Years published: 2019, 2023
NORD gratefully acknowledges Anne Ducros, MD, PhD, Professor of Neurology, Montpellier University, France; Head of the Headache and Migraine Unit, Neurology Department, Montpellier University Hospital, France, for assistance in the preparation of this report.
Hemiplegic migraine is a rare disorder in which affected individuals experience a migraine headache along with weakness on one side of the body (hemiplegia). Affected individuals are described as having a migraine with aura. Aura refers to additional neurological symptoms that occur with or sometimes before, the development of migraine headaches. Hemiplegia is an aura symptom. Additional aura symptoms usually affect vision, but also can affect speech, sensation and mental status. In some affected individuals, hemiplegic migraine occurs because of a change (variant or mutation) in a specific gene. This is called familial hemiplegic migraine. Abnormal variants in four genes, CACNA1A, ATP1A2, SCN1A and PRRT2, have all been shown to cause the familial forms. Some affected individuals are thought to develop the disorder because of a variant in an as-yet-unidentified gene. There is usually a family history of hemiplegic migraines in affected individuals. Some individuals may be the first person in their family with hemiplegic migraine; these individuals are described as having sporadic hemiplegic migraine.
Affected individuals experience hemiplegic migraine attacks. These attacks can range from about one a day to fewer than five in a lifetime. There can often be long episode-free periods during life. Generally, episodes become less frequent as a person ages. Individual episodes can vary in severity and duration. Hemiplegic migraine is a chronic disorder and can be extremely painful and debilitating.
Hemiplegic migraine attacks comprise an aura phase and a headache phase. Aura refers to additional neurological symptoms that occur with, or often shortly before, the development of migraine headaches. A migraine aura usually lasts about an hour but can take up to a week to completely resolve. Aura symptoms can often outlast the migraine headache itself.
Individuals with hemiplegic migraine experience weakness on one side of the body during the aura (hemiplegia), either just before or during the migraine headache. The degree of weakness can vary from mild to severe. Hemiplegia may affect only part of one side of the body, such as just the hand or the hands and arms, or the face. Weakness of the entire side of the body can occur. Hemiplegia is a distinct aura symptom that characterizes these disorders.
In hemiplegic migraine, the weakness is always associated with at least one other aura symptom. Vision is usually affected temporarily, and symptoms can include a sudden appearance of a bright light in the center of the field of vision causing blind spots (scintillating scotoma), double vision, flashing lights (photopsia) and bright, shimmering, jagged lines (fortification spectra). Visual symptoms can also include foggy vision or a loss of vision of one half of the visual field. Additional symptoms include numbness or a prickly sensation of the face or arms and legs (paresthesia), fever, imbalance, drowsiness or lethargy and an inability to understand or express speech (aphasia). The aura rarely involves abnormal movement of one hand or one arm preceding the motor weakness. The specific aura symptoms that develop during a migraine attack can vary from one attack to another. Some individuals with hemiplegic migraine may also have attacks with a so-called typical aura, including visual, sensory and speech troubles but no weakness.
During an attack of hemiplegic migraine, headache might start shortly before, during or after the aura. Migraine headaches cause throbbing, intense, sometimes debilitating pain and are notably stronger than regular headaches. The pain can cause nausea or vomiting, and affected individuals may be extremely sensitive to light (photophobia) and to sound (phonophobia).
In severe instances, affected individuals may experience prolonged weakness, seizures, confusion, memory loss, and personality or behavioral changes. Although uncommon, hemiplegic migraine attacks can be severe enough to cause coma. During such severe hemiplegic migraine attacks, weakness and speech troubles can last for several days or weeks but usually fully resolve. In rare instances, permanent complications can develop including intellectual disability.
A minority of individuals with hemiplegic migraine develop signs or symptoms of involvement of the cerebellum, the area of the brain that controls coordination and balance and is also involved in cognition and behavior. These signs or symptoms can include uncontrolled, repetitive movements of the eyes (nystagmus), slurred speech (dysarthria) and a lack of coordination of voluntary movements (ataxia). These symptoms are permanent and usually slowly progress with ageing.
A minority of individuals with hemiplegic migraine may develop epileptic seizures outside of hemiplegic migraine attacks.
A minority of individuals with familial hemiplegic migraine may have delayed acquisition of speech and motor features during early childhood, learning difficulties or rarely, cognitive disabilities.
Hemiplegic migraine can be classified as either familial or sporadic.
Variants in three genes have been identified as causing familial hemiplegic migraine. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the protein, this can affect many organ systems of the body, including the brain.
Variants in the CACNA1A gene cause familial hemiplegic migraine type 1. Variants in the ATP1A2 gene cause familial hemiplegic migraine type 2. Variants in the SCN1A gene cause familial hemiplegic migraine type 3. Variants in the PRRT2 gene can also cause familial hemiplegic migraine. Some individuals have familial hemiplegic migraine but do not have variants in these genes. Researchers think that there are additional genes that cause this disorder, but that have yet to be identified.
The four genes known to cause hemiplegic migraine produce proteins that are required for the normal function of nerve cells of the brain (neurons). These proteins play a role in the transport of electrically charged particles called ions across a channel that connects nerve cells (neurons), helping to regulate brain activity. Consequently, familial hemiplegic migraine can be classified as channelopathy, a group of disorders characterized by abnormalities in the flow of ions, such as sodium and calcium ions, through pores in cell membranes (ion channels). The proteins produced by these genes may also be involved in other areas or functions of the body as well.
Some researchers have shown that nerve cells are overactive (hyperexcitability) in hemiplegic migraine. This hyperexcitability may be associated with a phenomenon called cortical spreading depression that may play a role in the development of hemiplegic migraine. Cortical spreading depression is a slow wave of depolarization of nerve cells that spreads over the hemispheres of the brain. Depolarization refers to a change in the charge between the outside and inside of the membrane of nerve cells, which affects how or if ions can pass through the membrane. These theories are not proven as definitively playing a role in the development of hemiplegic migraine and more research is necessary to determine the complex, underlying factors that cause the signs and symptoms of this disorder.
Familial hemiplegic migraine is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
Sporadic hemiplegic migraine is the term used to describe individuals with hemiplegic migraine who are the first person in their family with the condition. Some of these individuals may represent a de novo variation of one of the three genes associated with the disorder. Others may have inherited the condition from a parent who did not have any symptoms (asymptomatic).
Like common migraines, there are a variety of ‘triggers’ that can cause a migraine attack. Triggers that can cause an episode of hemiplegic migraine include certain foods, certain odors, bright light, too little or too much sleep, physical exertion, stress or minor head trauma. A cerebral angiography can also trigger an episode. This is a type of x-ray exam that is used to assess the health and function of blood vessels in the brain. Sometimes, there are no identifiable triggers when an episode occurs.
The number of newly affected individuals within a year (incidence) and prevalence (the overall number of people with a disorder at a given time (prevalence) of hemiplegic migraine is unknown. Studies in a population of Denmark placed the prevalence at 1 in 10,000 individuals in the general population. The prevalence was the same for the familial and sporadic forms. Rare disorders often go misdiagnosed or undiagnosed making it difficult to determine the true frequency of disorders like hemiplegic migraine in the general population.
Hemiplegic migraine affects more females than males. The onset of the disorder is usually within the first or second decade of life but has ranged from early infancy to the elderly.
A diagnosis of hemiplegic migraine is based upon identification of characteristic symptoms, a detailed patient history, thorough clinical evaluation and a variety of specialized tests. Two proposed diagnostic criteria have been published (The International Classification of Headache Disorders, 3rd edition and a population-based study of familial hemiplegic migraine suggests revised diagnostic criteria, Thomsen et al. 2002) to help physicians diagnose hemiplegic migraine.
Generally, affected individuals must have two episodes of migraine with aura that exhibit specific signs or symptoms. Fully reversible muscle weakness on one side of the body (hemiplegia) that occurs with at least one other type of aura symptom (vision, sensory, speech or brainstem) must be present for a diagnosis. For the familial form, at least one first- or second-degree relative must also have the disorder.
Clinical Testing and Workup
Brain imaging is usually normal in individuals with hemiplegic migraine. A minority of individuals affected by hemiplegic migraine associated with permanent cerebellar symptoms have atrophy of the cerebellum.
Brain imaging by MRI during a prolonged episode of hemiplegic migraine can show swelling and/or cortical hyperintensity of the affected cerebral hemisphere on T2/FLAIR-weighted MRI. Blood-flow is modified in the affected hemisphere with hypoperfusion followed by persistent hyperperfusion. Brain arteries on angiography may be narrowed at the early phase of the aura and dilated in the second phase. MR angiography may sometimes show diffuse segmental vasoconstriction alternating with vasodilation. All these abnormalities are fully reversible. In very rare patients affected by hemiplegic migraine type 1, severe episodes may be followed by a brain atrophy of the affected hemisphere. An electroencephalogram can show a slowing of brain activity in the affected hemisphere. Usual blood tests are normal. Lumbar puncture is performed in some severe episodes with coma and fever, to rule out an infectious cause. The cerebrospinal fluid can be normal or show an inflammatory reaction with an elevated white blood cell count and an elevated protein level, but the glucose level is always normal and the tests for infectious agents are negative.
Molecular genetic testing can confirm a diagnosis of familial hemiplegic migraine in some individuals. Molecular genetic testing can detect variants in the genes known to cause the disorder but is available only as a diagnostic service at specialized laboratories.
The treatment of hemiplegic migraine is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in diagnosing and treating disorders of the brain and central nervous system in children (pediatric neurologists), neurologists, physicians who specialized in treating headaches or migraines, pain specialists, physicians who specialize in diagnosing and treating eye disorders (ophthalmologists), social workers and other healthcare professionals may need to plan treatment systematically and comprehensively. Psychosocial support for the entire family may be beneficial as well.
Genetic counseling is recommended for affected individuals and their families.
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with hemiplegic migraine. As in other common varieties of migraine, treatment is divided in acute treatment taken during the attack to reduce the severity of symptoms and preventive treatment that is taken every day to reduce the frequency of attacks.
Various medications may be used to treat an attack of hemiplegic migraine. Analgesics and non-steroid anti-inflammatory drugs can reduce the migraine headache. There are small studies investigating drugs such as verapamil, ketamine and naloxone for the acute treatment of hemiplegic migraine, but no acute treatment has been proven to reduce the intensity and the duration of the aura. For most patients, triptans and ergotamines should be avoided because they tend to cause blood vessels to narrow and there is a risk of stroke. This is based on the theory that there is a vascular cause of migraine. Some physicians think these medications should be reconsidered as a potential treatment. Triptans can be useful in cases with short hemiplegic auras followed by a severe migraine headache; the medication should be taken when the headache starts.
Standard preventive medications used to treat regular migraines can be tried for individuals with all types of hemiplegic migraine, to reduce the frequency of attacks. These drugs include tricyclic antidepressants, beta blockers, calcium channel blockers and anti-seizure (anti-convulsant or anti-epileptic) medications. There are small studies investigating drugs such as acetazolamide, verapamil, flunarizine, lamotrigine and botulinium toxin A, for the treatment of hemiplegic migraine. Individuals with hemiplegic migraine were excluded from the trials assessing efficacity and safety of anti-CGRP antibodies in the prevention of migraine. Recently, a small open study reported improvement of hemiplegic migraine in a few individuals with hemiplegic migraine. Further prospective studies are required. Sometimes, in individuals with rare attacks, no preventive treatment is needed.
Individuals who experience a severe migraine episode may require hospitalization, particularly for high fever, depressed consciousness or seizures. After alternative diagnoses are excluded, and in case of brain edema on imaging, a course of intravenous steroids may be used.
Anti-seizure medications may be used to treat seizures such as those seen in familial hemiplegic type 2.
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