The goal of this observational study is to study the relationship between cognitive problems and problems in eye movements in Multiple Sclerosis (MS).

The main questions it aims to answer are:

• What is the correlation between eye movement parameters (VDI AUC and VDI Pv/Am, left and right) and SDMT scores in patients with MS?
• What is the number of patients with VDI AUC>1.174 and/or VDI Pv/Am>1.180 assessed by infrared oculography during prosaccades at 15 degrees left or right?
• What is the correlation between eye movement parameters (VDI AUC and VDI Pv/Am, left and right) and cognitive test scores in patients with MS?

Participants will perform specific cognitive tests and eye movements will be measured through infrared oculography.

The primary hypothesis for the study is: participants who exceed the treshold (VDI AUC>1.174 and/or VDI Pv/Am>1.180, left or right) will perform worse on cognitive tests compared to those who don't.

As previously described in the brief summary, this clinical study aims to investigate the relationship between cognitive impairment and eye movement parameters in Multiple Sclerosis (MS).

Cognitive tests

Cognitive impairment is a common symptom in patients with MS. The most affected cognitive domains are information processing speed and visual memory, but also the domains of attention, executive function, working memory, visuospatial processing and verbal memory can be affected. There are different valid screening and evaluation tools for cognitive impairment (CI) described and used in the MS field. This clinical study will use the tests of the Brief International Cognitive Assessment for MS (BICAMS).

Infrared oculography

Another common symptom in MS is problems with eye movements. An eye condition commonly seen in these patients is internuclear ophthalmoplegia (INO). It is a specific conjugate horizontal gaze disorder characterized by slowed movement of the adducting eye relative to the abducting eye in horizontal saccades, resulting from damage to the medial longitudinal fasciculus (MLF). This may lead to (transient) diplopia or 'blurring of vision', particularly during horizontal gaze. INO can be diagnosed by using infrared oculography, a noninvasive method of quantifying eye movements. Recent research indicates that eye movements can reflect certain aspects of brain function and provide insights into cognitive impairments. Therefore, this study aims to investigate the prevalence of INO in MS using infrared oculography, compare the diagnosis of INO using infrared oculography with clinical examination by a physician and lastly explore the relationship between the presence of INO and cognitive decline.

Investigational plan

The study will be a prospective observational multi-center, cross-sectional cohort study.

Patients will be recruited at the National MS Center Melsbroek (NMSC) in close collaboration with Prof. Miguel D'haeseleer (Neurology), Prof. Daphne Kos (Rehabilitation and research coordinator) and Mieke D'hooge (Neuropsychologist). At any moment in time about 80 MS patients are in a short rehabilitation admission at the National MS Centre Melsbroek. Additionally, patients will be recruited from the MS department in the neurology wing of UZ Brussels. The MS team at UZ Brussel comprises Prof. Dr. Ir. Guy Nagels (Head of Departement), Prof. Dr. Miguel D'Haeseleer, Prof. Dr. Marie D'Hooghe, Dr. Stéphanie Hostenbach, and Annick Van Merhaegen.

When patients fulfill the inclusion criteria and give active informed consent, they will be contacted by phone to schedule their visit. If patients would like more information they can contact the investigator by phone.

During their visit, patients will undergo cognitive testing and infrared oculography. The investigators will start with the cognitive assessments, which include the BICAMS and the PASAT. The BICAMS is a 15-minute-long neuropsychological evaluation battery (9). The PASAT typically lasts 15-20 minutes. Altogether, the cognitive testing will take around 40 minutes. Following this, the infrared oculography measurements will be done. According to a study that provided a standardized and reproducible protocol for infrared oculography measurements, the total experiment duration was 21 minutes, excluding instructions. Thus, the oculography process will take roughly 30 minutes. To ensure enough time for each patient and avoid rushing, the total duration of the visit will be approximately 1,5 hours per patient.

After their first visit, there is no need for a follow-up. Should any questions arise afterward, they are welcome to reach out to us via phone or email.

Patients may withdraw from the study at any time for any reason.

Quality assurance plan/ data checks

After measurement, the variables that are needed for analysis have to be imported into Matlab. The analysis will be automated and checked for quality issues by researchers. To pass quality control, at least 50% of prosaccades at 15 degrees must be captured.

Source data verification To ensure accuracy and completeness, two researchers will evaluate and verify the source data. Any discrepancies will be documented and managed in line with the Good Clinical Practice guidelines.

Data dictionary

INO will be quantified through eye movement parameters Cognitive scores will be recorded.

Clinical parameters that will be recorded:

• EDSS score, a numeric value between 0 and 10
• Age, a numeric value > 18
• Disease duration, a numeric value (years)
• Sex, female or male

Standard Operating Procedures (SOPs)

Only the investigators will be responsible for data entry. As previously described, the analysis will be automated and checked for quality issues by researchers.

All data will be collected, encrypted, analyzed and stored on a dedicated sharepoint using the One Drive cloud service provided by the VUB, secured by password protection. All files from this server will be removed 5 years after the end of publication of the research results.

Sample size assessment

The investigators will use a one-tailed alpha of 0.05 (as the hypothesis is that worse visual scanning will relate to worse cognitive scores), a power of 0.8 (0.2 Type II error rate), and a correlation coefficient of 0.4 - corresponding to 16% of the variance of the SDMT being explained by eyesight - which leads to a sample size of 37. To be on the safe side and to account for possible data quality issues, the investigators will recruit N = 50 patients in this study.

Plan for missing data

In the exceptional case that some parameters are missing for some patients, those patients will be excluded from the specific analyses for which these datapoints are needed.

Statistical analyses plan

The correlation between eye movement parameters (VDI Pv/Am and VDI AUC, left and right), and cognitive test scores will be analyzed through Spearman correlation analysis.

Inclusion criteria:

• Diagnosed with clinically definite multiple sclerosis according to the 2017 McDonald criteria
• At least 18 years old
• Combined vision with optimal correction > 0,6 on Snellen Visual Acuity Test.
• Providing informed consent.

Exclusion criteria:

• Major medical or psychiatric pathology that potentially affects cognitive functioning.
• A score higher than 63 on the Fatigue Scale for Motor and Cognitive Functions is categorized as severe fatigue
• Start or switch in immunomodulatory treatment within three months before inclusion.
• Less than 3 months post exacerbation.
• Refusing informed consent.

MS patients recruited from the neurology department of UZ Brussels and NMSC Melsbroek in Belgium