Multiple sclerosis frequently compromises central white matter pathways, producing significant neurological disability across motor, visual, and cognitive domains. Consequently, routine screening for intellectual slowing has become standard in long-term disease monitoring. However, clinicians often overlook how brainstem ocular motor disruptions confound these diagnostic evaluations. When interpreting cognitive testing in MS, clinicians must carefully distinguish between genuine executive decline and saccadic eye movement abnormalities that artificially depress visual test performance.

Oculomotor Pathways and Cognitive Testing in MS

Internuclear ophthalmoplegia represents a distinctive brainstem manifestation encountered in demyelinating disease. This condition stems from focal inflammatory lesions within the medial longitudinal fasciculus, which coordinates conjugate horizontal gaze. Specifically, demyelination uncouples the abducens nucleus in the pons from the contralateral oculomotor nucleus in the midbrain. As a result, the ipsilateral eye exhibits slowed adduction saccades during lateral excursion. Simultaneously, the abducting eye displays dissociated horizontal nystagmus.

Because reading and visual scanning require coordinated binocular saccades, internuclear ophthalmoplegia disrupts ocular tracking. Neurologists commonly deploy instruments like the Symbol Digit Modalities Test and Concept Shifting Test to assess information processing speed. Unfortunately, these psychometric assessments depend heavily upon rapid saccadic fixations across the visual field. Therefore, an individual experiencing adduction lag cannot navigate between visual symbols with normal velocity. When patients struggle during timed visual tasks, examiners frequently misattribute this slower execution to central cognitive decline. Clinicians must recognize that medial longitudinal fasciculus demyelination impedes ocular kinematics rather than cortical processing efficiency. Understanding this neuroanatomical intersection remains vital for avoiding clinical misinterpretations that inappropriately alter treatment plans.

Methodological Rigour of the DEMoNS Protocol

To establish the true influence of eye movement pathology, investigators utilized the DEMoNS infrared oculography protocol. This sophisticated diagnostic methodology delivers objective, quantitative measurements of horizontal saccadic performance. Rather than relying on subjective clinical confrontation maneuvers, the research team analyzed versional dysconjugacy indices across specific gaze angles. Specifically, they recorded the area under the saccadic trajectory curve alongside the ratio of peak velocity to amplitude. These kinematic markers enabled precise detection of both overt and subclinical internuclear ophthalmoplegia.

The investigators recruited 197 people with multiple sclerosis, conducting comprehensive visual and auditory neuropsychological evaluations. Furthermore, researchers reassessed a longitudinal cohort of 102 individuals after six years. To isolate the specific contribution of ocular dysconjugacy, the statistical models adjusted for critical neurostructural and clinical confounders. These variables included disease duration, physical disability scores, normalized cortical grey matter volume, and thalamic volume. By incorporating advanced volumetric neuroimaging data, the investigators ensured that underlying cerebral atrophy did not obscure the true relationship between oculomotor performance and psychometric outcomes. Consequently, this rigorous methodological framework provided definitive clarity regarding how saccadic slowing directly impacts timed psychometric scores.

Key Findings: Differentiating Ocular Deficits from True Cognitive Decline

The investigation yielded critical distinctions between mild and advanced eye movement deficits. Interestingly, the mere presence of mild internuclear ophthalmoplegia did not correlate with reduced visual cognitive performance after controlling for disease characteristics. In contrast, severe right-sided internuclear ophthalmoplegia during leftward gaze exerted a profound, statistically significant negative influence. Every 0.1 increment in the versional dysconjugacy peak velocity amplitude ratio during leftward excursion caused a -0.08 reduction in Symbol Digit Modalities Test Z-scores. Similarly, the same kinematic shift produced a -0.14 decline in Concept Shifting Test Z-scores.

These findings highlight an essential directional asymmetry in visual scanning tests. Because standard Western cognitive batteries require left-to-right visual scanning, returning to the left margin requires rapid leftward saccades. Severe adduction weakness in the right eye impedes these crucial leftward movements, prolonging search intervals between visual stimuli. Longitudinal analyses further demonstrated that patients developing new right-sided deficits suffered acute drops in Concept Shifting Test performance. However, these longitudinal associations attenuated after full covariate adjustment, underscoring how concurrent brain volume changes parallel disease evolution. Ultimately, cross-sectional data confirm that severe ocular dysconjugacy mechanically slows test execution independent of genuine cortical capability.

Visual versus Auditory Cognitive Testing Paradigms

The selective vulnerability of visual batteries underscores the mechanical nature of this psychometric impairment. Notably, the study revealed that internuclear ophthalmoplegia produced no negative impact on the Paced Auditory Serial Addition Test. Because this auditory test measures processing speed and working memory entirely through spoken stimuli, ocular motor mechanics play no role in task completion. Therefore, patients with severe saccadic slowing achieved scores consistent with their true intellectual capabilities on auditory tasks.

This striking discrepancy between visual and auditory scores offers profound diagnostic utility for clinicians. When a patient exhibits marked deterioration on visual assessments but maintains stable auditory processing, examiners must suspect underlying oculomotor impairment. In contrast, generalized neurodegenerative progression typically degrades performance across all sensory modalities simultaneously. Moreover, the Concept Shifting Test proved even more sensitive to ocular dysconjugacy than the Symbol Digit Modalities Test. The spatial switching requirements of the Concept Shifting Test demand frequent multi-directional saccades across broader visual angles. Consequently, mechanical gaze restrictions compound the time penalties incurred during testing. Recognizing how specific psychometric formats interact with ocular kinematics allows clinicians to select optimal assessment batteries for each patient.

Practical Clinical Strategies for Neurologists and Clinicians

These empirical insights carry urgent practical implications for routine neurological management. Clinicians frequently use visual screening scores to determine disease progression, vocational fitness, and disease-modifying therapy efficacy. However, misinterpreting ocular dysconjugacy as cognitive worsening can lead to inappropriate changes in therapeutic regimens or unnecessary patient anxiety. Therefore, clinicians must thoroughly assess ocular motility before conducting any timed visual cognitive assessment.

When practitioners identify severe internuclear ophthalmoplegia or reading fatigue, they should adopt alternative neuropsychological evaluation strategies. For example, clinicians can substitute auditory processing batteries, such as the Paced Auditory Serial Addition Test or the Auditory Consonant Trigrams test. Alternatively, teams may utilize voice-activated digital adaptations that minimize demanding visual search trajectories. Furthermore, multidisciplinary collaboration between neurologists, neuro-ophthalmologists, and neuropsychologists ensures accurate diagnostic synthesis. If visual batteries remain unavoidable, clinicians must interpret depressed scores with extreme caution, documenting oculomotor status as an active confounder. By recognizing that impaired saccades mimic mental sluggishness, healthcare providers can protect people with multiple sclerosis from inaccurate diagnoses and deliver truly tailored care.

What is internuclear ophthalmoplegia, and why does it occur in multiple sclerosis?

Internuclear ophthalmoplegia is a conjugate horizontal gaze disorder caused by demyelinating lesions within the medial longitudinal fasciculus. This pathway coordinates communication between the brainstem abducens and oculomotor nuclei. As a result, the adducting eye slows or fails to move inward during lateral gaze, frequently producing diplopia and blurred vision.

Why does right-sided eye movement impairment specifically lower visual test scores?

Standard visual tests require reading and scanning printed sheets from left to right. Returning quickly to the left margin requires rapid leftward saccades. Because right-sided internuclear ophthalmoplegia impairs adduction during leftward gaze, affected individuals lose crucial seconds repositioning their eyes, which artificially lowers their scores on timed visual tests.

How should clinicians assess cognitive function in patients with severe ocular deficits?

Clinicians should bypass rapid visual scanning tools and implement auditory processing batteries, such as the Paced Auditory Serial Addition Test. Alternatively, clinicians can perform specialized neuro-ophthalmological evaluations to quantify oculomotor dysconjugacy, ensuring that subsequent cognitive assessments accurately reflect underlying intellectual processing rather than brainstem ocular motor slowing.

Disclaimer: This content is for informational and educational purposes only and should not be considered as medical advice. Healthcare professionals should make clinical decisions based on their independent clinical judgement and patient assessment. Refer to the latest local and national guidelines for clinical practice.

References

1. Hof SN et al. What if it is the eyes? The effect of eye movement disorders on cognitive testing in MS. J Neurol. 2026 Jun 02. doi: 10.1007/s00415-026-13905-y. PMID: 42228174.
2. Benedict RHB, Amato MP, Boringa J, et al. Brief International Cognitive Assessment for MS (BICAMS): international standards for validation. BMC Neurol. 2012;12:87. doi: 10.1186/1471-2377-12-87.
3. Frohman TC, Frohman EM, O’Suilleabhain P, et al. Accuracy of clinical detection of INO as validated by infrared oculography. J Neurol Sci. 2003;207(1-2):95-101. doi: 10.1016/s0022-510x(02)00401-4.