The Cerebellum and Migraine

Maurice Vincent, MD, PhD; Nouchine Hadjikhani, MD

Disclosures

Headache. 2007;47(6):820-833. 

In This Article

Familial Hemiplegic Migraine and the Cerebellum-Related Disorders

FHM is an autosomal dominant disorder characterized by migraine attacks with hemiplegic aura. The diagnosis is based on the presence of aura including motor weakness and at least one first- or second-degree relative suffering from migraine with aura that presents with motor deficits.[3] A multitude of associated symptoms may be present, including ataxia, seen in one-third of the families.[60] Three types of FHM have been described so far: FHM-1 is consequent to mutations of the CACNA1A gene coding for a P/Q calcium channel;[61] FHM-2 is due to the mutation of the ATP1A2 gene coding for the alpha2 subunit of the Na/K astrocytic ATPase;[62,63] and FHM-3 follows a mutation of the SCN1A gene coding for a neuron voltage-gated sodium channel.[64] The FHM phenotype includes hemiplegic migraine, seizure, prolonged coma, hyperthermia, sensory deficit, and transient or permanent cerebellar signs, such as ataxia, nystagmus, and dysarthria.[65]

In FHM-1, the CACNA1A gene encodes the α1A (CAV2.1) subunit of the high voltage-gated P/Q type of calcium channel. This channel is expressed throughout the central nervous system, particularly in the cerebellar Purkinje cells, where it mediates depolarization-induced Ca2+ influx into presynaptic terminals and glutamate release.[66,67] P/Q calcium channels play a pivotal role in neurotransmitter release[68] and influence neuronal excitability.[69] The consequences of different missense mutations in the CACNA1A gene may lead to gain-of-function of human P/Q-type calcium channels, although not all studies agree in this respect.[70] New animal models may provide important insights in this field. A knockin mouse expressing the human R192Q pure FHM-1 mutation was genetically engineered and recently studied. This mouse shows gain-of-function P/Q Ca2+ channel function as evidenced by opening of calcium channels at lower levels of depolarization, lower threshold for SD and faster propagation speed.[71] These findings open the possibility of SD-like phenomena in the cerebellum as a justification for cerebellar dysfunction in migraine patients. Human evidence confirming this hypothesis is however not yet available.

The mechanisms behind the neurological symptom complex linked to CACNA1A, ATP1A2, and SCN1A genes, respectively involved with FHM 1, 2, and 3, remain partially unclear. Noteworthy is the fact that, despite the type of ion channel involved, all mutations result in hyperexcitability and may be related to hemiplegic migraine, epilepsy, and/or ataxic disorders.

Cerebellar symptoms in FHM have been recognized in many families ( Table 1 ). Such symptoms may be produced by lesion in the cerebellum itself or in structures with afferent or efferent cerebellar connections, such as the brainstem. Thus, the exact origin of symptoms such as nystagmus and ataxia in migraine patients cannot be definitely related to the cerebellum. On the other hand, the atrophy found in FMH and the calcium channel abnormalities in the cerebellum indicate that symptoms are probably cerebellar in nature.

Around 20% of the hemiplegic migraine patients show permanent mild cerebellar deficits.[72] Unconsciousness, fever, and confusion may occur associated with the hemiplegic attacks and ataxia, usually accompanied by cerebellar atrophy.[73,74]

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