Course:MEDG550/Student Activities/Familial Hemiplegic Migraine

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A time-lapse depiction of cortical spreading depression, which causes many of the neurological symptoms during a migraine in those with FHM.

Familial hemiplegic migraine (FHM) is a type of migraine which causes temporary weakness on one side of the body[1]. Those with FHM often experience other common migraine symptoms during episodes. FHM is a genetic condition and is typically caused by changes in the genes CACNA1A, ATP1A2, or SCN1A[1][2]. FHM is divided into 3 subtypes depending on the underlying genetic cause: FHM1, FHM2, and FHM3.

Clinical Features

FHM is characterized by episodic migraines with accompanying weakness affecting one whole side of the body, known as hemiparesis. It is typically also accompanied by visual disturbances, headache, nausea, difficulty with coordinated muscle movements (ataxia), difficulty speaking (aphasia), and other common migraine symptoms. Symptoms can last minutes, hours, or days, but typically subside within 1-3 hours[1][3]. The symptoms most commonly experienced by those with FHM are sensory aura, which involves numbness / tingling in the face, tongue or extremities (98%), headache (95%), and visual aura, which may appear as flickering spots or zigzagging lines (89%)[4][5]. Typically, episodes begin with the onset of a visual aura, followed shortly after by headache and other symptoms. In some cases, individuals may experience more severe symptoms including seizures, loss of consciousness, coma, stroke, or permanent brain damage. Coma and prolonged loss of consciousness is more common in those with FHM1, while seizure is more commonly seen in those with FHM2[6][7].

Those with FHM will typically experience their first episode in early adolescence, but onset in later life is not uncommon. There is evidence suggesting an earlier age of onset in FHM compared to other types of migraine[2]. The frequency of episodes is highly variable, ranging from daily to only a few in one’s lifetime. It is common for the both the frequency and severity of FHM episodes to decrease with age however.

Prevalence

FHM is a rare condition affecting approximately 1/20000 individuals[8]. Like non-hemiplegic migraine, it is more frequently seen in women than in men. FHM is broadly categorized into 3 subtypes: FHM1, FHM2, and FHM3. FHM1 is caused by changes in the CACNA1A gene, and accounts for approximately 50% of all cases. FHM2 is caused by changes in the ATP1A2 gene, and accounts for approximately 25% of cases. FHM3 is caused by changes in the SCN1A gene, and it’s prevalence is not currently well known[7][9]. However, it is estimated that up to 25% of FHM cases do not fall into any of the above categories based on genetic analysis[7].

Diagnosis

There are currently several proposed diagnostic criteria proposed for FHM. The specific criteria differ slightly, but are generally intended to determine the following:

  • If an individual experiences migraines
  • If migraines are accompanied by reversible hemiparesis
  • If there is a family history of hemiplegic migraine
  • That there are no other likely explanations for the reported symptoms.

General Diagnostic Criteria

A diagnoses of FHM is likely to be made based on the following criteria:

  1. At least 2 episodes of reversible hemiparesis occurring with reversible sensory aura, visual aura, ataxia, or aphasia
  2. At least 2 episodes where one of the above symptoms develops over 5 minutes or more, and last less than 24 hours
  3. At least 2 episodes of headache occurring within 1 hour of the onset of any of the above symptoms
  4. At least one first degree relative (biological parent or full sibling) meeting criteria 1 – 3

If an individual meets criteria 1 – 3 but does not have any affected family members, they may be diagnosed with sporadic hemiplegic migraine (SHM)[3][4].

As other neurological disorders may have similar symptoms to hemiplegic migraine, brain imaging techniques such as MRI are often used to rule out other possible diagnoses.

A molecular diagnosis of FHM or SHM may be made by looking for changes in the genes CACNA1A, ATP1A2, or SCN1A. This is not required for a diagnosis of FHM or SHM however, as up to 25% of cases meeting the above criteria do not have a detectable change in these genes.

Management

A key aspect of FHM management is avoidance of things known to trigger migraine episodes. Those with FHM are often encouraged to keep a journal of their episodes to help identify potential triggers, which may include certain activities, foods, or lifestyle factors. Sports or activities with a risk of minor head trauma, such as concussions, should be avoided as this is a known trigger for serious episodes in those with FHM[6].

Treatment

Standard prophylactic migraine medications may be beneficial for those with frequent attacks, however those which cause restriction of blood vessels may be avoided due to an increased risk of stroke[10]. Medications used to treat epilepsy may also be advised in those with FHM2 due to their increased risk for seizures during episodes.

Genetics

All three subtypes of FHM are caused by mutations in genes which provide instructions for proteins involved in regulating the balance of calcium, sodium, and potassium in neurons. The balance of these ions is critical for normal electrical signaling, and these genetic changes can therefore disrupt electrical signaling in the brain. During a hemiplegic migraine, this disruption of normal electrical signaling can cause a temporary suppression of normal brain activity, a phenomenon known as cortical-spreading-depression. This is believed to be the primary cause of the symptoms seen in FHM and SHM[1].

Inheritance

Autosomal dominant inheritance pattern

FHM is inherited in an autosomal dominant manner. This means that inheritance of one copy of a defective gene from one parent is sufficient to cause FHM. Approximately 80% of individuals who inherit a defective copy of a gene known to cause FHM will themselves have FHM.

The severity of symptoms and frequency of episodes is suspected to be influenced by both environmental factors and inheritance of other genes, which is likely the reason that there is such variability in symptoms between affected families.

Genetic Counseling

Individuals with FHM or who have a family history of FHM may meet with a genetic counselor to learn more about the condition, or to find out about genetic testing options.

As a diagnosis of FHM requires an affected first degree relative, an affected individual will most likely have an affected parent. Genetic testing may be offered to affected individuals to try to identify the underlying genetic cause. If a mutation suspected to cause FHM is identified, other family members may be tested for this same mutation to determine their risk for FHM. If a diagnosis of SHM is made, genetic testing may still be offered to affected individual and their siblings. Parents of children with SHM are not at risk of FHM, because SHM is caused by a spontaneous new mutation in the affected individuals DNA during embryo development.

As FHM is an autosomal dominant condition, those affected by FHM or SHM have a 50% chance of having an affected child. If the causative mutation is known for an affected family, prenatal genetic testing can be performed during pregnancy. This is typically performed by either amniocentesis or chorionic villus sampling (CVS). Amniocentesis is performed by collecting a sample of the amniotic fluid after 15 weeks of pregnancy, and a CVS is performed by collecting a sample of the placenta between 11 – 13 weeks. The collected samples can then be analyzed to see if the fetus carries the FHM causing genetic mutation. It is important to note that both amniocentesis and CVS carry a low (0.5 – 1%) risk of loss of pregnancy.

Those with FHM may experience difficulty coping with the risk of serious complications such as stroke or coma. A genetic counselor can provide support to patients struggling with a diagnosis of FHM in themselves or a loved one, and can help connect patients and their families with additional support resources.

Patient Resources

The Migraine Trust

American Migraine Foundation

Migraine Research Foundation

References

  1. ↑ 1.0 1.1 1.2 1.3 Russell, Michael (2011). "Sporadic and familial hemiplegic migraine: pathophysiological mechanisms, clinical characteristics, diagnosis, and management". The Lancet Neurology. 10: 457–470.
  2. ↑ 2.0 2.1 Ducros, A (2001). "The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel". New England Journal of Medicine. 345: 17–24.
  3. ↑ 3.0 3.1 Jen, Joanna (2015). "Familial Hemiplegic Migraine". GeneReviews.
  4. ↑ 4.0 4.1 Thomson, L.L. (2002). "A population‐based study of familial hemiplegic migraine suggests revised diagnostic criteria". Brain: The Journal of Neurology. 125: 1379–1391.
  5. ↑ Thomson, L.L. (2003). "Evidence for a separate type of migraine with aura". Neurology. 60.
  6. ↑ 6.0 6.1 Kors, E. (2001). "Delayed cerebral edema and fatal coma after minor head trauma: role of the CACNA1A calcium channel subunit gene and relationship with familial hemiplegic migraine". Annals of Neurology. 49: 753–760.
  7. ↑ 7.0 7.1 7.2 Kumar, A. (2020). Hemiplegic Migraine. Treasure Island, FL: StatPearls Publishing.
  8. ↑ Thomson, L.L. (2002). "An epidemiological survey of hemiplegic migraine". Cephalagia. 22: 361–375.
  9. ↑ Shao, N. (2018). "Familial Hemiplegic Migraine Type 3 (FHM3) With an SCN1A Mutation in a Chinese Family: A Case Report". Frontiers in Neurology. 9: 976.
  10. ↑ Eikermann-Haeter, K. (2012). "Migraine Mutations Increase Stroke Vulnerability by Facilitating Ischemic Depolarizations". Circulation. 125: 335–345.
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