Multiple Sclerosis¶
Chapter 455 | Part 13: Neurologic Disorders
KEY CLINICAL POINTS¶
- Multiple sclerosis (MS) is an autoimmune disease of the CNS characterized by chronic inflammation, demyelination, gliosis, and neuronal loss.
- The clinical course is variable, ranging from relapsing-remitting (RRMS) to secondary progressive (SPMS) or primary progressive (PPMS).
- Epstein-Barr virus (EBV) infection and vitamin D deficiency are significant risk factors for MS.
- MRI is central to diagnosis, with dissemination in space and time required for clinical definite MS.
- Disease-modifying therapies (DMTs) like anti-CD20 agents, S1P modulators, and interferons are first-line treatments for relapsing MS.
1. DEFINITION & OVERVIEW¶
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by chronic inflammation, demyelination, gliosis (plaques or scarring), and neuronal loss. The course can be relapsing or progressive. MS plaques typically develop at different locations in the CNS.
Table 455-1 Initial Symptoms of Multiple Sclerosis (MS)¶
| SYMPTOM | PERCENTAGE OF CASES |
|---|---|
| Sensory loss | 37 |
| Optic neuritis | 36 |
| Weakness | 35 |
| Paresthesias | 24 |
| Diplopia | 15 |
| Facial palsy | 1 |
| Ataxia | 11 |
| Vertigo | 6 |
| Paroxysmal attacks | 4 |
| Bladder dysfunction | 4 |
| Falling | 1 |
1.1 Pathogenesis¶
MS is driven by autoimmune responses against CNS myelin and other neural elements. EBV infection, vitamin D deficiency, and genetic factors (e.g., HLA-DRB1*1501) contribute to pathogenesis. Neurodegeneration and inflammation coexist throughout the disease course.
1.2 Clinical Course¶
MS has three principal clinical forms: relapsing-remitting (RRMS, 90% of cases), secondary progressive (SPMS), and primary progressive (PPMS, ~10% of cases). Relapses are driven by inflammation, while progression involves neurodegeneration independent of relapses.
2. EPIDEMIOLOGY¶
MS prevalence is highest in temperate zones, with a north-south gradient. Women are three times more likely than men to develop MS. Risk factors include EBV infection, cigarette smoking, and vitamin D deficiency. Prevalence has increased globally over the past half-century.
Table 455-3 Risk of Developing Multiple Sclerosis (MS)¶
| Family Relationship | Risk Ratio |
|---|---|
| Identical twin | 1 in 3 |
| Fraternal twin | 1 in 15 |
| Sibling | 1 in 25 |
| Parent/half-sibling | 1 in 50 |
| First cousin | 1 in 100 |
| Spouse | 1 in 1000 |
| No family history | 1 in 1000 |
2.1 Geographic and Demographic Trends¶
MS is more common in temperate regions and less prevalent in tropical zones. Women are disproportionately affected (~3:1 ratio). Prevalence is 10–20 times higher in temperate zones compared to tropical regions.
2.2 Risk Factors¶
EBV infection, cigarette smoking, and vitamin D deficiency are strongly associated with MS risk. Genetic factors (e.g., HLA-DRB1*1501) and environmental triggers (e.g., low UVB exposure) also contribute.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
MS is driven by autoimmune responses against CNS myelin, with EBV infection and genetic susceptibility (HLA-DRB1*1501) playing key roles. Neuroinflammation and neurodegeneration coexist, with demyelination and gliosis as pathologic hallmarks.
3.1 Viral and Genetic Factors¶
EBV infection is strongly associated with MS risk, with serologic conversion to EBV being a prerequisite for MS development. Genetic variants in HLA-DRB1*1501 and other loci (e.g., ZNF638) influence disease severity and progression.
3.2 Neuroinflammation and Neurodegeneration¶
Inflammation drives relapses, while neurodegeneration underlies progressive disability. Demyelination reduces axonal trophic support, leading to distal and retrograde axonal degeneration (dying-back axonopathy).
4. CLINICAL FEATURES¶
MS presents with diverse symptoms including sensory loss, optic neuritis, weakness, and bladder dysfunction. Neurological examination reveals signs like spasticity, ataxia, and cognitive impairment.
4.1 Common Symptoms¶
Sensory symptoms (paresthesias, hypesthesia), optic neuritis, weakness, diplopia, ataxia, and bladder dysfunction are common. Lhermitte’s sign (electric shock-like sensation) and Uhthoff’s phenomenon (worsening symptoms with heat) are characteristic.
4.2 Neurological Examination Findings¶
Pyramidal signs (spasticity, hyperreflexia), cerebellar ataxia, and cognitive dysfunction (memory loss, executive deficits) are frequently observed. Paroxysmal symptoms (e.g., tonic seizures) may occur.
5. DIFFERENTIAL DIAGNOSIS¶
Conditions mimicking MS include neuromyelitis optica (NMO), myelin oligodendrocyte glycoprotein antibody disease (MOGAD), acute disseminated encephalomyelitis (ADEM), and vasculitis. Distinguishing these requires clinical and imaging features.
Table 455-5 Disorders That Can Mimic Multiple Sclerosis (MS)¶
| Condition |
|---|
| Acute disseminated encephalomyelitis (ADEM) |
| Antiphospholipid antibody syndrome |
| Behçet’s disease |
| CADASIL |
| Congenital leukodystrophies |
| GFAP autoimmunity |
| HIV infection |
| Ischemic optic neuropathy |
| Lyme disease |
| MELAS |
| MOGAD |
| Neoplasms |
| Neuromyelitis optica |
| Sarcoidosis |
| Sjögren’s syndrome |
| Stroke and ischemic cerebrovascular disease |
| Syphilis |
| Systemic lupus erythematosus |
| Tropical spastic paraparesis |
| Vascular malformations |
5.1 Mimicking Disorders¶
NMO (aquaporin-4 antibodies), MOGAD (myelin oligodendrocyte glycoprotein antibodies), ADEM (post-infectious), and vasculitis (e.g., antiphospholipid syndrome) must be excluded. MRI and CSF analysis help differentiate.
6. INVESTIGATIONS & DIAGNOSIS¶
MRI is central to diagnosis, showing dissemination in space and time. CSF analysis reveals oligoclonal bands and elevated IgG. Evoked potentials (EPs) and clinical criteria (McDonald 2017) confirm MS.
Table 455-4 Diagnostic Criteria for Multiple Sclerosis (MS)¶
| CLINICAL PRESENTATION | ADDITIONAL DATA NEEDED FOR MS DIAGNOSIS |
|---|---|
| 2 or more attacks; objective clinical evidence of 2 or more lesions or 1 lesion with reasonable historical evidence of a prior attack | None |
| 2 or more attacks; objective clinical evidence of 1 lesion with dissemination in space (‡1 T2 lesion in 2 of 4 MS-typical CNS regions) and dissemination in time (simultaneous asymptomatic gadolinium-enhancing and nonenhancing lesions at any time) | OR a new T2/gadolinium-enhancing lesion on follow-up MRI |
| 1 attack; dissemination in space and time (e.g., 1 lesion with simultaneous asymptomatic gadolinium-enhancing and nonenhancing lesions) OR a new T2/gad,enhancing lesion on follow-up MRI | OR await a second clinical attack |
6.1 MRI Findings¶
T2-weighted MRI shows periventricular, juxtacortical, and infratentorial white matter lesions. Gadolinium enhancement indicates active inflammation. Central vein sign and black holes (T1 hypointensity) are diagnostic features.
6.2 CSF and Evoked Potentials¶
CSF shows oligoclonal bands in >90% of MS patients. EPs (visual, somatosensory) detect subclinical demyelination. MRI and EPs are critical for diagnosing clinically isolated syndrome (CIS).
7. MANAGEMENT & TREATMENT¶
Treatment includes acute attack management, disease-modifying therapies (DMTs), and symptomatic care. High-efficacy DMTs (e.g., anti-CD20 agents) are first-line for relapsing MS. Symptomatic therapies address spasticity, fatigue, and bladder dysfunction.
Table 455-6 Disease-Modifying Therapies for Multiple Sclerosis¶
| CATEGORY AND MECHANISM | GENERIC NAME (TRADE NAME) | DOSE AND INTERVAL | CHARACTERISTIC S | COMMENTS |
|---|---|---|---|---|
| Anti-CD20 B cell MAbs | Ocrelizumab (Ocrevus) | 600-mg infusion q6 months | Humanized; ADCC > complement | Outstanding efficacy in RMS and PPMS |
| CATEGORY AND MECHANISM | GENERIC NAME (TRADE NAME) | DOSE AND INTERVAL | CHARACTERISTIC S | COMMENTS |
|---|---|---|---|---|
| Anti-CD20 B cell MAbs | Ofatumumab (Kesimpta) | 20-mg subcutaneous monthly | Fully human; Complement > ADCC | Home-based treatment; minor injection reactions |
| Anti-CD20 B cell MAbs | Ublituximab (Briumvi) | 450-mg infusion q6 months | Chimeric; ADCC > Complement | |
| Anti-CD20 B cell MAbs | Rituximab (Rituxan) | 1000-mg infusion q6 months | Chimeric; Complement > ADCC | Formally tested in RMS; used off-label in SPMS |
| Anti-a4 subunit of a4b1 integrin | Natalizumab (Tysabri) | 300-mg monthly infusion | Humanized | Risk of PML; requires JC virus antibody testing |
7.1 Acute Attacks¶
Glucocorticoids (IV methylprednisolone) reduce attack severity. Plasma exchange may be used for severe cases. Avoid corticosteroids for pseudoexacerbations (e.g., heat sensitivity).
7.2 Disease-Modifying Therapies¶
High-efficacy DMTs: anti-CD20 (ocrelizumab, ofatumumab), natalizumab, and alemtuzumab. Moderately effective: S1P modulators (fingolimod, ozanimod), interferons, and glatiramer acetate. Symptomatic therapies include baclofen for spasticity and anticonvulsants for paroxysmal symptoms.
8. PROGNOSIS & COMPLICATIONS¶
Prognosis has improved with DMTs, with relapses largely eliminated. Progressive MS (SPMS/PPMS) remains challenging, but therapies like ocrelizumab slow disability progression. Complications include fatigue, spasticity, and bladder dysfunction.
8.1 Long-Term Outcomes¶
Early treatment with high-efficacy DMTs delays disability progression. Ocrelizumab reduces SPMS progression by 25% and improves PPMS outcomes. Most patients with MS now achieve long-term stability with modern therapies.
8.2 Complications¶
Fatigue (most common cause of work disability), spasticity, bladder/bowel dysfunction, and cognitive impairment are major complications. PML risk with natalizumab and immunosuppressive side effects require careful monitoring.
9. SPECIAL CONSIDERATIONS¶
Pregnancy management involves discontinuing DMTs (e.g., natalizumab, S1P modulators) and using anti-CD20 agents preconception. MS patients with progressive disease may still worsen despite optimal therapy, highlighting the need for new treatments.
9.1 Pregnancy and Lactation¶
MS activity decreases during pregnancy but increases postpartum. DMTs are generally discontinued during pregnancy, with anti-CD20 agents preferred for preconception. Breastfeeding is generally safe with most DMTs.
9.2 Pediatric and Geriatric Considerations¶
Children with MS may present with atypical symptoms (e.g., optic neuritis without typical MRI findings). Elderly patients face higher risks of comorbidities and treatment-related side effects.
10. KEY POINTS & CLINICAL PEARLS¶
- MS is an autoimmune CNS disease with relapsing or progressive courses. 2. EBV infection and vitamin D deficiency are major risk factors. 3. MRI and clinical criteria (dissemination in space/time) are essential for diagnosis. 4. High-efficacy DMTs (e.g., anti-CD20 agents) are first-line for relapsing MS. 5. Symptomatic management addresses fatigue, spasticity, and bladder dysfunction. 6. Ocrelizumab is the only DMT shown to modify PPMS progression.