An MS exacerbation (relapse) is defined as new or worsening neurological symptoms lasting ≥24 hours, developing acutely or subacutely, in the absence of fever or infection. [1-2] The critical first step in the ED and primary care setting is distinguishing a true relapse from a pseudo-relapse (worsening of prior symptoms triggered by infection, heat, or metabolic derangement). [2-3]
1. History
- Onset and tempo: Symptoms develop over hours to days, with maximal deficit typically within 4 weeks [4]
- Symptom characterization: Ask about vision changes (blurred vision, pain with eye movement), limb weakness or numbness, gait instability, bowel/bladder dysfunction, Lhermitte sign (electric shock sensation down spine with neck flexion) [1][5]
- Timing and triggers: Recent infection (especially URI), heat exposure, emotional stress, postpartum period, DMT nonadherence or discontinuation [6-8]
- Associated symptoms: Fatigue, cognitive changes, diplopia, vertigo, dysarthria [5][9]
- Important negatives: Absence of fever, headache, meningismus, encephalopathy, seizures (these suggest alternative diagnoses) [4]
- Prior relapses: Pattern of previous attacks, residual deficits, baseline functional status, current DMT [9]
2. Alarm Features
- Bilateral optic neuritis or unilateral optic neuritis with poor visual recovery → consider NMOSD/MOGAD [4]
- Complete transverse myelopathy with bilateral motor and sensory involvement → consider NMOSD [4]
- Encephalopathy, seizures, or subacute cognitive decline → atypical for MS; consider ADEM, CNS lymphoma, PML [4][10]
- Intractable nausea/vomiting/hiccups → area postrema syndrome, consider NMOSD [4]
- Rapidly progressive or fulminant course → Marburg variant, tumefactive MS [11]
- New symptoms in a patient on natalizumab → must rule out PML (progressive multifocal leukoencephalopathy) [11]
- Respiratory compromise from high cervical cord lesion or severe brainstem involvement
3. Medications
- Acute relapse treatment:
- First-line: IV methylprednisolone 1,000 mg/day for 3–5 days [1][5][9]
- Oral methylprednisolone (1,000 mg) or oral prednisone (1,250 mg × 5 days) is noninferior to IV in randomized trials [1][12]
- No oral taper routinely required [1]
- Steroid-refractory relapses: Plasma exchange (TPE) — typically 5–7 exchanges over ~2 weeks; response rate ~77% in RRMS [13-15]
- Medications that can worsen MS: TNF-α inhibitors, atacicept (B-cell survival factor blocker), hormonal fertility treatments [6][16]
- Cautions: Screen for infection before steroids; hyperglycemia, insomnia, psychiatric effects with high-dose steroids; avoid steroids in active untreated infection [17]
- DMT discontinuation rebound: Abrupt cessation of fingolimod or natalizumab can trigger severe rebound relapses [18]
4. Diet
- Vitamin D: Low serum vitamin D levels are associated with increased relapse risk; supplementation is commonly recommended though optimal dosing is not standardized [6][19]
- Hydration: Adequate hydration helps with fatigue and urinary symptoms
- Heat avoidance: 60–80% of MS patients experience symptom worsening (Uhthoff phenomenon) with heat exposure; advise cooling strategies [20]
- Long-term: No specific diet has strong evidence for relapse prevention; a Cochrane review found insufficient evidence for dietary interventions on MS outcomes [21]
5. Review of Systems
- Neurologic: Vision changes, diplopia, weakness, numbness/tingling, gait difficulty, vertigo, Lhermitte sign, cognitive changes
- GU: Urinary urgency, frequency, incontinence, retention, erectile dysfunction [5]
- GI: Constipation, bowel incontinence
- Psychiatric: Depression, anxiety (highly prevalent comorbidities) [22]
- Constitutional: Fatigue (most common persistent symptom), fever (suggests pseudo-relapse or infection)
- Infectious: URI symptoms, UTI symptoms, skin infections (common pseudo-relapse triggers) [2][7]
6. Collateral History and Family History
- Collateral: Baseline functional status, DMT adherence, recent medication changes, prior relapse patterns, cognitive baseline from caregivers
- Family history: First-degree relatives with MS (2–4% risk); autoimmune diseases (thyroid, type 1 diabetes, IBD)
- Social context: Smoking status (accelerates disability progression by ~4.7% per year of smoking); employment/functional impact; support system for home discharge [5]
7. Risk Factors
- Relapse triggers (strong evidence): Infections (RR 2.07), postpartum period (RR 1.43 vs pre-pregnancy), stressful life events (RR 2.2 within 4 weeks) [7-8]
- Heat exposure: Temperature variations and high ambient temperature associated with increased MS clinic visits [20][23]
- DMT nonadherence or discontinuation [6]
- Low vitamin D levels [6][19]
- Protective factors: Pregnancy (RR 0.56), exclusive breastfeeding, sunlight exposure [6-7]
- Not associated with increased relapse risk: Surgery, general/epidural anesthesia, physical trauma, influenza/hepatitis B/tetanus vaccination [6]
8. Differential Diagnosis
- Pseudo-relapse (most common mimic): Worsening of prior deficits due to infection (UTI, URI), fever, heat, metabolic derangement — resolves when trigger is treated [2-3]
- NMOSD (AQP4+): Longitudinally extensive transverse myelitis (≥3 segments), bilateral/severe optic neuritis, area postrema syndrome [10][24]
- MOGAD: Optic neuritis (often bilateral), transverse myelitis, ADEM-like presentation; test MOG-IgG [24]
- Stroke/TIA: Sudden onset, vascular territory distribution; especially consider in older MS patients [22]
- PML: Subacute progressive deficits in immunosuppressed patients (especially natalizumab); characteristic MRI findings [11]
- CNS infection: Meningitis, encephalitis, brain abscess
- CNS lymphoma or tumor: Persistent enhancement >3 months, mass effect [22]
- Neurosarcoidosis: Nodular enhancement, persistent enhancement, cranial neuropathies [22]
- Cervical spondylotic myelopathy: Progressive myelopathy, especially in older patients [22]
- B12/copper deficiency: Subacute combined degeneration [22]
9. Past Medical History
- MS subtype: RRMS, SPMS, PPMS, CIS [9]
- Prior relapses: Frequency, severity, recovery pattern, residual deficits
- Current and prior DMTs: Response, adverse effects, adherence
- Baseline EDSS score: Critical for assessing change [25]
- Comorbidities: Depression, anxiety, UTIs (common pseudo-relapse triggers), vascular disease, diabetes (steroid caution)
- Prior steroid use: Frequency, response, adverse effects
- Immunosuppression status: Relevant for infection risk and PML screening
10. Physical Exam
- Vital signs: Temperature (fever → pseudo-relapse or infection), heart rate, blood pressure
- Focused neurologic exam:
- Visual: Acuity, color vision, afferent pupillary defect (Marcus Gunn pupil), fundoscopy [1]
- Cranial nerves: Internuclear ophthalmoplegia (bilateral INO is highly suggestive of MS), nystagmus, facial sensory loss [4]
- Motor: Asymmetric weakness, spasticity, hyperreflexia, extensor plantar responses [1]
- Sensory: Dermatomal or CNS-pattern sensory loss, Lhermitte sign [1][5]
- Cerebellar: Ataxia, dysmetria, intention tremor [4]
- Gait: Spastic, ataxic, or combined gait abnormality
- Compare to documented baseline to identify new vs. recurrent deficits
11. Lab Studies
- Rule out pseudo-relapse: CBC, CMP, urinalysis with culture, ESR/CRP [3][26]
- If first presentation or diagnostic uncertainty: CSF analysis — oligoclonal bands (present in 80–90% of MS), IgG index, cell count, protein [11]
- Antibody testing (when atypical features): AQP4-IgG (NMOSD), MOG-IgG (MOGAD) via cell-based assay [10][24]
- Vitamin D level: 25-OH vitamin D [6]
- Pre-steroid: Blood glucose (especially in diabetics)
- DMT monitoring labs: Per specific agent (e.g., CBC, LFTs for fingolimod/teriflunomide; JCV antibody for natalizumab)
- Emerging biomarkers: Serum neurofilament light chain (NfL) — elevated in active disease; not yet standard of care [2]
12. Imaging
- First-line: MRI brain without and with IV gadolinium — strongly recommended for all patients with new or progressive neurologic deficits [11]
- Active demyelination found in ~88% of confirmed exacerbations on ED MRI [27]
- Look for new/enlarging T2 lesions and gadolinium-enhancing lesions
- Typical MS lesion locations: periventricular, juxtacortical/cortical, infratentorial, spinal cord [11]
- Incomplete ring enhancement (open border facing gray matter) distinguishes MS from tumors/abscesses [11]
- MRI cervical/thoracic spine with contrast: When symptoms suggest spinal cord involvement or brain MRI is nondiagnostic [11]
- When imaging may be unnecessary: Known MS patient with mild sensory symptoms consistent with prior relapse pattern and clear pseudo-relapse trigger identified
- Gold standard features (2024 McDonald update): Central vein sign (≥6 lesions), paramagnetic rim lesions [11]
13. Special Tests
- EDSS (Expanded Disability Status Scale): 0–10 scale; most widely used disability measure; score before and after relapse to quantify change [25][28]
- Visual evoked potentials: Useful for subclinical optic nerve involvement [9]
- OCT (optical coherence tomography): Retinal nerve fiber layer thinning in optic neuritis
- Timed 25-foot walk, 9-hole peg test, SDMT: Components of the MS Functional Composite for quantitative assessment [29]
- Lumbar puncture: When diagnosis is uncertain — oligoclonal bands, kappa free light chains [11][24]
14. ECG
- Indications: Patients on S1P receptor modulators (fingolimod, siponimod, ozanimod) — risk of first-dose bradycardia (0.5–4%) and heart block (1.2–3%) [1]
- Pre-steroid: Consider in patients with cardiac history receiving high-dose IV methylprednisolone (risk of arrhythmia with rapid infusion)
- Not routinely indicated for the relapse itself unless cardiac symptoms are present
15. Assessment
A true MS exacerbation is a clinical diagnosis — new or worsening neurological symptoms lasting ≥24 hours, with objective findings, in the absence of fever or infection. [1-2] Severity stratification guides treatment:
- Mild relapse: Sensory symptoms only, no functional impairment → may not require treatment [1]
- Moderate relapse: Functional impairment (e.g., gait difficulty, visual loss) → corticosteroids indicated [1]
- Severe relapse: Major motor deficit, severe optic neuritis, brainstem/spinal cord syndrome → urgent steroids ± early consideration of plasma exchange [13][15]
Atypical presentations (encephalopathy, bilateral optic neuritis, longitudinally extensive myelitis, constitutional symptoms) should prompt evaluation for NMOSD, MOGAD, or non-MS diagnoses. [4][10]
16. Treatment Plan
Initial stabilization
- Rule out and treat infection (pseudo-relapse trigger)
- ABCs if severe brainstem or high cervical cord involvement
Pharmacologic treatment
- Mild relapse with no functional impairment: Observation; treatment may not be necessary [1]
- Moderate-severe relapse:
- IV methylprednisolone 1,000 mg/day × 3–5 days (first-line) [1][9]
- Oral methylprednisolone 1,000 mg/day × 3 days is a noninferior alternative [5][12]
- Oral taper is not routinely required
- Steroid-refractory relapse (no improvement after 2 weeks):
- Plasma exchange (TPE): 5–7 exchanges over ~2 weeks; TPE was superior to escalated IV steroids in one study (good recovery: 60.9% TPE vs 15.2% escalated IVMP) [15]
- IVIG (2 g/kg over 2–5 days) is an alternative, particularly in pediatric patients [30]
Outpatient vs. inpatient
- Many moderate relapses can be treated with outpatient IV or oral steroids
- Severe relapses, inability to ambulate, or need for plasma exchange typically require admission
DMT review
17. Disposition
Admission criteria
- Severe neurologic deficit (inability to ambulate, significant visual loss, bulbar symptoms)
- Need for plasma exchange
- Inability to perform ADLs or unsafe home environment
- Diagnostic uncertainty requiring urgent workup (LP, MRI)
- Concern for PML or other serious alternative diagnosis
Discharge criteria
- Mild-moderate relapse with preserved function
- Able to tolerate oral steroids as outpatient
- Reliable follow-up with neurology arranged
- Safe home environment with adequate support
Observation indications
Specialist consultation triggers
- Neurology: All confirmed or suspected relapses; DMT failure; diagnostic uncertainty [31]
- Ophthalmology: Optic neuritis
- Rehabilitation medicine: Significant functional decline
18. Follow Up / Return Precautions
- Follow-up timing: Neurology follow-up within 1–2 weeks of relapse treatment; MRI within 1–3 months to establish new baseline [11][32]
- Symptoms requiring immediate reassessment:
- Worsening weakness or new paralysis
- New visual loss or bilateral visual symptoms
- Difficulty breathing or swallowing
- Urinary retention
- Fever (may indicate infection complicating immunosuppression)
- Altered mental status
- Patient counseling:
- Steroids accelerate recovery but do not change long-term outcome of the relapse [1]
- Avoid heat exposure; use cooling strategies [20]
- Stress management and infection prevention [6][8]
- Smoking cessation — each smoke-free year decreases disability progression [5]
- DMT adherence is critical for relapse prevention [1]
- Expected recovery: Most relapse symptoms begin improving within days to weeks of steroid treatment; full recovery may take weeks to months; some relapses leave residual deficits [1][9]
Images
References
1. Diagnosis and Treatment of Multiple Sclerosis: A Review. — McGinley MP, Goldschmidt CH, Rae-Grant AD. The Journal of the American Medical Association. 2021.
2. Acute Clinical Events Identified as Relapses With Stable Magnetic Resonance Imaging in Multiple Sclerosis. — Gavoille A, Rollot F, Casey R, et al. JAMA Neurology. 2024.
3. Relapse Management in Multiple Sclerosis. — Thrower BW. The Neurologist. 2009.
4. Diagnosis of Multiple Sclerosis: Progress and Challenges. — Brownlee WJ, Hardy TA, Fazekas F, Miller DH. Lancet. 2017.
5. Multiple Sclerosis: A Primary Care Perspective. — Saguil A, Farnell Iv EA, Jordan TS. American Family Physician. 2022.
6. Modifiable Factors Influencing Relapses and Disability in Multiple Sclerosis. — D'hooghe MB, Nagels G, Bissay V, De Keyser J. Multiple Sclerosis. 2010.
7. Factors Associated With Relapses in Relapsing-Remitting Multiple Sclerosis: A Systematic Review and Meta-Analysis. — Xie Y, Tian Z, Han F, et al. Medicine. 2020.
8. Self Reported Stressful Life Events and Exacerbations in Multiple Sclerosis: Prospective Study. — Buljevac D, Hop WC, Reedeker W, et al. BMJ. 2003.
9. Multiple Sclerosis. — Jakimovski D, Bittner S, Zivadinov R, et al. Lancet. 2024.
10. Differential Diagnosis of Suspected Multiple Sclerosis: An Updated Consensus Approach. — Solomon AJ, Arrambide G, Brownlee WJ, et al. The Lancet. Neurology. 2023.
11. ACR Appropriateness Criteria® Demyelinating Diseases. — Expert Panel on Neurologic Imaging, Kalnins A, Lewis LM, et al. Journal of the American College of Radiology : JACR. 2026.
12. Oral Versus Intravenous High-Dose Methylprednisolone for Treatment of Relapses in Patients With Multiple Sclerosis (COPOUSEP): A Randomised, Controlled, Double-Blind, Non-Inferiority Trial. — Le Page E, Veillard D, Laplaud DA, et al. Lancet. 2015.
13. Therapeutic Plasma Exchange in Multiple Sclerosis Patients With an Aggressive Relapse: An Observational Analysis in a High-Volume Center. — Bunganic R, Blahutova S, Revendova K, et al. Scientific Reports. 2022.
14. Plasma Exchange or Immunoadsorption in Demyelinating Diseases: A Meta-Analysis. — Lipphardt M, Wallbach M, Koziolek MJ. Journal of Clinical Medicine. 2020.
15. Comparing Plasma Exchange to Escalated Methyl Prednisolone in Refractory Multiple Sclerosis Relapses. — Pfeuffer S, Rolfes L, Bormann E, et al. Journal of Clinical Medicine. 2019.
16. Cellular Immunology of Relapsing Multiple Sclerosis: Interactions, Checks, and Balances. — Bar-Or A, Li R. The Lancet. Neurology. 2021.
17. Managing Adverse Effects of Disease-Modifying Agents Used for Treatment of Multiple Sclerosis. — Moses H, Brandes DW. Current Medical Research and Opinion. 2008.
18. Therapeutic Management During Pregnancy and Relapse Risk in Women With Multiple Sclerosis. — Gavoille A, Rollot F, Casey R, et al. JAMA Neurology. 2025.
19. Factors Associated With Onset, Relapses or Progression in Multiple Sclerosis: A Systematic Review. — McKay KA, Jahanfar S, Duggan T, Tkachuk S, Tremlett H. Neurotoxicology. 2017.
20. Heat Exposure and Multiple Sclerosis-a Regional and Temporal Analysis. — Chacko G, Patel S, Galor A, Kumar N. International Journal of Environmental Research and Public Health. 2021.
21. Dietary Interventions for Multiple Sclerosis-Related Outcomes. — Parks NE, Jackson-Tarlton CS, Vacchi L, Merdad R, Johnston BC. The Cochrane Database of Systematic Reviews. 2020.
22. Differential Diagnosis of Suspected Multiple Sclerosis in Pediatric and Late-Onset Populations: A Review. — Hua LH, Solomon AJ, Tenembaum S, et al. JAMA Neurology. 2024.
23. Characteristics of Disease Relapses and Their Relationships With Weather Conditions in Patients With Multiple Sclerosis. — Sempik I, Pokryszko-Dragan A, Wieczorek M, Błaś M, Dziadkowiak E. Journal of Clinical Medicine. 2025.
24. Uncommon Non-MS Demyelinating Disorders of the Central Nervous System. — Mukherjee A, Roy D, Chakravarty A. Current Neurology and Neuroscience Reports. 2025.
25. Diagnosis of Progressive Multiple Sclerosis From the Imaging Perspective: A Review. — Filippi M, Preziosa P, Barkhof F, et al. JAMA Neurology. 2021.
26. Multiple Sclerosis: Diagnosis and the Management of Acute Relapses. — Leary SM, Porter B, Thompson AJ. Postgraduate Medical Journal. 2005.
27. Emergency Department MRI Scanning of Patients With Multiple Sclerosis: Worthwhile or Wasteful?. — Pakpoor J, Saylor D, Izbudak I, et al. AJNR. American Journal of Neuroradiology. 2017.
28. Changes in the Risk of Reaching Multiple Sclerosis Disability Milestones In Recent Decades: A Nationwide Population-Based Cohort Study in Sweden. — Beiki O, Frumento P, Bottai M, Manouchehrinia A, Hillert J. JAMA Neurology. 2019.
29. Progressive Multiple Sclerosis: Prospects for Disease Therapy, Repair, and Restoration of Function. — Ontaneda D, Thompson AJ, Fox RJ, Cohen JA. Lancet. 2017.
30. Paediatric Multiple Sclerosis and Antibody-Associated Demyelination: Clinical, Imaging, and Biological Considerations for Diagnosis and Care. — Fadda G, Armangue T, Hacohen Y, Chitnis T, Banwell B. The Lancet. Neurology. 2021.
31. Multiple Sclerosis: An Emergency Medicine-Focused Narrative Review. — Pelletier J, Sugar D, Koyfman A, Long B. The Journal of Emergency Medicine. 2024.
32. 2021 MAGNIMS-CMSC-NAIMS Consensus Recommendations on the Use of MRI in Patients With Multiple Sclerosis. — Wattjes MP, Ciccarelli O, Reich DS, et al. The Lancet. Neurology. 2021.