Dr. Marmura of Thomas Jefferson University Hospital received research support from Allergan and Teva; honorariums from Alder, Antres Pharma, Promius, Supernus, Theranica, and Valeant for consulting services; and honorariums from Amgen/Novartis, GammaCore, and Lilly for speaking engagements.)
Dr. Silberstein, Director of the Jefferson Headache Center at Thomas Jefferson University, received honorariums from Abbie, Curelator, Ipsen Therapeutics, Lundbeck Biopharmaceuticals, Supernus Pharmaceuticals, and Theranica for consulting. He is also the principal investigator for clinical trials conducted by Amgen, ElectroCore Medical, and Teva.)
This article discusses of hemiplegic migraine, familial hemiplegic migraine, FHM, SHM, and sporadic hemiplegic migraine. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Hemiplegic migraine is characterized by migraine with aura including motor weakness. Familial hemiplegic migraine is characterized by migraine with aura and motor weakness and at least 1 first- or second-degree relative with migraine aura and motor weakness. Familial hemiplegic migraine is separated into FHM-1, FHM-2, and FHM-3 due to mutations in CACNA1A, ATP1A2, and SCN1A genes, respectively, and other loci when genetic testing does not demonstrate a known mutation. Sporadic hemiplegic migraine has the same clinical features as familial hemiplegic migraine, but no family history of motor weakness. However, familial hemiplegic migraine mutations have been found in some sporadic hemiplegic migraine patients. Also, PRRT-2 mutations have been identified in some hemiplegic migraine patients. These mechanisms suggest predisposition to cortical spreading depression and hyperexcitability in hemiplegic migraine patients.
• Familial hemiplegic migraine is characterized by migraine with aura and reversible motor weakness, with family history of migraine with aura including motor weakness.
• Sporadic hemiplegic migraine has the same clinical features as familial hemiplegic migraine, but no family history of migraine with aura including motor weakness.
• Mutations in 3 genes are responsible for 50% to 70% of familial hemiplegic migraine, including CACNA1A for FHM-1, ATP1A2 for FHM-2, and SCN1A for FHM-3.
Historical note and terminology
Clinicians have recognized of unilateral weakness as a manifestation of migraine for centuries. Recent advances in genetics have increased our understanding of the disorder and of migraine itself. Transient hemiparesis during an attack of typical migraine was first reported by Liveing in 1873 (Liveing 1873). Livieing proposed that many different disorders such as migraine, visual aura or loss, nausea, or weakness were all in the same “pathological family,” which he conceptualized as a “nerve storm” (Weatherall 2012). The first description of familial hemiplegic migraine was made by Clarke (Clarke 1910). Whitty reported an autosomal dominant inheritance pattern of stereotyped episodes of migraine associated with prolonged hemiplegia and alteration of consciousness lasting days or weeks (Whitty 1953; Blau and Whitty 1955). A monograph on familial hemiplegic migraine was written by Heyck in 1956 (Heyck 1956). In 1965, Bradshaw and Parsons reported a clinical study of hemiplegic migraine patients (Bradshaw and Parsons 1965). In 1973, Heyck reported varieties of hemiplegic migraine (Heyck 1973). Permanent hemiplegia and progressive dementia attributed to hemiplegic migraine have been reported (Connor 1962; Heyck 1973). Familial hemiplegic migraine associated with other neurologic or ophthalmologic findings is well documented (Whitty 1953; Rosenbaum 1960; Ohta et al 1967; Young et al 1970). Reports began to recognize the increased heritability of hemiplegic migraine compared to other forms of migraine (Whitty 1953; Critchley 1962; Bruyn 1968; Lance 1969). In 1986, Bergouignan and associates reported a case of familial hemiplegic migraine that was provoked by head trauma (Bergouignan et al 1986). Multiple reports described hemiplegic migraine has been reported in children (Burke and Peters 1956; Holguin and Fenichel 1967; Isler 1971). A few case series noted important differences between alternating hemiplegia of childhood, a rare disorder of unknown cause associated with progressive neurologic deterioration, and hemiplegic migraine (Clarke 1910; Symonds 1952; Verret and Steele 1971; Aminian et al 1993).
The discovery of genes associated with migraine and hemiplegic migraine enhanced our understanding of familial hemiplegic migraine (FMH). Familial hemiplegic migraine is linked to chromosome 19p13 in about 50% of families tested (Joutel et al 1993; Joutel et al 1994; Ophoff et al 1994; Ophoff et al 1997). Mutations in this gene also produce episodic ataxia type 2 (EA-2), another autosomal dominant paroxysmal cerebral disorder characterized by acetazolamide-responsive attacks of cerebellar ataxia and migraine-like symptoms, interictal nystagmus, and cerebellar atrophy (Von Brederlow et al 1995). A locus for EA-2 was mapped to chromosome 19p13 in the same interval as the FHM-1 locus (Kramer et al 1995; Teh et al 1995; Von Brederlow et al 1995). In 1996, Ophoff characterized a brain-specific P/Q-type Ca2+ channel α1-subunit gene, CACNA1A, which was implicated as a cause of both FHM-1 and EA-2 (Ophoff et al 1996). CACNA1A mutations have a broad clinical spectrum due to different types of mutations (Ducros et al 2001).
Gardner and colleagues described a second locus in chromosome 1q33 related to a family with familial hemiplegic migraine features and a negative to CACNA1A mutations (Gardner et al 1997). Posteriorly, a dysfunction in the ATP1A2 gene on chromosome 1q21-23, encoding the Na+/K+pump, was associated with FHM-2 (De Fusco et al 2003; Marconi et al 2003).
A heterozygous mutation in EAAT1 can lead to decreased glutamate uptake, leading to neuronal hyperexcitability that can cause seizures, hemiplegia, and episodic ataxia (Jen et al 2005).
Dichgans and colleagues identified a third locus for familial hemiplegic migraine (FHM-3) on chromosome 2q24 due to a heterozygous missense mutation in the neuronal voltage-gated sodium channel gene SCN1A in 3 families. These mutations have also been associated with epilepsy (Dichgans et al 2005). The SCN1A mutation encodes an abnormal EAAT1 (excitatory amino acid transporter 1) causing decreased glutamate uptake, leading to neuronal hyperexcitability that can cause epileptic disorders, hemiplegia, and episodic ataxia (Jen et al 2005).
Sporadic hemiplegic migraine is clinically similar to familial hemiplegic migraine but with no family history of hemiplegic migraine. It is different from migraine with typical aura and classified with familial hemiplegic migraine, and both familial hemiplegic migraine and sporadic hemiplegic migraine are classified under migraine with aura in the International Classification of Headache Disorders, 3rd edition, beta version (ICHD-3 beta) (Headache Classification Subcommittee of the International Headache Society 2013).
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