Ocular motor biomarkers in Niemann-Pick disease type C: A prospective cross-sectional multicontinental study in 72 patients

Abstract

AbstractNiemann-Pick type C (NPC) is a rare lysosomal storage disorder with ocular motor involvement. In a multicontinental, cross-sectional study we characterized ocular motor function in 72 genetically proven patients from twelve countries by means of video-oculography. Interlinking with disease severity, we also searched for ocular motor biomarkers. Our study protocol comprised reflexive and self-paced saccades, smooth pursuit, and gaze-holding in horizontal and vertical planes. Data were compared with those of 158 healthy controls. The Modified Disability Rating Scale, Scale for Assessment and Rating of Ataxia, Spinocerebellar Ataxia Functional Index for neurological status, and Montreal Cognitive Assessment for cognition were also performed.In contrast to previous publications and the common belief that the “downward saccadic system degenerates to greater extent than the upward one”, our measurements of vertical saccades demonstrated that the involvement in both directions was similar. Mean saccadic peak velocity to 20° stimulus was 63.5°/s (SD, 95% CIs of the mean: 59.5, [47.9-79.2]) in NPC patients and 403.1°/s (69.0, [392.0-414.2°/s]) in healthy subjects (p<0.001). Downward saccades yielded 51°/s (68.9, [32.7-69.3]), whilst upward 78.8°/s (65.9, [60.8-96.8]) (p<0.001). Vertical position smooth pursuit gain was 0.649 (0.33, [0.554-0.744]) in NPC and 0.935 (0.149 [0.91-0.959]) in HC (p<0.001).The number of patient-specific saccadic patterns, incl. slow-pursuit like, hypometric and staircase-pattern saccades suggest varying involvement of the saccadic system with fragmentation of the velocity profile as a sign of omnipause neuron dysfunction. Observed compensating strategies, such as blinks to elicit saccades, head and upper body movements to overcome the gaze palsy, should be used clinically to establish a diagnosis.Vertical reflexive saccades were more impaired and slower than self-paced ones. Ocular motor performance depended on age of onset and disease duration.We found that peak velocity and latency of horizontal saccades, vertical saccadic duration and amplitude, and horizontal position smooth pursuit can be used as surrogate parameters for clinical trials, as they showed the strongest correlation to disease severity. By comparing saccadic with pursuit movements, we showed that 98.2% of patients generated vertical saccades (both up and down) that were below the 95% confidence intervals of the controls’ peak velocity. Only 46.9% of patients had smooth pursuit gain lower than that of 95% of healthy controls. Vertical supranuclear saccade palsy and not vertical supranuclear gaze palsy is the hallmark of NPC disease. The distinction between saccadic and gaze palsy is also important in other neurodegenerative diseases and inborn errors of metabolism with ocular motor involvement, such as progressive supranuclear palsy or Gaucher disease type 3.