MS Mimics: Distinguishing Conditions that Resemble Multiple Sclerosis

A concise, clinic-first guide to common mimics and overlaps—what to spot, what to test, and how management differs from MS.

Topic: Neuroimmunology Level: Intermediate Tags: MS, NMOSD, MOGAD, transverse-myelitis, optic-neuritis, ADEM, CADASIL, neurosarcoidosis, Susac

Overview

Several disorders can mimic MS on presentation or imaging. Early recognition avoids harmful therapies (e.g., MS DMTs in NMOSD) and guides correct testing and treatment. Hallmark “non‑MS” clues include longitudinally extensive myelitis, severe or bilateral optic neuritis, absence of CSF OCBs, callosal “holes,” and systemic features.

Clinician tip: In atypical demyelination, send AQP4‑IgG and MOG‑IgG early—before labeling as MS.

Core features

  • Longitudinally extensive myelitis (>3 vertebral segments) suggests NMOSD/MOGAD over MS.
  • Optic neuritis that is bilateral, severe, or steroid‑refractory argues against classic MS.
  • CSF OCB negativity and atypical MRI patterns (e.g., callosal “holes”) point to mimics.

Subtypes / related entities

NMOSD (AQP4‑IgG)

Severe optic neuritis and longitudinally extensive myelitis; distinct antibody; requires targeted long‑term immunotherapy.

MOG Antibody–Associated Disease (MOGAD)

MOG‑IgG positive; ADEM‑like lesions, frequent optic neuritis; OCBs typically negative; relapse prevention differs from MS.

Transverse Myelitis (idiopathic or secondary)

Segmental numbness/weakness and a sensory level; can follow infection/autoimmunity; short‑segment milder, long‑segment more severe.

Optic Neuritis (isolated)

Painful monocular vision loss, often steroid‑responsive; a subset later converts to MS.

Acute Disseminated Encephalomyelitis (ADEM)

Monophasic, often post‑infectious; large bilateral lesions; CSF OCB negative; many recover fully.

Susac Syndrome

Triad of encephalopathy, branch retinal artery occlusions, and hearing loss; callosal “holes” on MRI; treat aggressively.

Neurosarcoidosis

Granulomatous inflammation; cranial neuropathies, leptomeningeal enhancement; consider ACE/chest imaging; immunosuppression differs from MS.

SLE (neuro manifestations)

Systemic signs with serologies (ANA/dsDNA); demyelinating‑like lesions can occur but path is distinct from MS.

CADASIL

NOTCH3 mutation; early strokes, migraine, cognitive decline; confluent periventricular and temporal lobe WM changes.

Marburg Variant MS

Fulminant MS with rapid decline and tumefactive lesions; may require ICU‑level care.

Key differences at a glance

Item What to look for Why it matters
Spinal cord lesion length LETM (>3 segments) vs short‑segment LETM favors NMOSD/MOGAD over MS
Optic neuritis pattern Bilateral, severe, or steroid‑refractory Points away from classic MS; test AQP4/MOG
CSF OCBs Negative or scant bands Suggests MOGAD/ADEM or non‑MS inflammatory
MRI corpus callosum Central “holes”/snowball lesions Supports Susac over MS
Systemic features Rash, arthritis, pulmonary findings, uveitis Consider SLE, sarcoid or other systemic causes
Genetics NOTCH3 mutation testing Confirms CADASIL, avoids mislabeling as MS

Work-up snapshot

  • MRI brain/spine with contrast; look for LETM and callosal “holes”.
  • CSF: cell count, protein, oligoclonal bands.
  • Serology: AQP4‑IgG, MOG‑IgG; autoimmune panel (ANA/dsDNA/ENA) as indicated; ACE and chest imaging for sarcoid.
  • Targeted genetics (e.g., NOTCH3) when phenotype suggests CADASIL.
Red flag: Avoid initiating MS‑specific DMTs until NMOSD/MOGAD are excluded in atypical presentations.

Treatment snapshot

  • Acute attacks: high‑dose IV methylprednisolone; escalate to plasma exchange if refractory.
  • NMOSD/MOGAD: antibody‑guided relapse prevention (e.g., B‑cell therapy, IL‑6 pathway, complement inhibition per local protocols).
  • Neurosarcoid/SLE: immunosuppression tailored to systemic disease involvement.
  • ADEM: supportive care and steroids; many recover well.
Pearl: When the story doesn’t fit MS, a targeted serology panel often prevents months of diagnostic drift.

References

  1. Wingerchuk DM, et al. International consensus diagnostic criteria for NMOSD.
  2. Jurynczyk M, et al. MOG‑antibody disease: clinical and MRI features.
  3. Jarius S, et al. Update on AQP4‑IgG serostatus in NMOSD.
  4. Vernooij MW, et al. CADASIL imaging characteristics.
  5. Susac JO, et al. Susac syndrome review.

Educational discussion. Not a substitute for clinical judgment. Consider local protocols and individual factors.