Effect of 4-Aminopyridine on Upbeat and Downbeat Nystagmus Elucidates the Mechanism of Downbeat Nystagmus

The effects of the potassium-channel blocker 4-aminopyridine (4-AP) on upbeat nystagmus (UBN) and downbeat nystagmus (DBN) were investigated with the search-coil technique during fixation in different gaze positions and smooth pursuit in two patients before and after ingesting 10mg 4-AP. DBN of unknown etiology was reduced from -3.9 deg/s to 0.14 deg/s in light, and from -3.8 deg/s to 1.1 deg/s in darkness, thus changing to mild UBN. Impaired downward smooth pursuit was restored (gains: pre 0.42; post 0.68). In the second patient, UBN, possibly due to a small traumatic lesion, was reduced in light from 8.6 deg/s to 2.0 deg/s by 4-AP. Again, impaired upward smooth pursuit was restored (gains: pre 0.38; post 0.86). In contrast to DBN, UBN in darkness was not affected by 4-AP. We propose that 4-AP in both UBN and DBN improved the function of the cerebellar pathways that mediate gaze holding and smooth pursuit by intensifying the excitability of cerebellar Purkinje cells (PCs). Our finding is consistent with the hypothesis (Marti et al., this meeting) that DBN is caused by damage of floccular PCs, which predominantly show downward on-directions. In contrast, UBN may be caused by damage to brainstem structures receiving inhibition from these PCs. In line with this hypothesis, restoring the function of floccular downward PCs by 4-AP cancels DBN even without visual input. In contrast, UBN in darkness is not abolished by 4-AP. However, in light, 4-AP increases the excitability of floccular PCs and thereby helps to mediate smooth pursuit commands that cancel the unwanted downward drift in UBN.