Ocular Inflammation and Immune-Mediated Eye Disease

EAE is the most widely used preclinical model of MS and autoimmune optic neuritis, but its standard outcome measurement – the EAE clinical score based on tail and limb paresis – reflects spinal cord disease rather than optic nerve or retinal involvement. Optic neuritis occurs in approximately 50% of MS patients and is the presenting symptom in 25% of cases; in EAE, demyelinating lesions in the optic nerve and corresponding RGC death are well-documented but rarely quantified functionally in the context of individual experimental studies. The result is that immunological interventions are routinely evaluated by motor disability alone, potentially overlooking optic nerve-specific treatment benefits or optic nerve-specific treatment failures.

Visual evoked potentials (VEPs) provide a direct electrophysiological readout of optic nerve conduction velocity and are widely used in clinical MS diagnosis. In rodents, however, VEP recording requires anaesthesia and cortical electrode placement, limiting the frequency of measurement and adding procedural confounds in longitudinal studies. The OptoDrum resolves these limitations: it measures visual acuity and contrast sensitivity via the subcortical optomotor reflex (a retina-to-brainstem pathway that traverses the optic nerve and is therefore sensitive to optic nerve demyelination and RGC loss) in awake, freely moving mice without anaesthesia, surgical access, or specialist electrophysiology infrastructure. Results are obtained in approximately four minutes per animal and can be collected at any time point throughout the EAE disease course in the same animals being scored for motor disability, providing a parallel and independent functional dimension at no additional welfare cost.

Scope note for EAE researchers: the OptoDrum measures a subcortical reflex pathway (retina through nucleus of the optic tract), not a cortically processed visual response. Cortical visual pathway involvement in EAE models – including visual cortex lesions and cortical visual processing deficits – is not captured by OptoDrum; VEPs or AcuiSee (Striatech's operant conditioning-based visual acuity system, which requires cortical processing) are more appropriate instruments for those endpoints.

Also see: Neuroinflammation & Autoimmune CNS Disease, Optic Neuritis, Autoimmune Demyelinating Diseases. Experimental Autoimmune Encephalomyelitis and Multiple-Sclerosis.

For much of the past two decades, MOGAD and NMOSD were classified as variants of MS and studied primarily in conventional MOG_35-55 or MBP-based EAE models. The recognition that MOGAD is driven by pathogenic anti-MOG IgG antibodies while classical MS is predominantly T cell-mediated, and that NMOSD is driven by anti-aquaporin-4 (AQP4) antibodies with a distinct CNS lesion distribution, has created a need for disease-specific preclinical models that accurately replicate the immunopathology of each condition. This matters directly for visual research because MOGAD and NMOSD produce optic neuritis with different histopathological profiles – MOGAD causes predominantly demyelinating optic neuritis with relative axon sparing in early disease, while NMOSD causes more destructive astrocyte-targeted lesions with secondary axon loss and more severe visual functional deficits – and these differences should be reflected in the pattern of visual function decline measurable by OptoDrum.

Developing these models and validating their functional visual phenotypes with OptoDrum serves two scientific purposes. First, it provides model validation: confirming that a new EAE protocol produces the intended disease-specific pattern of optic nerve and visual pathway damage. Second, it enables the parallel evaluation of disease-specific treatments – anti-CD20 therapies (rituximab, ocrelizumab) for MOGAD and anti-AQP4 therapies (inebilizumab, satralizumab) for NMOSD – against the visual functional endpoint most directly relevant to their therapeutic target.

Also see: MOG-Antibody Associated Disorder and Optic Neuritis.

The relationship between diet, systemic metabolism, and neuroinflammation in MS and autoimmune demyelinating disease is an increasingly active research frontier. Saturated fatty acids activate Toll-like receptor 4 (TLR4) and NF-kappaB signalling in immune cells, promoting pro-inflammatory cytokine production and T cell skewing toward Th17 and Th1 phenotypes. This inflammatory priming is hypothesised to amplify the neuroinflammatory cascade in EAE lesions, including at the level of the optic nerve and retina. The gut microbiome, which is profoundly altered by dietary fat composition, provides an additional indirect route through which diet modulates CNS immune surveillance and neuroinflammatory severity.

What distinguishes Capper et al. (2025) methodologically is the use of OptoDrum to measure the specifically visual functional consequences of dietary fat-induced EAE exacerbation independently of motor disability. Motor scoring alone would capture the worsened spinal cord disease but would not specifically confirm optic nerve involvement or quantify the degree of visual circuit damage as a distinct pathological endpoint. OptoDrum provides this separation, enabling the optic nerve-specific consequences of dietary fat modulation to be quantified independently of limb motor deficits that may reflect spinal cord disease predominantly. This methodological design is directly applicable to any EAE study where dietary, metabolic, or microbiome-targeted interventions are evaluated for effects on optic nerve and visual pathway outcomes.

Also see: Neuroinflammation & Autoimmune CNS Disease and Experimental Autoimmune Encephalomyelitis.

Neuroinflammatory damage to the visual pathway in immune-mediated eye disease operates through multiple parallel and interacting mechanisms. Microglia, the resident innate immune cells of the CNS and retina, exist on a spectrum from homeostatic surveillance states to highly activated pro-inflammatory or disease-associated phenotypes. Their functional outcome is context-dependent, with CX3CR1-signalling microglia capable of both amplifying optic nerve lesions (as in Groh 2025) and providing neuroprotective myelin debris clearance (as in Groh 2023). CD8+ cytotoxic T cells represent an adaptive immune effector mechanism that inflicts direct axonal damage through perforin and granzyme B-mediated mechanisms, contributing to progressive axon degeneration in PLP-defect diseases and potentially in secondary progressive MS (Abdelwahab 2023). At the epigenetic level, BET bromodomain proteins drive the transcriptional upregulation of entire pro-inflammatory gene programmes, and their PROTAC-mediated degradation suppresses neuroinflammation more completely than classical BET inhibition (Zhu 2023).

The challenge in this mechanistically diverse field is selecting the right endpoint to confirm that a given mechanism is functionally significant at the circuit level and that targeting it produces a measurable clinical benefit, not merely structural or molecular changes. OptoDrum addresses this challenge uniformly across all of these mechanisms: regardless of whether the intervention targets microglia, T cells, epigenetic regulators, or axon growth inhibitors, the functional output – visual acuity and contrast sensitivity via the optomotor reflex – captures the net impact on the retinofugal visual circuit that these mechanisms collectively affect. This circuit-level integration is particularly valuable in complex neuroinflammatory models where multiple mechanisms operate simultaneously, because it reports the aggregate functional consequence rather than any single pathway's contribution in isolation.

Baya Mdzomba et al. (2020) add a translational dimension by demonstrating that Nogo-A antibody treatment – which both inhibits the Nogo-A-mediated axon growth block and attenuates neuroinflammation – can preserve and potentially restore visual function after inflammatory optic nerve damage, establishing OptoDrum as the functional endpoint for combined neuroprotective and regenerative strategies.

Also see: Axon Degeneration, Glial-suppression, Retinal Ganglion Cell Death, Optic-nerve-damage, Optic Nerve Regeneration, PLP-Defects and Retinal Degeneration & Inherited Retinal Disease.

Uveitis encompasses a clinically heterogeneous group of intraocular inflammatory conditions that produce visual dysfunction through multiple mechanisms: direct photoreceptor and RGC damage by inflammatory infiltrates, cystoid macular oedema, vitreous haze, and posterior segment complications including epiretinal membrane formation. Conventional assessment in rodent models relies on slit-lamp grading of anterior chamber inflammation, histological quantification of inflammatory cell infiltrates, and cytokine profiling from ocular fluid – all of which are either terminal or require technical expertise beyond standard laboratory capacity. None of these endpoints confirms whether the inflammatory episode has produced a functionally significant visual circuit deficit, which is the most clinically relevant outcome for any anti-inflammatory treatment evaluation.

OptoDrum resolves this gap: by measuring spatial visual acuity and contrast sensitivity before and during uveitis, and at defined intervals following treatment, researchers can directly assess whether the inflammatory episode has impaired the retinofugal visual circuit and whether intravitreal or systemic treatment has preserved or restored it. This functional readout is independent of structural or inflammatory grading and provides a circuit-level efficacy endpoint that bridges the preclinical and clinical research contexts in which visual acuity is the primary outcome measure for uveitis treatment trials.

Blast-related TBI represents a distinct but mechanistically relevant context: blast waves produce a combination of direct mechanical retinal damage and an intense post-traumatic immune response characterised by microglial activation, blood-retina barrier breakdown, and neutrophil infiltration that inflicts secondary retinal damage in the days to weeks following the primary injury. Harper et al. (2022) characterised this immune response and its visual functional consequences by OptoDrum, establishing the measurement paradigm for post-traumatic ocular immune response studies.

Also see: Trauma & Acute Injury and Optic Nerve Damage.

Rare inherited autoinflammatory disorders and systemic autoimmune conditions with ocular manifestations pose a distinct set of research challenges. Patient populations are small, genetic heterogeneity is substantial, and the relevant mouse models are often newly developed and incompletely characterised. Researchers entering these spaces face two sequential challenges: first, confirming that the genetic or immunological perturbation produces a quantifiable ocular phenotype. Second, demonstrating that an experimental treatment reverses or attenuates that phenotype at the functional circuit level. OptoDrum addresses both challenges through the same automated, non-invasive measurement protocol.

The diseases addressed span the spectrum from single-gene autoinflammatory disorders – ALPK1 gain-of-function (ROSAH syndrome) and other innate immune gene mutations – to polygenic and complex immune conditions including those driven by sex-biased immune cell depletion and age-related T cell accumulation. What unites them is that immune activation, in each case, damages the retinal ganglion cell layer and optic nerve in a way that is functionally measurable by the optomotor reflex. Fan et al. (2025) demonstrate this most precisely: selective ALPK1 inhibitor treatment restored or preserved RGC function in a ROSAH syndrome model, with OptoDrum providing the definitive functional confirmation.

Sex differences in immune-mediated ocular disease deserve particular attention, given that MS, MOGAD, and most other autoimmune conditions affecting vision show marked female predominance. Berve et al. (2020) demonstrated sex- and region-biased immune depletion with visual functional consequences in a rare neuroinflammatory disease model, establishing the methodological approach for sex-stratified immune-mediated visual function studies.

Also see: Rare & Inherited CNS and Eye Disorders, Rare-disease, Retinal Dystrophy and Systemic Aging & CNS Decline.