Saccadic eye movements and its use as clinical endpoints in lysosomal disorders: A literature review

Abstract

Saccadic eye movements (SEMs) are rapid eye movements that aid vision through the redirection of sight from target to target. Normal SEM is distinguished by a consistent relationship between peak velocity, amplitude, and duration (latency and termination). There are several disorders of the saccades that affect these parameters and are apparent in Gaucher disease type 3 (GD3) and monogangliosidosis 2 (GM2). A targeted literature review was conducted to describe SEM disorders and their manifestations in GM2 and GD3 and to assess its use as an endpoint in clinical trials. In both diseases, SEM disorders may include horizontal saccadic initiation failure and slowed horizontal and downward saccades. SEMs play a critical role in coordination and the ability to perform activities of daily living (reading, interpretation, navigation of the visual environment, and social interactions). In GD3, SEM disorders were associated with significant impairment in hand-eye coordination and manual dexterity. In clinical trials of lysosomal storage disorders, SEMs have been assessed using change from baseline in either horizontal or vertical SEM velocities (HSEM-α and VSEM-α) and horizontal and vertical SEM amplitudes (HSEM-β and VSEM-β) as a primary or secondary endpoint. The process for assessing SEM and the thresholds for improvement and deterioration varied across the trials. A clear definition for a clinically meaningful change was not always provided making comparisons across studies difficult. SEM is not routinely used in clinical practice and changes cannot be directly translated into clinical benefits. These aspects were highlighted by regulatory agencies in regulatory assessments of miglustat for the treatment of progressive neurological manifestations in Niemann-Pick Type C. Guidelines around the usefulness and acceptability of SEM endpoints in trials were not identified. More data is needed to establish a clear link between early sign of change in SEMs and clinical benefits. Supported by Sanofi