What is the appropriate initial work‑up for a patient suspected of having multiple sclerosis?

Workup for Multiple Sclerosis

Initial Diagnostic Approach

Obtain brain and spinal cord MRI with gadolinium immediately—this is the single most important diagnostic test and should be performed using a standardized protocol with at least 1.5T field strength, maximum 3mm slice thickness, and specific sequences including axial T2-weighted, T2-FLAIR, and gadolinium-enhanced T1-weighted images. 1, 2

Essential Clinical Assessment

• Document objective neurological findings on examination—symptoms alone are insufficient for diagnosis and patients with persistent neurological symptoms but normal examinations do not develop MS 1, 2, 3
• Focus history on prior episodes of optic neuritis, sensory disturbances, motor weakness, brainstem symptoms, or myelopathy, ensuring each "attack" lasted at least 24 hours and represents objective clinical findings 1
• Separate attacks must be at least 30 days apart from onset to onset 1

MRI Requirements and Interpretation

Dissemination in Space (DIS) requires lesions in ≥2 of 5 CNS locations: periventricular (≥3 lesions required), cortical/juxtacortical, infratentorial, spinal cord, and optic nerve 1

Dissemination in Time (DIT) is demonstrated by:

• Simultaneous gadolinium-enhancing and non-enhancing lesions on a single scan, OR 1
• New T2 or gadolinium-enhancing lesions on follow-up MRI performed ≥3 months after baseline, OR 1
• A second clinical attack 1

Critical imaging characteristics that confirm MS lesions include:

• Perivenular orientation (highly specific for MS) 1
• Lesions affecting the inferior corpus callosum asymmetrically 1
• Paramagnetic rim lesions indicating chronic active inflammation 1

Spinal Cord and Optic Nerve Imaging

• Perform whole spinal cord MRI (cervical, thoracic, lumbar) using fat-suppressed sequences when clinical presentation suggests spinal involvement, brain MRI shows only 1-2 lesions, or to exclude non-demyelinating pathology 1, 2
• Include fat-suppressed sequences of the optic nerves in atypical presentations 1

CSF Analysis

Obtain CSF analysis when imaging criteria fall short, clinical presentation is atypical, or in older patients where MRI findings may lack specificity 1, 2

• Positive CSF is defined as oligoclonal IgG bands (detected by isoelectric focusing) different from serum bands OR elevated IgG index 4, 1
• Lymphocytic pleocytosis should be <50/mm³ 1
• CSF analysis is mandatory for diagnosing primary progressive MS 2
• Ensure state-of-the-art technology as quality varies between laboratories 1

Visual Evoked Potentials

• Consider VEP when MRI abnormalities are few or have lesser specificity, particularly in primary progressive MS with progressive myelopathy, or when only one clinical lesion is apparent 1, 2
• Abnormal VEP shows delay with well-preserved waveform 4

Diagnostic Algorithm by Clinical Scenario

Two or More Attacks + Two or More Objective Lesions

• No additional testing required if clinical presentation is typical 4, 2
• If tests are performed and negative, extreme caution is required before diagnosing MS—alternative diagnoses must be considered 4

Two or More Attacks + One Objective Lesion

• Demonstrate DIS through MRI criteria (≥2 of 5 CNS locations) OR 1, 2
• Two or more MRI lesions consistent with MS plus positive CSF 4

One Attack + Two or More Objective Lesions

• Demonstrate DIT through MRI showing simultaneous enhancing and non-enhancing lesions, new lesions on follow-up MRI, or a second clinical attack 1, 2

One Attack + One Objective Lesion

• Demonstrate both DIS and DIT using MRI criteria or positive CSF 4, 1, 2

Primary Progressive MS

• Requires abnormal CSF with evidence of inflammation (oligoclonal bands or elevated IgG index) 1, 2
• Demonstrate DIS: 9 or more T2 brain lesions OR 2 or more spinal cord lesions OR 4-8 brain plus 1 spinal cord lesion 4
• Demonstrate DIT through continued progression for 1 year OR new MRI lesions 4, 1

Essential Differential Diagnosis Testing

Check the following based on clinical context to exclude MS mimics:

• Neuromyelitis optica spectrum disorder (NMOSD): AQP4-IgG antibodies—NMOSD shows longitudinally extensive transverse myelitis and different brain lesion patterns 1
• MOG-antibody disease: MOG antibodies 1
• Vascular disorders: Antiphospholipid antibodies, lupus serologies (particularly in patients with vascular risk factors) 1
• Infections: HTLV-1, Lyme serology, syphilis testing 1
• Genetic disorders: Consider leukodystrophies in children and teenagers 1

Critical Red Flags and Pitfalls

Age-Related Considerations

• Patients <10 years or >59 years require more stringent criteria 1, 2
• For patients >50 years or with vascular risk factors, require ≥3 periventricular lesions abutting the lateral ventricles to distinguish from age-related white matter changes 1
• In children <11 years, baseline MRI must show at least one T1 hypointense lesion AND at least one periventricular lesion to differentiate MS from monophasic demyelination 1

Imaging Red Flags Suggesting Non-MS Diagnosis

• Atypical contrast-enhancement patterns 1
• Lesions in regions not typical for MS 1
• Bilateral sudden hearing loss or sudden onset focal neurologic symptoms 1
• Isolated cranial nerve involvement (rare in MS at 10.4%; isolated eighth nerve palsy <1%) 1

Quality Control Measures

• Never diagnose MS on MRI alone—clinical correlation is mandatory 1
• Confirm lesions on multiple planes 1
• If baseline MRI shows lesions but doesn't fulfill DIS/DIT criteria, repeat brain MRI at 3-6 months; if inconclusive, obtain third scan at 6-12 months 1
• Poor quality paraclinical testing leads to misdiagnosis—ensure state-of-the-art technology 1, 2

Diagnostic Outcomes

• MS: All required criteria fulfilled 4, 1
• Possible MS: Criteria not completely met 4, 1
• Not MS: Criteria fully explored and not met, or alternative diagnosis identified 4, 1