Disease-Modifying Therapies
What Do You Need to Know?
- Treatment goal: NEDA-3 (no relapses, no disability progression, no MRI activity); trend toward early high-efficacy therapy (EHET) over escalation
- Natalizumab: anti-α4-integrin; highest PML risk (JCV+, prior immunosuppression, >24 months); ~68% relapse reduction; severe rebound on discontinuation
- Ocrelizumab: anti-CD20; only PPMS-approved DMT (ORATORIO trial); risk of hypogammaglobulinemia and HBV reactivation
- Fingolimod: S1P modulator; first-dose bradycardia (6-hour cardiac monitoring); macular edema; VZV risk; rebound on stopping
- Alemtuzumab: anti-CD52; secondary autoimmunity (thyroid 30–40%, ITP, anti-GBM nephritis); monthly monitoring for 4 years
- Teriflunomide: contraindicated in pregnancy and in females of reproductive potential not using effective contraception (FDA pregnancy letter categories were retired in 2015 with the PLLR); accelerated elimination with cholestyramine or activated charcoal if pregnancy occurs or rapid drug clearance is needed
- Glatiramer acetate and interferon-β: most reassuring pregnancy experience; either may be continued through conception/pregnancy in selected patients after risk-benefit discussion; no washout required
- Dimethyl fumarate: Nrf2 pathway; PML risk if sustained lymphopenia (ALC <500 for >6 months)
- Natalizumab + JCV antibody positive + >2 yr therapy + prior immunosuppression: highest PML risk — stratify by JCV index, switch to anti-CD20 if index rises
- Fingolimod first dose: 6-hour cardiac monitoring for bradycardia/AV block; baseline OCT for macular edema; VZV serology + vaccinate seronegative patients before starting
- Ocrelizumab: only DMT FDA-approved for PPMS (ORATORIO); screen HBV + vaccinate before infusion; watch hypogammaglobulinemia long-term
- Alemtuzumab: secondary autoimmunity (Graves 30–40%, ITP, anti-GBM glomerulonephritis) emerges months-years later → monthly CBC/Cr/UA + thyroid q3mo for 4 yr after last dose
- Teriflunomide: contraindicated in pregnancy and in females of reproductive potential not using effective contraception (FDA pregnancy letter categories retired in 2015); accelerated elimination protocol = cholestyramine 8 g TID × 11 days (or activated charcoal) if pregnancy occurs or rapid clearance is needed (men & women)
- Glatiramer acetate: among the most reassuring pregnancy DMTs (along with interferon-β) — may be continued through gestation in selected patients; immediate post-injection reaction (flushing/chest tightness/dyspnea) is self-limited, not anaphylaxis
- Natalizumab/fingolimod discontinuation: severe REBOUND disease activity — bridge to anti-CD20 with short washout to avoid lymphopenia overlap
- Dimethyl fumarate + sustained ALC <500 for >6 mo: PML risk — check CBC q3mo and hold if persistent lymphopenia
- Cladribine: 2-year oral course with durable lymphocyte depletion; pregnancy contraindicated × 6 mo after last dose (both sexes)
- Suspected PML on natalizumab: STOP drug + PLEX for accelerated removal + serial MRI/JCV PCR; IRIS may follow
Mechanism / drug class
- Anti-α4-integrin (VLA-4) blocks lymphocyte CNS entry → natalizumab
- S1P1 receptor internalization → lymphocyte sequestration in lymph nodes → fingolimod, siponimod, ozanimod, ponesimod
- Anti-CD20 B-cell depletion → ocrelizumab (IV), ofatumumab (SC), ublituximab (IV)
- Anti-CD52 depletes T & B cells × 2-yr induction course → alemtuzumab
- Nrf2 pathway activator (antioxidant response) → dimethyl/diroximel/monomethyl fumarate
- Dihydroorotate dehydrogenase (DHODH) inhibitor → pyrimidine synthesis → teriflunomide
- Random poly-amino-acid peptide mimics MBP → glatiramer acetate (Copaxone)
- Purine analog → selective lymphocyte depletion (oral 2-yr course) → cladribine
- Only DMT approved for PPMS (ORATORIO trial) → ocrelizumab
Adverse effects / monitoring
- First-dose bradycardia + 6-hr cardiac monitoring + macular edema (baseline OCT) → fingolimod
- PML with JCV+ antibody, prior immunosuppression, >24 mo therapy → natalizumab (also rare with fumarates, fingolimod)
- Secondary autoimmunity: Graves/thyroid 30–40%, ITP, anti-GBM glomerulonephritis → alemtuzumab
- Flu-like symptoms + injection site reactions + LFT elevation + neutralizing antibodies → IFN-β
- Immediate post-injection reaction (flushing, chest tightness, dyspnea, anxiety) + lipoatrophy → glatiramer acetate
- Flushing + GI upset + sustained lymphopenia → PML risk → dimethyl fumarate (Vumerity/Bafiertam reduce GI)
- Hair thinning + diarrhea + hepatotoxicity + pregnancy contraindication (accelerated elimination required) → teriflunomide
- Infusion reactions + HBV reactivation + hypogammaglobulinemia long-term → anti-CD20 (ocrelizumab, ofatumumab, ublituximab)
- Cryptococcal meningitis + VZV reactivation → S1P modulators (fingolimod)
- Cardiotoxicity (cumulative dose) + therapy-related AML → mitoxantrone (historical)
Pregnancy / switching / pearls
- Most reassuring pregnancy experience among MS DMTs — may be continued in selected patients → glatiramer acetate and interferon-β
- Pregnancy contraindicated — cholestyramine 8 g TID × 11 days for accelerated elimination if pregnancy occurs / before conception → teriflunomide
- Severe rebound disease activity on discontinuation → natalizumab, fingolimod (bridge to anti-CD20)
- Switching from S1P modulator to anti-CD20 → short washout to avoid lymphopenia overlap
- Aggressive highly active RRMS refractory to high-efficacy DMTs → autologous HSCT (RIC + cyclophosphamide + rATG)
- Early high-efficacy therapy (EHET) > escalation → better long-term outcomes (CLAIMS, NOVA registries)
- JCV antibody index annually (every 6 mo if positive) → natalizumab PML stratification
- Live vaccines avoided + complete vaccination before B-cell depletion or S1P modulator → ocrelizumab, fingolimod
- NEDA-3 (no relapse + no MRI activity + no disability progression) → current treatment goal — failure prompts escalation
Treatment Strategy
Escalation vs Early High-Efficacy Therapy (EHET)
| Approach | Strategy | When to Consider |
|---|
| Escalation |
Start moderate-efficacy DMT (interferon, glatiramer, teriflunomide, dimethyl fumarate); escalate if breakthrough disease |
Low relapse rate, low lesion burden, favorable prognostic features, older age, mild CIS |
| Early high-efficacy therapy (EHET) |
Start with high-efficacy DMT (natalizumab, ocrelizumab, alemtuzumab, cladribine) from diagnosis |
High relapse rate, high lesion burden, brainstem/spinal cord lesions, young age, poor prognostic features |
- Trend shifting toward EHET — observational data suggest better long-term outcomes when high-efficacy therapy started early
- No RCTs directly comparing escalation vs EHET — evidence from observational registries (MSBase, SUMMIT)
NEDA-3 (No Evidence of Disease Activity)
| Component | Definition |
|---|
| No relapses | No clinical attacks over assessment period |
| No disability progression | No confirmed EDSS worsening sustained for 3–6 months |
| No MRI activity | No new/enlarging T2 lesions and no Gd-enhancing lesions |
- NEDA-4 adds brain volume loss (<0.4%/year) as fourth measure (not yet standard in practice)
- NEDA-3 is the current treatment target — no relapses + no disability progression + no MRI activity
- Failure to achieve NEDA-3 should prompt consideration of switching to a higher-efficacy DMT
Injectable DMTs (Moderate Efficacy)
Interferons & Glatiramer Acetate
| Drug | Mechanism | Efficacy | Key Side Effects | Monitoring |
|---|
| IFN-β1a (Avonex — IM weekly; Rebif — SC 3×/wk) |
Immunomodulatory: ↓ T-cell activation, ↓ BBB permeability, Th1 → Th2 shift, antiviral |
~30% relapse reduction |
Flu-like symptoms, injection site reactions, hepatotoxicity, depression, leukopenia |
CBC, LFTs q3–6 months; neutralizing antibodies if breakthrough |
| IFN-β1b (Betaseron, Extavia — SC QOD) |
Same as IFN-β1a |
~30% |
Same; slightly more injection site reactions |
Same |
| Peginterferon-β1a (Plegridy — SC q2 weeks) |
Pegylated IFN-β1a; longer half-life |
~36% |
Same as interferons; less frequent dosing |
Same |
| Glatiramer acetate (Copaxone — SC daily or 40 mg 3×/wk) |
Synthetic MBP analog; induces Th2 shift; generates regulatory T cells |
~29% |
Injection site reactions, lipoatrophy, immediate post-injection reaction (chest tightness, flushing — benign, self-limited; occurs in ~10%) |
None required routinely; safest DMT in pregnancy |
- Glatiramer acetate is the safest DMT in pregnancy — no washout required; often used as bridge therapy
- Interferons: check neutralizing antibodies if breakthrough disease on therapy — up to 25–45% develop NAbs
- Interferons and glatiramer are moderate-efficacy (~30% relapse reduction) — adequate for mild disease, not for aggressive MS
Oral DMTs
S1P Receptor Modulators
| Drug | Selectivity | Efficacy | Key Side Effects | Monitoring |
|---|
| Fingolimod (Gilenya — 0.5 mg daily) |
Non-selective S1P1/3/4/5 |
~54% relapse reduction |
First-dose bradycardia/AV block (6-hr cardiac monitoring); macular edema; VZV reactivation; PML (rare); rebound on discontinuation |
First-dose 6-hr ECG; ophthalmology 3–4 months; CBC; VZV titer pre-treatment — vaccinate VZV-seronegative patients ≥1 month before initiation (live vaccine) |
| Siponimod (Mayzent) |
Selective S1P1/S1P5 |
Approved for active SPMS (EXPAND trial — 21% reduction in 3-month confirmed disability progression; benefit primarily in active SPMS with recent relapses or Gd+ lesions) |
Similar to fingolimod; requires CYP2C9 genotyping: contraindicated in CYP2C9 *3/*3; dose-reduce to 1 mg daily for *1/*3 or *2/*3 (intermediate metabolizers); standard 2 mg daily for *1/*1, *1/*2, *2/*2 |
CYP2C9 genotype before starting; first-dose cardiac monitoring; ophthalmology |
| Ozanimod (Zeposia) |
Selective S1P1/S1P5 |
High |
No first-dose observation required in patients without cardiac risk factors; 6-hour monitoring still required in patients with specific cardiac conditions (recent MI/UA/stroke/TIA, decompensated HF, Mobitz II/3rd-degree AV block, baseline HR <55); contraindicated with MAO inhibitors — ≥14 days should elapse between stopping ozanimod and starting an MAOI; per the Zeposia label, no clinically significant tyramine pressor response was observed at therapeutic doses, so routine tyramine-restricted diet counseling is not required; caution with serotonergic drugs |
CBC; cardiac evaluation if indicated; ophthalmology; ≥14-day separation from MAOIs |
| Ponesimod (Ponvory) |
Selective S1P1 |
Superior to teriflunomide (OPTIMUM trial) |
Gradual 14-day dose titration; similar class effects |
Cardiac evaluation; CBC; ophthalmology; LFTs |
Other Oral Agents
| Drug | Mechanism | Efficacy | Key Side Effects | Monitoring |
|---|
| Teriflunomide (Aubagio — 14 mg daily) |
Inhibits DHODH → ↓ pyrimidine synthesis → ↓ lymphocyte proliferation |
~30% (moderate) |
Contraindicated in pregnancy and in females of reproductive potential not using effective contraception (FDA pregnancy letter categories retired in 2015 with the PLLR); hepatotoxicity; hair thinning; diarrhea; peripheral neuropathy |
Baseline LFTs, then monthly × 6 months, then periodically; also TB screen and BP monitoring before/during; pregnancy test; accelerated elimination (cholestyramine or activated charcoal) if pregnancy occurs or before planned conception (drug otherwise persists up to 2 years) |
| Dimethyl fumarate (Tecfidera — 240 mg BID) |
Activates Nrf2 antioxidant pathway; depletes memory T cells |
~49% |
Flushing, GI upset (take with food); PML risk if ALC <500 sustained >6 months |
CBC q6 months; hold if ALC <500 for >6 months |
| Diroximel fumarate (Vumerity) |
Same active metabolite as dimethyl fumarate |
Same |
Better GI tolerability; otherwise same |
Same as dimethyl fumarate |
| Cladribine (Mavenclad) |
Purine analog → selective T and B cell depletion (immune reconstitution therapy) |
~58% |
Lymphopenia; herpes zoster; theoretical malignancy risk; teratogenic — both partners require contraception × 6 months after last dose |
CBC before each course; 2 treatment weeks in year 1 and 2 treatment weeks in year 2 (cumulative dose 3.5 mg/kg); no treatment in years 3–4 |
- Fingolimod first dose = 6 hours cardiac monitoring — S1P agonism causes transient bradycardia; vaccinate for VZV first
- Siponimod requires CYP2C9 genotyping — contraindicated in *3/*3 homozygotes; approved for active SPMS
- Teriflunomide is contraindicated in pregnancy (FDA PLLR replaced letter categories in 2015) — perform accelerated elimination (cholestyramine or activated charcoal) if pregnancy occurs or before planned conception; verify undetectable drug levels
- DMF/PML risk: sustained ALC <500 for >6 months → discontinue; monitor CBC q6 months
- Cladribine is immune reconstitution therapy (IRT) — 2 short courses then done; no continuous treatment
- Fingolimod rebound: severe disease reactivation 2–6 months after discontinuation; bridge or overlap with next DMT
Infusion DMTs (High Efficacy)
Anti-CD20 Therapies (B-Cell Depletion)
| Drug | Route/Dosing | Efficacy | Key Side Effects | Monitoring |
|---|
| Ocrelizumab (Ocrevus) |
IV q6 months |
OPERA I/II ARR ~46–47% reduction vs IFN-β1a (active comparator, not placebo); only PPMS-approved DMT (ORATORIO trial) |
Infusion reactions; infections; HBV reactivation; hypogammaglobulinemia; possibly slight ↑ breast cancer risk |
HBV screening; immunoglobulin levels; CBC; breast cancer screening |
| Ofatumumab (Kesimpta) |
SC monthly (self-administered) |
ASCLEPIOS I/II ~50–58% ARR reduction vs teriflunomide (active comparator) |
Injection site reactions; infections; HBV reactivation |
HBV screening; immunoglobulin levels |
| Ublituximab (Briumvi) |
IV q6 months (1-hour infusion) |
ULTIMATE I/II ~49–50% ARR reduction vs teriflunomide (active comparator) |
Infusion reactions; infections; similar to other anti-CD20s |
HBV screening; immunoglobulin levels |
| Rituximab (off-label) |
IV q6 months |
Widely used off-label; strong real-world evidence |
Same class effects; less expensive than ocrelizumab |
Same as other anti-CD20s |
- Anti-CD20 agents deplete CD20+ B cells but spare plasma cells (CD20-negative) and pro-B cells
- B-cell depletion is near-complete within 2 weeks and lasts 6 months
- Long-term use can lead to hypogammaglobulinemia → increased infection risk; monitor IgG levels
Other High-Efficacy Infusion Agents
| Drug | Mechanism | Efficacy | Key Side Effects | Monitoring |
|---|
| Natalizumab (Tysabri — IV q4 weeks) |
Anti-α4-integrin (VLA-4) → blocks lymphocyte migration across BBB |
~68% relapse reduction (AFFIRM trial); among highest efficacy |
PML (JCV reactivation); infusion reactions; hepatotoxicity; severe rebound on discontinuation |
JCV antibody + index q6 months; MRI q3–6 months for PML surveillance |
| Alemtuzumab (Lemtrada — 12 mg IV daily × 5 days year 1, then 12 mg IV daily × 3 days year 2) |
Anti-CD52 → pan-lymphocyte depletion (T, B, NK, monocytes); immune reconstitution therapy |
~55%; superior to IFN-β1a (CARE-MS I/II) |
Secondary autoimmunity: thyroid (30–40%), ITP (2–3%), anti-GBM nephritis (0.3%); infusion reactions; infections; boxed warning: stroke and cervicocephalic arterial dissection (typically within 3 days of infusion); Listeria precautions — avoid deli meats and unpasteurized dairy peri-infusion |
CBC + creatinine + urinalysis MONTHLY × 48 months; TSH every 3 months × 48 months; HPV screening annually in women |
| Mitoxantrone (rarely used) |
Topoisomerase II inhibitor; immunosuppressive |
High |
Cardiotoxicity (cumulative dose limit 140 mg/m²); therapy-related AML; blue urine/sclera |
LVEF before each dose; lifetime cumulative limit; rarely used now due to toxicity |
- Ocrelizumab is the ONLY FDA-approved DMT for PPMS (ORATORIO trial) — the single most tested DMT fact on boards
- Anti-CD20 agents spare plasma cells — they are CD20-negative; this is why OCBs persist despite B-cell depletion
- Natalizumab has the highest single-agent relapse reduction (~68%) but carries highest PML risk
- Alemtuzumab is immune reconstitution therapy — 2 courses then done; but monitoring continues 4+ years for secondary autoimmunity
- Alemtuzumab autoimmunity: thyroid disease (Graves most common, 30–40%), ITP, anti-GBM nephritis
PML Risk & Natalizumab Stratification
PML Risk Stratification
| JCV Status | Prior Immunosuppression | Duration >24 months | Estimated PML Risk |
|---|
| JCV antibody negative | Any | Any | ~0.1/1,000 (very low) |
| JCV antibody positive, no prior IS | No | ≤24 months | ~0.1–0.7/1,000 (depending on JCV index) |
| JCV antibody positive, index >1.5 | No | >24 months | ~6–13/1,000 |
| JCV antibody positive, index >1.5 | Yes | >24 months | ~13/1,000 (highest) |
- Recheck JCV antibody q6 months — seroconversion at ~2–3%/year
- Extended-interval dosing (EID): q6–8 weeks instead of q4 weeks may reduce PML risk while maintaining efficacy
PML with Other DMTs
| DMT | PML Risk | Mechanism |
|---|
| Natalizumab | Highest risk class; overall ~4/1,000 across treated patients; up to 13/1,000 in high-risk (JCV+, prior IS, >24 months) | Blocks immune surveillance of CNS by preventing T-cell entry |
| Fingolimod | Rare (much lower than natalizumab) | Lymphocyte sequestration in lymph nodes |
| Dimethyl fumarate | Rare; linked to sustained lymphopenia | Only if ALC <500 sustained >6 months |
| Ocrelizumab | Very rare; most cases carry-over from prior natalizumab/fingolimod, but rare de novo cases reported | B-cell depletion alone rarely causes PML |
PML Diagnosis & IRIS
- PML presentation: subacute progressive focal deficits (hemiparesis, cognitive changes, visual field cuts); no enhancement on MRI initially
- MRI: multifocal, asymmetric white matter lesions involving subcortical U-fibers; NO enhancement; NO mass effect
- Diagnosis: CSF JCV PCR — sensitivity ~95% with ultrasensitive assay; lower with standard PCR; can be negative early in low viral load disease
- Treatment: discontinue natalizumab; PLEX to accelerate drug clearance; supportive care
- PML-IRIS (immune reconstitution inflammatory syndrome): paradoxical worsening 1–4 weeks after natalizumab cessation as immune cells flood back into CNS; enhancement appears on MRI; treat with steroids; high morbidity
- Natalizumab PML risk triad: JCV+, prior immunosuppression, duration >24 months — risk is multiplicative
- PML on MRI: subcortical U-fiber white matter lesions, NO enhancement, NO mass effect — distinguishes from MS relapse
- PML-IRIS: paradoxical worsening after stopping natalizumab; MRI shows new enhancement; treat with high-dose steroids
- JCV antibody seroconversion occurs at ~2–3%/year — recheck every 6 months on natalizumab
Switching & Sequencing DMTs
Key Switching Considerations
| Scenario | Approach | Key Concern |
|---|
| Natalizumab → anti-CD20 | Start anti-CD20 within 4–6 weeks of last natalizumab dose | Minimize gap to prevent rebound disease; monitor for PML/IRIS during transition |
| Natalizumab → fingolimod | Start fingolimod within 4–8 weeks | Longer washout ↑ rebound risk; shorter washout ↑ additive immunosuppression risk |
| Fingolimod → any DMT | Wait for lymphocyte recovery (ALC >500–800); usually 4–8 weeks | Severe rebound disease 2–6 months after stopping fingolimod; overlap or bridge |
| Dimethyl fumarate → any DMT | Can switch relatively quickly; ensure ALC recovering | If ALC was sustained <500, wait for recovery before starting immunosuppressive DMT |
| Alemtuzumab → any DMT | Typically only if relapses recur after immune reconstitution | Wait for lymphocyte recovery; continue autoimmune monitoring regardless |
Washout Periods
| DMT | Washout | Notes |
|---|
| Interferons/Glatiramer | None needed | Can switch immediately; no significant immunosuppressive carryover |
| Teriflunomide | Cholestyramine 8 g TID × 11 days (or activated charcoal) | Without washout, drug persists up to 2 years; verify plasma level <0.02 mg/L |
| Fingolimod | 4–8 weeks for lymphocyte recovery | Severe rebound possible — bridge if needed |
| Natalizumab | 4–6 weeks (minimize gap) | Rebound disease peaks at 3–6 months post-discontinuation |
| Anti-CD20 | Wait for B-cell reconstitution (6–12+ months) | Rarely needed; most patients stay on anti-CD20 long-term |
- Natalizumab rebound: severe disease reactivation peaks 3–6 months after stopping; minimize washout gap
- Fingolimod rebound: severe relapses 2–6 months after discontinuation; bridge or overlap with next DMT
- Teriflunomide washout: cholestyramine 8 g TID × 11 days; without it, drug persists up to 2 years
Pregnancy & DMT Safety
DMT Pregnancy Safety Profile
| DMT | Pregnancy Status | Washout Before Conception | Key Notes |
|---|
| Glatiramer acetate | Most reassuring pregnancy experience | None required | May be continued through conception or pregnancy in selected patients after a clear risk-benefit discussion; often used as bridge |
| Interferon-β | Most reassuring pregnancy experience (alongside glatiramer acetate) | None routinely required | EMA label updated 2019; may be continued through conception or pregnancy in selected patients after risk-benefit discussion |
| Natalizumab | Use with caution | Case-by-case | May continue through 3rd trimester in highly active disease (risk of rebound > fetal risk); neonatal hematologic effects |
| Dimethyl fumarate | Insufficient data | Discontinue; short half-life | Limited human data; discontinue when planning conception |
| Fingolimod | Contraindicated | 2 months washout | Teratogenic in animal studies; risk of rebound during washout |
| Teriflunomide | Contraindicated (FDA letter categories retired 2015; PLLR-era label) | Accelerated elimination (cholestyramine or activated charcoal) before conception or if pregnancy occurs | Drug otherwise persists up to 2 years; verify undetectable plasma levels |
| Cladribine | Contraindicated | 6 months after last dose | Teratogenic; wait ≥6 months after last dose |
| Anti-CD20s | Avoid near delivery | Discontinue; wait for B-cell recovery | IgG crosses placenta → neonatal B-cell depletion; typically stop 6+ months before conception |
| Alemtuzumab | Avoid | 4 months after last dose | Secondary autoimmunity risk to mother continues regardless |
- Glatiramer acetate and interferon-β have the most reassuring pregnancy experience among MS DMTs — either may be continued through conception or pregnancy in selected patients after risk-benefit discussion; most other DMTs are stopped before conception per individual label guidance
- Teriflunomide is contraindicated in pregnancy (FDA PLLR replaced letter categories in 2015) — perform accelerated elimination with cholestyramine or activated charcoal before conception or if pregnancy occurs; confirm undetectable plasma levels
- MS relapse rate ↓ 3rd trimester, ↑ postpartum — consider resuming DMT immediately after delivery
- Both men and women on teriflunomide should undergo washout before conceiving (drug is present in semen)
Symptomatic Management
Treatment by Symptom
| Symptom | First-Line | Alternatives |
|---|
| Fatigue | Amantadine 100 mg BID | Modafinil 200 mg daily; exercise; sleep hygiene; treat depression |
| Spasticity | Baclofen (oral or intrathecal pump) | Tizanidine; diazepam; dantrolene; botulinum toxin for focal spasticity |
| Neuropathic pain | Gabapentin; pregabalin | Duloxetine; TCAs; carbamazepine for trigeminal neuralgia |
| Bladder (urgency) | Oxybutynin; tolterodine | Mirabegron; intermittent catheterization if PVR >100 mL; onabotulinum toxin injection |
| Walking impairment | Dalfampridine (4-AP) 10 mg every 12 hours | K+ channel blocker; improves speed in ~35%; contraindicated if CrCl ≤50 mL/min or seizure history |
| Paroxysmal symptoms | Carbamazepine (low dose) | Oxcarbazepine; gabapentin; treats ephaptic transmission |
| Depression | SSRIs/SNRIs | CBT; lifetime prevalence ~50% in MS |
| Tremor | No highly effective treatment | Isoniazid (with B6); clonazepam; DBS for severe cases |
- Dalfampridine (4-aminopyridine) is the only FDA-approved drug for MS walking impairment — blocks K+ channels in demyelinated axons
- Intrathecal baclofen pump for severe spasticity not responsive to oral agents
- Paroxysmal symptoms respond to low-dose carbamazepine — not treating seizures, treating ephaptic transmission
- Amantadine for MS fatigue — also has anti-glutamatergic properties; often first-line
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.
- Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis (OPERA I/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.
- Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis (AFFIRM). N Engl J Med. 2006;354(9):899-910.
- Kappos L, Bar-Or A, Cree BAC, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND). Lancet. 2018;391(10127):1263-1273.
- Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis (CARE-MS II). Lancet. 2012;380(9856):1829-1839.
- Confavreux C, Hutchinson M, Hours MM, et al. Rate of pregnancy-related relapse in multiple sclerosis (PRIMS). N Engl J Med. 1998;339(5):285-291.
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