Multiple Sclerosis Diagnosis
Diagnostic Criteria
MS diagnosis requires demonstrating inflammatory-demyelinating CNS injury disseminated in both space and time, with no better alternative explanation for the clinical presentation. 1
The diagnostic approach depends on the clinical scenario:
Clinical Scenarios and Required Evidence
Two or more attacks with objective evidence of two or more lesions: No additional testing required for MS diagnosis, though MRI, CSF, or other tests would typically be abnormal if performed 1
Two or more attacks with objective evidence of one lesion: Requires demonstration of dissemination in space through MRI (meeting specific criteria below) or positive CSF analysis 1
One attack with objective evidence of two or more lesions: Requires demonstration of dissemination in time through follow-up MRI (≥3 months after clinical event) showing new lesions, or a second clinical attack 1, 2
One attack with objective evidence of one lesion: Requires demonstration of both dissemination in space AND time 1
Insidious neurological progression suggestive of MS: Requires demonstration of dissemination in space and time, or continued progression for one year 1
Defining Clinical Attacks
An attack must last at least 24 hours and represent true neurological dysfunction, not pseudoattacks from fever or infection 3
Separate attacks must be separated by at least 30 days from onset of the first event to onset of the second event 3
Single paroxysmal episodes (e.g., one tonic spasm) do not constitute a relapse, but multiple episodes over 24 hours do 3
MRI Criteria
Dissemination in Space (DIS)
MRI is the most sensitive and specific test for MS diagnosis and can independently establish the diagnosis when specific criteria are met. 2, 3
Requires at least one T2 lesion in at least 2 of 5 locations: 2
- Three or more periventricular lesions
- Cortical/juxtacortical lesions
- Infratentorial lesions
- Spinal cord lesions
- Optic nerve lesions
Alternative older criteria: Three of four of the following: one gadolinium-enhancing lesion or nine T2-hyperintense lesions if no gadolinium enhancement, at least one infratentorial lesion, at least one juxtacortical lesion, or at least three periventricular lesions 1
No distinction is needed between symptomatic and asymptomatic MRI lesions for DIS 2
Dissemination in Time (DIT)
Presence of both gadolinium-enhancing and non-enhancing lesions on a single MRI scan demonstrates DIT 3
Alternatively, a new T2 or gadolinium-enhancing lesion on follow-up MRI (≥3 months after clinical event) compared with baseline demonstrates DIT 1, 3
No distinction is needed between symptomatic and asymptomatic MRI lesions for DIT 2
CSF Analysis
CSF analysis should be routinely performed in patients with a first clinical event suggestive of MS, particularly when MRI criteria fall short or clinical presentation is atypical. 2
Positive CSF Criteria
Oligoclonal IgG bands detected by isoelectric focusing that are different from any bands in serum, OR elevated IgG index 1, 2
Lymphocytic pleocytosis should be less than 50/mm³ 1
Role in Diagnosis
The presence of two or more MRI lesions consistent with MS plus positive CSF can substitute for full MRI DIS criteria 2
CSF analysis is particularly helpful when imaging criteria fall short, clinical presentation is atypical, or in older patients where MRI findings may lack specificity 1
Quality of CSF analysis varies between laboratories; testing should be done with state-of-the-art technology to avoid misdiagnosis 1
Additional Diagnostic Tests
Visual evoked potentials (VEP) showing delay with well-preserved waveform can provide objective evidence of a second lesion, particularly useful when the only clinically expressed lesion did not affect visual pathways 1, 3
VEPs are especially valuable in older individuals with vascular risk factors where MRI findings have less specificity 3
Biopsy should rarely be undertaken but can confirm the inflammatory and demyelinating nature of lesions; however, it cannot on its own lead to a diagnosis of MS 1, 3
Diagnostic Outcomes
If criteria are fulfilled: Diagnosis is MS 1
If criteria are not completely met: Diagnosis is "possible MS" 1
If criteria are fully explored and not met: Diagnosis is "not MS" 1
The outdated terms "clinically definite," "laboratory-supported definite MS," "clinically probable MS," and "laboratory-supported probable MS" are no longer recommended 3
Critical Pitfalls and Differential Diagnosis
Alternative diagnoses must always be considered—if tests (MRI, CSF) are negative or atypical, extreme caution should be taken before making an MS diagnosis. 1, 2
High-Risk Populations Requiring Extra Caution
Progressive onset without clear relapses 1
Atypical presentations including dementia, epilepsy, or aphasia 3
In older individuals, MRI findings may have less specificity due to microvascular ischemic disease 3
Key Differential Diagnoses to Exclude
Cerebral ischemia/infarction in young adults: Consider phospholipid antibody syndrome, lupus, CADASIL 1
Infections: HTLV-1, Lyme disease, syphilis 1
Paraneoplastic disorders 1
Monophasic demyelinating diseases: Acute disseminated encephalomyelitis, neuromyelitis optica (Devic's syndrome) 1
Genetic disorders of myelin: Leukodystrophies in children and teenagers 1
Recommended Testing Based on Clinical Context
Consider antiphospholipid antibodies, lupus serologies, HTLV-1, Lyme serology, and syphilis testing based on clinical context 1
Consider genetic testing for leukodystrophies in children and teenagers 1
MRI Features Suggesting Alternative Diagnoses
Persistent gadolinium enhancement greater than three months 4
Lesions with mass effect 4
Meningeal enhancement 4
MRI Features Favoring MS
Dawson Fingers (perivenular orientation) 4
Ovoid lesions 4
Corpus callosum lesions 4
Asymptomatic spinal cord lesions 4
Diagnostic Protocol
Initial Evaluation
Obtain brain and spinal cord MRI with gadolinium contrast 1, 3
Perform CSF analysis with oligoclonal bands and IgG index 2
Obtain baseline MRI prior to initiating therapy, which is helpful in differentiating subsequent MS symptoms from complications like PML 5
Timing Considerations
Careful consideration of timing between clinical events and MRI scans is crucial for establishing dissemination in time 1
After plasma exchange (PLEX), wait at least two weeks to test for anti-JCV antibodies to avoid false negative results 5
After intravenous immunoglobulin (IVIg), wait at least 6 months for clearance to avoid false positive anti-JCV antibody test results 5