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

Multiple Sclerosis Initial Work-Up

The initial work-up for suspected multiple sclerosis requires brain and spinal cord MRI with gadolinium, CSF analysis for oligoclonal bands, and a comprehensive neurological examination documenting objective clinical findings—symptoms alone are never sufficient for diagnosis. 1, 2

Essential Diagnostic Components

Neurological History and Examination

• Obtain a detailed history focusing specifically on prior episodes of optic neuritis, sensory disturbances, motor weakness, brainstem symptoms (diplopia, dysarthria), or myelopathy that may have resolved spontaneously 1
• Document objective clinical signs on neurological examination—subjective symptoms without objective findings do not support MS diagnosis and rarely lead to MS development even with prolonged follow-up 2, 3
• An "attack" must last at least 24 hours and represent objective clinical findings, not just patient-reported symptoms 1
• Separate attacks must be separated by at least 30 days from onset to onset 1

Brain and Spinal Cord MRI (First-Line Test)

Brain MRI with gadolinium is the single most important diagnostic test and should be performed immediately in all suspected cases. 1, 4

Required MRI Protocol

• Minimum field strength of 1.5 Tesla 1
• Maximum slice thickness of 3 mm with no inter-slice gap 1
• Required sequences:
  • Axial T2-weighted and T2-FLAIR sequences 1, 4
  • Sagittal T2-FLAIR to evaluate corpus callosum 1, 4
  • Gadolinium-enhanced T1-weighted sequences 1, 4

Spinal Cord MRI Indications

• Mandatory in patients with spinal cord symptoms at disease onset 1
• Strongly recommended even without spinal symptoms, as asymptomatic cord lesions are found in 30-40% of patients with clinically isolated syndrome 4
• Use whole spinal cord imaging (cervical, thoracic, lumbar) with fat-suppressed sequences 1
• Include sagittal dual-echo, sagittal STIR, and contrast-enhanced T1-weighted sequences 4

Optic Nerve Imaging

• Include fat-suppressed sequences of the optic nerves in atypical presentations 1

Cerebrospinal Fluid Analysis

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

• Test for oligoclonal IgG bands (by isoelectric focusing) that differ from serum bands 1, 2
• Measure IgG index (elevated index supports MS) 1, 2
• Document cell count—lymphocytic pleocytosis should be less than 50/mm³ 1
• Absence of oligoclonal bands is the strongest predictor of an alternative diagnosis (odds ratio 18.1) 5
• CSF is mandatory for primary progressive MS diagnosis 1, 2

Visual Evoked Potentials

• Obtain VEP when MRI abnormalities are few or have lesser specificity, particularly in older patients with vascular risk factors 1, 2
• VEP provides objective evidence of a second lesion when only one clinical lesion is apparent 1
• Abnormal VEP shows delayed latency with preserved waveform morphology 1
• Normal VEP is a red flag for alternative diagnosis (odds ratio 3.6) 5

MRI Diagnostic Criteria to Apply

Dissemination in Space (DIS)

DIS requires lesions in ≥2 of 5 CNS locations: 1

1. Periventricular (≥3 lesions required)
2. Cortical/juxtacortical (combined category)
3. Infratentorial
4. Spinal cord
5. Optic nerve

• No distinction is made between symptomatic and asymptomatic MRI lesions 1
• Lesions should show perivenular orientation (central vein sign)—highly specific for MS 1
• Lesions typically affect the inferior corpus callosum asymmetrically 1

Dissemination in Time (DIT)

DIT can be demonstrated by: 1

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

Critical Red Flags Suggesting Alternative Diagnosis

Clinical Red Flags

• Age younger than 10 or older than 59 years 1, 4
• Bilateral sudden hearing loss 1
• Sudden onset of focal neurologic symptoms 1
• Gaze-evoked or downbeat nystagmus 1
• Concurrent severe bilateral vestibular loss 1
• Progressive onset without relapses 1
• Unusual presentations: dementia, epilepsy, aphasia 1

MRI Red Flags

• Atypical MRI lesions (odds ratio 11.0 for alternative diagnosis) 5
• Absence of dissemination in space (odds ratio 5.2 for alternative diagnosis) 5
• Lesions not following typical MS distribution 1
• Atypical contrast-enhancement patterns 1

Laboratory Red Flags

• Absence of CSF oligoclonal bands (strongest predictor of alternative diagnosis) 5
• CSF pleocytosis >50 cells/mm³ 1

Essential Exclusion Testing

Before diagnosing MS, actively exclude these mimics based on clinical context: 1, 2

• Neuromyelitis optica spectrum disorder (NMOSD): Check AQP4-IgG antibodies—NMOSD shows longitudinally extensive transverse myelitis (≥3 vertebral segments) and different brain lesion patterns 1, 2
• MOG-antibody disease: Test for MOG antibodies 1
• Vascular disorders: Consider antiphospholipid antibodies, lupus serologies in young adults with vascular risk factors 1, 2
• Infections: HTLV-1, Lyme serology, syphilis testing based on clinical context 1, 2
• Vitamin B12 deficiency 6
• Sarcoidosis, systemic lupus erythematosus, Sjögren's syndrome 6

Diagnostic Algorithm by Clinical Scenario

≥2 Attacks + ≥2 Objective Lesions

• No additional testing required if clinical presentation is typical 1
• Critical caveat: If tests are performed and return negative or atypical, exercise extreme caution before confirming MS—actively consider alternative diagnoses 1

≥2 Attacks + 1 Objective Lesion

• Demonstrate DIS on MRI (≥2 of 5 locations) AND positive CSF (oligoclonal bands or elevated IgG index) 1

1 Attack + ≥2 Objective Lesions

• Demonstrate DIT through simultaneous enhancing/non-enhancing lesions, new lesions on follow-up MRI ≥3 months later, or second clinical attack 1

1 Attack + 1 Objective Lesion

• Demonstrate both DIS and DIT through MRI criteria or combination of MRI + positive CSF 1

Progressive Symptoms Without Attacks (Suspected Primary Progressive MS)

• Mandatory positive CSF with oligoclonal bands or elevated IgG index 1, 2
• DIS requires: ≥9 T2 brain lesions, OR ≥2 spinal cord lesions, OR 4-8 brain lesions + 1 spinal cord lesion 1
• DIT requires: continuous clinical progression for ≥1 year OR new MRI lesions on follow-up 1

Age-Specific Modifications

Pediatric Patients (<11 years)

• Require at least one T1 hypointense ("black-hole") lesion AND at least one periventricular lesion at baseline 1
• Serial MRI follow-up is essential to document new lesions over time 1

Older Adults (>50 years or with vascular risk factors)

• Require higher burden of periventricular lesions (≥3 abutting lateral ventricles) to distinguish from age-related white matter changes 1
• VEP becomes particularly valuable in this population 1

Follow-Up Strategy When Initial Criteria Not Met

• If baseline MRI shows lesions but doesn't fulfill DIS/DIT criteria, repeat brain MRI at 3-6 months 1
• If second scan is inconclusive, obtain third scan at 6-12 months 1
• Patients with normal examination, normal MRI, and normal CSF do not develop MS even with persistent symptoms—costly serial investigations should be avoided 3

Common Pitfalls to Avoid

• Never diagnose MS on MRI alone—clinical correlation is mandatory 1, 4
• Never diagnose MS based on symptoms without objective findings—this leads to misdiagnosis 2, 3
• Never ignore absent oligoclonal bands—this is the strongest predictor of an alternative diagnosis 5
• Never use non-standardized MRI protocols—poor quality imaging leads to misdiagnosis 1, 4
• Never assume a positive test for an MS mimic excludes MS—comorbidities can coexist 7
• In real-life practice, 24.4% of patients with suspected MS have alternative diagnoses, most commonly nonspecific neurologic symptoms with atypical vascular lesions (40 cases), migraine with atypical lesions (24 cases), and neuromyelitis optica (14 cases) 5