The Cerebellum and Migraine

Maurice Vincent, MD, PhD; Nouchine Hadjikhani, MD

Disclosures

Headache. 2007;47(6):820-833. 

In This Article

Spinocerebelar and Episodic Ataxias

The CACNA1A mutations are also involved with cerebellar diseases, namely episodic ataxia type 2 (EA-2) and spinocerebellar ataxia type 6 (SCA-6). Hereditary EAs are genetic conditions typically characterized by recurrent clumsiness triggered by exertion, stress, or fatigue with a favorable response to acetazolamide.[75,76] Spinocerebellar ataxias (SCA) are genetic non-paroxysmal, moderate to severe ataxias of late onset characterized by progressive cerebellar degeneration leading to incoordination. Other cerebellar symptoms associated with spinal cord signs, such as motor deficit, as well as vibratory and proprioceptive sensory loss.[75] The myriad of cerebellar symptoms include dysarthria, dysmetria, tremor, and nystagmus of various types.[77]

A series of EA mutations have been found so far,[76,78,79,80] and a complete loss of the P/Q function has been suggested to underlie the pathophysiology of EA-2.[81] Different nomenclature in successive descriptions have confused the understanding of non-progressive ataxias.[82,83,84] SCA-6 has been associated with small expansions of a CAG repeat at the 3' end of the CACNA1A gene, and point mutations are responsible for the allelic disorders related to EA-2.[60,79,85,86,87] The genetics behind these phenotypes, however, may vary.[88] Regardless of the mutation type, hyperexcitability seem to stand behind all the different phenotypes. Interestingly, a mutation in the glutamate transporter excitatory aminoacid transporter 1 (EAAT1) is also related to episodic ataxia (EA), seizures, migraine, and alternating hemiplegia.[89] EAAT1 is expressed particularly in the cerebellum and brain stem. The mutation in EAAT1 may lead to a reduced capacity for glutamate reuptake, increasing hyperexcitability. This reproduces the pathophysiological conditions present in channelopaties leading to FHM, episodic/progressive ataxias and coma after minor head trauma.

SCA-6 represents the form of progressive ataxia with closest relation to FHM pathophysiology, as this form of SCA is also linked to the CACNA1A gene.[90,91] Different mutations have been linked to the phenotype of SCA-6, sometimes associated with FHM.[92] There may be marked cerebellar atrophy on MR examination in these patients.[93] Not only mutations occur at the same gene, but in 20% of FHM patients permanent cerebellar symptoms are present.[94,95]

The phenotypes of such disorders may vary between and within families.[91,96] EA-2 patients may sometimes have non-hemiplegic migraine, which presents after the onset of the ataxic symptoms.[97] Interictally, EA patients may present constant cerebellar symptoms and signs such as nystagmus and cerebellar atrophy. The migraine-progressive episodic ataxias symptoms interchange indicate that the cerebellar disorders related to channelopathies intermingle and may represent different aspects from the same abnormality. Mechanisms behind ataxias in migraine disorders most probably involve membrane dysfunction. Purkinje cells, where P/Q-type calcium channels are mostly expressed, fire according to intrinsic regular spontaneous pacemaking.[98] This intrinsic pacemaking activity is irregular in P/Q-mutant Purkinje cells as well as in w-agatoxin IVA-blocked P/Q-type calcium channel in wild Purkinje cells. The defective P/Q calcium current decreases the function of calcium-activated potassium (KCa) channels, which are fundamental for the precision of the Purkinje cells intrinsic firing. EBIO, a channel activator that increases the affinity of KCa channels for calcium, recovers the regular firing in affected Purkinje cells.[99] This makes the KCa channel a potential therapeutic target not only for EA-2, but also for related symptoms in migraine disorders.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....