Immunotherapy & MS Pharmacology
Immunotherapy & MS Pharmacology
What Do You Need to Know?
- MS acute relapse treatment — IV methylprednisolone 1 g × 3–5 days speeds recovery but does NOT change long-term outcome; PLEX for steroid-refractory relapses
- MS DMT efficacy tiers — moderate (interferon-beta, glatiramer, teriflunomide, dimethyl fumarate) vs high (natalizumab, ocrelizumab, alemtuzumab, cladribine, S1P modulators)
- PML risk with natalizumab — stratify by JCV antibody index (>1.5 = high risk), prior immunosuppression, and duration of therapy (>24 months); also monitor lymphopenia with dimethyl fumarate
- NMOSD-specific therapies — eculizumab (anti-C5), ravulizumab (anti-C5, FDA April 2024 for AQP4+ NMOSD), inebilizumab (anti-CD19), satralizumab (anti-IL-6R); meningococcal vaccination required for C5 inhibitors; do NOT use MS DMTs (interferon, fingolimod, natalizumab) — they worsen NMO
- Autoimmune encephalitis — first-line (steroids, IVIG, PLEX), second-line (rituximab, cyclophosphamide), tumor removal if paraneoplastic
- General immunosuppressants — know mechanisms and monitoring: azathioprine (check TPMT), mycophenolate (teratogen), rituximab (HBV screen), cyclophosphamide (hemorrhagic cystitis)
- IVIG — Fc receptor/complement modulation; side effects include aseptic meningitis, thrombosis, renal failure, hemolysis in non-O blood types
🚩 Don’t Miss — Test-Day Priorities
- NMOSD ≠ MS: interferon-β, fingolimod, and natalizumab worsen NMOSD → always check AQP4-IgG before starting an MS DMT in atypical demyelination
- Eculizumab and ravulizumab (FDA April 2024 for AQP4+ NMOSD) require meningococcal vaccination (ideally ≥ 2 weeks before first dose) → terminal complement blockade → Neisseria risk
- Rituximab + HBV: screen HBsAg + anti-HBc before every course; entecavir prophylaxis if positive → fulminant reactivation can occur months after infusion
- Natalizumab PML risk stratified by JCV index (> 1.5), prior immunosuppression, and duration > 24 months → consider switching at this threshold
- ICI neurotoxicity: myasthenia + myocarditis + myositis overlap syndrome carries ≥ 30% mortality → high-dose steroids + IVIG/PLEX, hold ICI, check troponin and CK on every case
- Check TPMT before azathioprine and avoid live vaccines (MMR, VZV, yellow fever) on B-cell depletion, S1P modulators, or high-dose steroids
- Mycophenolate and methotrexate are teratogens → contraception required; glatiramer + interferon-β are the safest MS DMTs in pregnancy
- PJP prophylaxis (TMP-SMX) for prolonged high-dose steroids (≥ 20 mg prednisone ≥ 4 weeks) and cyclophosphamide
- Stress-dose steroids for major illness or surgery in any patient on > 5 mg prednisone > 3 weeks → adrenal suppression
- NEDA-3 (no relapses, no MRI activity, no disability progression) is the modern treatment target in MS
🔍 Buzzwords & Pathognomonic FindingsMechanism · Adverse effects · Use / monitoring
Mechanism
- Rituximab / ocrelizumab / ofatumumab / ublituximab → anti-CD20 B-cell depletion (chimeric, humanized, fully human SQ, glycoengineered)
- Inebilizumab → anti-CD19 (broader B-cell + plasmablast depletion) for NMOSD
- Eculizumab / ravulizumab → anti-C5 complement inhibitor (NMOSD, AChR+ MG, PNH)
- Satralizumab / tocilizumab → anti-IL-6R (NMOSD maintenance)
- Efgartigimod / rozanolixizumab → FcRn antagonist → accelerated IgG catabolism (MG)
- Azathioprine → 6-MP → purine synthesis inhibition (TPMT-dependent)
- Mycophenolate → IMPDH inhibitor → selective lymphocyte purine block
- Methotrexate → dihydrofolate reductase inhibitor
- Cyclophosphamide → alkylating agent (DNA cross-linking)
- Tacrolimus / cyclosporine → calcineurin inhibitors
Adverse effects / monitoring
- Anaphylaxis on first IVIG dose → selective IgA deficiency (use IgA-depleted product)
- Aseptic meningitis + thromboembolism + AKI → IVIG
- Hemorrhagic cystitis + bladder cancer + infertility → cyclophosphamide (MESNA + hydration)
- Pulmonary fibrosis + hepatotoxicity + stomatitis → methotrexate (folate rescue)
- PRES + nephrotoxicity + tremor + hirsutism + Mg wasting → calcineurin inhibitors
- HBV reactivation + late hypogammaglobulinemia + rare PML → rituximab / anti-CD20
- Citrate-induced hypocalcemia + hypotension + line complications → PLEX
- Secondary autoimmunity (ITP, Graves, anti-GBM) → alemtuzumab
- Severe TPMT deficiency → profound myelosuppression → azathioprine
- Meningococcal sepsis risk → eculizumab / ravulizumab (mandatory vaccination)
Use / pregnancy / pearls
- Methylprednisolone 1 g IV × 3–5 d → acute MS relapse, NMOSD attack, ADEM, transverse myelitis, autoimmune encephalitis
- PLEX (5–7 exchanges) → MG crisis, GBS, steroid-refractory NMOSD/MS, tumefactive/Marburg MS, autoimmune encephalitis
- Rituximab first-line → MuSK MG, refractory AChR MG, NMOSD, PCNS vasculitis, IgG4-related disease
- Mycophenolate / azathioprine → long-term maintenance for MG, NMOSD, AIE, sarcoid neuropathy
- Glatiramer acetate + interferon-β → safest MS DMTs in pregnancy; avoid teriflunomide, fingolimod, fumarates
- Anti-CD20 antibody crosses placenta → infant B-cell suppression up to 6 months postpartum → delay live vaccines
- Autologous HSCT → highly active / treatment-refractory relapsing MS, severe SSc, refractory SLE
- ICI-related myasthenia → methylprednisolone 1 g + IVIG/PLEX + hold ICI + screen for myocarditis (troponin) and myositis (CK)
- Live vaccines (MMR, VZV, yellow fever) contraindicated on B-cell depletion, S1P modulators, high-dose steroids; Shingrix (recombinant) is OK
- NEDA-3 = no relapses + no MRI activity + no disability progression → modern MS treatment target
MS Acute Relapse Management
Treatment Options
| Treatment | Regimen | Key Points |
|---|---|---|
| IV methylprednisolone | 1 g/day × 3–5 days | First-line; speeds recovery but does NOT alter long-term disability; no taper required for short courses |
| Oral methylprednisolone | 1250 mg PO × 3–5 days | Non-inferior to IV in the COPOUSEP trial (Le Page et al., Lancet 2015); alternative when IV access is impractical |
| PLEX (plasmapheresis) | 5–7 exchanges over 10–14 days | For steroid-refractory relapses; most effective for severe attacks with prominent demyelination |
| ACTH (Acthar gel) | 80 units IM/SC daily × 5 days | Alternative to IV steroids; stimulates endogenous cortisol + possible direct immunomodulatory effects; expensive |
- Treat only true relapses — new or worsening neurological symptoms lasting >24 hours, in the absence of fever or infection (pseudo-relapses)
- Rule out pseudo-relapse: UTI, other infections, heat exposure (Uhthoff phenomenon) can mimic relapse
- Steroid side effects in MS: insomnia, mood disturbance, hyperglycemia, GI upset, avascular necrosis (with repeated courses), transient worsening before improvement
Board Pearl
IV steroids speed recovery from MS relapses but do NOT change the degree of long-term recovery or prevent future relapses. The Optic Neuritis Treatment Trial (ONTT) showed IV methylprednisolone shortened recovery, while low-dose oral prednisone (1 mg/kg/day) increased the rate of new optic neuritis attacks vs placebo — this finding applies to LOW-dose oral prednisone, NOT to high-dose oral methylprednisolone (1250 mg), which is an accepted alternative to IV.
MS Disease-Modifying Therapies
Treatment Approach & Escalation Strategy
- Escalation approach: start with moderate-efficacy agent, escalate if breakthrough disease (relapses, new MRI lesions, disability progression)
- Early high-efficacy treatment (EHET): increasingly favored — start with high-efficacy DMT (e.g., natalizumab, ocrelizumab, alemtuzumab) in patients with poor prognostic features (high relapse rate, high lesion burden, spinal cord lesions, young age)
- Breakthrough disease on DMT: ≥1 relapse/year, new/enlarging T2 lesions, new Gd-enhancing lesions, or sustained disability worsening → switch to higher-efficacy agent
- Pregnancy planning: most DMTs require washout before conception; glatiramer acetate is considered low risk in pregnancy based on accumulated registry data and is the safest DMT during pregnancy; natalizumab may be continued until conception in high-activity disease
Platform / Moderate-Efficacy DMTs
| Drug | Mechanism | Route / Frequency | Key Side Effects | Monitoring |
|---|---|---|---|---|
| Interferon beta-1a (Avonex, Rebif) | Immunomodulatory; ↓ T-cell activation, ↓ BBB permeability, shifts Th1→Th2 | IM weekly (Avonex) or SC 3×/week (Rebif) | Flu-like symptoms, injection site reactions, hepatotoxicity, depression, leukopenia | CBC, LFTs q3–6 months; neutralizing antibodies (reduce efficacy) |
| Interferon beta-1b (Betaseron, Extavia) | Same as above | SC every other day | Same as above | Same as above |
| Glatiramer acetate (Copaxone) | Synthetic polypeptide; mimics MBP; shifts Th1→Th2; induces regulatory T cells | SC daily or 3×/week (40 mg) | Injection site reactions, lipoatrophy, immediate post-injection systemic reaction (chest tightness, flushing — benign, self-limited) | None required routinely |
| Teriflunomide (Aubagio) | Inhibits dihydroorotate dehydrogenase (DHODH) → ↓ pyrimidine synthesis → ↓ lymphocyte proliferation | PO daily | Contraindicated in pregnancy (boxed warning — teratogenic in animals); hepatotoxicity, hair thinning, diarrhea, peripheral neuropathy | LFTs monthly × 6 months then periodically; pregnancy test before starting; cholestyramine washout if pregnancy desired |
| Dimethyl fumarate (Tecfidera) | Activates Nrf2 pathway → antioxidant/anti-inflammatory; depletes memory T cells | PO BID | Flushing, GI upset (nausea, diarrhea), lymphopenia → PML risk if sustained ALC <500 | CBC q6 months; hold if ALC <500 for >6 months |
- Interferon neutralizing antibodies: develop in 2–40% depending on formulation; reduce drug efficacy; check if breakthrough disease occurs on interferon therapy
- Glatiramer acetate lipoatrophy: subcutaneous fat loss at injection sites; rotate injection sites to minimize; cosmetically distressing
- Teriflunomide washout: extremely long half-life (>2 weeks); cholestyramine 8 g TID × 11 days or activated charcoal for accelerated elimination (required before pregnancy)
- Dimethyl fumarate flushing: managed with aspirin 325 mg taken 30 minutes before dose; taking with food reduces GI symptoms
- Diroximel fumarate (Vumerity): same active metabolite as dimethyl fumarate but better GI tolerability; equivalent efficacy
- Monomethyl fumarate (Bafiertam): bioequivalent active metabolite of dimethyl fumarate; oral; similar efficacy with improved GI tolerability
High-Efficacy DMTs
| Drug | Mechanism | Route / Frequency | Key Side Effects | Monitoring |
|---|---|---|---|---|
| Natalizumab (Tysabri) | Anti-α4-integrin (VLA-4) monoclonal Ab → blocks lymphocyte migration across BBB | IV infusion q4 weeks | PML (JCV reactivation), infusion reactions, hepatotoxicity, rebound disease activity on discontinuation | JCV antibody & index q6 months; MRI for PML surveillance; LFTs |
| Fingolimod (Gilenya) | S1P receptor modulator → traps lymphocytes in lymph nodes → prevents CNS infiltration | PO daily | First-dose bradycardia/AV block (6-hour cardiac monitoring), macular edema, ↑ infections, PML (rare), rebound on discontinuation | First-dose 6h ECG monitoring; ophthalmology at 3–4 months; CBC; VZV titer (vaccinate if negative before starting) |
| Siponimod (Mayzent) | Selective S1P1/S1P5 modulator | PO daily (with dose titration) | Similar to fingolimod; requires CYP2C9 genotyping: *1/*3 or *2/*3 → maintenance 1 mg daily (vs standard 2 mg); *3/*3 contraindicated | CYP2C9 genotype before starting; first-dose cardiac monitoring; ophthalmology |
| Ozanimod (Zeposia) | Selective S1P1/S1P5 modulator | PO daily (with dose titration) | Similar to fingolimod; no genotyping needed but titration required; MAO-related dietary cautions | First-dose monitoring per titration; ophthalmology; LFTs |
| Ponesimod (Ponvory) | Selective S1P1 modulator | PO daily (with 14-day titration) | Similar to fingolimod; shorter half-life (~33 h) → faster washout; no genotyping | Titration kit; first-dose monitoring per protocol; ophthalmology; LFTs |
| Ocrelizumab (Ocrevus) | Anti-CD20 monoclonal Ab → depletes B cells (spares plasma cells and pro-B cells) | IV infusion q6 months | Infusion reactions, ↑ infections, HBV reactivation, hypogammaglobulinemia; early OPERA/ORATORIO trials suggested a possible breast cancer signal, but subsequent post-marketing data have NOT consistently confirmed increased risk | HBV screen before starting; immunoglobulin levels; CBC |
| Ofatumumab (Kesimpta) | Anti-CD20 monoclonal Ab (fully human) | SC monthly (self-injection) | Injection site reactions, ↑ infections, HBV reactivation. Anti-CD20 therapies (ofatumumab, ocrelizumab, ublituximab) — label advises contraception during and for 6 months after last dose; not taught as absolute pregnancy contraindication; individualize in high-activity MS, particularly because fetal/neonatal B-cell depletion is the key concern with late pregnancy exposure | HBV screen; immunoglobulin levels |
| Ublituximab (Briumvi) | Anti-CD20 monoclonal Ab; glycoengineered (low-fucose) → enhanced antibody-dependent cellular cytotoxicity (ADCC), allowing lower dose and shorter infusion | IV infusion q6 months (FDA Dec 2022 for RRMS); ULTIMATE I/II trials | Infusion reactions, ↑ infections, HBV reactivation, hypogammaglobulinemia | HBV screen; immunoglobulin levels; CBC |
| Alemtuzumab (Lemtrada) | Anti-CD52 → pan-lymphocyte depletion (T and B cells, monocytes, NK cells) | IV infusion: 5 days year 1, 3 days year 2 | Secondary autoimmunity: thyroid disease (30–40%), ITP, anti-GBM disease (Goodpasture); infusion reactions; ↑ infections | CBC, TSH, creatinine, urinalysis monthly for 4 years after last dose; monitor for autoimmune disease |
| Cladribine (Mavenclad) | Purine analog → selective lymphocyte depletion — preferentially depletes B cells more than T cells; B-cell recovery slower than T-cell recovery | PO: 2 short courses/year × 2 years, then no treatment needed | Lymphopenia, herpes zoster, ↑ malignancy risk (theoretical), teratogenic | CBC before each course; lymphocyte count must recover before re-dosing |
- Natalizumab rebound: discontinuation can lead to severe rebound disease activity (tumefactive lesions, IRIS-like) within 3–6 months; bridge therapy needed when switching
- Fingolimod rebound: similar rebound risk; do not abruptly stop; plan transition to next DMT carefully
- Alemtuzumab autoimmunity timeline: thyroid disease typically occurs 1–5 years after treatment; ITP peaks at ~2 years; anti-GBM nephritis is rare but can be fatal — monitor urinalysis for hematuria
Board Pearl
Fingolimod requires 6 hours of cardiac monitoring after the first dose because it can cause symptomatic bradycardia and AV block. This effect is mediated by S1P1 receptor agonism on atrial myocytes. Extend monitoring overnight if HR <45 bpm at hour 6, new ≥2nd-degree AV block, or QTc >500 ms. Patients on beta-blockers or calcium channel blockers are at higher risk. VZV vaccination should be done at least 1 month before starting fingolimod.
Autologous Hematopoietic Stem Cell Transplantation (aHSCT)
- Indication: considered for aggressive RRMS with breakthrough disease on high-efficacy DMT; younger patients with active inflammatory disease (relapses, Gd-enhancing lesions) and limited disability accrual respond best
- Procedure: mobilization of autologous HSCs → immunoablative conditioning (e.g., cyclophosphamide-based) → reinfusion of stem cells to “reset” the immune system
- Evidence: MIST trial (Burt et al., JAMA 2019) showed superiority of aHSCT to DMT for relapsing-remitting MS with breakthrough activity
- Risks: infection during aplastic phase, secondary autoimmunity, infertility, transplant-related mortality (<1% in experienced centers)
- Not typically effective in progressive MS without ongoing inflammatory activity
DMTs and Pregnancy
| DMT | Pregnancy Category | Washout Before Conception | Notes |
|---|---|---|---|
| Glatiramer acetate | Generally considered safe | None required | Safest DMT in pregnancy; can continue until positive pregnancy test; often used as bridge therapy |
| Interferon beta | Generally discontinued before conception; no longer considered absolutely contraindicated | Stop before conception ideally; may be continued if disease activity warrants | Increasing registry data (EMA label update; EFPIA cohorts) suggest relative safety if exposure occurs during pregnancy |
| Natalizumab | Use with caution | Typically stopped at conception | May continue through pregnancy in high-activity disease to prevent rebound; neonatal hematologic abnormalities reported |
| Teriflunomide | Contraindicated in pregnancy (boxed warning — teratogenic in animals) | Accelerated elimination: cholestyramine 8 g TID × 11 d OR activated charcoal 50 g BID × 11 d, then verify plasma teriflunomide concentration <0.02 mg/L (NOT just "undetectable"), generally on two tests separated by ≥14 days | MUST verify drug elimination (plasma level <0.02 mg/L on 2 tests ≥14 d apart) before conception; active metabolite persists for months without washout |
| Dimethyl fumarate | Limited pregnancy data; generally discontinued before conception | Stop before conception ideally | Short half-life allows relatively quick washout if needed mid-pregnancy |
| Fingolimod | Contraindicated | 2 months before conception | Teratogenic in animal studies; rebound disease risk during washout period |
| Ocrelizumab | Label advises contraception during treatment and for 6 months after the last infusion; NOT taught as absolute contraindication — individualize | Contraception during therapy and 6 months after last dose | B-cell depleting; key concern is neonatal B-cell depletion if exposed in 3rd trimester — timing is individualized in high-activity MS |
| Alemtuzumab | Contraindicated | 4 months after last dose | Risk of neonatal thyroid disease (from maternal anti-TSH receptor antibodies) |
| Cladribine | Teratogenic | 6 months for women; 6 months for men | Both male and female patients must use contraception during and after treatment |
MS Symptomatic Management
| Symptom | Pharmacologic Options | Key Points |
|---|---|---|
| Spasticity | Baclofen (oral or intrathecal), tizanidine, dantrolene, gabapentin, botulinum toxin (BoNT) | Intrathecal baclofen for severe refractory cases; tizanidine causes sedation and hepatotoxicity; BoNT for focal spasticity |
| Bladder dysfunction | Oxybutynin, tolterodine, mirabegron, sacral neuromodulation, intermittent catheterization | Antimuscarinics (oxybutynin/tolterodine) for detrusor overactivity; mirabegron (β3 agonist) avoids anticholinergic side effects; CIC for retention |
| Fatigue / cognition | Amantadine, modafinil, methylphenidate | Amantadine first-line for MS fatigue; modafinil for excessive daytime sleepiness; address sleep, mood, and thyroid first |
| Gait impairment | Dalfampridine (Ampyra, 4-aminopyridine) — 10 mg PO BID | K+ channel blocker; improves walking speed in ~35%; contraindicated in seizure history and CrCl ≤50 mL/min |
| Neuropathic pain / paroxysmal symptoms | Gabapentin, pregabalin, carbamazepine, oxcarbazepine, duloxetine, amitriptyline | Carbamazepine for trigeminal neuralgia and tonic spasms; SNRIs for chronic neuropathic pain |
| Depression | SSRIs, SNRIs, CBT | Prevalent (~50% lifetime); screen routinely; avoid interferons in active depression |
| Pseudobulbar affect | Dextromethorphan/quinidine (Nuedexta) | FDA-approved for PBA in MS and ALS |
Infection Prophylaxis & Bone Health on Immunotherapy
- PCP (Pneumocystis jirovecii) prophylaxis: TMP-SMX (or atovaquone or dapsone as alternatives) for patients on prednisone ≥20 mg/day for ≥4 weeks, cyclophosphamide, or combinations involving high-dose chronic immunosuppression. Routine PCP prophylaxis is generally NOT needed with rituximab or ocrelizumab as monotherapy in MS or NMOSD; reserve for patients on combination immunosuppression (e.g., concurrent chronic steroids, cyclophosphamide, or other lymphocyte-depleting therapy) or with significant lymphopenia
- Bone health on chronic steroids: calcium + vitamin D supplementation, baseline and serial DEXA, bisphosphonate consideration for sustained steroid exposure (especially ≥7.5 mg/day prednisone-equivalent for ≥3 months)
- HBV reactivation prophylaxis: entecavir or tenofovir for HBsAg+ patients receiving rituximab/ocrelizumab/ublituximab/inebilizumab
- TB screening: consider IGRA (QuantiFERON) before starting long-term immunosuppression in patients with TB risk
Monoclonal Antibody Targets in Neuroimmunology — Summary
| Target | Drug(s) | Indication(s) | Key Consideration |
|---|---|---|---|
| α4-integrin (VLA-4) | Natalizumab | MS | PML risk (JCV stratification) |
| CD20 | Ocrelizumab, ofatumumab, rituximab | MS, NMOSD, MG, autoimmune encephalitis | HBV screening; hypogammaglobulinemia with prolonged use |
| CD19 | Inebilizumab | NMOSD (AQP4+) | Broader B-cell depletion than anti-CD20 (includes plasmablasts) |
| CD52 | Alemtuzumab | MS | Secondary autoimmunity (thyroid, ITP, anti-GBM) |
| C5 complement | Eculizumab, ravulizumab (Ultomiris), zilucoplan (Zilbrysq) | NMOSD (AQP4+), MG (AChR+) | Meningococcal vaccination required for all C5 inhibitors |
| IL-6 receptor | Satralizumab, tocilizumab | NMOSD (AQP4+) | Blocks IL-6 → ↓ plasmablast survival and antibody production |
| FcRn (neonatal Fc receptor) | Efgartigimod (Vyvgart), rozanolixizumab (Rystiggo) | MG (AChR+ and MuSK+); efgartigimod SC also for CIDP | Accelerates IgG catabolism → lowers IgG; does NOT affect IgM or IgA — selective antibody class effect |
💎 Board Pearl — Anti-CD19 vs Anti-CD20
| Target | Cells Depleted | Key Clinical Implication |
|---|---|---|
| CD20 (rituximab, ocrelizumab, ofatumumab, ublituximab) | Mature B cells (pre-B through memory B); spares plasmablasts and plasma cells | Effective for B-cell–mediated disease; preserves established antibody production by plasma cells; first-line in MS, off-label in NMOSD |
| CD19 (inebilizumab) | Mature B cells PLUS plasmablasts (CD19+/CD20−) that produce pathogenic antibodies like AQP4-IgG | Broader B-cell depletion; rationale for use in NMOSD where short-lived plasmablasts drive AQP4-IgG production — explains why inebilizumab may outperform anti-CD20 here |
JCV & PML Risk Stratification
PML Risk Factors with Natalizumab
| Risk Factor | Details | Clinical Significance |
|---|---|---|
| JCV antibody status | Positive = prior JCV exposure; ~55–60% of MS patients are seropositive | JCV-negative patients have very low PML risk, NOT zero (false negatives + later seroconversion occur); continue periodic JCV Ab monitoring (q6 months) |
| JCV antibody index | Quantitative measure of anti-JCV antibody level | Index >1.5 = significantly higher PML risk; index <0.9 = lower risk even if seropositive |
| Prior immunosuppression | Previous use of azathioprine, mitoxantrone, cyclophosphamide, etc. | Approximately doubles PML risk at any JCV antibody level |
| Duration of natalizumab | Risk increases substantially after >24 months | Risk stratification: <24 months + JCV negative = very low; >24 months + JCV+ + index >1.5 = highest risk (~1/90) |
PML Surveillance & Switching Strategies
- MRI surveillance: q3–6 month brain MRI looking for new non-enhancing lesions not consistent with MS (subcortical U-fiber involvement, no mass effect initially)
- PML presentation: subacute cognitive/behavioral changes, visual deficits, or motor weakness; lesions involve subcortical white matter, cross vascular territories, and initially do NOT enhance
- PML vs MS lesion: PML lesions involve U-fibers (juxtacortical), have ill-defined borders, no mass effect, and do not enhance early; MS lesions enhance with gadolinium in acute phase and are periventricular/ovoid
- CSF JCV PCR: confirmatory test; sensitivity ~80% (can be false negative in early PML); ultrasensitive PCR may detect earlier
- PML-IRIS: immune reconstitution inflammatory syndrome after stopping natalizumab — paradoxical worsening with new enhancement as immune system recovers; treat with steroids
- Switching off natalizumab: washout period of 4–8 weeks before starting new DMT, but prolonged washout risks severe rebound disease activity; bridge with short steroid course or start new DMT as soon as feasible
- Extended-interval dosing (EID): natalizumab q6 weeks instead of q4 weeks reduces PML risk in JCV+ patients while maintaining efficacy (NOVA study data)
Board Pearl
The three factors for PML risk on natalizumab are: JCV antibody status/index, prior immunosuppression, and treatment duration >24 months. A JCV-negative patient has very low PML risk, NOT zero (false negatives + later seroconversion possible — continue periodic JCV Ab monitoring). If JCV+ with index >1.5 and >2 years on therapy, strongly consider switching. PML lesions do NOT enhance initially (unlike MS) and involve subcortical U-fibers.
NMOSD-Specific Therapies
FDA-Approved NMOSD Treatments
| Drug | Mechanism | Route / Frequency | Key Points |
|---|---|---|---|
| Eculizumab (Soliris) | Anti-C5 complement monoclonal Ab → blocks terminal complement activation | IV infusion q2 weeks | PREVENT trial; must vaccinate against Neisseria meningitidis ≥2 weeks before starting; for AQP4-IgG+ NMOSD |
| Ravulizumab (Ultomiris) | Anti-C5 complement monoclonal Ab (longer half-life than eculizumab) | IV infusion q8 weeks | CHAMPION-NMOSD trial; FDA-approved April 2024 for AQP4-IgG+ NMOSD; also approved for AChR+ gMG (2022); meningococcal vaccination required |
| Inebilizumab (Uplizna) | Anti-CD19 monoclonal Ab → broader B-cell depletion than anti-CD20 (includes plasmablasts) | IV infusion: days 1 & 15, then q6 months | N-MOmentum trial; for AQP4-IgG+ NMOSD; HBV screening required |
| Satralizumab (Enspryng) | Anti-IL-6 receptor monoclonal Ab → blocks IL-6 signaling | SC q4 weeks (after loading doses at weeks 0, 2, and 4) | SAkuraSky/SAkuraStar trials; for AQP4-IgG+ NMOSD; can be used as monotherapy or add-on |
Off-Label NMOSD Treatments
| Drug | Mechanism | Notes |
|---|---|---|
| Rituximab | Anti-CD20 → B-cell depletion | Most widely used off-label; infusion q6 months; monitor CD19/CD20 counts and immunoglobulins |
| Azathioprine | Purine analog → ↓ lymphocyte proliferation | Often used in resource-limited settings; check TPMT before starting; slower onset (3–6 months) |
| Mycophenolate mofetil | Inosine monophosphate dehydrogenase inhibitor | Alternative maintenance therapy; teratogenic; GI side effects common |
- Rationale for complement inhibition: AQP4-IgG is pathogenic via complement-dependent cytotoxicity; eculizumab directly blocks this pathway
- Anti-CD19 vs anti-CD20: CD19 is expressed on a broader range of B lineage cells including plasmablasts that produce AQP4-IgG; anti-CD20 spares these cells
- IL-6 in NMOSD: IL-6 promotes plasmablast survival and AQP4-IgG production; elevated in CSF during NMOSD attacks
Board Pearl
Do NOT use MS-specific DMTs in NMOSD — interferon-beta, fingolimod, and natalizumab can all WORSEN NMO attacks. Always confirm AQP4-IgG status. FDA-approved AQP4+ NMOSD therapies = eculizumab, ravulizumab (FDA April 2024), inebilizumab, satralizumab. C5 inhibitors (eculizumab, ravulizumab) require meningococcal vaccination before starting.
MOGAD Treatment
Acute Treatment
- IV methylprednisolone 1 g × 5 days with slow oral taper (often over 3–6 months — MOGAD is steroid-dependent with high relapse rates during taper)
- IVIG for steroid-refractory cases or as initial therapy in children
- PLEX for severe steroid-refractory presentations (e.g., severe transverse myelitis, bilateral optic neuritis)
- Key difference from MS: MOGAD relapses occur frequently during steroid taper, necessitating slower tapers than in MS relapse treatment
Maintenance Treatment
| Treatment | Notes |
|---|---|
| Chronic IVIG | Emerging as a preferred first-line maintenance therapy; monthly infusions; well-tolerated; reduces relapse rate |
| Azathioprine | Steroid-sparing agent; slower onset (3–6 months); check TPMT; bridge with steroids |
| Mycophenolate mofetil | Alternative steroid-sparing agent; teratogenic; also requires steroid bridge |
| Rituximab | Used off-label; less robust evidence than in NMOSD; some patients relapse despite B-cell depletion |
- No FDA-approved DMTs for MOGAD — treatment is based on expert consensus and observational data
- MOGAD is highly steroid-responsive but steroid-dependent — relapses often occur during steroid taper
- Unlike MS, many patients with MOGAD have monophasic disease (especially children); maintenance therapy reserved for relapsing MOGAD
- MS DMTs (especially fingolimod and natalizumab) are ineffective in MOGAD and should not be used; data for other DMTs is limited but generally negative
Autoimmune Encephalitis Treatment
Treatment Algorithm
| Line | Treatments | Key Details |
|---|---|---|
| First-line | Corticosteroids, IVIG, PLEX | Start empirically while awaiting antibody results; often used in combination; improvement within 2–4 weeks |
| Second-line | Rituximab, cyclophosphamide | For patients who fail first-line therapy; rituximab preferred in younger patients (less toxicity than cyclophosphamide) |
| Tumor removal | Resect underlying neoplasm | Ovarian teratoma in anti-NMDAR encephalitis — removal is essential for recovery; screen all young women with pelvic imaging |
| Chronic immunotherapy | Rituximab, mycophenolate, azathioprine | For relapse prevention in antibody-mediated (LGI1, CASPR2, NMDAR) subtypes with relapsing course |
Antibody-Specific Considerations
- Anti-NMDAR encephalitis: most responsive to immunotherapy; ~80% have good outcomes with aggressive treatment; young women — always look for ovarian teratoma; recovery can take months
- LGI1 encephalitis: responds well to steroids and immunotherapy; faciobrachial dystonic seizures (FBDS) may respond to immunotherapy better than AEDs alone; associated with hyponatremia
- CASPR2 encephalitis: associated with Morvan syndrome (peripheral nerve hyperexcitability + encephalitis); screen for thymoma
- Paraneoplastic with intracellular antibodies (Hu, Yo, Ri, CV2): often less responsive to immunotherapy; tumor treatment is primary; neurological damage is frequently irreversible
- Timing matters: earlier immunotherapy initiation (<4 weeks from onset) is associated with better outcomes in anti-NMDAR encephalitis
- GAD65 antibodies: associated with stiff-person syndrome, cerebellar ataxia, and limbic encephalitis; these conditions respond variably to immunotherapy; high titers are more clinically significant than low titers
Surface vs Intracellular Antibody — Treatment Implications
| Feature | Cell-Surface Antibodies | Intracellular Antibodies |
|---|---|---|
| Examples | NMDAR, LGI1, CASPR2, AMPAR, GABA-B | Hu (ANNA-1), Yo (PCA-1), Ri (ANNA-2), CV2/CRMP5, amphiphysin |
| Pathogenicity | Directly pathogenic (antibody-mediated) | Marker of T-cell mediated cytotoxicity |
| Response to immunotherapy | Good — often reversible with treatment | Poor — neuronal damage often irreversible |
| Tumor association | Variable (teratoma in NMDAR; thymoma in CASPR2) | Strong (SCLC with Hu; ovarian/breast with Yo) |
| Primary treatment strategy | Immunotherapy + tumor removal if present | Tumor removal is primary; immunotherapy often limited benefit |
Clinical Pearl
In anti-NMDAR encephalitis, always screen for ovarian teratoma with pelvic ultrasound or CT/MRI. Teratoma removal is a critical part of treatment and dramatically improves outcomes. Up to 50% of young women with anti-NMDAR encephalitis have an underlying teratoma.
Myasthenia Gravis — Treatment
Symptomatic and Immunotherapy
| Category | Agent(s) | Key Points |
|---|---|---|
| Symptomatic (AChE inhibitor) | Pyridostigmine (Mestinon) | First-line symptomatic; cholinergic side effects (cramps, diarrhea, salivation); does not modify disease |
| Corticosteroids | Prednisone | First-line immunotherapy; start low and titrate up to avoid transient worsening / myasthenic crisis |
| Steroid-sparing oral IS | Azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, methotrexate | Slow onset (months); used to taper steroids; check TPMT before AZA |
| Rituximab | Anti-CD20 | Preferred in MuSK+ MG (often dramatic response); also used for refractory AChR+ disease |
| Thymectomy | Transsternal or VATS | MGTX trial: benefit in AChR+ generalized MG, age <60, non-thymomatous; mandatory if thymoma present |
| Complement (C5) inhibitors | Eculizumab, ravulizumab, zilucoplan | For refractory AChR+ gMG; all require meningococcal vaccination; zilucoplan is SC daily |
| FcRn inhibitors | Efgartigimod (Vyvgart), rozanolixizumab (Rystiggo) | Cyclic IgG-lowering therapy; AChR+ gMG (efgartigimod) and AChR+/MuSK+ gMG (rozanolixizumab) |
| Crisis / exacerbation | IVIG or PLEX | Both effective; PLEX may be faster; treat respiratory failure with NIV/intubation |
- Avoid in MG: aminoglycosides, fluoroquinolones, macrolides, beta-blockers, magnesium, neuromuscular blockers, telithromycin, immune checkpoint inhibitors (can trigger or worsen MG)
- MuSK+ MG: often poor response to AChE inhibitors; rituximab is particularly effective; thymectomy not typically beneficial
- Thymoma: seen in ~10–15% of MG (AChR+); chest CT mandatory at diagnosis; thymectomy required regardless of age
CIDP — Treatment
- First-line trio: IVIG, corticosteroids, or PLEX — comparable efficacy; choice based on patient factors, access, and side-effect profile
- IVIG: 2 g/kg induction over 2–5 days, then 1 g/kg q3 weeks maintenance; preferred when steroid avoidance is desirable (diabetes, osteoporosis)
- Corticosteroids: oral prednisone or pulse IV methylprednisolone; cost-effective; long-term side effects limit chronic use
- PLEX: 5–6 exchanges over 2 weeks; effective but requires venous access
- Refractory disease: azathioprine, mycophenolate, cyclophosphamide, rituximab
- Efgartigimod SC (Vyvgart Hytrulo) — FDA-approved 2024 for CIDP; weekly SC injection; first FcRn inhibitor approved for CIDP
- Subcutaneous Ig (SCIg): alternative to IVIG for maintenance; allows home administration
- Pure motor CIDP / MMN: responds to IVIG; steroids may worsen MMN
GBS — Treatment
- First-line: IVIG 0.4 g/kg/day × 5 days OR PLEX (5 exchanges) — equally effective; start within 2 (ideally) to 4 weeks of symptom onset
- STEROIDS NOT RECOMMENDED — ineffective in GBS and may worsen outcomes (do not combine with IVIG)
- Do NOT combine IVIG and PLEX (no added benefit); do not give IVIG immediately after PLEX (will be removed)
- Supportive care is critical: monitor FVC and NIF (intubate if FVC <20 mL/kg, NIF <−30 cmH2O, or rapid decline); cardiac telemetry for dysautonomia; DVT prophylaxis; pain control (often neuropathic)
- Treatment-related fluctuations: some patients deteriorate 1–3 weeks after initial improvement; consider repeat IVIG course
- Variants: Miller Fisher (ophthalmoplegia/ataxia/areflexia — GQ1b antibody), AMAN, AMSAN, pharyngeal-cervical-brachial — treated similarly
General Immunosuppressants in Neurology
Commonly Used Agents
| Drug | Mechanism | Key Uses in Neurology | Important Side Effects | Monitoring |
|---|---|---|---|---|
| Azathioprine | Purine analog → inhibits DNA/RNA synthesis → ↓ lymphocyte proliferation | MG, NMOSD, MOGAD, neuroimmunology | Myelosuppression, hepatotoxicity, GI, pancreatitis, ↑ lymphoma risk | Check TPMT before starting (low TPMT = severe myelosuppression); CBC, LFTs regularly |
| Mycophenolate mofetil | Inosine monophosphate dehydrogenase (IMPDH) inhibitor → selective lymphocyte antiproliferative | MG, NMOSD, MOGAD, CNS vasculitis | GI upset (diarrhea), myelosuppression, contraindicated in pregnancy (REMS — mandatory contraception), ↑ infections, PML (rare) | CBC monthly initially; pregnancy test; LFTs |
| Rituximab | Anti-CD20 monoclonal Ab → B-cell depletion | NMOSD, MG, autoimmune encephalitis, CIDP, CNS vasculitis | Infusion reactions, HBV reactivation, hypogammaglobulinemia, PML (rare), late-onset neutropenia | HBV serologies before starting; immunoglobulin levels; CD19/CD20 counts |
| Cyclophosphamide | Alkylating agent → cross-links DNA → kills proliferating lymphocytes | CNS vasculitis, refractory autoimmune encephalitis, severe NMOSD, neurosarcoidosis | Hemorrhagic cystitis, bladder cancer, myelosuppression, infertility, secondary malignancies, SIADH | CBC; urinalysis; hydration + MESNA to prevent bladder toxicity; fertility preservation discussion |
IVIG (Intravenous Immunoglobulin)
| Feature | Details |
|---|---|
| Mechanism | Fc receptor blockade, complement modulation, anti-idiotype antibodies, cytokine modulation, ↓ pathogenic antibody production |
| Key neurologic uses | GBS, CIDP, MG exacerbation, MOGAD, autoimmune encephalitis, MMN, dermatomyositis |
| Dosing | Typically 2 g/kg divided over 2–5 days (induction); 1–2 g/kg q3–4 weeks (maintenance) |
| Side effects | Headache, aseptic meningitis, fever/chills, thrombosis (VTE, stroke, MI), renal failure (especially sucrose-containing formulations), hemolysis in non-type-O blood (anti-A/anti-B isohemagglutinins) |
| Contraindications | IgA deficiency (anaphylaxis risk — use IgA-depleted product); severe renal insufficiency |
| Pre-treatment | Check IgA level, renal function, blood type; premedicate with acetaminophen, diphenhydramine; slow infusion rate initially |
Plasmapheresis (PLEX / Therapeutic Plasma Exchange)
| Feature | Details |
|---|---|
| Mechanism | Removes pathogenic antibodies, immune complexes, complement, and cytokines from circulation |
| Key neurologic uses | GBS, MG crisis, NMOSD acute attacks, CIDP, steroid-refractory MS relapse, autoimmune encephalitis |
| Regimen | Typically 5–7 exchanges over 10–14 days (every other day) |
| Side effects | Hypotension, hypocalcemia (from citrate anticoagulant → paresthesias, tetany), coagulopathy (removes clotting factors), line infections, electrolyte derangements |
| Key pearl | Do NOT give IVIG immediately before PLEX — PLEX will remove the infused immunoglobulin (give IVIG after PLEX if using both) |
FcRn Inhibitors — Emerging Agents
- Mechanism: block neonatal Fc receptor (FcRn) → accelerate IgG catabolism → rapidly lower pathogenic IgG antibody levels
- Efgartigimod (Vyvgart): FDA-approved for generalized MG (AChR-Ab positive); IV infusion in 4-week cycles; rapid onset of action
- Rozanolixizumab (Rystiggo): SC injection; approved for generalized MG (both AChR-Ab and MuSK-Ab positive)
- Advantage over PLEX: selectively reduces IgG without removing other immunoglobulins, clotting factors, or albumin; no central line required
- Side effects: headache, nasopharyngitis, URIs, UTIs; potential infection risk from reduced IgG
IVIG vs PLEX — Comparison
| Feature | IVIG | PLEX |
|---|---|---|
| Mechanism | Immunomodulation (multiple mechanisms) | Antibody/immune complex removal |
| Access required | Peripheral IV | Central venous catheter (usually) |
| Speed of effect | Days to weeks | Rapid (within days of first exchange) |
| Key advantage | Easier access; no coagulopathy; outpatient possible | Faster onset; directly removes pathogenic antibodies |
| GBS | Equivalent to PLEX (preferred in many centers for ease) | Equivalent to IVIG; start within 4 weeks of onset |
| MG crisis | Equivalent to PLEX | Equivalent to IVIG |
| CIDP | First-line maintenance | Alternative if IVIG fails |
| MS relapse | Not standard | Second-line for steroid-refractory relapse |
Clinical Pearl
Check TPMT enzyme activity before starting azathioprine. Homozygous TPMT deficiency (~0.3% of patients) causes life-threatening myelosuppression. Heterozygotes (~11%) need dose reduction. Screen HBV serologies before rituximab — reactivation can cause fulminant hepatitis.
Clinical Pearl
IVIG causes hemolysis most commonly in patients with blood types A, B, or AB (non-type-O). The pooled immunoglobulin contains anti-A and anti-B isohemagglutinins. Monitor hemoglobin after infusion, especially with high-dose IVIG, and check a DAT (direct antiglobulin test) if hemolysis is suspected.
Vaccination Considerations with Immunotherapy
- Live vaccines are contraindicated in patients on immunosuppressive therapy (fingolimod, ocrelizumab, rituximab, alemtuzumab, mycophenolate, azathioprine, cyclophosphamide, chronic corticosteroids)
- VZV vaccination: must be given ≥1 month BEFORE starting fingolimod or other S1P modulators; check VZV IgG titer and vaccinate if negative
- Meningococcal vaccination: REQUIRED ≥2 weeks before starting eculizumab (complement inhibitor increases risk of Neisseria infections)
- Hepatitis B screening: required before all anti-CD20 therapies (ocrelizumab, ofatumumab, rituximab) and inebilizumab; HBV reactivation risk
- Timing of inactivated vaccines: ideally administer ≥2 weeks before starting DMT; for patients already on anti-CD20 therapy, time vaccines for ~4–6 months after the last anti-CD20 dose (just before the next scheduled infusion, when B-cell recovery is maximal) for the best humoral response
- COVID-19 vaccination: blunted humoral response in patients on anti-CD20 therapies and fingolimod; T-cell response may still be partially preserved; time vaccination ≥12 weeks after last anti-CD20 dose if possible
- Influenza and pneumococcal vaccines: recommended for all immunosuppressed patients (inactivated formulations are safe)
Quick Reference Table
Immunotherapy & MS Pharmacology — At a Glance
| Topic | Key Point | Board-Yield Detail |
|---|---|---|
| MS relapse | IV methylprednisolone 1 g × 3–5 days | Speeds recovery; does NOT change long-term outcome; PLEX for steroid-refractory |
| Natalizumab & PML | Anti-VLA-4; highest efficacy but PML risk | JCV index >1.5 + >24 months + prior IS = highest risk; extended-interval dosing reduces risk |
| Fingolimod | S1P modulator; first-dose bradycardia | 6-hour cardiac monitoring; macular edema at 3–4 months; VZV vaccination before starting |
| Ocrelizumab | Anti-CD20; first DMT approved for PPMS | HBV screening mandatory; infusion reactions; ORATORIO trial; monitor immunoglobulins |
| Alemtuzumab | Anti-CD52; highly effective but autoimmunity | Thyroid (30–40%), ITP, anti-GBM — monitor monthly for 4 years after last dose |
| Dimethyl fumarate | Nrf2 pathway; moderate efficacy | Lymphopenia → PML if ALC <500 sustained >6 months; GI/flushing common |
| Teriflunomide | DHODH inhibitor; contraindicated in pregnancy | Boxed warning (teratogenic in animals); accelerated elimination with cholestyramine or activated charcoal; hepatotoxicity; hair thinning |
| NMOSD | Do NOT use MS DMTs — they worsen NMO | FDA-approved AQP4+ NMOSD therapies: eculizumab (anti-C5), ravulizumab (anti-C5, FDA April 2024), inebilizumab (anti-CD19), satralizumab (anti-IL-6R); meningococcal vaccination for C5 inhibitors |
| MOGAD | Steroid-responsive but steroid-dependent | No FDA-approved DMT; IVIG emerging as preferred maintenance; slow steroid taper |
| Autoimmune encephalitis | First-line: steroids, IVIG, PLEX | Second-line: rituximab, cyclophosphamide; tumor removal in paraneoplastic (teratoma in NMDAR) |
| IVIG | Aseptic meningitis, thrombosis, renal failure | Hemolysis in non-type-O blood; contraindicated in IgA deficiency (anaphylaxis) |
| Azathioprine | Check TPMT before starting | Homozygous deficiency → fatal myelosuppression; purine analog |
| Cyclophosphamide | Alkylating agent; hemorrhagic cystitis | Give MESNA + hydration; risk of bladder cancer; fertility preservation |
| PLEX | Removes antibodies; hypocalcemia from citrate | Do NOT give IVIG before PLEX (will be removed); used in GBS, MG crisis, NMOSD |
Board Pearl
Siponimod is the only S1P modulator approved specifically for active SPMS (secondary progressive MS). It requires CYP2C9 genotyping before starting — patients homozygous for CYP2C9*3 cannot receive siponimod due to markedly reduced metabolism and increased drug exposure.
Board Pearl
Ocrelizumab is the first and only FDA-approved DMT for primary progressive MS (PPMS) based on the ORATORIO trial. All other DMTs are approved only for relapsing forms of MS. Anti-CD20 agents require HBV screening (HBsAg, anti-HBc, anti-HBs) before initiation due to risk of fatal HBV reactivation.
References
- Rae-Grant A, Day GS, Marrie RA, et al. Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis. Neurology. 2018;90(17):777–788.
- Wingerchuk DM, Banwell B, Bennett JL, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85(2):177–189.
- Pittock SJ, Berthele A, Fujihara K, et al. Eculizumab in aquaporin-4-positive neuromyelitis optica spectrum disorder (PREVENT). N Engl J Med. 2019;381(7):614–625.
- Cree BAC, Bennett JL, Kim HJ, et al. Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum). Lancet. 2019;394(10206):1352–1363.
- Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis (OPERA I and II). N Engl J Med. 2017;376(3):221–234.
- Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis (ORATORIO). N Engl J Med. 2017;376(3):209–220.
- Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis. Lancet Neurol. 2013;12(2):157–165.
- Bhatt A. Ultimate Review for the Neurology Boards. 3rd ed. Demos Medical; 2016.
- Ropper AH, Samuels MA, Klein JP, Prasad S. Adams and Victor’s Principles of Neurology. 12th ed. McGraw-Hill; 2023.
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