Neuromuscular Synapse Function in Typical Migraine

Previously, Ambrosini and coworkers have presented interesting clinical electrophysiological indications for the existence of subtle subclinical defects in neuromuscular synaptic transmission in certain patients with typical forms of migraine (1, 2). The idea of neuromuscular defects in migraine was based on the presence of mutations in the CACNA1A gene coding for the pore-forming subunit of P/Q-type Ca²⁺ channels in an inherited rare form of migraine, familial hemiplegic migraine, in combination with the fact that this particular type of Ca²⁺ channel is present at motor nerve terminals where it mediates the release of the neurotransmitter acetylcholine. Furthermore, in vitro electrophysiological studies at neuromuscular junctions (NMJs) of the P/Q-type Ca²⁺ channel in mutant tottering mice have revealed abnormalities in acetylcholine release (3), and, moreover, impaired neuromuscular transmission has been demonstrated in episodic ataxia type-2 patients, which also have mutations in CACNA1A (4).

In this issue of Cephalalgia, Ambrosini and colleagues report their continued research on this topic (5). In an open pilot study on a small group of five different migraine patients with mild stimulated single-fibre electromyography (SFEMG) abnormalities they investigated the effect of acetazolamide, a drug which has been demonstrated to be effective in some cases of migraine aura status (6). It appeared that the SFEMG abnormalities were abolished after 1–4 months of acetazolamide treatment. In one patient, who was followed for a period of 11 months, the abnormalities returned after acetazolamide was withdrawn, and were again abolished upon resumption of drug treatment. Interestingly, SFEMG normalization was paralleled by reduction of migraine symptoms in four of the five patients. The authors argue that the present findings further support the hypothesis that P/Q-type Ca²⁺ channel dysfunction underlies the SFEMG abnormalities, and discuss the possible involvement of P/Q-type Ca²⁺ channel dysfunction in the evolution of migraine symptoms in some patient groups. It is hypothesized that the beneficial effects of acetazolamide on SFEMG and migraine symptoms might be due to correction of (mutant) P/Q-type Ca²⁺ channel dysfunction, through either a direct or an indirect action.

With respect to these observations and hypotheses, it should be noted that there is ongoing debate on the possibility that P/Q-type Ca²⁺ channel mutation or dysfunction may underlie typical migraine, and genetic studies have so far yielded an inconsistent picture (7, 8). Furthermore, acetazolamide is a carbonic anhydrase inhibitor which creates metabolic acidosis and is not known to act specifically on (mutant) P/Q-type Ca²⁺ channels. Therefore, caution is appropriate in the interpretation of the present preliminary data in terms of P/Q-type Ca²⁺ channel involvement in SFEMG abnormalities as well as in migraine symptoms. Furthermore, a beneficial effect of acetazolamide on symptoms of typical migraine seems controversial (9). The authors correctly conclude that the present results should be confirmed in a placebo-controlled study with well-defined groups of migraineurs. Poor tolerability of acetazolamide might, however, limit such studies (9).

In any case, the present clinical observations seem to warrant a direct in vitro experimental approach to the issue, for instance through electrophysiological studies on the effects of acetazolamide on NMJs of P/Q-type Ca²⁺ channel mutant mice or on (mutant) channel function in expression systems or neuronal cells.

AMJM van den Maagdenberg^1,2 & JJ Plomp^{2,3 1}Departments of Human Genetics, ²Departments of Neurology and ³Departments of Neurophysiology, Leiden University Medical Centre, Leiden, The Netherlands