Multiple Sclerosis

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Article initiated by:
Chantal Josee Boisvert, MD, Ngoc-Anh Tran
All contributors:
Andrew Go Lee, MD, Qiancheng Wang, Shruthi Harish Bindiganavile, MBBS, MS, Nita Bhat, MBBS, MS, Nagham Al-Zubidi, MD, Chantal Josee Boisvert, MD, Shruthi Harish Bindiganavile, MBBS, MS, Danah Albreiki, MBBS FRCSC, William Sanfelippo, MD
Assigned editor:
Danah Albreiki, MBBS FRCSC
Review:
Assigned status Up to Date
 by Danah Albreiki, MBBS FRCSC on August 19, 2025.


Multiple Sclerosis
OCT of the nerve fiber layer
Optical coherence tomography (OCT) of the nerve fiber layer from a 42-year-old patient who presented with painful vision loss OS suggestive of optic neuritis. Examination showed temporal pallor of both optic discs. Magnetic resonance imaging showed enhancement of the retrobulbar optic nerve and multiple demyelinating lesions. Cerebrospinal fluid analysis confirmed the diagnosis of multiple sclerosis. OCT on presentation showed thinning of the temporal nerve fiber layer OD and OS suggestive of old optic nerve damage from previously undiagnosed optic neuritis. © 2019 American Academy of Ophthalmology [1]
DiseasesDB
8412
ICD-10
[1]35
OMIM
126200
MedlinePlus
000737
MeSH
D009103


Disease Entity

Disease

Multiple sclerosis (MS) is a neurodegenerative disease of the central nervous system (CNS) that results from the immune-mediated inflammation and demyelination of axons. It is characterized by focal demyelinating lesions in the white matter of the brain or spinal cord that vary temporally and spatially, thereby leading to the classic presentation of episodic neurologic symptoms. These symptoms vary depending on the location of lesions, and can include changes in autonomic, motor or sensory functions. Of interest, MS often presents with ocular manifestations secondary to inflammatory demyelination of the visual pathway, and a majority of patients experience at least one episode of ocular involvement in the course of their disease.

Epidemiology

MS affects an estimated 400,000 people in the United States and 2.1 million people worldwide, with a more prevalent geographic distribution among the northern and southern hemispheres.[2] The average age of onset ranges from 15 to 45 years while the average age at diagnosis is 30 years. Females are more commonly affected than males, at a ratio of about 2 to 1.[3]

Etiology

The underlying cause of MS remains enigmatic, though multiple factors have been proposed to contribute to the development and progression of the disease. The leading theories suggest a complex interplay between genetic predisposition and environmental factors.

A genetic component in MS is supported by twin studies showing a concordance rate of 25-30% in monozygotic twins, 5% in dizygotic twins, and 3% in non-twin siblings.[4] In addition, a number of genome-wide association studies have identified more than 100 risk loci in MS, and a majority of these genes have been found to encode for proteins involved in immune modulation. Although polymorphisms in the human leukocyte antigen (HLA) have been identified as the strongest susceptibility loci, other non-HLA genes have also been found.[5][6]

Despite data suggesting significant genetic influence in MS, genes alone do not fully contribute to the development of the disease. A number of environmental factors such as infection, location, climate, stress, occupation and diet have been postulated to be involved.[7] There is evidence suggesting the development or exacerbation of MS following post-viral syndromes, such as those from Epstein-Barr virus (EBV) and human herpes virus (HHV).[8][9] The geographic variation of MS further supports an environmental role. Although the underlying cause remains unclear, factors such as decreased sun exposure and low levels of vitamin D have been proposed to explain the latitudinal gradient.[2]

Pathophysiology

MS is thought to be an autoimmune disease and this theory is supported by its shared characteristics with other autoimmune disorders. These features include the predominance of women affected, the association with HLA polymorphisms, and the presence of autoantibodies to myelin antigens in CSF.[7]

The chronic inflammation, degeneration and demyelination of axons in the CNS lead to the clinical presentation of neurologic dysfunction. The inflammatory process is mediated by T lymphocytes that recognize myelin as a foreign entity and trigger other immune cells, macrophages, cytokines and antibodies that together lead to myelin and axonal breakdown. These T cells are thought to gain entry into the brain from disruptions in the blood-brain barrier, which can result from post-viral infections.[10] With the loss of myelin, the protective and insulating fatty sheath that surrounds axons, the conduction of electrical impulses is compromised.

This impaired transmission of neurologic signal can occur anywhere within the CNS, including the visual system. Ophthalmic involvement can be categorized into lesions of the afferent or efferent visual pathways. The afferent pathway is responsible for the transmission of sensory information from the retina to the brain. The optic nerve is most commonly involved and leads to a number of visual symptoms. Infrequently, the optic chiasm and optic tracts are involved which lead to visual field defects such as bitemporal hemianopsia and homonymous hemianopsia, respectively.

The efferent pathway is responsible for motor output to the pupillary muscles and extraocular muscles. Disorders of ocular movement affect more than 40% of patients with MS.[11] Lesions can involve the brainstem, cerebellum or cranial nerves and result in ocular misalignment resulting in diplopia, and nystagmus resulting in oscillopsia. A condition termed internuclear ophthalmoplegia (INO) occurs with lesions in the medial longitudinal fasciculus (MLF), a highly myelinated tract between the abducens nucleus to the contralateral medial rectus sub-nucleus of the oculomotor nucleus. MLF lesions result in impaired ipsilateral adduction with contralateral abducting nystagmus.

Diagnosis

History

Demographic information such as age, sex, race, country of origin and migration status is relevant. MS is more common in women ages 15-45. Family history of MS is also relevant as there is a genetic predisposition to the disease. Recent stressors, viral infections, and the presence of sick contacts should also be explored.

MS is classically described as a condition in which neurologic symptoms vary in time and space. Because demyelination can have diffuse involvement within the CNS, patients often complain of a constellation of seemingly unrelated symptoms. In 75% of patients, the initial presentation of MS involves an isolated complaint; 45% are motor or sensory and 20% are visual.[12] Therefore, a thorough review of systems is crucial. Symptoms of MS can be autonomic, visual, motor or sensory. Changes in sensation can present as pain, numbness, tingling, or pins and needles sensation. Motor involvement manifests as muscle weakness, muscle spasms, impaired coordination and balance or difficulty with speech and swallowing. Autonomic symptoms include bowel dysfunction (diarrhea or constipation) and bladder dysfunction (urinary incontinence). Cognitive complaints in MS include fatigue, decreased attention span, concentration, memory, and judgment. Psychological symptoms include depression and mood instability. MS is associated with other clinical findings such as: Charcot triad of dysarthria, ataxia, and tremor; Uhthoff’s phenomenon of worsening of symptoms in higher temperatures; Lhermitte’s sign of an electrical sensation running down the back when the neck is flexed; and trigeminal neuralgia presenting as facial pain or weakness.

Ocular manifestations are common in MS. Up to 20% of patients have optic neuritis as the initial clinical presentation and 75% of patients have at least one episode throughout the course of their lives.[13] Optic neuritis associated with MS typically presents as a monocular painful vision loss that occurs over hours to days and lasts a few weeks. Orbital pain occurs in 92% of patients and is usually worse with extraocular movement.

It is equally important to elicit the onset, duration and temporal relationship of symptoms. Exacerbations or “flare-ups” can be acute or subacute in onset and typically lasting days to months. These episodes are usually transient, with improvement or even complete resolution of symptoms in 85% of cases. However, symptoms can worsen or become permanent in the remaining 10-15% of those affected.[14]

Physical Examination

A detailed neuro-ophthalmic examination should take place. This includes the afferent system: best corrected visual acuity, color vision, RAPD check, and visual field testing. Efferent exam includes checking for anisocoria, EOM range of motion, saccades, smooth pursuit, and presence of nystagmus along with an alignment testing. Orbits and cranial nerves should be assessed. Anterior segment and IOP. Fundus exam particularly assessing the optic nerves.

In addition, the use of optical coherence tomography (OCT) can provide information about the extent of involvement and allow for quantitative measures for disease progression over time.

In patients with optic neuritis, changes in visual acuity can range from mild to severe; 10% of patients are 20/20, 25% are 20/30-20/40, 29% are 20/50-20/190 and 36% are 20/200 or worse.[15] Patients will also present with diminished color vision (dyschromatopsia in 88%, best assessed by red desaturation), diminished contrast sensitivity, visual field loss (most commonly central scotoma) and a relative afferent pupillary defect (RAPD). Slit lamp examination will reveal optic disc swelling in one-third of patients.[15] Papillitis is more common in postviral and infectious neuritis than demyelinating neuritis, but considerable overlap exists. Retinal nerve fiber layer (RNFL) thinning reflecting axonal damage is observed in about 70% of patients with acute optic neuritis, while visual evoked potential (VEP) increases in latency and decreases in amplitude are found in 65%.[16][17]

Internuclear ophthalmoplegia occurs in about 30% of patients.[18] This condition presents with diplopia, nystagmus, and loss of depth perception (stereopsis) secondary to an adduction deficit or adduction lag on conjugate gaze. Other patterns of ocular misalignment include skew deviation, gaze paresis and impaired smooth pursuit.[19] Uveitis can occur in 1-2% of patients with MS, a rate that is 10 times more common than that of the general population.[20] Symptoms of uveitis include pain, photophobia, and conjunctival injection.

The neurologic exam can provide useful information regarding localization of the lesion(s), as well as severity and extent of involvement. The exam consists of the evaluation of cranial nerves, deep tendon reflexes, motor strength, sensation, gait, balance and coordination.

Clinical Diagnosis

There is a revised criteria for MS of which the goal is to facilitate early diagnosis of this condition in typical presentations. This is a modified criteria of the 2017 Mcdonald Criteria. The optic nerve has been introduced as a fifth topographic site for lesions present in MS in the revised Mcdonald criteria for 2024. The involvement of the optic nerve, in the right clinical context of the typical history and clinical exam of optic neuritis in MS, and in some cases in asymptomatic patients is supported by ancillary testing, optical coherence topography (OCT), MRI of the orbits (evidence of optic nerve injury either by T2 hyperintensity or post gadolinium enhancement), and or visual evoked potentials (VEP). Moreover, inter-eye asymmetry in retinal nerve fiber layer (RNFL) thickness on OCT and/or ganglion cell layer (GCL) thickness could help distinguish between eyes with previous optic neuritis attack. Topographic CNS locations for dissemination in space: Optic nerve, Periventricular, Juxtacortical/cortical, Infratentorial, and or Spinal cord[21]

MS is classified into four subtypes depending on its clinical course: relapsing-remitting (RRMS), secondary progressive (SPMS), primary progressive (PPMS), and progressive relapsing (PRMS).[22]

In an atypical presentation of optic neuritis, suspicion for a non-MS cause should prompt additional laboratory testing. Atypical features include bilaterality, painless vision loss, lack of characteristic MRI findings, lack of response to corticosteroids, and presence of severe optic nerve head swelling or peripapillary hemorrhages to name a few.[23] Lab testing includes oligoclonal bands and more recently added to the new diagnostic criteria is the kappa-free light chain index.

Diagnostic Procedures

Repeated episodes of demyelination result in the formation of plaques that are seen as hyperintense T2 lesions or post-gadolinium enhancement on magnetic resonance imaging (MRI). MRI of the orbits, head and spine is performed to evaluate for these demyelinating plaques in the Optic nerve, Periventricular, Juxtacortical/cortical, Infratentorial, and or Spinal cord. Optic neuritis in MS is typically seen as a unilateral T2 lesion of the optic nerve. Optical coherence tomography can aid in diagnosis of optic neuritis and MS and monitor progression[24]. Thinning of the peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell layer and inner plexiform layer (GCIPL) are observed in MS patients both with and without optic neuritis[25]. Spectral domain optic coherence tomography (SD-OCT) is a recommended diagnostic tool for identifying and monitoring these retinal changes in MS patients[25][26]. Serial imaging is useful for comparing episodes and monitoring disease progression.

Laboratory test

Lumbar punctures can be performed for evaluation of the CSF for oliclonal bands and intrathecal immunoglobulin G (IgG). More recently, kappa-free light chain index which reflects intrathecal B cell activity was shown to be elevated in MS and this was added to the new McDonald criteria 2024. This marker fulfills the dissemination in time. notably there was an 87% concordance between oligoclonal bands and the kappa-free light chain index. [27]



In atypical cases, the following laboratory tests should be considered given a patient’s history, risk factors and clinical findings:

Infectious:

  • Venereal Disease Research Laboratories [VDRL], rapid plasma reagin [RPR] and fluorescent treponemal antibody (FTA-ABS) for syphilis
  • Tuberculin skin test, chest x-ray or Quantiferon-TB for tuberculosis
  • Lyme titers for Lyme disease (in an endemic area)

Inflammatory:

  • Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) for inflammatory disorders

Other demyelinating:

  • Anti-aquaporin 4 [AQP4] IgG antibody for neuromyelitis optica (NMO)
  • Myelin oligodendrocyte glycoprotein antibody (MOG)
  • Serum neurofilament light chain test

Lymphoproliferative

  • CBC with differential


Leber's hereditary optic neuropathy

should be considered in cases that are painless, steroid resistant unilateral or bilateral simultaneous or sequential subacute optic neuropathy with mild or no optic nerve head swelling especially with cecocentral scotomas that might be overall be mistaken for optic neuritis, even in the presence of subcortical white matter lesions that are atypical for MS

Differential diagnosis

The differential diagnosis for optic neuritis is broad, and accurate assessment is important for the proper treatment of the underlying etiology.[28][29] They include:

Management

There is no cure for MS. Management involves pharmacotherapy for immune modulation and symptomatic relief. The Optic Neuritis Treatment Trial (ONTT) has shown that high-dose intravenous methylprednisolone improves recovery time for visual function, contrast sensitivity and color vision. However, corticosteroids have not been shown to improve final visual outcomes.[30] To treat an acute relapse of MS, a 3-5 day course of IV methylprednisolone at a daily dose of 500-1000mg can be given.[31] Plasmapheresis may be used short term for severe attacks if steroids are contraindicated or ineffective.[32] Intravenous immunoglobulin (IVIg) has not been shown to improve long-term visual acuity, contrast sensitivity or color vision and is not recommended for routine use in MS relapses.[31][33] However, for patients who cannot receive intravenous methylprednisolone, IVIg may be used at dose of 2g/kg over 5 days.[31][34][35]

There are now many different medications approved by the FDA for MS which range in mechanisms from immunomodulation to interference with cell trafficking to immune cell depletion.[31][36]

*For many of the medications listed, vision changes may be a sign of Progressive Multifocal Leukoencephalopathy (PML).
Generic Medication Brand Name Mechanism of Action[31] Administration Efficacy[37][38][39][40][41][42] Ocular Side Effects*
Interferons-beta Betaseron®; Avonex®; Rebif® Modify T and B cell activity, cytokine secretion, and T regulatory cells. Self-Injectable Relative risk of 0.71 (95% CI, 0.52–0.97) of disability progression compared to placebo. Retinopathy (less common)
Glatiramer acetate Copaxone®; Glatopa® Modulates T regulatory cells. Self-Injectable Relative risk of 0.82 (95% CI, 0.690.97) of at least 1 relapse at 2 years compared to placebo. Nystagmus; ocular HSV; eye pain (rare)
Natalizumab Tysabri® Selective adhesion molecule inhibitor - interferes with the influx of inflammatory cells into the CNS. Infusion Relative risk of R of 0.56 (95% CI, 0.49–0.64) of at least 1 relapse at 2 years compared to placebo. Blurred vision; HSV related eye infections including ARN (rare)
Fingolimod Gilenya®; Tascenso ODT® Sphingosine1-phosphate receptor modulator - reduces infiltration of potentially auto-aggressive lymphocytes into the CNS. Oral Therapy Relative risk of 0.65 (95% CI, 0.59–0.71) of new or enlarging T2 lesions at 2 years compared to placebo. Macular edema; blurred vision (rare)
Teriflunomide Aubagio® Reversible inhibitor of dihydro-orotate dehydrogenase which mediates de novo synthesis of pyrimidine in rapidly proliferating immune cells. Oral Therapy Relative risk of 0.76 (95% CI, 0.62–0.93) of disability progression sustained for 12 weeks compared to placebo. Blurred vision (less common); red irritated eyes (rare)
Dimethyl Fumarate Tecfidera® Activation of Nuclear Factor-erythroid 2-related factor 2 and nuclear factor-kappa beta to reduce oxidative cell stress and inflammation. Oral Therapy Relative risk of 0.64 (95% CI, 0.54–0.77) of at least 1 relapse at 2 years compared to placebo. Ocular HSV; swelling of eyelids (rare)
Alemtuzumab Lemtrada® Monoclonal antibody that targets the CD52 surface protein present at high levels on T and B lymphocytes. Infusion Relative risk of 0.44 (95% CI, 0.28–0.70) of disability progression sustained for 6 months over 2 years compared to interferon beta. Systemic thyroid disease leading to TED (rare); eye swelling; ocular HSV
Ocrelizumab Ocrevus® Monoclonal antibody that binds to CD20 surface protein on B lymphocytes, leading to their depletion. Infusion Relative risk of 0.67 (95% CI, 0.50–0.89) of disability progression confirmed for 6 months over 2 years compared to interferon beta. Conjunctivitis (common); blurred vision; ocular HSV (rare)
Siponimod Mayzent® Sphingosine1-phosphate receptor modulator - reduces infiltration of potentially auto-aggressive lymphocytes into the CNS. Oral Therapy Relative risk of 0.78 (95% CI 0.65–0.94) of disability progression at six months compared to placebo. Macular edema (common)
Cladribine Mavenclad® Nucleoside analogue that leads to inhibition of DNA synthesis and repair, and subsequent apoptosis, with preference for lymphocytes. Oral Therapy Relative risk of 0.78 (95% CI, 0.44–1.42) of disability progression at 1 year compared to placebo. Conjunctivitis; blepharitis (common); retinopathy (rare)
Diroximel Fumarate Vumerity® Activation of Nuclear Factor-erythroid 2-related factor 2 and nuclear factor-kappa beta to reduce oxidative cell stress and inflammation. Oral Therapy Adjusted annualized relapse rate reduced by 78.7% [rate ratio 0.21, 95% CI 0.14, 0.31] compared to interferon beta. Ocular HSV; blurred vision; swelling of eyelids (rare)
Ozanimod Zeposia® Sphingosine1-phosphate receptor modulator - reduces infiltration of potentially auto-aggressive lymphocytes into the CNS. Oral Therapy Adjusted annualized relapse rate of 0.098 (95% CI, 0.082–0.117) compared to interferon beta. Macular edema (less common)
Ofatumumab Kesimpta® Monoclonal antibody that binds to CD20 surface protein on B lymphocytes, leading to their depletion. Self-Injectable Adjusted annualized relapse rate of 0.05 (95% CI, 0.04–0.07) compared to teriflunomide. None reported
Monomethyl Fumarate Bafiertam™ Activation of Nuclear Factor-erythroid 2-related factor 2 and nuclear factor-kappa beta to reduce oxidative cell stress and inflammation. Oral Therapy Efficacy established through studies of dimethyl fumarate. Ocular HSV (rare)
Ublituximab Briumvi™ An anti-CD20 monoclonal antibody that leads to increased antibody-dependent cellular cytolysis and B-cell depletion. Infusion Annualized relapse rate of 0.08 (rate ratio, 0.41; 95% CI, 0.27–0.62) compared to teriflunomide. None reported

Prognosis

Multiple sclerosis can have severe debilitating effects within 20-25 years of onset. Up to 30% of patients eventually require assistance for ambulation, and 22% become wheelchair bound.[43] There is a 5 to 10 year decrease in life expectancy, and death secondary to cardiovascular disease, infection and suicide is higher in MS compared to the general population.[44]

Higher lesion load, more numerous active lesions, and higher cortical lesions at disease onset are associated with less favorable prognosis of overall MS disease[45][46]. Higher NfLc levels is also associated with less favorable prognosis and progression of MS[47].

Many of the clinical findings of optic neuritis come from the Optic Neuritis Treatment Trial (ONTT), a multi-institutional study of 454 patients with acute unilateral optic neuritis carried out between 1988 and 1991. The 15-year follow-up of the Optic Neuritis Treatment Trial (ONTT) showed that clinically definite MS developed in 50% of ONTT patients in 15 years. However, the probability of developing clinically definite MS based on MRI scan appearance ranged from 25% for patients with no lesions on the brain MRI to 72% with 1 or more lesions.

Visual prognosis following the first episode of optic neuritis is typically good with or without the use of corticosteroids. Visual symptoms such as decreased visual acuity, visual field defects, and color vision defects recover within weeks to months. A majority of patients achieve 20/20 vision one year after an acute episode while 8% of patients retain a visual acuity worse than 20/40.[48] However, recurrent episodes are associated with less favorable prognosis.

References

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  2. ↑ 2.0 2.1 Simpson S Jr., Blizzard L, Otahal P, et al. Latitude is significantly associated with the prevalence of multiple sclerosis: A meta-analysis. J Neurol Neurosurg Psychiatry 2011; 82: 1132–1141.
  3. ↑ World Health Organization (2008). Atlas: Multiple Sclerosis Resources in the World 2008 (PDF). Geneva: World Health Organization. Pp. 15–16. ISBN 92-4-156375-3
  4. ↑ Willer CJ, Dyment DA, Risch NJ, Sadovnick AD, Ebers GC; Twin concordance and sibling recurrence rates in multiple sclerosis. Canadian Collaborative Study Group. Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12877-82.
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