What is the top differential diagnosis for a 36-year-old female with 4 brain lesions and a history of only 5 auras, with 2 new lesions appearing in 2.5 years?

Top Differential Diagnosis

Multiple sclerosis (MS) is the top differential diagnosis for this 36-year-old female with 4 brain lesions and 2 new lesions appearing over 2.5 years, as this presentation demonstrates dissemination in both space and time—the hallmark diagnostic criteria for MS. 1

Why Multiple Sclerosis is Most Likely

Dissemination in Time and Space

• The appearance of 2 new lesions over 2.5 years fulfills MS criteria for dissemination in time, as new T2 lesions appearing on follow-up MRI at least 3 months apart from initial imaging satisfy diagnostic requirements 1
• Four brain lesions demonstrate dissemination in space, meeting the threshold for multiple CNS lesions separated anatomically 1
• The patient's age (36 years) and sex (female) fit the classic MS demographic, as MS predominantly affects women in their 20s-40s 2

The Aura History is a Red Herring

• The 5 auras in her lifetime do NOT suggest migraine as the primary diagnosis because migraine-related white matter lesions are typically bilateral, small (0.3-0.6 cm), punctate, and scattered—not focal progressive lesions 2
• Migraine does not cause focal, lateralized lesions that develop progressively over years, as this pattern strongly suggests demyelinating disease 2
• Auras can occur with structural brain lesions including MS, demyelinating diseases, and even focal epilepsy from lesional pathology 3, 4, 5

Critical Diagnostic Features to Evaluate

MRI Characteristics That Support MS

• Lesion location: Look for periventricular lesions perpendicular to the corpus callosum ("Dawson's fingers"), juxtacortical U-fibers, and infratentorial areas 2
• Lesion characteristics: MS lesions are typically ovoid, ≥3 mm, well-demarcated, and may show gadolinium enhancement if active 2
• Spinal cord involvement: Short-segment focal lesions (<2 vertebral segments) in lateral/dorsal columns strongly support MS 2

Immediate Workup Required

• Obtain brain AND cervical/thoracic spine MRI with gadolinium to assess for additional lesions, enhancement patterns, and spinal cord involvement 2
• Evaluate for dissemination in space: Look for lesions in ≥2 of 4 characteristic regions (periventricular, juxtacortical, infratentorial, spinal cord) 2
• CSF analysis for oligoclonal bands and elevated IgG index if MRI criteria are not fully met, as positive CSF findings coupled with MRI lesions can establish MS diagnosis 1

Other Differential Diagnoses to Consider

Brain Metastases (Less Likely but Must Exclude)

• Multiple enhancing lesions in a young patient without known cancer makes metastases less likely, but approximately 20-40% of brain metastases present as multiple lesions 1
• Brain metastases typically show rim enhancement with extensive surrounding vasogenic edema on T2/FLAIR sequences 1
• Requires systemic workup including CT chest/abdomen or PET scan to identify primary malignancy if imaging characteristics suggest metastases 1

Tumefactive Demyelinating Lesions

• Can mimic neoplasms but are part of the MS/demyelinating disease spectrum 6
• May require brain biopsy if imaging is atypical and diagnosis remains uncertain 6

CNS Vasculitis, Neurosarcoidosis, or Infectious Etiologies

• These can present with multiple brain lesions but are less common 6
• Brain biopsy may be necessary if standard MS workup is negative and lesions progress despite treatment 6

Common Pitfalls to Avoid

• Do not dismiss this as "migraine with white matter changes" based solely on the aura history—the progressive nature of new lesions over 2.5 years is incompatible with typical migraine-related changes 2
• Do not delay spinal cord imaging—spinal lesions are present in most MS patients and can clinch the diagnosis 2
• Do not assume all auras are migrainous—auras can result from structural lesions, demyelination, or focal epilepsy 3, 4, 5
• Ensure gadolinium is administered to detect active inflammation and assess for enhancement patterns that distinguish MS from other pathologies 1, 2