Clinical Diagnosis

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]

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

• Headaches fulfill criteria for MA*.
• Aura includes some degree of hemiparesis and may be prolonged.
• At least one first-degree relative (i.e., parent, sib, and/or offspring) has identical attacks.

*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

Molecular Genetic Testing

Genes. Three genes are known to be associated with familial hemiplegic migraine:

• CACNA1A. Familial hemiplegic migraine type 1 (FHM1), commonly presenting with nystagmus and other cerebellar signs [Ophoff et al 1996], was previously estimated to account for 50% of FHM. However, in a recent population-based study in Denmark, molecular genetic testing revealed that three of 42 (7%) of the 44 families tested had FHM1 [Thomsen et al 2007].
• ATP1A2. Familial hemiplegic migraine type 2 (FHM2), frequently occurring with epilepsy [DeFusco et al 2003], appeared in the past to be less prevalent than FHM1, with far fewer case reports in the literature. In a recent population-based study in Denmark, molecular genetic testing revealed that three of 42 (7%) of the 44 families tested had FHM2 [Thomsen et al 2007].
• SCN1A. Familial hemiplegic migraine type 3 (FHM3) [Dichgans et al 2005a] has been reported in several unrelated families in the literature.

Other loci

• 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 testing

CACNA1A

• Sequence analysis. Direct sequencing of all known exons and flanking introns would reliably reveal point mutations or very small frameshift mutations, but the actual mutation detection frequency is unknown.
  
  Note: The sensitivity of screening by SSCP or dHPLC as performed in various research laboratories has been estimated to be greater than 80% but imperfect.
• Deletion/duplication analysis. 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]. The frequency of other partial- or whole-gene deletions is unknown.

ATP1A2

• Sequence analysis. Direct sequencing of all known exons and flanking introns would reliably reveal point mutations or very small frameshift mutations, but the actual mutation detection frequency is unknown.

SCN1A

• Sequence analysis/mutation scanning. Direct sequencing of all known exons and flanking introns would reliably reveal point mutations or very small frameshift mutations, but the actual mutation detection frequency is unknown.
• Deletion/duplication analysis. To date, no report of SCN1A deletions or duplications as causative of FHM has been published.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To establish the genetic basis of FHM in a proband, identification of mutation in one of the three known associated genes by molecular genetic testing is necessary.

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 mutations in the three known FHM-related genes are not major causes of simplex hemiplegic migraine (i.e., hemiplegic migraine in a single person in a family).

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

CACNA1A. Two other phenotypes are associated with different kinds of mutations in CACNA1A:

• Episodic ataxia type 2 (EA2) involving episodes of ataxia and sometimes migrainous headache with interictal nystagmus associated with predominantly nonsense, frameshift, or splice site mutations that disrupt the open reading frame; some affected individuals have missense mutations.
• Spinocerebellar ataxia type 6 (SCA6) with late-onset progressive ataxia associated with expansion of a CAG trinucleotide repeat in the CACNA1A coding region. Of note, the CAG trinucleotide repeat expansion typical of SCA6 has not been observed in families with FHM [Carrera et al 1999, Ducros et al 1999]; however, some individuals with SCA6 may have migraine.

Overlap has been described between the FHM1 phenotype (associated with missense mutations) and the phenotypes of SCA6 and EA2, but more so between the phenotypes of EA2 and SCA6.

• One family with a CAG trinucleotide repeat expansion characteristically observed in individuals with SCA6 had purely episodic ataxia and another family with a CAG repeat expansion had some members with episodic ataxia and others with progressive ataxia [Jodice et al 1997].
• In one family with EA2, affected members experienced hemiplegia; one family member had migraine during episodes of ataxia [Jen 1999].
• In one large family with a CACNA1A mutation, some individuals had only HM, some had only ataxia, and some had both [Alonso et al 2003].

SCN1A. SCN1A-related seizure disorders encompass a spectrum that ranges from simple febrile seizures (FS) and generalized epilepsy with febrile seizures plus (GEFS+) at the mild end to Dravet syndrome and intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC) at the severe end. Phenotypes with intractable seizures including Dravet syndrome, also known as severe myoclonic epilepsy in infancy (SMEI) or polymorphic myoclonic epilepsy in infancy (PMEI), are usually associated with progressive dementia. Less commonly observed phenotypes include myoclonic-astatic epilepsy (MAE or Doose syndrome), Lennox-Gastaut syndrome (LGS), infantile spasms, and vaccine-related encephalopathy and seizures. The phenotype can vary even within the same family.

Natural History

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 mutation 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 FHM 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 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 head 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 mutations commonly presenting with nystagmus and other cerebellar signs [Ophoff et al 1996]:

• p.Arg192Gln and p.Val1457Leu [Carrera et al 1999] are associated with hemiplegic attacks only, whereas unconsciousness occurs commonly during attacks with mutation p.Val714Ala [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 mutations [Terwindt et al 1998]. Kors et al [2003] reported a family with the p.Thr666Met mutation 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 mutation 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 mutation p.Thr1384Cys 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 mutation in ATP1A2 [Spadaro et al 2004].
• A severe phenotype with seizures and intellectual disability has been reported with the mutations p.Asp718Asn and p.Pro979Leu [Jurkat-Rott et al 2004].

See Table 3.

Penetrance

Penetrance 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.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with familial hemiplegic migraine (FMH), 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.

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. Limited correlation exists between drug response and hemiplegic migraine type.

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 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.

Mode of Inheritance

Familial hemiplegic migraine is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• 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 de novo gene mutations is unknown but probably low, although only limited data for FHM1 have been reported [Carrera et al 1999, Ducros et al 1999].
• Recommendations for the evaluation of parents of an individual with an apparent de novo mutation include clinical interview, neurologic examination, and molecular genetic testing if the disease-causing mutation has been identified in the proband.

Sibs of a proband

• The risk to the sibs of a proband depends on the genetic status of the parents.
• If a parent of the proband is affected, the risk to the sibs is 50%.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
• If the disease-causing mutation in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband. Each child of an individual with familial hemiplegic migraine has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being affected.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for FHM is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like FHM) do not affect intellect or life span are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

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Author History

Kathy Lou Gardner, MD; University of Pittsburgh (2001-2009)
Joanna C Jen, MD, PhD (2009-present)

Revision History

• 8 September 2009 (me) Comprehensive update posted live
• 4 January 2007 (cd) Revision: mutations in SCN1A associated with familial hemiplegic migraine type 3
• 14 December 2004 (cd) Revision: sequence analysis of CACNA1A clinically available
• 15 March 2004 (me) Comprehensive update posted to live Web site
• 30 December 2003 (cd) Revision: change in test availability
• 3 October 2002 (kg) Author revisions
• 16 September 2002 (kg) Author revisions
• 17 July 2001 (me) Review posted to live Web site
• October 2000 (kg) Original submission