What are the steps to diagnose multiple sclerosis (MS)?

Diagnosing Multiple Sclerosis

The diagnosis of MS requires demonstrating inflammatory-demyelinating CNS lesions disseminated in both space and time, combined with clinical evidence and exclusion of alternative diagnoses—this cannot be made on MRI alone and requires at least one clinical event consistent with acute demyelination. 1, 2

Core Diagnostic Requirements

The fundamental principle is proving dissemination in space (multiple CNS locations) and time (lesions occurring at different times), while ruling out MS mimics. 2, 3

Clinical Scenarios and Required Evidence

Two or more attacks with objective evidence of two or more lesions:

• No additional testing required for diagnosis (though MRI/CSF would typically be abnormal if performed) 2

Two or more attacks with objective evidence of one lesion:

• Requires demonstration of dissemination in space via MRI (see criteria below) or positive CSF analysis 2

One attack with objective evidence of two or more lesions:

• Requires demonstration of dissemination in time via MRI or a second clinical attack 2

One attack with objective evidence of one lesion:

• Requires demonstration of both dissemination in space AND time 2

Insidious neurological progression suggestive of MS:

• Requires demonstration of dissemination in space and time, OR continued progression for one year 2

MRI Criteria (Essential Component)

MRI is the most sensitive and specific paraclinical test for MS diagnosis. 3 Scans must be performed on scanners with minimum 1.5T field strength using appropriate protocols. 4

Dissemination in Space Requires 3 of 4:

• One gadolinium-enhancing lesion OR nine T2-hyperintense lesions (if no gadolinium enhancement)
• At least one infratentorial lesion
• At least one juxtacortical lesion
• At least three periventricular lesions (abutting the lateral ventricles) 4, 2

Dissemination in Time Demonstrated By:

• Gadolinium-enhancing lesion (not at site of original event) on scan ≥3 months after clinical event, OR
• New T2 lesion on follow-up scan compared to baseline 2, 3

Key imaging requirement: At least one typical MS lesion in at least two characteristic regions (periventricular, juxtacortical, infratentorial, and spinal cord). 4

Essential MRI Sequences:

• T2-weighted and T2-FLAIR for brain
• T1 post-gadolinium for brain and spinal cord
• Cervical, thoracic, and lumbar spine imaging (MS lesions can occur anywhere in CNS) 4

Cerebrospinal Fluid Analysis

CSF analysis is particularly valuable when imaging criteria fall short, clinical presentation is atypical, or in older patients where MRI findings may lack specificity. 2, 3

Positive CSF Defined As:

• Oligoclonal IgG bands (detected by isoelectric focusing) different from serum bands, OR
• Elevated IgG index
• Lymphocytic pleocytosis should be <50/mm³ 2

Additional Diagnostic Tests

Visual Evoked Potentials (VEP):

• Can provide objective evidence of a second lesion, particularly when the only clinical lesion did not affect visual pathways 2
• Especially useful in older patients with vascular risk factors where MRI has less specificity 3

Age-Specific Considerations

Pediatric cases (under age 11):

• Require special diagnostic care
• Presence of at least one black hole (T1-hypointense lesion) AND at least one periventricular lesion helps distinguish MS from monophasic demyelination 4, 1

Patients older than 50 years or with vascular risk factors:

• Apply more stringent criteria (e.g., higher number of periventricular lesions)
• MRI findings have less specificity due to microvascular ischemic disease 4, 1, 3

Typical presentations apply best to ages 10-59 years. 1

Critical Differential Diagnoses to Exclude

Must always consider and rule out:

• Neuromyelitis optica spectrum disorder (NMOSD) 1
• Cerebrovascular disease (multifocal ischemia/infarction, especially with phospholipid antibody syndrome, lupus, CADASIL) 1, 2
• Infectious diseases (HTLV-1, Lyme disease, syphilis) 1, 2
• Paraneoplastic disorders 1, 2
• Monophasic demyelinating diseases (acute disseminated encephalomyelitis, Devic's syndrome) 1, 2
• Genetic disorders of myelin (leukodystrophies in children/teenagers) 1, 2

Consider testing based on clinical context:

• Antiphospholipid antibodies, lupus serologies
• HTLV-1, Lyme serology, syphilis testing
• Genetic testing for leukodystrophies in young patients 2

Defining Clinical Attacks

An attack must:

• Last at least 24 hours
• Represent true neurological dysfunction (not pseudoattacks from fever/infection)
• Be separated from other attacks by at least 30 days from onset to onset 3

Note: Single paroxysmal episodes (e.g., one tonic spasm) do not constitute a relapse, but multiple episodes over 24 hours do. 3

Diagnostic Outcomes

If criteria fulfilled: Diagnosis is MS 2

If criteria not completely met: Diagnosis is "possible MS" 2

If criteria fully explored and not met: Diagnosis is "not MS" 2

Critical Pitfalls to Avoid

Diagnosis should not be made solely on MRI results—at least one clinical event consistent with acute demyelination is the cornerstone. 1

• Diagnosis must be made by a specialist familiar with MS, its differential diagnoses, and interpretation of paraclinical assessments 1
• If tests (MRI, CSF) are negative or atypical, exercise extreme caution before making an MS diagnosis 2
• Ensure high-quality paraclinical analyses; poor quality MRI or CSF testing can lead to misdiagnosis 2
• Interpretation of MRI scans should be performed by trained neuroradiologists or clinicians deeply familiar with MS features 4
• Biopsy is rarely needed but can confirm inflammatory demyelinating lesions when diagnosis remains uncertain despite comprehensive workup 1, 2