Inclusion Criteria:

1. All groups:

• - Age >18 years old.

2. Patients with Multiple Sclerosis:

• - Diagnosis of Multiple Sclerosis, according to the last revisions of the McDonald Criteria (2017) 3.

Patients with other neuroinflammatory diseases:

• - Diagnosis of Neuromyelitis optica spectrum disorder or Myelin oligodendrocyte glycoprotein antibody disease or other neuroinflammatory disorders other than Multiple Sclerosis.

Exclusion Criteria:

1. All groups:

• - Inability to undergo Optical Coherence Tomography (OCT) and/or retinal vessel imaging (e.g. severe nystagmus that prevents eye fixation on both eyes) - Presence of any ocular pathology that may interfere with the validity of the OCT/retinal vessel analysis (cataracts, glaucoma, history of refractive defects >6 D etc.).

• - Pregnancy and Lactation.

2. Healthy Controls. - History of other neurological conditions: participants with a history of other significant neurological conditions that might interfere with the assessment or interpretation of the signs and symptoms will be excluded (e.g. confirmed Stroke, Acute disseminated encephalomyelitis, Chronic inflammatory Demyelinating Disease, Polyneuropathy, etc.)

Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) and represents one of the most common neurological disorders affecting young adults worldwide and often leads to significant disability over time. While MS typically presents with recurrent neurological symptoms known as relapses, most patients also experience progressive neurological deterioration independent of relapses, referred to as progression independent of relapse activity (PIRA). PIRA is a major contributor to long-term disability and represents a significant challenge in the management of MS. Early identification of patients at high risk to develop PIRA is crucial for therapeutic decisions and testing treatment efficacy, highlighting the urgent need for accurate predictive markers of progression in MS. The primary objective of this longitudinal, observational, prospective, single center study is to investigate the predictive value of various retinal markers in predicting PIRA in MS patients. The study assesses several easily obtained, non-invasive retinal measures:

• - Neuroaxonal loss in the retina: This serves as a marker of neurodegeneration in the CNS.

It will be assessed by measuring the volume of the ganglion cell-inner plexiform layer and the thickness of the peripapillary retinal nerve fiber layer using optical coherence tomography (OCT).

• - Neuroinflammation in the retina: This will be assessed by evaluating thickening of other retinal layers in OCT, particularly the inner nuclear layer.

• - Fixation instability of the patients: This serves as a marker of global neuronal dysfunction in the CNS.

It will be measured using Scanner Laser Ophthalmoscopy-OCT.

• - Structural changes of the retinal vessels: Particularly, the arteriolar and venular diameters will be assessed.

This serves as a marker of systemic microvascular health and will be measured using static retinal vessel analysis.

• - Functional/perfusional changes of the retinal vessels: For a subgroup of patients, this will be evaluated using OCT-angiography, and/or dynamic retinal vessel analysis, and/or laser speckle flowgraphy.

These measures provide insights into the functional and perfusional changes of the retinal vessels. As secondary objectives, this study comprises:

• - Comparison with other biomarkers of neuroaxonal damage to determine whether the retinal markers are independent and/or stronger predictors of PIRA.

• - Comparison with the retinal markers of Healthy Controls and patients with other neuroinflammatory diseases of the CNS to understand the differences in mechanisms of damage.

• - Investigating the associations among the various retinal measures to understand the relationship between neuroaxonal loss, functional deficits and vascular changes in MS.

Data will be collected at baseline and annually over up to 5 years, or for some MS patients, up to 10 years, to evaluate changes in retinal markers and their correlation with disease progression. This comprehensive assessment will provide valuable insights into the utility of retinal markers in predicting PIRA and their relationship with disease severity and progression in MS.

Arms

: Healthy Controls

Healthy control subjects without neurological diseases

: Patients with Multiple Sclerosis

: Patients with other neuroinflammatory diseases of the CNS

Interventions

Diagnostic Test: - Optical coherence tomography (OCT)

OCT is used to measure: peripapillary retinal nerve fiber layer (mean thickness in μm) ganglion cell-inner plexiform layer (volume in mm^3 and mean thickness in μm) other retinal layers (inner nuclear layer, outer plexiform layer, outer nerve layer; volumes in mm^3 and mean thickness in μm). The "scanner laser ophthalmoscopy"-function of the OCT device is used to continuously record the exact location of each participant's fixation point in relation to their fovea and thereby allows the assessment of the fixation instability. In a subgroup of participants, the "angiography"-module of the OCT device is used to image the retinal blood flow and thereby allows to measure the vascular area density of the superficial retinal capillary plexus and deep retinal capillary plexus.

Diagnostic Test: - Static retinal vessel analyzer

Static retinal vessel analyzer is used to determine: central retinal arteriolar diameter equivalents (in μm) central retinal venular diameter equivalents (in μm) arteriolar-to-venular diameter ratio

Diagnostic Test: - Dynamic retinal vessel analyzer

In a subgroup of participants, the dynamic retinal vessel analyzer is used to determine the arteriolar ficker light-induced dilatation, venular ficker light-induced dilatation, and Arteriolar constriction, measured in % dilatation in comparison to baseline.

Diagnostic Test: - Laser speckle flowgraphy system

In a subgroup of participants, the laser speckle flowgraphy system is used to measure the relative ocular blood flow as expressed in arbitary units of Mean Blur Rate.

Other: - Questionnaire

All study participants will be asked to fill in a questionnaire with various questions regarding existing eye diseases, other diseases (including vascular diseases/risk factors), and daily physical activity that could influence the results of the retinal examinations. Physical activity will be assessed using an adapted form of the standardized Global Physical Activity Questionnaire.