Oculomotor deficits are common in hereditary cerebellar ataxias (HCAs) and their quantitative assessment offers a sensitive and reliable manner to capture disease-severity and progression. As a group of experts of the Ataxia Global Initiative to support trial readiness, we previously established harmonized methodology for quantitative oculomotor assessments in HCAs. Here, we aimed to identify to most promising oculomotor/vestibular outcomes as endpoints for future trials. Through a systematic MEDLINE search we identified 130 articles reporting oculomotor/vestibular recordings in patients with HCAs. A total of 2,018 subjects were included: 1,776 with genetically-confirmed and 242 with clinically-defined HCAs. Studied diseases included spinocerebellar ataxias (SCA) 1/2/3/6/7/27B, episodic ataxia type 2, Friedreich ataxia, RFC1-related ataxia, fragile X-associated tremor/ataxia syndrome, cerebrotendinous xanthomatosis, ataxia-telangiectasia, ataxia with oculomotor apraxia types 1&2, and Niemann-Pick disease type C. We identified up to four oculomotor/vestibular outcomes per diagnostic entity, based on their ability to robustly discriminate patients from controls, correlate with disease-severity, detect longitudinal change, and represent different disease stages. For each parameter we provide recommendations for recordings. While the implementation of quantitative assessments into clinical trials offers a unique opportunity to track dysfunction of oculomotor/vestibular networks and to assess the impact of interventions, in some HCAs, endpoint qualification of available outcomes requires further validation to characterize their reliability, sensitivity to change, and minimally important change to patients. For all HCAs for which quantitative data are scarce or lacking, there is an urgent need for prospective studies covering a broader range of oculomotor/vestibular domains as approaching new treatments require harmonized and reliable endpoints.

• Keywords
• Eye movement recordings, Hereditary ataxia, Oculomotor, Recommendations, Systematic review, Vestibular,
• Publication type
• Journal Article MeSH

Oculomotor deficits are common in hereditary ataxia, but disproportionally neglected in clinical ataxia scales and as outcome measures for interventional trials. Quantitative assessment of oculomotor function has become increasingly available and thus applicable in multicenter trials and offers the opportunity to capture severity and progression of oculomotor impairment in a sensitive and reliable manner. In this consensus paper of the Ataxia Global Initiative Working Group On Digital Oculomotor Biomarkers, based on a systematic literature review, we propose harmonized methodology and measurement parameters for the quantitative assessment of oculomotor function in natural-history studies and clinical trials in hereditary ataxia. MEDLINE was searched for articles reporting on oculomotor/vestibular properties in ataxia patients and a study-tailored quality-assessment was performed. One-hundred-and-seventeen articles reporting on subjects with genetically confirmed (n=1134) or suspected hereditary ataxia (n=198), and degenerative ataxias with sporadic presentation (n=480) were included and subject to data extraction. Based on robust discrimination from controls, correlation with disease-severity, sensitivity to change, and feasibility in international multicenter settings as prerequisite for clinical trials, we prioritize a core-set of five eye-movement types: (i) pursuit eye movements, (ii) saccadic eye movements, (iii) fixation, (iv) eccentric gaze holding, and (v) rotational vestibulo-ocular reflex. We provide detailed guidelines for their acquisition, and recommendations on the quantitative parameters to extract. Limitations include low study quality, heterogeneity in patient populations, and lack of longitudinal studies. Standardization of quantitative oculomotor assessments will facilitate their implementation, interpretation, and validation in clinical trials, and ultimately advance our understanding of the evolution of oculomotor network dysfunction in hereditary ataxias.

• Keywords
• Eye movement recordings, Hereditary ataxia, Oculomotor, Recommendations, Systematic review, Vestibular,
• MeSH
• Biomarkers MeSH
• Consensus * MeSH
• Humans MeSH
• Eye Movements physiology   MeSH
• Ocular Motility Disorders diagnosis   physiopathology   genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Systematic Review MeSH