Aminopyridines for the treatment of cerebellar and ocular motor disorders

Downbeat nystagmus (DBN) is the most frequent form of acquired persisting fixation nystagmus. It is hypothesized to occur when physiological inhibitory cerebellar input, namely of the flocculus, to the vestibular nuclei is inhibited. The second most frequent form of acquired nystagmus is upbeat nystagmus (UBN). UBN is probably caused by an imbalance of vertical vestibulo-ocular reflex tone. GABA-ergic substances like baclofen have been used to treat DBN and UBN, but they have had only moderate success. Animal experiments have shown that aminopyridines [3,4-diaminopyridine (3,4-DAP) and 4-aminopyridine (4-AP)], nonselective blockers of the Kv family of voltage-gated potassium channels, increase Purkinje-cell (PC) excitability. It was assumed that such enhancement of PC activity could restore to normal levels the inhibitory influence of the cerebellar cortex on vertical eye movements. On the basis of these assumptions, we evaluated the efficacy and underlying mechanisms of aminopyridines in DBN and UBN as well as in another cerebellar disorder with an impaired PC function: episodic ataxia type 2 (EA2), which is caused by mutations of the PQ-calcium channel. In a placebo-controlled trial on 17 patients we demonstrated that 3,4-DAP significantly reduces the intensity of DBN. This was confirmed in a recent study with 4-AP, which also showed that 4-AP restores gaze-holding ability independently of fixation in DBN. The efficacy of 4-AP in UBN was demonstrated in single patients. Finally, in an open trial on three patients with EA2 we showed that 4-AP prevents attacks of ataxia. This was also found in an animal model (the tottering mouse) of EA2. The clinical efficacy of 4-AP in EA2 is being further evaluated in an ongoing randomized controlled crossover trial. In conclusion, the use of aminopyridines in DBN, UBN, and EA2 is a new treatment principle for vestibular, cerebellar, and ocular motor disorders.