Familial Hemiplegic Migraine

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2021-01-18

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Summary

Clinical characteristics.

Familial hemiplegic migraine (FHM) falls within the category of migraine with aura. In migraine with aura (including familial hemiplegic migraine) the neurologic symptoms of aura are unequivocally localizable to the cerebral cortex or brain stem and include visual disturbance (most common), sensory loss (e.g., numbness or paresthesias of the face or an extremity), and dysphasia (difficulty with speech); FHM must include motor involvement, i.e., hemiparesis (weakness of an extremity). Hemiparesis occurs with at least one other symptom during FHM aura. Neurologic deficits with FHM attacks can be prolonged for hours to days and may outlast the associated migrainous headache. FHM is often earlier in onset than typical migraine, frequently beginning in the first or second decade; the frequency of attacks tends to decrease with age. Approximately 40%-50% of families with FHM1 have cerebellar signs ranging from nystagmus to progressive, usually late-onset mild ataxia. Cerebral infarction and death have rarely been associated with hemiplegic migraine.

Diagnosis/testing.

Diagnostic criteria for FHM: (1) fulfills criteria for migraine with aura; (2) aura includes some degree of hemiparesis and may be prolonged; (3) at least one first-degree relative (i.e., parent, sib, offspring) has identical attacks. Three genes are known to be associated with FHM: CACNA1A (FHM1), ATP1A2 (FHM2), and SCN1A (FHM3).

Management.

Treatment of manifestations: A trial of acetazolamide for individuals with FHM1 or a trial of standard migraine prophylactic drugs (tricyclic antidepressants, beta blockers, calcium channel blockers) for all FHM types may be warranted for frequent attacks. Antiepileptic treatment may be necessary for seizures, which are prevalent in FHM2.

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

Genetic counseling.

FHM is inherited in an autosomal dominant manner. Because the diagnosis of FHM requires at least one affected first-degree relative, most individuals diagnosed with familial hemiplegic migraine have an affected parent. The proportion of cases caused by a de novo pathogenic variant is unknown. Each child of an individual with familial hemiplegic migraine has a 50% chance of inheriting the pathogenic variant. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant in the family has been identified.

Diagnosis

Diagnostic Criteria

The diagnosis of familial hemiplegic migraine (FHM) relies on clinical diagnostic criteria. Two sets of criteria have been proposed.

Criteria adapted from the Headache Classification Subcommittee of the International Headache Society [2004] (full text)

Familial hemiplegic migraine (HM) is a category of migraine with aura (MA). Diagnostic criteria for HM are as follows:

Headaches fulfill criteria for MA (see Note).
Aura includes some degree of hemiparesis and may be prolonged but fully reversible.
HM is categorized as familial if at least one first-degree relative (i.e., parent, sib, and/or offspring) or second-degree relative has identical attacks.
HM is sporadic if no first- or second-degree relative meets criteria for hemiplegic migraine.

Note: Migraine with aura (MA) is an idiopathic, recurring disorder of neurologic symptoms unequivocally localizable to the cerebral cortex or brain stem. The aura usually develops over a period of five to 20 minutes and lasts less than 60 minutes. Headache, nausea and/or photophobia usually follow neurologic aura symptoms, either immediately or after a symptom-free interval of less than an hour. The headache usually lasts four to 72 hours but may be completely absent (acephalagia). Diagnostic criteria for MA:

At least two episodes characterized by three or more of the following:
- One or more aura symptoms are fully reversible, indicating focal cerebral cortical and/or brain stem dysfunction.
- At least one aura symptom develops gradually over more than four minutes, or two or more symptoms occur in succession.
- No aura symptom lasts more than 60 minutes. If more than one aura symptom is present, duration of symptoms is proportionally increased.
- Headache follows aura with a symptom-free interval of less than 60 minutes (headache may also begin before or simultaneously with the aura).
Ruling out of other classes of headache (i.e., head trauma, vascular disorders, nonvascular intracranial disorders, substance use or their withdrawal, non-cephalic infection, metabolic disorder, pain associated with other facial or cranial disorders)

Criteria proposed by Thomsen et al [2002]*

At least two attacks that meet all of the following criteria:

Fully reversible symptoms including motor weakness and at least one of the following: visual, sensory, or speech disturbance
At least two of the following:
- At least one aura symptom develops gradually over at least five minutes, or symptoms occur in succession.
- Each aura symptom lasts less than 24 hours.
- Some degree of headache is associated with the aura.
Not attributed to another disorder
At least one first- or second-degree relative with migraine with aura including motor weakness and fulfilling all of the criteria above

*Based on findings in 147 affected individuals from 44 families

Establishing the Genetic Cause

The genetic basis of FHM is established in a proband who meets diagnostic criteria when a heterozygous pathogenic variant is identified in one of the three genes known to be associated with FHM (CACNA1A, ATP1A2, and SCN1A) (see Table 1).

Note: (1) In the majority of persons with adult-onset hemiplegic migraine without nystagmus, seizures, or other unusual associated neurologic features, the yield for genetic testing is low. (2) Multiple studies have shown that pathogenic variants in the three known FHM-related genes are not a major cause of simplex hemiplegic migraine (i.e., hemiplegic migraine in a single person in a family).

One genetic testing strategy is serial single-gene molecular genetic testing based on the individual’s clinical findings (see Clinical Characteristics) and/or the order in which pathogenic variants most commonly occur (i.e., CACNA1A, ATP1A2, and SCN1A). Note that those with pathogenic variants in CACNA1A commonly present with nystagmus and other cerebellar signs [Ophoff et al 1996], and those with pathogenic variants in ATP1A2 frequently have epilepsy [De Fusco et al 2003].

An alternative genetic testing strategy is use of a multigene panel that includes CACNA1A, ATP1A2, and SCN1A and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in Familial Hemiplegic Migraine

Gene ¹ (Locus Name)	Proportion of FHM Attributed to Pathogenic Variants in Gene	Method
CACNA1A (FHM1)	3/42 (7%) ²	Sequence analysis ³
CACNA1A (FHM1)	3/42 (7%) ²	Gene-targeted deletion/duplication analysis ^4, 5
ATP1A2 (FHM2)	3/42 (7%) ²	Sequence analysis ³
SCN1A (FHM3)	Unknown ⁶	Sequence analysis ³
SCN1A (FHM3)	Unknown ⁶	Gene-targeted deletion/duplication analysis ^4, 7
Unknown ⁸	Unknown	NA

1.: See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.
2.: Thomsen et al [2007]
3.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single exon deletions or duplications.
6.: Dichgans et al [2005a]
5.: A 39.5-kb CACNA1A deletion of the last 16 coding exons was reported in three affected members of one family with episodic ataxia [Riant et al 2008].
7.: To date, no SCN1A deletions or duplications as causative of FHM have been reported.
8.: Possible locus heterogeneity: Gardner et al [1997] identified an FHM susceptibility locus on 1q31, designated FHM4/MGR6, which is telomeric to FHM2 (OMIM 607516). Cuenca-León et al [2009] mapped an FHM locus to 14q32 in a large Spanish kindred.

Clinical Characteristics

Clinical Description

In migraine with aura, including familial hemiplegic migraine, the neurologic symptoms of aura are unequivocally localizable to the cerebral cortex or brain stem and include visual disturbance (most common), sensory loss (e.g., numbness or paresthesias of the face or an extremity), and dysphasia (difficulty with speech), and for FHM must include motor involvement (e.g., hemiparesis [weakness of an extremity]) [Thomsen et al 2002]:

Visual disturbances can include scotoma (blind spots), photopsia (flashing lights), fortification spectra (zigzag pattern), and diplopia (double vision).
Dysphasia usually occurs when hemiplegia is right-sided.
Hemiparesis occurs with at least one other symptom during FHM aura [Ducros et al 2000].
Note: Recent family studies found that approximately 10% of family members with a CACNA1A pathogenic variant do not have hemiplegic attacks but often have migraine with or without aura [Ducros et al 2001].

Some confusion and/or drowsiness may be present even without dysphasia. Impaired consciousness ranging from drowsiness to coma is well described in FHM [Terwindt et al 1998, Chabriat et al 2000, Vahedi et al 2000]. Intermittent confusion and psychosis have been reported [Feely et al 1982] including one probable family with FHM1 and ataxia [Spranger et al 1999].

Neurologic deficits with HM attacks can be prolonged for hours to days and may outlast the associated migrainous headache. Persistent attention and memory loss can last weeks to months [Kors et al 2003]. Permanent motor, sensory, language, or visual symptoms are extremely rare [Ducros et al 2001].

Cerebral infarction and death have rarely been associated with hemiplegic migraine and should instead raise the possibility of other disorders associated with migraine and stroke (see Differential Diagnosis).

Familial hemiplegic migraine is often earlier in onset than typical migraine, frequently beginning in the first or second decade. In the report of Ducros et al [2001], the attacks started at a young age in the majority of subjects (mean: 11.7 ±8 years; range: 1-51 years). The natural history was variable. The frequency of attacks ranged from one per day to fewer than five in a lifetime (mean: 2-3/year). Long attack-free intervals were often reported (range: 2-37 years). The frequency of FHM attacks tends to decrease with age. The eventual neurologic outcome is often benign in the pure FHM group, although FHM1 can have progressive cerebellar deficit.

FHM attacks may be provoked by typical migraine triggers (e.g., foods, odors, exertion, stress), minor head trauma, and cerebral angiography.

Among families with hemiplegic migraine, the major significant clinical differences are presence or absence of cerebellar signs ranging from nystagmus to progressive, usually late-onset mild ataxia, which occurs in up to 40%-50% of families with FHM1 [Ducros et al 2000]; within such families, up to 60% of affected individuals have permanent cerebellar signs [Ducros et al 2001].

Seizures during severe attacks have been reported in some families with FHM2 along with recurrent coma in one individual [Echenne et al 1999]. Focal seizures during severe attacks have been described in two individuals with FHM1 who have no family history of FHM1 [Chabriat et al 2000], including one with severe intellectual disability, congenital ataxia, and early cerebellar atrophy [Vahedi et al 2000].

Imaging studies. The only abnormalities observed on traditional imaging studies are vermian cerebellar atrophy in some families with FHM1 [Battistini et al 1999]. Rare exceptions include transient diffusion-weighted signal changes on brain MRI suggesting cytotoxic edema during severe prolonged attacks in individuals with FHM1 [Chabriat et al 2000, Vahedi et al 2000] with hemispheric cerebral atrophy usually contralateral to the hemiparesis [Hayashi et al 1998, Chabriat et al 2000, Vahedi et al 2000].

Abnormalities in the cerebellum on magnetic resonance spectroscopy (MRS) have been reported [Dichgans et al 2005b].

Genotype-Phenotype Correlations

CACNA1A. Although further correlation is needed, some suggestive genotype-phenotype correlations exist based on limited data regarding CACNA1A pathogenic variants commonly presenting with nystagmus and other cerebellar signs [Ophoff et al 1996, Ducros et al 2001].

p.Arg192Gln and p.Val1457Leu [Carrera et al 1999] are associated with hemiplegic attacks only, whereas unconsciousness occurs commonly during attacks with the p.Val714Ala pathogenic variant [Terwindt et al 1998].
p.Thr666Met, p.Ile1811Leu, p.Arg583Gln [Alonso et al 2003], and p.Asp715Glu [Ducros et al 1999] have been associated with hemiplegic attacks plus ataxia. In the Ducros et al [2001] study, p.Thr666Met was associated with the highest frequency of hemiplegic migraine, severe attacks of coma, and nystagmus. During attacks, unconsciousness sometimes occurs in individuals with the p.Thr666Met and p.Ile1811Leu pathogenic variants [Terwindt et al 1998]. Kors et al [2003] reported a family with the p.Thr666Met pathogenic variant and progressive cognitive dysfunction.
p.Arg583Gln can be associated with stupor, fever, and progressive ataxia [Battistini et al 1999, Ducros et al 2001]. Affected individuals were thought to have fewer attacks after treatment with acetazolamide.
p.Asp715Glu has the lowest frequency (64%) of attacks of hemiplegic migraine [Ducros et al 2001].
A de novo variant, p.Tyr1385Cys, identified in a single individual with no known family history of FHM, has been associated with prolonged severe attacks including focal seizures, coma, fever, and CSF neutrophilic pleocytosis [Chabriat et al 2000, Vahedi et al 2000]. Cerebral hemispheric and cerebellar atrophy are seen on imaging studies [Vahedi et al 2000] with reversible MRI signal changes suggestive of cytotoxic edema during attacks [Chabriat et al 2000]. Additionally, the single individual with the p.Thr1384Cys pathogenic variant had otherwise unexplained severe intellectual disability, developmental delay, and congenital or early-onset ataxia.
p.Ser218Leu has been associated with delayed cerebral edema and fatal coma after minor head trauma [Kors et al 2001].

See Table 2.

ATP1A2

In the first two families in which FHM2 was genetically defined, De Fusco et al [2003] noted the history of seizures in several affected individuals. Subsequent reports of FHM2 further suggest seizures as an associated clinical feature.
A severe phenotype with seizures, coma, and elevated temperature has been reported with a p.Gly301Arg pathogenic variant in ATP1A2 [Spadaro et al 2004].
A severe phenotype with seizures and intellectual disability has been reported with the pathogenic variants p.Asp718Asn and p.Pro979Leu [Jurkat-Rott et al 2004].

See Table 3.

Penetrance

Penetrance for FHM1, 2, and 3 appears to be high and is estimated to be approximately 80% [Jurkat-Rott et al 2004, Riant et al 2005].

Nomenclature

Although families with FHM in which attacks are strikingly identical do exist, the term familial hemiplegic migraine is often used inconsistently to describe families in which different forms of migraine occur, as most individuals with hemiplegic attacks have these attacks intermingled with more frequent attacks of migraine without hemiparesis.

Prevalence

In Denmark, Thomsen et al [2002] found the prevalence of hemiplegic migraine to be 0.01% with a M:F sex ratio of 1:3 and equal prevalence of familial and sporadic cases.

Differential Diagnosis

Migraine without aura (OMIM 157300). Migraine without aura (MO or MOA) (common migraine) is an idiopathic, recurring headache disorder manifesting in attacks lasting four to 72 hours. Typical characteristics of the headache are unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity, and association with nausea, photophobia, and phonophobia. This headache occurs without neurologic aura symptoms and specifically without hemiparesis.

Typical migraine is thought to be genetically complex and to have undefined environmental components. A clinical distinction between familial and nonfamilial cases has long been entertained, beginning with the first report of FHM by Clarke [1910]. Wieser et al [2003] found no pathogenic variants in CACNA1A in individuals with common migraine. Some families having migraine without aura have shown linkage to 4q21 [Björnsson et al 2003] and 14q21.2-q22.3 [Soragna et al 2003]. One family having migraine with or without aura showed linkage to 6p12.2-p21.1 [Carlsson et al 2002].

Migraine with aura (OMIM 157300). Brugnoni et al [2002] found no CACNA1A pathogenic variants in individuals with familial migraine with aura. Some families having migraine with aura show linkage to 4q24 [Wessman et al 2002].

"Sporadic" hemiplegic migraine (SHM). "Sporadic" hemiplegic migraine refers to simplex cases (i.e., affected individuals with no relatives with hemiplegic migraine). Such individuals may or may not have other family members with typical migraine. To investigate the genetic basis of hemiplegic migraine in simplex cases:

Terwindt et al [2002] evaluated 27 individuals who had no family history of hemiplegic migraine and found a pathogenic variant in CACNA1A in two, one of whom had ataxia, nystagmus, and cerebellar atrophy on cranial CT; the other did not.
de Vries et al [2007] sequenced all three FHM-related genes in 39 individuals with SHM and found one CACNA1A pathogenic variant (FHM1), five ATP1A2 pathogenic variants (FHM2), and one SCN1A benign variant (FHM3).
Thomsen et al [2008] examined 100 individuals with SHM and found only a handful of novel, not clearly pathogenic nucleotide variants in CACNA1A and ATP1A2, suggesting that FHM-related genes are not major genes in SHM.

Other inherited disorders associated with migrainous headache that may include hemiplegic aura:

MELAS, MERRF, and other mitochondrial disorders. MELAS is a multisystem disorder with onset typically between ages two and ten years. The most common initial symptoms are generalized tonic-clonic seizures, recurrent headaches, anorexia, and recurrent vomiting. Seizures are often associated with stroke-like episodes of transient hemiparesis or cortical blindness, which may be associated with altered consciousness and may be recurrent. The cumulative residual effects of the stroke-like episodes gradually impair motor abilities, vision, and cognition, often by adolescence or young adulthood. Sensorineural hearing loss is common. The most common mitochondrial DNA (mtDNA) pathogenic variant, present in more than 80% of individuals with typical clinical findings of MELAS, is an A-to-G transition at nucleotide 3243 in the tRNALeu(UUR) of mtDNA.
CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is characterized by history of migraine with aura, mid-adult (30s-60s) onset of cerebrovascular, mood disturbance, apathy, cognitive disturbance progressing to dementia, and diffuse white matter lesions and subcortical infarcts on neuroimaging. One family with CADASIL was reported to have hemiparetic aura [Hutchinson et al 1995]. The pathologic hallmark of CADASIL is electron-dense granules in the media of arterioles that can often be identified by electron microscopic (EM) evaluation of skin biopsies. More than 90% of individuals have pathogenic variants in NOTCH3. Inheritance is autosomal dominant.
RVCL (retinal vasculopathy with cerebral leukodystrophy) is characterized by systemic microvasculopathy with adult onset (30s-40s) of retinal vasculopathy and cerebrovascular disease variably associated with migraine. The pathologic hallmark of RVCL is multi-laminated subendothelial basement membrane by EM evaluation of multiple organs including skin. Affected individuals have pathogenic variants in TREX1. Inheritance is autosomal dominant.
Hereditary hemorrhagic telangiectasia (HHT) is characterized by the presence of multiple arteriovenous malformations (AVMs) that lack intervening capillaries and result in direct connections between arteries and veins. Small AVMs, or telangiectases, close to the surface of skin and mucous membranes often rupture and bleed after slight trauma. The most common clinical manifestation is spontaneous and recurrent nosebleeds beginning at approximately age 12 years. Large AVMs often cause symptoms when they occur in brain, lung, or the gastrointestinal tract; complications from bleeding or shunting may be sudden and catastrophic. Migraine with aura has been reported in 50% of affected individuals. HHT is caused by pathogenic variants in ENG, ACVRL1, SMAD4, and at least two other as-yet unidentified genes. Inheritance is autosomal dominant.
Familial cerebral cavernous malformations (CCMs) are vascular malformations in the brain and spinal cord consisting of closely clustered enlarged capillary channels (caverns) with a single layer of endothelium without normal intervening brain parenchyma or mature vessel wall elements. CCMs have been reported in infants and children, but the majority of individuals present with symptoms between the second and fifth decades. Approximately 50%-75% of persons with CCM have symptoms, including seizures, focal neurologic deficits, nonspecific headaches, and cerebral hemorrhage. Up to 50% of individuals with CCM remain symptom free throughout their lives. The three genes associated with familial CCM are KRIT1, CCM2, and CCM3. Inheritance is autosomal dominant.
Dutch form of hereditary cerebral amyloid angiopathy (OMIM 605714). Migraines often precede the onset of cerebral and cerebellar hemorrhage in the fourth or fifth decade. Senile plaques and vascular wall amyloid are found in the brain in association with amino acid changes in the APP beta-amyloid precursor protein, a protease inhibitor. Inheritance is autosomal dominant.

Alternating hemiplegia of childhood (AHC) is a rare condition with clinical features that overlap with FHM. AHC is characterized by recurrent hemiplegia with onset before age 18 months, variable other transient neurological findings, and progressive cognitive decline. Some individuals with AHC have a heterozygous pathogenic variant in ATP1A2 (the gene that is mutated in FHM2) [Bassi et al 2004, Swoboda et al 2004]; however, the majority are heterozygous for a pathogenic variant in ATP1A3 [Heinzen et al 2012] and are allelic with rapid-onset dystonia parkinsonism and CAPOS. Inheritance is autosomal dominant.

Hemiplegia. The differential diagnosis of hemiplegia includes post-ictal weakness following seizure, transient ischemic attack (TIA), stroke, and other non-genetic causes of transient hemiparesis.

Stroke. When family history is positive for hemiparetic attacks with migraine, the presence of infarct on imaging studies raises the possibility of other inherited disorders such as MELAS, CADASIL, or thrombophilia, such as factor V Leiden [Gaustadnes et al 1999]. Additional stroke risk factors may also be present.

Caution: Even with normal imaging studies and description of spreading aura, an age-appropriate stroke evaluation should be considered at presentation. Overlap in clinical features, inaccuracies of historical family information, rarity of true FHM, and the seriousness of stroke-related disorders warrant this cautious approach. Stroke or other CNS-related disorders should be even more strongly considered if family history is negative for hemiplegic migraine.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with familial or sporadic hemiplegic migraine, the following evaluations are recommended:

Quantitative eye movement examination in individuals with nystagmus or complaints of incoordination or imbalance to look for additional clues of cerebellar involvement
EEG and neuroimaging studies if seizures are present in order to further characterize the seizure disorder.
Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Symptomatic support during an episode of hemiplegic migraine is the only therapy available.

A trial of acetazolamide for individuals with FHM1 or a trial of standard migraine prophylactic drugs (tricyclic antidepressants, beta blockers, calcium channel blockers, anti-epileptic medications) for all FHM types may be warranted for frequent attacks. Limited correlation exists between drug response and hemiplegic migraine type.

There are anecdotal reports of therapeutic response to antiepileptic medications including topiramate, lacosamide, levetiracetam, and valproate, along with other medications commonly used for migraine prophylaxis.

Antiepileptic treatment may be necessary for seizures that are prevalent in FHM2 (caused by pathogenic variants in ATP1A2).

Agents/Circumstances to Avoid

In general, vasoconstricting agents should be avoided because of the risk of stroke.

Cerebral angiography is hazardous as it may precipitate a severe attack [Chabriat et al 2000].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.