Nervous System & Special Senses

Multiple sclerosis: diagnosis and disease-modifying therapy

Clinical Overview and When to Suspect Multiple Sclerosis

— Peak onset 20–40 years, female:male ≈ 3:1

— Higher prevalence with increasing latitude, low vitamin D, EBV infection (now considered a near-necessary trigger), smoking, childhood/adolescent obesity, HLA-DRB1*15:01

— Family history raises risk modestly (sibling ~3%, monozygotic twin ~25%)

— Relapsing-remitting MS (RRMS) — 85% at onset; discrete attacks with partial/complete recovery

— Secondary progressive MS (SPMS) — gradual accumulation of disability after an RRMS course

— Primary progressive MS (PPMS) — ~10–15%; steady progression from onset, older men, more cord involvement

— Clinically isolated syndrome (CIS) — first demyelinating event; high conversion risk if MRI lesions present

— Radiologically isolated syndrome (RIS) — incidental MRI lesions without clinical attack

— Young adult with transient neurologic symptoms lasting >24 h that are separated in time and anatomic location

— Recurrent optic neuritis, internuclear ophthalmoplegia (INO), Lhermitte sign, Uhthoff phenomenon, transverse myelitis, or sensory level

— Symptoms worsen with heat (hot shower, exercise, fever) — Uhthoff phenomenon (pseudo-relapse)

Board pearl: A young woman with bilateral INO has MS until proven otherwise; a unilateral INO in an older patient suggests stroke. The Step 3 vignette frequently buries the diagnosis in a primary-care follow-up visit where the patient describes "an old episode of blurry vision last year that got better." Recognize this as the prior demyelinating event establishing DIT.

Multiple sclerosis (MS) is an immune-mediated, inflammatory demyelinating disease of the CNS characterized by dissemination in space (DIS) and time (DIT) of demyelinating lesions in the brain, spinal cord, and optic nerves.

Epidemiology and risk:

Disease phenotypes:

When to suspect on Step 3:

Presentation Patterns and Key History

— Optic neuritis (ON): subacute monocular vision loss over hours–days, painful with eye movement, red desaturation, central scotoma, RAPD; ~50% develop MS within 15 years

— Transverse myelitis (partial): sensory level, band-like truncal tightness ("MS hug"), bladder urgency, Lhermitte sign (electric shock down spine on neck flexion)

— Brainstem/cerebellar: diplopia from INO (lesion in MLF), vertigo, dysarthria, ataxia, trigeminal neuralgia in a young person

— Cerebral: subtle cognitive slowing, fatigue, depression

— Each attack develops over hours to days, plateaus, and improves over weeks

— Symptoms lasting >24 hours without fever/infection define a clinical attack

— Symptoms lasting seconds (paroxysmal) or <24 h with fever suggest pseudo-relapse, not a new attack

— Prior unexplained neurologic events (the "forgotten" optic neuritis)

— Heat sensitivity (Uhthoff), fatigue out of proportion to activity

— Bladder symptoms (urgency, hesitancy, retention) — often missed

— Sexual dysfunction, constipation

— Pseudobulbar affect, depression (lifetime risk ~50%)

— Postpartum period (relapse risk rises in first 3 months after delivery)

— Infections (UTI especially) often unmask old deficits

— Stress, sleep deprivation

Key distinction: A true MS relapse requires new/worsening neurologic symptoms lasting >24 hours, ≥30 days from prior attack, in absence of fever or infection. If the patient has a UTI and old symptoms recrudesce, that is a pseudo-relapse — treat the infection, do not give steroids or escalate DMT. This distinction drives management on the exam: the wrong answer is always "start IV methylprednisolone" when the patient is febrile with a UTI.

Common presenting syndromes (memorize — these are the Step 3 stems):

Symptom temporal pattern:

High-yield historical features to elicit:

Triggers and modifiers:

Physical Exam Findings

— Afferent pupillary defect (RAPD/Marcus Gunn) in optic neuritis

— Decreased color vision (red desaturation) — often the most sensitive sign

— Optic disc usually normal acutely (retrobulbar neuritis); pallor develops weeks later

— Internuclear ophthalmoplegia: impaired adduction of the affected eye with nystagmus of the abducting eye on lateral gaze; convergence preserved

— Upper motor neuron signs: spasticity, hyperreflexia, Babinski, clonus

— Pyramidal weakness, often asymmetric; spastic paraparesis in cord disease

— Patchy sensory loss not fitting a single nerve/root distribution

— Lhermitte sign: electric sensation down spine with neck flexion (posterior column demyelination)

— Sensory level on torso suggests myelitis

— Intention tremor, dysmetria, scanning dysarthria — Charcot triad (nystagmus, intention tremor, scanning speech)

— Tandem gait abnormalities

— Post-void residual >100 mL is common; check bladder scan

— Spastic (small, hyperreflexic) or atonic bladder

— Vital signs typically normal; fever should prompt search for infection causing pseudo-relapse

— Check temperature before attributing worsening to a relapse

Step 3 management: On a follow-up visit, the EDSS (Expanded Disability Status Scale) drives long-term decisions; document ambulation distance, bladder function, vision, and cognition at each visit. A patient whose EDSS rises from 2.0 to 4.0 over a year despite DMT signals treatment failure — escalate therapy. Always perform a post-void residual in MS patients with new urinary symptoms before prescribing anticholinergics, because urinary retention with overflow masquerades as urge incontinence and worsens with oxybutynin.

Visual system:

Motor:

Sensory:

Cerebellar:

Autonomic/bladder:

Hemodynamic/general:

Diagnostic Workup — Initial Labs and MRI

— T2/FLAIR hyperintense lesions: ovoid, perpendicular to ventricles (Dawson fingers), in periventricular, juxtacortical/cortical, infratentorial, and spinal cord locations

— Gadolinium-enhancing lesions indicate active inflammation (open blood-brain barrier <6 weeks)

— Simultaneous enhancing + non-enhancing lesions on a single MRI satisfy DIT

— DIS: ≥1 T2 lesion in ≥2 of 4 typical areas (periventricular, cortical/juxtacortical, infratentorial, spinal cord)

— DIT: new T2/enhancing lesion on follow-up MRI OR simultaneous enhancing and non-enhancing lesions OR CSF-specific oligoclonal bands (substitute for DIT)

— CBC, CMP, TSH, B12, HIV, RPR/treponemal, ANA, ESR/CRP

— Aquaporin-4 IgG (NMO-IgG) — must be negative to call it MS when myelitis is longitudinally extensive

— MOG-IgG if atypical features (bilateral ON, encephalitis)

— Vitamin D level (baseline; supplement to >40 ng/mL)

— Consider HTLV-1 in endemic areas, Lyme if exposure

— OCT (optical coherence tomography): retinal nerve fiber layer thinning supports MS

— Visual evoked potentials: delayed P100 latency confirms subclinical optic pathway demyelination

Board pearl: A longitudinally extensive transverse myelitis (LETM, ≥3 vertebral segments) is not typical MS — think NMOSD (aquaporin-4) or MOG-associated disease. Sending NMO and MOG antibodies is mandatory before starting MS DMTs, because interferon-β and natalizumab worsen NMOSD.

MRI brain and spinal cord with and without gadolinium is the cornerstone — order this first when MS is suspected.

2017 McDonald criteria for RRMS diagnosis:

Labs to exclude mimics before committing to diagnosis:

Ancillary:

Diagnostic Workup — CSF and Advanced Studies

— McDonald DIT criteria not met on imaging alone

— Atypical features, older patient, primary progressive course

— Need to exclude infection/malignancy

— Oligoclonal bands (OCBs) present in CSF but not in serum — sensitivity ~95%, supports diagnosis and substitutes for DIT

— Elevated IgG index (>0.7)

— Mild lymphocytic pleocytosis (usually <50 cells/µL; >50 should prompt reconsidering)

— Normal glucose, normal-to-mildly elevated protein

— WBC >50, neutrophilic predominance, low glucose, very high protein

— Positive infectious workup (VDRL, cultures)

— Negative OCBs in a patient with progressive course (consider PPMS still, but reconsider mimics)

— 1 year of disability progression independent of relapses, plus 2 of 3:

— ≥1 T2 brain lesion in typical MS location

— ≥2 T2 spinal cord lesions

— Positive CSF (OCBs or elevated IgG index)

— Evoked potentials (visual, somatosensory, brainstem auditory) — detect subclinical lesions, useful when MRI equivocal

— Repeat MRI in 3–6 months if CIS to capture DIT

Step 3 management: When MS is on the differential but criteria aren't fully met, do not initiate DMT prematurely — the correct next step is often LP for OCBs or repeat MRI in 3–6 months. Starting DMT before diagnosis exposes the patient to immunosuppression risks and may obscure an alternative diagnosis like neurosarcoidosis. Document baseline JC virus antibody, hepatitis B/C, TB, and varicella status before any DMT — these inform later drug selection.

Lumbar puncture — not always required if MRI is unambiguous, but useful when:

Characteristic CSF findings in MS:

Findings that argue against MS:

Diagnosing PPMS (2017 McDonald):

Other advanced studies:

Acute Relapse Management and Treatment Logic

— High-dose IV methylprednisolone 1 g daily × 3–5 days is first-line

— Oral prednisone 1250 mg daily × 3–5 days is bioequivalent and acceptable

— Steroids shorten relapse duration but do not change long-term disability

— If severe deficit (e.g., paraplegia, blindness) not responding to steroids after 5–7 days → plasma exchange (PLEX) 5–7 sessions

— Rule out infection (UA, CBC) — pseudo-relapse from UTI is the classic Step 3 trap

— Check glucose (steroids precipitate hyperglycemia)

— GI prophylaxis (PPI), monitor mood

— Spasticity: baclofen, tizanidine, gabapentin; PT

— Neuropathic pain: gabapentin, pregabalin, duloxetine, carbamazepine for trigeminal neuralgia

— Fatigue: amantadine, modafinil; address sleep and depression first

— Bladder urgency: oxybutynin only after PVR confirmed <100 mL; otherwise CIC

— Gait/walking speed: dalfampridine (4-aminopyridine) improves walking in selected patients (contraindicated if seizure history or CrCl <50)

— Even after CIS with MRI lesions, early DMT delays conversion to clinically definite MS

— Choose moderate-efficacy vs high-efficacy DMT based on disease activity, age, and patient preference; recent trend favors early high-efficacy in active disease

CCS pearl: Order in this sequence for acute relapse — vitals, UA, glucose, MRI with gad, IV methylprednisolone 1 g daily × 5 days, neuro consult, PT/OT, DVT prophylaxis, then schedule outpatient MS specialist follow-up at 4 weeks. Don't forget to advance the clock and reassess deficit after the steroid course.

Treatment of an acute relapse (new or worsening deficit >24 h, no infection):

Before steroids:

Symptomatic management of an established attack:

Long-term logic — start DMT as early as possible:

Disease-Modifying Therapy — First-Line and Platform Agents

— Interferon β-1a (IM weekly, SC 3×/week), interferon β-1b (SC every other day)

— AEs: flu-like symptoms, injection site reactions, transaminitis, leukopenia, depression worsening, thyroid dysfunction

— Monitor CBC, LFTs, TSH every 3–6 months

— Contraindicated in NMOSD (worsens disease)

— Glatiramer acetate (SC daily or 3×/week)

— Random amino acid polymer; very safe, pregnancy-compatible

— AEs: lipoatrophy at injection sites, transient post-injection chest tightness/flushing (benign)

— Dimethyl fumarate / diroximel fumarate: AEs flushing, GI upset, lymphopenia, rare PML if ALC <500 prolonged

— Teriflunomide: AEs hair thinning, hepatotoxicity, teratogenic (Category X) — requires cholestyramine washout before pregnancy

— Fingolimod / siponimod / ozanimod (S1P modulators): first-dose bradycardia (cardiac monitoring 6 h for fingolimod), macular edema, lymphopenia, herpes reactivation, need VZV immunity before starting

— Anti-CD20 monoclonal antibodies — ocrelizumab, ofatumumab, rituximab (off-label): IV/SC, deplete B cells; AEs infusion reactions, hypogammaglobulinemia, infections; ocrelizumab is the only FDA-approved drug for PPMS

— Natalizumab (anti-α4 integrin): highly effective; PML risk rises with JCV+ status, duration >2 years, prior immunosuppression — check JCV antibody index every 6 months

— Cladribine, alemtuzumab: pulsed induction agents; significant autoimmune and infection risks

Board pearl: JCV antibody status dictates natalizumab safety: JCV-negative patients have very low PML risk; JCV-positive patients beyond 2 years of therapy have risk exceeding 1:100 — switch DMT.

Goal of DMT: reduce relapse rate, MRI activity, and long-term disability. No DMT reverses existing damage.

Injectable platform therapies (moderate efficacy, strong safety record):

Oral moderate-efficacy DMTs:

High-efficacy DMTs (increasingly first-line in active disease):

DMT Selection, Switching, and Monitoring

— Low disease activity, patient preference for safety: glatiramer acetate or interferon

— Active RRMS (≥2 relapses/year, multiple enhancing lesions, or disabling attack): high-efficacy upfront — ocrelizumab, ofatumumab, or natalizumab (if JCV-negative)

— PPMS: ocrelizumab is the only approved option

— Highly active despite first DMT: escalate to high-efficacy agent

— CBC, CMP, LFTs, TSH

— HIV, hepatitis B (HBsAg, anti-HBc, anti-HBs), hepatitis C, TB (IGRA), VZV IgG

— JCV antibody index before natalizumab

— Pregnancy test, contraception counseling

— Vaccinations updated — ideally 4–6 weeks before starting (especially live vaccines like VZV, which are contraindicated once on immunosuppression)

— HPV, influenza, COVID, pneumococcal as appropriate

— MRI brain at 6 months after starting, then annually; spinal cord if new symptoms

— CBC, LFTs every 3–6 months (more frequent on fumarates, teriflunomide)

— Annual ophthalmology if on fingolimod (macular edema)

— JCV antibody every 6 months on natalizumab

— Immunoglobulin levels annually on anti-CD20 agents

— ≥1 clinical relapse, ≥2 new T2 lesions, or any enhancing lesion while on therapy → switch DMT

— Concept of NEDA-3 (No Evidence of Disease Activity): no relapses, no MRI activity, no disability progression — increasingly the target

Step 3 management: When switching from natalizumab to another DMT, the washout interval matters — too long risks rebound disease activity (severe relapse within 3 months of stopping); coordinate with neurology to bridge promptly. Always re-screen for JCV, infections, and vaccinations before each DMT change.

Choosing initial DMT — Step 3 framework:

Pre-DMT screening checklist (memorize):

Routine monitoring on DMT:

Defining treatment failure:

Special Populations — Elderly and Renal/Hepatic Impairment

— Inflammatory activity declines with age; neurodegeneration predominates

— DMTs become less effective and riskier (infection, malignancy) after age 55–60

— Consider DMT discontinuation in patients >55 with no relapses or MRI activity for ≥5 years — discuss shared decision making

— Vaccinate aggressively (pneumococcal, zoster recombinant — non-live and safe on immunosuppression, influenza, COVID)

— Address falls, osteoporosis (especially after repeated steroid courses), cognitive screening

— Teriflunomide: caution; not removed by dialysis (highly protein bound)

— Dalfampridine: contraindicated if CrCl <50 (seizure risk from accumulation)

— Gadolinium: avoid in eGFR <30 (NSF risk with older agents); use macrocyclic agents cautiously

— Adjust gabapentin, pregabalin, baclofen for renal function

— Interferons, teriflunomide, fumarates — all hepatotoxic; avoid in active liver disease; monitor LFTs

— Teriflunomide contraindicated in severe hepatic impairment

— Hepatitis B reactivation risk with anti-CD20 agents — screen and prophylax with entecavir/tenofovir if HBcAb+

— Fingolimod — first-dose bradycardia, AV block; contraindicated in recent MI, unstable angina, class III/IV HF, QT prolongation, sick sinus syndrome

— Siponimod requires CYP2C9 genotyping (avoid in CYP2C93/3)

Board pearl: A 62-year-old woman with stable MS for 7 years on glatiramer with no relapses and no new MRI lesions asks if she still needs DMT — the evidence-supported answer is shared decision to consider discontinuation, with continued annual MRI surveillance. This is a classic Step 3 ambulatory longitudinal-care question.

Older MS patients (>55 years):

Renal impairment:

Hepatic impairment:

Cardiac comorbidity:

Special Populations — Pregnancy, Pediatrics, and Family Planning

— Relapse rate decreases during pregnancy (especially 3rd trimester) and rises in first 3 months postpartum

— Pre-pregnancy counseling is essential — MS does not reduce fertility and does not worsen pregnancy outcomes

— Vaginal delivery and epidural anesthesia are safe

— Teriflunomide: Category X — teratogenic; requires cholestyramine 8 g TID × 11 days accelerated elimination before conception, then confirm plasma level <0.02 mg/L

— Fingolimod, siponimod, ozanimod: stop 2 months before conception; rebound risk

— Natalizumab: can be continued into early pregnancy if disease very active; placental transfer in 3rd trimester (neonatal cytopenias)

— Glatiramer acetate: safest option, can be continued through pregnancy

— Interferons: generally avoided but considered low risk

— Anti-CD20 (ocrelizumab, ofatumumab): stop ≥6 months before conception; if dosed within 6 months of pregnancy, avoid live vaccines in the infant (rotavirus, BCG)

— Exclusive breastfeeding may reduce postpartum relapse risk

— Glatiramer, interferons, and likely ocrelizumab are compatible

— Restart pre-pregnancy DMT as soon as feasible postpartum if not breastfeeding

— Usually RRMS, high relapse rate, fast MRI lesion accumulation

— Differentiate from ADEM (monophasic, encephalopathy, larger lesions) and MOG-associated disease

— Approved pediatric DMTs: fingolimod, teriflunomide, dimethyl fumarate (age ≥10); ocrelizumab and natalizumab used off-label

Key distinction: ADEM — child, post-infectious, encephalopathy, large confluent lesions, monophasic, often resolves; Pediatric MS — recurrent attacks, smaller ovoid lesions, no encephalopathy. Misdiagnosis affects DMT decisions.

Pregnancy and MS:

DMT and pregnancy:

Breastfeeding:

Pediatric MS (<18 years, ~3–5% of MS cases):

Complications and Adverse Outcomes

— Progressive disability: by 15 years, ~50% need walking aid if untreated

— Cognitive impairment: processing speed and memory; affects employment

— Depression and suicide: suicide rate ~2× general population — screen at every visit

— Bladder/bowel dysfunction: recurrent UTIs, urosepsis (leading cause of mortality)

— Sexual dysfunction

— Osteoporosis from immobility and steroids — DEXA, vitamin D, calcium

— Dysphagia in advanced disease → aspiration pneumonia

— Spasticity contractures, pressure ulcers, DVT in non-ambulatory patients

— PML (progressive multifocal leukoencephalopathy) — natalizumab > fingolimod, dimethyl fumarate; presents as subacute cognitive/behavioral/motor decline with non-enhancing confluent white matter lesions; diagnose with CSF JCV PCR; treat by stopping the drug ± PLEX to remove natalizumab; high mortality

— Hepatotoxicity: interferons, teriflunomide, fumarates

— Lymphopenia, opportunistic infections: fumarates, S1P modulators, alemtuzumab

— Cardiac: fingolimod bradycardia/AV block

— Macular edema: S1P modulators

— Secondary autoimmunity: alemtuzumab causes Graves disease, ITP, anti-GBM nephritis — monthly monitoring × 4 years

— Infusion reactions: ocrelizumab, natalizumab

— Hypogammaglobulinemia, recurrent infections: anti-CD20 long-term

— Reactivation of HBV, TB, VZV, HSV

Step 3 management: In an MS patient on natalizumab >2 years (JCV+) with new cognitive decline and non-enhancing confluent lesions on MRI → stop natalizumab immediately, LP for JCV PCR, PLEX to accelerate clearance. Do not give steroids first — they worsen PML by deepening immunosuppression unless IRIS develops later.

Disease-related complications:

DMT-related complications:

Pseudo-relapse triggers to recognize and treat — UTI, pneumonia, fever, dehydration, hyperthermia.

When to Escalate Care — Hospitalization and Consultation

— Severe disabling relapse requiring IV steroids and monitoring (paraplegia, severe vision loss, brainstem deficits)

— Failure of outpatient steroid response → PLEX initiation

— Suspected PML, encephalitis, or opportunistic infection

— Acute urinary retention requiring catheterization, urosepsis

— Aspiration, respiratory compromise (rare, advanced disease)

— New severe psychiatric symptoms or active suicidality

— Respiratory failure from high cervical cord or brainstem lesions

— Status epilepticus (rare in MS but seen with cortical lesions)

— Severe dysautonomia

— Neurology/MS specialist — confirm diagnosis, initiate/escalate DMT

— Ophthalmology — optic neuritis evaluation, fingolimod monitoring

— Urology — recurrent UTI, retention, neurogenic bladder

— PM&R / PT/OT — gait, ADLs, assistive devices

— Psychiatry — depression, pseudobulbar affect (dextromethorphan-quinidine)

— Obstetrics / maternal-fetal medicine — pregnancy planning

— Discharge after relapse with steroid taper if used (usually no taper after pulse), GI prophylaxis, glucose monitoring, DVT prophylaxis if non-ambulatory

— Schedule outpatient MS clinic within 2–4 weeks

— Reassess DMT — a relapse on therapy = treatment failure → consider switch

— Coordinate home health, PT, OT before discharge

CCS pearl: For a CCS case of acute severe relapse — admit, place foley if retention, IV methylprednisolone 1 g daily × 5 days, neurology consult on day 1, PT/OT day 2, ophthalmology if visual involvement, MRI brain/cord with gad, schedule DMT initiation/reassessment, discharge with 2-week neuro follow-up. Advance the clock and look for new orders at each interval.

Inpatient admission indications:

ICU triage:

Consultations:

Transitions of care:

Key Differentials — Other Demyelinating and Inflammatory Diseases

— Aquaporin-4 IgG positive (highly specific)

— Severe optic neuritis (often bilateral, profound vision loss) and longitudinally extensive transverse myelitis (LETM, ≥3 segments)

— Area postrema syndrome (intractable hiccups, nausea, vomiting)

— Brain MRI often normal or atypical (periependymal lesions around 3rd/4th ventricles)

— Treatment differs: acute attacks with steroids + PLEX; chronic prevention with eculizumab, inebilizumab, satralizumab, rituximab — interferons and natalizumab worsen NMOSD

— Bilateral optic neuritis, ADEM-like presentations, often monophasic or recurrent

— MOG-IgG positive; AQP4 negative

— Generally responsive to steroids; some require chronic immunosuppression

— Post-infectious/post-vaccination, monophasic

— Encephalopathy distinguishes from MS

— Large, poorly demarcated white matter lesions, often with deep gray involvement

— First demyelinating event — may or may not progress to MS depending on MRI

— MRI lesions without clinical attacks; ~30% develop MS over 5 years

— Cranial neuropathies (especially CN VII), hypothalamic/pituitary involvement, basal meningeal enhancement; elevated ACE, hilar adenopathy on CT chest

— Headache, encephalopathy, multifocal strokes; angiography shows beading

Key distinction: A young woman with bilateral severe optic neuritis and LETM is NMOSD until AQP4 is back. Starting interferon-β empirically would be a medical error — always check NMO/MOG antibodies before MS DMT.

Neuromyelitis optica spectrum disorder (NMOSD):

MOG antibody–associated disease (MOGAD):

Acute disseminated encephalomyelitis (ADEM):

Clinically isolated syndrome (CIS):

Radiologically isolated syndrome (RIS):

Neurosarcoidosis:

CNS vasculitis / primary angiitis of CNS:

Susac syndrome: triad of encephalopathy, branch retinal artery occlusions, sensorineural hearing loss — corpus callosum "snowball" lesions

Key Differentials — Non-Demyelinating Mimics

— Subacute combined degeneration — dorsal columns + corticospinal tracts; macrocytic anemia, glossitis

— Copper deficiency from zinc excess, bariatric surgery — similar myelopathy with cytopenias

— Always check B12, MMA, homocysteine, copper, ceruloplasmin in suspected MS

— Vacuolar myelopathy, HIV dementia, PML, opportunistic infections

— Check HIV in every new MS workup

— Tabes dorsalis, general paresis, Argyll Robertson pupils

— RPR + treponemal test, CSF VDRL

— Facial palsy, painful radiculitis, meningitis; exposure history; Lyme serologies + CSF

— Progressive spastic paraparesis, bladder involvement; endemic regions (Caribbean, Japan)

— Can cause CNS lesions; check ANA, SS-A/B, schirmer test

— Tumor, disc, abscess — MRI cord with contrast

— Young men with progressive spastic paraparesis + adrenal insufficiency → check VLCFAs

— Migraine with aura, recurrent subcortical strokes, dementia; anterior temporal pole T2 hyperintensities; NOTCH3 mutation

— Small punctate subcortical lesions, no Dawson fingers, no cord lesions; clinical history is key

— Inconsistent exam, normal MRI

Board pearl: Before labeling progressive myelopathy as PPMS, check B12, copper, HIV, RPR, HTLV-1, VLCFAs, and MRI of the entire cord with contrast to exclude compressive and metabolic mimics — failure to do so is the most common diagnostic error.

Vitamin B12 / copper deficiency:

HIV-related CNS disease:

Neurosyphilis:

Lyme neuroborreliosis:

HTLV-1 associated myelopathy / tropical spastic paraparesis:

Sjögren syndrome, SLE, Behçet:

Spinal cord compression:

Hereditary leukodystrophies / adrenomyeloneuropathy:

CADASIL:

Migraine with white matter lesions:

Functional neurologic disorder:

Long-Term Plan, Secondary Prevention, and Wellness

— Continue DMT based on activity; reassess annually

— Annual MRI brain (and cord if symptoms); compare for new T2 or enhancing lesions

— Track relapses, EDSS, MRI — define NEDA-3 target

— Smoking cessation — smoking accelerates disability and reduces DMT efficacy

— Vitamin D supplementation to 25-OH-D >40 ng/mL (1000–4000 IU daily)

— Exercise — aerobic + resistance; improves fatigue, mood, gait

— Mediterranean or low-saturated-fat diet (limited evidence but reasonable)

— Weight management, especially in adolescents and young adults

— Limit alcohol, ensure sleep hygiene

— Annual influenza, COVID-19 boosters, pneumococcal (PCV15/20 + PPSV23), recombinant zoster (Shingrix) — all non-live, safe on DMT

— Avoid live vaccines (MMR, varicella, yellow fever, live influenza, oral typhoid) while on immunosuppressive DMT

— Time live vaccines ≥4 weeks before starting DMT when possible

— HPV vaccination in eligible age range

— DEXA at baseline and periodically; calcium 1000–1200 mg, vitamin D 800–1000 IU

— Manage HTN, diabetes, lipids per standard guidelines — MS does not change these targets

— Spasticity (baclofen, tizanidine, botulinum toxin), bladder (PVR-driven), constipation, neuropathic pain, fatigue, depression, sexual dysfunction

— Pseudobulbar affect: dextromethorphan-quinidine

Step 3 management: At every annual visit, the structured checklist is — relapses since last visit, EDSS, MRI review, DMT adherence/side effects, vitamin D level, smoking status, mood/PHQ-9, vaccination status, bone health, bladder/bowel/sexual function, and DMT continuation vs switch vs discontinuation. This longitudinal frame is exactly what Step 3 tests.

Cornerstones of long-term MS care:

Modifiable risk factors and lifestyle:

Vaccination strategy:

Cardiovascular and bone health:

Symptomatic management refresh:

Follow-Up, Monitoring, and Rehabilitation

— MS specialist neurology every 6 months for active disease; annually if stable

— MRI brain (± cord) at 6 months after DMT initiation, then annually

— Drug-specific labs:

— Interferons, fumarates, teriflunomide: CBC, LFTs every 3 months × 1 year, then every 6 months

— Fingolimod: CBC, LFTs, annual ophthalmology, ECG before first dose

— Natalizumab: JCV antibody every 6 months

— Anti-CD20: quarterly CBC, annual IgG levels, screen for infections

— Alemtuzumab: monthly CBC, creatinine, urinalysis, and quarterly TSH × 48 months after last dose

— PT for strength, gait training, balance — every MS patient benefits

— OT for ADLs, energy conservation, workplace accommodations

— Speech therapy for dysarthria, dysphagia, cognitive remediation

— Assistive devices — cane → walker → wheelchair as needed; AFO for foot drop

— Driving evaluation if cognitive or motor concerns

— Discuss prognosis honestly but emphasize wide variability and treatment progress

— Family planning, contraception (some DMTs interact with OCPs)

— Employment, disability paperwork, FMLA

— Connect with National MS Society resources, peer support

— Advance care planning in progressive disease

— Fall prevention assessment

— Home health, durable medical equipment

Board pearl: A patient on fingolimod presents with new blurry vision — the differential is macular edema (drug AE), optic neuritis (MS relapse), or PML (rare). The correct next step is dilated fundus exam / OCT before assuming an MS attack. Don't reflexively give steroids.

Outpatient follow-up cadence:

Rehabilitation:

Counseling and shared decision-making:

Caregiver support and home safety:

Ethical, Legal, and Patient Safety Considerations

— Patients must understand PML risk with natalizumab (and JCV antibody implications), secondary autoimmunity with alemtuzumab, infection and infusion risks with anti-CD20, and teratogenicity with teriflunomide

— Document discussion of alternatives, including no-DMT option (especially in older or stable patients considering discontinuation)

— Teriflunomide is Category X — both partners (male and female) must use contraception

— Pregnancy planning conversations should occur before DMT initiation in any patient of reproductive age

— Accelerated elimination protocol must be offered before conception

— Cognitive impairment, visual deficits, or motor weakness may impair driving — physicians should counsel and document, and report per state-specific impaired driver laws (e.g., California, Oregon mandate reporting; most states do not but encourage)

— Help with disability paperwork and workplace accommodations under ADA

— DMT discontinuation rebound: stopping natalizumab, fingolimod, or ozanimod abruptly can cause severe rebound relapses within weeks to months — never let a patient run out without a bridge plan; this is a high-yield Step 3 patient safety scenario

— Hospital admission for unrelated reasons (surgery, infection) — coordinate DMT timing with neurology; hold natalizumab during active infection

— Medication reconciliation at every visit and transition

— Live vaccine in an immunosuppressed patient is a serious safety event — verify VZV immunity and complete inactivated vaccines before starting immunosuppressive DMT

— Advanced MS with cognitive impairment may impair decisional capacity — assess and document; involve surrogate decision-makers and advance directives early

Step 3 management: A patient lost to follow-up while on natalizumab stops the drug without bridging — at 8 weeks she has a severe relapse. Root-cause analysis points to systems failure in transitions of care; the correct safety intervention is a panel registry, automated infusion reminders, and structured DMT bridging protocol — classic value-based, patient-safety Step 3 content.

Informed consent for DMT:

Reproductive ethics:

Driving and disability:

Transitions of care risks:

Vaccination ethics:

Capacity and end-of-life:

High-Yield Associations and Rapid-Fire Facts

Board pearl: "Painful monocular vision loss with red desaturation in a 28-year-old woman" — this is optic neuritis, MRI brain looking for additional lesions is the next step. Don't waste the answer on a CT head.

Dawson fingers — periventricular ovoid lesions perpendicular to ventricles → MS

Internuclear ophthalmoplegia — MLF lesion; bilateral INO in a young person = MS

Lhermitte sign — neck flexion → electric shock down spine; posterior column demyelination

Uhthoff phenomenon — heat (shower, exercise, fever) transiently worsens symptoms; not a relapse

MS hug — band-like truncal tightness from thoracic cord lesion

Charcot triad — nystagmus, intention tremor, scanning speech (cerebellar MS)

Marcus Gunn pupil (RAPD) — optic neuritis

CSF oligoclonal bands present in CSF but not serum — supports MS

JCV antibody — risk-stratifies PML on natalizumab

EBV infection — near-necessary risk factor for MS

HLA-DRB1*15:01 — strongest genetic association

AQP4-IgG — NMOSD, not MS

MOG-IgG — MOGAD, often pediatric ADEM-like

Ocrelizumab — only DMT approved for PPMS

Teriflunomide — Category X; cholestyramine washout

Fingolimod first dose — 6-hour cardiac monitoring; bradycardia/AV block

Alemtuzumab — Graves, ITP, anti-GBM nephritis; monthly labs × 4 years

Natalizumab + JCV+ + >2 years — PML risk >1:100

PLEX — for steroid-refractory severe relapses and for natalizumab-associated PML

Pseudo-relapse — UTI/fever unmasking old deficits; treat infection, not steroids

Postpartum — relapse risk peaks in first 3 months

Vitamin D <20 ng/mL — associated with higher relapse rate; supplement to >40

Smoking — worst modifiable risk factor for disability progression

Dalfampridine — improves walking speed; seizure risk if CrCl <50

Pseudobulbar affect — dextromethorphan-quinidine

Trigeminal neuralgia in a young patient — think MS

Suicide risk — ~2× general population; screen at every visit

Bladder dysfunction with PVR >100 mL — do not use anticholinergics alone; consider CIC

NEDA-3 — no relapses, no MRI activity, no progression; the treatment target

Board Question Stem Patterns

— 26-year-old woman with diplopia, exam shows impaired adduction bilaterally with nystagmus of abducting eye → MRI brain with gad → MS. Next step: LP if MRI equivocal; otherwise begin DMT planning.

— Young woman, painful vision loss, RAPD, red desaturation → MRI brain. If ≥2 typical lesions → high risk for MS → consider early DMT.

— Known MS patient with "worsening leg weakness" but also dysuria, fever 38.5 °C → UA shows UTI → treat UTI, not steroids.

— MS patient on teriflunomide wants to conceive → cholestyramine washout and confirm plasma level <0.02 mg/L before conception.

— Patient on natalizumab × 3 years (JCV+) with new cognitive changes, confluent non-enhancing white matter lesions → stop natalizumab, LP for JCV PCR, PLEX.

— 50-year-old man with 2 years of progressive spastic paraparesis, MRI brain shows few lesions but cord MRI shows 2 lesions, CSF OCBs+ → PPMS → ocrelizumab.

— Woman with bilateral severe optic neuritis and LETM (4 segments) → check AQP4-IgG → if positive, NMOSD → do NOT start interferon; treat with steroids + PLEX, then rituximab/eculizumab.

— Asks about monitoring → ECG, 6-hour observation, VZV immunity, ophthalmologic exam.

— Paraplegia, no infection → IV methylprednisolone 1 g × 5 days; if no improvement at day 7 → PLEX.

— Patient on glatiramer has 2 relapses and 3 new T2 lesions over a year → treatment failure → switch to high-efficacy DMT (ocrelizumab or natalizumab if JCV-).

— Relapse 6 weeks postpartum → IV steroids; resume DMT promptly; discuss breastfeeding-compatible options.

— Symptoms after hot shower → Uhthoff phenomenon, not a relapse; reassure.

Key distinction: The exam loves to test recognition of pseudo-relapse vs true relapse and NMOSD vs MS — get these two right and you've banked a lot of MS points.

Stem 1 — Bilateral INO:

Stem 2 — Optic neuritis:

Stem 3 — Pseudo-relapse:

Stem 4 — Pregnancy planning:

Stem 5 — Natalizumab and PML:

Stem 6 — PPMS:

Stem 7 — NMOSD vs MS:

Stem 8 — Fingolimod first dose:

Stem 9 — Acute severe relapse:

Stem 10 — DMT switch:

Stem 11 — Postpartum:

Stem 12 — Heat sensitivity:

One-Line Recap

Multiple sclerosis is a relapsing-remitting CNS demyelinating disease diagnosed by clinical attacks plus MRI evidence of dissemination in space and time (2017 McDonald criteria), treated acutely with IV methylprednisolone and longitudinally with early disease-modifying therapy chosen by disease activity, comorbidities, JCV/pregnancy status, and patient preference, with NEDA-3 as the target.

Board pearl: When the Step 3 stem mentions a young woman with transient neurologic symptoms separated in time and place, the answer pathway is MRI brain with gadolinium → exclude mimics → confirm McDonald criteria → start DMT early — and the trap is always either pseudo-relapse from a UTI or NMOSD masquerading as MS.

Diagnosis — McDonald 2017: ≥1 T2 lesion in ≥2 of 4 typical regions (periventricular, cortical/juxtacortical, infratentorial, spinal cord) for DIS; new lesion on follow-up MRI or simultaneous enhancing + non-enhancing lesions or CSF OCBs for DIT. Always exclude NMOSD (AQP4-IgG), MOGAD, B12 deficiency, HIV, syphilis, neurosarcoidosis, and compressive myelopathy before locking in.

Acute relapse — IV methylprednisolone 1 g daily × 3–5 days; PLEX if steroid-refractory; rule out infection first to avoid treating a pseudo-relapse.

DMT selection — early high-efficacy therapy (ocrelizumab, ofatumumab, natalizumab) increasingly preferred in active disease; PPMS gets ocrelizumab; pregnancy planning demands washout for teriflunomide and bridging for natalizumab/fingolimod to prevent rebound; never give live vaccines on immunosuppressive DMT.

Long-term care — annual MRI, vitamin D >40, smoking cessation, vaccinations, bladder/bowel/mood/cognition surveillance, EDSS tracking, structured transitions of care, and shared decision-making about DMT continuation in patients >55 with prolonged stable disease.