On average, patients report having two to three attacks per year, and some patients go for extended periods without a recurrent attack. Motor aura may occur on the same or opposite side of the body as headache and may alternate affected sides with each attack. Differential diagnoses that should be ruled out include transient ischemic attacks, infections (eg, meningitis, encephalitis), tumors, seizures, other inherited disorders, and metabolic issues.
Like other forms of migraine with aura, FHM is treated with abortive and/or preventive medications. Given the rarity of FHM, there are few studies specifically in families with this phenotype. Patients should be counseled on trigger avoidance to limit exposure. Acute treatment includes nonsteroidal anti-inflammatory drugs, acetaminophen, and other nonopioid pain relievers. The class of calcitonin gene-related peptide (CGRP) antagonists (rimegepant, ubrogepant, zavegepant) may be considered. However, with FHM, medications associated with ischemia must be avoided. As such, triptans and ergotamines are generally contraindicated, as are beta-blockers. Patients with FHM and more frequent or severe attacks may be considered for preventive treatment to improve function and quality of life and avoid reliance on acute therapies. Options include CGRP monoclonal antibodies (mAbs), administered subcutaneously or by intravenous infusion, and onabotulinumtoxinA injection. Current CGRP mAbs include eptinezumab, erenumab, fremanezumab, and galcanezumab. Combined CGRP mAb therapy with onabotulinumtoxinA may be an effective alternative for patients with resistant FHM.
Heidi Moawad, MD, Clinical Assistant Professor, Department of Medical Education, Case Western Reserve University School of Medicine, Cleveland, Ohio.
Heidi Moawad, MD, has disclosed no relevant financial relationships.
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