What is the initial workup for a patient suspected of having Multiple Sclerosis (MS)?

Initial Workup for Suspected Multiple Sclerosis

The initial workup for suspected MS centers on brain and spinal cord MRI with gadolinium as the primary diagnostic tool, combined with clinical assessment demonstrating objective neurological signs disseminated in time and space, supplemented by CSF analysis when imaging criteria are not fully met or the clinical picture is atypical. 1

Clinical Assessment

Objective neurological examination is essential - historical symptoms alone cannot establish the diagnosis. 2 You must document:

• Objective clinical signs of CNS lesions (not just patient-reported symptoms) 2
• Attack definition: Neurological disturbance lasting ≥24 hours, excluding pseudoattacks from fever or infection 2
• Temporal separation: At least 30 days between onset of separate attacks 2
• Age considerations: Criteria apply best to patients 18-50 years, though can be used in pediatric cases with special attention under age 11 2, 3

Imaging Studies (Primary Diagnostic Tool)

Brain MRI with gadolinium is the most sensitive and specific test for MS diagnosis. 2, 1 The standardized protocol must include:

• Axial T1-weighted sequences (pre- and post-gadolinium) 1
• Axial T2-weighted and proton-density sequences 1
• Sagittal 2D or isotropic 3D T2-FLAIR sequences 1
• Minimum 1.5T field strength, preferably using 3D acquisitions or 2D with 3-mm slices and no gap 2

Spinal cord MRI is mandatory even without spinal symptoms, as 30-40% of clinically isolated syndrome patients have asymptomatic cord lesions. 1, 4 The protocol includes:

• Sagittal dual-echo sequences 1
• Sagittal STIR sequences 1
• Contrast-enhanced T1-weighted spin-echo sequences 1
• Consider cervical, thoracic, and lumbar spine imaging 2

MRI criteria for dissemination in space require lesions in ≥2 of 4 characteristic CNS regions: periventricular, cortical/juxtacortical, infratentorial, and spinal cord. 4 Dissemination in time is demonstrated by simultaneous gadolinium-enhancing and non-enhancing lesions on a single MRI, or new T2/enhancing lesions on follow-up imaging. 4

Critical MRI Red Flags

In patients >50 years or with vascular risk factors, demand more stringent criteria including a higher number of periventricular lesions abutting the lateral ventricles. 2, 3 Atypical MRI lesions (odds ratio 10.977 for alternative diagnosis) should trigger reconsideration of the diagnosis. 5

Cerebrospinal Fluid Analysis

CSF examination is indicated when:

• Imaging criteria are not fully satisfied 2
• Clinical presentation is atypical 2, 3
• To exclude alternative diagnoses 1

Key CSF findings include:

• Oligoclonal IgG bands (absence has odds ratio 18.113 for alternative diagnosis) 5
• Elevated IgG index 1, 4
• Albumino-cytological dissociation 1

The absence of CSF oligoclonal bands is the strongest predictor of an alternative diagnosis and should prompt extensive reconsideration. 5

Laboratory Studies

Blood tests are essential to exclude MS mimics:

• Complete blood count and comprehensive metabolic panel 1
• Vitamin B12 levels (deficiency mimics MS) 6
• Anti-aquaporin-4 antibodies (mandatory to exclude neuromyelitis optica spectrum disorder, which requires different treatment) 4, 3
• Lyme serology, syphilis testing in endemic areas 3, 6
• Consider ANA, anti-Ro/La (for lupus, Sjögren's syndrome) 6

Evoked Potentials

Visual evoked potentials (VEP) provide additional support when:

• MRI abnormalities are few (e.g., primary progressive MS with myelopathy) 2
• MRI has lesser specificity (older patients with vascular disease) 2
• Normal VEP (odds ratio 3.550) suggests alternative diagnosis 5

Other evoked potentials contribute little to diagnosis. 2

Critical Differential Diagnoses to Exclude

The most common MS mimics in real-world practice (representing 24.4% of suspected cases) are: 5

1. Nonspecific neurologic symptoms with atypical vascular MRI lesions (most common mimic) 5
2. Migraine with atypical white matter lesions 5
3. Neuromyelitis optica spectrum disorder (requires anti-aquaporin-4 testing) 4, 5
4. Cerebrovascular disease (especially in young adults with vascular risk factors) 3, 6
5. CNS infections (Lyme disease, syphilis, HTLV-1) 3, 6
6. Spinal cord compression (cervical spine MRI mandatory with cord symptoms) 6, 7

Common Diagnostic Pitfalls

Never diagnose MS based solely on MRI findings - at least one clinical event consistent with acute demyelination is essential. 1, 3 Radiologically isolated syndrome alone does not constitute MS. 1

Do not rely on MRI overread by radiologists lacking clinical context - this leads to misdiagnosis in up to one-third of cases. 7 Diagnosis must be made by a specialist experienced in MS and its mimics. 3, 8

Absence of dissemination in space on MRI (odds ratio 5.164) strongly predicts alternative diagnosis. 5

Diagnostic Criteria Application

The 2017 McDonald Criteria require:

• Two or more attacks with objective clinical evidence of ≥2 lesions, OR 1
• One attack with objective evidence of one lesion PLUS dissemination in space and time demonstrated by MRI or subsequent clinical attack 1

In pediatric cases under 11 years, look for at least one T1 hypointense lesion (black hole) and one periventricular lesion to distinguish MS from monophasic demyelination. 2, 3