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.

APHPSorbonne Université Paris Brain Institute Inserm CNRS Pitié Salpêtrière Hospital DMU Biogem APHP 75013 Paris France

Balance Disorders and Ataxia Service Royal Victoria Eye and Ear Hospital East Melbourne Melbourne VIC 3002 Australia

Cantonal Hospital of Baden Baden Switzerland

Clinic for Neurology University Clinical Center of Serbia Belgrade Serbia

Departamento de Medicina Interna Universidade Federal Do Rio Grande Do Sul Porto Alegre Brazil

Department of Neurology 2nd Faculty of Medicine Centre of Hereditary Ataxias Charles University and Motol University Hospital Prague Czech Republic

Department of Neurology Massachusetts General Hospital Harvard Medical School Boston MA USA

Department of Neurology Medical School University of Pécs Pécs Hungary

Department of Neurosciences and Reproductive and Odontostomatological Sciences University of Naples Federico 2 Naples Italy

Department of Otology and Laryngology and Department of Neurology Harvard Medical School Boston MA USA

Faculty of Medicine University of Zurich Zurich Switzerland

German Center for Neurodegenerative Diseases University of Tübingen Tübingen Germany

Hertie Institute for Clinical Brain Research and Center of Neurology Division Translational Genomics of Neurodegenerative Diseases University of Tübingen Tübingen Germany

Institute of Psychiatry and Neurology Warsaw Poland

NeuroMetrology Lab Nuffield Department of Clinical Neurosciences Clinical Neurology Medical Sciences Division University of Oxford Oxford OX3 9DU UK

Nuffield Department of Clinical Neurosciences University of Oxford Oxford UK

Oxford Centre for Genomic Medicine Oxford University Hospitals NHS Trust Oxford UK

Roche Pharma Research and Early Development Neuroscience and Rare Diseases Roche Innovation Center Basel Basel Switzerland

Serviço de Genética Médica Centro de Pesquisa Clínica E Experimental Hospital de Clínicas de Porto Alegre Porto Alegre Brazil

The Bionics Institute East Melbourne Melbourne VIC 3002 Australia

Unit of Neurology Centre Hospitalier Universitaire Vaudoise Lausanne Lausanne Switzerland

University of California Los Angeles Los Angeles CA USA

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