Familial hemiplegic migraine (FHM) is a hereditary variant of migraine with aura. A Migraine is characterized by episodes of headaches between which the patient is in good health. The classification proposed by the International Headache Society (IHS) separates two main types of attack - migraine without aura (MwoA) and migraine with aura (MwA) during which the headache is preceded or accompanied by transient neurological symptoms affecting sight, sensory perception, language and, in rare cases, movement.
FHM is defined by the presence of a loss of motor ability during the aura, associated with at least one other symptom (visual, sensory, aphasic) and by the existence of hemiplegic migraine (HM) in at least one 1st or 2nd-degree relative. More than 150 FHM families have been reported in the literature since 1910. Their description creates a distinction between families affected by “pure FHM” and families affected by “FHM with permanent cerebellar signs” in which some of the patients suffer from permanent ataxia and/or nystagmus. There are also sporadic cases of pure HM or HM with cerebellar signs. Previously, such patients were classified as suffering from migraine with typical aura or migraine with prolonged aura.
In 2004, the second version of the International Headache Society classification recognised sporadic hemiplegic migraine (SHM) as a specific sub-type of migraine with aura.
IHS’s diagnostic criteria for HM
At least two attacks fulfilling criteria B and C.
Aura including a fully reversible motor deficit and at least one of the following signs:
At least 2 of the following characteristics:
At least one first- or second-degree relative has had attacks that fulfill criteria A to E.
At least one of the following characteristics:
A study carried out among the general population in Denmark allowed researchers to estimate the prevalence of HM at 1 in every 10,000 people, with equal frequency of familial and sporadic cases.
The prevalence of FHM in Denmark is, therefore, of the order of 5 cases per 100,000 people. It is probably similar in other countries. In a Danish study, 147 FHM patients were identified as being part of 44 families. Permanent cerebellar signs were detected in 2 of the 44 families (4.5%).
Sporadic hemiplegic migraine (SHM) also has a prevalence of 5 cases per 100,000 people among the general population. SHM cases can be divided between two groups. Some of them are associated with a mutation of one of the FHM genes (de novo mutation absent in biological parents or mutation passed on by a healthy carrier parent). Other sporadic cases are probably more similar to the more usual cases of migraine with aura and are of multifactorial origin, with a combination of environmental factors and complex genetic factors. SHM cases may be “pure” or include permanent cerebellar signs.
Hemiplegic episodes attacks are attacks of migraine with a motor aura. The motor deficit is always associated with at least one other symptom. In order of frequency, these are sensory disorders (98%), visual disorders (89%) and language difficulties (79%).
In most cases, the aura begins with sensory or visual impairment. The motor deficit varies in severity, from heaviness in a limb to weakness in one half of the body. Sensory disorders are often noticed in the deficient limb and include signs that are either subjective (paresthesia, sometimes pain) or objective (superficial and/or proprioceptive sensory deficit). Sensory-motor deficit may be one-sided or bilateral. When it is one-sided, it affects at least the upper limb and may not affect the face and/or the lower limb. Numerous patients (30 to 59%) state that the hemiplegia always affects the same half of the body while others describe alternation between the right and left side from one attack to the next. Sensory-motor deficit is bilateral in 25% to 49% of patients, affecting one side then the other or both sides simultaneously.Language difficulties occur independently of the side affected by the motor deficit and include dysarthria, loss of verbal fluency and, less frequently, paraphasia. Reasoning impairment is rare (10%). Visual signs are often negative (homonymous hemianopsia, blurred vision) but positive signs have also been reported (scintillating scotoma, phosphenes). In addition to these four main symptoms, up to 70% of patients report “basilar signs” e.g. vertigo, loss of balance, double vision, tinnitus, hearing loss, confusion or loss of consciousness. The average duration of the aura is 1 to 6 hours but it can vary from 10 minutes to 2 or 3 days.
The headache usually occurs after the disappearance of the aura but it may precede it or occur at the same time. Some 95% of patients have a headache at each HM attack. 4% sometimes have a headache and 1% never have a headache. The headache lasts from a few hours to a few days and may be unilateral or bilateral and, in this case, affect the same side as the motor deficit or the other side. Its intensity varies from moderately trouble to unbearably painful. The accompanying signs are the same as those observed with other types of migraine i.e. nausea, vomiting, photophobia, phonophobia or pallor.
Approximately 2/3 of patients indicate one or more factors that trigger HM attacks, the most frequent are stress and benign cranial trauma. Fewer than 10% of patients blame factors usually found in the other types of migraine such as dietary or climatic factors, visual or auditory stimulation, or even menstruation.
Other types of migraine can alternate with HM attacks. Between 10% and 60% of FHM patients also have migraines with aura but no motor deficit.
FHM is distinguished by its wide clinical variation. The onset sequence, progression, location, intensity and duration of the various symptoms of aura, and the characteristics of the headache, can vary from one attack to another in the same patient, between the various sufferers within the same family or between different families.
In addition to their usual attacks, approximately 40% of patients have at least one severe attack with prolonged aura (lasting up to several weeks), confusion, hyperthermia up to 41°C, meningeal signs and problems of awareness ranging from confusion to deep coma. In some patients, the deep coma is accompanied by respiratory difficulties requiring artificial ventilation. Generalized or partial epileptic seizure may occur. Finally, persistent confusion with agitation, delirium, and visual and auditory hallucinations have been reported. One-half of these severe episodes occur before the age of 20. They mark the onset of migraine and are difficult to diagnose. They may be triggered by minor head trauma. The symptoms usually regress spontaneously within a few days or weeks, leaving no clinical or radiological sequellae (CT scan, MRI). In a few patients, recovery takes longer, and language, memory and concentration difficulties persist for several months. A small number of deaths after a severe HM attack have been reported. The occurrence of a severe attack always requires hospitalisation, with systematic additional investigations to screen for any other cause and, where appropriate, to initiate resuscitation.
Other clinical signs may become apparent with FHM. Permanent cerebellar signs are the most frequent. They are described in 20% of the families reported in the literature (probable bias) but are observed in only 4.5% of families in population studies. In these families, the cerebellar syndrome is passed on with the FHM but its effect is less marked - Nystagmus (horizontal, vertical or multidirectional) is found in approximately 75% of patients and moderate and slowly progressive stato-kinetic ataxia affects 40%. Cerebellar signs may be the only indication of the illness. The age of onset is difficult to specify. Nystagmus and ataxia may be noted before the first FHM attack and the development of ataxia seems to be independent of the frequency and severity of the attacks. In most cases, the severity of the ataxia does not prevent independent walking. In some patients, brain scans reveal cerebellar atrophy, predominantly in the anterior area of the vermis.
There are other possible associations. Essential tremor, cognitive disorders in adults and mental retardation in children have been observed in several patients from several families. Epilepsy (generalized or partial attacks) may be associated with FHM, with epileptic seizures occurring either during or independently of severe attacks of HM. A range of associations have been published i.e. FHM and benign familial infantile convulsions in one family; FHM, epilepsy and repeated transitory amaurosis (blurred vision) in another.
Generally speaking, the initial attacks appear on average at about the age of 12 but early onset before the age of 2 or, on the contrary, very late onset (75 years of age) have also been reported. The frequency of attacks varies from more than one per week to a few over an entire lifetime, with an average of 3 to 4 per year. Frequency seems to be highest at certain periods, especially between the ages of 5 and 25. In some patients, frequency can vary from daily attacks, especially when the disease first appears, to periods of several years with no attacks. There is usually complete recovery after such attacks. Most of the patients questioned during family studies lead a normal life. However, in certain patients, difficulties with speech, concentration or memory persist for several days or weeks until recovery. Severe forms are rare and are seen mainly in childhood, with no significant progression with age.
FHM is an autosomal dominant genetic disease. This means that it is transmitted by either the father or the mother and that 50% of children inherit the mutated gene. There is incomplete penetrance (approximately 90%) and, therefore, the disease may jump a generation. A family history is sometimes difficult to detect.
The three genes identified in MHF patients encode for ionic channels, making FHM a cerebral ionic channel disease.
The first gene identified, CACNA1A, is located on chromosome 19p13; it encodes for sub-unit 1A of the neuronal calcium channels Cav2.1 (or of the P/Q type). CACNA1A is involved in 40% to 50% of FHM families published (FHM1) and in most of the families affected with HM associated with permanent cerebellar signs. Ca2.1 channels are expressed in the presynaptic ends where they modulate the release of neurotransmitters including monoamines, acetylcholine, glutamate and CGRP. Various mutations of CACNA1A are associated with different neurological diseases. FHM1 is linked to “function gain” mutations that modify the properties of the Ca2.1 calcium currents. Other mutations of CACNA1A are implicated in Type 2 paroxysmal ataxia while the expansion of a CAG triplet is responsible for progressive cerebellar ataxia (SCA6). Certain mutations are associated with mild forms of pure FHM (e.g. R192Q); others to the existence of permanent cerebellar signs and the presence of severe attacks with cerebral edema (S218L).
On an electrophysiological level, the mutations responsible for FHM1 lower the activation threshold for Ca2.1 channels and increase the probability of their opening. These mutations lower the threshold at which invasive cortical depression appears and it then spreads at increased speed.
The second gene identified, ATP1A2, is located on the long arm of chromosome 1q23 and encodes for sub-unit 2 of a Na+/K+ ATP dependent pump. It is involved in approximately 20% of FHM families (FHM2). The Na+/K+ pump uses ATP hydrolysis to pump K+ into the cell inexchange for Na+ against transmembrane gradients. The maintenance of a steep transmembrane sodium gradient is essential for the transport of amino acids (e.g. glutamate) and calcium. In newborns, sub-unit 2 is expressed mainly in the neurones whereas in adults it is expressed mainly in the astrocytes. The mutations responsible for FHM2 use various mechanisms to cause a decrease in pumping activity within the glial cells and a subsequent drop in the recapture of glutamate and K+ in the synaptic cleft, probably increasing neuronal excitability. The clinical variability of FHM2 is as wide-ranging as the diversity in FHM1 with the possibility of severe attacks with coma and, in certain patients, association with mental retardation. Moreover, two characteristics of FHM2 seem to be clear – the penetrance of FHM2 is lower than that of FHM1 (not all carriers of the mutation suffer from the disease) and epilepsy appears to be more frequently associated with FHM2 than with FHM1. A few cases associated with permanent cerebellar ataxia have been observed. However, the frequency of these permanent cerebellar signs remains much lower in FHM2 than in FHM1.
The third gene, SCN1A, is located on chromosome 2q24 and codes for a neurone-dependent voltage sodium channel. SCN1A does not appear to be involved in many families (FHM3). A single mutation has been analysed in electrophysiological terms and its presence increases neuronal excitability.
Finally, some FHM families are not related to these three loci, demonstrating the existence of at least a fourth, mutated gene.
Sensitivity to cortical spreading depression might be the common denominator for attacks of FHM.The mutations in three totally different ionic carriers, including two neuronal channels and one glial pump, have the same consequences – an increase in K+ and glutamate in the synaptic cleft responsible for neuronal hyperexcitability. This hyperexcitability might render patients’ brains more susceptible to the occurrence of prolonged cortical spreading depression and, therefore, to the occurrence of complex, prolonged auras.
Diagnosis (methods - criteria)
A positive diagnosis of FHM in a given case is based on the identification of a relative with the same type of attacks. Because of the incomplete penetrance of the disease, a family history must be taken for both first-degree and second-degree relatives. When the family history is negative, a diagnosis of hemiplegic migraine cannot be eliminated because this may be a case of SHM. Finally, migraine with motor aura may occasionally occur in a patient who normally has migraine with typical non-hemiplegic aura or migraine without aura. The connections between these cases and FHM or SHM are unclear.
The final diagnosis of FHM or SHM requires the occurrence of at least two distinct attacks. When the first attack occurs, no final diagnosis can be made. When a patient is hospitalized for an initial episode of motor deficit with or without headache, he/she must be screened for all possible causes (vascular, infectious, inflammatory, toxic etc.). A CT scan is essential following by an MRI, an electroencephalogram (EEG), an CSF analysis and full blood tests. These additional investigations may be abnormal during severe attacks of HM (cf. Table 2).
Abnormalities compatible with a diagnosis of FHM/SHM
CT scanor MRI
If all the investigations are normal or show abnormalities compatible with an HM attack and if the clinical signs are fully compatible (gradual onset and succession of neurological signs then full recovery), a diagnosis of possible initial FHM attack can be suggested if there is a positive family history. If the family history is negative, no precise diagnosis can be established before the onset of a second attack.
Severe attacks of HM with confusion, coma, prolonged deficit and fever pose diagnostic problems even when they occur in a patient known to suffer from FHM or SHM. These attacks should be systematically explored to eliminate any infection or vascular cause. Because of the risk of respiratory failure and cerebral edema, these patients should always be hospitalized and monitored until they regain consciousness.
HM attacks may be part of the clinical pictures (they are then considered as symptoms) of various other neurological diseases for which the overall prognosis is more severe than for FHM e.g. certain hereditary arteriopathies such as CADASIL or amyloid angiopathy, certain mitochondrial diseases such as MELAS.
The main indications for the molecular diagnosis of HM are :
- sporadic cases with particularly severe attacks (recurrent comas) or permanent signs other than ataxia
- familial cases that are atypical for their severity or presentation compared to other members of the family.
The discovery of a pathogenic mutation in CACNA1A, ATP1A2 or SCN1A may avoid diagnostic error. On the other hand, the discovery of a mutation does not change the treatment for these patients or the diagnosis of severe attacks.
Molecular diagnosis of HM is not indicated in antenatal situations or in asymptomatic patients in FHM families because the prognosis of this disease is usually benign and there are no preventive measures.
The genetic diagnosis has limits in terms of specificity and sensitivity. It has low sensitivity (approximately 60%) because, firstly, the three genes tested are responsible for only 60% to 70% of cases of FHM and, secondly, the current screening technique does not detect all mutations. Its specificity is also incomplete – a mutation may be a non-pathogenic polymorphism. A mutation must fulfill stringent criteria before it is considered as responsible for the disease.
For familial types, these criteria are: co-transmission of the mutation with the disease in the family, absence of the mutation in a large control population, and alteration of a major functional area of the protein. In sporadic forms, the criteria for unquestionable diagnosis are: mutation already identified in a familial form of HM or an undoubted de novo mutation (absent in the biological parents). In the absence of the last two criteria, only mutations which are absent in a large control population and which alter an important functional area of the protein can be retained.
In practical terms, this means that it is essential to sample and analyze the index case and the two parents, whether it is a familial or sporadic form.
In very large FHM families with several generations of sufferers, adult patients consult very little because they know that it is a family problem and, with a certain fatalism, they rest up during attack and wait to recover, more or less patiently. People seen in consultations are therefore often children suffering their first attack (their parents are typically more concerned about them than they are about themselves), patients of all ages with severe or atypical attacks, patients suffering frequent debilitating attacks and sporadic cases.
The first stage is to establish the diagnosis and to inform the patients about the nature of the disease.
Factors triggering the attacks must be sought and measures taken to combat them. For example, sports with a high risk of cranial trauma would not be recommended. Lifestyle counseling is useful (regular sleep, not to skip meals, regular physical activity, combating “stress”).
Medication is useful but its efficacy is often disappointing. Treatment of an attack is aimed at reducing the headache accompanying the aura while preventive treatment aims to decrease the frequency of attacks.
No effective, easily administered treatment exists to prevent the aura, although a few publications referring to a very small number of cases report an improvement in aura after the administration of intranasal ketamine, intravenous naloxone or intravenous verapamil.
Specific “vasoconstrictive” treatments for migraine headaches (ergot and triptans) are not recommended for FHM or SHM. During typical attacks, patients can use simple analgesics such as aspirin or NSAIDS to decrease headache and take anti-emetics if necessary. The treatment must be taken as soon as possible during the aura, even before the onset of headache, to prevent and decrease the intensity of the headache at a later stage. The same applies to typical migraine with aura.
Severe attacks with confusion, coma, fever and epileptic seizures require a range of symptomatic measures i.e. hospitalisation in Intensive Care, oxygen therapy or ventilation depending on the case, antipyretics, IV analgesics and anti-epileptics.
Since the mean frequency of HM attacks is low (3 or 4 a year), preventive therapy is not useful in most patients. In patients suffering frequent attacks or who want preventive therapy (with the aim of reducing the frequency of the attacks), a number of different drugs can be offered. Betablockers can be used although there has been a report of more severe attacks with propranolol (Inderal), possibly linked to the natural development of the disease and the ineffectiveness of the treatment rather than a direct deleterious effect. Verapamil (Isoptin) has been proposed. In FHM with permament cerebellar signs, acetazolamide (Diamox) can be tried (500 mg/d in two doses). Given the hyperexcitability of the cerebral cortex, anti-epilpetics such as sodium valproate, topiramate and, to a lesser extent, gabapentin can be prescribed because of their proven effectiveness as a preventive treatment for migraine in general. Moreover, typical migraine with aura or FHM/SHM may respond to anti-epileptics that are not effective for migraine without aura. Lamotrigine, for example, may provide effective prevention from migraine with aura as shown in open-ended trials (including cases of HM). Doses of between 75 and 150 mg of lamotrigine have been trialled.
In patients suffering from FHM/SHM associated with epilepsy, preventive therapy is the same as for epilepsy. On the other hand, the occurrence of partial or generalised seizures only during a severe HM, without any other association with epilepsy, is not a formal indication for long-term epilepsy treatment.