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

Diagnosis of Multiple Sclerosis

Core Diagnostic Principle

MS diagnosis requires demonstrating inflammatory-demyelinating CNS injury disseminated in both space and time, with no better alternative explanation for the clinical presentation. 1, 2

The diagnosis fundamentally rests on three pillars: clinical assessment showing typical neurological dysfunction, MRI evidence of characteristic lesion patterns, and exclusion of MS mimics through careful differential diagnosis. 1, 3

Clinical Presentation Requirements

Defining an Attack

• An attack must last at least 24 hours and represent true neurological dysfunction, not pseudoattacks from fever or infection 1
• Single paroxysmal episodes (e.g., one tonic spasm) do not constitute a relapse, but multiple episodes occurring over 24 hours do 1
• Separate attacks must be separated by at least 30 days from onset of the first event to onset of the second event 1

Typical Clinical Presentations

MS typically presents in young adults aged 20-30 years with: 4, 5

• Unilateral optic neuritis
• Partial myelitis
• Sensory disturbances
• Brainstem syndromes (e.g., internuclear ophthalmoplegia)
• Symptoms develop over several days 4

MRI Diagnostic Criteria

Dissemination in Space (DIS)

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

• Periventricular (≥3 lesions required) 6
• Cortical/juxtacortical 6
• Infratentorial 1
• Spinal cord 1
• Optic nerve 6

Key 2016 MAGNIMS modifications that inform current practice: 6

• Three or more periventricular lesions are required (not just one)
• Optic nerve lesions now count as an additional CNS area
• Cortical and juxtacortical lesions are combined into a single category
• No distinction between symptomatic and asymptomatic MRI lesions for both DIS and DIT 6
• Whole spinal cord imaging is recommended 6

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 the site of the original clinical event), OR
• A new T2 or gadolinium-enhancing lesion on follow-up MRI compared with baseline (performed ≥3 months after clinical event) 2

Cerebrospinal Fluid Analysis

Positive CSF is defined as: 2

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

CSF analysis is particularly valuable when: 1, 2

• Imaging criteria fall short of full diagnostic requirements
• Clinical presentation is atypical
• Patients are older (>59 years) where MRI findings may lack specificity due to microvascular disease 1

Critical advancement: CSF oligoclonal bands can now substitute for demonstrating DIT in relapsing MS, allowing diagnosis at the time of first attack if MRI shows typical spatial distribution 7, 4

Diagnostic Algorithm by Clinical Scenario

Two or More Attacks + Two or More Objective Lesions

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

Two or More Attacks + One Objective Lesion

• Requires demonstration of DIS through: 2
  • MRI meeting spatial criteria, OR
  • Positive CSF analysis

One Attack + Two or More Objective Lesions

• Requires demonstration of DIT through: 2
  • MRI showing simultaneous enhancing and non-enhancing lesions, OR
  • New lesions on follow-up MRI, OR
  • Second clinical attack

One Attack + One Objective Lesion

• Requires demonstration of both DIS and DIT through MRI and/or CSF criteria 2

Insidious Neurological Progression (Primary Progressive MS)

• Requires demonstration of DIS and DIT, OR continued progression for one year 2
• PPMS shows less inflammatory activity on MRI (only ~5% of new lesions enhance with gadolinium vs. 80% in relapsing-remitting MS) 8

Additional Diagnostic Tests

Visual Evoked Potentials (VEPs)

• VEPs showing delay with preserved waveform can provide objective evidence of a second lesion 1, 2
• Particularly useful when: 1
  • Few MRI abnormalities are present
  • MRI findings have less specificity (older patients with vascular risk factors)
  • The only clinically expressed lesion did not affect visual pathways 2

Brain Biopsy

• Rarely needed but can confirm inflammatory demyelination 1, 2
• Cannot alone establish MS diagnosis 1

Diagnostic Outcomes

After complete evaluation, classify patients as: 1, 2

• MS - if criteria are fulfilled
• Possible MS - if criteria are not completely met (patient at risk with equivocal evaluation)
• Not MS - if criteria are fully explored and not met

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

Critical Differential Diagnoses to Exclude

Always consider these alternative diagnoses: 2

Vascular Disorders

• Cerebral ischemia/infarction in young adults (phospholipid antibody syndrome, lupus, CADASIL, Takayasu's disease, carotid dissection) 2

Infections

• HTLV-1 2
• Lyme disease 2
• Syphilis 2

Other Inflammatory/Demyelinating Conditions

• Neuromyelitis optica spectrum disorders (NMOSD) - distinct entity with anti-AQP4 antibodies 7
• Acute disseminated encephalomyelitis (ADEM) 2
• MOG antibody-associated disease 7

Other Conditions

• Paraneoplastic disorders 2
• Leukodystrophies (in children and teenagers) 2

High-Risk Situations Requiring Extra Caution

Exercise extreme caution when diagnosing MS in: 1, 2

• Patients <10 years or >59 years of age
• Progressive onset from disease start
• Atypical presentations (dementia, epilepsy, aphasia)
• When MRI or CSF tests are negative or atypical

In older individuals (>59 years), MRI findings may have less specificity due to microvascular ischemic disease, requiring cautious interpretation 1

Quality Assurance Considerations

Ensure high-quality paraclinical testing: 2

• CSF analysis quality varies between laboratories - use state-of-the-art technology (isoelectric focusing for oligoclonal bands) 2
• Poor quality MRI, CSF, or evoked potential testing can lead to misdiagnosis 2

Common Pitfalls to Avoid

• Do not diagnose MS based on historical symptom accounts alone - objective clinical evidence is required 2
• Do not ignore alternative diagnoses - a positive test for an MS mimic does not automatically exclude MS, but demands careful consideration 3
• Do not overlook the importance of timing - careful consideration of intervals between clinical events and MRI scans is crucial 2
• Do not rely on single paroxysmal episodes as evidence of an attack 1