A novel eye-movement impairment in multiple sclerosis indicating wide-spread cortical damage.

In multiple sclerosis remyelination trials have yet to deliver success alike to what has been achieved for relapse rates with disease course modifying treatment trials. The challenge is to have a clinical, functional outcome measure. Currently there are none which are validated, other than visual evoked potentials in optic neuritis. Like vision, quick eye movements (saccades) are heavily dependent on myelination. We hypothesised 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 (DEMoNS 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 (EDSS) and visual functioning in daily life (NEI-VFQ-25). 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 significantly larger double-step dysmetric saccadic error in multiple sclerosis (mean vertical error -1.18 ± 1.20 degrees) compared to controls (-0.54 ± 0.86 degrees, 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 which revealed a novel eye movement impairment in individuals with multiple sclerosis. Double-step saccades outperformed other saccadic task 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.