What is multiple sclerosis?

What is Multiple Sclerosis?

Multiple sclerosis is a chronic autoimmune-mediated neurodegenerative disease of the central nervous system characterized by inflammatory demyelination with axonal transection, leading to physical disability, cognitive impairment, and decreased quality of life. 1

Pathophysiology

MS involves an aberrant attack by the host immune system on oligodendrocytes, which synthesize and maintain myelin sheaths in the CNS, resulting in demyelination, inflammation, neuronal loss, and gliosis (scarring). 2, 3

• Autoreactive CD4+ T cells, particularly the T helper 1 (Th1) subtype, are the leading initiators of myelin destruction. 2
• These immunogenic T cells produce proinflammatory cytokines after activation outside the CNS, often following viral infections. 2
• Recent evidence shows that myelin injury precedes axonal injury by approximately 1 year and occurs roughly 7 years before symptomatic onset, while astrocyte involvement becomes evident only at clinical onset. 4

Epidemiology

• MS affects approximately 900,000 people in the United States and 2.3 million worldwide. 1, 3
• The disease typically presents in young adults with a mean age of onset between 20-30 years. 1, 3
• MS more commonly affects women, with a female-to-male sex distribution of nearly 3:1. 1
• Worldwide prevalence ranges from 5 to 300 per 100,000 people and increases at higher latitudes. 1
• Overall life expectancy is reduced compared to the general population (75.9 vs 83.4 years). 1

Clinical Presentations

MS typically presents with subacute neurological symptoms developing over several days, including: 1

• Unilateral optic neuritis – painful unilateral vision loss with loss of color vision 5
• Partial myelitis – incomplete transverse myelitis with sensory level, weakness, or bladder dysfunction 5
• Sensory disturbances – numbness, tingling, or paresthesias 1
• Brainstem syndromes – diplopia and internuclear ophthalmoplegia 5, 1
• Motor weakness and impaired gait 6
• Lhermitte sign – electric shock sensation down the spine with neck flexion 6
• Fatigue – one of the most disabling symptoms 6

Disease Courses

Approximately 85% of people with MS present with relapsing-remitting MS (RRMS), characterized by discrete acute attacks (relapses) followed by periods of remission with stable neurological disability between episodes. 6, 3

• Secondary progressive MS develops in many RRMS patients, characterized by steadily increasing neurological disability following a relapsing course, with or without ongoing inflammatory activity. 1
• Primary progressive MS is characterized by steadily increasing neurological disability from onset without distinct relapses. 7, 1
• Clinically isolated syndrome (CIS) and radiologically isolated syndrome (RIS) are additional categories for patients with findings concerning for MS who do not yet meet full diagnostic criteria. 6

Diagnostic Approach

Diagnosis requires a combination of clinical history, neurologic examination, MRI findings, and laboratory tests, applied according to the 2017 McDonald Criteria (recently updated in 2024). 8, 6, 1

MRI Criteria for Dissemination in Space (DIS)

At least one lesion in two or more of the following locations: 5

• Periventricular (≥3 periventricular lesions is highly specific) 5
• Juxtacortical 8, 5
• Infratentorial (e.g., pons, brainstem) 5
• Spinal cord 5

Dissemination in Time (DIT)

Evidence of lesions occurring at different time points, demonstrated by: 8

• Simultaneous presence of gadolinium-enhancing and non-enhancing lesions on a single MRI 8
• New T2 lesions or gadolinium-enhancing lesions on follow-up MRI compared to baseline 8

Laboratory Testing

• CSF oligoclonal bands specific to CSF are present in 85-95% of MS patients and support the diagnosis, particularly when MRI findings are borderline. 9, 7
• Serum AQP4-IgG and MOG-IgG testing must be obtained at the first clinical encounter to exclude neuromyelitis optica spectrum disorder (NMOSD) and MOG-antibody disease, which require distinct immunotherapies. 9
• Visual evoked potentials may show delayed conduction, particularly useful in suspected optic nerve involvement. 9, 7

Critical Red Flags Requiring Immediate Alternative Diagnosis Consideration

The following features suggest NMOSD or MOG-antibody disease rather than MS: 9

• Bilateral simultaneous optic neuritis 9
• Prominent optic disc edema or papilledema 9
• Longitudinally extensive optic nerve lesions (≥4 of 5 segments) 9
• Longitudinally extensive transverse myelitis (≥3 contiguous vertebral segments) 9
• Area postrema syndrome (intractable nausea, vomiting, or hiccups) 9

Common Diagnostic Pitfalls

• Never diagnose MS based solely on MRI findings without at least one clinical event consistent with acute demyelination. 7
• Do not initiate MS disease-modifying therapies before excluding NMOSD, as certain MS treatments (e.g., interferon-β) can worsen NMOSD outcomes and increase relapse rates. 9
• Applying diagnostic criteria to atypical presentations without additional supportive evidence increases the risk of misdiagnosis. 8, 7
• Do not postpone antibody testing while awaiting evidence of dissemination in space, as many NMOSD and MOG-antibody disease patients present with isolated syndromes. 9

Treatment Overview

Disease-modifying therapies (DMTs) are the standard of care for relapsing forms of MS and should be initiated as early as possible. 6, 3

• Nine classes of DMTs are available for relapsing-remitting MS and secondary progressive MS with activity, including interferons, glatiramer acetate, teriflunomide, sphingosine 1-phosphate receptor modulators, fumarates, cladribine, and three types of monoclonal antibodies. 1
• Current DMTs reduce annualized relapse rates by 29-68% compared with placebo or active comparators and reduce MRI lesions (new T2 lesions, gadolinium-enhancing lesions). 1
• Ocrelizumab is approved for primary progressive MS. 1
• Steroids are the mainstay of treatment for acute relapses, with plasmapheresis reserved for patients who do not adequately respond. 6

Symptom Management

• Spasticity: Physiotherapy, baclofen or gabapentin as first-line, tizanidine or dantrolene as second-line, benzodiazepines as third-line. 2
• Urinary incontinence: Anticholinergics (oxybutynin), tricyclic antidepressants (amitriptyline), or intermittent self-catheterization. 2
• Bowel problems: Stool softeners and high-fiber diet. 2
• Fatigue, depression, movement disorders, and pain require individualized symptom-based care. 6

Prognosis and Disease Burden

MS significantly impairs patient quality of life and is associated with substantial costs to patients, healthcare systems, and society. 3 The disease is often diagnosed in the second or third decade of life and can lead to progressive physical disability and cognitive impairment. 1, 3