Clinical manifestations

Presentation and course

The core clinical manifestation of hemiplegic migraine is the presence of migraine with aura accompanied by fully reversible motor weakness, although other cortical symptoms are usually related. Current diagnostic criteria of hemiplegic migraine are presented in the ICHD-3 beta version (105) under migraine with aura (Table 1).

Hemiplegic migraine. Hemiplegic migraine is migraine with aura including motor weakness.

Table 1. Diagnostic Criteria for Hemiplegic Migraine

A. At least 2 attacks fulfilling criteria B and C B. Aura consisting of both of the following:
	• Fully reversible motor weakness • Fully reversible visual, sensory, and/or speech/language symptoms
C. At least 2 of the following 4 characteristics:
	• At least 1 aura symptom spreads gradually over more than or equal to 5 minutes, and/or 2 or more symptoms occur in succession • Each individual nonmotor aura symptom lasts 5 to 60 minutes, and motor symptoms last less than 72 hours • At least 1 aura symptom is unilateral • The aura is accompanied, or followed, within 60 minutes by headache
D. Not better accounted for by another ICHD-3 diagnosis, and transient ischemic attack and stroke have been excluded

Familial hemiplegic migraine. Familial hemiplegic migraine is migraine with aura including motor weakness, and at least 1 first- or second-degree relative has migraine aura including motor weakness.

Table 2. Diagnostic Criteria for Familial Hemiplegic Migraine

	A. Fulfills criteria for 1.2.3 hemiplegic migraine
	B. At least 1 first- or second-degree relative has had attacks fulfilling criteria for 1.2.3 hemiplegic migraine
Table 2.1. Diagnostic Criteria for Familial Hemiplegic Migraine Type 1
	A. Fulfills criteria for 1.2.3.1 familial hemiplegic migraine
	B. A causative mutation on the CACNA1A gene has been demonstrated
Table 2.2. Diagnostic Criteria for Familial Hemiplegic Migraine Type 2
	A. Fulfills criteria for 1.2.3.1 familial hemiplegic migraine
	B. A causative mutation on the ATP1A2 gene has been demonstrated
Table 2.3. Diagnostic Criteria for Familial Hemiplegic Migraine Type 3
	A. Fulfills criteria for 1.2.3.1 familial hemiplegic migraine
	B. A causative mutation on the SCN1A gene has been demonstrated
Table 2.4. Diagnostic Criteria for Familial Hemiplegic Migraine, Other Loci
	A. Fulfills criteria for 1.2.3.1 familial hemiplegic migraine
	B. Genetic testing has demonstrated no mutation on the CACNA1A, ATP1A2, or SCN1A genes

Sporadic hemiplegic migraine. Sporadic hemiplegic migraine is migraine with aura including motor weakness and no first- or second-degree relative has migraine aura including motor weakness.

Table 3. Diagnostic Criteria for Sporadic Hemiplegic Migraine

A. Fulfills criteria for 1.2.3 hemiplegic migraine B. No first- or second-degree relative fulfills criteria for 1.2.3 hemiplegic migraine

In familial hemiplegic migraine, most auras last approximately 60 minutes, followed by a headache that lasts 30 minutes to 5 days. Many of patients have prolonged auras lasting more than 1 hour, occasionally lasting more than 1 day (64; 207). A wide range of aura and clinical phenotypes, including spinocerebellar ataxia type 6 (SCA6), EA-2, and FHM-1, occur in members of the same familial hemiplegic migraine family with the same mutation (233; 145; 180; 123). Recurrent coma, encephalitis, or cerebellar ataxia in a patient with a family history of migraine and cerebellar ataxia could be the presenting symptoms of familial hemiplegic migraine (135; 156). One patient, a member of a family diagnosed with FHM-1 and cerebellar ataxia, presented with progressive parkinsonism, increased signal of the globus pallidus bilaterally, and a decreased DAT-binding potential in the putamen (25). Over 20% of attacks include impairment of consciousness, ranging from mild somnolence or confusion to diffuse encephalopathy or coma (64). Coma typically resolves spontaneously but in severe cases can last days and require intubation (146). Attacks may be provoked by emotional stress, mild head trauma, angiography, or exertion (237; 23; 175; 204). Most hemiplegic patients recover completely between attacks, but permanent sequelae, including dementia, intellectual disability, hemiplegia, cerebellar atrophy, migrainous infarction, persistent cognitive and sensory impairment, and even death, have been reported. These findings could be from irreversible neuronal damage (237; 127; 20; 76; 191). The impaired cognitive functions, including figural memory, executive function, some aspects of attention, and dexterity, may reflect disturbances in functional connectivity (120). Episodes of transient psychotic symptoms after migraine lasting up to a week have been documented in 2 family members with negative genetic tests (129). In FHM-2, a transient nonverbal learning disorder in children and an acute psychosis during the aura phase of migraine have been reported (172; 12). Roth and associates reported 3 families with asymptomatic carriers, patients presenting migraine with or without aura, and patients presenting episodes lasting up to 6 weeks with transient hemiplegia and aphasia with FHM-2 (183). Symptoms of migraine with brainstem aura, such as vertigo, dysarthria, bilateral paresthesias, and numbness, occurred in approximately 66% of patients with familial hemiplegic migraine (94). Most familial hemiplegic migraine patients also experience attacks of typical migraine with aura and migraine without aura (211).

The clinical symptoms of sporadic hemiplegic migraine are similar to familial hemiplegic migraine, but no other family members are affected (23; 28; 175; 62; 64). Thomsen and colleagues identified 105 sporadic hemiplegic migraine patients with a mean age of 24 and 33 years in men and women, respectively. The mean age at onset was 16 years in men and 21 years in women. Sporadic hemiplegic migraine attacks varied from 2 attacks in a lifetime to more than 100 attacks, with no sex difference. Most patients had 4 types of auras, including visual, sensory, aphasic, and motor. All had at least 2 auras during their sporadic hemiplegic migraine attacks. Auras were usually unilateral, but 16% of patients said that they shifted from 1 side of the body to the other during an attack. Brainstem migraine symptoms occurred in 72% of sporadic hemiplegic migraine patients. The mean progression time of the motor symptoms was 28 minutes. Forty-nine percent of patients had prolonged aura (longer than 60 minutes), but only 8% had aura symptoms lasting more than 24 hours (211). The digiti quinti sign (a wider space between the fourth and fifth fingers at the affected side when the patient extends both arms horizontally to the front with the palms down) was noted in a few patients with sporadic hemiplegic migraine (230). Transient unilateral spatial neglect during aura was observed in a sporadic hemiplegic migraine patient during a right-sided migraine attack with left sensory-motor hemisyndrome (59). Cerebellar signs may be less common in sporadic hemiplegic migraine than in familial hemiplegic migraine (64; 204; 208). A presentation including acute encephalopathy, migrainous infarction, and epistaxis occurs in a few patients with sporadic hemiplegic migraine (11; 130; 154). An episode of paranoic psychosis with anxiety and visual hallucination was presented in a sporadic hemiplegic migraine patient. FDG-PET/CT indicates primary neuronal dysfunction as the cause of the deficit (216). When diagnosing young patients who present with hemiplegic migraine, alternative possibilities should be considered. Examination of family members and long-term clinical and MRI follow-up may reveal other diagnoses, such as CADASIL (149).

Pelzer and colleagues reviewed the clinical characteristics of 281 patients with familial hemiplegic migraine or sporadic hemiplegic migraine (166). Patients with autosomal dominant mutations in CACNA1A, ATP1A2, or SCN1A were significantly more likely to have familial hemiplegic migraine, attacks triggered by mild head trauma, severe weakness, brain stem features, brain edema, or confusion during attacks. Only patients with mutations had either mental retardation or progressive ataxia (166).

A large case-control study by Young and colleagues illustrated migraine with unilateral motor symptoms in a tertiary care center (242). Patients with migraine with unilateral motor symptoms had subjective weakness involving the arm and objective weakness involving both the arm and leg. Give-way weakness, defined as a sudden loss of resistance during muscle strength testing of at least 2 sites on 1 side of the body, was always present. Weakness was ipsilateral to unilateral headache in two thirds of the patients. Motor symptoms begin with pain onset or worsen as the pain intensifies. Compared with patients who had migraine without weakness, patients with migraine with unilateral motor symptoms had similar pain intensities but were more likely to report other migraine symptoms, including allodynia and unilateral autonomic symptoms. Onset of symptoms of migraine with unilateral motor symptoms usually occurs when patients are in their 30s to 40s, which is later than the usual onset of familial hemiplegic migraine and sporadic hemiplegic migraine (242). The weakness in these patients is most likely a functional neurologic disorder, potentially related to migraine severity or other factors, which are not understood.

The true prevalence of motor symptoms in migraine outside of tertiary headache centers is unclear (108). Questionnaire-based studies of hemiplegic migraine, such as a study of 293 patients in Finland with familial hemiplegic migraine, found only 7% had mutations in CACNA1A, ATP1A2, and SCN1A genes. These patients reported significantly higher headache severity, unilateral pain, and disability than migraine with aura controls (108).

Table 4. Hemiplegic Migraine and Migraine with Unilateral Motor Symptoms

Clinical feature	Hemiplegic migraine	Unilateral motor symptoms
Family history of weakness	Common	Uncommon
Age of onset	Childhood-young adult	Often middle age
Onset of attacks	Stereotyped sequence of symptoms. Weakness onset before headache	Cannot usually describe in detail. Weakness onset after headache. Give-way weakness
Allodynia	Common during attacks	Severe, common during and between attacks
Headache frequency	Variable	Often daily
Headache duration	Hours to days	Usually constant with exacerbations
Interictal symptoms	Usually resolve within days	May be constant

Coexistence of hemiplegic migraine with other types of headache, such as short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) or short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA), has been reported (131).

Prognosis and complications

The prognosis of hemiplegic migraine is usually good. Hemiplegic migraine patients often stop experiencing attacks after the age of 50 or earlier (23; 64). In long-term follow-up, brain imaging and EEG data generally remain stable (112). Young patients with migraine with aura are at increased risk for stroke compared to healthy patients of the same age. Brain atrophy due to cytotoxic edema is a potential complication of repeated attacks, as seen in a case of CACNA1A mutation, but effective treatment may prevent this (165). Other causes of ischemia, including patent foramen ovale, lupus anticoagulant, cervical carotid dissection, arteriovenous malformation, and hyperactivity of the clotting system, should be identified in patients with migraine (235). The data on the incidence of migrainous infarction are unclear and lacking. Cerebral angiography carries a 1% risk of stroke, and the risk is not more common in migraineurs than in nonmigraineurs (196). However, it can precipitate a severe migraine attack leading to stroke in patients with familial hemiplegic migraine (102). An increased release of glutamate could have a role in increased susceptibility to ischemic cerebral tissue in familial hemiplegic migraine models (67). Although attacks may resolve in young adulthood, there is the change for recurrence later in life (112).

Ischemic stroke and migraine with aura are major parts of various syndromes, including MELAS (162), CADASIL (218; 220), and autosomal dominant vascular retinopathy, migraine, and Raynaud phenomenon (203). The prognosis of these syndromes depends on the presenting disorder. A 7-year follow-up assessment in 6 members of a familial hemiplegic migraine family revealed no global cognitive decline, but figural memory, attention, and some executive functions were impaired (121).

Clinical vignette

A 17-year-old woman had a visual aura characterized by flashing lights, blurred vision, and then loss of vision in 1 eye, followed by paresthesia in her left hand and face, followed by hemiplegia. These symptoms progressed over 30 minutes and were followed by a left- or right-sided, moderately severe, throbbing headache with nausea, vomiting, photophobia, phonophobia, and irritability. Her neurologic examination was normal between attacks. She had a grandmother on her father’s side with migraine with aura but no family history of hemiplegic migraine. Complete blood count, Protein C, Protein S, Factor V Leiden, and MRI were normal. She had a history of migraine without aura 2 to 3 times a month.

Biological basis

Etiology and pathogenesis

Familial hemiplegic migraine is an autosomal dominant, genetically heterogeneous disorder. Mutations in 3 genes are responsible for 50% to 70% of published families with familial hemiplegic migraine. The FHM-1 (CACNA1A) gene is located on chromosome 19p13. The FHM-2 (ATP1A2) gene is located on chromosome 1q23. The FHM-3 (SCN1A) gene is located on chromosome 2q24. Sporadic hemiplegic migraine has been associated with CACNA1A, ATP1A2, and SCN1A gene mutations. PRRT-2 mutations have been identified in hemiplegic migraine patients.

CACNA1A, the first gene associated with familial hemiplegic migraine (on chromosome 19), encodes the α1A subunit of voltage-gated P/Q-type calcium channels (117; 159; 157; 28). FHM-1 with cerebellar signs has been linked to mutations in CACNA1A in some families (157; 205; 13; 63; 77; 222). As of 2005, 17 different missense mutations in CACNA1A have been linked with FHM-1 (169). The T666M mutation is the major CACNA1A mutation. Haplotype studies suggested that this mutation arose independently on different chromosomes by recurrent mutational events (63). In 2006, new families with a CACNA1A mutation were reported. An S218L mutation was found in a patient with sporadic hemiplegic migraine and minor head trauma-induced hemiplegic migraine coma (47), which confirmed the role of this specific mutation in (fatal) coma after minor head trauma (127). The mechanisms underlying a dramatic hemiplegic migraine syndrome in S218L CACNA1A mutation is the particularly low cortical spreading depression (CSD) threshold and the strong tendency to respond with multiple CSD events after a single stimulus (223). The clinical manifestation found in the S218L mutation was reported in a child with a mutation in CACNA1A (p.Arg1349Gln) (141). This patient had reduced level of consciousness, seizure, and cerebral edema after a head injury and returned to her previous clinical state subsequently. The cortical spreading depression in familial hemiplegic migraine knock-in mice expressing the S218L (seizure, coma, hemiplegia) or R192Q (hemiplegia only) propagated into subcortical structures; the subcortical spread was limited to the striatum in R192Q but spread to the hippocampus and thalamus in S218L mutants (69). The thalamic nuclei of knock-in mice expressing the CACNA1A R192Q mutation suggested that the mutation affects more rostral brain structures (161). Other manifestations found in a novel missense CACNA1A mutation include an EA-2-like phenotype (G533A), nonfluctuating limb and trunk ataxia with an early age at onset, and childhood periodic syndromes that evolved into hemiplegic migraine (Y1245C) (193; 215; 195). The susceptibility to spreading depression and neurologic deficits in FHM-1 is affected by allele dosage and hormonal factors (66). Coexistence of 2 single nucleotide polymorphisms of the CACNA1A gene may influence the calcium channel function in migraine with brainstem aura, hemiplegic migraine, migraine with aura, and migraine without aura (61).

There is also a polymorphism of the CACNA1E gene that is more common in patients with hemiplegic and brain stem migraine (04).

A region on chromosome 1q21-23 was found to cosegregate with the FHM-2 in 3 French families (65). Marconi and colleagues refined the 1q23 locus for FHM-2 by studying a large Italian family affected by this disease (144). They showed that mutations in the ATP1A2 gene encoding the alpha2 subunit of the Na+,K+-ATPase pump are associated with FHM-2 on 1q23 (50).

FHM-2 has been found to be associated with 27 different missense mutations in the ATP1A2 gene. Cerebellar signs are rare in FHM-2 families; however, transient and permanent cerebellar signs were reported in an Italian family with a G301R mutation (197). ATP1A2 mutations have also been associated with migraine with brainstem aura and alternating hemiplegia of childhood. Many patients also suffer from epilepsy (55). In 26 unrelated familial hemiplegic migraine probands in whom CACNA1A screening was negative, a total of 8 different ATP1A2 mutations were identified in 11 of the probands (41%) (176). A novel mutation in the ATP1A2 gene (R548H) has been detected in members of a family with migraine with brainstem aura, suggesting that this and familial hemiplegic migraine may be allelic disorders (05). Many novel ATP1A2 mutations manifested as pure familial hemiplegic migraine were revealed in different families: R593W in a Dutch family, V628M in a Turkish family, and M731T and T376M in 2 Portuguese families (225; 32). Some patients with novel ATP1A2 mutations had additional clinical features, including mood alteration and mental impairment (31). The ATP1A2 mutation in a proband of a Dutch familial hemiplegic migraine family had a clinical phenotype consisting of both episodic and permanent severe neurologic features and mental retardation. The episodic symptoms were precipitated by mild head trauma and included hemiplegia, epileptic seizures, and cortical blindness (227). A case of 2 allelic, novel ATP1A2 missense mutations in a patient with hemiplegic migraine was described (226). The presence of 2 ATP1A2 mutations in the proband causes a more severe phenotype, compared with the milder familial hemiplegic phenotype of an aunt, who carries only 1 mutation.

Patients with both epilepsy and migraine and a positive family history of either migraine or epilepsy can be screened for mutations in the ATP1A2 gene (52; 78). Mutations in the ATP1A3 gene can also present with dystonia, alternating hemiplegia, EEG abnormalities, and seizure (163).

In 2005, a Q1489K mutation in SCN1A, the gene encoding the neuronal voltage-gated sodium channel type 1A (FHM-3), was identified in 3 German familial hemiplegic migraine families of common ancestry. The missense mutation encodes the neuronal voltage-gate sodium channel Nav1.1 on chromosome 2q24 (57). SCN1A mutations were found in a familial hemiplegic migraine family with or without associated diseases such as ataxia, epilepsy, and myoclonus (81; 224; 33). Visual disturbances, including severe vision loss, due to SCN1A has been described (190).

Mutations in the CACNA1A, ATP1A2, and SCN1A genes explain 50% to 70% of published families with familial hemiplegic migraine. However, these families are selected from hospitals or specialist practices and very likely represent families with higher penetrance and more severe symptomatology compared with cases from the general population. It is, therefore, possible that the frequency of mutations in the CACNA1A, ATP1A2, and SCN1A genes may be different in families with familial hemiplegic migraine than those from the general population (209). Novel gene mutations were detected in CACNA1A, ATP1A2, and SCN1A genes during the past few years.

The possibility of developing either migraine or epilepsy from mutations in the same gene establishes the link between the disorders. In epilepsy, the hyperexcitable brain leads to discharges characterized by hypersynchronous neuronal firing and rhythmic recruitment of large populations of neurons, whereas in migraine cortical spreading depression leads to neuronal and glial depolarization, which propagates much more slowly (143). A systematic review was conducted that identified 28 families consisting of 195 patients to better define the linkage between the CACNA1A, ATP1A2, SCNA1A, and PRRT2 gene mutations and epilepsy and hemiplegic migraine (103). It was found that in patients with epilepsy, 7.7% had an CACNA1A mutation, 57.7% had an ATP1A2 mutation, 16.7% had a SCN1A mutation, and 17.9% had a PRRT2 mutation. For FHM-1 and CACNA1A mutations, there were 8 patients and of those patients, 5 had and hemiplegic migraine. Typically, hemiplegic migraine was diagnosed after the diagnosis of epilepsy. For FHM-2 and ATP1A2 mutations, 132 patients were identified and of them, 33 had epilepsy and hemiplegic migraine together. It was not clear whether onset of hemiplegic migraine or epilepsy occurred first in this group. For FHM-3 and SCN1A mutation, there were 33 patients, and 10 had epilepsy and hemiplegic migraine. Typically, hemiplegic migraine was diagnosed after the diagnosis of epilepsy. In the final group of FHM-4 and PRRT2 mutation, there were 22 patients, of which 9 had epilepsy and hemiplegic migraine together. In this group, it was noted that epilepsy was typically diagnosed before hemiplegic migraine. These results highlight the fact that there may be an underdiagnosis of familial hemiplegic migraine due to the fact that hemiplegic migraine attacks and seizures could occur independently (103).

A study in the Danish population identified 147 familial hemiplegic migraine patients from 44 different families. The linkage analysis showed clear linkage to the FHM-1 locus, supportive linkage to the FHM-2 locus, but no linkage to the FHM-3 locus. CACNA1A gene mutations were identified in 3 familial hemiplegic migraine families: 2 known familial hemiplegic migraine mutations, R583Q and T666M, and 1 novel C1369Y mutation. Three familial hemiplegic migraine families had novel mutations in the ATP1A2 gene: 1 has a V138A mutation, 1 has a R202Q mutation, and another a R763C mutation. None of the Danish familial hemiplegic migraine families had the Q1489K mutation in the SCN1A gene. Only 14% of familial hemiplegic migraine families in the general Danish population have familial hemiplegic migraine mutations in the CACNA1A or ATP1A2 gene. The families with familial hemiplegic migraine mutations in the CACNA1A and ATP1A2 genes were extended, multiple-affected families, whereas the remaining familial hemiplegic migraine families were smaller. The existence of many small families in the Danish familial hemiplegic migraine cohort may reflect less bias in familial hemiplegic migraine family ascertainment and/or more locus heterogeneity than described previously (209). Linkage analysis in a large Spanish kindred with familial hemiplegic migraine revealed a disease locus in a 4.15 Mb region on 14q32, which does not overlap with the reported migraine loci on 14q21-22. This finding suggested that genetic heterogeneity in familial hemiplegic migraine may be greater than previously suspected (46).

No mutations have been found in any of the 3 familial hemiplegic migraine genes among patients with migrainous vertigo (124; 232). CACNA1A mutations can cause atypical alternating hemiplegia of childhood, indicating an overlap of molecular mechanisms causing alternating hemiplegia of childhood and familial hemiplegic migraine (56).

Sporadic hemiplegic migraine is a heterogenous disorder. Three patients with sporadic hemiplegic migraine who had cerebellar signs were analyzed for mutations in the familial hemiplegic migraine gene CACNA1A. Two mutations were found: a T666M mutation in a patient with sporadic hemiplegic migraine and cerebellar ataxia and a Y1384C mutation in a woman with mental retardation, sporadic hemiplegic migraine, coma, seizures, and permanent cerebellar ataxia and atrophy (221). In another 27 sporadic hemiplegic migraine patients, 2 mutations were found: a T666M mutation in a patient with sporadic hemiplegic migraine and cerebellar ataxia and an R583Q mutation in a patient with sporadic hemiplegic migraine but without cerebellar ataxia. No mutations were identified in the remaining 25 sporadic hemiplegic migraine patients (204). A systematic analysis of 3 familial hemiplegic migraine genes was performed in 39 well-characterized patients with sporadic hemiplegic migraine without associated neurologic features. Sequence variants were identified in 7 sporadic hemiplegic migraine patients: 1 CACNA1A mutation (R583Q), 5 ATP1A2 mutations (E120A, E492K, P786L, R908Q, R834X), and 1 SCN1A polymorphism (R1928G). All 6 mutations caused functional changes in cellular assays. One sporadic hemiplegic migraine patient was reclassified to familial hemiplegic migraine when another family member developed familial hemiplegic migraine attacks. An ATP1A2 sequence variant was found in 5 of the 7 sporadic hemiplegic migraine cases, which is 13% of the overall sporadic hemiplegic migraine sample (54). In a population-based sample of sporadic hemiplegic migraine, all exons and promoter regions of the CACNA1A and ATP1A2 genes in 100 patients were sequenced to search for sporadic hemiplegic migraine mutations. Very few DNA variants were identified and the causal role of the variants is unknown. Thus, the CACNA1A and ATP1A2 genes may not be major genes in sporadic hemiplegic migraine (210). In a group of sporadic hemiplegic migraine patients referred for a genetic diagnosis, familial hemiplegic migraine gene mutations in CACNA1A or ATP1A2 were identified in 23 of the 25 patients (177). SCN1A analysis did not show any mutation. The results from this study were different from the previous studies, which could be due to early-onset cases (age at onset below 16 years) and associated neurologic signs, including cerebellar ataxia, epileptic seizures, or various degrees of intellectual disability. In some sporadic hemiplegic migraine patients, the diagnosis was changed into familial hemiplegic migraine after 9 to 14 years (198). Long-term follow-up of the patients and families is important.

FHM-1 mutations produce gain-of-function of the Ca(V)2.1 channel. This increases calcium influx into presynaptic terminals, enhances glutamate release at pyramidal cell synapses without altered inhibitory neuron transmission at fast-spiking interneuron synapses (217), and facilitates induction and propagation of cortical spreading depression. Functional consequence of FHM-1 mutations appears as the consequence of the alteration of intrinsic biophysical properties and of the main inhibitory G-protein pathway of Ca(V)2.1 channels (236). Alternative splicing in FHM-1 mutations generate multiple functional, distinct calcium channel variants that affect the recovery from inactivation and accumulation of inactivation during tonic and burst firing differently (02). In the mutant mouse central nervous system, FHM-1 mutations affect both P/Q-type channel Ca(2+)-dependent facilitation and short-term synaptic facilitation (03).

In a knock-in mouse model of FHM-1, TNFα was a major factor in sensitizing trigeminal ganglia and contributing to migraine pain (75). Culture of a knock-in mouse model with a R192Q mutation had a basal neuroinflammatory profile that might facilitate the release of endogenous mediators to activate hyperfunctional P2X3 receptors and amplify nociceptive signaling by trigeminal sensory neurons (74). ATP-gated P2X3 receptors of sensory ganglion neurons are important transducers of pain. The role of calcium/calmodulin-dependent serine protein kinase (CASK) in controlling P2X3 receptor expression and function in trigeminal ganglia from a FHM-1 genetic model showed more abundant CASK/P2X3 receptor complex at the membrane level and resulted in gain of function. The expression of this complex depends on intracellular calcium and related signaling (86). Mutations W1684E and V1696I, which cause FHM-1 with and without cerebellar ataxia, respectively, altered the G protein-Ca(2+) channel affinity (83). The significant reduction of the extent of G-protein-mediated inhibition in the K1336E mutant CaV2.1 Ca2+ channels renders the neuronal network hyperexcitable (82). The functional impact of the E1015K amino acid substitution located in the synprint domain of the alpha-1A subunit is characterized by a gain-of-function. This variant is associated with hemiplegic migraine and migraine with aura (42).

FHM-2 mutations result in loss or diminished function of the sodium potassium pump and reduced uptake of potassium and glutamate into glial cells. The uptake is slowed because of Na+,K+-ATPase haploinsufficiency (50). Functional properties of ATP1A2 mutation are diverse, and mutations that disrupt distinct interdomain H-bond patterns can cause abnormal conformational flexibility and exert long range consequences (202). Temperature-sensitive effects on protein stability were proposed as an underlying cause of ATP1A2 loss of function (201). An additional pathway in the Na(+)/K(+)-ATPase pump function is the C terminus, which controls the gate to the pathway. Mutations in the region cause severe neurologic disease and are established as the cause of FHM-2 (173). In a study of 9 FHM-2 mutations, different mechanisms of phosphorylation inhibition of Na+, K+-ATPase were demonstrated (189). A novel missense mutation, L425H, was reported in an Italian family (07). Software models indicate this mutation changes the 3D structure of ATP1A2 cytoplasmic loop between TM4 and TM5. Mild symptoms were reported with only one patient in the family presenting with transient hemiparesis.

FHM-3 mutation accelerates recovery from fast inactivation of Na(V)1.5 (presumably Na(V)1.1) channels. SCN1A mutation has effects on the gating properties of neuronal voltage-gated Na(V)1.1 Na+channel consistent with both hyperexcitability and hypoexcitability. This self-limited capacity may be a specific characteristic of migraine mutations (35). Some FHM-3 mutations resulted in gain of function (familial hemiplegic migraine and generalized epilepsy) such as L263V and L1649Q, but some mutations resulted in loss of function (typical familial hemiplegic migraine) such as Q1489K (119; 36). These results emphasize that migraine and epilepsy may share common molecular mechanisms. These findings are consistent with the hypothesis that familial hemiplegic migraine mutations share the ability to render the brain more susceptible to cortical spreading depression by causing either excessive synaptic glutamate release (FHM-1), decreased removal of K+ and glutamate from the synaptic cleft (FHM-2), or excessive extracellular K+ (FHM-3) (170).

The T1174S SCN1A mutation can lead to a gain of function in some conditions and loss of function in other conditions. These findings may help to explain the coexistence of epilepsy and familial hemiplegic migraine without epilepsy in the same family (34). Bioinformatics analysis of the 3 familial hemiplegic migraine mutations shows that FHM-3 is more resistant to mutation within the amino acid sequence when compared with others (239).

Accumulating evidence found in familial hemiplegic migraine patients suggest that the pathophysiology of migraine headache in FHM-1 and FHM-2 may be different from common types of migraine. These include calcitonin gene-related peptide, a migraine trigger that did not induce an aura in familial hemiplegic migraine patients (99; 97). FHM-1 and FHM-2 patients do not show hypersensitivity of the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, as seen in migraine patients with and without aura (100; 98; 101). Possible differences in frontal cortical nitric oxide vascular sensitivity between pure familial hemiplegic migraine patients and familial hemiplegic migraine patients with a coexisting common type of migraine have been suggested (192). Other evidence suggests that the difference between familial hemiplegic migraine and common forms of migraine is an increased habituation in cortical/brainstem-evoked activities in familial hemiplegic migraine, not a habituation deficit found in common forms of migraine (95). However, in certain families, it is possible that the hemiplegic aura is a more severe and complex form of typical aura due to the combination of polygenic traits and endogenous or environmental factors (10). To explain unusual and severe aura signs and symptoms in familial hemiplegic migraine patients, spreading depression may propagate between cortex and subcortical structures. The reciprocal spread and reverberating waves can explain protracted attacks (68).

Common trigger factors for familial hemiplegic migraine are stress, bright light, intense emotional influences, and sleeping too much or too little. These triggers are the same as for migraine with aura (95). Regadenoson, a selective A2A adenosine receptor agonist, was also found to trigger an episode of hemiplegic migraine (70).

In 2012, proline-rich transmembrane protein (PRRT2) mutations have been identified in patients with paroxysmal kinesigenic dyskinesia and other paroxysmal disorders. The paroxysmal disorders include paroxysmal dyskinesias, infantile seizures, paroxysmal torticollis, migraine, hemiplegic migraine, and episodic ataxia (79; 179; 30; 147). PRRT2 should be considered as a fourth category for autosomal dominant genes mutations, which cause familial hemiplegic migraine (178).

Epidemiology

The estimated prevalence of hemiplegic migraine (in Denmark) is 0.01%. Sporadic hemiplegic migraine and familial hemiplegic migraine occurred with approximately equal prevalence in this study of 5.2 million people. Two hundred and ninety-one hemiplegic migraine patients were identified: 147 had familial hemiplegic migraine, 105 sporadic hemiplegic migraine, and 39 were unclassifiable hemiplegic migraine. The sex ratio (M:F) was 1:3. Sporadic hemiplegic migraine patients had no increased risk of migraine without aura, but the risk of typical migraine with aura was increased compared with the general population (208).

Hemiplegic attacks in familial hemiplegic migraine may begin as early as 5 to 7 years of age, with a mean age of onset of 12 years (range 1 to 51 years) in 1 study and 17 years (range 1 to 45 years) in another study (64; 207). One third of patients will have their first hemiplegic migraine by 30 years of age, and 97% will have the onset of sporadic hemiplegic migraine by 45 years of age (23; 212). Hemiplegic migraine patients often stop experiencing attacks after the age of 50. Female-to-male gender ratios for hemiplegic migraine range from 2.5:1 to 4.3:1 (23; 64; 212).

Prevention

Hemiplegic migraine attacks may be prevented by nonpharmacologic and pharmacologic management. Patient identification of trigger factors may prevent attacks. Genetic counseling may be helpful in families with familial hemiplegic migraine but the variable clinical manifestations, even in families with the same mutation, make predicting outcomes difficult.

Differential diagnosis

The differential diagnosis of hemiplegic migraine includes epilepsy (postictal weakness or Todd paralysis) and other types of motor symptoms with migraine as reported by Young and colleagues (242). Prolonged progression of aura over 30 minutes to hours distinguishes hemiplegic migraine from epilepsy. Transient ischemic attack and stroke (84), metabolic abnormalities associated with focal deficits (ie, hypercapnia, hyponatremia, hypocalcemia, hepatic failure, and renal failure), Epstein-Barr virus, meningitis, encephalitis (134), carotid dissection (18), antiphospholipid syndrome (194), systemic lupus erythematosus (160; 60), ornithine transcarbamylase deficiency (51), Sturge-Weber syndrome (125; 62), and meningioma (229). Glut1 deficiency syndrome (DS) should also be considered as differential diagnoses (85).

An isolated hemiplegic migraine in a patient with Sturge-Weber syndrome could be precipitated by the alteration of cerebral hemodynamics (171). Syndrome of transient headache and neurologic deficits with CSF lymphocytosis (HaNDL syndrome) or pseudomigraine with CSF pleocytosis may mimic hemiplegic migraine, but CSF pleocytosis is uniformly present in HaNDL syndrome (73). This syndrome should be suspected in patients who are male, around the third or fourth decade of life, and who have 1 or more episodes of moderate to severe bilateral or hemicranial headache accompanied by changing temporary neurologic deficits, usually cheiro-oral numbness plus speech disorder. PMP is occasionally accompanied by fever. Total resolution of the recurrent episodes usually occurs within 2 months (87).

Inherited disorders associated with migraine headache that may include hemiparesis are CADASIL (58), MELAS (174), hereditary hemorrhagic telangiectasia (199), a form of hereditary amyloid angiopathy (93), familial cerebral cavernous malformation (92), and benign familial infantile convulsions (206).

Diagnostic workup

The history and the physical and neurologic examinations are the most important tools for diagnosing hemiplegic migraine. The methods of investigation depend on the clinical data, age of onset, number of attacks, duration of aura, and neurologic findings. Tests include a complete blood count (to exclude anemia, polycythemia, or platelet dysfunction), electrolytes, drug screen, electroencephalogram, magnetic resonance imaging, magnetic resonance angiography, carotid ultrasound, lactate, erythrocyte sedimentation rate, antiphospholipid antibody panel, special coagulation profiles, and a transesophageal echocardiogram (19). Even in the patients with sporadic hemiplegic migraine, a thrombophilia work-up to detect coagulation abnormalities that may further increase stroke risk should also be done (01). EEG of a familial hemiplegic migraine patient presenting with an acute confusional state after an initially typical migraine showed slowing of alpha rhythm and continuous rhythmical delta activity in the left hemisphere. After recovery, the EEG showed resolution of abnormal slowing of the alpha waveforms (148).

During hemiplegic migraine attacks, neuroimaging studies are generally normal, but case reports using either magnetic resonance imaging or positron emission tomogram modalities have documented decreased water diffusion and cerebral hyperperfusion or hypoperfusion contralateral to the hemiplegia, with subsequent complete resolution of both clinical and imaging abnormalities (104; 37; 09; 89; 139; 27; 20; 153; 16; 150). These abnormalities typically resolve within a few weeks (49). Irreversible visual impairment and cortical necrosis due to prolonged hemiplegic migraine attacks have been noted (110). CT with perfusion sequences and MRI with perfusion study in the early phase (within 20 to 70 minutes after onset) of hemiplegic migraine aura revealed cerebral hypoperfusion in the relevant cortical area. These findings possibly related to the time of imaging (96). During a sporadic hemiplegic migraine attack, susceptibility-weighted imaging (SWI) revealed cerebral venous prominence and increase of magnetic susceptibility affecting brain regions that corresponded with a patient’s neurologic deficit and resolution of all susceptibility abnormalities when migraine was recovered (72). MRI, DWI, and SWI have an important role in a typical attack of hemiplegic migraine to exclude acute ischemic stroke (22). Proton magnetic resonance spectroscopy showed reduced neuronal metabolic activity on the affected side of a sporadic hemiplegic migraine patient (114). Multimodality imaging of a familial hemiplegic migraine patient with prolonged aura demonstrated hemispheric cytotoxic edema with evidence of hypometabolism, whereas there was no evidence of hypoperfusion (128). These findings reflect a primary cortical metabolic dysfunction in familial hemiplegic migraine (91). Tc-99m ethyl cysteinate dimer single-photon emission computed tomography demonstrated hypoperfusion during the aura phase, hyperperfusion in the headache phase, and reversion of regional cerebral perfusion to normal during a symptom-free period. This perfusion SPECT could be a useful tool for the work-up of an atypical case of migraine (40; 214). Proton MRS and skeletal muscle phosphorus MRS in a group of FHM-2 patients demonstrated the defect in multisystem energy metabolism, which is associated with microstructural cerebellar changes detected by diffusion-weighted imaging. These findings revealed the interictal cerebellar dysfunction in familial hemiplegic migraine patients (90).

Cerebral perfusion SPECT with Tc-HMPAO in a patient with severe headache and motor weakness showed a significant change of cerebral blood flow before and after intravenous infusion with nimodipine (116).

Familial hemiplegic migraine is a rare disease. Genetic testing is now available and may confirm diagnosis. At this point, however, genetic testing does not guide treatment. It also might be important in terms of informing families of risks from contact sports (38). Although a diagnosis of familial hemiplegic migraine may have relevance for children of those affected, clinical symptoms vary widely in patients with the same genotype.

Management

The principles for the preventive treatment of hemiplegic migraine are similar to those of migraine with aura. No randomized, controlled trials of specific hemiplegic migraine therapy have been done. Management consists of both nonpharmacologic and pharmacologic therapy. Patients should eat regular meals, maintain regular sleep habits, avoid stress and migraine triggers, and use biofeedback. Analgesics such as acetaminophen, or NSAIDs, in combination with antiemetics or a dopamine agonist, are often the first choice in acute treatment. Triptans can be prescribed when headaches are not relieved with common analgesics. Preventive treatment is preferred in patients with hemiplegic migraine due to the accompanying neurologic deficit. Flunarizine, sodium valproate, lamotrigine, verapamil, and acetazolamide are among the suggested treatments (168).

Verapamil has been used effectively as a preventive and an acute medication for hemiplegic migraine. The starting dose is 120 mg orally once or twice a day, increased up to 3 times a day. Patients in 1 case series experienced a significant reduction or complete resolution of attacks, usually within the first month of treatment (244). The intravenous form of verapamil could resolve hemiplegic migraine symptoms within minutes (152; 243).

Flunarizine, 2.5 to 10 mg per day, appears to be more effective in children with hemiplegic migraine than in those who have migraine with or without aura (164).

Acetazolamide is effective in hypokalemic periodic paralysis and episodic ataxia type-2, which are channelopathies and allelic with FHM-1 (157; 219). This drug may be effective as a preventive treatment for hemiplegic migraine and progressive cerebellar ataxia. The usual dose is 250 mg twice a day (08).

Intranasal ketamine, an N-methyl-D-aspartate receptor antagonist, was reported to reduce the intensity and duration of aura in some familial hemiplegic migraine patients (122).

Lamotrigine, a sodium channel blocker, was effective in reducing migraine attacks and migraine aura symptoms, including visual and sensory symptoms as well as unilateral paresis and bilateral paresis of arm and leg, dysarthria, and speech deficit (132; 187). Sodium valproate and lamotrigine reduced attack frequency of a FHM-2 family, and these drugs could be tried in the treatment of patients with familial or sporadic hemiplegic migraine (167). Corticosteroids can suppress cortical spreading depression and edema and decrease pain and duration of an acute attack. A 100 mg per day of methylprednisolone for 5 days improved weakness and consciousness in a patient with severe and prolonged hemiplegic migraine attacks (188).

For the prolonged migrainous aura, IV furosemide 20 mg (184), prochlorperazine and magnesium (185), or magnesium sulfate alone (17), have been used to abort the attack. Patent foramen ovale is associated with sporadic hemiplegic migraine, and its closure may prevent hemiplegic migraine attacks (24; 136). Greater occipital nerve blockade could abort prolonged aura in hemiplegic migraine patients. The blockade may modulate activity at the trigeminal nucleus caudalis and inhibit cortical spreading depression (186; 29).The alternative explanation for greater occipital nerve blockade reversing the weakness is that the patients might have suffered from migraine with unilateral motor symptoms, in which weakness often improves after treatment of headache or allodynia (241). A novel neurostimulation technique (occipital nerve stimulation or bilateral subcutaneous temporal region stimulation) in a patient with occipital neuralgia and hemiplegic migraine decreased headache frequency more than 50%, and neurologic symptoms that accompanied headache ceased (53).

Occipital single-pulse repetitive transcranial magnetic stimulation (oTMS) is an attractive option for prevention and acute treatment of migraine with aura. Stimulation with oTMS may help distinguish between migraine aura and vascular disorders (151). However, there is no evidence to date for the use of oTMS to treat hemiplegic migraine.

The prooxidant tert-butyl dihydroquinone (BHQ) helps offset the gain of function and reduced Ca2+-dependent facilitation of CaV2.1 channels with S218L mutation (111).

Chen and colleagues reported successful treatment with onabotulinumtoxinA in 9 of 11 patients with hemiplegic migraine including 4 with familial hemiplegic migraine and 7 with sporadic hemiplegic migraine (39). OnabotulinumtoxinA also improved headache and aura outcomes.

In the rare case of patients with Glut1 deficiency syndrome presenting with hemiplegic migraine, initiation of ketogenic diets have been found to be successful treatments for preventing hemiplegic migraine (85). There are few cases reported of hemiplegic migraine in patients with Glut1 deficiency syndrome. It is important to initiate ketogenic diet to preserve cognitive function in patients suffering from Glut1 deficiency syndrome with hemiplegic migraines (85).

In a case study of a patient needing emergency management of hemiplegic migraine, intravenous nimodipine was used. The patient suffered from ATP1A2 gene linked hemiplegic migraine. The use of nimodipine should be considered for patients who have prolonged hemiplegic migraine attacks and have the ATP1A2 mutation (48).

Based on initial clinical trials, triptans and ergotamine are contraindicated in the treatment of sporadic and familial hemiplegic migraine. However, patients with migraine with brainstem aura, familial hemiplegic migraine, or migraine with prolonged aura have received triptans with no adverse events (126), and triptans have been used safely and effectively as acute treatment for both familial and sporadic hemiplegic migraine patients.

Special considerations

Pregnancy

Hemiplegic migraine may occur during pregnancy in patients with or without a history of hemiplegic migraine (182; 14; 142). Diffusion-weighted MRI performed in a pregnant woman who had a hemiplegic migraine attack found no evidence of cerebral ischemia (88), but another patient had evidence of hyperperfusion on SPECT scan (09).

Migraine exacerbation, including complicated migraine exacerbation, is most likely to occur in the first trimester. In a 5-year follow-up, case-control study of 41 women with transient central nervous system disorder in pregnancy, migraine with aura was the most common cause, but only 1 patient had hemiplegic migraine (71).

Migraine management during pregnancy should be conservative. If pharmacologic therapy is needed, an obstetrician should be consulted.

Anesthesia

Some hemiplegic migraine patients have developed migraine with hemiparesis, hemisensory loss, and aphasia following general anesthesia (213; 138; 238). A hemiplegic migraine attack following general anesthesia with interscalene block in a man with no history of hemiplegic migraine was reported (44). After the first episode, he had many attacks on the same side and was on preventive treatment with a good result. Spinal morphine administration in a patient with migraine initiated a hemiplegic migraine attack. The author hypothesized that spinal morphine induced a central motor deficit, facilitated by spinal cord vascular dysfunction (137). Hemiplegic migraine patients should have appropriate preoperative and postoperative care.