Neurology · PANCE / PANRE

Multiple Sclerosis

Autoimmune CNS demyelinating disease with relapsing or progressive course.

Also known as: MS, multiple sclerosis, RRMS, SPMS, PPMS

Overview

Chronic autoimmune inflammatory demyelinating disease of the central nervous system, characterized by lesions disseminated in space (multiple CNS locations) and time (multiple episodes or accumulation over time). Phenotypes: relapsing-remitting (RRMS, ~85%), secondary progressive (SPMS, evolves from RRMS), primary progressive (PPMS, ~10-15%), and clinically isolated syndrome (CIS, first demyelinating event).

Epidemiology

Prevalence ~1 million in the US. Typical onset age 20-40. Female-to-male ratio ~3:1. Higher prevalence at higher latitudes (vitamin D, EBV link).

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Risk factors

Female sex
Age 20-40
Higher latitude of residence (especially before age 15)
Vitamin D deficiency
Epstein-Barr virus infection (EBV — strong epidemiologic association; recent prospective evidence supports causal role)
Smoking
Obesity in adolescence
Family history (HLA-DRB1*15:01 strongest genetic association)
Northern European ancestry

Pathophysiology

Autoreactive T cells (and B cells) cross a disrupted blood-brain barrier, attack myelin and oligodendrocytes, and produce demyelinating plaques in white matter (and increasingly recognized cortical lesions). Acute inflammation causes relapses; chronic neurodegeneration with axonal loss drives progressive disability. B cell roles (antibody, antigen presentation) explain efficacy of anti-CD20 therapies.

Clinical presentation

Symptoms

Optic neuritis: subacute monocular vision loss with pain on eye movement, dyschromatopsia (red desaturation), afferent pupillary defect
Internuclear ophthalmoplegia (INO): impaired adduction of the ipsilateral eye on horizontal gaze with nystagmus of the abducting eye — bilateral INO in a young patient is highly suggestive of MS
Sensory: paresthesias, numbness, Lhermitte sign (electric shock down spine with neck flexion)
Motor: weakness, spasticity, hyperreflexia
Cerebellar: ataxia, intention tremor, dysarthria
Bowel/bladder dysfunction (urgency, incontinence, retention)
Fatigue (most common and disabling symptom)
Uhthoff phenomenon: symptom worsening with heat (exercise, hot shower, fever)
Cognitive impairment, depression

Signs / physical exam

Optic disc pallor (chronic optic neuritis), RAPD
INO, abnormal smooth pursuit, gaze-evoked nystagmus
Spastic paraparesis, hyperreflexia, Babinski sign
Sensory level (in transverse myelitis), impaired vibration/proprioception
Cerebellar findings: dysmetria, dysdiadochokinesia

Classic findings

Young woman with optic neuritis + INO + multiple episodes of neurologic symptoms over time.

Differential diagnosis

Neuromyelitis optica spectrum disorder (NMOSD) — Longitudinally extensive transverse myelitis (≥3 vertebral segments), severe optic neuritis often bilateral, AQP4-IgG antibody positive
MOG antibody-associated disease (MOGAD) — Optic neuritis, transverse myelitis, ADEM-like in children; MOG-IgG positive
Acute disseminated encephalomyelitis (ADEM) — Monophasic, post-infectious or post-vaccination, encephalopathy prominent, multifocal lesions, often pediatric
Lyme disease, neurosyphilis, HIV — Serology, CSF studies; geographic and risk-factor clues
Vitamin B12 deficiency (subacute combined degeneration) — Posterior column dysfunction, megaloblastic anemia, low B12
Vasculitis (CNS or systemic) — Constitutional symptoms, multi-system involvement, ESR/CRP, ANCA, biopsy
Sarcoidosis — Pulmonary findings, ACE level, basal meningeal enhancement on MRI
Migraine with white matter lesions — Headache history, lesions typically subcortical and asymptomatic; clinical correlation

Diagnostic workup

Diagnostic criteria

2017 McDonald criteria: dissemination in space (≥1 T2 lesion in ≥2 of 4 CNS regions: periventricular, cortical/juxtacortical, infratentorial, spinal cord) AND dissemination in time (simultaneous gadolinium-enhancing and non-enhancing lesions OR new lesion on follow-up MRI OR oligoclonal bands in CSF unique from serum).

Labs

CBC, BMP, LFTs, TSH, B12, RPR, HIV, vitamin D, ANA
Aquaporin-4 (AQP4) IgG — rules out NMOSD
MOG IgG — rules out MOGAD
Lyme serology if regional exposure

Imaging

MRI brain with and without gadolinium — periventricular, juxtacortical, infratentorial, and spinal cord lesions; ovoid lesions perpendicular to ventricles (Dawson fingers); enhancement indicates active inflammation (~6 weeks)
MRI cervical and thoracic spine — short-segment cord lesions (<2 vertebral segments — contrasts with NMOSD)
Optical coherence tomography (OCT) — retinal nerve fiber layer thinning
Visual evoked potentials — delayed P100 (subclinical optic nerve involvement)

Diagnostic algorithm

Subtype	Course	Frequency
Clinically isolated syndrome (CIS)	First demyelinating event; may convert to MS	~initial presentation
Relapsing-remitting (RRMS)	Acute relapses with recovery; stable between	~85% at onset
Secondary progressive (SPMS)	Gradual worsening after initial RRMS phase	Evolves from RRMS over 10-20 years
Primary progressive (PPMS)	Gradual worsening from onset, no clear relapses	~10-15%
Radiologically isolated syndrome (RIS)	MRI findings without symptoms	Pre-clinical; some convert to MS

Multiple sclerosis clinical phenotypes (2013 Lublin revision).

Treatment

First-line

Acute relapse: IV methylprednisolone 1 g/day × 3-5 days (speeds recovery; does not change long-term disability)
Plasma exchange (PLEX) for severe relapses unresponsive to steroids
Disease-modifying therapy (DMT) — start early for RRMS
Moderate efficacy DMTs: interferon beta (Avonex, Rebif, Betaseron, Plegridy), glatiramer acetate (Copaxone), teriflunomide, dimethyl fumarate, diroximel fumarate
High efficacy DMTs (often first-line now): anti-CD20 monoclonal antibodies — ocrelizumab (also FDA-approved for PPMS), ofatumumab, rituximab (off-label); fingolimod (S1P modulator); natalizumab (anti-VLA4 — caution PML risk with JCV+); cladribine; alemtuzumab

Second-line / adjunct

Symptomatic management: spasticity (baclofen, tizanidine, gabapentin, botulinum toxin), neuropathic pain (gabapentin, pregabalin, duloxetine), fatigue (amantadine, modafinil, lifestyle), bladder (oxybutynin, mirabegron, intermittent catheterization), depression (SSRIs), gait (dalfampridine)
Vitamin D supplementation (>1000 IU/day target serum 25-OH-D >30 ng/mL)
Vaccinations BEFORE starting immunosuppressive DMT (avoid live vaccines during therapy)
Smoking cessation
Physical therapy, occupational therapy, multidisciplinary MS care

Complications

Progressive disability accumulation (EDSS scale)
Cognitive impairment (~40-70% of patients)
Depression (high rates, increased suicide risk)
Bladder dysfunction with recurrent UTIs
Mobility loss, falls
PML (progressive multifocal leukoencephalopathy) — opportunistic JC virus infection in natalizumab- or other immunosuppressant-treated patients
Increased infection risk with anti-CD20 and other immunosuppressive DMTs
Pseudo-relapse: symptom worsening from infection, heat, or stress without new inflammation

PANCE pearls

MS lesions are 'separated in time and space' — the diagnostic hallmark.
Bilateral INO in a young patient is MS until proven otherwise.
Long-segment (≥3 vertebrae) transverse myelitis suggests NMOSD, NOT MS — check AQP4-IgG.
Oligoclonal bands in CSF (unique from serum) support MS diagnosis and predict conversion from CIS.
Start DMT early — disability accrual is fastest in the first decade; high-efficacy first-line therapy is favored in many recent algorithms.
EBV is now considered a causal factor in MS (Bjornevik et al., Science 2022).

References

AAN 2018 — Practice Guideline Recommendations Summary: Disease-Modifying Therapies for Adults With MS (Rae-Grant et al., Neurology 2018)
McDonald 2017 — Diagnosis of MS: 2017 Revisions of the McDonald Criteria (Thompson et al., Lancet Neurol 2018)
ECTRIMS 2018 — ECTRIMS/EAN Guideline on Pharmacological Treatment of People with MS (Montalban et al., Mult Scler 2018)
EBV-MS — Longitudinal Analysis Reveals High Prevalence of EBV Associated with MS (Bjornevik et al., Science 2022)

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