TY - JOUR
T1 - A novel eye-movement impairment in multiple sclerosis indicating widespread cortical damage
AU - Nij Bijvank, Jenny A.
AU - Hof, Sam N.
AU - Prouskas, Stefanos E.
AU - Schoonheim, Menno M.
AU - Uitdehaag, Bernard M. J.
AU - van Rijn, Laurentius J.
AU - Petzold, Axel
N1 - Funding Information: J.A.N.B. reports no competing interests. S.N.H. reports no competing interests. S.P. is supported by a research grant from the Dutch MS Research Foundation. M.M.S. serves on the Editorial Boards of Neurology and Frontiers in Neurology, receives research support from the Dutch MS Research Foundation, ARSEP, Amsterdam Neuroscience and ZonMW, and has received compensation for consulting services or speaker honoraria from Atara Biotherapeutics, Biogen, Celgene/Bristol Meyers Squibb, Sanofi-Genzyme, MedDay and Merck. B.M.J.U. has received consultancy fees from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche and Teva. L.J.v.R. reports no competing interests. A.P. reports personal fees from Novartis, Heidelberg Engineering and Zeiss, grants from Novartis outside the submitted work, and is part of the steering committee of the OCT multiple sclerosis study, which is sponsored by Novartis and the Angio-OCT steering committee, which is sponsored by Zeiss. He does not receive compensation for these activities Publisher Copyright: © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.
PY - 2023/6/1
Y1 - 2023/6/1
N2 - In multiple sclerosis, remyelination trials have yet to deliver success like that achieved for relapse rates with disease course modifying treatment trials. The challenge is to have a clinical, functional outcome measure. Currently, there are none that have been validated, other than visual evoked potentials in optic neuritis. Like vision, quick eye movements (saccades) are heavily dependent on myelination. We proposed that it is possible to extrapolate from demyelination of the medial longitudinal fasciculus in the brainstem to quantitative assessment of cortical networks governing saccadic eye movements in multiple sclerosis. We have developed and validated a double-step saccadic test, which consists of a pair of eye movements towards two stimuli presented in quick succession (the demonstrate eye movement networks with saccades protocol). In this single-centre, cross-sectional cohort study we interrogated the structural and functional relationships of double-step saccades in multiple sclerosis. Data were collected for double-step saccades, cognitive function (extended Rao's Brief Repeatable Battery), disability (Expanded Disability Status Scale) and visual functioning in daily life (National Eye Institute Visual Function Questionnaire). MRI was used to quantify grey matter atrophy and multiple sclerosis lesion load. Multivariable linear regression models were used for analysis of the relationships between double-step saccades and clinical and MRI metrics. We included 209 individuals with multiple sclerosis (mean age 54.3 ± 10.5 years, 58% female, 63% relapsing-remitting multiple sclerosis) and 60 healthy control subjects (mean age 52.1 ± 9.2 years, 53% female). The proportion of correct double-step saccades was significantly reduced in multiple sclerosis (mean 0.29 ± 0.22) compared to controls (0.45 ± 0.22, P < 0.001). Consistent with this, there was a significantly larger double-step dysmetric saccadic error in multiple sclerosis (mean vertical error -1.18 ± 1.20°) compared to controls (-0.54 ± 0.86°, P < 0.001). Impaired double-step saccadic metrics were consistently associated with more severe global and local grey matter atrophy (correct responses-cortical grey matter: β = 0.42, P < 0.001), lesion load (vertical error: β = -0.28, P < 0.001), progressive phenotypes, more severe physical and cognitive impairment (correct responses-information processing: β = 0.46, P < 0.001) and visual functioning. In conclusion, double-step saccades represent a robust metric that revealed a novel eye-movement impairment in individuals with multiple sclerosis. Double-step saccades outperformed other saccadic tasks in their statistical relationship with clinical, cognitive and visual functioning, as well as global and local grey matter atrophy. Double-step saccades should be evaluated longitudinally and tested as a potential novel outcome measure for remyelination trials in multiple sclerosis.
AB - In multiple sclerosis, remyelination trials have yet to deliver success like that achieved for relapse rates with disease course modifying treatment trials. The challenge is to have a clinical, functional outcome measure. Currently, there are none that have been validated, other than visual evoked potentials in optic neuritis. Like vision, quick eye movements (saccades) are heavily dependent on myelination. We proposed that it is possible to extrapolate from demyelination of the medial longitudinal fasciculus in the brainstem to quantitative assessment of cortical networks governing saccadic eye movements in multiple sclerosis. We have developed and validated a double-step saccadic test, which consists of a pair of eye movements towards two stimuli presented in quick succession (the demonstrate eye movement networks with saccades protocol). In this single-centre, cross-sectional cohort study we interrogated the structural and functional relationships of double-step saccades in multiple sclerosis. Data were collected for double-step saccades, cognitive function (extended Rao's Brief Repeatable Battery), disability (Expanded Disability Status Scale) and visual functioning in daily life (National Eye Institute Visual Function Questionnaire). MRI was used to quantify grey matter atrophy and multiple sclerosis lesion load. Multivariable linear regression models were used for analysis of the relationships between double-step saccades and clinical and MRI metrics. We included 209 individuals with multiple sclerosis (mean age 54.3 ± 10.5 years, 58% female, 63% relapsing-remitting multiple sclerosis) and 60 healthy control subjects (mean age 52.1 ± 9.2 years, 53% female). The proportion of correct double-step saccades was significantly reduced in multiple sclerosis (mean 0.29 ± 0.22) compared to controls (0.45 ± 0.22, P < 0.001). Consistent with this, there was a significantly larger double-step dysmetric saccadic error in multiple sclerosis (mean vertical error -1.18 ± 1.20°) compared to controls (-0.54 ± 0.86°, P < 0.001). Impaired double-step saccadic metrics were consistently associated with more severe global and local grey matter atrophy (correct responses-cortical grey matter: β = 0.42, P < 0.001), lesion load (vertical error: β = -0.28, P < 0.001), progressive phenotypes, more severe physical and cognitive impairment (correct responses-information processing: β = 0.46, P < 0.001) and visual functioning. In conclusion, double-step saccades represent a robust metric that revealed a novel eye-movement impairment in individuals with multiple sclerosis. Double-step saccades outperformed other saccadic tasks in their statistical relationship with clinical, cognitive and visual functioning, as well as global and local grey matter atrophy. Double-step saccades should be evaluated longitudinally and tested as a potential novel outcome measure for remyelination trials in multiple sclerosis.
KW - cognitive dysfunction
KW - eye movements
KW - grey matter atrophy
KW - multiple sclerosis
KW - neuro-ophthalmology
UR - http://www.scopus.com/inward/record.url?scp=85160965499&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/brain/awac474
DO - https://doi.org/10.1093/brain/awac474
M3 - Article
C2 - 36535900
SN - 0006-8950
VL - 146
SP - 2476
EP - 2488
JO - Brain
JF - Brain
IS - 6
ER -