Abstract
BackgroundNiemann-Pick Type C disease (NPC), is an autosomal recessive neurovisceral disorder of lipid metabolism. One characteristic feature of NPC is a vertical supranuclear gaze palsy particularly affecting saccades. However, horizontal saccades are also impaired and as a consequence a parameter related to horizontal peak saccadic velocity was used as an outcome measure in the clinical trial of miglustat, the first drug approved in several jurisdictions for the treatment of NPC. As NPC-related neuropathology is widespread in the brain we examined a wider range of horizontal saccade parameters and to determine whether these showed treatment-related improvement and, if so, if this was maintained over time.MethodsNine adult NPC patients participated in the study; 8 were treated with miglustat for periods between 33 and 61 months. Data were available for 2 patients before their treatment commenced and 1 patient was untreated. Tasks included reflexive saccades, antisaccades and self-paced saccades, with eye movements recorded by an infrared reflectance eye tracker. Parameters analysed were reflexive saccade gain and latency, asymptotic peak saccadic velocity, HSEM-α (the slope of the peak duration-amplitude regression line), antisaccade error percentage, self-paced saccade count and time between refixations on the self-paced task. Data were analysed by plotting the change from baseline as a proportion of the baseline value at each test time and, where multiple data values were available at each session, by linear mixed effects (LME) analysis.ResultsExamination of change plots suggested some modest sustained improvement in gain, no consistent changes in asymptotic peak velocity or HSEM-α, deterioration in the already poor antisaccade error rate and sustained improvement in self-paced saccade rate. LME analysis showed statistically significant improvement in gain and the interval between self-paced saccades, with differences over time between treated and untreated patients.ConclusionsBoth qualitative examination of change scores and statistical evaluation with LME analysis support the idea that some saccadic parameters are robust indicators of efficacy, and that the variability observed across measures may indicate locally different effects of neurodegeneration and of drug actions.
Highlights
Niemann-Pick Type C disease (NPC), is an autosomal recessive neurovisceral disorder of lipid metabolism
While no symptom in isolation is pathognomonic for NPC, the presence of a vertical supranuclear gaze palsy (VSGP), of saccadic eye movements, is strongly indicative of NPC when seen in the presence of splenomegaly, ataxia, psychosis and/or cognitive decline [3]
Peak duration is defined as the amplitude of a saccade divided by its peak velocity and HSEM-α corresponds to the inverse of the asymptote Vmax of an exponential curve fitted directly to peak velocity versus amplitude plots [6], sometimes termed the “main sequence.”
Summary
Niemann-Pick Type C disease (NPC), is an autosomal recessive neurovisceral disorder of lipid metabolism. While essentially normal in the earlier stages of the disease [4, 5], definite abnormalities can be identified in horizontal saccadic function as the disease progresses Their state of being impaired, but not absent, led to the use of the slope of the peak duration versus amplitude regression line, termed horizontal saccadic eye movement alpha (HSEM-α) [6] as one of the principal outcome measures in the clinical trial of miglustat, the first medication approved in a range of jurisdictions for the treatment of NPC [7, 8]. Two reports arising from this clinical trial have reported that HSEM-α and other improvements seen; e.g., ambulation and swallowing, at 12 months were maintained at 24 months [7, 9] This implies that neurons responsible for generating the burst of innervation which determines peak saccadic velocity—excitatory burst neurons in the paramedian pontine reticular formation (PPRF)—benefitted from miglustat treatment
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