Multiple Sclerosis
Multiple Sclerosis
What Do You Need to Know?
- McDonald 2017 criteria: diagnosis requires dissemination in space (DIS: ≥2 of 4 CNS regions) AND dissemination in time (DIT: simultaneous Gd+ and non-enhancing lesions, new lesions on follow-up, OR CSF-specific OCBs)
- Subtypes: CIS → RRMS (85%) → SPMS; PPMS (10–15%) is primary progressive from onset; Lublin 2013 adds active/inactive and progressing/not progressing modifiers
- Classic presentations: optic neuritis (painful vision loss, RAPD), INO (MLF lesion), partial transverse myelitis, Lhermitte sign, Uhthoff phenomenon
- MRI hallmarks: periventricular Dawson fingers, ovoid lesions perpendicular to ventricles, open ring enhancement, central vein sign, short spinal cord lesions (<2 vertebral segments)
- CSF: ≥2 oligoclonal bands unique to CSF (85–95%); elevated IgG index; CSF-specific OCBs can substitute for DIT in McDonald 2017
- Acute relapses: IV methylprednisolone 1 g/day × 3–5 days; PLEX for steroid-refractory relapses; oral prednisone alone is NOT recommended for optic neuritis
- Prognosis: favorable — young onset, female, sensory/ON presentation, RRMS; poor — male, older onset, motor/cerebellar symptoms, PPMS, high lesion burden
Epidemiology
Key Epidemiological Data
| Feature | Details |
|---|---|
| Prevalence | ~1 million in the US; ~2.8 million worldwide |
| Female:Male ratio | 3:1 (increasing over time, especially in RRMS); PPMS is ~1:1 |
| Age of onset | 20–40 years (peak ~30); PPMS peaks later (~40–50 years) |
| Geographic gradient | Prevalence increases with distance from equator; highest in Northern Europe, Canada, northern US |
| Migration effect | Migrating before age 15 adopts risk of destination country; after age 15, retains risk of origin |
| Vitamin D | Low serum 25(OH)D associated with ↑ MS risk and ↑ relapse rate; partially explains latitude gradient |
| EBV association | Strongest environmental risk factor; OR >30 for MS after EBV seroconversion; virtually all MS patients are EBV seropositive |
| Smoking | 1.5× increased risk; dose-dependent; accelerates conversion to SPMS |
| Genetics | HLA-DRB1*15:01 is strongest genetic risk factor (OR ~3); >200 non-HLA susceptibility loci; MZ twins ~25–30%, DZ twins ~5% |
| Family risk | 15–20% have affected relative; first-degree relatives 10–20× risk; both parents with MS → ~30% risk to children |
💎 Board Pearl
- EBV seroconversion → 32-fold increased MS risk (Bjornevik et al., Science 2022) — MS risk is negligible in EBV-seronegative individuals
- HLA-DRB1*15:01 is the single strongest genetic risk factor for MS — chromosome 6
- Migration before age 15 = adopt new risk — suggests environmental exposure during adolescence is critical
- Monozygotic twin concordance is only ~25–30% — genetics important but NOT sufficient
Pathophysiology
Immunopathogenesis
| Immune Component | Role in MS |
|---|---|
| CD4+ T cells (Th1/Th17) | Cross BBB → recognize myelin antigens via MHC class II → release IFN-γ, IL-17 → activate macrophages |
| CD8+ T cells | Most abundant T cells in MS lesions; direct cytotoxic damage to oligodendrocytes and axons |
| B cells | Antigen presentation, cytokine production, intrathecal antibody secretion (OCBs); anti-CD20 therapy efficacy confirms B-cell centrality |
| Macrophages/microglia | Phagocytose myelin; release reactive oxygen species; drive slowly expanding lesions in progressive MS |
| Complement | Deposition in active lesions (Pattern II pathology); contributes to demyelination |
| Astrocytes | Gliotic scar formation in chronic lesions; impede remyelination; contribute to BBB dysfunction |
Neuropathology
- 5 pathologic criteria for demyelination: (1) myelin sheath destruction, (2) relative axonal sparing, (3) perivascular inflammatory infiltrate, (4) perivenular white matter distribution, (5) absence of Wallerian degeneration
- Demyelinating plaques: pink-gray lesions; perivenular distribution; primarily white matter but gray matter commonly affected
- Favored locations: periventricular white matter, optic nerves/chiasm, spinal cord, brainstem, cerebellar peduncles
- Dawson’s fingers: perivenular demyelination perpendicular to corpus callosum at the callosal–septal interface
- Axonal loss: significant even early in disease and in normal-appearing white matter — not purely demyelinating
- Gray matter pathology: cortical demyelination is common; subpial cortical lesions (Type III) are most MS-specific
- Lesions do NOT extend beyond root entry zones of cranial or spinal nerves
Lesion Types
| Lesion Type | Description | Significance |
|---|---|---|
| Active/acute plaques | Dense macrophage infiltration, Gd enhancement | Correspond to clinical relapses |
| Chronic active (slowly expanding) | Rim of activated microglia at edge; smoldering inflammation | Drive silent progression; paramagnetic rim lesions (PRLs) on MRI |
| Chronic inactive | Demyelinated, gliotic, no active inflammation | “Burned out” lesions |
| Shadow plaques | Partial remyelination (thin myelin sheaths) | Evidence of attempted repair |
Physiologic Effects of Demyelination
- Loss of saltatory conduction → slowed or blocked signal transmission
- Uhthoff phenomenon: transient worsening (classically visual blurring) with increased temperature — 0.5°C rise can block conduction in demyelinated fibers
- Lhermitte sign: electric-like tingling down spine/limbs with neck flexion — cervical posterior column demyelination
- Heat, exercise, fever, hot baths, and smoking can all transiently worsen symptoms
💎 Board Pearl
- CD8+ T cells outnumber CD4+ T cells in MS lesions — a common board question
- Slowly expanding lesions (SELs) with paramagnetic rims drive disability in progressive MS — “smoldering MS”
- Dawson’s fingers = perivenular demyelination perpendicular to ventricles along callosal–septal interface
- MS is NOT purely demyelinating — significant axonal loss occurs early, even in normal-appearing white matter
Clinical Subtypes
MS Phenotypes
| Subtype | Frequency | Definition | Key Features |
|---|---|---|---|
| CIS | — | First clinical demyelinating event; does not yet fulfill DIT | 50–70% convert to MS within 20 years if brain MRI is abnormal; <25% if MRI is normal |
| RRMS | ~85% | Defined relapses with full or partial recovery; no progression between attacks | Most common at onset; ~0.5–1 relapse/year untreated; ~50% convert to SPMS within 15–20 years |
| SPMS | — | Initial RRMS followed by gradual progression ± superimposed relapses | Transition is insidious; confirmed retrospectively over 6–12 months of worsening |
| PPMS | 10–15% | Progressive decline from onset without early relapses | Equal M:F; older onset (~40–50); spinal cord predominant; fewer Gd-enhancing lesions; ocrelizumab only approved DMT |
Lublin 2013 Phenotypic Modifiers
| Modifier | Definition |
|---|---|
| Active | Clinical relapses AND/OR new/enlarging MRI lesions within past year |
| Not active | No relapses AND no new MRI activity |
| Progressing | Steadily increasing disability independent of relapses, confirmed over 6–12 months |
| Not progressing | Stable disability |
- Progressive-relapsing MS is no longer recognized — now classified as PPMS with activity
MS Variants
| Variant | Key Features |
|---|---|
| Marburg variant | Fulminant; rapid progression to stupor/coma/death over weeks–months; confluent large plaques; no remission |
| Baló concentric sclerosis | Alternating bands of demyelination and preserved myelin; concentric ring pattern on MRI |
| Schilder disease | Large bilateral hemispheric demyelination; children/young adults; high myelin basic protein |
| Tumefactive MS | Large (>2 cm) lesions mimicking tumor; open-ring enhancement (ring opens toward cortex) |
💎 Board Pearl
- CIS + abnormal brain MRI = high conversion risk — treat with DMT early; CIS with normal MRI has <25% conversion risk
- PPMS has equal M:F ratio — unlike RRMS (3:1 F:M); boards love this distinction
- Tumefactive MS: open-ring enhancement (ring opens toward cortex) = demyelination; closed ring = abscess or tumor
- Marburg variant: fulminant MS with rapid progression to death without remission
Classic Clinical Presentations
High-Yield Presentations
| Presentation | Key Features | Localization | Board Points |
|---|---|---|---|
| Optic neuritis | Painful vision loss (worse with eye movement), central scotoma, dyschromatopsia, RAPD | Optic nerve (retrobulbar > anterior) | ONTT: IV steroids speed recovery but do NOT change final outcome; oral prednisone alone ↑ recurrence; 20–25% of initial MS presentations |
| INO | Impaired adduction ipsilateral eye + abducting nystagmus contralateral eye | MLF | Bilateral INO in young patient = MS; unilateral INO in elderly = stroke |
| One-and-a-half syndrome | INO + ipsilateral horizontal gaze palsy — only abduction of contralateral eye remains | MLF + ipsilateral PPRF or CN VI nucleus | Think MS in young patient |
| Partial transverse myelitis | Asymmetric motor/sensory deficits, bladder involvement, partial cord on MRI | Spinal cord (cervical > thoracic) | MS: short segment, partial, peripheral; partial myelitis predicts higher MS risk than complete myelitis |
| Lhermitte sign | Electric shock down spine/limbs on neck flexion | Cervical posterior columns | Not specific to MS (cervical spondylosis, B12 deficiency, post-radiation) |
| Uhthoff phenomenon | Transient worsening with heat/exercise | Previously demyelinated pathways | NOT a true relapse — temperature-dependent conduction block; no steroids needed |
| Trigeminal neuralgia | Lancinating facial pain; may be bilateral | Trigeminal root entry zone | TN in patient <40, especially bilateral → suspect MS (~1% of MS patients) |
Symptoms of Established Disease
- Fatigue: most common symptom (~80%); treat with amantadine or modafinil
- Cognitive impairment: 40–65%; processing speed, memory, executive function; correlates with brain atrophy and cortical lesions
- Spasticity: baclofen (oral or intrathecal pump), tizanidine, botulinum toxin
- Bladder dysfunction: detrusor hyperreflexia (urgency/frequency) most common; PVR >100 mL → intermittent catheterization
- Walking impairment: dalfampridine (4-AP) 10 mg BID — blocks K+ channels; improves walking speed in ~35%; avoid if seizure history
- Neuropathic pain: dysesthesias, painful tonic spasms, trigeminal neuralgia
- Paroxysmal symptoms: brief stereotyped episodes (tonic spasms, dysarthria-ataxia) — respond to low-dose carbamazepine
- Charcot triad: nystagmus + scanning speech + intention tremor (advanced cerebellar disease)
- Seizures: 2–3% of MS patients
- Classic adage: MS presents with symptoms of one leg but signs in both
💎 Board Pearl
- Bilateral INO + young adult = MS; unilateral INO + elderly = brainstem stroke
- Best predictor of MS after optic neuritis: abnormal brain MRI at presentation
- Best predictor of MS after transverse myelitis: subclinical brain lesions on MRI at presentation
- Partial transverse myelitis predicts higher MS risk than complete myelitis
- Paroxysmal symptoms respond to low-dose carbamazepine — ephaptic transmission in demyelinated fibers
- Dalfampridine is the only FDA-approved drug specifically for MS walking impairment
McDonald Criteria 2017
Core Principle
- Diagnosis requires dissemination in space (DIS) + dissemination in time (DIT)
- Both can be satisfied clinically OR by MRI — no need to wait for second clinical attack
- Must exclude alternative diagnoses (no better explanation)
Dissemination in Space (DIS)
- ≥1 T2 lesion in ≥2 of 4 characteristic CNS regions:
| CNS Region | Notes |
|---|---|
| Periventricular | Most common location; Dawson fingers; ≥1 lesion required |
| Cortical/Juxtacortical | 2017 update: cortical lesions now count (not just juxtacortical); best on DIR sequences |
| Infratentorial | Brainstem, cerebellum, cerebellar peduncles |
| Spinal cord | Short-segment, peripheral, partial cross-section |
- 2017 update: symptomatic lesion CAN be used to fulfill DIS criteria (changed from 2010)
Dissemination in Time (DIT)
| DIT Criterion | Explanation |
|---|---|
| Simultaneous Gd+ and non-enhancing lesions | Both on a single MRI = lesions of different ages |
| New T2 or Gd+ lesion on follow-up MRI | Compared to baseline scan |
| CSF-specific oligoclonal bands | New in 2017: OCBs in CSF but not serum can substitute for DIT — allows earlier diagnosis |
Clinical Application
| Presentation | Additional Data Needed |
|---|---|
| ≥2 attacks + ≥2 objective lesions | None — DIS and DIT satisfied clinically |
| ≥2 attacks + 1 objective lesion | DIS by MRI OR second attack at different site |
| 1 attack + ≥2 objective lesions | DIT by MRI OR CSF OCBs OR second attack |
| 1 attack + 1 objective lesion (CIS) | DIS + DIT by MRI (or OCBs) OR second attack |
| Progressive from onset (PPMS) | ≥1 year progression PLUS ≥2 of: (1) ≥1 brain lesion in MS-typical region, (2) ≥2 spinal cord lesions, (3) CSF OCBs |
💎 Board Pearl
- CSF OCBs can replace DIT — the biggest change in McDonald 2017; DIS + OCBs = MS diagnosis at first presentation
- Cortical lesions now count for DIS — another 2017 update; previously only juxtacortical
- Symptomatic lesion counts for DIS in 2017 (could not in 2010)
- PPMS requires 1 year of progression + 2 of 3 (brain DIS, ≥2 cord lesions, positive CSF)
MRI Findings
Brain MRI
| Finding | Description | Significance |
|---|---|---|
| Dawson fingers | Ovoid T2/FLAIR hyperintensities perpendicular to ventricles along perivenular spaces | Most characteristic MS lesion; best seen on sagittal FLAIR |
| Corpus callosum lesions | T2 lesions at callosal-septal interface | Highly specific; unusual in small vessel disease or NMOSD |
| Open ring enhancement | Incomplete rim of Gd enhancement; open side faces gray matter | Specific for demyelination; closed ring = abscess or tumor |
| Central vein sign (CVS) | Central vein visible within lesion on T2*/SWI | ≥40% of lesions with central vein = MS; distinguishes from mimics |
| Paramagnetic rim lesion (PRL) | Dark rim on susceptibility imaging around chronic lesion | Chronic active/slowly expanding; iron-laden microglia; predicts faster disability |
| Cortical lesions | Within or abutting cortex; best on DIR sequences | Count for DIS (2017); correlate with cognitive decline |
| T1 black holes | Chronic T1 hypointensities | Represent axonal loss; correlate with disability better than T2 lesion load |
Spinal Cord MRI: MS vs NMOSD vs MOGAD
| Feature | MS | NMOSD | MOGAD |
|---|---|---|---|
| Length | <2 vertebral segments | ≥3 segments (LETM) | ≥3 segments (LETM) |
| Cross-section | Partial, eccentric/peripheral | Central, ≥50% cross-section | Central gray matter (H-sign) |
| Location | Cervical > thoracic; dorsal/lateral | Cervical > thoracic; central | Thoracic > cervical; conus predilection |
💎 Board Pearl
- Open ring = demyelination; closed ring = abscess or tumor — open side faces gray matter
- Dawson fingers on sagittal FLAIR = single most recognizable MS MRI finding
- T1 black holes correlate with disability better than T2 lesion burden — represent irreversible axonal loss
- Central vein sign 40% rule: ≥40% lesions with central vein = MS; <40% = consider mimic
- MS cord lesions: short segment, partial, eccentric; NMOSD: longitudinally extensive, central
- Persistent Gd enhancement >2 months should raise concern for alternative diagnosis
CSF Analysis & Evoked Potentials
CSF Findings
| Test | Expected Finding | Clinical Significance |
|---|---|---|
| Oligoclonal bands (OCBs) | ≥2 bands in CSF not in serum | Present in 85–95%; can substitute for DIT (McDonald 2017); NOT specific (infections, sarcoidosis, SSPE) |
| IgG index | Elevated (>0.7) | Reflects intrathecal IgG synthesis; >1.7 highly suggestive |
| Cell count | Mild lymphocytic pleocytosis (<50) | >50 cells → consider alternative diagnosis |
| Protein | Normal or mildly elevated | >100 mg/dL suggests alternative diagnosis |
| Myelin basic protein | Elevated during relapses | Nonspecific; marker of active demyelination |
| Glucose | Normal | Low glucose = infection, sarcoidosis, NOT MS |
Evoked Potentials
| Test | Finding in MS | Key Points |
|---|---|---|
| Visual evoked potentials (VEP) | Prolonged P100 latency (>100 ms) | Most sensitive EP for MS (~80% in definite MS); detects subclinical optic neuritis; demyelination → prolonged latency |
| Somatosensory EP (SSEP) | Prolonged central conduction time | Detects subclinical cord/brainstem demyelination; ~69% in definite MS |
| Brainstem auditory EP (BAEP) | Prolonged interpeak latencies | Least sensitive for MS (~47%); detects pontine demyelination |
💎 Board Pearl
- OCBs must be CSF-specific — bands in BOTH serum and CSF = systemic immune activation, NOT intrathecal synthesis
- CSF pleocytosis >50 = not MS until proven otherwise — think NMOSD, infection, sarcoidosis
- OCBs persist for life regardless of treatment — compartmentalized intrathecal immune response
- Prolonged P100 on VEP = most commonly tested EP finding for MS on boards
- Demyelination = prolonged latency; axonal loss = reduced amplitude
Acute Relapse Management
Relapse Definition
- New or worsening symptoms lasting ≥24 hours, in absence of fever or infection, ≥30 days from prior relapse
- Pseudorelapse: worsening from UTI, fever, heat, stress — treat the trigger, NOT with steroids
Treatment
| Treatment | Regimen | Key Points |
|---|---|---|
| IV methylprednisolone | 1 g/day × 3–5 days | First-line; speeds recovery but does NOT alter long-term disability or prevent future relapses |
| High-dose oral prednisone | 1250 mg PO × 3–5 days | Bioequivalent to IV (TREAT trial); alternative when IV impractical |
| Plasma exchange (PLEX) | 5–7 exchanges over 10–14 days | For steroid-refractory severe relapses; ~40% respond |
| ACTH gel | 80 units IM/SC daily × 5 days | Alternative to steroids; expensive; rarely first-line |
💎 Board Pearl
- IV methylprednisolone speeds recovery but does NOT change final outcome — classic ONTT finding
- Oral prednisone alone for optic neuritis is contraindicated — ONTT showed increased recurrence rate
- Always rule out pseudorelapse (UTI, infection, fever) before treating with steroids
- PLEX is reserved for severe, steroid-refractory relapses
Prognostic Factors
Favorable vs Unfavorable
| Favorable Prognosis | Unfavorable Prognosis |
|---|---|
| Young age at onset | Older age at onset (>40) |
| Female sex | Male sex |
| Optic neuritis or sensory onset | Motor or cerebellar onset |
| Complete recovery from first relapse | Incomplete recovery from first relapse |
| Low T2 lesion burden on initial MRI | High T2 lesion burden; T1 black holes |
| Long interval between first and second relapse | Short inter-relapse interval; frequent early relapses |
| RRMS phenotype | Progressive course from onset (PPMS) |
| Minimal disability at 5 years | Early brain atrophy; spinal cord/brainstem lesions |
💎 Board Pearl
- Cerebellar ataxia at onset predicts poor prognosis without significant remission
- Optic neuritis and sensory onset = most favorable presenting features
- Best early predictor of long-term disability: degree of recovery from first relapse
- T1 black holes on MRI represent irreversible axonal loss and correlate with disability
Special Situations
MS and Pregnancy
| Period | Relapse Rate | Key Points |
|---|---|---|
| 1st–2nd trimester | Decreased | Immunomodulatory state of pregnancy is protective |
| 3rd trimester | Lowest (~70% reduction) | Shift toward Th2 immune response |
| Postpartum (first 3 months) | Increased (rebound) | 20–40% relapse rate; consider resuming DMT immediately postpartum |
- Pregnancy does NOT worsen long-term MS prognosis
- Glatiramer acetate: safest DMT in pregnancy; no washout required
- Teriflunomide: Category X — requires cholestyramine washout before conception
- Acute relapse in pregnancy: IV methylprednisolone can be used (avoid 1st trimester if possible)
Pediatric MS
- Onset before age 18 in ~3–5% of MS patients; almost exclusively RRMS
- Higher relapse rate than adult MS but better relapse recovery
- Must distinguish from ADEM: ADEM = monophasic, encephalopathy required, bilateral; MS = relapsing, no encephalopathy
- MOG antibodies more common in pediatric patients — test MOG-IgG in all pediatric demyelinating events
- Fingolimod: FDA-approved for pediatric MS (age ≥10; PARADIGMS trial)
Radiologically Isolated Syndrome (RIS)
- Incidental MRI findings meeting DIS criteria without clinical symptoms
- ~34% develop a clinical event within 5 years; ~50% within 10 years
- Highest conversion risk: spinal cord lesions, age <37, male, positive OCBs, Gd-enhancing lesions
- ARISE trial: dimethyl fumarate reduced time to first clinical event in RIS — first RCT for DMT in RIS
💎 Board Pearl
- Relapse rate ↓ in 3rd trimester, ↑ postpartum — among most commonly tested MS facts
- Pediatric MS vs ADEM: ADEM = monophasic + encephalopathy; MS = relapsing, no encephalopathy
- RIS with spinal cord lesions = highest conversion risk — may benefit from early DMT
- Fingolimod is FDA-approved for pediatric MS (age ≥10; PARADIGMS trial)
Differential Diagnosis
Key MS Mimics
| Category | Conditions | Distinguishing Features |
|---|---|---|
| Demyelinating | NMOSD, MOGAD, ADEM | NMOSD: AQP4+, LETM, area postrema; MOGAD: MOG+, bilateral ON; ADEM: monophasic, encephalopathy |
| Autoimmune | SLE, Sjögren, Behçet, sarcoidosis | Systemic features; specific serologies; leptomeningeal enhancement in sarcoidosis |
| Vascular | CNS vasculitis, CADASIL, microvascular disease | CADASIL: anterior temporal + external capsule WML; microvascular: older age, no enhancement |
| Infectious | HIV, HTLV-1, Lyme, syphilis, PML | PML: JC virus, no enhancement, subcortical U-fibers |
| Metabolic | B12 deficiency, copper deficiency | Posterior column + corticospinal without brain lesions |
| Genetic | Adrenoleukodystrophy, leukodystrophies | VLCFA for ALD; symmetric confluent WM changes |
Red Flags Suggesting Alternative Diagnosis
- CSF protein >100 mg/dL or pleocytosis >50 cells
- Persistent Gd enhancement >2 months
- Longitudinally extensive cord lesions (≥3 segments)
- Bilateral simultaneous optic neuritis
- Absence of oligoclonal bands
- Prominent encephalopathy or seizures at onset
- Systemic inflammatory symptoms (rash, oral ulcers, uveitis)
Clinical Pearl
- Always check VLCFA in young men with progressive myelopathy and white matter changes — rule out adrenomyeloneuropathy/ALD
- CADASIL: anterior temporal + external capsule WML in young patient with migraine and strokes — NOTCH3 mutation
- Minimum workup to exclude mimics: CBC, CMP, ESR, ANA, B12, RPR, TSH; MRI brain + spine with contrast
References
- Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17(2):162-173.
- Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83(3):278-286.
- Bjornevik K, Cortese M, Healy BC, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022;375(6578):296-301.
- Filippi M, Bar-Or A, Piehl F, et al. Multiple sclerosis. Nat Rev Dis Primers. 2018;4(1):43.
- Optic Neuritis Study Group. Visual function 15 years after optic neuritis. Ophthalmology. 2008;115(6):1079-1082.
- Ropper AH, Samuels MA, Klein JP, Prasad S. Adams and Victor’s Principles of Neurology. 12th ed. McGraw-Hill; 2023.