Table 1.

Ocular structures and their associated pathological changes in Multiple Sclerosis.

Ocular and Functional Biomarker	Diagnostic Modality and Key Findings
Tears	• Elevated levels of alpha-1 antichymotrypsin [49] are detected in the tears of Multiple Sclerosis (MS) patients, accompanied by higher grades of conjunctival impression cytology, increased ocular surface disease index scores, and lower tear break-up time grades and Schirmer test scores [52, 53].
Cornea	• Corneal sensitivity and tear function decline in neurodegenerative diseases, evidenced by reduced corneal nerve fibre and nerve branch density in MS patients [55, 56]. Additionally, higher total corneal immune cell density, particularly in patients with MS and RRMS [58], alongside increased immune cell near-nerve distance, distinguishes MS subtypes from healthy controls [58].
Pupil	• Cognitive fatigue is linked to a shortened pupil response time, particularly evident in MS patients under high cognitive load conditions [59, 61].
Retina	Fundoscopy • Optic neuritis frequently emerges as an early indicator of MS, manifesting in around 50% patients [37, 38]. Scanning Laser Ophthalmoscopy (SLO) • MS patients show thinner retinal arteries and veins, notably in the nasal inferior quadrant [43], and SLO images are useful for analysing microcystic macular oedema and peripheral retinal blood vessels when OCT is unavailable [42]. Optical Coherence Tomography (OCT) Retinal Nerve Fibre Layer • RNFL thinning is prominent in MS, with affected eyes displaying a substantial average reduction of 46% (P < 0.01), and a specific 28% reduction when compared to unaffected eyes. Additionally, when comparing unaffected eyes to control eyes, there is an average RNFL reduction of 26% (P < 0.01) [26, 27]. Peripapillary retinal nerve fibre layer (pRNFL) and macular ganglion cell layer, and inner plexiform layer (GCIPL) also demonstrated significant atrophy [13]. Ganglion Cell and Inner Plexiform Layer (GCIPL) • GCIPL is consistently reduced across all MS subtypes, with a notably more significant reduction in secondary progressive MS (SPMS) relative to relapsing-remitting MS (RRMS) [24, 25]. Total macular volume also emerges as a differentiating parameter, being more reduced in SPMS and primary progressive MS (PPMS) relative to RRMS eyes [27]. GCIPL is identified as a valuable predictor of visual impairment and disability accumulation in early relapsing MS. [14, 20–23] Optical Coherence Tomography-Angiography (OCTA) In MS patients, both with or without optic neuritis, there is a significant decrease in the superficial vascular complex (SVC) and peripapillary vessel densities compared to the control group [36]. VEP • VEP latency was significantly associated with reduced whole brain volume, grey matter volume, and white matter volume [65]
Choroid	Swept-source OCT (SS-OCT) • The outer macular ring of the choroid was found to be significantly reduced in MS patients relative to healthy controls [22]. OCT • Subfoveal choroidal thickness is diminished in correlation with prolonged disease duration [32]. However, findings by Masala et al. in 2022 did not reveal a significant difference in choroidal thickness compared to control eyes [33].
Visual acuity and sensitivity	Low contrast letter acuity (LCLA) • A significant reduction in LCLA is evident in MS patients compared to disease-free controls [68, 69], and deficiencies in LCLA and contrast sensitivity are linked to diminished retinal nerve fibre layer (RNFL) thickness [73, 74].
Stereopsis/Depth Perception	• Depth perception may be significantly impaired in MS patients due to lesions in Brodmann Areas 17 and 18 [80]
Eye Movements	• Patients with internuclear ophthalmoplegia (INO) demonstrate increased peak velocity compared to normal controls [86, 87]. The disparity in peak velocity between abducting and adducting eyes during saccades can be measured using infrared oculography, scleral search coil, or video oculography-based techniques [85].