Conversion of upbeat to downbeat nystagmus in Wernicke encephalopathy.

OBJECTIVE: To explain (1) why an initial upbeat nystagmus (UBN) converts to a permanent downbeat nystagmus (DBN) in Wernicke encephalopathy (WE) and (2) why convergence and certain vestibular provocative maneuvers may transiently switch UBN to DBN. METHODS: Following a literature review and study of our 2 patients, we develop hypotheses for the unusual patterns of vertical nystagmus in WE. RESULTS: Our overarching hypothesis is that there is a selective vulnerability and a selective recovery from thiamine deficiency of neurons within brainstem gaze-holding networks. Furthermore, since the circuits affected in WE are commonly paraventricular, especially medially, just under the floor of the fourth ventricle where lie structures important for control of vertical gaze, we suggest the patterns of involvement in WE also reflect a breakdown in vulnerable areas of the blood-brain barrier. Many of the initial deficits of our patients improved over time, but their DBN did not. Irreversible changes in paramedian tract neurons, which project to the cerebellar flocculus, may be the cause. Here we suggest that conversion of UBN to permanent DBN points to thiamine deficiency and may argue for a chronic, nonprogressive DBN/truncal ataxia syndrome. Finally, we posit that the transient switch of UBN to DBN reflects abnormal processing of otolith information about linear acceleration, and often points to a diagnosis of WE. CONCLUSION: Recognizing the unusual patterns of transient switching and then permanent conversion of UBN to DBN in WE is vital since long-term disability from WE may be prevented by timely, parenteral high-dose thiamine.

Glycinergic projection neurons of the cerebellum.

The cerebellum funnels its entire output through a small number of presumed glutamatergic premotor projection neurons in the deep cerebellar nuclei and GABAergic neurons that feed back to the inferior olive. Here we use transgenic mice selectively expressing green fluorescent protein in glycinergic neurons to demonstrate that many premotor output neurons in the medial cerebellar (fastigial) nuclei are in fact glycinergic, not glutamatergic as previously thought. These neurons exhibit similar firing properties as neighboring glutamatergic neurons and receive direct input from both Purkinje cells and excitatory fibers. Glycinergic fastigial neurons make functional projections to vestibular and reticular neurons in the ipsilateral brainstem, whereas their glutamatergic counterparts project contralaterally. Together, these data suggest that the cerebellum can influence motor outputs via two distinct and complementary pathways.

Long-lasting increases in intrinsic excitability triggered by inhibition.

Although experience-dependent changes in neural circuits are commonly assumed to be mediated by synaptic plasticity, modifications of intrinsic excitability may serve as a complementary mechanism. In whole-cell recordings from spontaneously firing vestibular nucleus neurons, brief periods of inhibitory synaptic stimulation or direct membrane hyperpolarization triggered long-lasting increases in spontaneous firing rates and firing responses to intracellular depolarization. These increases in excitability, termed firing rate potentiation, were induced by decreases in intracellular calcium and expressed as reductions in the sensitivity to the BK-type calcium-activated potassium channel blocker iberiotoxin. Firing rate potentiation is a novel form of cellular plasticity that could contribute to motor learning in the vestibulo-ocular reflex.