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  • Updated 12.06.2020
  • Released 09.02.1994
  • Expires For CME 12.06.2023

Hemiplegic migraine

Introduction

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.

Overview

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.

Key points

• 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 (134). 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” (227). The first description of familial hemiplegic migraine was made by Clarke (40). Whitty reported an autosomal dominant inheritance pattern of stereotyped episodes of migraine associated with prolonged hemiplegia and alteration of consciousness lasting days or weeks (230; 20). A monograph on familial hemiplegic migraine was written by Heyck in 1956 (101). In 1965, Bradshaw and Parsons reported a clinical study of hemiplegic migraine patients (22). In 1973, Heyck reported varieties of hemiplegic migraine (102). Permanent hemiplegia and progressive dementia attributed to hemiplegic migraine have been reported (42; 102). Familial hemiplegic migraine associated with other neurologic or ophthalmologic findings is well documented (230; 174; 149; 233). Reports began to recognize the increased heritability of hemiplegic migraine compared to other forms of migraine (230; 44; Bruyn 1968; 127). In 1986, Bergouignan and associates reported a case of familial hemiplegic migraine that was provoked by head trauma (14). Multiple reports described hemiplegic migraine has been reported in children (25; 104; 107). 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 (40; 193; 221; 06).

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 (111; 112; 153; 152). 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 (224). 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; 224). 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 (151). CACNA1A mutations have a broad clinical spectrum due to different types of mutations (62).

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 (77). Posteriorly, a dysfunction in the ATP1A2 gene on chromosome 1q21-23, encoding the Na+/K+pump, was associated with FHM-2 (48; 138).

A heterozygous mutation in EAAT1 can lead to decreased glutamate uptake, leading to neuronal hyperexcitability that can cause seizures, hemiplegia, and episodic ataxia (109).

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 (55). 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 (109).

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) (100).

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 (100) 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 (62; 200). A wide range of aura and clinical phenotypes, including SCA6, EA-2, and FHM-1, occur in members of the same familial hemiplegic migraine family with the same mutation (226; 139; 173; 117). 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 (129; 150). 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 (24). Over 20% of attacks include impairment of consciousness, ranging from mild somnolence or confusion to diffuse encephalopathy or coma (62). Coma typically resolves spontaneously but in severe cases can last days and require intubation (140). Attacks may be provoked by emotional stress, mild head trauma, angiography, or exertion (230; 22; 169; 197). 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 (230; 121; 19; 73; 184). The impaired cognitive functions, including figural memory, executive function, some aspects of attention, and dexterity, may reflect disturbances in functional connectivity (114). Episodes of transient psychotic symptoms after migraine lasting up to a week have been documented in 2 family members with negative genetic tests (123). In FHM-2, a transient nonverbal learning disorder in children and an acute psychosis during the aura phase of migraine have been reported (166; 11). 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 (176). Symptoms of migraine with brainstem aura, such as vertigo, dysarthria, bilateral paresthesias, and numbness, occurred in approximately 66% of patients with familial hemiplegic migraine (90). Most familial hemiplegic migraine patients also experience attacks of typical migraine with aura and migraine without aura (204).

The clinical symptoms of sporadic hemiplegic migraine are similar to familial hemiplegic migraine, but no other family members are affected (22; 27; 169; 60; 62). 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 (204). 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 (223). 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 (57). Cerebellar signs may be less common in sporadic hemiplegic migraine than in familial hemiplegic migraine (62; 197; 201). A presentation including acute encephalopathy, migrainous infarction, and epistaxis occurs in a few patients with sporadic hemiplegic migraine (10; 124; 148). 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 (209). 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 (143).

Pelzer and colleagues reviewed the clinical characteristics of 281 patients with familial hemiplegic migraine or sporadic hemiplegic migraine (160). 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.

A large case-control study by Young and colleagues illustrated migraine with unilateral motor symptoms in a tertiary care center (235). 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 (235).

The true prevalence of motor symptoms in migraine outside of tertiary headache centers is unclear (103). 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.

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 (125).

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 (22; 62). In long-term follow-up, brain imaging and EEG data generally remain stable (106). 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 (159). 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 (228). 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 (189). However, it can precipitate a severe migraine attack leading to stroke in patients with familial hemiplegic migraine (98). An increased release of glutamate could have a role in increased susceptibility to ischemic cerebral tissue in familial hemiplegic migraine models (65). Although attacks may resolve in young adulthood, there is the change for recurrence later in life (106).

Ischemic stroke and migraine with aura are major parts of various syndromes, including MELAS (156), CADASIL (211; 213), and autosomal dominant vascular retinopathy, migraine, and Raynaud phenomenon (196). 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 (115).

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 (111; 153; 151; 27). FHM-1 with cerebellar signs has been linked to mutations in CACNA1A in some families (151; 198; 12; 61; 74; 215). As of 2005, 17 different missense mutations in CACNA1A have been linked with FHM-1 (163). The T666M mutation is the major CACNA1A mutation. Haplotype studies suggested that this mutation arose independently on different chromosomes by recurrent mutational events (61). 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 (46), which confirmed the role of this specific mutation in (fatal) coma after minor head trauma (121). 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 (216). The clinical manifestation found in the S218L mutation was reported in a child with a mutation in CACNA1A (p.Arg1349Gln) (135). 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 (67). The thalamic nuclei of knock-in mice expressing the CACNA1A R192Q mutation suggested that the mutation affects more rostral brain structures (155). 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) (186; 208; 188). The susceptibility to spreading depression and neurologic deficits in FHM-1 is affected by allele dosage and hormonal factors (64). 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 (59).

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 (63). Marconi and colleagues refined the 1q23 locus for FHM-2 by studying a large Italian family affected by this disease (138). 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 (48).

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 (190). ATP1A2 mutations have also been associated with migraine with brainstem aura and alternating hemiplegia of childhood. Many patients also suffer from epilepsy (53). 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%) (170). 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 (218; 31). Some patients with novel ATP1A2 mutations had additional clinical features, including mood alteration and mental impairment (30). 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 (220). A case of 2 allelic, novel ATP1A2 missense mutations in a patient with hemiplegic migraine was described (219). 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 (50; 75). Mutations in the ATP1A3 gene can also present with dystonia, alternating hemiplegia, EEG abnormalities, and seizure (157).

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 (55). SCN1A mutations were found in a familial hemiplegic migraine family with or without associated diseases such as ataxia, epilepsy, and myoclonus (78; 217; 32). Visual disturbances, including severe vision loss, due to SCN1A has been described (183).

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 (202). 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 (137).

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 (202). 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 (45).

No mutations have been found in any of the 3 familial hemiplegic migraine genes among patients with migrainous vertigo (118; 225). CACNA1A mutations can cause atypical alternating hemiplegia of childhood, indicating an overlap of molecular mechanisms causing alternating hemiplegia of childhood and familial hemiplegic migraine (54).

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 (214). 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 (197). 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 (52). 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 (203). 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 (171). 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 (191). 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 (210), 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 (229). 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 (72). 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 (71). 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 (82). Mutations W1684E and V1696I, which cause FHM-1 with and without cerebellar ataxia, respectively, altered the G protein-Ca(2+) channel affinity (80). The significant reduction of the extent of G-protein-mediated inhibition in the K1336E mutant CaV2.1 Ca2+ channels renders the neuronal network hyperexcitable (79). 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 (41).

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 (48). 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 (195). Temperature-sensitive effects on protein stability were proposed as an underlying cause of ATP1A2 loss of function (194). 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 (167). In a study of 9 FHM-2 mutations, different mechanisms of phosphorylation inhibition of Na+, K+-ATPase were demonstrated (182).

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 (34). 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 (113; 35). 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) (164).

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 (33). 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 (232).

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 (95; 93). 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 (96; 94; 97). 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 (185). 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 (91). 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 (09). 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 (66).

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 (91).

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 (76; 172; 29; 141).

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 (201).

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 (62; 200). 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 (22; 205). 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 (22; 62; 205).

Prevention

Hemiplegic migraine attacks may be prevented by nonpharmacologic and pharmacologic management. Patient education for avoidance of trigger factors may reduce hemiplegic migraine 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 (235). Prolonged progression of aura over 30 minutes to hours distinguishes hemiplegic migraine from epilepsy. Transient ischemic attack and stroke (81), metabolic abnormalities associated with focal deficits (ie, hypercapnia, hyponatremia, hypocalcemia, hepatic failure, and renal failure), Epstein-Barr virus, meningitis, encephalitis (128), carotid dissection (17), antiphospholipid syndrome (187), systemic lupus erythematosus (154; 58), ornithine transcarbamylase deficiency (49), Sturge-Weber syndrome (119; 60), and meningioma (222) should also be considered as differential diagnoses.

An isolated hemiplegic migraine in a patient with Sturge-Weber syndrome could be precipitated by the alteration of cerebral hemodynamics (165). 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 (70). 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 (83).

Inherited disorders associated with migraine headache that may include hemiparesis are CADASIL (56), MELAS (168), hereditary hemorrhagic telangiectasia (192), a form of hereditary amyloid angiopathy (89), familial cerebral cavernous malformation (88), and benign familial infantile convulsions (199).

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 (18). 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 (142).

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 (99; 36; 08; 85; 133; 26; 19; 147; 15; 144). These abnormalities typically resolve within a few weeks (de Amorim et al 2017). 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 (92). 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 (69). MRI, DWI, and SWI have an important role in a typical attack of hemiplegic migraine to exclude acute ischemic stroke (21). Proton magnetic resonance spectroscopy showed reduced neuronal metabolic activity on the affected side of a sporadic hemiplegic migraine patient (108). 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 (122). These findings reflect a primary cortical metabolic dysfunction in familial hemiplegic migraine (87). 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 (39; 207). 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 (86).

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 (110).

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 (37). 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 (162).

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 (237). The intravenous form of verapamil could resolve hemiplegic migraine symptoms within minutes (146; 236).

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 (158).

Acetazolamide is effective in hypokalemic periodic paralysis and episodic ataxia type-2, which are channelopathies and allelic with FHM-1 (151; 212). 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 (07).

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 (116).

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 (126; 180). 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 (161). 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 (181).

For the prolonged migrainous aura, IV furosemide 20 mg (177), prochlorperazine and magnesium (178), or magnesium sulfate alone (16), have been used to abort the attack. Patent foramen ovale is associated with sporadic hemiplegic migraine, and its closure may prevent hemiplegic migraine attacks (23; 130). 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 (179; 28).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 (234). 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 (51).

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 (145). 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 (105).

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 (38). OnabotulinumtoxinA also improved headache and aura outcomes.

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 (120), 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 (175; 13; 136). Diffusion-weighted MRI performed in a pregnant woman who had a hemiplegic migraine attack found no evidence of cerebral ischemia (84), but another patient had evidence of hyperperfusion on SPECT scan (08).

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 (68).

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 (206; 132; 231). A hemiplegic migraine attack following general anesthesia with interscalene block in a man with no history of hemiplegic migraine was reported (43). 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 (131). Hemiplegic migraine patients should have appropriate preoperative and postoperative care.

References

01
Aceves J, Mungall D, Kirmani BF. Sporadic hemiplegic migraine with ATP1A2 and prothrombin gene mutations. Case Rep Neurol Med 2013;2013:895057. PMID 24396618
02
Adams PJ, Garcia E, David LS, Mulatz KJ, Spacey SD, Snutch TP. Ca(V)2.1 P/Q-type calcium channel alternative splicing affects the functional impact of familial hemiplegic migraine mutations: implications for calcium channelopathies. Channels (Austin) 2009;3(2):110-21. PMID 19242091
03
Adams PJ, Rungta RL, Garcia E, van den Maagdenberg AM, MacVicar BA, Snutch TP. Contribution of calcium-dependent facilitation to synaptic plasticity revealed by migraine mutations in the P/Q-type calcium channel. Proc Natl Acad Sci U S A 2010;107(43):18694-9. PMID 20937883
04
Ambrosini A, D'Onofrio M, Buzzi MG, et al. Possible involvement of the CACNA1E gene in migraine: a search for single nucleotide polymorphism in different clinical phenotypes. Headache 2017;57(7):1136-44. PMID 28573794
05
Ambrosini A, D'Onofrio M, Grieco GS, et al. Familial basilar migraine associated with a new mutation in the ATP1A2 gene. Neurology 2005;65(11):1826-8. PMID 16344534
06
Aminian A, Strashun A, Rose A. Alternating hemiplegia of childhood: studies of regional cerebral blood flow using 99mTc-hexamethylpropylene amine oxime single-photon emission computed tomography. Ann Neurol 1993;33:43-7. PMID 8494333
07
Athwal BS, Lennox GG. Acetazolamide responsiveness in familial hemiplegic migraine. Ann Neurol 1996;40(5):820-1. PMID 8957029
08
Barbour PJ, Castaldo JE, Shoemaker EI. Hemiplegic migraine during pregnancy: unusual magnetic resonance appearance with SPECT scan correlation. Headache 2001;41(3):310-6. PMID 11264693
09
Barros J, Barreto R, Brandao AF, et al. Monozygotic twin sisters discordant for familial hemiplegic migraine. J Headache Pain 2013;14:77. PMID 24041236
10
Barros J, Damásio J, Tuna A, Pereira-Monteiro J. Migraine-induced epistaxis and sporadic hemiplegic migraine: unusual features in the same patient. Case Rep Neurol 2012a;4(2):116-9. PMID 22807908
11
Barros J, Mendes A, Matos I, Pereira-Monteiro J. Psychotic aura symptoms in familial hemiplegic migraine type 2 (ATP1A2). J Headache Pain 2012b;13(7):581-5. PMID 22661290
12
Battistini S, Stenirri S, Piatti M, et al. A new CACNA1A gene mutation in acetazolamide-responsive familial hemiplegic migraine and ataxia. Neurology 1999;53:38-43. PMID 10408534
13
Bending JJ. Recurrent bilateral reversible migrainous hemiparesis during pregnancy. Can Med Assoc J 1982;127(6):508-9. PMID 7116268
14
Bergouignan FX, Ferrer X, Julien J. Familial hemiplegic migraine: a new case. Headache 1986;26(10):498-9. PMID 3818262
15
Bhatia R, Desai S, Tripathi M, et al. Sporadic hemiplegic migraine: report of a case with clinical and radiological features. J Headache Pain 2008;9(6):385-8. PMID 18810316
16
Bigal ME, Bordini CA, Tepper SJ, Speciali JG. Intravenous magnesium sulphate in the acute treatment of migraine without aura and migraine with aura. A randomized, double-blind, placebo-controlled study. Cephalalgia 2002;22(5):345-53. PMID 12110110
17
Biousse V, D’Anglejan-Chatillon J, Touboul PJ, Amarenco P, Bousser MG. Time course of symptoms in extracranial carotid artery dissections. A series of 80 patients. Stroke 1995;26(2):235-9. PMID 7831694
18
Black DF. Sporadic and familial hemiplegic migraine: diagnosis and treatment. Semin Neurol 2006;26(2):208-16. PMID 16628531
19
Black DF, Kung S, Sola CL, Bostwick MJ, Swanson JW. Familial hemiplegic migraine, neuropsychiatric symptoms, and Erdheim-Chester disease. Headache 2004;44(9):911-5. PMID 15447701
20
Blau JN, Whitty CW. Familial hemiplegic migraine. Lancet 1955;269(6900):115-6. PMID 13272341
21
Bosemani T, Burton VJ, Felling RJ, et al. Pediatric hemiplegic migraine: role of multiple MRI techniques in evaluation of reversible hypoperfusion. Cephalalgia 2014;34(4):311-5. PMID 24142848
22
Bradshaw P, Parsons M. Hemiplegic migraine, a clinical study. Q J Med 1965;34:65-85. PMID 14252427
23
Brighina F, Gurgone G, Gaglio RM, Palermo A, Cosentino G, Fierro B. A case of atypical sporadic hemiplegic migraine associated with PFO and hypoplasia of vertebro-basilar system. J Headache Pain 2009;10(4):303-6. PMID 19421707
24
Bruun M, Hjermind L, Thomsen C, et al. Familial hemiplegic migraine type 1 associated with parkinsonism: a case report. Case Rep Neurol 2015;7(1):84-9. PMID 25969684
25
Burke EC, Peters GA. Migraine in childhood: a preliminary report. Am J Dis Child 1956;92:330-6. PMID 13361760
26
Butteriss DJ, Ramesh V, Birchall D. Serial MRI in a case of familial hemiplegic migraine. Neuroradiology 2003;45(5):300-3. PMID 12669159
27
Carrera P, Piatti M, Stenirri S, et al. Genetic heterogeneity in Italian families with familial hemiplegic migraine. Neurology 1999;53(1):26-33. PMID 10408532
28
Casas-Limón J, Aledo-Serrano Á, Abarrategui B, Cuadrado ML. Greater occipital nerve blockade: a safe and effective option for the acute treatment of hemiplegic aura. Headache 2015;55(7):1000-3. PMID 26140423
29
Castiglioni C, López I, Riant F, Bertini E, Terracciano A. PRRT2 mutation causes paroxysmal kinesigenic dyskinesia and hemiplegic migraine in monozygotic twins. Eur J Pediatr Neurol 2013;17(3):254-8. PMID 23182655
30
Castro MJ, Nunes B, de Vries B, et al. Two novel functional mutations in the Na+,K+-ATPase alpha2-subunit ATP1A2 gene in patients with familial hemiplegic migraine and associated neurological phenotypes. Clin Genet 2008;73(1):37-43. PMID 18028456
31
Castro MJ, Stam AH, Lemos C, et al. Recurrent ATP1A2 mutations in Portuguese families with familial hemiplegic migraine. J Hum Genet 2007;52(12):990-8. PMID 17952365
32
Castro MJ, Stam AH, Lemos C, et al. First mutation in the voltage-gated Nav1.1 subunit gene SCN1A with co-occuring familial hemiplegic migraine and epilepsy. Cephalalgia 2009;29(3):308-13. PMID 19220312
33
Cestele S, Labate A, Rusconi R, et al. Divergent effects of the T1174S SCN1A mutation associated with seizures and hemiplegic migraine. Epilepsia 2013b;54(5):927-35. PMID 23398611
34
Cestele S, Scalmani P, Rusconi R, Terragni B, Franceschetti S, Mantegazza M. Self-limited hyperexcitability: functional effect of a familial hemiplegic migraine mutation of the Nav1.1(SCN1A)Na+ channel. J Neurosci 2008;28(29):7273-83. PMID 18632931
35
Cestele S, Schiavon E, Rusconi R, Franceschetti S, Mantegazza M. Nonfunctional NaV1.1 familial hemiplegic migraine mutant transformed into gain of function by partial rescue of folding defects. Proc Natl Acad Sci USA 2013a;110(43):17546-51. PMID 24101488
36
Chabriat H, Vahedi K, Clark CA, et al. Decreased hemispheric water mobility in hemiplegic migraine related to mutation of the CACNA1A gene. Neurology 2000;54(2):510-2. PMID 10668728
37
Chand MR, Kanwar S, Peck E. Mild traumatic brain injury in a high school football player with familial hemiplegic migraine: a case report. PM R 2018;10(4):431-6. PMID 28918117
38
Chen TY, Garza I, Dodick DW, Robertson CE. The effect of onabotulinumtoxinA on aura frequency and severity in patients with hemiplegic migraine: case series of 11 patients. Headache 2018;58(7):973-85. PMID 29762872
39
Cheng MF, Wu YW, Tang SC. Cerebral perfusion changes in hemiplegic migraine: illustrated by Tc-99m ECD brain perfusion scan. Clin Nucl Med 2010;35(6):456-8. PMID 20479602
40
Clarke JM. On recurrent motor paralysis in migraine: with report of a family in which recurrent hemiplegia accompanied the attacks. Br Med J 1910;1:1534-8. PMID 20765161
41
Condliffe SB, Fratangeli A, Munasinghe NR, et al. The E1015K variant in the synprint region of the CaV2.1 channel alters channel function and is associated with different migraine phenotypes. J Biol Chem 2013;288(47):33873-83. PMID 24108129
42
Connor RC. Complicated migraine. A study of permanent neurological and visual defects by migraine. Lancet 1962;2(7265):1072-5. PMID 14022628
43
Cook CJ, Jones D. Hemiplegic migraine associated with interscalene block and general anaesthesia. Anaesthesia 2008;63(6):678-9. PMID 18477293
44
Critchley M. Migraine: general remarks. Proc R Soc Med 1962;55:165-7. PMID 13882267
45
Cuenca-León E, Corominas R, Montfort M, et al. Familial hemiplegic migraine: linkage to chromosome 14q32 in a Spanish kindred. Neurogenetics 2009;10(3):191-8. PMID 19153782
46
Curtain RP, Smith RL, Ovcaric M, Griffiths LR. Minor head trauma-induced sporadic hemiplegic migraine coma. Pediatr Neurol 2006;34(4):329-32. PMID 16638514
47
de Amorim IL, Antunes AP, Nunes GS, Martins IP. Reversible cortical thickening in hemiplegic migraine. Cephalalgia 2018;38(3):604-5. PMID 28120619
48
De Fusco M, Marconi R, Silvestri L, et al. Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2. Nat Genet 2003;33(2):192-6. PMID 12539047
49
De Grauw TJ, Smit LM, Brockstedt M, Meijer Y, vd Klei-von Moorsel J, Jakobs C. Acute hemiparesis as the presenting sign in a heterozygote for ornithine transcarbamylase deficiency. Neuropediatrics 1990;21(3):133-5. PMID 2234317
50
Deprez L, Weckhuysen S, Peeters K, et al. Epilepsy as part of the phenotype associated with ATP1A2 mutations. Epilepsia 2008;49(3):500-8. PMID 18028407
51
Deshpande KK, Wininger KL. Feasibility of combined epicranial temporal and occipital neurostimulation: treatment of a challenging case of headache. Pain Physician 2011;14:37-44. PMID 21267040
52
de Vries B, Freilinger T, Vanmolkot KR, et al. Systematic analysis of three FHM genes in 39 sporadic patients with hemiplegic migraine. Neurology 2007;69(23):2170-6. PMID 18056581
53
de Vries B, Haan J, Frants RR, Van den Maagdenberg AM, Ferrari MD. Genetic biomarkers for migraine. Headache 2006;46(7):1059-68. PMID 16866710
54
de Vries B, Stam AH, Beker F, et al. CACNA1A mutation linking hemiplegic migraine and alternating hemiplegia of childhood. Cephalalgia 2008;28(8):887-91. PMID 18498393
55
Dichgans M, Freilinger T, Eckstein G, et al. Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet 2005;366(9483):371-7. PMID 16054936
56
Dichgans M, Mayer M, Uttner I, et al. The phenotypic spectrum of CADASIL: clinical findings in 102 cases. Ann Neurol 1998;44(5):731-9. PMID 9818928
57
Di Stefano F, Floris G, Vacca M, et al. Transient unilateral spatial neglect during aura in a woman with sporadic hemiplegic migraine. Cephalalgia 2013;33(14):1194-7. PMID 23674829
58
Doi H, Tateishi T, Isobe N, Yamasaki R, Ohyagi Y, Kira J. [Sporadic hemiplegic migraine-like headache in a patient with systemic lupus erythematosus]. [Article in Japanese] Rinsho Shinkeigaku 2010;50(5):332-4. PMID 20535984
59
D’Onofrio M, Ambrosini A, Di Mambro A, et al. The interplay of two single nucleotide polymorphisms in the CACNA1A gene may contribute to migraine susceptibility. Neurosci Lett 2009;453(1):12-5. PMID 19429006
60
Dora B, Balkan S. Sporadic hemiplegic migraine and Sturge-Weber syndrome. Headache 2001;41(2):209-10. PMID 11251712
61
Ducros A, Denier C, Joutel A, et al. Recurrence of the T666M calcium channel CACNA1A gene mutation in familial hemiplegic migraine with progressive cerebellar ataxia. Am J Hum Genet 1999;64(1):89-98. PMID 9915947
62
Ducros A, Denier C, Joutel A, et al. The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel. N Engl J Med 2001;345:17-24. PMID 11439943
63
Ducros A, Joutel A, Vahedi K, et al. Mapping of a second locus for familial hemiplegic migraine to 1q21-q23 and evidence of further heterogeneity. Ann Neurol 1997;42:885-90. PMID 9403481
64
Eikermann-Haerter K, Dileköz E, Kudo C, et al. Genetic and hormonal factors modulate spreading depression and transient hemiparesis in mouse models of familial hemiplegic migraine type 1. J Clin Invest 2009;119(1):99-109. PMID 19104150
65
Eikermann-Haerter K, Lee JH, Yuzawa I, et al. Migraine mutations increase stroke vulnerability by facilitating ischemic depolarizations. Circulation 2012;125(2):335-45. PMID 22144569
66
Eikermann-Haerter K, Negro A, Ayata C. Spreading depression and the clinical correlates of migraine. Rev Neurosci 2013;24(4):353-63. PMID 23907418
67
Eikermann-Haerter K, Yuzawa I, Qin T, et al. Enhanced subcortical spreading depression in familial hemiplegic migraine type 1 mutant mice. J Neurosci 2011;31(15):5755-63. PMID 21490217
68
Ertresvg JM, Stovner LJ, Kvavik LE, et al. Migraine aura or transient ischemic attacks. A five-year follow-up case-control study of women with transient central nervous system disorders in pregnancy. BMC Med 2007;5:19. PMID 17640340
69
Fedak EM, Zumberge NA, Heyer GL. The diagnostic role for susceptibility-weighted MRI during sporadic hemiplegic migraine. Cephalalgia 2013;33(15):1258-63. PMID 23766355
70
Filina T, Feja KN, Tolan RW Jr. An adolescent with pseudomigraine, transient headache, neurological deficits, and lymphocytic pleocytosis (HaNDL Syndrome): case report and review of the literature. Clin Pediatr (Phila) 2013;52(6):496-502. PMID 23559488
71
Franceschini A, Hullugundi SK, van den Maagdenberg AM, Nistri A, Fabbretti E. Effects of LPS on P2X3 receptors of trigeminal sensory neurons and macrophages from mice expressing the R192Q Cacna1a gene mutation of familial hemiplegic migraine-1. Purinergic Signal 2013a;9(1):7-13. PMID 22836594
72
Franceschini A, Vilotti S, Ferrari MD, van den Maagdenberg AM, Nistri A, Fabbretti E. TNFα levels and macrophages expression reflect an inflammatory potential of trigeminal ganglia in a mouse model of familial hemiplegic migraine. PLoS One 2013b;8(1):e52394. PMID 23326332
73
Freilinger T, Bohe M, Wegener B, Müller-Myhsok B, Dichgans M, Knoblauch H. Expansion of the phenotypic spectrum of the CACNA1A T666M mutation: a family with familial hemiplegic migraine type1, cerebellar atrophy and mental retardation. Cephalalgia 2008;28(4):403-7. PMID 18279427
74
Friend KL, Crimmins D, Phan TG, et al. Detection of a novel missense mutation and second recurrent mutation in the CACNA1A gene in individuals with EA-2 and FHM. Hum Genet 1999;105(3):261-5. PMID 10987655
75
Gallanti A, Tonelli A, Cardin V, Bussone G, Bresolin N, Bassi MT. A novel de novo nonsense mutation in ATP1A2 associated with sporadic hemiplegic migraine and epileptic seizures. J Neurol Sci 2008;273(1-2):123-6. PMID 18644608
76
Gardiner AR, Bhatia KP, Stamelou M, et al. PRRT2 gene mutations: From paroxysmal dyskinesia to episodic ataxia and hemiplegic migraine. Neurology 2012;79(21):2115-21. PMID 23077024
77
Gardner K, Barmada MM, Ptacek LJ, Hoffman EP. A new locus for hemiplegic migraine maps to chromosome 1q31. Neurology 1997;49(5):1231-8. PMID 9371899
78
Gargus JJ, Tournay A. Novel mutation confirms seizure locus SCN1A is also familial hemiplegic migraine locus FHM3. Pediatr Neurol 2007;37(6):407-10. PMID 18021921
79
Garza-Lopez E, Gonzalez-Ramirez R, Gandini MA, Sandoval A, Felix R. The familial hemiplegic migraine type 1 mutation K1336E affects direct G protein-mediated regulation of neuronal P/Q-type Ca2+ channels. Cephalalgia 2013;33(6):398-407. PMID 23430985
80
Garza-Lopez E, Sandoval A, González-Ramĺrez R, et al. Familial hemiplegic migraine type1 mutations W1684R and V1696I alter G protein-mediated regulation of Ca(V)2.1 voltage-gated calcium channels. Biochim Biophys Acta 2012;1822(8):1238-46. PMID 22549042
81
Gaustadnes M, Rudiger N, Moller J, Rasmussen K, Bjerregaard Larsen T, Ingerslev J. Thrombophilic predisposition in stroke and venous thromboembolism in Danish patients. Blood Coagul Fibrinolysis 1999;10(5):251-9. PMID 10456616
82
Gnanasekaran A, Bele T, Hullugundi S, et al. Mutated CaV2.1 channels dysregulate CASK/P2X3 signaling in mouse trigeminal sensory neurons of R192Q Cacna1a knock-in mice. Mol Pain 2013;9:62. PMID 24294842
83
Gomez-Aranda F, Canadillas F, Marti-Masso JF, et al. Pseudomigraine with temporary neurological symptoms and lymphocytic pleocytosis. A report of 50 cases. Brain 1997;120(Pt 7):1105-13. PMID 9236623
84
Gonzalez-Alegre P, Tippin J. Prolonged cortical electrical depression and diffuse vasospasm without ischemia in a case of severe hemiplegic migraine during pregnancy. Headache 2003;43(1):72-5. PMID 12864763
85
Grant PE, He J, Halpern EF, et al. Frequency and clinical context of decreased diffusion coefficient reversal in the human brain. Radiology 2001;221(1):43-50. PMID 11568319
86
Grimaldi D, Tonon C, Cevoli S, et al. Clinical and neuroimaging evidence of interictal cerebellar dysfunction in FHM2. Cephalalgia 2010;30(5):552-9. PMID 19673908
87
Guedj E, Belenotti P, Serratrice J, et al. Partially reversible cortical metabolic dysfunction in familial hemiplegic migraine with prolonged aura. Headache 2010;50(5):872-7. PMID 20236346
88
Gunel M, Awad IA, Anson J, Lifton RP. Mapping a gene causing cerebral cavernous malformation to 7q11.2-q21. Proc Natl Acad Sci USA 1995;92:6620-4. PMID 7604043
89
Haan J, Algra PR, Roos RA. Hereditary cerebral hemorrhage with amyloidosis–Dutch type. Clinical and computed tomographic analysis of 24 cases. Arch Neurol 1990;47(6):649-53. PMID 2346393
90
Haan J, Terwindt GM, Ophoff RA. Is familial hemiplegic migraine a hereditary form of basilar migraine. Cephalalgia 1995;15(6):477-81. PMID 8706110
91
Hansen JM, Bolla M, Magis D, et al. Habituation of evoked responses is greater in patients with familial hemiplegic migraine than in controls: a contrast with the common forms of migraine. Eur J Neurol 2011a;18(3):478-85. PMID 20727009
92
Hansen JM, Hauge AW, Ashina M, Olesen J. Trigger factors for familial hemiplegic migraine. Cephalalgia 2011b;31(12):1274-81. PMID 21784774
93
Hansen JM, Schytz HW, Larsen VA, Iversen HK, Ashina M. Hemiplegic migraine aura begins with cerebral hypoperfusion: Imaging in the acute phase. Headache 2011c;51:1289-96. PMID 21797860
94
Hansen JM, Thomsen LL, Marconi R, Casari G, Olesen J, Ashina M. Familial hemiplegic migraine type 2 does not share hypersensitivity to nitric oxide with common types of migraine. Cephalalgia 2008c;28(4):367-75. PMID 18294248
95
Hansen JM, Thomsen LL, Olesen J, Ashina M. Calcitonin gene-related peptide does not cause the familial hemiplegic migraine phenotype. Neurology 2008a;71(11):841-7. PMID 18779512
96
Hansen JM, Thomsen LL, Olesen J, Ashina M. Familial hemiplegic migraine type 1 shows no hypersensitivity to nitric oxide. Cephalalgia 2008b;28(5):496-505. PMID 18384418
97
Hansen JM, Thomsen LL, Olesen J, Ashina M. Coexisting typical migraine in familial hemiplegic migraine. Neurology 2010;74(7):594-600. PMID 20157162
98
Harrison MJ. Hemiplegic migraine. J Neurol Neurosurg Psychiatry 1981;44(7):652-3. PMID 7288457
99
Hayashi R, Tachikawa H, Watanabe R, Honda M, Katsumata Y. Familial hemiplegic migraine with irreversible brain damage. Intern Med 1998;37(2):166-8. PMID 9550598
100
Headache Classification Subcommittee of the International Headache Society. The international classification of headache disorders, 3rd edition (beta version). Cephalalgia 2013;33(9):648-50. PMID 23771276
101
Heyck H. Neue Beitrage zur Klinik und Pathogenese der Migrane. G. Stuggart: Thieme Verlag, 1956.
102
Heyck H. Varieties of hemiplegic migraine. Headache 1973;12(4):135-42. PMID 4682551
103
Hiekkala ME, Vuola P, Artto V, et al. The contribution of CACNA1A, ATP1A2 and SCN1A mutations in hemiplegic migraine: a clinical and genetic study in Finnish migraine families. Cephalalgia 2018;38(12):1849-63. PMID 29486580
104
Holguin J, Fenichel G. Migraine. J Pediatrics 1967;70:290-7. PMID 6018115
105
Inagaki A, Frank CA, Usachev YM, Benveniste M, Lee A. Pharmacological correction of gating defects in the voltage-gated Ca(v)2.1 Ca2+ channel due to a familial hemiplegic migraine mutation. Neuron 2014;81(1):91-102. PMID 24411734
106
Indelicato E, Nachbauer W, Eigentler A, et al. Ten years of follow-up in a large family with familial hemiplegic migraine type 1: clinical course and implications for treatment. Cephalalgia 2018;38(6):1167-76. PMID 28856914
107
Isler W. Acute hemiplegia and hemisyndromes in childhood. In: Clinics in developmental medicine. London: Heinemann Medical, 1971:41-2.
108
Jacob A, Mahavish K, Bowden A, Smith ET, Enevoldson P, White RP. Imaging abnormalities in sporadic hemiplegic migraine on conventional MRI, diffusion and perfusion MRI and MRS. Cephalalgia 2006;26(8):1004-9. PMID 16886937
109
Jen JC, Wan J, Palos TP, Howard BD, Baloh RW. Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures. Neurology 2005;65(4):529-34. PMID 16116111
110
Jimenez-Hoyuela JM, Amrani-Raissouni T, Gallardo-Tur A, Moya-Espinosa F, Padilla-Parrado F. Impact of 99mTc-HMPAO brain perfusion scan in the diagnosis of hemiplegic migraine. Clin Nucle Med 2013;38(2):e103-5. PMID 23334140
111
Joutel A, Bousser MG, Biousse V, et al. A gene for familial hemiplegic migraine maps to chromosome 19. Nat Genet 1993;5:40-5. PMID 8220421
112
Joutel A, Ducros A, Vahedi K, et al. Genetic heterogeneity of familial hemiplegic migraine. Am J Hum Genet 1994;55(6):1166-72. PMID 7977376
113
Kahlig KM, Rhodes TH, Pusch M, et al. Divergent sodium channel defects in familial hemiplegic migraine. Proc Natl Acad Sci U S A 2008;105(28):9799-804. PMID 18621678
114
Karner E, Delazer M, Benke T, Bösch S. Cognitive functions, emotional behavior, and quality of life in familial hemiplegia migraine. Cogn Behav Neurol 2010;23(2):106-11. PMID 20535059
115
Karner E, Nachbauer W, Bodner T, Benke T, Boesch S, Delazer M. Long-term outcome of cognitive functions, emotional behavior, and quality of life in a family with familial hemiplegic migraine. Cogn Behav Neurol 2012;25(2):85-92. PMID 22596110
116
Kaube H, Herzog J, Kaufer T, Dichgans M, Diener HC. Aura in some patients with familial hemiplegic migraine can be stopped by intranasal ketamine. Neurology 2000;55(1):139-41. PMID 10891926
117
Kinder S, Ossig C, Wienecke M, et al. Novel frameshift mutation in the CACNA1A gene causing a mixed phenotype of episodic ataxia and familiar hemiplegic migraine. Eur J Paediatr Neurol 2015;19(1):72-4. PMID 25468264
118
Kirchmann M, Thomsen LL, Olesen J. The CACNA1A and ATP1A2 genes are not involved in dominantly inherited migraine with aura. Am J Med Genet B Neuropsychiatr Genet 2006;141B(3):250-6. PMID 16508934
119
Klapper J. Headache in Sturge-Weber syndrome. Headache 1994;34(9):521-2. PMID 8002325
120
Klapper J, Mathew N, Nett R. Triptans in the treatment of basilar migraine and migraine with prolonged aura. Headache 2001;41(10):981-4. PMID 11903526
121
Kors EE, Terwindt GM, Vermeulen FL, et al. Delayed cerebral edema and fatal coma after minor head trauma: role of the CACNA1A calcium channel subunit gene and relationship with familial hemiplegic migraine. Ann Neurol 2001;49(6):753-60. PMID 11409427
122
Kumar G, Topper L, Maytal J. Familial hemiplegic migraine with prolonged aura and multimodality imaging: a case report. Headache 2009;49(1):139-42. PMID 18624711
123
LaBianca S, Jensen R, van den Maagdenberg A, Baandrup L, Bendtsen L. Familial hemiplegic migraine and recurrent episodes of psychosis: a case report. Headache 2015;55(7):1004-7. PMID 26087244
124
Lai TH, Hong CT. Prolonged symptoms in sporadic hemiplegic migraine: aura or migrainous infarction. Acta Neurol Taiwan 2012;21(3):129-32. PMID 23196733
125
Lambru G, Nesbitt A, Shanahan P, Matharu MS. Coexistence of hemiplegic migraine with SUNCT or SUNA: a case series. Cephalalgia 2012;32(3):258-62. PMID 22238357
126
Lampl C, Katsarava Z, Diener HC, Limmroth V. Lamotrigine reduces migraine aura and migraine attacks in patients with migraine with aura. J Neurol Neurosurg Psychiatry 2005;76(12):1730-2. PMID 16291905
127
Lance JW. The mechanism and management of headache. London: Butterworth, 1969.
128
Leavell R, Ray CG, Ferry PC, Minnich LL. Unusual acute neurologic presentations with Epstein-Barr virus infection. Arch Neurol 1986;43(2):186-8. PMID 3004399
129
Lee H, Aramideh M, Ginjaar HB. Familial hemiplegic migraine resulting in recurrent coma. Ned Tijdschr Geneeskd 2008;152(7):393-6. PMID 18380388
130
Lemka M, Pienczk-Reclawowicz K, Pilarska E, Szmuda M. Cessation of sporadic hemiplegic migraine attacks after patent foramen ovale closure. Dev Med Child Neurol 2009;51(11):923-4. PMID 19758362
131
Lentschener C, Dousset B, Zuber M, Ozier Y. Central sensory-motor deficit after uneventful single-dose spinal morphine administration in a patient with preexisting migraine headaches. Anesth Analg 2009;109(5):1688-90. PMID 19843810
132
Lin L, Adey C. Presentation of hemiplegic migraine--hemiplegia and hemi-sensory loss following general anaesthesia. Anaesth Intensive Care 2007;35(3):418-22. PMID 17591140
133
Lindahl AJ, Allder S, Jefferson D, Allder S, Moody A, Martel A. Prolonged hemiplegic migraine associated with unilateral hyperperfusion on perfusion weighted magnetic resonance imaging. J Neurol Neurosurg Psychiatry 2002;73(2):202-3. PMID 12122185
134
Liveing E. On megrin, sick-headache, and some allied disorders: a contribution to the pathology of nerve-storms. London: J & A Churchill, 1873.
135
Malpas TJ, Riant F, Tournier-Lasserve E, Vahedi K, Neville BG. Sporadic hemiplegic migraine and delayed cerebral oedema after minor head trauma: a novel de novo CACNA1A gene mutation. Dev Med Child Neurol 2010;52(1):103-4. PMID 19811514
136
Mandel S. Hemiplegic migraine in pregnancy. Headache 1988;28(6):414-6. PMID 3049450
137
Mantegazza M, Cestèle S. Pathophysiological mechanisms of migraine and epilepsy: Similarities and differences. Neurosci Lett 2018;667:92-102. PMID 29129678
138
Marconi R, De Fusco M, Aridon P, et al. Familial hemiplegic migraine type 2 is linked to 0.9Mb region on chromosome 1q23. Ann Neurol 2003;53(3):376-81. PMID 12601705
139
Marti S, Baloh RW, Jen JC, Straumann D, Jung HH. Progressive cerebellar ataxia with variable episodic symptoms--phenotypic diversity of R1668W CACNA1A mutation. Eur Neurol 2008;60(1):16-20. PMID 18437043
140
McClain IJ, Tsai MA, Guardia CF 3rd. Prolonged postictal coma in hemiplegic migraine: a case report. Headache 2019;59(9):1641-2. PMID 31339554
141
Meneret A, Gaudebout C, Riant F, Vidailhet M, Depienne C, Roze E. PRRT2 mutations and paroxysmal disorders. Eur J Neurol 2013;20(6):872-8. PMID 23398397
142
Merwick A, Fernandez D, McNamara B, Harrington H. Acute encephalopathy in familial hemiplegic migraine with ATP1A2 mutation. BMJ Case Rep 2013;2013. PMID 23761507
143
Monteiro C, Barros J, Taipa R, Pereira-Monteiro J. Sporadic hemiplegic migraine with normal imaging as the initial manifestation of CADASIL. Cephalalgia 2012;32(3):255-7. PMID 22250206
144
Mourand I, Menjot de Champfleur N, Carra-Dallière C, et al. Perfusion-weighted MR imaging in persistemt hemiplegic migraine. Neuroradiology 2012;54(3):255-60. PMID 21833737
145
Naeije G, Fogang Y, Ligot N, Mavroudakis N. Occipital transcranial magnetic stimulation discriminates transient neurological symptoms of vascular origin from migraine aura without headache. Neurophysiol Clin 2017;47(4):269-74. PMID 28571630
146
Ng TM, Kohli A, Fagan SC, Mohamed AE, Geiszt G. The effect of intravenous verapamil on cerebral hemodynamics in a migraine patient with hemiplegia. Ann Pharmacother 2000;34(1):39-43. PMID 10669185
147
Oberndorfer S, Wober C, Nasel C, et al. Familial hemiplegic migraine: follow-up findings of diffusion-weighted magnetic resonance imaging (MRI), perfusion-MRI and [99mTc] HMPAO-SPECT in a patient with prolonged hemiplegic aura. Cephalalgia 2004;24(7):533-9. PMID 15196295
148
Ohmura K, Suzuki Y, Saito Y, Wada T, Goto M, Seto S. Sporadic hemiplegic migraine presenting as acute encephalopathy. Brain Dev 2012;34(8):691-5. PMID 22136990
149
Ohta M, Araki S, Kuroiwa Y. Familial occurrence of migraine with a hemiplegic syndrome and cerebellar manifestations. Neurology 1967;17:813-7. PMID 15088544
150
Omata T, Takanashi J, Wada T, Arai H, Tanabe Y. Genetic diagnosis and acetazolamide treatment of familial hemiplegic migraine. Brain Dev 2011;33(4):332-4. PMID 20542393
151
Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 1996;87:543-52. PMID 8898206
152
Ophoff RA, Terwindt GM, Vergouwe MN, et al. A 3 Mb region for the familial hemiplegic migraine locus on 19p13.1-p13.2: exclusion of PRKCSH as a candidate gene. Dutch Migraine Genetic Research Group. Eur J Hum Genet 1997;4(6):321-8.
153
Ophoff RA, Van Eijk R, Sandkuijl LA, et al. Genetic heterogeneity of familial hemiplegic migraine. Genomics 1994;22(1):21-6. PMID 7959770
154
Parikh S, Swaiman KF, Kim Y. Neurologic characteristics of childhood lupus erythematosus. Pediatr Neurol 1995;13(3):198-201. PMID 8554656
155
Park J, Moon H, Akerman S, et al. Differential trigeminovascular nociceptive responses in the thalamus in the familial hemiplegic migraine1 knock-in mouse: a Fos protein study. Neurobiol Dis 2014;64:1-7. PMID 24355314
156
Pavlakis SG, Phillips PC, DiMauro S, De Vivo DC, Rowland LP. Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes: a distinct clinical syndrome. Ann Neurol 1984;16(4):481-8. PMID 6093682
157
Pavlidis E, Uldall P, Gøbel Madsen C, et al. Alternating hemiplegia of childhood and a pathogenic variant of ATP1A3: a case report and pathophysiological considerations. Epileptic Disord 2017;19(2):226-30. PMID 28637637
158
Peer Mohamed B, Goadsby PJ, Prabhakar P. Safety and efficacy of flunarizine in childhood migraine: 11 years’ experience, with emphasis on its effect in hemiplegic migraine. Dev Med Child Neurol 2012;54(3):274-7. PMID 22268377
159
Pelzer N, Haan J, Stam AH, et al. Clinical spectrum of hemiplegic migraine and chances of finding a pathogenic mutation. Neurology 2018a;90(7):e575-82. PMID 29343472
160
Pelzer N, Hoogeveen ES, Ferrari MD, Poll-The BT, Kruit MC, Terwindt GM. Brain atrophy following hemiplegic migraine attacks. Cephalalgia 2018b;38(6):1199-202. PMID 28750589
161
Pelzer N, Stam AH, Carpay JA, et al. Familial hemiplegic migraine treated by sodium valproate and lamotrigine. Cephalalgia 2014;34(9):708-11. PMID 24443394
162
Pelzer N, Stam AH, Haan J, Ferrari MD, Terwindt GM. Familial and sporadic hemiplegic migraine: diagnosis and treatment. Curr Treat Options Neurol 2013;15(1):13-27. PMID 23203776
163
Pietrobon D. Migraine: new molecular mechanisms. Neuroscientist 2005;11(4):373-86. PMID 16061523
164
Pietrobon D. Familial hemiplegic migraine. Neurotherapeutics 2007;4(2):274-84. PMID 17395138
165
Planche V, Chassin O, Leduc L, Reqnier W, Kelly A, Colamarino R. Sturge-Weber syndrome with late onset hemiplegic migraine-like attacks and progressive unilateral cerebral atrophy. Cephalalgia 2014;34(1):73-7. PMID 24045571
166
Podesta B, Briatore E, Boghi A, Marenco D, Calzolari S. Transient nonverbal learning disorder in a child suffering from Familial Hemiplegic migraine. Cephalalgia 2011;31(14):1497-502. PMID 21908445
167
Poulsen H, Khandelia H, Morth JP, et al. Neurological disease mutations compromise a C-terminal ion pathway in the Na(+)/K(+)-ATPase. Nature 2010;467(7311):99-102. PMID 20720542
168
Prayson RA, Wang N. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome: an autopsy report. Arch Pathol Lab Med 1998;122(11):978-81. PMID 9822126
169
Razavi B, Fattal D, Afifi A, Adams HP Jr. Hemiplegic migraine induced by exertion. Arch Neurol 2000;57(9):1363-5. PMID 10987906
170
Riant F, De Fusco M, Aridon P, et al. ATP1A2 mutations in 11 families with familial hemiplegic migraine. Hum Mutat 2005;26(3):281. PMID 16088919
171
Riant F, Ducros A, Ploton C, Barbance C, Depienne C, Tournier-Lasserve E. De novo mutations in ATP1A2 and CACNA1A are frequent in early-onset sporadic hemiplegic migraine. Neurology 2010;75(11):967-72. PMID 20837964
172
Riant F, Roze E, Barbance C, et al. PRRT2 mutations cause hemiplegic migraine. Neurology 2012;79(21):2122-4. PMID 23077016
173
Romaniello R, Zucca C, Tonelli A, et al. A wide spectrum of clinical, neurophysiological and neuroradiological abnormalities in a family with a novel CACNA1A mutation. J Neurol Neurosurg Psychiatry 2010;81(8):840-3. PMID 20682717
174
Rosenbaum HE. Familial hemiplegic migraine. Neurology 1960;10:164-70. PMID 13854572
175
Ross RT. Hemiplegic migraine. Can Med Assoc J 1958;78(1):10-6. PMID 13489617
176
Roth C, Freilinger T, Kirovski G, et al. Clinical spectrum in three families with familial hemiplegic migraine type 2 including a novel mutation in the ATP1A2 gene. Cephalalgia 2014;34(3):183-90. PMID 24096472
177
Rozen T. Treatment of a prolonged migrainous aura with intravenous furosemide. Neurology 2000;55(5):732-3. PMID 10980751
178
Rozen T. Aborting a prolonged migrainous aura with intravenous prochlorperazine and magnesium sulfate. Headache 2003;43(8):901-3. PMID 12940813
179
Rozen T. Cessation of hemiplegic migraine auras with greater occipital nerve blockade. Headache 2007;47(6):917-9. PMID 17578545
180
Russell MB, Ducros A. Sporadic and familial hemiplegic migraine: pathophysiological mechanisms, clinical characteristics, diagnosis, and management. Lancet Neurol 2011;10(5):457-70. PMID 21458376
181
Sanchez-Albisua I, Schoning M, Jurkat-Rott K, Lerche H. Possible effect of corticoids on hemiplegic attacks in severe hemiplegic migraine. Pediatr Neurol 2013;49(4):286-8. PMID 23831250
182
Schack VR, Holm R, Vilsen B. Inhibition of phosphorylation of Na+, K+-ATPase by mutations causing familial hemiplegic migraine. J Biol Chem 2012;287(3):2191-202. PMID 22117059
183
Schubert V, Auffenberg E, Biskup S, Jurkat-Rott K, Freilinger T. Two novel families with hemiplegic migraine caused by recurrent SCN1A mutation p.F1499L. Cephalalgia 2017. [Epub ahead of print] PMID 29145747
184
Schwedt TJ, Zhou J, Dodick DW. Sporadic hemiplegic migraine with permanent neurological deficits. Headache 2014;54(1):163-6. PMID 24117121
185
Schytz HW, Hansen JM, Philip D, Selb J, Boas DA, Ashina M. Nitric oxide modulation of low-frequency oscillations in cortical vessels in FHM--a NIRS study. Headache 2012;52(7):1146-54. PMID 22352839
186
Scoggan KA, Friedman JH, Bulman DE. CACNA1A mutation in a EA-2 patient responsive to acetazolamide and valproic acid. Can J Neurol Sci 2006;33(1):68-72. PMID 16583725
187
Seleznick MJ, Silveira LH, Espinoza LR. Avascular necrosis associated with anticardiolipin antibodies. J Rheumatol 1991;18(9):1416-7. PMID 1757948
188
Serra SA, Fernàndez-Castillo N, Macaya A, Cormand B, Valverde MA, Fernàndez-Fernàndez JM. The hemiplegic migraine-associated Y1245C mutation in CACNA1A results in a gain of channel function due to its effect on the voltage sensor and G-protein-mediated inhibition. Pflugers Arch 2009;458(3):489-502. PMID 19189122
189
Shuaib A, Hachinski VC. Migraine and the risks from angiography. Arch Neurol 1988;45:911-2. PMID 3395265
190
Spadaro M, Ursu S, Lehmann-Horn F, et al. A G301R Na+/K+ -ATPase mutation causes familial hemiplegic migraine type 2 with cerebellar signs. Neurogenetics 2004;5(3):177-85. PMID 15459825
191
Stam AH, Louter MA, Haan J, et al. A long-term follow-up study of 18 patients with sporadic hemiplegic migraine. Cephalalgia 2011;31(2):199-205. PMID 20974584
192
Steele JG, Nath PU, Burn J, Porteous ME. An association between migrainous aura and hereditary haemorrhagic telangiectasia. Headache 1993;33(3):145-8. PMID 8486513
193
Symonds C. Migrainous variants. Trans Med Soc Lond 1952;67:237-50.
194
Tavraz NN, Dürr KL, Koenderink JB, et al. Impaired plasma membrane targeting or protein stability by certain ATP1A2 mutations identified in sporadic or familial hemiplegic migraine. Channels (Austin) 2009;3(2):82-7. PMID 19372756
195
Tavraz NN, Friedrich T, Dürr KL, et al. Diverse functional consequences of mutations in the Na+/K+-ATPase alpha2-subunit causing familial hemiplegic migraine type 2. J Biol Chem 2008;283(45):31097-106. PMID 18728015
196
Terwindt GM, Haan J, Ophoff RA. Clinical and genetic analysis of a large Dutch family with autosomal dominant vascular retinopathy, migraine and Raynaud's phenomenon. Brain 1998b;121(Pt 2):303-16. PMID 9549508
197
Terwindt G, Kors E, Haan J. Mutation analysis of the CACNA1A calcium channel subunit gene in 27 patients with sporadic hemiplegic migraine. Arch Neurol 2002;59(6):1016-18. PMID 12056940
198
Terwindt GM, Ophoff RA, Haan J, et al. Variable clinical expression of mutations in the P/Q-type calcium channel gene in familial hemiplegic migraine. Neurology 1998a;50:1105-10. PMID 9566402
199
Terwindt GM, Ophoff RA, Lindhout D, et al. Partial cosegregation of familial hemiplegic migraine and benign familial infantile epileptic syndrome. Epilepsia 1997;38(8):915-21. PMID 9579893
200
Thomsen LL, Eriksen MK, Roemer SF, Andersen I, Olesen J, Russell MB. A population-based study of familial hemiplegic migraine suggests revised diagnostic criteria. Brain 2002a;125(Pt 6):1379-91. PMID 12023326
201
Thomsen LL, Eriksen MK, Roemer SF, et al. An epidemiological survey of hemiplegic migraine. Cephalalgia 2002b;22(5):361-75.
202
Thomsen LL, Kirchmann M, Bjornsson A, et al. The genetic spectrum of a population-based sample of familial hemiplegic migraine. Brain 2007;130(Pt 2):346-56. PMID 17142831
203
Thomsen LL, Oestergaard E, Bjornsson A, et al. Screen for CACNA1A and ATP1A2 mutations in sporadic hemiplegic migraine patients. Cephalalgia 2008;28(9):914-21. PMID 18513263
204
Thomsen LL, Olesen J, Russell MB. Increased risk of migraine with typical aura in probands with familial hemiplegic migraine and their relatives. Eur J Neurol 2003b;10(4):421-7. PMID 12823495
205
Thomsen LL, Ostergaard E, Olesen J, Russell MB. Evidence for a separate type of migraine with aura: sporadic hemiplegic migraine. Neurology 2003a;60(4):595-601. PMID 12601098
206
Thurlow JA. Hemiplegia following general anaesthesia: an unusual presentation of migraine. Eur J Anaesthesiol 1998;15(5):610-2. PMID 9785080
207
Toldo I, Cecchin D, Sartori S, et al. Multimodal neuroimaging in a child with sporadic hemiplegic migraine: A contribution to understanding pathogenesis. Cephalalgia 2011;31(6):751-6. PMID 21172953
208
Tonelli A, D'Angelo MG, Salati R, et al. Early onset, non fluctuating spinocerebellar ataxia and a novel missense mutation in CACNA1A gene. J Neurol Sci 2006;241(1-2):13-7. PMID 16325861
209
Topakian R, Pischinger B, Stieglbauer K, Pichler R. Rare clinical findings in a patient with sporadic hemiplegic migraine: FDG-PET provides diminished brain metabolism at 10-year follow-up. Cephalalgia 2014;34(5):392-6. PMID 24270521
210
Tottene A, Conti R, Fabbro A, et al. Enhanced excitatory transmission at cortical synapses as the basis for facilitated spreading depression in Ca(v)2.1 knockin migraine mice. Neuron 2009;61(5):762-73. PMID 19285472
211
Tournier-Lasserve E, Joutel A, Melki J, et al. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12. Nat Genet 1993;3:256-9. PMID 8485581
212
Tricarico D, Barberi M, Camerino DC. Acetazolamide opens the muscular KCa2+ channel: a novel mechanism of action that may explain the therapeutic effect of the drug in hypokalemic periodic paralysis. Ann Neurol 2000;48(3):304-12. PMID 10976636
213
Vahedi K, Chabriat H, Levy C, Joutel A, Tournier-Lasserve E, Bousser MG. Migraine with aura and brain magnetic resonance imaging in patients with CADASIL. Arch Neurol 2004;61(8):1237-40. PMID 15313840
214
Vahedi K, Denier C, Ducros A, et al. Sporadic hemiplegic migraine with de novo CACNA1A missense mutation. Neurology 1999;52(Suppl. 2):A274.
215
Vahedi K, Denier C, Ducros A, et al. CACNA1A gene de novo mutation causing hemiplegic migraine, coma, and cerebellar atrophy. Neurology 2000;55(7):1040-2. PMID 11061267
216
van den Maagdenberg AM, Pizzorusso T, Kaja S, et al. High cortical spreading depression susceptibility and migraine-associated symptoms in Ca(v)2.1 S218L mice. Ann Neurol 2010;67(1):85-98. PMID 20186955
217
Vanmolkot KR, Babini E, de Vries B, et al. The novel L1649Q mutation in the SCN1A epilepsy gene is associated with familial hemiplegic migraine: genetic and functional studies. Hum Mutat 2007a;28(5):522. PMID 17397047
218
Vanmolkot KR, Kors EE, Turk U, et al. Two de novo mutations in the Na, K-ATPase gene ATP1A2 associated with pure familial hemiplegic migraine. Eur J Hum Genet 2006a;14(5):555-60. PMID 16538223
219
Vanmolkot KR, Stam AH, Raman A, et al. First case of compound heterozygosity in Na,K-ATPase gene ATP1A2 in familial hemiplegic migraine. Eur J Hum Genet 2007b;15(8):884-8. PMID 17473835
220
Vanmolkot KR, Stroink H, Koenderink JB, et al. Severe episodic neurological deficits and permanent mental retardation in a child with a novel FHM2 ATP1A2 mutation. Ann Neurol 2006b;59(2):310-4. PMID 16437583
221
Verret S, Steele JC. Alternating hemiplegia in childhood: a report of eight patients with complicated migraine beginning in infancy. Pediatrics 1971;47:675-80. PMID 5089756
222
Vetvik KR, Dahl M, Russell MB. Symptomatic sporadic hemiplegic migraine. Cephalalgia 2005;25(11):1093-5. PMID 16232163
223
Vincent MB. A note on the digiti quinti sign in hemiplegic migraine. Cephalalgia 2009;29(5):580-2. PMID 19025551
224
Von Brederlow B, Hahn AF, Koopman WJ, Ebers GC, Bulman DE. Mapping the gene for acetazolamide responsive hereditary paroxysmal cerebellar ataxia to chromosome 19p. Hum Mol Gene 1995;4(2):279-84.
225
Von Brevern M, Ta N, Shankar A, et al. Migrainous vertigo: mutation analysis of the candidate genes CACNA1A, ATP1A2, SCN1A, and CACNB4. Headache 2006;46(7):1136-41. PMID 16866717
226
Wada T, Kobayashi N, Takahashi Y, Aoki T, Watanabe T, Saitoh S. Wide clinical variability in a family with a CACNA1A T666M mutation: hemiplegic migraine, coma, and progressive ataxia. Pediatr Neurol 2002;26(2):47-50. PMID 11814735
227
Weatherall MW. The migraine theories of Liveing and Latham: a reappraisal. Brain 2012;135(Pt 8):2560-8. PMID 22382360
228
Weinberger J. Stroke and migraine. Curr Cardiol Rep 2007;9(1):13-9. PMID 17362679
229
Weiss N, Sandoval A, Felix R, Van den Maagdenberg A, De Waard M. The S218L familial hemiplegic migraine mutation promotes deinhibition of Ca(v)2.1 calcium channels during direct G-protein regulation. Pflugers Arch 2008;457(2):315-26. PMID 18581134
230
Whitty CW. Familial hemiplegic migraine. J Neurol Neurosurg Psychiatry 1953;16:172-7. PMID 13085199
231
Willson J, Kapur S. Apnoeic spells following general anaesthesia in a patient with familial hemiplegic migraine. Anaesthesia 2007;62(9):956-8. PMID 17697227
232
Wiwanitkit V. FHM3 in familial hemiplegic migraine is more resistant to mutation than FHM1 and FHM2. J Neurol Sci 2009;277(1-2):76-9. PMID 19007941
233
Young GF, Leon-Barth CA, Green J. Familial hemiplegic migraine, retinal degeneration, deafness, and nystagmus. Arch Neurol 1970;23:201-9. PMID 5311627
234
Young WB. Cessation of hemiplegic migraine auras with greater occipital nerve blockade: a comment. Headache 2008;48(3):481. PMID 18205798
235
Young WB, Gangal KS, Aponte RJ, Kaiser RS. Migraine with unilateral motor symptoms: a case-control study. J Neurol Neurosurg Psychiatry 2007;78(6):600-4. PMID 17056632
236
Yu W, Horowitz SH. Familial hemiplegic migraine and its abortive therapy with intravenous verapamil. Neurology 2001;57(9):1732-3. PMID 11706128
237
Yu W, Horowitz SH. Treatment of sporadic hemiplegic migraine with calcium-channel blocker verapamil. Neurology 2003;60(1):120-1. PMID 12525732

Contributors

Author

  • Michael J Marmura MD

    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.

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Editor

  • Apss2

    Stephen D Silberstein MD

    Dr. Silberstein, Director of the Jefferson Headache Center at Thomas Jefferson University, receives 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.

    See Profile

Former Authors

  • K Michael A Welch MD (original author), Mario F P Peres MD, Petcharat Dusitanond MD, and Juan B Gomez MD

Patient Profile

Age range of presentation
  • 02-05 years
  • 06-12 years
  • 13-18 years
  • 19-44 years
  • 45-64 years
Sex preponderance
  • female>male, >2:1
  • female>male, >1:1
Heredity
  • autosomal dominant in familial hemiplegic migraine
  • heredity may be a factor in sporadic hemiplegic migraine
Population groups selectively affected
  • none selectively affected
Occupation groups selectively affected
  • none selectively affected

ICD & OMIM codes

ICD-9
  • Hemiplegic migraine: 346.8
ICD-10
  • Hemiplegic migraine: G43.1

Questions or Comment?

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