The Cerebellum and Migraine

Maurice Vincent, MD, PhD; Nouchine Hadjikhani, MD


Headache. 2007;47(6):820-833. 

In This Article

The Acetazolamide Effect

Acetazolamide, a reversible inhibitor of the enzyme carbonic anhydrase, is a drug known for its benefit in EA-2.[79,113,114] Acetazolamide-responsive episodic symptoms, typical of EA-2, have also been shown in SCA-6.[115] The effect of acetazolamide in EAs was found in 1978 by chance, when patients received this drug after being erroneously diagnosed as periodic paralysis.[114] Acetazolamide response has been described in FHM with associated ataxia[74] and in migraineurs without cerebellar symptoms.[116]

Acetazolamide does not usually diminish the frequency or intensity of FHM, being mostly indicated for use in EA-2. However, there are 2 FHM reports with clear acetazolamide response.[74,116] Formal trials using acetazolamide in migraine are few. In an open uncontrolled pilot study, the efficacy and tolerability of acetazolamide were addressed in 22 MWA patients. 68.2% reported a reduction of MA episodes higher than 50%.[117] A randomized clinical trial was performed comparing 500 mg oral acetazolamide versus placebo in 53 IHS migraine patients (27 in the placebo group). This study had to be interrupted prematurely due to many side effects related withdrawals. So far, the authors did not find a difference between the active drug and placebo.[118] Acetazolamide was also shown to interrupt aura status in 3 patients.[119]

The acetazolamide mechanism of action in episodic ataxia type 2 (EA-2) is still mysterious. It is interesting that topiramate, an effective antimigraine prophylactic agent, shares with acetazolamide the property of carbonic anhydrase inhibition.[120] Besides, it was recently reported to suppress the susceptibility to cortical spreading depression in experimental animals.[121] Acetazolamide induces metabolic acidosis. It is possible that this drug increases the extracelullar concentration of free protons in the brain tissue including the cerebellum.[113] Since calcium channels are sensitive to pH changes, acetazolamide could restore normal function in mutant calcium channels through acidification. However, acetazolamide does not modify the channel properties through either pH-dependent or pH-independent mechanisms.[122] Alternatively, since acetazolamide activate large-conductance KCa channels, which are in normal conditions exclusively activated in Purkinje cells by P/Q-type calcium channels, it is possible that this drug acts by restoring Purkinje cells pacemaking properties.[99]


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