Characterizing bedside oculomotor deficits is a critical factor in defining the clinical presentation of hereditary ataxias. Quantitative assessments are increasingly available and have significant advantages, including comparability over time, reduced examiner dependency, and sensitivity to subtle changes. To delineate the potential of quantitative oculomotor assessments as digital-motor outcome measures for clinical trials in ataxia, we searched MEDLINE for articles reporting on quantitative eye movement recordings in genetically confirmed or suspected hereditary ataxias, asking which paradigms are most promising for capturing disease progression and treatment response. Eighty-nine manuscripts identified reported on 1541 patients, including spinocerebellar ataxias (SCA2, n = 421), SCA3 (n = 268), SCA6 (n = 117), other SCAs (n = 97), Friedreich ataxia (FRDA, n = 178), Niemann-Pick disease type C (NPC, n = 57), and ataxia-telangiectasia (n = 85) as largest cohorts. Whereas most studies reported discriminatory power of oculomotor assessments in diagnostics, few explored their value for monitoring genotype-specific disease progression (n = 2; SCA2) or treatment response (n = 8; SCA2, FRDA, NPC, ataxia-telangiectasia, episodic-ataxia 4). Oculomotor parameters correlated with disease severity measures including clinical scores (n = 18 studies (SARA: n = 9)), chronological measures (e.g., age, disease duration, time-to-symptom onset; n = 17), genetic stratification (n = 9), and imaging measures of atrophy (n = 5). Recurrent correlations across many ataxias (SCA2/3/17, FRDA, NPC) suggest saccadic eye movements as potentially generic quantitative oculomotor outcome. Recommendation of other paradigms was limited by the scarcity of cross-validating correlations, except saccadic intrusions (FRDA), pursuit eye movements (SCA17), and quantitative head-impulse testing (SCA3/6). This work aids in understanding the current knowledge of quantitative oculomotor parameters in hereditary ataxias, and identifies gaps for validation as potential trial outcome measures in specific ataxia genotypes.

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

Cantonal Hospital of Baden Baden Switzerland

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

Department of Clinical Neurophysiology Institute of Psychiatry and Neurology Warsaw Poland

Department of Genetics Neurogene National Reference Centre for Rare Diseases Pitié Salpêtrière University Hospital Assistance Publique Hôpitaux de Paris Paris France

Department of Neurology Centre of Hereditary Ataxias 2nd Faculty of Medicine 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 Pecs Pecs 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

Institut du Cerveau Paris Brain Institute ICM Inserm U1127 CNRS UMR7225 Sorbonne Université Paris France

NeuroMetrology Lab Nuffield Department of Clinical Neurosciences 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

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

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 Florey Institute of Neuroscience and Mental Health Parkville Melbourne VIC 3052 Australia

University of California Los Angeles Los Angeles CA USA

See more in PubMed

Park JY, Joo K, Woo SJ. Ophthalmic manifestations and genetics of the polyglutamine autosomal dominant spinocerebellar ataxias: a review. Front Neurosci. 2020;14:892. doi: 10.3389/fnins.2020.00892. PubMed DOI PMC

Leigh RJ, Zee DS. Appendix C - Tables of ocular motor findings in hereditary ataxia. The neurology of eye movements, 5th edition. New York, USA, Oxford University Press; 2015. pp. 1035–48.

Zeigelboim BS, Teive HAG, Santos GJB, Severiano MIR, Fonseca VR, Faryniuk JH, Marques JM. Otoneurological findings prevalent in hereditary ataxias. Arq Neuropsiquiatr. 2018;76:131–138. doi: 10.1590/0004-282x20180001. PubMed DOI

Barsottini OG, Pedroso JL, Jr, Martins CR, Jr, Franca MC, Albernaz PM. Deafness and vestibulopathy in cerebellar diseases: a practical approach. Cerebellum (London, England) 2019;18:1011–6. doi: 10.1007/s12311-019-01042-4. PubMed DOI

Szmulewicz DJ. Combined central and peripheral degenerative vestibular disorders: CANVAS, idiopathic cerebellar ataxia with bilateral vestibulopathy (CABV) and other differential diagnoses of the CABV phenotype. Curr Otorhinolaryngol Rep. 2017;5:167–174. doi: 10.1007/s40136-017-0161-5. DOI

Szmulewicz DJ, Waterston JA, MacDougall HG, Mossman S, Chancellor AM, McLean CA, Merchant S, Patrikios P, Halmagyi GM, Storey E. Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS): a review of the clinical features and video-oculographic diagnosis. Ann N Y Acad Sci. 2011;1233:139–147. doi: 10.1111/j.1749-6632.2011.06158.x. PubMed DOI

Tarnutzer AA, Straumann D, Salman MS. Neuro-ophthalmologic assessment and investigations in children and adults with cerebellar diseases. Handb Clin Neurol. 2018;154:305–327. doi: 10.1016/B978-0-444-63956-1.00019-9. PubMed DOI

Rodríguez-Labrada R, Velázquez-Pérez L, Auburger G, Ziemann U, Canales-Ochoa N, Medrano-Montero J, Vázquez-Mojena Y, González-Zaldivar Y. Spinocerebellar ataxia type 2: measures of saccade changes improve power for clinical trials. Mov Disord Off J Mov Disord Soc. 2016;31:570–578. doi: 10.1002/mds.26532. PubMed DOI

de Oliveira CM, Leotti VB, Bolzan G, Cappelli AH, Rocha AG, Ecco G, Kersting N, Rieck M, Martins AC, Sena LS, Saraiva-Pereira ML, Jardim LB. Pre-ataxic changes of clinical scales and eye movement in Machado-Joseph disease: BIGPRO study. Mov Disord. 2021;36(4):985–94 . 10.1002/mds.28466. PubMed

Luis L, Costa J, Munoz E, de Carvalho M, Carmona S, Schneider E, Gordon CR, Valls-Sole J. Vestibulo-ocular reflex dynamics with head-impulses discriminates spinocerebellar ataxias types 1, 2 and 3 and Friedreich ataxia. J Vestib Res Equilibrium Orientation. 2016;26:327–334. doi: 10.3233/VES-160579. PubMed DOI

Jensen K, Beylergil SB, Shaikh AG. Slow saccades in cerebellar disease. Cerebellum Ataxias. 2019;6:1. doi: 10.1186/s40673-018-0095-9. PubMed DOI PMC

Costales M, Casanueva R, Suárez V, Asensi JM, Cifuentes GA, Diñeiro M, Cadiñanos J, López F, Álvarez-Marcos C, Otero A, Gómez J, Llorente JL, Cabanillas R. CANVAS: a new genetic entity in the otorhinolaryngologist's differential diagnosis. Otolaryngol Head Neck Surg. 2022;166(1):74–9. 10.1177/01945998211008398. PubMed

Lee SU, Kim JS, Kim HJ, Choi JY, Park JY, Kim JM, Yang X. Evolution of the vestibular function during head impulses in spinocerebellar ataxia type 6. J Neurol. 2020;267:1672–1678. doi: 10.1007/s00415-020-09756-w. PubMed DOI

Tang SY, Shaikh AG. Past and present of eye movement abnormalities in ataxia-telangiectasia. Cerebellum (London, England) 2019;18:556–564. doi: 10.1007/s12311-018-0990-x. PubMed DOI PMC

Anderson TJ, MacAskill MR. Eye movements in patients with neurodegenerative disorders. Nat Rev Neurol. 2013;9:74–85. doi: 10.1038/nrneurol.2012.273. PubMed DOI

Mariani LL, Rivaud-Pechoux S, Charles P, Ewenczyk C, Meneret A, Monga BB, Fleury MC, Hainque E, Maisonobe T, Degos B, Echaniz-Laguna A, Renaud M, Wirth T, Grabli D, Brice A, Vidailhet M, Stoppa-Lyonnet D, Dubois-d'Enghien C, Le Ber I, Koenig M, Roze E, Tranchant C, Durr A, Gaymard B, Anheim M. Comparing ataxias with oculomotor apraxia: a multimodal study of AOA1, AOA2 and AT focusing on video-oculography and alpha-fetoprotein. Sci Rep. 2017;7:15284. doi: 10.1038/s41598-017-15127-9. PubMed DOI PMC

Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009;6:e1000100. doi: 10.1371/journal.pmed.1000100. PubMed DOI PMC

Schober P, Boer C, Schwarte LA. Correlation coefficients: appropriate use and interpretation. Anesth Analg. 2018;126:1763–1768. doi: 10.1213/ANE.0000000000002864. PubMed DOI

Alexandre MF, Rivaud-Péchoux S, Challe G, Durr A, Gaymard B. Functional consequences of oculomotor disorders in hereditary cerebellar ataxias. Cerebellum (London, England) 2013;12:396–405. doi: 10.1007/s12311-012-0433-z. PubMed DOI

Reetz K, Rodríguez-Labrada R, Dogan I, Mirzazade S, Romanzetti S, Schulz JB, Cruz-Rivas EM, Alvarez-Cuesta JA, Aguilera Rodríguez R, Gonzalez Zaldivar Y, Auburger G, Velázquez-Pérez L. Brain atrophy measures in preclinical and manifest spinocerebellar ataxia type 2. Ann Clin Transl Neurol. 2018;5:128–137. doi: 10.1002/acn3.504. PubMed DOI PMC

Walterfang M, Abel LA, Desmond P, Fahey MC, Bowman EA, Velakoulis D. Cerebellar volume correlates with saccadic gain and ataxia in adult Niemann-Pick type C. Mol Genet Metab. 2013;108:85–89. doi: 10.1016/j.ymgme.2012.11.009. PubMed DOI

Walterfang M, Macfarlane MD, Looi JC, Abel L, Bowman E, Fahey MC, Desmond P, Velakoulis D. Pontine-to-midbrain ratio indexes ocular-motor function and illness stage in adult Niemann-Pick disease type C. Eur J Neurol. 2012;19:462–467. doi: 10.1111/j.1468-1331.2011.03545.x. PubMed DOI

Seifried C, Velázquez-Pérez L, Santos-Falcón N, Abele M, Ziemann U, Almaguer LE, Martínez-Góngora E, Sánchez-Cruz G, Canales N, Pérez-González R, Velázquez-Manresa M, Viebahn B, Stuckrad-Barre S, Klockgether T, Fetter M, Auburger G. Saccade velocity as a surrogate disease marker in spinocerebellar ataxia type 2. Ann N Y Acad Sci. 2005;1039:524–527. doi: 10.1196/annals.1325.059. PubMed DOI

Bremova T, Malinova V, Amraoui Y, Mengel E, Reinke J, Kolnikova M, Strupp M. Acetyl-dl-leucine in Niemann-Pick type C: a case series. Neurology. 2015;85:1368–1375. doi: 10.1212/WNL.0000000000002041. PubMed DOI

Coin JT, Vance JM. Gabapentin relieves vertigo of periodic vestibulocerebellar ataxia: 3 cases and possible mechanism. Mov Disord. 2021;36(5):1264–67. 10.1002/mds.28491. PubMed

Ribaï P, Pousset F, Tanguy ML, Rivaud-Pechoux S, Le Ber I, Gasparini F, Charles P, Béraud AS, Schmitt M, Koenig M, Mallet A, Brice A, Dürr A. Neurological, cardiological, and oculomotor progression in 104 patients with Friedreich ataxia during long-term follow-up. Arch Neurol. 2007;64:558–564. doi: 10.1001/archneur.64.4.558. PubMed DOI

Rodríguez-Díaz JC, Velázquez-Pérez L, Rodríguez Labrada R, Aguilera Rodríguez R, Laffita Pérez D, Canales Ochoa N, Medrano Montero J, Estupiñán Rodríguez A, Osorio Borjas M, Góngora Marrero M, Reynaldo Cejas L, González Zaldivar Y, Almaguer GD. Neurorehabilitation therapy in spinocerebellar ataxia type 2: a 24-week, rater-blinded, randomized, controlled trial. Mov Disord Off J Mov Disord Soc. 2018;33:1481–1487. doi: 10.1002/mds.27437. PubMed DOI

Rosini F, Federighi P, Pretegiani E, Piu P, Leigh RJ, Serra A, Federico A, Rufa A. Ocular-motor profile and effects of memantine in a familial form of adult cerebellar ataxia with slow saccades and square wave saccadic intrusions. PloS one. 2013;8:e69522. doi: 10.1371/journal.pone.0069522. PubMed DOI PMC

Shaikh AG, Marti S, Tarnutzer AA, Palla A, Crawford TO, Zee DS, Straumann D. Effects of 4-aminopyridine on nystagmus and vestibulo-ocular reflex in ataxia-telangiectasia. J Neurol. 2013;260:2728–2735. doi: 10.1007/s00415-013-7046-4. PubMed DOI

Velázquez-Pérez L, Rodríguez-Chanfrau J, García-Rodríguez JC, Sánchez-Cruz G, Aguilera-Rodríguez R, Rodríguez-Labrada R, Rodríguez-Díaz JC, Canales-Ochoa N, Gotay DA, Almaguer Mederos LE, Laffita Mesa JM, Porto-Verdecia M, Triana CG, Pupo NR, Batista IH, López-Hernandez OD, Polanco ID, Novas AJ. Oral zinc sulphate supplementation for six months in SCA2 patients: a randomized, double-blind, placebo-controlled trial. Neurochem Res. 2011;36:1793–1800. doi: 10.1007/s11064-011-0496-0. PubMed DOI

Velázquez-Pérez L, Rodríguez-Labrada R, Álvarez-González L, Aguilera-Rodríguez R, Álvarez Sánchez M, Canales-Ochoa N, Galicia Polo L, Haro-Valencia R, Medrano-Montero J, Vázquez-Mojena Y, Peña-Acosta A, Estupiñán-Rodríguez A, Rodríguez PN. Lisuride reduces involuntary periodic leg movements in spinocerebellar ataxia type 2 patients. Cerebellum (London, England) 2012;11:1051–1056. doi: 10.1007/s12311-012-0382-6. PubMed DOI

Wu C, Chen DB, Feng L, Zhou XX, Zhang JW, You HJ, Liang XL, Pei Z, Li XH. Oculomotor deficits in spinocerebellar ataxia type 3: potential biomarkers of preclinical detection and disease progression. CNS Neurosci Ther. 2017;23:321–328. doi: 10.1111/cns.12676. PubMed DOI PMC

Fielding J, Corben L, Cremer P, Millist L, White O, Delatycki M. Disruption to higher order processes in Friedreich ataxia. Neuropsychologia. 2010;48:235–242. doi: 10.1016/j.neuropsychologia.2009.09.009. PubMed DOI

Fahey MC, Cremer PD, Aw ST, Millist L, Todd MJ, White OB, Halmagyi M, Corben LA, Collins V, Churchyard AJ, Tan K, Kowal L, Delatycki MB. Vestibular, saccadic and fixation abnormalities in genetically confirmed Friedreich ataxia. Brain J Neurol. 2008;131:1035–1045. doi: 10.1093/brain/awm323. PubMed DOI

Hocking DR, Corben LA, Fielding J, Cremer PD, Millist L, White OB, Delatycki MB. Saccade reprogramming in Friedreich ataxia reveals impairments in the cognitive control of saccadic eye movement. Brain Cogn. 2014;87:161–167. doi: 10.1016/j.bandc.2014.03.018. PubMed DOI

Hocking DR, Fielding J, Corben LA, Cremer PD, Millist L, White OB, Delatycki MB. Ocular motor fixation deficits in Friedreich ataxia. Cerebellum (London, England) 2010;9:411–418. doi: 10.1007/s12311-010-0178-5. PubMed DOI

Rodríguez-Labrada R, Vázquez-Mojena Y, Canales-Ochoa N, Medrano-Montero J, Velázquez-Pérez L. Heritability of saccadic eye movements in spinocerebellar ataxia type 2: insights into an endophenotype marker. Cerebellum Ataxias. 2017;4:19. doi: 10.1186/s40673-017-0078-2. PubMed DOI PMC

Federighi P, Cevenini G, Dotti MT, Rosini F, Pretegiani E, Federico A, Rufa A. Differences in saccade dynamics between spinocerebellar ataxia 2 and late-onset cerebellar ataxias. Brain J Neurol. 2011;134:879–891. doi: 10.1093/brain/awr009. PubMed DOI

Velázquez-Pérez L, Seifried C, Abele M, Wirjatijasa F, Rodríguez-Labrada R, Santos-Falcón N, Sánchez-Cruz G, Almaguer-Mederos L, Tejeda R, Canales-Ochoa N, Fetter M, Ziemann U, Klockgether T, Medrano-Montero J, Rodríguez-Díaz J, Laffita-Mesa JM, Auburger G. Saccade velocity is reduced in presymptomatic spinocerebellar ataxia type 2. Clin Neurophysiol Off J Int Fed Clin Neurophysiol. 2009;120:632–635. doi: 10.1016/j.clinph.2008.12.040. PubMed DOI

Velázquez-Pérez L, Rodríguez-Labrada R, Cruz-Rivas EM, Fernández-Ruiz J, Vaca-Palomares I, Lilia-Campins J, Cisneros B, Peña-Acosta A, Vázquez-Mojena Y, Diaz R, Magaña-Aguirre JJ, Cruz-Mariño T, Estupiñán-Rodríguez A, Laffita-Mesa JM, González-Piña R, Canales-Ochoa N, González-Zaldivar Y. Comprehensive study of early features in spinocerebellar ataxia 2: delineating the prodromal stage of the disease. Cerebellum (London, England) 2014;13:568–579. doi: 10.1007/s12311-014-0574-3. PubMed DOI

Huh YE, Kim JS, Kim HJ, Park SH, Jeon BS, Kim JM, Cho JW, Zee DS. Vestibular performance during high-acceleration stimuli correlates with clinical decline in SCA6. Cerebellum (London, England) 2015;14:284–291. doi: 10.1007/s12311-015-0650-3. PubMed DOI

Hübner J, Sprenger A, Klein C, Hagenah J, Rambold H, Zühlke C, Kömpf D, Rolfs A, Kimmig H, Helmchen C. Eye movement abnormalities in spinocerebellar ataxia type 17 (SCA17) Neurology. 2007;69:1160–1168. doi: 10.1212/01.wnl.0000276958.91986.89. PubMed DOI

Havla J, Moser M, Sztatecsny C, Lotz-Havla AS, Maier EM, Hizli B, Schinner R, Kümpfel T, Strupp M, Bremova-Ertl T, Schneider SA. Retinal axonal degeneration in Niemann-Pick type C disease. J Neurol. 2020;267:2070–2082. doi: 10.1007/s00415-020-09796-2. PubMed DOI PMC

Baloh RW, Konrad HR, Honrubia V. Vestibulo-ocular function in patients with cerebellar atrophy. Neurology. 1975;25:160–168. doi: 10.1212/wnl.25.2.160. PubMed DOI

Dale RT, Kirby AW, Jampel RS. Square wave jerks in Friedreich's ataxia. Am J Ophthalmol. 1978;85:400–406. doi: 10.1016/s0002-9394(14)77738-4. PubMed DOI

Ell J, Prasher D, Rudge P. Neuro-otological abnormalities in Friedreich's ataxia. J Neurol Neurosurg Psychiatry. 1984;47:26–32. doi: 10.1136/jnnp.47.1.26. PubMed DOI PMC

Furman JM, Perlman S, Baloh RW. Eye movements in Friedreich's ataxia. Arch Neurol. 1983;40:343–346. doi: 10.1001/archneur.1983.04050060043006. PubMed DOI

Moschner C, Perlman S, Baloh RW. Comparison of oculomotor findings in the progressive ataxia syndromes. Brain J Neurol. 1994;117(Pt 1):15–25. doi: 10.1093/brain/117.1.15. PubMed DOI

Spieker S, Schulz JB, Petersen D, Fetter M, Klockgether T, Dichgans J. Fixation instability and oculomotor abnormalities in Friedreich's ataxia. J Neurol. 1995;242:517–521. doi: 10.1007/bf00867423. PubMed DOI

Baloh RW, Yee RD, Boder E. Eye movements in ataxia-telangiectasia. Neurology. 1978;28:1099–1104. doi: 10.1212/wnl.28.11.1099. PubMed DOI

Lewis RF, Crawford TO. Slow target-directed eye movements in ataxia-telangiectasia. Invest Ophthalmol Vis Sci. 2002;43:686–691. PubMed

Lewis RF, Lederman HM, Crawford TO. Ocular motor abnormalities in ataxia telangiectasia. Ann Neurol. 1999;46:287–295. doi: 10.1002/1531-8249(199909)46:3<287::aid-ana3>3.0.co;2-0. PubMed DOI

Velazquez-Perez L, Rodriguez-Labrada R, Gonzalez-Garces Y, Vazquez-Mojena Y, Perez-Rodriguez R, Ziemann U. Neurophysiological features in spinocerebellar ataxia type 2: prospects for novel biomarkers. Clin Neurophysiol Off J Int Fed Clin Neurophysiol. 2021;135:1–12. doi: 10.1016/j.clinph.2021.12.005. PubMed DOI

Cronbach LJ, Meehl PE. Construct validity in psychological tests. Psychol Bull. 1955;52:281–302. doi: 10.1037/h0040957. PubMed DOI

Schmitz-Hubsch T, du Montcel ST, Baliko L, Berciano J, Boesch S, Depondt C, Giunti P, Globas C, Infante J, Kang JS, Kremer B, Mariotti C, Melegh B, Pandolfo M, Rakowicz M, Ribai P, Rola R, Schols L, Szymanski S, van de Warrenburg BP, Durr A, Klockgether T, Fancellu R. Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology. 2006;66:1717–1720. doi: 10.1212/01.wnl.0000219042.60538.92. PubMed DOI

Subramony SH, May W, Lynch D, Gomez C, Fischbeck K, Hallett M, Taylor P, Wilson R, Ashizawa T, Cooperative AG. Measuring Friedreich ataxia: interrater reliability of a neurologic rating scale. Neurology. 2005;64:1261–1262. doi: 10.1212/01.WNL.0000156802.15466.79. PubMed DOI

Trouillas P, Takayanagi T, Hallett M, Currier RD, Subramony SH, Wessel K, Bryer A, Diener HC, Massaquoi S, Gomez CM, Coutinho P, Ben Hamida M, Campanella G, Filla A, Schut L, Timann D, Honnorat J, Nighoghossian N, Manyam B. International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. The Ataxia Neuropharmacology Committee of the World Federation of Neurology. J Neurol Sci. 1997;145:205–11. doi: 10.1016/s0022-510x(96)00231-6. PubMed DOI

Jacobi H, du Montcel ST, Bauer P, Giunti P, Cook A, Labrum R, Parkinson MH, Durr A, Brice A, Charles P, Marelli C, Mariotti C, Nanetti L, Panzeri M, Rakowicz M, Sulek A, Sobanska A, Schmitz-Hubsch T, Schols L, Hengel H, Baliko L, Melegh B, Filla A, Antenora A, Infante J, Berciano J, van de Warrenburg BP, Timmann D, Szymanski S, Boesch S, Kang JS, Pandolfo M, Schulz JB, Molho S, Diallo A, Klockgether T. Long-term disease progression in spinocerebellar ataxia types 1, 2, 3, and 6: a longitudinal cohort study. Lancet Neurol. 2015;14:1101–1108. doi: 10.1016/S1474-4422(15)00202-1. PubMed DOI

Nigri A, Sarro L, Mongelli A, Castaldo A, Porcu L, Pinardi C, Grisoli M, Ferraro S, Canafoglia L, Visani E, Bruzzone MG, Nanetti L, Taroni F, Mariotti C. Spinocerebellar ataxia type 1: one-year longitudinal study to identify clinical and MRI measures of disease progression in patients and presymptomatic carriers. Cerebellum. 2022;21(1):133–44. 10.1007/s12311-021-01285-0. PubMed

Diallo A, Jacobi H, Tezenas du Montcel S, Klockgether T. Natural history of most common spinocerebellar ataxia: a systematic review and meta-analysis. J Neurol. 2021;268:2749–56. doi: 10.1007/s00415-020-09815-2. PubMed DOI

Reetz K, Dogan I, Hilgers RD, Giunti P, Mariotti C, Durr A, Boesch S, Klopstock T, de Rivera FJR, Schols L, Klockgether T, Burk K, Rai M, Pandolfo M, Schulz JB, Group ES Progression characteristics of the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS): a 2 year cohort study. Lancet Neurol. 2016;15:1346–54. doi: 10.1016/S1474-4422(16)30287-3. PubMed DOI

Jacobi H, Reetz K, du Montcel ST, Bauer P, Mariotti C, Nanetti L, Rakowicz M, Sulek A, Durr A, Charles P, Filla A, Antenora A, Schols L, Schicks J, Infante J, Kang JS, Timmann D, Di Fabio R, Masciullo M, Baliko L, Melegh B, Boesch S, Burk K, Peltz A, Schulz JB, Dufaure-Gare I, Klockgether T. Biological and clinical characteristics of individuals at risk for spinocerebellar ataxia types 1, 2, 3, and 6 in the longitudinal RISCA study: analysis of baseline data. Lancet Neurol. 2013;12:650–658. doi: 10.1016/S1474-4422(13)70104-2. PubMed DOI

Stephen CD, Schmahmann JD. Eye movement abnormalities are ubiquitous in the spinocerebellar ataxias. Cerebellum (London, England) 2019;18:1130–1136. doi: 10.1007/s12311-019-01044-2. PubMed DOI

Administration USFD. Patient-focused drug development: selecting, developing, or modifying fit-for-purpose clinical outcome assessments. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/patient-focused-drug-development-selecting-developing-or-modifying-fit-purpose-clinical-outcome. Accessed 9th Sept 2022.

Chang Z, Chen Z, Stephen CD, Schmahmann JD, Wu HT, Sapiro G, Gupta AS. Accurate detection of cerebellar smooth pursuit eye movement abnormalities via mobile phone video and machine learning. Sci Rep. 2020;10:18641. doi: 10.1038/s41598-020-75661-x. PubMed DOI PMC

Anastasopoulos D, Haslwanter T, Fetter M, Dichgans J. Smooth pursuit eye movements and otolith-ocular responses are differently impaired in cerebellar ataxia. Brain J Neurol. 1998;121(Pt 8):1497–1505. doi: 10.1093/brain/121.8.1497. PubMed DOI

Bour LJ, van Rootselaar AF, Koelman JH, Tijssen MA. Oculomotor abnormalities in myoclonic tremor: a comparison with spinocerebellar ataxia type 6. Brain J Neurol. 2008;131:2295–2303. doi: 10.1093/brain/awn177. PubMed DOI

Bürk K, Fetter M, Skalej M, Laccone F, Stevanin G, Dichgans J, Klockgether T. Saccade velocity in idiopathic and autosomal dominant cerebellar ataxia. J Neurol Neurosurg Psychiatry. 1997;62:662–664. doi: 10.1136/jnnp.62.6.662. PubMed DOI PMC

Crowdy KA, Hollands MA, Ferguson IT, Marple-Horvat DE. Evidence for interactive locomotor and oculomotor deficits in cerebellar patients during visually guided stepping. Exp Brain Res. 2000;135:437–454. doi: 10.1007/s002210000539. PubMed DOI

Kim JS, Kim JS, Youn J, Seo DW, Jeong Y, Kang JH, Park JH, Cho JW. Ocular motor characteristics of different subtypes of spinocerebellar ataxia: distinguishing features. Mov Disord Off J Mov Disord Soc. 2013;28:1271–1277. doi: 10.1002/mds.25464. PubMed DOI

Yue Q, Jen JC, Nelson SF, Baloh RW. Progressive ataxia due to a missense mutation in a calcium-channel gene. Am J Hum Genet. 1997;61:1078–1087. doi: 10.1086/301613. PubMed DOI PMC

Zee DS, Yee RD, Cogan DG, Robinson DA, Engel WK. Ocular motor abnormalities in hereditary cerebellar ataxia. Brain J Neurol. 1976;99:207–234. doi: 10.1093/brain/99.2.207. PubMed DOI

Saglam M, Lehnen N. Gaze stabilization in chronic vestibular-loss and in cerebellar ataxia: interactions of feedforward and sensory feedback mechanisms. J Vestib Res Equilibrium Orientation. 2014;24:425–431. doi: 10.3233/VES-140538. PubMed DOI

Ciuffreda KJ, Kenyon RV, Stark L. Eye movements during reading: further case reports. Am J Optom Physiol Opt. 1985;62:844–852. doi: 10.1097/00006324-198512000-00005. PubMed DOI

Wessel K, Moschner C, Wandinger KP, Kömpf D, Heide W. Oculomotor testing in the differential diagnosis of degenerative ataxic disorders. Arch Neurol. 1998;55:949–956. doi: 10.1001/archneur.55.7.949. PubMed DOI

Bürk K, Abele M, Fetter M, Dichgans J, Skalej M, Laccone F, Didierjean O, Brice A, Klockgether T. Autosomal dominant cerebellar ataxia type I clinical features and MRI in families with SCA1, SCA2 and SCA3. Brain J Neurol. 1996;119(Pt 5):1497–1505. doi: 10.1093/brain/119.5.1497. PubMed DOI

Buttner N, Geschwind D, Jen JC, Perlman S, Pulst SM, Baloh RW. Oculomotor phenotypes in autosomal dominant ataxias. Arch Neurol. 1998;55:1353–1357. doi: 10.1001/archneur.55.10.1353. PubMed DOI

Kerber KA, Jen JC, Perlman S, Baloh RW. Late-onset pure cerebellar ataxia: differentiating those with and without identifiable mutations. J Neurol Sci. 2005;238:41–45. doi: 10.1016/j.jns.2005.06.006. PubMed DOI

Rufa A, Federighi P. Fast versus slow: different saccadic behavior in cerebellar ataxias. Ann N Y Acad Sci. 2011;1233:148–154. doi: 10.1111/j.1749-6632.2011.06126.x. PubMed DOI

Pretegiani E, Piu P, Rosini F, Federighi P, Serchi V, Tumminelli G, Dotti MT, Federico A, Rufa A. Anti-saccades in cerebellar ataxias reveal a contribution of the cerebellum in Executive functions. Front Neurol. 2018;9:274. doi: 10.3389/fneur.2018.00274. PubMed DOI PMC

Ghasia FF, Wilmot G, Ahmed A, Shaikh AG. Strabismus and micro-opsoclonus in Machado-Joseph disease. Cerebellum (London, England) 2016;15:491–497. doi: 10.1007/s12311-015-0718-0. PubMed DOI

Caspi A, Zivotofsky AZ, Gordon CR. Multiple saccadic abnormalities in spinocerebellar ataxia type 3 can be linked to a single deficiency in velocity feedback. Invest Ophthalmol Vis Sci. 2013;54:731–738. doi: 10.1167/iovs.12-10689. PubMed DOI

Lemos J, Novo A, Duque C, Castelhano J, Eggenberger E, Januário C. "Pinball" intrusions in spinocerebellar ataxia type 3. Neurology. 2018;90:36–37. doi: 10.1212/wnl.0000000000004772. PubMed DOI

Gordon CR, Zivotofsky AZ, Caspi A. Impaired vestibulo-ocular reflex (VOR) in spinocerebellar ataxia type 3 (SCA3): bedside and search coil evaluation. J Vestib Res Equilibrium Orientation. 2014;24:351–355. doi: 10.3233/ves-140527. PubMed DOI

Geisinger D, Elyoseph Z, Zaltzman R, Mintz M, Gordon CR. Angular vestibulo ocular reflex loss with preserved saccular function in Machado-Joseph disease. J Neurol Sci. 2021;424:117393. doi: 10.1016/j.jns.2021.117393. PubMed DOI

Ribeiro RS, Pereira MM, Pedroso JL, Braga-Neto P, Barsottini OG, Manzano GM. Cervical and ocular vestibular evoked potentials in Machado-Joseph disease: Functional involvement of otolith pathways. J Neurol Sci. 2015;358:294–298. doi: 10.1016/j.jns.2015.09.013. PubMed DOI

Takegoshi H, Murofushi T. Vestibular evoked myogenic potentials in patients with spinocerebellar degeneration. Acta Otolaryngol. 2000;120:821–824. doi: 10.1080/000164800750061660. PubMed DOI

Christova P, Anderson JH, Gomez CM. Impaired eye movements in presymptomatic spinocerebellar ataxia type 6. Arch Neurol. 2008;65:530–536. doi: 10.1001/archneur.65.4.530. PubMed DOI

Takeichi N, Fukushima K, Sasaki H, Yabe I, Tashiro K, Inuyama Y. Dissociation of smooth pursuit and vestibulo-ocular reflex cancellation in SCA-6. Neurology. 2000;54:860–866. doi: 10.1212/wnl.54.4.860. PubMed DOI

Gomez CM, Thompson RM, Gammack JT, Perlman SL, Dobyns WB, Truwit CL, Zee DS, Clark HB, Anderson JH. Spinocerebellar ataxia type 6: gaze-evoked and vertical nystagmus, Purkinje cell degeneration, and variable age of onset. Ann Neurol. 1997;42:933–950. doi: 10.1002/ana.410420616. PubMed DOI

Matsuda S, Matsumoto H, Furubayashi T, Fukuda H, Emoto M, Hanajima R, Tsuji S, Ugawa Y, Terao Y. Top-down but not bottom-up visual scanning is affected in hereditary pure cerebellar ataxia. PloS one. 2014;9:e116181. doi: 10.1371/journal.pone.0116181. PubMed DOI PMC

Shaikh AG, Marti S, Tarnutzer AA, Palla A, Crawford TO, Straumann D, Taylor AM, Zee DS. Gaze fixation deficits and their implication in ataxia-telangiectasia. J Neurol Neurosurg Psychiatry. 2009;80:858–864. doi: 10.1136/jnnp.2008.170522. PubMed DOI

Shaikh AG, Marti S, Tarnutzer AA, Palla A, Crawford TO, Straumann D, Carey JP, Nguyen KD, Zee DS. Ataxia telangiectasia: a "disease model" to understand the cerebellar control of vestibular reflexes. J Neurophysiol. 2011;105:3034–3041. doi: 10.1152/jn.00721.2010. PubMed DOI

Bremova T, Krafczyk S, Bardins S, Reinke J, Strupp M. Vestibular function in patients with Niemann-Pick type C disease. J Neurol. 2016;263:2260–2270. doi: 10.1007/s00415-016-8247-4. PubMed DOI

Solomon D, Winkelman AC, Zee DS, Gray L, Büttner-Ennever J. Niemann-Pick type C disease in two affected sisters: ocular motor recordings and brain-stem neuropathology. Ann N Y Acad Sci. 2005;1039:436–445. doi: 10.1196/annals.1325.041. PubMed DOI

Moreno-Ajona D, Álvarez-Gómez L, Manrique-Huarte R, Rivas E, Martínez-Vila E, Pérez-Fernández N. VEMPs and dysautonomia assessment in definite cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS): a case series study. Cerebellum. 2021;20(5):717–23. 10.1007/s12311-019-01061-1. PubMed

Yacovino DA, Zanotti E, Hain TC. Is cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) a vestibular ganglionopathy? J Int Adv Otol. 2019;15:304–308. doi: 10.5152/iao.2019.7068. PubMed DOI PMC

Rey-Martinez J, Batuecas-Caletrio A, Matino E, Trinidad-Ruiz G, Altuna X, Perez-Fernandez N. Mathematical methods for measuring the visually enhanced vestibulo-ocular reflex and preliminary results from healthy subjects and patient groups. Front Neurol. 2018;9:69. doi: 10.3389/fneur.2018.00069. PubMed DOI PMC

Quantitative Oculomotor Assessment in Hereditary Ataxia: Systematic Review and Consensus by the Ataxia Global Initiative Working Group on Digital-motor Biomarkers