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Multiple Sclerosis

Chapter 455 | Part 13: Neurologic Disorders · Part 13 – Neurologic Disorders · Chapter 455

Key Clinical Points

  1. MS is an autoimmune CNS disease characterized by inflammation, demyelination, gliosis (plaques), and neuronal loss.
  2. Diagnosis requires dissemination in space (DIS) and time (DIT).
  3. EBV infection is a near-universal prerequisite; history of mononucleosis increases risk >2x.
  4. HLA-DRB1*1501 is the strongest genetic signal, contributing to ~10% of disease risk.
  5. Clinical courses: Relapsing-remitting (RRMS), Secondary progressive (SPMS), and Primary progressive (PPMS).
  6. PIRA (Progression Independent of Relapse Activity) describes 'silent' progression in both RRMS and progressive forms.
  7. Common clinical features include optic neuritis, sensory loss, motor weakness, and paresthesias.
  8. Specific markers: Uhthoff's symptom (heat sensitivity), Lhermitte's symptom, and internuclear ophthalmoplegia (INO).
  9. Neuroimaging hallmarks: Dawson's fingers, 'black holes' on T1, and gadolinium enhancement for active inflammation.
  10. Treatment has shifted toward B-cell targeted therapies and S1P modulators to manage both relapses and progression.

DEFINITION & CLASSIFICATION

• Definition (Harrison's 25e): autoimmune disease of the central nervous system (CNS) characterized by chronic inflammation, demyelination, gliosis (plaques or scarring), and neuronal loss. • Core Pathophysiology: ◦ Dissemination in space: Plaques develop at different times and locations. ◦ Clinical Variability: Ranges from benign to rapidly escalating disability. ◦ Radiologically Isolated Syndrome (RIS): Evidence of MS on MRI without clinical symptoms.

Disease Course Classifications

• Relapsing-remitting MS (RRMS): ◦ Prevalence: ~90% of cases. ◦ Character: Discrete attacks of dysfunction over days to weeks; substantial recovery often follows. ◦ Note: Most RRMS patients experience 'silent' progression even when relapse-free. • Secondary progressive MS (SPMS): ◦ Transition: Begins as RRMS, then shifts to progressive deterioration independent of acute attacks. ◦ Definition: Patient has developed some level of permanent walking disability not due exclusively to relapses. ◦ Diagnostic Support: EDSS ≥ 4 + FSS motor score ≥ 2. ◦ Progression Rate: In the pre-treatment era, ~3% per year; currently <1% per year due to effective therapies. • Primary progressive MS (PPMS): ◦ Prevalence: ~10% of cases. ◦ Character: Steady decline from onset without distinct attacks. ◦ Demographics: More even sex distribution, later onset (mean age ~40), faster disability progression relative to first symptom. • Active Progressive MS: ◦ Definition: Progressive MS (SPMS or PPMS) patients with relapses or new lesions on serial MRI.

EPIDEMIOLOGY

• Geographic Gradient: Higher prevalence in temperate zones; 10- to 20-fold lower in tropical regions. • Demographics: ◦ Sex: Women affected ~3x more often than men. ◦ Age: Typically 20–40 years (slightly later in men). • Trends: Increasing prevalence over the last 50 years, particularly in women and non-white populations. • Risk Factors: ◦ EBV Infection: Near-universal requirement; risk is ~20-fold higher in EBV+ individuals. ◦ Mononucleosis: History of infection increases risk >2x. ◦ Vitamin D Deficiency: Linked to lower levels of UV radiation and lack of sun exposure. ◦ Smoking: Associated with increased MS risk.

ETIOLOGY & PATHOPHYSIOLOGY

• Genetic Factors: ◦ Polygenic inheritance; each gene has a small effect. ◦ HLA-DRB11501: Strongest signal (approx. 10% of risk). ◦ Other variants: >230 identified, involving IL-7R (CD127), IL-2R (CD25), and LFA-3 (CD58). • Immune Mechanisms: ◦ B Cells: Central to demyelinating lesions; produce oligoclonal immunoglobulins in CSF. ◦ T Cells: CD4+ T cells respond to self-peptides presented by HLA-DR2. ◦ Molecular Mimicry: Potential cross-reactivity between EBV/bacterial peptides and myelin antigens. • Pathology of Progression:* ◦ Relapsing MS: Focal perivenular infiltration, BBB disruption, active demyelination. ◦ Progressive MS: Diffuse inflammation, microglial proliferation, 'dirty white matter' (reduced myelin, axonal injury). ◦ Chronic Active Plaques: Preexisting lesions with persistent inflammation and expansion without initial BBB disruption.

Pathology

• Demyelination: ◦ Initial stage: Perivenular cuffing by T cells/macrophages; BBB disruption (but vessel wall preserved). ◦ Axonal Injury: Primary contributor to irreversible disability; 70% of axons lost in paraplegia. ◦ Shadow Plaques: Areas where surviving oligodendrocytes partially remyelinate axons. • Gliosis: ◦ Sclerosis refers to the hardened, gliotic texture of plaques at autopsy. ◦ Microglial Activation: Triggered by pro-inflammatory B/T cells or tissue injury signals.

Physiology

• Normal Conduction: Saltatory; impulses jump between Nodes of Ranvier (faster, ~70 m/s). ◦ Mechanism: Na+ channels concentrated at nodes. • Demyelinated Conduction: ◦ Conduction Block: Occurs when membrane becomes hyperpolarized due to exposed K+ channels. ◦ Compensation: Na+ channels redistribute along the naked axon, allowing continuous but slower propagation. ◦ Clinical Impact: Conduction block is often temperature/metabolism dependent (Uhthoff's symptom).

CLINICAL FEATURES

• General: Symptoms reflect lesion location; patients may present with symptoms in one limb but signs in both. ◦ Risk of asymptomatic MS (RIS) found on incidental imaging.

Sensory & Pain

• Sensory Loss: Includes paresthesias (tingling, burning) and hypesthesia (numbness). ◦ Sensory Level: Indicates spinal cord involvement; often accompanied by a band of tightness. ◦ Pain: Experienced by >50% of patients; can be localized or wandering. ◦ Table 1 Data: Sensory loss reported in 37% of cases.

Visual Symptoms

• Optic Neuritis (ON): Diminished acuity, dimness, or color desaturation; usually monocular. ◦ Associated Signs: Periorbital pain (preceding/accompanying), afferent pupillary defect. ◦ Fundoscopy: May show optic disc swelling (papillitis) or later atrophy.

Motor & Coordination

• Weakness: Upper motor neuron type; includes spasticity, hyperreflexia, and extensor plantar responses. ◦ Exercise-induced weakness: Characteristic of MS. ◦ Facial Palsy: May mimic Bell's palsy but lacks ipsilateral loss of taste or retroauricular pain. ◦ Ataxia: Often manifests as cerebellar tremors; can cause 'scanning speech'. ◦ Internuclear Ophthalmoplegia (INO): Impaired adduction due to medial longitudinal fasciculus lesion; bilateral INO is highly suggestive of MS.

Ancillary Symptoms

• Paroxysmal Symptoms: Brief (10s-2min), high frequency, no change in consciousness. ◦ Lhermitte's: Electric shock sensation upon neck flexion; indicates cervical spinal cord involvement. ◦ Uhthoff's Symptom: Transient worsening of symptoms due to increased core temperature (e.g., hot shower, exercise). ◦ Trigeminal Neuralgia: Atypical features (age <50, bilateral) suggest MS etiology. ◦ Bladder Dysfunction: Present in most patients; involves detrusor muscle and sphincter coordination.

DIFFERENTIAL DIAGNOSIS

• Common Mimics (Table 5): 1. Acute disseminated encephalomyelitis (ADEM) 2. Antiphospholipid antibody syndrome 3. Behçet’s disease 4. CADASIL 5. Congenital leukodystrophies (e.g., adrenoleukodystrophy, metachromatic leukodystrophy) 6. Glial Fibrillary Acidic Protein (GFAP) Autoimmunity 7. HIV infection 8. Ischemic optic neuropathy (arteritic and nonarteritic) 9. Lyme disease 10. MELAS 11. MOGAD 12. Neoplasms (lymphoma, glioma, meningioma) 13. Neuromyelitis optica 14. Sarcoidosis 15. Sjögren’s syndrome 16. Stroke and ischemic cerebrovascular disease 17. Syphilis 18. SLE and related collagen vascular disorders 19. Tropical spastic paraparesis (HTLV-1/2) 20. Vascular malformations (e.g., spinal dural AV fistulas) 21. Vasculitis (primary CNS or other) 22. Vitamin B12 deficiency

DIAGNOSTIC APPROACH

  1. Clinical Presentation Assessment:
  2. Identify 2 or more attacks (objective) OR
  3. 1 attack with reasonable historical evidence of a prior attack.
  4. Dissemination in Space (DIS):
  5. Demonstrated by ≥1 T2 lesion on MRI in at least 2 out of 4 MS-typical areas.
  6. Dissemination in Time (DIT):
  7. Evidence of 2 or more attacks OR
  8. Objective evidence of 1 lesion with reasonable history of prior attack.
  9. MRI Findings:
  10. T2/FLAIR: Identify hyperintense lesions (plaques).
  11. T1 Post-Contrast: Identify areas of active inflammation (gadolinium enhancement).
  12. Specific Markers: Dawson's Fingers, 'black holes', and spinal cord involvement.

MANAGEMENT & TREATMENT

  1. Therapeutic Goals:
  2. Reduce relapse frequency.
  3. Slow progression of disability (addressing PIRA).
  4. Manage acute symptoms (e.g., pain, spasticity).
  5. Highly Effective Anti-CD20 B cell MAbs:
  6. Ocrelizumab (Ocrevus): 600-mg infusion q6 months (first dose: two 300-mg infusions 14 days apart). Approved for RRMS and PPMS.
  7. Ofatumumab (Kesimpta): 20-mg subcutaneous injections monthly (after 3 weekly 20-mg loading doses).
  8. Ublituximab (Briumvi): 450-mg infusion q6 months (first dose: 150-mg, then 450-mg 14 days later).
  9. Rituximab (Rituxan): 1000-mg infusion q6 months (or 500 mg IV q6 months).
  10. Other High Efficacy Agents:
  11. Natalizumab (Tysabri): 300-mg monthly infusion.
  12. Alemtuzumab (Lemtrada): 12 mg/m² infusion for 5 consecutive days; second 3-day course after 1 year. (High risk of complications: thyroid, ITP, infection).
  13. Moderately Effective S1P Modulators:
  14. Fingolimod (Gilenya): 0.5 mg oral once daily.
  15. Ozanimod (Zeposia): 1 mg oral once daily.
  16. Ponesimod (Ponvory): 20 mg oral once daily.
  17. Siponimod (Mayzent): 1 mg oral daily (Dose adjusted for CYP2C9 genotype; reduced if 3/*3).
  18. Fumarates:
  19. Dimethyl fumarate (Tecfidera): 240 mg oral twice daily (half-dose first 7 days). Monitor LFTs and lymphopenia.
  20. Diroximel fumarate (Vumerity): 262 mg oral twice daily.
  21. Purine Analogue:
  22. Cladribine (Mavenclad): Weight-based (3.5 mg/kg) over 4–5 days; repeated 23–27 days later; second course after 1 year.

Monitoring & Safety

• Siponimod: First-dose monitoring required for patients with sinus bradycardia, heart block, or prior MI/HF. • Ponesimod: 4-hour cardiac monitoring required for patients with prior MI or heart failure. • Cladribine: Monitor for malignancy, teratogenicity, and infection (including PML).

PROGNOSIS & COMPLICATIONS

• Progression: Disability is driven by both relapses and 'silent' progression (PIRA). • Complications: - Spinal cord damage leading to permanent walking disability. - Potential for PML with certain therapies. - Chronic complications: Bladder dysfunction, fatigue, and sensory loss.

KEY PEARLS & HIGH-YIELD POINTS

• Risk Calculation (Table 3): - Identical twin with MS → 1 in 3 risk. - Sibling with MS → 1 in 25 risk. - First cousin with MS → 1 in 100 risk. - No family history → 1 in 1000 risk. • Diagnostic Rule: Diagnosis requires DIS and DIT. • Clinical Pearls: - Uhthoff's = Heat sensitivity; Lhermitte's = Neck flexion shock. - Bilateral INO is highly specific for MS. - Dawson's Fingers are pathognomonic for MS on MRI.

Reference Tables

TABLE 455-1 Initial Symptoms of Multiple Sclerosis (MS) SYMPTOM Sensory loss Optic neuritis Weakness Paresthesias…

Harrison's 22e, p.3577

SYMPTOM PERCENTAGE
OF CASES		 SYMPTOM PERCENTAGE
OF CASES
Sensory loss 37 Lhermitte 3
36 Pain
Weakness 35 Dementia 2
24 Visual loss
Diplopia 15 Facial palsy 1
11 Impotence
Vertigo 6 Myokymia 1
4 Epilepsy
Bladder 4 Falling 1
455 Multiple Sclerosis
Bruce A. C. Cree, Stephen L. Hauser

TABLE 455-2 Scoring Systems for Multiple Sclerosis (MS) Expanded Disability Status Scale (EDSS) 0.0 = Normal neurologic…

Harrison's 22e, p.3580

Expanded Disability Status Scale (EDSS)
0.0 = Normal neurologic examination (all grade 0 in functional status [FS])
1.0 = No disability, minimal signs in one FS (i.e., grade 1)
1.5 = No disability, minimal signs in more than one FS (more than one grade 1)
2.0 = Minimal disability in one FS (one FS grade 2, others 0 or 1)
2.5 = Minimal disability in two FS (two FS grade 2, others 0 or 1)
3.0 = Moderate disability in one FS (one FS grade 3, others 0 or 1) or mild disability
in three or four FS (three/four FS grade 2, others 0 or 1) although fully
ambulatory
3.5 = Fully ambulatory but with moderate disability in one FS (one grade 3) and one
or two FS grade 2; or two FS grade 3; or five FS grade 2 (others 0 or 1)
4.0 = Ambulatory without aid or rest for ~500 m
4.5 = Ambulatory without aid or rest for ~300 m
5.0 = Ambulatory without aid or rest for ~200 m		 5.5 = Ambulatory without aid or rest for ~100 m
6.0 = Unilateral assistance required to walk about 100 m with or without resting
6.5 = Constant bilateral assistance required to walk about 20 m without resting
7.0 = Unable to walk beyond about 5 m even with aid; essentially restricted to
wheelchair; wheels self and transfers alone
7.5 = Unable to take more than a few steps; restricted to wheelchair; may need aid
to transfer
8.0 = Essentially restricted to bed or chair or perambulated in wheelchair, but out
of bed most of day; retains many self-care functions; generally has effective
use of arms
8.5 = Essentially restricted to bed much of the day; has some effective use of
arm(s); retains some self-care functions
9.0 = Helpless bed patient; can communicate and eat
9.5 = Totally helpless bed patient; unable to communicate or eat
10.0 = Death due to MS
Functional Status (FS) Score
A. Pyramidal functions
0 = Normal
1 = Abnormal signs without disability
2 = Minimal disability
3 = Mild or moderate paraparesis or hemiparesis, or severe monoparesis
4 = Marked paraparesis or hemiparesis, moderate quadriparesis, or monoplegia
5 = Paraplegia, hemiplegia, or marked quadriparesis
6 = Quadriplegia
B. Cerebellar functions
0 = Normal
1 = Abnormal signs without disability
2 = Mild ataxia
3 = Moderate truncal or limb ataxia
4 = Severe ataxia all limbs
5 = Unable to perform coordinated movements due to ataxia
C. Brainstem functions
0 = Normal
1 = Signs only
2 = Moderate nystagmus or other mild disability
3 = Severe nystagmus, marked extraocular weakness, or moderate disability of
other cranial nerves
4 = Marked dysarthria or other marked disability
5 = Inability to swallow or speak
D. Sensory functions
0 = Normal
1 = Vibration or figure-writing decrease only, in 1 or 2 limbs
2 = Mild decrease in touch or pain or position sense, and/or moderate decrease in
vibration in 1 or 2 limbs, or vibratory decrease alone in 3 or 4 limbs
3 = Moderate decrease in touch or pain or position sense, and/or essentially lost
vibration in 1 or 2 limbs, or mild decrease in touch or pain, and/or moderate
decrease in all proprioceptive tests in 3 or 4 limbs
4 = Marked decrease in touch or pain or loss of proprioception, alone or
combined, in 1 or 2 limbs or moderate decrease in touch or pain and/or severe
proprioceptive decrease in >2 limbs		 5 = Loss (essentially) of sensation in 1 or 2 limbs or moderate decrease in touch or
pain and/or loss of proprioception for most of the body below the head
6 = Sensation essentially lost below the head
E. Bowel and bladder functions
0 = Normal
1 = Mild urinary hesitancy, urgency, or retention
2 = Moderate hesitancy, urgency, retention of bowel or bladder, or rare urinary
incontinence
3 = Frequent urinary incontinence
4 = In need of almost constant catheterization
5 = Loss of bladder function
6 = Loss of bowel and bladder function
F. Visual (or optic) functions
0 = Normal
1 = Scotoma with visual acuity (corrected) better than 20/30
2 = Worse eye with scotoma with maximal visual acuity (corrected) of 20/30 to
20/59
3 = Worse eye with large scotoma, or moderate decrease in fields, but with
maximal visual acuity (corrected) of 20/60 to 20/99
4 = Worse eye with marked decrease of fields and maximal acuity (corrected) of
20/100 to 20/200; grade 3 plus maximal acuity of better eye of 20/60 or less
5 = Worse eye with maximal visual acuity (corrected) <20/200; grade 4 plus
maximal acuity of better eye of ≤20/60
6 = Grade 5 plus maximal visual acuity of better eye of ≤20/60
G. Cerebral (or mental) functions
0 = Normal
1 = Mood alteration only (does not affect EDSS score)
2 = Mild decrease in mentation
3 = Moderate decrease in mentation
4 = Marked decrease in mentation
5 = Chronic brain syndrome—severe or incompetent

TABLE 455-3 Risk of Developing Multiple Sclerosis (MS) 1 in 3 1 in 15 1 in 25 1 in 50 1 in 100 1 in 1000 1 in 1000

Harrison's 22e, p.3581

1 in 3 If an identical twin has MS
1 in 25 If a sibling has MS
1 in 100 If a first cousin has MS
1 in 1000 If no one in the family has MS

TABLE 455-4 Diagnostic Criteria for Multiple Sclerosis (MS)

Harrison's 22e, p.3583

CLINICAL PRESENTATION ADDITIONAL DATA NEEDED FOR MS DIAGNOSIS
2 or more attacks; objective
clinical evidence of 2 or
more lesions or objective
clinical evidence of 1 lesion
with reasonable historical
evidence of a prior attack		 None

TABLE 455-5 Disorders That Can Mimic Multiple Sclerosis (MS) Acute disseminated encephalomyelitis (ADEM)…

Harrison's 22e, p.3585

  • Acute disseminated encephalomyelitis (ADEM)
  • Antiphospholipid antibody syndrome
  • Behçet’s disease
  • Cerebral autosomal-dominant arteriopathy, subcortical infarcts, and
    leukoencephalopathy (CADASIL)
  • Congenital leukodystrophies (e.g., adrenoleukodystrophy, metachromatic
    leukodystrophy)
  • Glial Fibrillary Acidic Protein (GFAP) Autoimmunity
    Human immunodeficiency virus (HIV) infection
  • Ischemic optic neuropathy (arteritic and nonarteritic)
  • Lyme disease
  • Mitochondrial encephalopathy with lactic acidosis and stroke (MELAS)
  • Myelin oligodendrocyte glycoprotein-associated disease (MOGAD)
    Neoplasms (e.g., lymphoma, glioma, meningioma)
  • Neuromyelitis optica
  • Sarcoidosis
  • Sjögren’s syndrome
  • Stroke and ischemic cerebrovascular disease
  • Syphilis
  • Systemic lupus erythematosus and related collagen vascular disorders
  • Tropical spastic paraparesis (HTLV-1/2 infection)
  • Vascular malformations (especially spinal dural AV fistulas)
  • Vasculitis (primary CNS or other)
  • Vitamin B deficiency
    12

TABLE 455-6 Disease-Modifying Therapies for Multiple Sclerosis

Harrison's 22e, p.3586

CATEGORY AND MECHANISM
OF ACTION		 GENERIC NAME
(TRADE NAME)		 DOSE AND INTERVAL CHARACTERISTICS COMMENTS (USE, ADVERSE EFFECTS, ETC.)
Highly Effective
Anti-CD20 B cell MAbs:
Depletes B lymphocytes,
especially motile B cells in
peripheral blood; B cells in
lymphoid organs variably
protected; plasma cells
preserved		 Ocrelizumab
(Ocrevus)		 600-mg infusion q6 months
(first dose given as two 300-mg
infusions 14 days apart)		 Humanized
ADCC > complement		 Infusion reactions usually mild;
outstanding efficacy and safety in long-
term RMS extension trials; also approved
for PPMS
Ofatumumab
(Kesimpta)		 20-mg subcutaneous injections
monthly (after 3 weekly 20-mg
loading doses)		 Fully human
Complement > ADCC		 Advantage of home-based treatment; only
very minor injection- related reactions
Ublituximab
(Briumvi)		 450-mg infusion q6 months (first
dose given as 150-mg, followed
14 days later by 450-mg,
infusions)		 Chimeric
ADCC > Complement
Rituximab
(Rituxan and
biosimilars)		 1000-mg infusion q6 months
(dose used in phase 2 trial in
RMS); some clinicians use
500 mg IV q6 months		 Chimeric
Complement > ADCC		 Formally tested only in preliminary (phase 2)
study
Natalizumab
(Tysabri)		 300-mg monthly infusion Humanized
Anti-CD52 MAb: Depletes
lymphocytes and monocytes		 Alemtuzumab
(Lemtrada)		 12 mg/m2 infusion for 5
consecutive days; a second
3-day course administered
1 year later		 Long-lasting benefits but
serious risks limit use; approval
in United States only for
patients who have failed at
least two other drugs		 Multiple autoimmune complications including
thyroid (~25%) and ITP (1–3%), malignancies,
infection risk
Moderately Effective
Fingolimod
(Gilenya)		 0.5 mg oral once daily Binds to S1P1, S1P3, S1P4, and
S1P5 receptors
Ozanimod
(Zeposia)		 1 mg oral once daily S1P1- and S1P5-selective
inhibitor (cardiac receptors are
mostly S1P3 and only weakly
engaged by ozanimod)
Ponesimod
(Ponvory)		 20 mg oral once daily S1P1-selective modulator
Siponimod
(Mayzent)		 Based on CYP2C9 genotype.
1 mg oral daily for pts with
CYP2C9 1/3 or 2/3
Dose reduced in patients with
the CYP2C9 3/3 genotype
(<0.5% of the population) due
to substantially elevated drug
levels		 S1P1- and S1P5-selective
modulator
Fumarate: Immunomodulator;
reduces proinflammatory and
increases regulatory cytokines;
inhibits degradation of Nrf2,
increasing natural antioxidants		 Dimethyl
fumarate
(Tecfidera)		 240 mg oral twice daily (half-
dose for first 7 days)		 Metabolized to active
compound monomethyl
fumarate		 Gastrointestinal side effects, flushing;
these may improve over time; monitor for
LFT abnormalities and for lymphopenia
(which can persist after drug cessation);
rare PML cases
Diroximel
fumarate
(Vumerity)		 262 mg oral twice daily Metabolized to active
compound monomethyl
fumarate		 Similar side effect profile as dimethyl
fumarate
Cladribine
(Mavenclad)		 Weight-based oral dosing
(3.5 mg/kg) divided over
4–5 days, repeated 23–27 days
later; a second identical course
is administered 1 year later		 Purine analogue prodrug
phosphorylated in lymphocytes
and incorporated into
DNA, triggering apoptosis;
long-lasting