Multiple Sclerosis

Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system in which the immune system targets myelin, causing demyelination, axonal injury, and progressive neurodegeneration. The disease is now understood as biphasic — an early, focal inflammatory phase most responsible for relapses, followed by a more diffuse degenerative phase that drives long-term disability largely independent of relapse activity.^[1] Management has shifted decisively toward early, activity-matched disease-modifying therapy (DMT) rather than a uniform start-low, wait-and-see approach — treatment decisions made in the first months after diagnosis meaningfully shape the long-term disease course.^[2]

Symptom range

MS produces a very wide range of neurologic symptoms depending on lesion location, so no single presentation is typical. Common findings include optic neuritis (subacute, often painful, monocular vision loss), sensory disturbances (numbness, tingling, or a band-like tightness), Lhermitte's sign (an electric-shock sensation radiating down the spine or limbs with neck flexion, suggesting a cervical cord lesion), motor weakness, spasticity, gait ataxia and tremor, bladder and bowel dysfunction, cognitive slowing and memory difficulty, clinically significant fatigue, depression and anxiety, and neuropathic pain.^[1]

Uhthoff phenomenon — a transient worsening of pre-existing neurologic symptoms triggered by heat, exercise, or fever — reflects temperature-sensitive conduction failure in already-demyelinated axons rather than new inflammatory disease activity, and resolves once the trigger is removed. It is not a relapse and does not need corticosteroids.

• A first-degree relative with MS — family history meaningfully raises risk, though no single causative gene has been identified.
• Low sun exposure and low vitamin D status, particularly at higher latitudes.
• Low vitamin D levels during pregnancy or in the neonatal period.
• Epstein-Barr virus infection, including a history of infectious mononucleosis.
• Cigarette smoking.
• Childhood obesity, dietary and nutritional factors.
• Female sex — MS is substantially more common in women, though men who develop MS are more likely to follow the primary progressive course.

Differentiating MS from its key mimics

MS is a diagnosis of exclusion, and several conditions can mimic its presentation closely enough to change treatment entirely if missed.

History

• Characterize the current episode — subacute onset over hours to days, evolution over days to weeks, then a plateau and gradual recovery is typical of a relapse.
• Ask about prior episodes, their location, and their recovery, since dissemination in time is part of the diagnosis.
• Screen for atypical features that argue against MS — onset after age 50, prominent early seizures, prominent systemic symptoms, or rapidly progressive disability from onset without a clear relapsing pattern — and pursue a mimic workup if present.
• Screen for comorbid depression and anxiety, which are common in MS and affect both quality of life and adherence.

Investigations

• CBC with differential, ALT and AST.
• Antinuclear antibody (ANA), rheumatoid factor (RF), and CRP — to screen for an alternative autoimmune or inflammatory cause.
• TSH.
• Vitamin D level.
• Vitamin B12 — deficiency can mimic MS symptoms and must be excluded.
• Epstein-Barr virus antibodies — negative serology argues against MS and supports looking for an alternative diagnosis.
• MRI of the brain, with spinal cord imaging as indicated, with and without gadolinium — to identify and quantify lesions and assess for new gadolinium-enhancing activity.
• Cerebrospinal fluid analysis for oligoclonal bands, and visual evoked potentials, to support the diagnosis when the clinical/imaging picture is not definitive alone.
• AQP4-IgG and MOG-IgG when the presentation raises the differential above.
• A complete neurologic examination at diagnosis and at every relapse assessment.

Diagnostic criteria

The 2024 McDonald criteria are the current internationally agreed diagnostic standard, replacing the 2017 revision.^[3] Diagnosis requires demonstrating dissemination in space (lesions in at least 2 of the characteristic CNS locations — now including the optic nerve as a fifth anatomical region) and dissemination in time (new lesions on sequential imaging, or simultaneous enhancing and non-enhancing lesions), in a patient whose presentation is not better explained by an alternative diagnosis. Supportive imaging and CSF biomarkers — including the central vein sign, paramagnetic rim lesions, and the CSF kappa free light chain index — can add specificity in equivocal cases.^[3]

When testing is not indicated

Do not diagnose MS from a single clinical event without imaging-confirmed dissemination in space and time — a single non-specific white-matter lesion, especially in an older patient with vascular risk factors, is more likely small-vessel ischemic change than MS, and over-calling it delays the correct workup.

• Reduce the frequency, severity, and duration of relapses.
• Suppress MRI disease activity — no new or enlarging T2 lesions and no new gadolinium-enhancing lesions on surveillance imaging.
• Slow or prevent accumulation of permanent disability and delay conversion to a progressive course.
• Achieve and maintain "no evidence of disease activity" (NEDA) — no relapses, no disability progression, and no new MRI lesion activity — as the working treat-to-target endpoint.
• Preserve cognitive function and overall quality of life.
• Match the DMT's efficacy and toxicity profile to the individual patient's disease activity and life circumstances, rather than defaulting to the least potent option for every patient.

• Physiotherapy, stretching, and structured exercise for spasticity and gait disturbance.
• Fluid intake modification and pelvic floor exercises for bladder symptoms.
• Respiratory muscle training for patients with mild-to-moderate inspiratory/expiratory weakness.
• Stereotactic thalamotomy or deep brain stimulation, referred to a movement disorders specialist, for localized, medication-refractory tremor.
• Smoking cessation — smoking is linked to earlier conversion from RRMS to SPMS and to worsening cognitive impairment, so cessation counselling is a genuine disease-modifying intervention, not just general health advice.
• Screen for and treat comorbid depression and anxiety — untreated psychiatric comorbidity is linked to worse MS outcomes.
• Vitamin D supplementation (at least 1000 units daily) for patients able to tolerate it, particularly with low measured levels — evidence of a direct MS benefit is limited, but the intervention carries other health benefits and no known harm.
• Confirm and complete recommended immunizations before starting an immunosuppressive DMT wherever possible (see Monitoring & Follow-up) — live vaccines are generally avoided once a moderate-to-high-risk immunosuppressive DMT has started.
• Autologous hematopoietic stem cell transplant is an option for relapsing MS refractory to disease-modifying therapy in carefully selected patients — significant mortality risk means this needs a specialist-directed, individualized risk-benefit discussion rather than routine consideration.

Breastfeeding: most clinicians favour stopping DMT during breastfeeding, since breastfeeding itself appears to have a protective effect against postpartum relapse and most DMTs lack robust infant safety data. When DMT genuinely cannot be deferred, glatiramer acetate and interferon beta are the options with the most reassuring breastfeeding data. Corticosteroids can be used for an acute relapse while breastfeeding.

Pediatric: pediatric-onset MS is uncommon and specialist-directed; DMT selection, dosing, and monitoring in this population should be managed by a pediatric neurologist or MS specialist rather than extrapolated from adult dosing.

Renal/hepatic impairment: teriflunomide and dimethyl fumarate require baseline and periodic liver-enzyme monitoring, and significant hepatic impairment needs specialist input before starting either. Fampridine is contraindicated in renal impairment given a dose-related seizure risk from reduced clearance — confirm renal function before prescribing.

Older adults: confirm vaccination status and screen for latent infection (e.g., tuberculosis, hepatitis B/C, varicella-zoster immunity) before starting an immunosuppressive DMT, since older adults and those with more comorbidity carry a higher baseline infection risk on these agents.

DMT-specific monitoring

Every DMT in this chapter has its own laboratory and clinical monitoring schedule — see Drug Tables for the complete, drug-specific list (CBC, liver enzymes, renal function, thyroid function, and infection surveillance at drug-specific intervals).

Natalizumab and PML risk

Check anti-JC virus (JCV) antibody status before starting natalizumab, and periodically (commonly every 6 months) during treatment, since seroconversion changes risk over time.^[6] In a JCV antibody-positive patient, risk is further stratified by antibody index (a higher index, generally above 1.5, corresponds to higher risk; an index below 0.9 corresponds to risk similar to a JCV-antibody-negative patient), prior immunosuppressant use, and treatment duration — risk rises meaningfully with duration beyond 2 years.^[6] Extended-interval dosing (roughly every 5-6 weeks rather than every 4 weeks) may reduce PML risk and is a reasonable discussion point for a patient continuing natalizumab long-term.

MRI surveillance

Obtain a baseline MRI before starting or switching DMT, then a follow-up MRI roughly 6 months after starting or switching to establish a new treatment baseline, then annually (or per the individual DMT's own surveillance schedule) to screen for subclinical disease activity — new or enlarging lesions on a routine surveillance scan, even without a clinical relapse, are breakthrough disease activity and should prompt the same escalation discussion as a clinical relapse.

Other routine follow-up

• Track relapse frequency, severity, and recovery at every visit.
• Review vaccination status regularly, particularly before starting or restarting any immunosuppressive DMT.
• Screen for depression, anxiety, and cognitive change at routine intervals — these are common and often undertreated in MS.
• Reassess vitamin D level periodically in a patient on supplementation.
• Confirm ongoing contraception in any patient of childbearing potential taking teriflunomide, cladribine, or an S1P receptor modulator.

1. Confirm true adherence to the current DMT and rule out a pseudo-relapse (infection, fever, heat exposure — Uhthoff phenomenon) before concluding the drug has failed.
2. Confirm genuine breakthrough disease activity — a new clinical relapse, or a new/enlarging MRI lesion — rather than reacting to a single ambiguous symptom or an old, stable finding.
3. If the patient is on a platform-tier DMT, escalate to a higher-efficacy DMT rather than switching to a different platform-tier agent, which rarely resolves genuine breakthrough activity.
4. If the patient is already on a higher-efficacy DMT, switch within or across the higher-efficacy classes based on mechanism, JC virus antibody status, prior treatment exposure, and washout/safety considerations between agents — this decision should involve an MS specialist.
5. Re-examine the diagnosis for an MS mimic (see the differential table in Assessment & Diagnosis) if disease activity remains genuinely refractory across DMT classes.
6. For aggressive, treatment-refractory relapsing MS, refer for evaluation for autologous hematopoietic stem cell transplant at a specialized centre.

• Starting or continuing teriflunomide, cladribine, or an S1P receptor modulator in a patient of childbearing potential without first confirming reliable contraception.
• Stopping natalizumab or fingolimod abruptly without a bridging plan — both carry a real risk of severe rebound disease activity.
• Treating Uhthoff phenomenon (heat- or fever-triggered worsening of existing symptoms) as a true relapse and giving unnecessary corticosteroids.
• Starting an S1P receptor modulator or alemtuzumab without confirming varicella-zoster immunity first.
• Continuing natalizumab past 2 years without reassessing progressive multifocal leukoencephalopathy risk (JC virus antibody status/index, prior immunosuppressant use, treatment duration).
• Giving a live vaccine too close to a dose of an immunosuppressive DMT — check the specific drug's required interval before and after vaccination.
• Defaulting to a relapsing-MS-only DMT for a patient with active PPMS — ocrelizumab is the only DMT with a PPMS indication.
• Skipping mandatory premedication (corticosteroid, antihistamine, antipyretic) before an ocrelizumab or alemtuzumab infusion.
• Assuming a presentation is straightforward MS without considering NMOSD or MOGAD when atypical features are present — several MS DMTs can worsen NMOSD specifically.

How to use this table: doses are adult doses and require patient-specific confirmation, including renal/hepatic adjustment. Select any drug name to open its complete Pharmasist Drug Database page.

Acute relapse therapy

First-line for any functionally limiting relapse; reserve plasma exchange for relapses that do not respond to a full corticosteroid course.

Platform-tier DMTs — Immunomodulators

Lower relative toxicity, reasonable initial choice under the traditional escalation approach.

Higher-efficacy DMTs — Sphingosine 1-phosphate (S1P) receptor modulators

All require first-dose cardiac monitoring in appropriate patients and carry a shared interaction/monitoring profile; none should be combined with other immunosuppressants.

Higher-efficacy DMTs — Monoclonal antibodies

Each requires specific premedication and/or pre-treatment screening — see Comments for each agent.

Higher-efficacy DMTs — Purine analog

Adjunctive therapy — walking ability

Symptomatic management (brief cross-reference): spasticity is generally managed with baclofen or tizanidine, escalating to intrathecal baclofen for severe refractory cases; clinically significant fatigue may be trialed on amantadine or modafinil; neuropathic pain is generally managed with gabapentin, pregabalin, or duloxetine; bladder dysfunction is generally managed with oxybutynin or mirabegron, or intermittent self-catheterization for retention. Full dosing and selection guidance for each of these belongs to its own condition-specific reference — this chapter covers MS-specific relapse and disease-modifying therapy only.