Multiple Sclerosis

Key Points at a Glance

1. What is Multiple Sclerosis?

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, with the peripheral nervous system spared.

Epidemiology

The estimated prevalence in the United States is 1 to 1.5 per 1,000 people ¹⁾. Worldwide, 2.1 million people are affected, with higher distribution in high-latitude regions of the Northern and Southern Hemispheres. The average age of onset is 15 to 45 years, and the mean age at diagnosis is 30 years. The peak age of onset is 15 to 50 years, with a female predominance (peak in late 20s) and a female-to-male ratio of 1:2.9.

Clinical Subtypes

MS has four main subtypes. RRMS (relapsing-remitting) often begins at ages 25–29, and SPMS often begins 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: Disability accumulates progressively from onset. Slowly progressive without relapses.

CIS

Clinically Isolated Syndrome: The first clinical episode that may lead to MS. Enables early treatment initiation.

Q What types of multiple sclerosis are there?

MS is classified into four subtypes: RRMS (relapsing-remitting), SPMS (secondary progressive), PPMS (primary progressive), and CIS (clinically isolated syndrome). The most common is RRMS, characterized by relapses and remissions. SPMS transitions from RRMS, and PPMS is progressive from onset.

2. Main Symptoms and Clinical Findings

MRI image of demyelinating lesions in the brain in multiple sclerosis

Lahmam G, et al. Paroxysmal motor signs in multiple sclerosis: an illustrative videotaped case. Oxf Med Case Reports. 2026. Figure 2. PMCID: PMC13007868. License: CC BY.

(A) T2 hyperintensity in the left posterior limb of internal capsule, (B) periventricular and subcortical, (C) right midbrain, (D) gadolinium enhancement in the right centrum semiovale and midbrain. Corresponds to demyelinating lesions discussed in section “2. Main Symptoms and Clinical Findings”.

Subjective Symptoms

In 75% of patients, the initial symptom is a single complaint; 45% present with motor/sensory symptoms, and 20% with visual symptoms.

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 unilateral painful vision loss, developing over hours to days and lasting for weeks.
Ocular pain: Present in 92%, worsened by eye movement.
Distribution of visual acuity: Reported as 10% with visual acuity 1.0 or better, 25% with 0.5–0.7, 29% with 0.1–0.4, and 36% with less than 0.1.
Color vision abnormality: Present in 88%. Accompanied by decreased contrast sensitivity and central scotoma (the 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 one hour.
Diplopia: Caused by internuclear ophthalmoplegia or brainstem lesions leading to eye movement disorders.

General neurological symptoms

Limb weakness/muscle weakness, pyramidal tract signs (Babinski sign)
Numbness, painful tonic spasms, trigeminal neuralgia
Lhermitte sign (electric shock-like pain running 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 persist for days to months. Symptoms improve or resolve in 85% of cases, but sequelae remain in 10–15%.

Clinical Findings

RAPD (relative afferent pupillary defect): A highly sensitive finding that indicates abnormality even with mild dysfunction in optic neuritis.
Optic disc edema: Seen in one-third of patients. Anterior optic neuritis with disc swelling is observed in about 50% of cases in Japan (about 35% in Western countries).
Retrobulbar optic neuritis: No disc abnormality in the early stage; 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. Characterized by adduction limitation/delay on the affected side and nystagmus of the contralateral eye on abduction. 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 reported as 1–3 per 1,000 MS cases ²⁾.
Uveitis: Occurs in 1–2% of cases (about 10 times the general population).

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

It often presents as unilateral painful vision loss. Orbital pain is present in 92% of cases and is characteristically worsened by eye movement. Additionally, Uhthoff phenomenon, a temporary worsening of symptoms with increased body temperature (e.g., bathing, exercise), may occur.

3. Causes and Risk Factors

The exact cause of MS is unknown, but autoimmune mechanisms are thought to be involved in its onset.

Genetic Factors

Concordance rate: 25–30% in monozygotic twins, 5% in dizygotic twins, 3% in non-twin siblings.
HLA polymorphism is the strongest susceptibility locus
More than 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
High prevalence in high-latitude regions: suggested link to reduced sunlight exposure and lower vitamin D levels
Involvement of infection, location, climate, stress, occupation, and diet has also been reported

Q Is genetics involved in the development of multiple sclerosis?

Genetic factors are involved, but the concordance rate in monozygotic twins is only 25-30%. Although HLA polymorphisms and over 100 risk loci have been identified, it is thought that not only genetic predisposition but also environmental factors play an important role in the onset of the disease.

4. Diagnosis and testing methods

Diagnostic criteria

The 2017 McDonald criteria (2024 revision) are used. The basic principle is to demonstrate dissemination in time and space (DIT/DIS) of demyelinating lesions in the central nervous system. In the 2024 revision, the optic nerve was added as a fifth topographic region. In Japan, the 2015 Ministry of Health, Labour and Welfare diagnostic criteria for multiple sclerosis also exist.

The five topographic regions for dissemination in space (DIS) are as follows.

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

Demonstration of dissemination in time (DIT): two or more attacks, or simultaneous presence of enhancing and non-enhancing lesions on MRI, new T2 lesions, or CSF oligoclonal bands can be used as alternatives 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.

Typical MS lesions: T2 hyperintense, round/oval, long axis ≥3 mm ¹⁾
Dawson’s fingers: Lesions arranged along the flow of cerebrospinal fluid in the periventricular region (characteristic finding)
Characteristic locations: Periventricular, juxtacortical/cortical, infratentorial, spinal cord (cervical cord most common) ¹⁾
Gadolinium enhancement: Seen in acute lesions, usually resolves within 4 weeks ¹⁾
Optic nerve MRI: Fat-suppressed contrast-enhanced T1-weighted coronal view is essential
Differentiation from NMO/MOGAD: Optic neuritis in MS is characterized by unilateral and short lesions

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.
Inter-eye difference in RNFL thickness and GCL thickness is useful for detecting previous optic neuritis attacks.
SD-OCT is the recommended diagnostic tool.

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 the 2024 McDonald criteria. Concordance rate with oligoclonal bands is 87%.

VEP (Visual Evoked Potentials)

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

Differential Diagnosis and Additional Tests

Differentiation from the following diseases is important, and additional tests should be 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 disease	NAION, LHON, toxic/metabolic optic neuropathy

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

5. Standard Treatment

Acute Phase Treatment

The standard treatment in Japan is steroid pulse therapy with intravenous methylprednisolone 1,000 mg/day for 3 consecutive days. Oral prednisolone (maintenance therapy) after the 3-day infusion is not performed. Oral steroid therapy is thought to increase the relapse rate and should not be performed.

Even without treatment, visual improvement begins within 3 weeks of onset in about 80% of cases, but pulse therapy shortens the recovery period. Visual recovery can be expected in over 90% of optic neuritis cases.

If steroid pulse therapy is ineffective, blood purification therapy (plasma exchange) is performed. Overseas, methylprednisolone 500–1,000 mg/day for 3–5 days is used. The Optic Neuritis Treatment Trial (ONTT) showed that high-dose intravenous methylprednisolone improved recovery time for visual function, contrast sensitivity, and color vision, but did not show improvement in final visual prognosis.

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.

Major DMTs and their efficacy are shown below.

Drug	Mechanism of action	Administration	Relative risk reduction
Interferon beta	Modulation of T/B cell activity and cytokine secretion	Self-injection	Disability progression RR 0.71
Glatiramer acetate	Regulation of regulatory T cells	Self-injection	Relapse RR 0.82
Natalizumab	Inhibition of inflammatory cell entry into CNS	Intravenous infusion	Relapse RR 0.56
Fingolimod	S1P receptor modulator	Oral	New T2 lesions RR 0.65
Teriflunomide	Pyrimidine synthesis inhibitor	Oral	Disability progression RR 0.76
Dimethyl fumarate	Reduces oxidative stress and inflammation	Oral	Relapse RR 0.64
Alemtuzumab	Anti-CD52 monoclonal antibody	Intravenous	Disability progression RR 0.44

Anti-CD20 monoclonal antibodies (ocrelizumab, rituximab, ofatumumab) have become established as standard therapy for relapsing MS ³⁾.

Even in optic neuritis without brain lesions, MS develops in 25% after 15 years, and in cases with brain lesions, transition to MS is seen in 78%.

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

Even without brain MRI lesions, MS develops in 25% after 15 years; with brain lesions, transition to MS occurs in 78%. Patients who develop optic neuritis should be evaluated for DMT to prevent relapse in collaboration with neurology.

6. Pathophysiology and detailed mechanisms

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 electrical impulse conduction and disrupts neural signal transmission.

Role of T cells and B cells

Dendritic cells become hyperactivated → cross the blood-brain barrier (BBB) → induce Th1/Th17 differentiation in the CNS ¹⁾
Th17: release mucosal pemphigoid and GM-CSF → increase BBB permeability and recruit monocytes ¹⁾
B cells: demyelination and axonal destruction via autoantibody production. Memory B cells → CSF plasma cells → oligoclonal band production ¹⁾
It has become clear that B cell antigen presentation and cytokine secretion (rather than antibody production) are major mediators of tissue damage ³⁾

Visual Pathway Disorders

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 disorders occur in more than 40% of cases.
INO (Internuclear Ophthalmoplegia): Lesion of the medial longitudinal fasciculus (MLF) → adduction deficit/delay on the ipsilateral side + nystagmus on abduction of the contralateral eye.

Pathological Features

Active Plaque

Foamy macrophages: Accumulation of macrophages that have phagocytosed myelin.

Perivascular cuffing: Characteristic finding of lymphocytes surrounding 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⁾. It depends on adult oligodendrocyte precursor cells (OPCs), but existing mature oligodendrocytes cannot contribute to remyelination¹⁾.

The main causes of remyelination failure are as follows¹⁾.

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

Additionally, gray matter damage in the cortex and subcortical regions is 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 (new gadolinium-enhancing lesions at 8–12 weeks), and a reduction in serum NfL, a biomarker of neuronal tissue damage, was also confirmed³⁾. For progressive MS, it is also expected to inactivate microglia and macrophages, and neuroprotection via blockade of CD40L signaling in microglia at the plaque edge is theoretically possible³⁾.

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 neuronal cell death in MS.

Tang et al. (2025) reviewed the study by Woo et al. (Cell, 2024) and reported a cascade: glutamate excitotoxicity → calcium overload → endoplasmic reticulum stress → STING1 dissociates from STIM1 → atypical pathway activation → autophagy → autophagic degradation of GPX4 (an enzyme that neutralizes lipid peroxidation) → ferroptosis ⁴⁾. Increased STING1 expression in neurons was confirmed in both human MS specimens and mouse models. STING1 inhibitors (C176, H151) reduced autophagy-dependent GPX4 degradation in animal models and showed neuroprotective effects ⁴⁾.

Q Are there new therapeutic approaches for progressive MS?

At 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. Both are currently in clinical trial or research stages 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.

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