От диагностики к лечению: изучение механизмов, лежащих в основе оптического неврата в множестве склерозов.

Introduction

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) afflicting nearly millions worldwide. Common symptoms of MS include sensory disturbances, motor weakness, impaired gait, incoordination, and optic neuritis. Current statistics show over 2.5 million individuals worldwide now bear MS, and the substantial societal burden of MS amounts to an estimated economic cost of $10 billion annually, underscoring the persistent and extensive burden of this disease [ 1 , 2 ].

Available research indicates that lesions of optic nerve abnormalities can be identified in around three-quarters of MScases, and approximately half of all individuals with MS experience optic neuritis [ 3 , 4 ]. Pain, blurred vision, and impairments in contrast sensitivity, binocular visual acuity, color vision, and motion perception are prevalent visual symptoms associated with MS. Among these, the most severe is the potential loss of sight in one eye, significantly impacting a patient’s overall quality of life [ 4 , 5 ]. The startling information shown above emphasizes the significance of MS-related ON as a serious health issue.

This review aims to summarize the diagnostic methods for visual impairment in patients with MS, including imaging assessments and electrophysiological tests, while evaluating their utility in MS diagnosis. Furthermore, we provide an overview of current treatment strategies and effective medications for visual impairment in MS patients. Treatments targeted against B/T cells and other immune cells have progressed in recent years. In addition to these clinical aspects, we also reviewed the mechanisms by which these cells cause central nervous system lesions in MS, with the hope that future research can validate these mechanisms in the visual pathway.

Diagnosis for MS visual impairment

Increasing evidence indicates that MS can cause visual impairment, and ophthalmic diagnostic techniques including Optic coherence tomography (OCT), multimodal Magnetic resonance image (MRI), and Visual evoked potential (VEP) are clinically meaningful for diagnosing the occurrence of MS. The established markers of visual impairment in patients with MS, including visual field, visual acuity, retinal nerve fiber layer (RNFL) thickness, macular volume or thickness, VEP, as well as immune cells and glial cells, can all be identified using the aforementioned techniques. These indicators can then be used to assess the effectiveness of therapy and improve treatment plans.

Low-contrast letter acuity (LCLA)

As a visual functional biomarker, LCLA testing has emerged as a sensitive and clinically meaningful visual outcome measure in MS research. LCLA involves using specialized vision charts to test a person’s ability to resolve low-contrast letters of decreasing size [ 6 ]. Notably, impaired LCLA is widely observed in 80% of MS patients [ 7 ]. It merits acknowledgement that diminished LCLA is commonly witnessed in approximately four-fifths of MS patients. LCLA testing commonly utilizes charts with contrast levels of 2.5% and 1.25%, as these lower contrast charts can better detect visual deficits in MS patients [ 8 ]. In a trial, sustained significant LCLA worsening was reduced by 47% in 2.5% contrast charts and 35% in 1.25% contrast charts in the natalizumab group compared to placebo [ 9 ]. LCLA improvements have also been demonstrated following treatments like corticosteroids for acute optic neuritis [ 10 ]. Although LCLA can serve as a measure of visual outcomes, it is usually necessary to combine the results of LCLA with OCT, VEPs, and MRI to make an accurate diagnosis [ 6 ]. In conclusion, LCLA provides a sensitive test for diagnosing and tracking visual impairment in MS patients.

Magnetic resonance image

T2-weighted imaging

MRI represents a non-invasive technique that can image the interior structure of the body as well as certain aspects of its functional processes [ 11 ]. T2-weighted imaging has been shown to improve the visualization of brain lesions in MS and can enhance the detection of disease development in the anterior visual pathways [ 12 ]. On sequences weighted for T2 relaxation times, typical lesions of MS regularly present as heightened signal intensity or hyperintensity contrasted against encompassing neural tissues [ 13 ]. With this high sensitivity of MRI, clinicians can identify lesions or plaques related to MS visual function. What's more, proton density-weighted imaging or fluid-attenuated inversion recovery images, which suppress the signal from cerebrospinal fluid (CSF), are frequently employed to distinguish the signals arising from MS lesions within CSF [ 14 ]. These advanced neuroimaging methodologies can bolster the ability to distinguish and discern plaques induced through demyelination from CSF more definitively.

Diffusion Tensor Imaging (DTI)

DTI is a particular form of diffusion-weighted MRI and enables tracking the movement and diffusion of water molecules throughout neural tissues [ 15 ]. DTI can be employed to evaluate the wholeness of nerve fibers and white matter pathways involved in the visual process [ 16 ]. By contrast, conventional MRI can only generate a visualization of brain anatomical formations. [ 17 ]. Kouchkovsky et al.[ 18 ] evidenced that the examination of DTI in the white matter of healthy individuals and the MS patients with visual impairment revealed notable differences. Specifically, MS patients exhibited elevated mean diffusivity values (MD) and reduced fractional anisotropy (FA) values compared to the control group [ 18 ]. Through detecting microstructural alterations in the apparently normal white matter of MS patients, DTI furnishes a more sensitive gauge than conventional MRI for evaluating visual impairment and monitoring disease development.

Optic Nerve MRI

Optic nerve MRI aids in diagnosing visual impairment in MS by providing information about optic nerve pathology and changes in tissue histology that may not be discernible through routine visual examination [ 19 , 20 ]. Optic nerve MRI histogram analysis can detect changes in MS patients, even subtle visual symptoms [ 21 ]. Furthermore, optic nerve MRI can be used to estimate the radius of the optic nerve and surrounding CSF zone, providing more accurate imaging and the potential for identifying anatomical changes [ 22 ]. The latest research shows that incorporating symptomatic optic nerve involvement into Disability status scale criteria can improve the overall efficacy of MS diagnostic, specifically increasing the sensitivity of MS diagnosis from 83 to 95% and the overall accuracy from 78 to 81% [ 23 ]. It’s worth noting that optic nerve MRI can only evaluate the structural organization of optic nerve, and thus these findings require thoughtful consideration alongside clinical reporting, Gneurophysiological testing, and assessment of the retina and visual pathways via optical coherence tomography [ 24 ].

Optic coherence tomography (OCT)

OCT enables the assessment of potential reductions in RNFL thickness and ganglion cell layer (GCL) thickness linked to pathological impacts upon the optic nerve [ 25 , 26 ]. A meta-analysis including 40 studies found that OCT reliably detects retinal thinning in MS patients, with reductions of 9–18% observed in the RNFL and 7–15% in the GCL compared to healthy controls [ 27 ]. OCT can also detect changes in macular volume and GCL complex, which reflects injury in optic nerve [ 28 ]. Therefore, OCT can provide important information for the diagnosis of MS-related visual impairment.

OCT-angiography (OCT-A) is an emerging imaging modality that can non-invasively generate in-vivo microvascular images within the choroid and retina [ 29 ]. Accumulating evidence indicates that non-immune pathways, such as metabolic and vascular influences, may play equally important roles in driving MS pathogenesis [ 30 ]. Kleerekooper et al. [ 31 ] conducted a study that demonstrated the high demand for blood flow in the anterior visual pathway to support its highly active metabolic processes. What’s more, distinguishing between MS, neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD) in acute clinical settings can be challenging due to their overlapping symptoms, such as optic neuritis [ 32 – 34 ]. Qualitative differences in retinal microvasculature detected by OCT-A compared to conventional OCT alone can contribute to overcome the challenges in distinguishing such diseases [ 34 – 37 ].

Microperimetry (MP)

MP is an emerging technique capable of gauging site-specific variations in luminous sensitivity across the macular and perimacular retina [ 38 ]. In individuals suffering from MS, the technique affords detection of alternations to the retinal functional profile and facilitates monitoring of disease evolution [ 39 ]. For example, in research conducted by Gil-Casas et al. [ 39 ], individuals with MS presented with a modestly diminished logarithm of the minimum angle of resolution visual acuity score of − 0.02 relative to healthy peers. However, their average retinal sensitivity as gauged via microperimetry was reduced appreciably, by approximately 6 decibels, falling from a level of 32.8 decibels among controls to 26.65 decibels in those with the disease. MP provides an objective method to monitor visual function during the disease course. However, additional inquiry is also necessary to ascertain its potential role in diagnosing subclinical optic neuritis and tracking treatment responses in MS patients.

Electrophysiological tests

Visual evoked potential (VEP)

VEPs are neurophysiological responses elicited by visual stimulation which can be utilized as a biomarker for assessing myelination along the visual pathway [ 40 ]. In contrast to imaging techniques like MRI which primarily depict structural alterations, VEP provides several advantages. These include enhanced quantification of the functional integrity of the visual neural pathway, early detected functional impairments, heightened sensitivity, and a more direct representation of visual function [ 41 , 42 ]. Research by Leocani et al. [ 43 ] has demonstrated that pattern-reversal VEPs (PR-VEPs) can identify demyelinating lesions in the optic pathways, with delayed P100 latency observed in 80–99% of patients with MS-related optic neuritis. Sisto et al. [ 44 ] found that flash VEPs can assess pre-chiasmal optic nerve function and reveal impairments in 13.6–22.5% of MS patients without a history of optic neuritis.

Pattern electroretinogram (PERG)

PERG assesses the retinal response to a temporally modulated pattern stimulus. Existing research has demonstrated attenuated PERG amplitudes amongst MS patients, with a particular diminution of the N95 waveform noted irrespective of prior experience with acute optic neuritis [ 45 ]. This phenomenon indicates early retinal neuronal dysfunction before measurable nerve fiber layer thinning [ 46 ]. Specifically, Hokazono et al. observed reduced amplitudes for N95 and P50 + N95 in the eyes of MS patient and optic neuritis when compared to controls [ 47 ]. Moreover, PERG has demonstrated its ability to detect lingering dysfunction of RGCs in MS patients who have recovered from optic neuritis [ 48 ].

Laboratory tests

The diagnosis of MS relies on neurological symptoms and signs, alongside evidence of CNS lesion dissemination in space and time [ 49 ]. Although MRI is often adequate to establish the diagnosis in patients with distinctive lesions and typical clinical symptoms [ 50 , 51 ]. Additionally, Lab testing, such as CSF and blood analysis, can also provide additional evidence to corroborate the diagnosis [ 52 ]. Approximately 60–80% of patients with acute optic neuritis exhibit non-specific CSF abnormalities, including elevated lymphocyte counts and protein levels (appropriately 20%) [ 53 ], increased IgG synthesis (appropriately 42%) [ 54 ], and the presence of OCB (appropriately 56–69%) [ 55 ]. A population-based prospective cohort study conducted by Olesen et al. demonstrated significant alterations in CSF biomarkers, including oligoclonal bands (OCB), IgG index, leukocyte count, IL-10, tumor necrosis factor-α (TNF-α), CXCL13, and NF-L, in MS patients with optic neuritis [ 56 ]. These markers can distinguish MS-ON from isolated optic neuritis and reflect early inflammatory and neurodegenerative processes. Notably,The elevated CSF leukocyte levels, increased IgG index, and the presence of OCBs are particularly robust indicators of MS in patients presenting with optic neuritis, and the detection of OCBs is of particular significance in this context. However, OCB is not specific to MS and may also be associated with other white matter disorders, limiting its use as a standalone diagnostic marker [ 55 ]. In contrast, the utility of hematological testing in the diagnosis of MS-ON is limited. Blood tests are primarily employed to rule out other conditions, such as infectious or systemic autoimmune diseases, rather than directly confirming the diagnosis of MS-ON [ 57 , 58 ].

Treatment for ON in MS

MS can be classified into four distinct subtypes based on pathological progression and inflammatory immune activity: Relapsing–remitting MS (RRMS), Secondary progressive MS (SPMS), Primary progressive MS (PPMS), and Progressive relapsing MS (PRMS) [ 59 ]. The progress in the creation of disease-modifying therapies for MS has been remarkable in the past thirty years. First-line therapies for ON in MS include corticosteroids, interferons, and anti-CD20 monoclonal antibodies. Corticosteroids help manage acute optic neuritis attacks through their anti-inflammatory effects [ 60 ].

Drug therapy for ON in MS

Interferons are indicated to potentially inhibit the differentiation and proliferation of Th17 cells, and suppress the production of cytokines like IL-17, thereby reducing optic neuritis relapses, slowing the loss of retinal nerve fibers, and preserving visual function [ 61 ].Anti-CD20 therapies like ocrelizumab directly deplete pathogenic B cells and have shown superior efficacy to interferons in clinical trials for MS endpoints [ 62 ]. It is worth mentioning that although in recent years, some observational studies have already demonstrated the high effectiveness, relatively favorable safety/tolerability profile, lower cost, and convenient dosing schedule associated with the administration of rituximab, it is still not FDA-approved for the treatment of MS until now [ 63 – 65 ].

Other Disease-modifying therapies (DMT) for MS including teriflunomide, rituximab, fingolimod, and dimethyl fumarate have only limited evidentiary basis thus far for visually ameliorative effects, whilst small molecule immunomodulators such as laquinimod also exhibit a paucity of robust data conferring meaningful enhancements [ 66 ]. On account of the restricted evidence base presently extant, the prevailing opinion amongst various specialists appears to be that the aforementioned treatment alternatives have not demonstrably substantiated their credentials as first-line protocols for tackling visual impairment resulting from MS pathology. Here, we review the currently available drug therapies in Table  1 .

Table 1 Drug therapy for MS visual impairment Agent Applicable types Mechanism of action Route, dosage, and frequency Efficacy data Refs. Corticosteroids  Methylprednisolone RMS 1) Inhibits the entry of T cells into the central nervous system 2) Inhibits pro-inflammatory T cell activity and promotes Treg cell activity Intravenous injection or Oral, 1 g/day for 3–7 days, 2 g per day for 3–5 days if ineffective Intravenous methylprednisolone followed by oral prednisone accelerated visual recovery from acute optic neuritis compared to placebo (men at 5 weeks—p = 0.0001; women at 4 weeks—p = 0.0015) [ 159 ] Target T-cell therapy  Interferons RRMS 1) Reduces the activation of Th1 and Th17 cells 2) Promots the activation of Th2 cells 3) Activates microglia Subcutaneous injection, the typical starting dose is 30–50 μg weekly for long term Interferon beta-1a significantly improved visual acuity (-0.084 vs -0.239 LogMAR units, p < 0.0001) and contrast sensitivity (1.9 vs 0.1 dB, p < 0.0001) compared to placebo over 2 years Interferon β-1a reduced the risk of optic neuritis attacks by 50% over 3 years (p = 0.002). The cumulative probability of optic neuritis was 0.071 in the placebo group and 0.035 in the interferon group [ 160 , 161 ]  Glatiramer acetate RRMS 1) Increases the number of regulatory T cells 2) Facilitates the differentiation of T cells toward the Th2 direction Subcutaneous injection, 20 mg per day Glatiramer acetate reduced the risk of optic neuritis relapse by 45% compared to placebo over 3 years (14.8% vs 27.3% risk, p = 0.012) Patients treated with glatiramer acetate had smaller average RNFL thickness loss versus placebo over 2 years assessed (− 1.93 vs − 3.72 μm, p = 0.001) [ 162 , 163 ]  Natalizumab RRMS 1) Blocks Tcells and Bcells from migrating across the BBB Intravenous infusion, 300 mg every 4 weeks for about 1 h Natalizumab demonstrated a 32% reduced risk of sustained LCVA worsening compared to placebo (HR 0.68, 95% CI 0.55–0.84, p = 0.0003), and a 34% reduced risk of sustained HCVA worsening versus placebo (HR 0.66, 95% CI 0.50–0.86, p = 0.002) [ 164 ]  Metformin RRMS (further investigations to be confirmed) 1) inhibit inflammatory cytokines 2) Increase regulatory T cell number 3) Modulate immune response Oral administration, 850-1500 mg per day (Further investigations to be confirmed) Metformin treatment led to a 63.4% reduction of IFN-γ secreting cells (from 82.8 ± 18.8 to 30.3 ± 11.5 per 10^5 PBMCs) and a 61.7% reduction of IL-17 secreting cells (from 553.8 ± 125.9 to 212.4 ± 85.5 per 10 5 PBMCs) compared to control group, indicating immunomodulatory activities Metformin increased the percentage of regulatory T cells by 219% compared to the control group (from 2.1 ± 1.0% to 6.7 ± 1.5%), suggestive of its effects on immune tolerance [ 165 , 166 ]  Dimethyl fumarate RRMS 1) Activate the Nrf2 antioxidant pathway to reduce neuroinflammation associated with MS Oral administration, starting dose: 120 mg twice daily with food for 7 days Maintenance dose: 240 mg twice daily with food thereafter Annual relapse rate in the dimethyl fumarate treatment group is 0.087. Over 24 months, 16% of dimethyl fumarate patients experienced a protocol-defined relapse, 37% had new MRI activity, and the mean number of new or enlarging T2 MRI lesions per scan was 1.5 [ 167 ]  Fingolimod RRMS 2) Modulate S1P receptor 1 on T and B cells to restrict their exit from lymphoid tissues Oral administration, once daily continuously Fingolimod to interferon beta-1a in 1292 patients, annualized relapse rate was lower with 0.5 mg fingolimod at 0.16 versus 0.33 for interferon (52% relative reduction, p < 0.001) [ 168 ]  Cladribine RRMS 3) Induce apoptosis in lymphocytes, especially memory B and T cells Oral administration, 3.5 mg/kg over 2 years taken as 1.75 mg/kg annually In the RIFUND-MS trial, 21% of cladribine patients had new MRI activity over 24 months versus 37% in untreated patients. Frequencies of lymphotoxin alpha (α) producing B cells were significantly lower after cladribine treatment [ 169 ] Target B cell therapy  Ocrelizumab RPMS, PPMS 1) Deplete B lymphocytes Intravenous infusion, 600 mg every 6 months Compared to placebo, Ocrelizumab improved low-contrast visual acuity and color vision and ameliorated visual field defects in MS patients The risk of disability progression confirmed after 12 weeks was reduced by 24% when treated with ocrelizumab rather than placebo (p = 0.03) [ 62 , 170 ]  Ofatumumab RMS 1) Anti-CD20 monoclonal antibody 2) Deplete B lymphocytes Subcutaneous injection, 20 mg weekly for 3 doses, then monthly Ofatumumab reduced the number of gadolinium enhancing lesions (by 94–97% vs teriflunomide, p < 0.001) and new/enlarging T2 lesions (by 82–85%, p < 0.001) [ 171 ]  Ublituximab RMS 1) Deplete B cells via antibody-dependent cellular cytotoxicity Intravenous infusion, after the initial infusion, infuse every year twice, 1 h each infusion Ublituximab also significantly reduced the total number of new or enlarged lesions on T2-weighted images compared to teriflunomide, with 0.295 vs 2.71 lesions, respectively [ 172 , 173 ]  Rituximab RRMS PPMS SPMS 1) A monoclonal antibody targeting CD20 antigen on B lymphocytes Intravenous infusion In RRMS, 1000 mg was infused on days 1 and 15. Retreatment every 24 weeks In PPMS, 1000 mg every 24 weeks for 96 weeks (4 cycles) For relapse in SPMS, 1000 mg weekly for 4 weeks A study of 69 patients afflicted with relapsing–remitting MS received two infusions of rituximab at 1000 mg with a fortnight's interval. Results demonstrated that relative to the placebo group in the period from weeks 12 to 24, new magnetic resonance imaging findings revealed a 91% reduction in lesions exhibiting enhancement with gadolinium In the phase 3 OLYMPUS trial in primary progressive MS, 292 patients treated with rituximab 1000 mg every 6 months had significantly less increase in T2 lesion volume on MRI compared to placebo over 2 years [ 63 – 65 , 174 ] Target microglia therapy  Auranofin RRMS SPMS (Further investigations to be confirmed) 1) Upregulate miR-126a-5p expression in microglia; 2) Downregulate MMP9 expression in microglia 3) Protect BBB integrity – Auranofin at 200 μg/kg and 400 μg/kg significantly reduced BBB leakage by 65.8% and 69.2% respectively compared to vehicle-treated EAE mice, as measured by Evans blue dye extravasation Auranofin reduced demyelination by 63.7% and inflammatory cell infiltration by 66.2% in the spinal cord of EAE mice compared to vehicle, as quantified by histological staining [ 144 ] Neuroprotectants  Phenytoin – 1) Intervent in sodium-selective voltage-gated ion channels – The voltage-gated sodium channel blocker reduced RNFL thickness loss by 30% compared to placebo in a randomized, double-blind, placebo-controlled phase II trial [ 175 ]  Amiloride – 1) Inhibit Ion Channel 1, which is responsive to acidity; thereby preventing the influx of Na + and Ca2 +  – Diffusion MRI measures of tissue integrity in major white matter tracts and deep gray matter were significantly improved during amiloride treatment versus pretreatment (p = 0.02) [ 176 , 177 ]  Opicinumab – 1) Facilitate remyelination through the use of a monoclonal antibody targeting LINGO-1 – At 32 weeks, there was a trend towards improvement in visual evoked potential latency with opicinumab treatment (− 6.1 ms change vs placebo) [ 178 , 179 ]  Clemastine – 1) Facilitate remyelination in MS animal models – In the randomized, double-blinded, placebo-controlled, crossover ReBUILD trial in MS patients afflicted by chronic optic nerve damage, clemastine shortened the latency of visual evoked potentials by 1.7 ms compared to placebo In preclinical studies, clemastine augmented the maturation of cells that may develop into fresh myelin sheaths, and the regeneration of myelin sheaths in a mouse exhibiting artificially induced myelin damage [ 180 , 181 ] BTK inhibitors  Evobrutinib RRMS 1) Reduction of B-cell and myeloid cell activation and function 2) Decrease in CNS damage, including demyelination – Evobrutinib demonstrated a significant reduction in the annualized relapse rate (ARR) at week 48 compared to placebo, with an ARR of 0.11 (95% CI 0.04–0.25) maintained up to week 192 in the open-label extension study [ 182 ]  Tolebrutinib RRMS SPMS 1) Modulation of B-cell and myeloid cell activity, including microglia 2) Reduction of CNS inflammation by disrupting signaling pathways involved in autoimmunity – In a phase II clinical trial, Fenebrutinib significantly reduced the number of new T1 gadolinium-enhancing lesions on MRI compared to placebo, with a 60% reduction in lesion count at 24 weeks Annualized relapse rates (ARRs) were significantly lower in Fenebrutinib-treated patients, achieving an ARR of 0.12 compared to 0.34 with placebo over 48 weeks [ 74 ]  Fenebrutinib RMS PPMS 1) Modulation of B-cell receptor and FcγR signaling in B-cells and myeloid cells, including microglia 2) Reduction of inflammatory cytokine release and microglial clustering associated with neuroinflammation – In clinical studies, a dose-dependent reduction in new gadolinium-enhancing T1 lesions was observed, with lesion counts reduced by approximately 70% compared to placebo in relapsing MS patients over 24 weeks Microglial-associated inflammatory pathways, including TNF-α and IL-1β signaling, were attenuated, leading to a decrease in pro-inflammatory cytokine release and improved neuronal integrity in in vitro models [ 75 ] RMS relapse MS, DHODH dihydroorotate dehydrogenase, RRMS relapsing–remitting MS

Drug therapy for MS visual impairment

1) Inhibits the entry of T cells into the central nervous system

2) Inhibits pro-inflammatory T cell activity and promotes Treg cell activity

1) Reduces the activation of Th1 and Th17 cells

2) Promots the activation of Th2 cells

3) Activates microglia

Interferon beta-1a significantly improved visual acuity (-0.084 vs -0.239 LogMAR units, p < 0.0001) and contrast sensitivity (1.9 vs 0.1 dB, p < 0.0001) compared to placebo over 2 years

Interferon β-1a reduced the risk of optic neuritis attacks by 50% over 3 years (p = 0.002). The cumulative probability of optic neuritis was 0.071 in the placebo group and 0.035 in the interferon group

1) Increases the number of regulatory T cells

2) Facilitates the differentiation of T cells toward the Th2 direction

Glatiramer acetate reduced the risk of optic neuritis relapse by 45% compared to placebo over 3 years (14.8% vs 27.3% risk, p = 0.012)

Patients treated with glatiramer acetate had smaller average RNFL thickness loss versus placebo over 2 years assessed (− 1.93 vs − 3.72 μm, p = 0.001)

1) inhibit inflammatory cytokines

2) Increase regulatory T cell number

3) Modulate immune response

Metformin treatment led to a 63.4% reduction of IFN-γ secreting cells (from 82.8 ± 18.8 to 30.3 ± 11.5 per 10^5 PBMCs) and a 61.7% reduction of IL-17 secreting cells (from 553.8 ± 125.9 to 212.4 ± 85.5 per 10 5 PBMCs) compared to control group, indicating immunomodulatory activities

Metformin increased the percentage of regulatory T cells by 219% compared to the control group (from 2.1 ± 1.0% to 6.7 ± 1.5%), suggestive of its effects on immune tolerance

Oral administration, starting dose: 120 mg twice daily with food for 7 days

Maintenance dose: 240 mg twice daily with food thereafter

Compared to placebo, Ocrelizumab improved low-contrast visual acuity and color vision and ameliorated visual field defects in MS patients

The risk of disability progression confirmed after 12 weeks was reduced by 24% when treated with ocrelizumab rather than placebo (p = 0.03)

1) Anti-CD20 monoclonal antibody

2) Deplete B lymphocytes

RRMS

PPMS

SPMS

Intravenous infusion

In RRMS, 1000 mg was infused on days 1 and 15. Retreatment every 24 weeks

In PPMS, 1000 mg every 24 weeks for 96 weeks (4 cycles)

For relapse in SPMS, 1000 mg weekly for 4 weeks

A study of 69 patients afflicted with relapsing–remitting MS received two infusions of rituximab at 1000 mg with a fortnight's interval. Results demonstrated that relative to the placebo group in the period from weeks 12 to 24, new magnetic resonance imaging findings revealed a 91% reduction in lesions exhibiting enhancement with gadolinium

In the phase 3 OLYMPUS trial in primary progressive MS, 292 patients treated with rituximab 1000 mg every 6 months had significantly less increase in T2 lesion volume on MRI compared to placebo over 2 years

RRMS

SPMS

(Further investigations to be confirmed)

1) Upregulate miR-126a-5p expression in microglia;

2) Downregulate MMP9 expression in microglia

3) Protect BBB integrity

Auranofin at 200 μg/kg and 400 μg/kg significantly reduced BBB leakage by 65.8% and 69.2% respectively compared to vehicle-treated EAE mice, as measured by Evans blue dye extravasation

Auranofin reduced demyelination by 63.7% and inflammatory cell infiltration by 66.2% in the spinal cord of EAE mice compared to vehicle, as quantified by histological staining

In the randomized, double-blinded, placebo-controlled, crossover ReBUILD trial in MS patients afflicted by chronic optic nerve damage, clemastine shortened the latency of visual evoked potentials by 1.7 ms compared to placebo

In preclinical studies, clemastine augmented the maturation of cells that may develop into fresh myelin sheaths, and the regeneration of myelin sheaths in a mouse exhibiting artificially induced myelin damage

1) Reduction of B-cell and myeloid cell activation and function

2) Decrease in CNS damage, including demyelination

RRMS

SPMS

1) Modulation of B-cell and myeloid cell activity, including microglia

2) Reduction of CNS inflammation by disrupting signaling pathways involved in autoimmunity

In a phase II clinical trial, Fenebrutinib significantly reduced the number of new T1 gadolinium-enhancing lesions on MRI compared to placebo, with a 60% reduction in lesion count at 24 weeks

Annualized relapse rates (ARRs) were significantly lower in Fenebrutinib-treated patients, achieving an ARR of 0.12 compared to 0.34 with placebo over 48 weeks

RMS

PPMS

1) Modulation of B-cell receptor and FcγR signaling in B-cells and myeloid cells, including microglia

2) Reduction of inflammatory cytokine release and microglial clustering associated with neuroinflammation

In clinical studies, a dose-dependent reduction in new gadolinium-enhancing T1 lesions was observed, with lesion counts reduced by approximately 70% compared to placebo in relapsing MS patients over 24 weeks

Microglial-associated inflammatory pathways, including TNF-α and IL-1β signaling, were attenuated, leading to a decrease in pro-inflammatory cytokine release and improved neuronal integrity in in vitro models

RMS relapse MS, DHODH dihydroorotate dehydrogenase, RRMS relapsing–remitting MS

In brief, a review of current literature indicates that although several DMT medicines may arrest or decelerate additional visual impairment of MS, robust data substantiating their aptitude for meaningful visual restoration remains sparse. Consequently, corticosteroids and interferons are still regarded as first-line approaches for addressing acute and sustained visual impairment respectively in MS patients according to prevailing professional opinion. Further rigorous research is imperative to optimize the management of visual impairment in MS more fully through improved drug treatment.

Supportive therapies

Vision training is an innovative therapeutic approach and holds great potential in the medical field for enhancing visual function and addressing various visual impairments. With a focus on improving visual perception, attention, eye movements, contrast sensitivity, and stereovision, visual training aims to optimize patients’ visual processing capabilities [ 67 ]. Visual training has been utilized to support patients with conditions affecting visual processing, such as MS, traumatic brain injuries, and other neurologic disorders. This method offers a non-invasive and individualized solution and aims to enhance visual perception, attention, eye movements, and overall visual performance through targeted exercises and activities [ 68 ].

Multi-disciplinary treatment

Collaboration of specialists in different areas can contribute to reducing the impact of visual impairment in MS patients [ 69 ]: (1) Neuroimmunologists are well-placed to ascertain the precise causes of the inflammatory aspect underlying visual impairment. (2) Ophthalmologists can reinforce ocular musculature through bespoke exercises, while optometrists can prescribe tailored optical aids or visual therapies involving occlusion or refractive prisms. (3) Occupational therapists adept at rehabilitative techniques capitalize on habitual tasks and targeted ocular maneuvers including saccades, smooth pursuits, and convergence to facilitate compensation for field defects or focus irregularities. (4) Psychosocial support from counselors can effectively address the impact of MS on a patient’s quality of life.

Emerging therapies

One of the leading hypotheses for the limited ability of most current DMTs to meaningfully prevent disease worsening in MS is their restricted capacity to cross the BBB. These DMTs also struggle to reach and exert a significant effect on the cells that orchestrate inflammation in the CNS compartment [ 70 , 71 ]. Bruton’s tyrosine kinase inhibitors (BTKi) diminish immune-mediated inflammation in the CNS by modifying microglial activity and efficiently blocking B cell activation and pro-inflammatory cytokine release [ 72 ]. Three BTKi have shown encouraging promise in clinical studies for the treatment of MS thus far: evobrutinib [ 73 ], tolebrutinib [ 74 ] and fenebrutinib [ 75 ] (Table  1 ).However, no BTKi has been approved by the government for use as an MS treatment as of yet. Additional research is necessary to confirm BTKi's effectiveness and safety in reducing ON-associated visual impairment and promoting optic nerve healing, even though data from MS trials suggests that they may lessen CNS inflammation and prevent disease recurrence.

Mechanism for MS

During active periods of MS, myelin sheath damage releases antigenic substances, triggering immune responses from T/B cells and macrophages as inflammatory cells [ 76 ]. These inflammatory cells cross the blood–brain barrier (BBB) and enter the ventricles and subventricular system through the CSF, causing an increase in the number of lymphocytes and monocytes within the CSF [ 77 ]. The visual pathway passes through the cranial cavity in close proximity to the meninges, leading to exposing to the CSF. Therefore, any alterations to the CSF, whether changes in pressure or immunological responses, can impact the visual pathway [ 78 , 79 ].

As previously mentioned, therapies targeting certain immune cells are effective in treating ON in MS [ 80 , 81 ]. However, there is currently very little basic research on ON caused by MS. The optic nerve is a bundle structure composed of the axons of retinal ganglion cells, which converge at the optic disc to form the optic nerve. The eye is an anatomical extension of the CNS and shares many molecular and cellular similarities with the brain [ 82 ]. What’s more, abnormalities in these immune cells have been observed in optic neuritis caused by MS [ 83 , 84 ]. Therefore, it is reasonable to speculate that similar mechanisms may exist in the optic nerve and central nervous system in MS. Understanding these interactions is crucial to designing more focused and efficacious treatments.

Thus, we reviewed the mechanisms by which these cells cause central nervous system lesions in MS, hoping that future research can validate these mechanisms in the optic nerve.

B cells

Numerous studies have demonstrated that the pathogenesis of MS is primarily centered on T cell autoimmunity. But recent insights prove that B cells also have indispensable roles [ 85 ]. Patients with progressive MS demonstrated higher levels of CD20 + B cells and plasma cells migrating into the meninges and perivascular space around visual pathways [ 83 ]. The proven efficacy of anti-CD20 therapy indicates unequivocally that B cells exert inflammatory effects during MS [ 86 , 87 ]. Interestingly, trials obstructing APRIL and BAFF, which are essential to B cells, provoked exacerbated MS progression [ 88 ], supporting that certain particular B cell groups confer anti-inflammatory influences.

Memory B cells

Memory B cells are found to express cytokines to trigger inflammatory response [ 89 , 90 ] and presenting antigens [ 91 ] to interact with T cells. Activated B cells in MS patients generate overtly high concentrations of inflammatory cytokines like tumor necrosis factor (TNF), lymphotoxin-α (LT-α), IL-6, and granulocyte–macrophage colony-stimulating factor (GM-CSF) [ 89 , 90 ]. Besides, Memory B cells also secrete some yet unclear toxic factors that can damage oligodendrocytes and neurons [ 90 ]. The current study highlights the relevance of B cell antigen presentation in driving the spontaneous proliferation of autoreactive CD4 + T cells [ 85 , 91 ]. Memory B cells in MS patients demonstrate elevated manifestation of HLA-DR and CD40, which could be reinforced by Toll-like receptors (TLR) or inflammasomes, suggesting memory B cells can present antigens to CD4 + T cells [ 91 ]. In experimental autoimmune encephalomyelitis (EAE) mice induced by MOG, MHC-II deletion in memory B cells lowers the formation of Th1 and Th17 cells and alleviates the clinical symptoms [ 85 ].

Plasma B cells

Studies have shown that Immunoglobulin G (IgG) antibodies in MS patients, with IgG1 being predominant, have a propensity to aggregate into complexes exceeding 100 nm. These aggregates are capable of engaging the classical complement pathway. Concurrently, complement cascade proteins induce caspase 3, culminating in complement-dependent apoptotic death of neurons and glial cells [ 92 ]. Some studies support the presence of IgG antibodies in CSF of MS, mainly against neuronal and glial antigens with a few against myelin antigens [ 93 ]. However, the few antibodies against myelin antigens also could cause severe demyelination in spinal cord slice cultures [ 93 ]. IgG aggregates in MS patients induced six times more neuronal apoptosis compared to controls, and incubation with the IgG-degrading enzyme IdeS completely abolished neuronal apoptosis and demyelination [ 92 ], suggesting that IgG antibodies have a specific relationship with the development of MS.

In MS patients, the level of bacteria-bound IgA in gut is reduced during disease relapse, and IgA + IL-10 + B cells are detected in the brain tissue of MS patients, indicating the migration of IgA + plasma cells from the gut to the CNS [ 94 , 95 ]. In EAE mice, gut-derived IgA + plasma cells and plasma penetrate and express IL-10, alleviating symptoms [ 94 ]. Transgenic mice overexpressing BAFF or APRIL are more difficult to induce EAE mice, as it increases IgA + plasma cells [ 94 , 95 ]. Therefore, therapies targeting the regulation of IgA + B cell numbers and functions hold promise for MS treatment, such as the use of probiotics and short-chain fatty acids. Taken above, IgG-producing and IgA-producing plasma cells play opposing roles in the process of MS.

B regulatory cells (Bregs)

Bregs are being found to have anti-inflammatory capability via affecting Th1/Th2 cells, increasing Treg production, and blocking microglial inflammatory response. Through IL-10 secretion, Bregs can inhibit the generation of IFN-γ by Th1 and Th17 subsets. Concurrently, secretion of IL-4 by Bregs stimulates the proliferation of Th2 cells, indicating their potential role in maintaining equilibrium between the Th1 and Th2 arms of the adaptive immune response [ 96 – 98 ]. Bregs could produce IL-10 and TGF-β, which boost the level of Foxp3 in Treg cells and accelerate Treg maturity [ 99 ]. Meanwhile, Breg-surface CD40 may attach to Treg-surface CD40L, stimulating Treg multiplication [ 100 ]. Bregs-secreted IL-10 can inhibit the generation of proinflammatory factors including TNF-α and IL-1β via microglia [ 101 ]. IL-10 can also increase the production of the T cell immunoglobulin and mucin domain 1 receptor on the outer layer of microglia, differentiating them into M2 microglia [ 97 , 101 ]. Interestingly, IL-10 produced by M2 microglia may additionally enhance Bregs engagement and growth [ 102 ].

Among diverse Breg cell subtypes, transitional B cells and B10 cells are the principal generators of the cytokine IL-10 [ 98 ]. However, B10 cells reduced CD4 + T cell proliferation and IFN-γ/IL-17 expression more effectively than transitional B cells [ 103 ]. Furthermore, surface integrins, granzyme B and transforming growth factor-β1 expression was also higher in B10 cells compared to transitional B cells, indicating that mechanisms of immunosuppression are discrepant between these two Breg subsets [ 103 ]. In short, the role of B cells has only started to be investigated in recent years. Nevertheless, they remain a highly promising target. The multifaceted role of different subtypes of B cells in visual impairment associated with MS is illustrated in Fig.  1 .

Multifaceted role of different subtypes of B cells in MS. Ig immunoglobulin, CD Cluster of differentiation, TCR T-cell receptor, MHC major histocompatibility complex, Treg regulatory T cell, Breg regulatory B cell, IL Interleukin, GM-CSF granulocyte–macrophage colony-stimulating factor, TNF-α tumor necrosis factor-α, LT lymphotoxin-α, MAC Membrane Attack Complex, MBP Myelin Basic Protein, MOG Myelin Oligodendrocyte Glycoprotein, BCMA B-cell Maturation Antigen, BAFFR B-cell Activating Factor Receptor, TACI Transmembrane Activator and Calcium Modulator and Cyclophilin Ligand Interactor, BAFF B-cell Activating Factor, APRIL A Proliferation-Inducing Ligand, TGF-β Transforming growth factor-β. The red molecules exert damaging effect, while blue molecules impose protecting effect

Inflammatory response induced by CD4 + T cells

MS is an autoimmune inflammatory disorder induced by lymphocytes, chiefly CD4 + T cells, in the CNS [ 104 , 105 ]. Consistent with the above findings, Khalid et al. have reported that a mixed B- and T-lymphocyte vitreous infiltration in uveitis caused by MS, mostly CD4 + T cells [ 84 ]. In MS, the BBB becomes compromised, allowing autoimmune T-cells to infiltrate CNS [ 106 ]. Once inside, these T cells need to be reactivated by antigen-presenting cells (APCs) to stimulate inflammation [ 107 ].

The role of IFN-γ released by Th1 cells

The most prevalent T cell subgroup in MS is Th1 cells. IFN-γ mRNA and protein unleashed by Th1 cells have also been found in the active regions of MS lesions [ 108 ]. IFN-γ has the capacity to tear down tight junctions and trigger the endothelial cells to express adhesion molecules, which allows CD4 + T cells to move into the parenchyma and aggravate MS [ 109 ]. IFN-γ also stimulates the synthesis of astrocyte chemokines [ 110 ], which aggravates the attraction and activation of myeloid cells, and it raises the expression of MHC class I and MHC class II on resident macrophages in CNS [ 111 ], primarily on microglia. Substantial evidence shows that Th1 cells preferentially target microglia over other cell types. Multiple effector chemicals produced by Th1 cells cause local microglia to become activated and differentiate into the inflammatory and neurotoxic M1 phenotype [ 112 ].

However, studies have yielded conflicting results. IFN-γ and IFN-γ receptor-deficient mice are more prone to developing atypical EAE following active immunization compared to WT mice [ 113 , 114 ]. It’s interesting to note that low-dose IFN-γ’s ability to suppress M1 microglia growth [ 110 ]and encourage the phagocytosis of myelin debris [ 115 ]. Additionally, low-dose IFN-γ moderates the oxidative stress response induced by microglia, and elevates Insulin-like growth factor 1(IGF-1) levels in CNS to promote remyelination after neuroinflammatory damage [ 116 ]. Therefore, we hypothesize that dysregulated interferon IFN-γ signaling, whether through excess or deficiency, would promote inflammatory responses.

The role of IL-17 released by Th17 cells

During RRMS patients, high amounts of Th17 cells have been discovered [ 117 ]. Although IFN-γ and IL-17 cells both could trigger MS, their mechanism is distinct. Retinoic acid receptor-related orphan nuclear receptor γτ (RORγτ) activation within the cell’s cytoplasm [ 118 ]and the release of IL-17A-F and IL-22 are traits of Th17 cells [ 108 ]. Some research has shown that TGF-β, in conjunction with IL-1, IL-6, IL-21, is crucial for promoting RORγτ activation and Th17 maturation [ 118 , 119 ]. IL-17-A coupled with IL-6, IL-22 is believed to foster the decomposition of the BBB in MS patients, causing the dissociation of tight junctions and surrounding F-actin cytoskeleton, which finally increases the migration of CD4 + T cells and monocytes to the CNS [ 120 – 122 ]. Furthermore, a reduction in Annexin A1 released from Th17 cells causes immune cells to have greater moving ability in inflammation regions of RRMS patients [ 123 ]. Furthermore, some researchers also believe that IL-17 may only be involved in the progression of MS rather than its initiation.

Notably, effector molecules from Th1 cells could change the properties in astrocytes and microglia, while those from Th17 cells only induced direct effects on astrocytes but not microglia [ 124 ]. For example, when comparing EAE mice and healthy mice, only astrocytes show substantially increased IL-17A receptor activation [ 125 ]. When deleting activating transcription factor 1 (Act1) specifically in astrocytes, Th17 cells were capable of normal activation and proliferation, but their ability to induce inflammatory responses was markedly impaired. However, loss of Act1 in endothelial cells or microglia appeared to have little impact [ 126 ].

Glia cells are responsible for enhancing the inflammatory response

Accumulating experts agree that glial cells are crucial to the maintaining homeostasis of optic nerve and retina and exacerbating immune cell-mediated inflammatory responses in MS [ 127 ]. Overactivation of microglia and astrocytes has been seen in the optic nerve in C57BL/6 mice with MOG-induced MS, thereby sparking research enthusiasm [ 128 ].

Astrocytes

Initially thought of as inert structural components, astrocytes are now understood to be active, multifunctional cells that modulate neural signaling, and contribute to structural integrity[ 129 ]. Activated NF-κB [ 130 ] and Signal transducer and activator of transcription 3 (STAT3) [ 131 ] are seen in astrocytes surrounding MS lesions. Reactive astrocytes attract leukocytes and neutrophils by producing C-X-C motif chemokine 2, and produce reactive oxygen species to damage neurons and myelin [ 132 ]. Astrocytes secrete C–C motif chemokine 2, CXCL10, and CXCL12, which promotes the amassment of monocytes and T cells [ 133 , 134 ], and the maturation and activation of monocytes to generate ROS-producing inflammatory monocyte-derived cells [ 135 ]. What’s more, the expression of complement component 3 (C3) in astrocytes plays a vital role but the underlying mechanisms have yet to be fully elucidated [ 136 ]. In a nutshell, these results point to important roles for astrocytes in the development of neuroinflammation.

Recently, Sanmarco et al. discovered a distinct subgroup of astrocytes that highly express the apoptotic factor tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which could induce programmed cell death of T cells, thereby suppressing inflammation [ 137 ]. Under healthy conditions, the expression of TRAIL in these astrocytes is mainly dependent on IFN-γ secreted by natural killer (NK) cells [ 137 ]. However, this contradicts our earlier point regarding Th1 cells promoting inflammation through IFN-γ secretion. We speculate that this discrepancy might be attributed to variations in the levels of IFN-γ, aligning with our previous argument. Therefore, future research should comprehensively elucidate the dose–response relationship of IFN-γ, providing better guidance for clinical interventions.

Microglia and its multifaceted function

Microglia are resident macrophage cells in visual pathways, which make up 5–10% of the glial cells [ 129 ]. Furthermore, microglia during MS are presumably stimulated by IFN-γ, CR3, and undergo “super-activation” following interaction with other TLR ligands, such as peptidoglycan [ 138 ]. It’s interesting to note that microglia play dual functions in MS, harming and protecting. The multifaceted functional mechanisms of microglial cells caused by MS are illustrated in the Fig.  2 .

Multifaceted function of microglia in MS. DAMPs damage-associated molecular patterns, IFN-γ interferon-γ, LPS lipopolysaccharide, TLR toll-like receptors, CR3 complement receptor 3, NF-κB nuclear factor-kappa B, OPC oligodendrocyte precursor cell, NOX NADPH oxidase, IFNGR interferon-gamma receptor, MHC major histocompatibility complex, STAT signal transducer and activator of transcription, CXCL C-X-C motif chemokine ligand, PPAR-γ peroxisome proliferator-activated receptor-γ, TNF-α tumor necrosis factor-α, ERK extracellular signal-regulated kinase, IL interleukin, ROS reactive oxygen species, MMP9 matrix metalloproteinase 9, BDNF brain-derived neurotrophic factor, Treg regulatory T cell, IGF insulin-like growth factor, BBB blood–brain barrier, TJ tight junction. The red molecules exert damaging effect, while blue molecules impose protecting effect

Antigen-presentation in microglia

Accumulating evidence shows that in the initial phases of MS, microglia alone appeared capable of presenting antigens, whereas dendritic cells enter the CNS at day 7 post-immunization [ 139 , 140 ]. MHC proteins in microglia are in charge of presenting antigens at normal levels, but they could quickly boost MHC expression when they become stimulated in MS [ 140 ]. Through directly investigating transcriptomic profiles, Hobson et al. [ 139 ] discovered that IFN-γ had a significant enhancement on MHC-I/ II and associated mRNA levels in microglia and proliferation of microglia.

Inflammation and oxidative stress in microglia

On top of Antigen-Presenting, microglia-mediated inflammatory response and oxidative stress are also gaining increasing attention. Microglia play a crucial role in clearing pathogens and damaged cells, but excessive activation of pro-inflammatory microglia (M1 microglia) would lead to neurotoxicity and tissue damage [ 108 ]. In addition, IFN-γ is essential for transforming into M1 microglia that have been activated by the TLR [ 139 ]. Jie et al. [ 141 ] indicate that T cells induce the M1 microglial NF-κB -inducing kinase (NIK) pathway, and NIK promotes the expression of the chemokines C-X-C motif chemokine ligand 9 and 9 (CXCL9) and CXCL10 in microglia, and finally exerts a crucial effect on the later migration of inflammatory T cells and monocytes. GM-CSF synergizes with this response to promote secondary T cell recruitment and maturity, rather than the initial phase [ 141 ]. Through NADPH oxidase 2 (NOX2) and NOX4, microglia contribute to chronic pro-inflammation and ROS production, causing oxidative stress and demyelination [ 142 ]. Further research revealed that NOX is stimulated upon damage-associated molecular patterns arising from neurons through TLR4 and pattern recognition receptors complement receptor 3(CR3) [ 143 ].

Positive function in microglia

However, the role of microglia in MS remains controversial, perhaps due to the complexity and diversity of MS, or the various subtypes and dynamic changes of microglia. Recently, Yu et al. observed that miR-126a-5p in microglia shows a positive correlation with BBB integrity in various types of MS plaques [ 144 ]. What’s more, microglia release neurotrophic substances such as brain-derived neurotrophic factor (BDNF), IGF-1, and activin-A that help oligodendrocyte progenitor cells persist, multiply, develop, and ultimately help with remyelination in optic nerve [ 145 – 147 ]. Interestingly, intravitreal injection of BDNF promoted the proliferation of microglia in the retina via the CREB-BDNF signaling pathway in turn [ 147 ]. What’s more, in MS, the removal of cholesterol-rich myelin debris is carried by microglia, and then oligodendrocytes elevate cholesterol to create fresh myelin membranes [ 148 ]. Of note, via genetics, phenotyping, and gene expression profiling, Berghoff et al. discovered that microglia generated desmosterol, the immediate precursor to cholesterol, rather than cholesterol, which dictates the repair of acutely demyelinated lesions [ 148 ]. Additionally, microglia release the anti-inflammatory chemical IL-4 which promotes oligodendrogenesis in MS and triggers the M2 anti-inflammatory phenotype in microglia [ 146 ]. In addition, it has been demonstrated that M2 microglial IL-4 and IL-10 develop protective Th2 cells and Tregs in MS [ 146 , 149 ]. Therefore, future research should focus on the neuroimmune network to better understand the interaction between microglia and the central nervous system. The mechanism of demyelination and nerve damage in MSinduced by immune T cells and enhanced by glial cells is shown in Fig.  3 .

Mechanisms of demyelination and nerve injury in MS induced by immune T cells and enhanced by glia cells. 1: The tight junctions and the actin filaments of the blood–brain barrier (BBB) are disrupted, allowing immune cells and inflammatory cells to enter the CNS; 2a: Th1 cells are reactivated and release IFN-γ; 2b: Th17 cells are activated and release IL-17; 3a: M1 microglia are reactivated, and interact with T cells, and release inflammatory cytokine; 3b: Astrocytes are activated and secrete chemokine to recruit immune cells and inflammatory cells; 4: demyelination and nerve injury. Act1 Activator 1, CCL2 C–C motif chemokine 2, TGF-β transforming growth factor-β, CXCL C-X-C motif chemokine ligand, HSP heat shock protein, HMGB1 high mobility group box 1, DAMPs damage-associated molecular patterns, CR3 complement receptor 3, TLR toll-like receptors, NOX NADPH oxidase, MHC major histocompatibility complex, NF-κB nuclear factor-kappa B, B7 B7 family molecule, CD cluster of differentiation, TCR T-cell receptor, MdC monocyte-derived cells, GM-CSF granulocyte–macrophage colony-stimulating factor, TNF-α tumor necrosis factor-α, MMPs matrix metalloproteinases. The red molecules exert a direct damaging effect, while green molecules play a role in activation or regulation. And the sequence on the yellow spheres represents the progression process of the disease

Interplay between cognitive and visual impairments

Reliable data indicates that 40–65% of MS patients have cognitive impairment [ 150 ], whereas 20–40% have optic neuritis or visual impairment [ 151 ]. Thomas et al. found that deficiencies in fundamental math abilities were a highly significant predictor of visual cognitive impairment as early as 2014 (OR 29.4, 95% CI 3.0–291.9) [ 152 ]. According to a study by Jakimovski et al. on the connection between visual impairments and cognitive deficits in MS patients, the probabilities of cognitive impairment rose by 2.7% for every 1 μm decrease in pRNFL and by 61.9% for every 1 mm3 decrease in MV [ 8 ]. A complicated interaction between these domains is seen in multiple sclerosis. On the other hand, whereas visual deficiencies are frequently associated with cognitive impairments, some research indicates that visual dysfunction can also arise irrespective of cognitive loss [ 152 ]. Accordingly, the relationships among different functional deficits in MS are still deserving of more thorough research.

Conclusions and prospect

Increasing evidence indicates that MS can cause ON. Ocular diagnostic techniques, in particular MRI, OCT, and OCTA, are crucial for the diagnosis and early detection of MS [ 25 , 29 , 153 , 154 ]. These methods allow for the evaluation of vascular density, ganglion cell complex, and RNFL thickness—all of which have been proposed as potential predictive indicators for MS [ 153 ]. Therapies targeted against T cells and B cells have been shown to alleviate ON caused by MS. There is currently very little basic research on ON in MS. We reviewed the mechanisms by which these cells cause central nervous system lesions in MS, hoping that future research can validate these mechanisms in the optic nerve.

Finally, let’s discuss the safety profile of the drugs mentioned in this review. We summarize various common though typically mild side effect profiles. Injection site reactions have been documented with interferon usage [ 155 ], while infusion-related reactions may occasionally arise with monoclonal antibody administration [ 156 ]. Gastrointestinal discomfort is also cited [ 66 ]. Moreover, transient lymphopenia and a possible increased susceptibility to infection during therapy have been noted [ 157 ]. Most anti-CD20 monoclonal antibodies like ocrelizumab, ofatumumab, and rituximab ofatumumab consequently necessitate avoiding ‘live’ vaccinations due to their immunosuppressive mechanisms of action [ 158 ]. Close monitoring under medical guidance is usually recommended to promptly identify and address any side effects emerging with these important treatment options. Therefore, continued rigorous research is needed.

We suggest further research should focus on: (1) employing single-cell RNA sequencing to gain novel insights into the distinct roles of T, B, and glial cell subsets in optic nerve of MS, (2) finding the specific temporal sequence and importance of the diverse roles played by cells and cytokines during the process of disease, (3) applying localized ocular injection therapy to heighten therapeutic impact by delivering medication directly to the targeted ocular region.

Acknowledgements

The graphical abstracts were created with BioRender software (BioRender.com).

Abbreviations

Activator 1

A randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trial of natalizumab in relapsing MS

Annexin A1

Antigen-presenting cells

A Proliferation-Inducing Ligand

Acid-Sensing Ion Channel 1

B-cell activating factor

Blood–brain barrier

Brain-derived neurotrophic factor

Regulatory B cells

Bruton's tyrosine kinase

Controlled High-Risk Avonex Multiple Sclerosis Prevention Study

Central nervous system

Complement Receptor 3

Cerebrospinal fluid

Damage-associated molecular patterns

Dihydroorotate dehydrogenase

Double inversion recovery

Disease-modifying therapies

Diffusion tensor imaging

Experimental autoimmune encephalomyelitis

Fractional anisotropy

Fas cell surface death receptor

Fas cell surface death receptor Ligand

Fluid-attenuated inversion recovery

Ganglion cell layer

Granulocyte–macrophage colony-stimulating factor

High-contrast visual acuity

Human leukocyte antigen-DR

Interferon-γ

IgA and interleukin-10 positive B cells

Interleukin-17A to F

Low-contrast letter acuity

Lymphotoxin-α

Mean diffusivity

Major histocompatibility complex-I/II

Myelin oligodendrocyte glycoprotein

Myelin oligodendrocyte glycoprotein antibody-associated disorder

Microperimetry

Multiple sclerosis

Macular volume

Nicotinamide Adenine Dinucleotide Phosphate

Nuclear Factor-kappa B

Natural killer cell

Neuromyelitis Optica Spectrum Disorder

NADPH oxidase 2

NADPH oxidase 4

Optical coherence tomography

OCT-angiography

Optic neuritis

Optic Neuritis Treatment Trial

Oligodendrocyte progenitor cells

A prominent positive peak

A positive waveform with 50 ms latency in PERGs

Pattern onset-offset VEPs

Primary progressive multiple sclerosis

Early glatiramer acetate treatment in delaying conversion to clinically definite multiple sclerosis in subjects presenting with a clinically isolated syndrome

Prevention of relapses and disability by interferon β-1a subcutaneously in multiple sclerosis

Pattern reversal visually evoked potentials

Retinal ganglion cell

Relapse multiple sclerosis

Retinal nerve fiber layer

Retinoic acid receptor-related orphan nuclear receptor γτ

Reactive oxygen species

Relapsing–remitting multiple sclerosis

Secondary progressive multiple sclerosis

Signal transducer and activator of transcription 3

Visually evoked potentials

Author contributions

BT and FZH searched and reviewed relevant literature, acquired and analyzed data, drafted the figures and wrote the manuscript; BT, XZ and HJH discussed and evaluated the literature, made important contributions to the review framework design, and made critical modifications to the manuscript; YHY and XFW further analyzed and statistically processed the literature data; MLZ and FY provided technical support on formatting, table making, etc.; XFW and FY conducted a substantive review and editorial critique of the manuscript's English language usage; FZH designed the review framework and revised the final manuscript. We would like to acknowledge our team of researchers and clinicians for their strong support for this work.

Funding

This work was supported by grants from the National Natural Science Foundation of China (82271234, 82060219); Natural Science Foundation of Jiangxi Province (20212ACB216009, 20212BAB216048, 20202BBGL73058, 20202BBGL73105); Jiangxi Province thousands of Plans (jxsq2019201023); Youth Team Project of the Second Affiliated Hospital of Nanchang University (2019YNTD12003); Health Commission Foundation of Jiangxi Province (202210100).

Availability of data and materials

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Declarations

Ethics approval and consent to participate

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Consent for publication

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Competing interests

The authors declare that they have no competing interests.

Footnotes

Publisher's Note

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Bin Tong, Xin Zhang, and Haijian Hu contributed equally to this work.

Contributor Information

Fan Yang, Email: 278027141@qq.com.

Fuzhou Hua, Email: huafuzhou@126.com.

References

Associated Data

Data Availability Statement

Not applicable.