What are the diagnostic criteria for multiple sclerosis (MS)?

Diagnostic Criteria for Multiple Sclerosis

Core Diagnostic Framework

The diagnosis of MS requires demonstrating inflammatory-demyelinating lesions disseminated in both space (DIS) and time (DIT) through MRI combined with clinical assessment, while excluding alternative diagnoses. 1, 2, 3

The diagnosis fundamentally rests on three pillars:

• Clinical evidence of CNS involvement separated in time and space 2, 4
• MRI demonstration of characteristic lesion patterns 1, 3
• Exclusion of conditions that mimic MS 1, 3

Clinical Requirements for Diagnosis

Defining an Attack

• Must last at least 24 hours and represent objective neurological dysfunction, not pseudoattacks from fever or infection 1, 2
• Separate attacks must be separated by at least 30 days from onset to onset 1, 2
• Multiple paroxysmal episodes occurring over 24 hours count as a single attack; isolated single episodes do not constitute a relapse 1
• Objective clinical findings are mandatory—symptoms alone are insufficient for diagnosis 2, 3

Diagnostic Scenarios Based on Clinical Presentation

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

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

Two or more attacks with objective evidence of one lesion:

• Requires demonstration of DIS through MRI or positive CSF 2, 3

One attack with objective evidence of two or more lesions:

• Requires demonstration of DIT through MRI (simultaneous enhancing and non-enhancing lesions, or new lesions on follow-up) or a second clinical attack 2, 3

One attack with objective evidence of one lesion:

• Requires demonstration of both DIS and DIT 2, 3

Insidious neurological progression suggestive of MS (Primary Progressive MS):

• Requires demonstration of DIS and DIT, or continued progression for one year 2
• Consider CSF results for clinically uncertain PPMS cases 5
• Use identical DIS criteria as for relapse-onset MS 5

MRI Criteria for Dissemination in Space (DIS)

DIS requires lesions in at least 2 of 5 CNS locations: 5, 1, 2, 3

1. Periventricular: ≥3 lesions required (increased from prior single lesion requirement to improve specificity) 5
2. Cortical/juxtacortical: Combines cortical and juxtacortical lesions into single category 5, 1, 2
3. Infratentorial: At least one lesion 5, 1
4. Spinal cord: At least one lesion 5, 1
5. Optic nerve: Newly added as fifth CNS location 5, 1, 2

Key MRI Specifications

• No distinction between symptomatic and asymptomatic lesions for both DIS and DIT 5, 1
• Whole spinal cord imaging is recommended to define DIS, particularly when brain MRI doesn't fulfill DIS criteria 5, 1
• Limited role of spinal cord imaging for DIT 5

Critical Lesion Characteristics

• Lesions typically affect the inferior corpus callosum asymmetrically 2
• Perivenular orientation is highly specific for MS (central vein sign) 2
• Lesions should be evaluated for both individual characteristics and overall pattern 2

MRI Criteria for Dissemination in Time (DIT)

DIT can be demonstrated by: 1, 2

• Simultaneous presence of gadolinium-enhancing and non-enhancing lesions on a single MRI (not at site of original clinical event) 1, 2
• New T2 or gadolinium-enhancing lesion on follow-up MRI (≥3 months after baseline) compared to baseline scan 1, 2
• A second clinical attack 1, 2

The DIT criteria remain unchanged from prior revisions 5

Technical MRI Requirements

Minimum technical specifications: 2

• Field strength: At least 1.5 Tesla
• Maximum slice thickness: 3mm
• In-plane spatial resolution: 1×1mm
• Scan duration: 25-30 minutes

Required sequences: 2

• Axial T2-weighted and proton-density (or T2-FLAIR)
• Sagittal T2-FLAIR to evaluate corpus callosum
• Gadolinium-enhanced T1-weighted sequences

Cerebrospinal Fluid Analysis

Positive CSF is defined as: 1, 2, 3

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

When to Obtain CSF

CSF analysis is particularly valuable when: 1, 2, 3

• Imaging criteria fall short of diagnostic thresholds
• Clinical presentation is atypical
• Patient is older (>59 years) where MRI findings may lack specificity due to vascular changes
• Evaluating for PPMS with uncertain clinical features 5

Important caveat: Quality of CSF analysis varies between laboratories—testing should use state-of-the-art technology (isoelectric focusing) to avoid misdiagnosis 2

Additional Diagnostic Tests

Visual Evoked Potentials (VEP)

• Provides objective evidence of a second lesion when only one clinical lesion is apparent 1, 2
• Particularly useful in PPMS with progressive myelopathy 2
• Helpful in older patients with vascular risk factors where MRI has lesser specificity 1, 2
• Shows delay with well-preserved waveform in MS 1

Biopsy

• Rarely needed but can confirm inflammatory demyelination when diagnosis remains uncertain despite comprehensive workup 2, 3
• Cannot alone establish MS diagnosis—only confirms lesion is inflammatory and demyelinating 1, 3
• Requires interpretation by neuropathologists experienced in demyelinating diseases 3

Diagnostic Categories and Outcomes

After evaluation, patients are classified as: 1, 2

• MS (if criteria fulfilled)
• Possible MS (if criteria not completely met but suspicion remains)
• Not MS (if criteria fully explored and not met)

Outdated terms no longer recommended: "clinically definite," "laboratory-supported definite MS," "clinically probable MS," "laboratory-supported probable MS" 1, 2

Special Populations Requiring Caution

Age-Related Considerations

Patients >59 years or <10 years require special care: 2, 3

• MRI findings may have lesser specificity in older patients due to microvascular ischemic disease 1, 2
• Periventricular capping on T2-weighted images in older patients represents age-related changes 2
• Patients over 50 with vascular risk factors require more stringent criteria, including higher number of periventricular lesions 2

Pediatric Patients

Children ≥11 years with non-ADEM presentation: 5

• Use identical MRI DIS and DIT criteria as adults

Children <11 years: 5

• Use caution when applying criteria solely at baseline, even with non-ADEM presentation
• Clinical and MRI serial evaluation to confirm new lesions over time is particularly important
• At least one T1 hypointense lesion and one periventricular lesion help distinguish MS from monophasic demyelination 2

Progressive Onset

Patients with progressive onset from disease start require additional scrutiny and consideration of alternative diagnoses 2, 3

Atypical Presentations

Exercise extreme caution with: 2, 3

• Dementia as presenting feature
• Epilepsy as presenting feature
• Aphasia as presenting feature
• Isolated cranial nerve involvement (rare in MS at 10.4%) 2
• Isolated eighth nerve palsy (extremely rare, <1%) 2

Critical Differential Diagnoses to Exclude

Antibody-Mediated Diseases (Must Exclude)

Neuromyelitis Optica Spectrum Disorder (NMOSD): 2, 3

• Check AQP4-IgG antibodies
• Shows longitudinally extensive transverse myelitis
• Different brain lesion patterns than MS

MOG-antibody disease: 2

• Must be excluded before MS diagnosis

Other Conditions to Consider Based on Clinical Context

Vascular disorders: 2, 3

• Phospholipid antibody syndrome (check antiphospholipid antibodies)
• Systemic lupus erythematosus (lupus serologies)
• CADASIL
• Takayasu's disease
• Meningovascular syphilis (syphilis testing)
• Carotid dissection

Infections: 2, 3

• HTLV-1 (HTLV-1 testing)
• Lyme disease (Lyme serology)
• Syphilis (syphilis testing)

Monophasic demyelinating diseases: 2, 3

• Acute disseminated encephalomyelitis (ADEM)
• Devic's syndrome

Genetic disorders: 2, 3

• Leukodystrophies (particularly in children and teenagers—consider genetic testing)

Paraneoplastic disorders: 2, 3

• Cerebellar ataxia and other paraneoplastic syndromes

Red Flags Suggesting Non-MS Diagnosis

Clinical red flags: 2

• Bilateral sudden hearing loss
• Sudden onset of focal neurologic symptoms
• Gaze-evoked or downbeat nystagmus
• Concurrent severe bilateral vestibular loss
• Isolated cranial nerve involvement

Imaging red flags: 2

• Lesions not following typical MS distribution patterns
• Lesion patterns more consistent with vascular disease in older patients

Quality Control and Diagnostic Pitfalls

Critical Quality Measures

Never diagnose MS on MRI alone—clinical correlation is mandatory 2

Ensure high-quality paraclinical testing: 2, 3

• Poor quality MRI, CSF analysis, or evoked potentials can lead to misdiagnosis
• Use state-of-the-art technology
• Confirm lesions on multiple imaging planes 2

Common Pitfalls to Avoid

• Misinterpreting MRI in patients with few lesions carries high risk of misdiagnosis 2
• If tests are negative or atypical, extreme caution should be taken before making MS diagnosis 2, 3
• A positive test for a putative MS "mimic" does not exclude MS diagnosis 4
• Both individual lesion characteristics AND overall lesion patterns must be evaluated 2

Follow-Up Strategy When Initial Imaging Inconclusive

If baseline MRI shows lesions but doesn't fulfill DIS/DIT criteria: 2

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

Radiologically Isolated Syndrome (RIS)

Apply identical DIS and DIT MRI criteria as used for MS: 5

• When a clinical attack occurs in RIS-DIT positive subjects (who by definition have DIS), MS diagnosis can be made 5

Geographic Considerations

MRI criteria apply equally well to MS in Asia and Latin America, once alternative neurological conditions (especially NMOSD) have been carefully excluded 5