What is the recommended diagnostic workup for a patient in whom multiple sclerosis is suspected?

Multiple Sclerosis Diagnostic Workup

The diagnostic workup for suspected MS requires brain and spinal cord MRI with gadolinium as the primary test, combined with clinical assessment to demonstrate dissemination in space and time, with CSF analysis reserved for cases where imaging is equivocal or the presentation is atypical. 1

Initial Clinical Assessment

Obtain objective neurological findings—subjective symptoms alone are insufficient for diagnosis. 1 Focus your history on prior episodes of:

• Unilateral optic neuritis (vision loss developing over days) 2
• Partial myelitis with sensory level or bladder dysfunction 2
• Brainstem syndromes (internuclear ophthalmoplegia, diplopia) 2
• Sensory disturbances in limbs or trunk 2
• Lhermitte's phenomenon (electric shock sensation down spine with neck flexion) 3

An "attack" must last ≥24 hours and represent true neurological dysfunction, not pseudoattacks from fever or infection. 4 Separate attacks must be ≥30 days apart from onset to onset. 4

MRI Protocol (First-Line Diagnostic Test)

Perform brain and spinal cord MRI with gadolinium immediately in all suspected cases. 1 This is the single most sensitive and specific test for MS diagnosis. 4

Required MRI Sequences:

• Axial T2-weighted and T2-FLAIR sequences 1
• Sagittal T2-FLAIR (to evaluate corpus callosum) 1
• Gadolinium-enhanced T1-weighted sequences 1
• Fat-suppressed sequences for spinal cord 1
• Fat-suppressed sequences for optic nerves (in atypical presentations) 1

Technical Requirements:

• Minimum 1.5T field strength 1
• Maximum 3mm slice thickness with no inter-slice gap 1
• In-plane spatial resolution of 1×1mm 1

Dissemination in Space (DIS) Criteria

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

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

Critical imaging characteristics that confirm MS lesions: 1

• Perivenular orientation (highly specific for MS) 1
• Lesions affecting inferior corpus callosum asymmetrically 1
• Ovoid lesions perpendicular to ventricles (Dawson's fingers) 1

Dissemination in Time (DIT) Criteria

DIT can be demonstrated by any of the following: 1

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

Diagnostic Algorithm by Clinical Presentation

≥2 Attacks + ≥2 Objective Lesions

No additional testing required if clinical picture is typical. 1 However, if you perform MRI/CSF and results are negative or atypical, exercise extreme caution before diagnosing MS and actively consider alternative diagnoses. 1

≥2 Attacks + 1 Objective Lesion

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

1 Attack + ≥2 Objective Lesions

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

1 Attack + 1 Objective Lesion

Both DIS and DIT must be satisfied through MRI criteria, or MRI combined with positive CSF. 1 This typically represents clinically isolated syndrome requiring the most comprehensive workup. 2

Insidious Progressive Course (Suspected Primary Progressive MS)

Requires all of the following: 5, 1

• Abnormal CSF with oligoclonal bands or elevated IgG index (mandatory) 5
• DIS demonstrated by: ≥9 T2 brain lesions OR ≥2 spinal cord lesions OR 4-8 brain lesions plus 1 spinal cord lesion 1
• DIT demonstrated by: continuous clinical progression for ≥1 year OR new MRI lesions on follow-up 1

CSF Analysis (When to Obtain)

Perform lumbar puncture in the following scenarios: 1

• Imaging criteria fall short of DIS/DIT requirements 1
• Atypical clinical presentation 1
• Age >50 years (to distinguish from vascular disease) 1
• Suspected primary progressive MS (mandatory) 5

Positive CSF is defined as: 1

• Oligoclonal IgG bands (by isoelectric focusing) different from serum bands, OR
• Elevated IgG index
• Lymphocytic pleocytosis should be <50/mm³ 5

Visual Evoked Potentials (Adjunctive Test)

Consider VEP when: 1, 4

• MRI shows few lesions or has lesser specificity 4
• Patient has progressive myelopathy (suspected PPMS) 1
• Older patients with vascular risk factors 4

Abnormal VEP shows delayed latency with preserved waveform morphology. 1

Critical Differential Diagnoses to Exclude

Always test for these MS mimics based on clinical context: 1

Mandatory Exclusions:

• Neuromyelitis optica spectrum disorder (NMOSD): Check AQP4-IgG antibodies, especially with longitudinally extensive transverse myelitis (≥3 vertebral segments) 1
• MOG-antibody disease: Check MOG-IgG antibodies 1

Context-Dependent Testing:

• Antiphospholipid antibodies and lupus serologies (young adults with stroke-like presentations) 1
• Lyme serology (endemic areas) 1
• HTLV-1 serology (endemic areas, progressive myelopathy) 1
• Syphilis testing (atypical presentations) 1

Red Flags Suggesting Non-MS Diagnosis

Age-related red flags: 1

• Age <10 years or >59 years requires more stringent criteria 1
• In patients >50 years, require ≥3 periventricular lesions to distinguish from age-related white matter changes 1

Clinical red flags: 1

• Bilateral sudden hearing loss 1
• Isolated cranial nerve involvement (rare in MS, <10%) 1
• Dementia, epilepsy, or aphasia as presenting features 4
• Gaze-evoked or downbeat nystagmus 1

MRI red flags: 1

• Atypical contrast-enhancement patterns 1
• Lesions in regions not typical for MS 1
• Absence of perivenular orientation 1

Pediatric Considerations (<11 Years)

Require at baseline MRI: 1

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

Follow-Up Imaging Strategy

If baseline MRI shows lesions but doesn't fulfill DIS/DIT: 1

• Repeat brain MRI at 3-6 months 1
• If second scan is inconclusive, obtain third scan at 6-12 months 1

Diagnostic Outcome Categories

After completing the workup, assign one of three diagnoses: 1

• Multiple Sclerosis: All required criteria fulfilled 1
• Possible Multiple Sclerosis: Criteria not fully met but patient remains at risk 1
• Not Multiple Sclerosis: Criteria exhaustively evaluated and not met, or alternative diagnosis identified 1

Common Pitfalls to Avoid

Never diagnose MS on MRI alone without clinical correlation. 1 The diagnosis requires both clinical and radiographic evidence of dissemination in space and time. 5

Do not mistake age-related white matter changes for MS lesions. In patients >50 years, periventricular capping on T2-weighted images is common and non-specific. 1

Ensure high-quality paraclinical testing. Poor quality MRI, CSF analysis, or evoked potentials can lead to misdiagnosis. 5, 1

A positive test for an MS mimic does not automatically exclude MS. Some patients may have coexisting conditions. 6 However, if alternative diagnoses better explain the clinical picture, do not diagnose MS. 5

Biopsy is rarely indicated but can confirm inflammatory demyelination when diagnosis remains uncertain despite comprehensive workup. 1 However, biopsy alone cannot diagnose MS—it only confirms the lesion is inflammatory and demyelinating. 4