Multiple Sclerosis (MS) is one of the most common diseases of the central nervous system. Worldwide, about 2.8 million people are currently affected by MS (as of 202021). MS often begins between the ages of 20 and 40 and affects more women than men21. The measurement of eye and pupil movement has an important prognostic potential.

Multiple Sclerosis (MS) is a neurological inflammatory disorder where the heavily myelinated regions of the nervous system including the optic nerves, cerebellum, brainstem and spinal cord, are affected.The assessment of visual pathways is critical, considering that MS can affect multiple components of the visual pathway, including optic nerves, uvea, retina and occipital cortex.

Optic neuritis is one of the most common forms of presentation in multiple sclerosis: in 25% of new MS cases optic neuritis is the initial clinical event. Moreover, studies show that 50-70% of all patients with MS will experience optic neuritis at some stage of the condition. Optic neuritis presents with acute unilateral vision loss1 - 3. Visual field defects are present in almost all patients with optic neuritis (97.5%)1. Relative afferent pupillary defects (RAPD) occur in 96% of acute unilateral optic neuritis cases4. 

Eye movement impairments are common in all MS phenotypes, even at the earliest stages15. They have the potential of being used as structural and functional biomarkers of early cognitive deficit, and possibly help in assessing disease status and progression, as well as to serve as a functional outcome to test novel therapeutic agents for MS13.  

Two studies from the same research group in 50 MS patients found that those with abnormal eye movements were more disabled than those with normal eye movements, even though the age and duration of disease were similar in both groups16, 17. A two-year follow up study showed that patients who had abnormal eye movements remained significantly more disabled (median EDSS of 7.0) than those with normal eye movements (median EDSS of 5.0)18. MRI scans showed abnormal signals in the brain stem or cerebellum of 60% of patients with abnormal eye movements and only 28% of patients with normal eye movements. The eye-movement disorders most commonly noted in these studies were saccadic dysmetria, INO, and nystagmus18. Another study on 37 patients reported that the presence of compensatory saccades were associated with a greater MS-related disability, as measured by EDSS scores19. 

The most frequently observed eye movement disorders in MS are saccadic dysmetria (91%), INO (68%), vestibulo-ocular reflex abnormalities and gaze-evoked nystagmus (36%), fixation instability, and impaired smooth pursuit 1,5 - 10. These oculomotor dysfunctions in MS have been attributed to lesions of either the brainstem or the eye fields.

Internuclear ophthalmoplegia (INO) could potentially be a biomarker of axonal and myelin integrity in MS13. A study in 76 patients with MS showed that video-oculography can be useful to detect demyelinating process at preclinical stage by highlighting subclinical eye movement impairments even in absence of characteristic lesions visible on MRI15. 

INO is characterized by ipsilateral adduction palsy and horizontal jerk nystagmus of the contralateral eye during abduction8. It is due to a lesion within the medial longitudinal fasciculus12. In patients with MS, INO is frequently bilateral. Slowing of adducting saccades may sometimes be the only manifestation of INO8. Recording of eye movements can increase detection of slowed adduction in INO. 

Because of its close connection with ocular nerve impairment, saccadic tests are popular and frequently used to assess oculomotor function in MS7, 9. Saccadic initiation time (saccadic latency) is longer in MS patients than in healthy subjects. Saccadic peak velocity and amplitude are also decreased in MS11. 

A study in 111 patients with MS and 100 healthy controls showed that microsaccades could be an objective measurement of MS disability level and disease worsening: a greater number of microsaccades showed significant association with higher Expanded Disability Status Scale score (EDSS), nine-hole peg test, Symbol Digit Modalities Test (SMDT), and Functional Systems Scores (FSS) including brainstem, cerebellar, and pyramidal14. 

Smooth pursuit may also be an early disease marker. A study in 20 patients with clinically isolated syndrome (CIS) and in 40 patients with early MS patients showed that smooth pursuit integrity is already substantially affected in both conditions. The authors concluded that low pursuit gain and increased saccadic amplitudes may be markers of disseminated pathology in CIS and in MS20.

In addition, there is a diagnostic and prognostic potential of eye tracking to assess cognitive function and disease severity in MS2,3. 

CASE EXAMPLES
Horizontal Saccades RRMS

Horizontal saccades, measured using a VR-based VOG system, in a patient with clinically diagnosed relapsing-remitting MS.

The upper panels show horizontal saccades to 10° and 20° targets. The eye position traces (red/blue) follow these steps over time (x-axis).

In a healthy subject, both eyes would make rapid, conjugate, step-like deflections closely aligned in time with the target jump.

In this patient, the adducting eye is slower and hypometric compared with the abducting eye, producing disconjugate movements characteristic of bilateral INO. The lower horizontal main-sequence plots display peak velocity (y-axis) as a function of saccade amplitude (x-axis), with the shaded band indicating the normative range. Data points for the adducting eye fall clearly below the reference band due to markedly reduced peak velocities, while abducting-eye velocities lie closer to the normal range.

braincomms MS pupils pursuit
Afferent pupillary function and smooth pursuit, measured using a VR-based VOG system, in a patient with clinically diagnosed relapsing-remitting MS.

(A) Afferent pupillary function (swinging flashlight paradigm). The top bar summarizes the relative afferent pupillary defect (RAPD) estimate. The lower plots show pupil diameter (y-axis) over time (x-axis) for the right and left pupils during alternating monocular illumination.

In a healthy response, pupil size is symmetric in light and darkness, and both pupils dilate similarly after darkening the screens, reflecting intact parasympathetic and sympathetic efferent pathways.

In this patient, illumination of the left eye produces a much smaller and less sustained constriction in both pupils, followed by a pupillary escape, whereas illumination of the right eye elicits a larger, more sustained response. This asymmetry is consistent with a left RAPD, consistent
with a history of left optic neuritis.

 

(B) Horizontal smooth pursuit. Slow and fast horizontal smooth-pursuit traces are plotted alongside the sinusoidal target trajectory.

In a healthy individual, eye traces would closely overlap the target, with minimal lag and few corrective saccades.

Here, pursuit gain is reduced: the tracking is interspersed with catch-up saccades, giving the trace a jerky appearance.

Advances in ocular motor and pupil biomarkers for neurological disorders
Coito A, Brügger D, Brémovà-Ertl T, Massatsch P, Abegg M, Weber K, Salmen A
Brain Communications, Volume 8, Issue 2, 2026, doi: 10.1093/braincomms/fcag102

REFERENCES

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  2. Dhanapalaratnam R, Markoulli M, Krishnan AV. Disorders of vision in multiple sclerosis. Clin Exp Optom. 2022;105(1):3-12. doi.org/10.1080/08164622.2021.1947745

  3. Sheehy CK, Beaudry-Richard A, Bensinger E, Theis J, Green AJ. Methods to Assess Ocular Motor Dysfunction in Multiple Sclerosis. J Neuroophthalmol. 2018;38(4):488-493.
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  4. Cox TA, Thompson HS, Corbett JJ. Relative afferent pupillary defects in optic neuritis. Am J Ophthalmol. 1981;92(5):685-690. doi.org/10.1016/S0002-9394(14)74662-8

  5. Niestroy A, Rucker JC, Leigh RJ. Neuro-ophthalmologic aspects of multiple sclerosis: Using eye movements as a clinical and experimental tool. Clin Ophthalmol. 2007;1(3):267-272.

  6. De Santi L, Lanzafame P, Spanò B, et al. Pursuit ocular movements in multiple sclerosis: a video-based eye-tracking study. Neurol Sci. 2011;32(1):67-71. doi: 10.1007/s10072-010-0395-1

  7. Dillenseger A, Weidemann ML, Trentzsch K, et al. Digital Biomarkers in Multiple Sclerosis. Brain Sci. 2021;11(11):1519. doi:10.3390/brainsci11111519

  8. Nerrant E, Tilikete C. Ocular Motor Manifestations of Multiple Sclerosis. J Neuroophthalmol. 2017;37(3):332-340. doi:10.1097/WNO.0000000000000507

  9. Tao L, Wang Q, Liu D, Wang J, Zhu Z, Feng L. Eye tracking metrics to screen and assess cognitive impairment in patients with neurological disorders. Neurol Sci Off J Ital Neurol Soc Ital Soc Clin Neurophysiol. 2020;41(7):1697-1704. doi:10.1007/s10072-020-04310-y

  10. Gil-Casas A, Piñero DP, Molina-Martin A. Binocular, Accommodative and Oculomotor Alterations In Multiple Sclerosis: A Review. Semin Ophthalmol. 2020;35(2):103-115. doi:10.1080/08820538.2020.1744671

  11. Finke C, Pech LM, Sömmer C, et al. Dynamics of saccade parameters in multiple sclerosis patients with fatigue. J Neurol. 2012;259(12):2656-2663. doi:10.1007/s00415-012-6565-8

  12. Fiester P, Baig SA, Patel J, Rao D. An Anatomic, Imaging, and Clinical Review of the Medial Longitudinal Fasciculus. J Clin Imaging Sci. 2020;10:83. doi:10.25259/JCIS_49_2020

  13. Serra A, Chisari CG, Matta M. Eye Movement Abnormalities in Multiple Sclerosis: Pathogenesis, Modeling, and Treatment. Front Neurol. 2018;9:31. doi.org/10.3389/fneur.2018.0003

  14. Sheehy CK, Beaudry-Richard A, Bensinger E, Theis J, Green AJ. Methods to Assess Ocular Motor Dysfunction in Multiple Sclerosis. J Neuro-Ophthalmol Off J North Am Neuro-Ophthalmol Soc. 2018;38(4):488-493. doi:10.1097/WNO.0000000000000734

  15. Polet K, Hesse S, Cohen M, et al. Video-oculography in multiple sclerosis: Links between oculomotor disorders and brain magnetic resonance imaging (MRI). Mult Scler Relat Disord.
    2020;40:101969. doi.org/10.1016/j.msard.2020.101969

  16. Downey DL, Stahl JS, Bhidayasiri R, et al. Saccadic and vestibular abnormalities in multiple sclerosis: sensitive clinical signs of brainstem and cerebellar involvement. Ann N Y Acad Sci.
    2002;956:438-440. doi:10.1111/j.1749-6632.2002.tb02849.x

  17. Serra A, Derwenskus J, Downey DL, Leigh RJ. Role of eye movement examination and subjective visual vertical in clinical evaluation of multiple sclerosis. J Neurol. 2003;250(5):569-575.
    doi:10.1007/s00415-003-1038-8

  18. Derwenskus J, Rucker JC, Serra A, et al. Abnormal eye movements predict disability in MS: two-year follow-up. Ann N Y Acad Sci. 2005;1039:521-523. doi:10.1196/annals.1325.058

  19. Grove CR, Wagner A, Yang VB, Loyd BJ, Dibble LE, Schubert MC. Greater Disability Is Associated with Worse Vestibular and Compensatory Oculomotor Functions in People Living with
    Multiple Sclerosis. Brain Sci. 2022;12(11):1519. doi:10.3390/brainsci12111519

  20. Lizak N, Clough M, Millist L, Kalincik T, White OB, Fielding J. Impairment of Smooth Pursuit as a Marker of Early Multiple Sclerosis. Front Neurol. 2016;7:206. doi:10.3389/fneur.2016.00206
  21. https://www.msif.org/about-ms/what-is-ms/

 

 

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