Optic Neuritis Associated with Multiple Sclerosis (MS)

Key Points at a Glance

MS is an immune-mediated demyelinating disease of the central nervous system, and optic neuritis can be the initial symptom.
MS-related optic neuritis typically presents with unilateral painful vision loss and is the initial symptom in about 30% of patients.
Diagnosis uses the 2017 McDonald criteria (revised 2024) with MRI and cerebrospinal fluid analysis.
Acute treatment involves methylprednisolone 1,000 mg/day for 3 days as steroid pulse therapy.
Relapse prevention uses DMTs such as interferon beta, natalizumab, fingolimod, and anti-CD20 drugs.
It is important to understand clinical and imaging differences from MOGAD and NMOSD for differential diagnosis.
If brain MRI shows demyelinating lesions, 72% progress to MS after 15 years, so long-term follow-up is essential.

1. Optic Neuritis Associated with Multiple Sclerosis (MS)

Multiple sclerosis (MS) is a disease in which inflammatory demyelinating lesions occur in the white matter of the central nervous system (CNS), causing various neurological symptoms that relapse and remit. It is characterized by sclerotic lesions due to gliosis, and typically only the CNS is affected, not the peripheral nervous system.

Oligodendrocytes appear from the posterior lamina cribrosa where the optic nerve becomes myelinated, and are present from the intraorbital optic nerve to the central side. The central myelin sheaths formed by these oligodendrocytes are the targets of demyelination. About 30% of MS patients have visual impairment at onset, and 75% of patients experience at least one episode of optic neuritis in their lifetime.

Epidemiology

The male-to-female ratio is 1:2.9, with a female predominance, and the peak age of onset is in the 20s. The estimated prevalence in the United States is 1 to 1.5 per 1,000 people ¹⁾, and 2.1 million people worldwide are affected. The average age of onset is 15 to 45 years, and it is more common in high-latitude regions of the Northern and Southern Hemispheres.

Clinical Subtypes

MS has four main subtypes. RRMS (relapsing-remitting) typically begins at ages 25–29, while SPMS often starts at ages 40–49¹⁾.

RRMS

Relapsing-Remitting MS: The most common subtype. Relapses last more than 24 hours, with complete or partial remission between attacks.

SPMS

Secondary Progressive MS: Transition from RRMS. Disability accumulates progressively even during remission.

PPMS

Primary Progressive MS: Progressive accumulation of disability from onset, without relapses.

CIS

Clinically Isolated Syndrome: The first clinical episode that may lead to MS. Optic neuritis is a typical CIS, and brain MRI findings are crucial for deciding early DMT intervention.

Q If I develop optic neuritis, what is the likelihood of developing MS in the future?

If brain MRI shows demyelinating lesions, the 15-year conversion rate to MS is 72%. Even without lesions, 25% develop MS within 15 years; overall, it is 50% (US ONTT). Patients with optic neuritis should undergo brain MRI and long-term follow-up in collaboration with neurology.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

In 75% of patients, the initial symptom is a single complaint: 45% motor/sensory, 20% visual.

Ocular symptoms

Optic neuritis: Up to 20% present as the initial symptom, and 75% experience it at least once in their lifetime. It presents as painful vision loss in one eye, developing over hours to days and lasting for weeks.
Orbital pain: Present in 92%, worsened by eye movement.
Distribution of visual acuity loss: Reported as visual acuity ≥1.0 in 10%, 0.5–0.7 in 25%, 0.1–0.4 in 29%, and <0.1 in 36%.
Color vision abnormality: Present in 88%. Accompanied by decreased contrast sensitivity and central scotoma (most common visual field defect).
Uhthoff phenomenon: Temporary worsening of symptoms due to increased body temperature (e.g., bathing, exercise). Occurs within minutes of temperature rise and resolves within an hour. The mechanism is thought to be conduction block in demyelinated axons due to temperature increase.
Diplopia: Caused by internuclear ophthalmoplegia or brainstem lesions leading to eye movement disorders.

Systemic neurological symptoms

Limb weakness, pyramidal tract signs (Babinski sign)
Numbness, painful tonic spasms, trigeminal neuralgia
Lhermitte sign (electric shock-like pain radiating down the spine upon neck flexion)
Urinary dysfunction, ataxia, tremor
Charcot’s triad (dysarthria, ataxia, tremor)
Nystagmus, euphoria, depression

Exacerbations develop acutely to subacutely and last for days to months. Symptoms improve or resolve in 85%, but sequelae remain in 10–15%.

Clinical findings

RAPD (Relative Afferent Pupillary Defect): A highly sensitive finding that shows abnormalities even with mild dysfunction in optic neuritis.
Optic disc edema: Seen in one-third of patients. Anterior optic neuritis with disc swelling initially shows no disc abnormality (retrobulbar optic neuritis), and disc pallor develops after 4–6 weeks.
RNFL thinning: Observed in about 70% of acute optic neuritis cases. It may also be observed in asymptomatic MS patients.
Internuclear ophthalmoplegia (INO): Occurs in about 30% of cases. Caused by demyelinating lesions of the medial longitudinal fasciculus (MLF). Characterized by adduction limitation/delay on the affected side and nystagmus of the abducting eye on the contralateral side. Convergence is preserved.
Tumefactive MS: A rare subtype with demyelinating lesions ≥2 cm in diameter, showing mass effect, edema, and open-ring enhancement. Prevalence is estimated at 1–3 per 1,000 MS cases ²⁾.

MS-ON, MOG-ON, AQP4-ON Clinical Comparison

MS-related optic neuritis and optic neuritis associated with MOGAD and NMOSD have different clinical features, and differentiation influences treatment decisions.

Feature	MS-ON	MOG-ON	AQP4-ON
Sex ratio (F:M)	3:1	1:1	7–9:1
Bilateral simultaneous	Extremely rare	Frequent (31–84%)	Present (13–82%)
Visual acuity nadir	Mild to moderate	Moderate to severe	Moderate to severe
Optic disc swelling	Mild or rare	Moderate to severe (45–92%)	Present (7–52%)
MRI optic nerve lesion	Focal, short	Long (>50%), perineuritis	Long, posterior predominance (chiasm)
OCT acute pRNFL	Thickening (median 103 μm)	Marked thickening (median 164 μm)	Thickening
Steroid responsiveness	Moderate	High (may be steroid-dependent)	May be low
Long-term visual recovery	Good	Good (if no relapse)	May be poor
CSF oligoclonal bands	Very frequent	Rare (0–20%)	Present

If the acute-phase pRNFL is 118 μm or more, the sensitivity and specificity for differentiating from MOG-ON are reported to be 74% and 82%, respectively ⁵⁾.

Q What symptoms often lead to the detection of optic neuritis?

It often presents as unilateral painful vision loss. Orbital pain is observed in 92% of cases and is characteristically worsened by eye movement. Additionally, Uhthoff phenomenon, where symptoms temporarily worsen with increased body temperature (e.g., bathing, exercise), may occur. Even without treatment, vision improvement begins within 3 weeks of onset in about 80% of patients.

3. Causes and Risk Factors

The exact cause of MS is unknown, but autoimmune mechanisms are thought to be involved. T lymphocytes recognize myelin as foreign and activate macrophages, cytokines, and antibodies to destroy myelin and axons.

Genetic Factors

Concordance rate of 25–30% in monozygotic twins, 5% in dizygotic twins, and 3% in non-twin siblings
HLA polymorphism is the strongest susceptibility locus
Over 100 risk loci have been identified, most of which encode proteins involved in immune regulation

Environmental Factors

Association with onset and exacerbation after EBV and HHV infection has been reported ¹⁾
High prevalence in high-latitude regions: suggested association with reduced sunlight exposure and lower vitamin D levels
Involvement of infection, location, climate, stress, occupation, and diet has also been reported

Risk of Transition from Optic Neuritis to MS

The risk of transition to MS after the first episode of optic neuritis varies greatly depending on the presence or absence of demyelinating lesions on brain MRI.

Brain MRI demyelinating lesions present (≥1 lesion): 15-year MS conversion rate 72%
No brain MRI demyelinating lesions: 15-year MS conversion rate 25%
Overall (US ONTT): 15-year MS conversion rate 50%

4. Diagnosis and Examination Methods

Diagnostic Criteria

The 2017 McDonald criteria (2024 revision) are used. The basic principle is to demonstrate dissemination in time (DIT) and dissemination in space (DIS) of demyelinating lesions in the central nervous system. In the 2024 revision, the optic nerve was added as the fifth topographic region. Additionally, the κ free light chain index was added as an alternative marker equivalent to oligoclonal bands (concordance rate 87%).

Five Topographic Regions for Dissemination in Space (DIS)

Optic nerve (added in the 2024 revision)
Periventricular
Subcortical/Cortical
Infratentorial
Spinal cord

Proof of Dissemination in Time (DIT): Can be demonstrated by two or more attacks, or simultaneous presence of enhancing and non-enhancing lesions on MRI, new T2 lesions, or CSF oligoclonal bands ¹⁾.

For the diagnosis of PPMS, in addition to disability progression for at least one year, findings from at least two of the following are required: brain T2 lesions, spinal cord T2 lesions (two or more), or CSF oligoclonal bands ¹⁾.

MRI Examination

Demyelinating plaques are detected as T2 hyperintense lesions or gadolinium-enhancing lesions.

Brain MRI: FLAIR is excellent for depicting demyelinating plaques (MS plaques). They characteristically appear as horizontally oriented oval lesions in the white matter on axial sections. Typical findings are T2 hyperintense, round/oval, with a long axis of 3 mm or more ¹⁾.
Dawson’s fingers: Lesions arranged along the flow of cerebrospinal fluid in the periventricular region (characteristic finding).
Optic nerve MRI: Depicted as hyperintensity of the optic nerve on coronal STIR images. Fat-suppressed contrast-enhanced T1-weighted coronal images are essential.
Gadolinium enhancement: Seen in acute lesions and usually disappears within 4 weeks ¹⁾.
Differentiation between MS-ON and MOGAD: MS-ON is characterized by unilateral and short lesions. In MOGAD, long lesions (>50%), optic nerve sheath enhancement, and bilaterality are supportive findings ⁷⁾.

OCT Examination

Thinning of the peripapillary RNFL (retinal nerve fiber layer) and macular GCIPL (ganglion cell inner plexiform layer) is observed in MS patients regardless of the presence of optic neuritis.
The inter-eye difference in RNFL thickness and GCL thickness is useful for detecting previous optic neuritis attacks.
Median acute pRNFL: 103 μm in MS-ON, 164 μm in MOG-ON (using a cutoff of 118 μm, sensitivity 74%, specificity 82% for differentiation ⁵⁾).

VEP (Visual Evoked Potentials)

VEP is useful when MRI is inconclusive or for predicting disease progression ¹⁾. It can detect early, asymptomatic demyelination before it is visible on MRI. Prolonged latency and reduced amplitude are observed in 65% of cases.

Cerebrospinal Fluid Examination

Oligoclonal bands (IgG), increased IgG, increased myelin basic protein
CSF white blood cell count is only mildly elevated (>50/mm³ suggests infection ¹⁾)
Kappa free light chain index: added to 2024 McDonald criteria. 87% concordance with oligoclonal bands

Differential Diagnosis and Additional Tests

Differentiation from the following diseases is important; additional tests are performed in atypical cases.

Disease Category	Main Differential Diagnoses
Demyelinating diseases	NMO (Devic’s disease), ADEM, MOGAD
Infectious	Sarcoidosis, tuberculosis, syphilis, Lyme disease
Autoimmune	SLE, Sjögren’s syndrome, Behçet’s disease
Optic nerve diseases	NAION, LHON, toxic/metabolic optic neuropathy

Additional tests for atypical cases: anti-AQP4 antibody (to rule out NMOSD), anti-MOG antibody (to rule out MOGAD), serum NfL test, syphilis serology (VDRL/RPR/FTA-ABS), ANA (SLE), ACE/lysozyme (sarcoidosis).

Overview of the 2023 International MOGAD Diagnostic Criteria

Diagnosis of MOGAD requires a typical clinical phenotype (optic neuritis, myelitis, ADEM, brainstem/cerebellar symptoms, cortical encephalitis) and positive serum MOG antibodies. If the titer is unknown or low, one or more supportive findings (bilateral simultaneous optic neuritis, optic nerve lesion length >50%, optic nerve sheath enhancement, papilledema) are required. Validation studies of these diagnostic criteria report sensitivity 96.5%, specificity 98.9%, PPV 94.3%, NPV 99.3% ⁶⁾, with specificity in adults improving from 95.6% (MOG antibody testing alone) to 98.9% (p=0.0005) ⁶⁾.

Q How does MS-related optic neuritis differ from optic neuritis in MOGAD and NMOSD?

MS-ON is characterized by unilateral, focal short optic nerve lesions, with frequent CSF oligoclonal bands. MOG-ON often presents with bilateral simultaneous onset, long extensive optic nerve lesions with optic disc swelling, and is highly steroid-responsive but steroid-dependent. AQP4-ON tends to involve the posterior optic nerve and chiasm, and may have poor visual prognosis. Since treatment differs for each disease, accurate differentiation by measuring anti-AQP4 and anti-MOG antibodies is important.

5. Standard Treatment

Acute Phase Treatment

Standard treatment is steroid pulse therapy with intravenous methylprednisolone 1,000 mg/day for 3 consecutive days. Oral prednisolone (tapering) after the 3-day infusion is not performed. Oral steroid therapy should not be used as it increases relapse rate.

Even without treatment, visual improvement begins within 3 weeks of onset in about 80% of cases, but pulse therapy shortens the recovery period. In the ONTT (Optic Neuritis Treatment Trial), high-dose intravenous methylprednisolone improved recovery time for visual function, contrast sensitivity, and color vision, but did not show improvement in final visual prognosis. If steroid pulse therapy is ineffective, blood purification therapy (plasma exchange) is performed.

Early treatment (within 7 days of onset) is considered effective in reducing residual disability ⁷⁾. In MOGAD and NMOSD, a 5-day course may be used ⁷⁾.

Relapse Prevention (Disease-Modifying Therapy: DMT)

After improvement of visual acuity and visual field defects, DMT should be considered in collaboration with a neurologist to prevent relapse. If brain MRI shows demyelinating lesions, early initiation of DMT from the CIS stage should be considered.

Major DMTs and their efficacy are shown below.

Drug	Mechanism of Action	Administration	Relative Risk Reduction
Interferon beta	Modifies T/B cell activity and cytokine secretion	Self-injection	Disability progression RR 0.71
Glatiramer acetate	Regulatory T cell modulation	Self-injection	Relapse RR 0.82
Natalizumab	Inhibits inflammatory cell entry into CNS	Intravenous infusion	Relapse RR 0.56
Fingolimod	S1P receptor modulation	Oral	New T2 lesion RR 0.65
Teriflunomide	Pyrimidine synthesis inhibition	Oral	Disability progression RR 0.76
Dimethyl fumarate	Reduction of oxidative stress and inflammation	Oral	Relapse RR 0.64
Alemtuzumab	Anti-CD52 monoclonal antibody	Intravenous infusion	Disability progression RR 0.44
Ocrelizumab	Anti-CD20 monoclonal antibody	Intravenous infusion	Standard treatment for RRMS
Ofatumumab	Anti-CD20 monoclonal antibody	Subcutaneous injection	Standard treatment for RRMS

Anti-CD20 monoclonal antibodies (ocrelizumab, rituximab, ofatumumab) have become standard treatment for relapsing MS ³⁾. It has become clear that B cell antigen presentation and cytokine secretion (rather than antibody production) are major mediators of tissue damage ³⁾.

Differences in treatment from MOGAD and NMOSD

DMTs for MS (such as interferon beta and fingolimod) may be ineffective or worsen MOGAD and NMOSD ⁵⁾, so accurate differential diagnosis directly affects treatment choice.

MOGAD: Maintenance therapy is generally started after the second attack (since more than 50% are monophasic) ⁷⁾. Maintenance therapy includes IVIg (1 g/kg every 4 weeks or more) or rituximab ⁵⁾⁷⁾
NMOSD: Maintenance therapy is started after the first attack. Eculizumab, satralizumab, and inebilizumab are used ⁷⁾

6. Pathophysiology and detailed pathogenesis

MS is considered an autoimmune disease. T lymphocytes recognize myelin as foreign and activate macrophages, cytokines, and antibodies to destroy myelin and axons. Loss of myelin impairs conduction of electrical impulses, leading to delayed or lost nerve signal transmission.

Roles of T cells and B cells

Dendritic cells become hyperactivated → cross the blood-brain barrier (BBB) → induce Th1/Th17 differentiation in the CNS¹⁾
Th17: release GM-CSF → increased BBB permeability and monocyte recruitment¹⁾
B cells: demyelination and axonal destruction via autoantibody production. Memory B cells → CSF plasma cells → oligoclonal band production¹⁾
It has become clear that antigen presentation and cytokine secretion by B cells are major mediators of tissue damage³⁾

Damage to the visual pathway

Afferent pathway: sensory transmission from the retina to the brain. The optic nerve is most frequently affected. Rarely, the optic chiasm and optic tract are also affected.
Efferent pathway: motor output to the pupillary muscles and extraocular muscles. Ocular motor disturbances occur in more than 40% of cases.
INO (internuclear ophthalmoplegia): lesion of the medial longitudinal fasciculus (MLF) → adduction deficit and slowing on the ipsilateral side + nystagmus on abduction of the contralateral eye. Convergence is preserved.
Distribution of oligodendrocytes: they are present on the central side of the optic nerve beyond the lamina cribrosa, making the optic nerve susceptible to demyelinating lesions in MS.

Pathophysiological differences among MS, MOGAD, and NMOSD

The different pathophysiological mechanisms of each disease explain the differences in treatment response.

MS: CD8+ T cell-predominant oligodendrogliopathy. Chronic progressive forms also show cortical and subcortical gray matter damage.
MOGAD: CD4+ T cell-predominant oligodendrogliopathy. Complement activation is limited⁷⁾
NMOSD: anti-AQP4 antibodies → astrocyte damage → complement activation → secondary demyelination⁷⁾

Pathological Features

Active Plaque

Foamy macrophages: Accumulation of macrophages that have phagocytosed myelin.

Perivascular cuffing: A characteristic finding where lymphocytes surround blood vessels.

Edematous focal demyelinating lesions: Seen during acute exacerbations.

Chronic Plaque

Myelin loss: Can be confirmed with Luxol fast blue staining. Axons are preserved but remyelination is incomplete.

NAWM lesions: Diffuse gliosis, microglial activation, and BBB disruption in normal-appearing white matter. They show a higher correlation with clinical disability than focal white matter lesions.

Remyelination

Oligodendrocytes are responsible for remyelination in the CNS¹⁾. This process depends on adult oligodendrocyte precursor cells (OPCs), while existing mature oligodendrocytes cannot contribute to remyelination¹⁾.

The main causes of remyelination failure are as follows¹⁾:

Quiescence and differentiation failure of OPCs
Secretion of inhibitory factors by reactive astrocytes
Impaired clearance of myelin debris
Age-related dysfunction of the mTOR pathway in OPCs → reduced differentiation response

In addition, gray matter lesions in the cortex and subcortex are observed, and when B-cell follicle-like lymphoid structures form in the meninges, it is known to lead to a more severe clinical course¹⁾.

7. Latest Research and Future Perspectives (Investigational Reports)

Frexalimab (CD40 ligand inhibitor)

By inhibiting CD40L, this novel approach blocks co-stimulation between T cells and antigen-presenting cells (including B cells).

In a phase 2 trial by Vermersch et al. (N Engl J Med 2024), frexalimab showed clear efficacy over placebo in MRI outcomes, and a reduction in serum NfL, a biomarker of neuronal tissue damage, was also confirmed³⁾. Establishing clinical superiority over current high-efficacy DMTs (anti-CD20 drugs) remains a future challenge³⁾.

STING1-mediated autophagy-dependent ferroptosis

Ferroptosis, an iron-dependent cell death, has been shown to be involved in MS neuronal death. A cascade has been reported: glutamate excitotoxicity → calcium overload → endoplasmic reticulum stress → STING1 dissociates from STIM1 → atypical pathway activation → autophagy → autophagic degradation of GPX4 → ferroptosis⁴⁾. STING1 inhibitors (C176, H151) reduced autophagy-dependent GPX4 degradation in animal models and showed neuroprotective effects⁴⁾.

Clinical trials targeting MOGAD

Development of therapies specific to MOGAD is also progressing. Rituximab (NCT05545384), satralizumab (NCT05271409), and rozanolixizumab (NCT05063162) are advancing to phase 3 trials⁵⁾⁷⁾.

Development as an OCT biomarker

pRNFL thinning has been shown to be useful for monitoring MS progression, and reports of decreased retinal microvascular density by OCT-A are also accumulating.

Q Are there new therapeutic approaches for progressive MS?

In the research stage, neuroprotection through inactivation of microglia and macrophages by the CD40L inhibitor frexalimab ³⁾ and suppression of ferroptosis (iron-dependent cell death) by STING1 inhibition ⁴⁾ are considered promising. For MOGAD, phase 3 trials of rituximab and satralizumab are ongoing ⁷⁾. All of these are currently at the trial/research stage and are not standard treatments.

8. References

Pape A, Wellman LL, Conran RM. Educational Case: Multiple sclerosis. Acad Pathol. 2022;9:100036.
Tosunoglu B, Gökçe Çokal B, Güneş HN, et al. Tumefactive multiple sclerosis. Proc (Bayl Univ Med Cent). 2024;37(2):344-347.
Hauser SL. Silencing Immune Dialogue in Multiple Sclerosis. N Engl J Med. 2024;390(7):662-663.
Tang D, Kang R, Klionsky DJ. Autophagy-dependent ferroptosis mediates multiple sclerosis. Autophagy. 2025;21(2):257-259.
Jeyakumar N, Lerch M, Dale RC, Ramanathan S. MOG antibody-associated optic neuritis. Eye. 2024;38:2289-2301.
Varley JA, Champsas D, Prossor T, et al. Validation of the 2023 International Diagnostic Criteria for MOGAD in a Selected Cohort of Adults and Children. Neurology. 2025;104(3):e210201.
Cacciaguerra L, Flanagan EP. Updates in NMOSD and MOGAD Diagnosis and Treatment: A Tale of Two Central Nervous System Autoimmune Inflammatory Disorders. Neurol Clin. 2024;42(1):77-114.

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