What are the revised McDonald criteria 2024 for diagnosing and treating multiple sclerosis (MS) in a patient presenting with a clinically isolated syndrome (CIS)?

Revised McDonald Criteria 2024 for Multiple Sclerosis Diagnosis

The 2024 McDonald criteria introduce three major changes: the optic nerve now counts as a fifth anatomical location for dissemination in space (DIS), CSF-specific oligoclonal bands can substitute for dissemination in time (DIT), and radiologically isolated syndrome can now be classified as MS when specific conditions are met. 1, 2

Key Changes in the 2024 Revision

Dissemination in Space (DIS) - Now Five Locations

• DIS requires lesions in at least 2 of 5 CNS locations: periventricular, cortical/juxtacortical (combined category), infratentorial, spinal cord, and optic nerve (newly added) 1, 2
• The optic nerve inclusion is particularly valuable for patients presenting with optic neuritis, as symptomatic optic nerve lesions detected on fat-saturated MRI sequences now contribute to DIS 2
• At least 3 periventricular lesions are required when counting the periventricular region 3

Dissemination in Time (DIT) - Expanded Options

• DIT can be demonstrated through three pathways: simultaneous gadolinium-enhancing and non-enhancing lesions on a single MRI, new T2 or gadolinium-enhancing lesions on follow-up MRI (≥3 months after baseline), or CSF-specific oligoclonal bands 1, 2
• This CSF biomarker addition allows for MS diagnosis without requiring follow-up imaging when oligoclonal bands are present 1

Radiologically Isolated Syndrome (RIS)

• RIS can now be classified as MS when patients have typical MRI lesions fulfilling DIS criteria plus either DIT criteria or CSF-specific oligoclonal bands, even without clinical symptoms 1, 2
• This represents a significant shift, allowing diagnosis before clinical manifestations appear 2

Advanced Imaging Biomarkers (Optional but High Specificity)

Central Vein Sign and Paramagnetic Rim Lesions

• The 2024 criteria incorporate two optional high-specificity markers identified on susceptibility-sensitive MRI sequences (T2*-weighted or susceptibility-weighted imaging) 1, 2
• Central vein sign: perivenular orientation of lesions, highly specific for MS and useful when conventional findings are ambiguous 4, 2
• Paramagnetic rim lesions: indicate chronic active inflammation and help distinguish MS from mimics 2
• These markers are particularly valuable in diagnostically challenging cases but are not required for standard diagnosis 2

Clinical Scenarios and Diagnostic Pathways

Two or More Attacks with Two or More Objective Lesions

• MS diagnosis is confirmed without additional testing, though MRI and CSF would typically be abnormal if performed 3

Two or More Attacks with One Objective Lesion

• Requires demonstration of DIS through MRI (lesions in ≥2 of 5 locations) or CSF oligoclonal bands 3

One Attack with Two or More Objective Lesions

• Requires demonstration of DIT through: simultaneous enhancing and non-enhancing lesions, new lesions on follow-up MRI, second clinical attack, or CSF oligoclonal bands 3, 1

One Attack with One Objective Lesion (CIS)

• Requires both DIS and DIT to be demonstrated 3
• The 2024 criteria show 13.7% higher diagnostic yield compared to 2017 criteria in this population, particularly when 4-5 topographies are involved 5

Primary Progressive MS

• Requires one year of disability progression plus DIS (≥2 of 5 locations) and either DIT (new MRI lesions) or CSF oligoclonal bands 3

Critical MRI Technical Requirements

Minimum Standards

• Field strength: at least 1.5T (3T preferred) 3
• Maximum slice thickness: 3mm with no gap between slices 4, 3
• In-plane spatial resolution: 1×1mm 3

Required Sequences

• Brain imaging: axial T2-weighted and T2-FLAIR, sagittal T2-FLAIR (to evaluate corpus callosum), gadolinium-enhanced T1-weighted sequences 3
• Optic nerve imaging: fat-saturated sequences (T2-weighted with fat suppression or STIR) to detect symptomatic optic nerve lesions 2
• Spinal cord imaging: whole spinal cord (cervical, thoracic, lumbar) with T2-weighted and gadolinium-enhanced T1-weighted sequences 4, 3
• Susceptibility-sensitive sequences: T2*-weighted or SWI for central vein sign and paramagnetic rim lesions (optional but recommended) 2

Lesion Characteristics That Support MS Diagnosis

• Periventricular location with asymmetric involvement of inferior corpus callosum 3
• Perivenular orientation (Dawson's fingers) 4, 3
• Ovoid morphology perpendicular to ventricles 4
• Juxtacortical lesions extending to cortical gray matter 4

Age-Specific Modifications and Stricter Thresholds

Patients Over Age 50 or With Vascular Risk Factors

• More stringent criteria required: higher number of periventricular lesions (abutting lateral ventricles) to distinguish from age-related white matter changes 4, 1
• Careful evaluation for vascular mimics including small vessel disease, CADASIL, and cerebral ischemia 3

Pediatric Patients (10-17 Years)

• Criteria apply well to children over 11 years 4
• For children under 11 years: at least one T1 hypointense lesion (black hole) and at least one periventricular lesion help distinguish MS from monophasic demyelination 4, 6
• Special caution needed as differential diagnosis includes acute disseminated encephalomyelitis (ADEM) and genetic leukodystrophies 3

Patients With Headache Disorders

• Stricter diagnostic thresholds applied to avoid misdiagnosis, as migraine-associated white matter lesions can mimic MS 1

Critical Diagnostic Pitfalls to Avoid

Red Flags Suggesting Non-MS Diagnosis

• Bilateral sudden hearing loss or isolated eighth nerve palsy (extremely rare in MS, <1%) 3
• Sudden onset focal neurologic symptoms (more suggestive of stroke) 3
• Gaze-evoked or downbeat nystagmus 3
• Concurrent severe bilateral vestibular loss 3
• Lesions that do not follow typical MS distribution patterns 4

Common Mimics Requiring Exclusion

• Vascular disorders: small vessel disease, CADASIL, antiphospholipid syndrome, lupus cerebritis 3
• Infections: Lyme disease, HTLV-1, neurosyphilis 3
• Antibody-mediated diseases: neuromyelitis optica spectrum disorders (NMOSD), MOG-antibody disease 4
• Age-related changes: periventricular capping on T2-weighted images in older patients 4
• Monophasic demyelination: ADEM, particularly in pediatric cases 3

Quality Control Measures

• Never diagnose MS on MRI alone - at least one clinical event consistent with acute demyelination is essential 6
• Confirm lesions on multiple planes to avoid false positives from artifacts 4
• Ensure high-quality paraclinical testing, as poor quality leads to misdiagnosis 3
• If tests are negative or atypical, extreme caution is required before making MS diagnosis 3

CSF Analysis Integration

When CSF is Particularly Valuable

• Imaging criteria fall short of DIS or DIT requirements 3
• Clinical presentation is atypical 3
• Older patients where MRI findings may lack specificity 3
• Can substitute for DIT when oligoclonal bands are present 1, 2

CSF Criteria

• Positive CSF: oligoclonal IgG bands (detected by isoelectric focusing) different from serum bands, or elevated IgG index 3
• Lymphocytic pleocytosis should be <50/mm³ 3
• Quality of CSF analysis varies between laboratories - use state-of-the-art technology 3

Diagnostic Outcomes and Follow-Up Strategy

If Criteria Are Fulfilled

• Diagnosis is MS 3
• Consider early disease-modifying therapy, particularly high-efficacy DMTs for active disease 7

If Criteria Are Not Completely Met

• Diagnosis is "possible MS" 3
• Repeat brain MRI at 3-6 months if baseline shows lesions but doesn't fulfill DIS/DIT 3
• If second scan is inconclusive, obtain third scan at 6-12 months 3

If Criteria Are Fully Explored and Not Met

• Diagnosis is "not MS" 3
• Pursue alternative diagnoses aggressively 3

Impact of 2024 Revisions on Clinical Practice

Increased Diagnostic Yield

• The 2024 criteria identify 13.7% more MS cases compared to 2017 criteria, with low concordance (κ = 0.112) 5
• Greatest gains occur in: patients <50 years (+27 cases), typical clinical presentations (+26 cases), and those with 4-5 MRI topographies (+27 cases) 5
• Key contributors include optic nerve inclusion (51.9% of additional cases) and ability to diagnose with four topographies without requiring DIT (74.1% of additional cases) 5

No Change in Older or Atypical Presentations

• Complete concordance (κ = 1.0) between 2017 and 2024 criteria in patients ≥50 years and atypical presentations, reflecting maintained specificity in high-risk groups 5