What is the recommended workup for a young to middle-aged adult, possibly female, presenting with symptoms suggestive of multiple sclerosis (MS), such as vision loss, numbness, weakness, or balance problems?

Workup for Multiple Sclerosis

Initial Clinical Assessment

The diagnosis of MS requires demonstrating CNS lesions disseminated in both time and space through clinical evaluation combined with MRI findings, while systematically excluding alternative diagnoses. 1, 2

Key Clinical Features to Identify

• Typical presenting symptoms include unilateral optic neuritis, partial myelitis, sensory disturbances (numbness/tingling), diplopia, internuclear ophthalmoplegia, balance/gait dysfunction, and bladder urgency developing over hours to days 2, 3, 4
• Age consideration: Diagnostic criteria apply best to patients aged 10-59 years with typical presentations 1, 2
• Attack characteristics: Symptoms must last at least 24 hours and represent new or worsening neurological dysfunction 5, 6
• Female predominance: MS affects women nearly 3:1 compared to men 3

Red Flags Suggesting Alternative Diagnoses

• Bilateral sudden hearing loss suggests a condition other than MS 1
• Sudden onset focal symptoms with headache, confusion, or focal weakness may indicate stroke rather than MS 1
• Atypical presentations including dementia, epilepsy, or aphasia require additional investigation 1, 5

Essential Diagnostic Testing

MRI (Primary Diagnostic Tool)

MRI with gadolinium contrast is the preferred imaging modality and cornerstone of diagnosis. 1, 2

• Required sequences: T2-weighted and gadolinium-enhanced T1-weighted imaging of brain and spinal cord 2, 3
• Classic MS lesion characteristics: Focal T2 hyperintense lesions with sharp edges, ovoid/flame-shaped orientation perpendicular to ventricles, periventricular location 2, 5
• Key anatomic locations: Periventricular, juxtacortical, infratentorial, and spinal cord regions 5
• Active inflammation: Gadolinium-enhancing lesions indicate ongoing inflammatory activity 2
• Timing: Obtain baseline MRI during or following first attack; repeat MRI at least 3 months later to demonstrate dissemination in time 7

Lumbar Puncture for CSF Analysis

• Oligoclonal bands: CSF-specific oligoclonal bands (not present in serum) support the diagnosis 2, 5, 3
• When to obtain: Essential in atypical presentations, progressive onset, or when diagnosis is uncertain 8, 1
• Additional value: Helps exclude infectious and inflammatory mimics 4, 7

Visual Evoked Potentials (VEP)

• Indication: May show delayed conduction and help secure diagnosis in atypical cases or when additional evidence is needed 8, 2
• Particularly useful: In patients with suspected optic nerve involvement or when MRI access is limited 8

Mandatory Exclusion of MS Mimics

A diagnosis of MS cannot be made if there is a better explanation for the clinical and paraclinical abnormalities. 8, 1

Critical Differential Diagnoses to Exclude

• Cerebrovascular disease: Multifocal cerebral ischemia/infarction from phospholipid antibody syndrome, lupus, CADASIL, Takayasu's disease, meningovascular syphilis 8, 1
• Infectious diseases: HTLV-1, Lyme disease, syphilis, HIV 1, 7
• Neuromyelitis optica spectrum disorder (NMOSD): Must be distinguished from MS; consider aquaporin-4 antibody testing 1
• Other inflammatory conditions: Sarcoidosis, systemic lupus erythematosus, Sjögren's syndrome 7
• Metabolic: Vitamin B12 deficiency 7
• Structural: Spinal cord compression 7

Laboratory Tests to Exclude Mimics

• Complete blood count, comprehensive metabolic panel 4
• Vitamin B12 level 7
• Antinuclear antibody (ANA), antiphospholipid antibodies if clinically indicated 8
• Lyme serology in endemic areas 1
• Aquaporin-4 antibody (NMO-IgG) to exclude NMOSD 1

Diagnostic Criteria Application

2017 McDonald Criteria Framework

At least one clinical event consistent with acute demyelination is essential; diagnosis cannot be made on MRI alone. 1, 2

• Objective evidence required: Clinical findings must be objective, not symptoms alone 8
• Dissemination in space: Lesions in at least 2 of 4 characteristic CNS locations (periventricular, juxtacortical, infratentorial, spinal cord) 2, 9
• Dissemination in time: New T2 lesions or gadolinium-enhancing lesions on follow-up MRI, or simultaneous presence of enhancing and non-enhancing lesions 2, 9

Special Populations Requiring Extra Caution

• Pediatric patients (under age 11): Presence of at least one black hole (T1 hypointense lesion) and one periventricular lesion helps distinguish MS from monophasic demyelination 1
• Patients over 50 years or with vascular risk factors: Apply more stringent criteria (higher number of periventricular lesions required) 1
• Progressive onset: Additional CSF and VEP evidence may be necessary to secure diagnosis 8, 1

Specialist Referral

Diagnosis should be made by a specialist familiar with MS, its differential diagnoses, and interpretation of paraclinical assessments. 1

• Neurology consultation is essential for definitive diagnosis and treatment initiation 4, 6
• Biopsy is rarely needed but can confirm inflammatory demyelinating lesions when diagnosis remains uncertain; requires interpretation by experienced neuropathologists 1

Common Pitfalls to Avoid

• Do not diagnose MS based solely on MRI findings without at least one clinical event consistent with demyelination 1, 2
• Do not accept symptoms alone as evidence of an attack; objective clinical findings are required 8
• Do not overlook alternative diagnoses: A positive test for an MS mimic does not automatically exclude MS, but requires careful clinical correlation 9
• Do not rush diagnosis in atypical presentations: Follow-up assessments over time are critical when features are unusual 8, 1
• Ensure imaging quality: Accurate repositioning and coregistration of scans may be necessary to determine if lesions are truly new 8