Therapy of downbeat nystagmus: 4-aminopridine versus 3,4-diaminopyridine

Introduction: Aminopyridines, nonselective blockers of the Kv family of voltage-gated potassium channels, are effective in the symptomatic therapy of vestibular, cerebellar, and ocular motor disorders. Animal experiments have shown that aminopyridines increase Purkinje-cell (PC) excitability. This enhancement of PC activity could restore the inhibitory influence of the cerebellar cortex on vertical eye movements towards normal levels by an increase in GABA release. We showed the efficacy of aminopyridines for the treatment of downbeat nystagmus (DBN).

Here, we compared the effects of 4-aminopyridine (4-AP) versus 3,4-diaminopyridine (3,4-DAP) in patients with DBN in a double-blind study with crossover design. The purpose of this work was to analyze DBN before and after administration of aminopridines, to determine whether both medications would differ in terms of slow-phase velocity (SPV) changes.

Methods: We studied 8 patients with DBN due to different etiologies (cerebellar atrophy, n=4; idiopathic DBN, n=4). Subjects received randomly capsules with 10mg 3,4-DAP or 10mg 4-AP and 1 week later, the treatment was switched. Recordings were done with 2D videooculography prior, 45 and 90 minutes after administration of medications.

Results: 3,4-DAP reduced SPV from 5.679 deg/s (pre) to 3.29 deg/s (post 45) to 2.962 deg/s (post 90) (Scheffé post hoc tests <0.01). 4-AP reduced SPV from 6.037 deg/s (pre) to 1.576 deg/s (post 45) to 1.206 deg/s (post 90) (Scheffé<0.01). Throughout time (pre vs. post 45 vs. post 90), there was a significant effect between both medications, F(2,14)=8.876, p<0.01. Both post 45 and post 90 SPV-measurements were significantly better in 4-AP than in 3,4-DAP (Scheffé post hoc tests <0.05). Additional significant findings were main effects for light, F(1,7)=14.14, p<0.01 (SPV was higher in darkness vs. light) and time (pre vs. post 45 vs. post 90), F(1,7)=10.72, p<0.01).

Conclusion: Both aminopyridines result in a significant SPV-improvement. 10mg of 4-AP is more efficient than 10mg 3,4-DAP. This difference is probably due to a better ability to cross the blood-brain barrier and a longer half-life of 4-AP.