Acquired pendular nystagmus (APN) consists of ocular oscillations that are often visually disabling, because they induce excessive motion of images on the retina.1
Although a number of neurological disorders have been reported to cause APN, it most commonly occurs in central demyelination disorders, especially multiple sclerosis (MS)2
and as a component of the syndrome of oculopalatal tremor (OPT).3
In both, the APN is often characterized by oscillations with variable horizontal, vertical, and torsional components. However, these two forms of APN also show distinctive differences. APN in MS usually consists of oscillations at a single frequency (3–5 Hz)4
that are either transiently stopped or “reset” (phase-shifted) by large saccades.5,6
APN in OPT often consists of irregular oscillations with a frequency of 1–3 Hz.7,8
Consideration of these findings and the locations of associated neurological lesions have led to the development of distinct hypotheses to account for the mechanism underlying APN in MS versus OPT.
It was hypothesized that the oscillations of APN in MS arise from an unstable neural integrator, which normally ensures steady gaze-holding.6
Such patients often show brainstem lesions on MRI2
that could involve cell groups of the paramedian tracts (PMT), which relay a copy of most ocular motor signals back to the cerebellar flocculus9
and thereby contribute to normal gaze-holding function. Arnold and colleagues10
showed that injection of the hyperpolarizing agent muscimol at the putative site of neural integrator made it more unstable, while injection of a depolarizing agent (glutamate) reversed the effect. We hypothesize that the degree of instability of the neural integrator, which is determined by the excitability of the network neurons, determines the amplitude of APN. This suggests that drugs that can depolarize the cells of the neural integrator would reduce the amplitude of the APN. Reducing the Purkinje cell–induced GABAergic inhibition is the safe way to depolarize the neural integrator in human patients. Gabapentin and memantine can reduce the GABAergic inhibitory influence of cerebellar Purkinje neurons, gabapentin by blocking the alpha-2-delta subunit of calcium channels and both drugs by antagonizing NMDA receptors.11–13
Therefore, these drugs can indirectly depolarize the cells of the nucleus prepositus hypoglossi (and thereby make the neural integrator less unstable) and reduce the amplitude of APN in patients with MS. We also hypothesize that baclofen, a GABAergic drug that hyperpolarizes the cell membrane, may not reduce the amplitude of APN and may even increase it.
APN in OPT is attributed to hypertrophic degeneration of the inferior olivary nucleus (IO) following a breach in the “Guillain–Mollaret triangle,” which comprises connections between the IO and deep cerebellar relay nuclei (DCRN), via climbing fiber axon collaterals, and between DCRN and IO, via the superior cerebellar peduncle and central tegmental tract.3,14–19
Following a lesion, usually of the central tegmental tract, gap junctions (connexins), which are normally restricted to the dendrites of IO, develop between adjacent neural cell bodies. Consequently, local patches of IO neurons begin to fire in synchrony and act as “pacemakers.” The pacemaker output pulses are small and jerky, but learning by the cerebellar cortex smoothes and amplifies them in the DCRN—the dual-mechanism hypothesis.8,20
We propose that drugs affecting the IO output, such as memantine blocking of NMDA receptors,21
, would reduce the amplitude of APN. Drugs reducing the output of the cerebellum, such as gabapentin and memantine, 11–13
would reduce the amplitude and frequency variability of the nystagmus waveform, but not the fundamental frequency of APN.
The goal of this study was to measure the effects of drugs known to influence APN in MS or OPT (i.e., gabapentin, memantine, and baclofen), using them as tests of the two hypotheses summarized above.