Neuroinflammation and Autoimmune CNS Disease: Visual Endpoints in EAE, Multiple Sclerosis, Optic Neuritis, and MOGAD Research

EAE is a dynamic, multi-phase disease: the acute inflammatory peak typically occurs at days 12-18 post-immunisation in MOG35-55 C57BL/6 models, followed by a chronic phase in which persistent demyelination and axon degeneration drive ongoing neurological deterioration. In relapsing-remitting models (PLP-SJL), this is followed by further attack-remission cycles. Measuring visual function at a single end-point time point captures only a snapshot of this dynamic process, and – because visual recovery can occur between relapses – end-point measurements may miss the functional disability accumulated over the full disease course. Longitudinal optical acuity tracking in the same animals provides a continuous functional record that correlates with EAE severity scores, optic nerve histology, and molecular neuroinflammatory markers across the full disease trajectory.

Classical visual assessment methods – ERG and VEP – require anaesthesia and specialised electrophysiology equipment, and in the EAE context carry the additional confound that anaesthesia alters neuroinflammatory signalling, potentially blunting or exaggerating the measured response. The OptoDrum's anaesthesia-free, automated paradigm eliminates both problems, delivering a functional visual acuity measurement that can be repeated daily during peak EAE without any additional procedural burden. Remlinger et al. (2022, Neurol. Neuroimmunol. Neuroinflamm.) demonstrated that this approach is sensitive enough to detect the differential visual outcomes produced by FcRn blockade in an antibody-driven EAE/MOG model , and Morin et al. (2021, J. Immunol.) used OptoDrum to confirm histaminergic modulation of EAE as a functional visual endpoint. Capper et al. (2025, Front Immunol.) showed that OptoDrum detects diet-driven differences in EAE visual outcomes, confirming its sensitivity across a range of effect sizes and intervention types.

An important consideration for MS researchers is the distinction between subcortical and cortical visual pathway involvement. The OptoDrum measures the OMR, which is mediated by the subcortical accessory optic system and is therefore sensitive to retinal and optic nerve damage but not to selective cortical demyelination. In EAE models with significant cortical lesion burden, AcuiSee provides the complementary cortical endpoint: its operant forced-choice paradigm requires cortical visual processing and specifically detects deficits arising from demyelinating lesions in the optic radiation, lateral geniculate nucleus, or primary visual cortex. This distinction is particularly relevant for models of progressive MS in which cortical atrophy is a key pathological feature.

Also see: Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

Mechanistic neuroinflammation research produces a rich catalogue of molecular findings – elevated cytokine levels, complement deposition, microglial transcriptomic signatures, axon degeneration markers – but connecting these molecular events to a functionally meaningful visual outcome requires a behavioural endpoint that integrates the combined effect of all these processes on the retina-to-brainstem pathway. This integration is precisely what the OptoDrum provides. A single OptoDrum measurement captures the cumulative functional effect of everything happening between the photoreceptor and the brainstem: if TNF-alpha is killing RGCs, if complement is disrupting synaptic function, if axon degeneration is reducing optic nerve conduction fidelity – all of these processes will reduce the optomotor acuity threshold in a graded, dose-sensitive way.

TNF-alpha is the most therapeutically targeted neuroinflammatory cytokine in both experimental and clinical autoimmune CNS disease. Its role in RGC death is well established: TNF receptor 1 (TNFR1) activation triggers both apoptotic and necrotic RGC death cascades, while TNF receptor 2 (TNFR2) may have neuroprotective functions in some contexts. Li et al. (2025, Neurosci Bull.) used OptoDrum to demonstrate the functional magnitude of TNF-alpha-driven RGC degeneration, establishing the OMR as a sensitive endpoint for testing TNFR-selective therapeutic strategies. Complement activation – a parallel amplification system engaged downstream of both antibody- mediated and innate immune triggers – was validated as a visual dysfunction driver by Zhao et al. (2025, Invest Ophthalmol Vis Sci.), who demonstrated that C3/C3aR inhibition preserves OMR-measured visual acuity.

Also see: Optic Nerve Damage, Retinal Ganglion Cell Death, Retinal Ganglion Cell Dysfunction, Retinal Degeneration and Inherited Retinal Disease, Retinal Degeneration, Glaucoma and Optic Nerve Neurodegeneration and Glaucoma

Optic neuritis in rodent EAE and related models follows a reproducible time course that mirrors the human clinical course in its broad features but compresses the time frame: acute demyelination and optic nerve inflammation typically peak between days 12 and 20 post- immunisation in MOG-EAE, producing rapid RGC loss and visual acuity decline; partial remyelination and some functional recovery may follow, but a proportion of RGCs are permanently lost due to secondary axon degeneration. Identifying the therapeutic window within which an intervention must be applied to prevent this secondary irreversible loss is one of the most clinically consequential questions in optic neuritis research.

The mechanistic complexity of optic neuritis – involving T cell and B cell infiltration of the optic nerve, microglial activation, oligodendrocyte and myelin loss, axon degeneration driven by energy failure and calcium overload, and secondary RGC apoptosis via deprivation of retro-axonal trophic support – means that individual histological and molecular endpoints each capture only one component of the overall pathological process. OptoDrum provides the integrative functional endpoint that reflects the combined output of all these processes: the optomotor acuity threshold declines when enough optic nerve conduction fidelity has been lost to impair the visual signal reaching brainstem targets, regardless of which specific pathological mechanism drove that loss.

The key insight from Groh et al. (2025, Nat Neurosci) is that microglial CX3CR1 signalling is a central orchestrator of optic nerve demyelination, providing a specific molecular target whose inhibition alters the functional visual trajectory in a way OptoDrum can detect longitudinally. This type of longitudinal OptoDrum monitoring – with pre-immunisation baseline, repeated measurements through the acute phase, and tracking into the chronic or remission phase – is the design recommended for any study aiming to characterise the timing and kinetics of optic neuritis onset and recovery.

Also see: Optic Neuritis, Autoimmune Demyelinating Diseases, Axon Degeneration, Glial Suppression and Ocular Inflammation and Immune-Mediated Eye Disease

MOGAD and NMOSD have been recognised as entities distinct from MS only in the last decade, and their preclinical modelling remains less standardised than EAE. The key pathological distinction is the effector mechanism: NMOSD is driven primarily by aquaporin-4 antibody (AQP4-IgG) attack on astrocytic endfeet, producing tissue-destructive lesions at the blood-CNS barrier; MOGAD is driven by MOG-IgG attack on oligodendrocyte cell surfaces and myelin. Both produce more severe optic neuritis than classical T cell-driven EAE, with less tendency for spontaneous remission, more extensive RGC loss, and greater functional visual deficits at equivalent disease duration. These clinical and pathological differences must be captured by the functional endpoint used in preclinical model development: an endpoint insensitive to the difference between EAE and MOGAD visual profiles cannot serve as a valid translational model characterisation tool.

OptoDrum provides the necessary discriminating sensitivity. Its graded threshold-seeking algorithm detects visual acuity across the full range from near-normal to near-abolished, making it capable of documenting the more severe and sustained deficits characteristic of MOGAD/NMOSD models as well as the partial, fluctuating deficits of classical relapsing- remitting EAE. Remlinger et al. (2023, Neurol. Neuroimmunol. Neuroinflamm.) exploited this range to characterise the distinct visual deficit profile of NMOSD/MOGAD in rodents, providing a functional benchmark against which therapeutic interventions in these models can be evaluated.

Also see: MOG Antibody-Associated Disorder, Autoimmune Demyelinating Diseases, Experimental Autoimmune Encephalomyelitis, Multiple Sclerosis and Ocular Inflammation and Immune-Mediated Eye Disease.

The preclinical MS and optic neuritis field has a well-documented translational gap: many interventions that reduce clinical EAE scores, decrease spinal cord lesion burden, or improve histological RGC counts fail to produce robust functional visual recovery as measured by behavioural endpoints. This gap exists because EAE clinical scoring (predominantly measuring hindlimb paralysis) does not capture optic nerve functional integrity, and because histological RGC counts confirm cell survival but not whether surviving cells are functionally contributing to the visual circuit. OptoDrum bridges this gap by providing the behavioural functional endpoint that confirms whether a neuroprotective or immunomodulatory treatment has actually preserved the retina-to-brainstem visual pathway sufficiently to support a tracking response.

The EAE neuroprotection literature has moved beyond classical immunosuppression to target specific molecular pathways: HIF-1-driven hypoxia in demyelinating lesions (Anders et al., 2023, Front Immunol.) , BET protein-dependent inflammatory transcription (Zhu et al., 2023, J. Neuroinflammation), cholesterol metabolism (Godwin et al., 2022, Biomolecules | covered in FAQ 3) , and optic nerve regeneration through Nogo-A pathway inhibition (Baya Mdzomba et al., 2020, Cell Death Dis.). Each of these intervention strategies has been validated with OptoDrum as the functional visual endpoint, providing a set of published precedents for researchers designing new neuroprotection studies in this application area.

Also see: Optic Nerve Regeneration and Gene Therapy, Optogenetics and Regeneration

CNS neuroinflammation research in areas outside ophthalmology – brain inflammation, spinal cord disease, meningitis, encephalitis, systemic autoimmunity – faces the fundamental problem that CNS functional endpoints are difficult to measure non-invasively in rodents. Motor scoring (rotarod, beam walk, EAE clinical scale), cognitive tests (Morris water maze, novel object recognition), and biopsy or imaging-dependent measures each capture one aspect of CNS function but require significant procedural resources, suffer from high variability and floor/ceiling effects, or are terminal. Visual acuity measured by OptoDrum provides a non-invasive, rapidly repeatable, quantitative CNS functional endpoint that can be incorporated into any neuroinflammatory research protocol at minimal additional cost, simultaneously with other behavioural and imaging assessments.

The scientific basis for this biomarker argument is solid. Sheng et al. (2026, Invest Ophthalmol Vis Sci.) demonstrated that neuroinflammatory amyloid accumulation in the retina – a hallmark of Alzheimer's disease pathology – produces OptoDrum-measurable visual acuity deficits, validating visual function as a biomarker of neuroinflammatory burden in a non-demyelinating neurodegenerative context. Kinuthia et al. (2025, JCI Insight.) demonstrated that OptoDrum tracks the functional visual benefit of immunomodulation in inflammatory retinopathy with metabolic overlap, and Xue et al. (2023, Brain Pathol.) showed that alleviating ischaemic demyelination preserves OptoDrum- measured visual function, bridging vascular and neuroinflammatory mechanisms.

Also see: Alzheimer's Disease, Retinal Degeneration, Vascular and Metabolic Disease, Retinal Ischaemia-Reperfusion Injury and Blindness

Progressive CNS diseases – whether age-related, rare-inherited, or degenerative – typically evolve over months to years, demanding monitoring tools that are practical for long-duration studies in the same animals, non-invasive enough to avoid cumulative welfare burden, and sensitive enough to detect gradual functional changes that might be missed by infrequent end-point measurements. Rare inherited neuroinflammatory CNS diseases present the additional challenge that most are ultrarare, meaning that any given research laboratory works with a small number of animals and cannot afford to sacrifice animals at multiple time points for histological monitoring – each animal must provide repeated functional data points across the study.

OptoDrum is ideally designed for this role. Its four-minute, anaesthesia-free paradigm is low enough burden to be applied weekly or even more frequently in long-duration natural history or treatment studies, generating a rich longitudinal dataset of visual function trajectories in the same animals across the full study period. In aging studies, this longitudinal sensitivity was demonstrated by Groh et al. (2021, Nat Aging), who tracked progressive visual acuity loss as a readout of immunosenescence-driven CNS axon degeneration across the mouse lifespan. In rare disease models, the same approach was validated in CLN1 disease by Groh et al. (2021, Brain Commun.) and in HSP by Hörner et al. (2024, Thesis). The sex-dimorphic microglial dynamics documented by (Berve et al., 2020, J. Neuroinflammation) add an important experimental design consideration: researchers studying microglial neuroinflammation in rare or aging models should include sex as a biological variable and track visual function separately in male and female cohorts.

Also see: Rare and Inherited CNS and Eye Disorders, Rare Disease, Systemic Aging and CNS Decline, Aging, Axon Degeneration, Alzheimer's Disease and Age-Related Macular Degeneration