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

Presentation and Diagnosis of Multiple Sclerosis

Core Diagnostic Principle

The diagnosis of MS requires objective demonstration of inflammatory-demyelinating lesions disseminated in both time and space through a combination of clinical assessment, MRI findings, and exclusion of alternative diagnoses. 1

Clinical Presentations

Typical Initial Symptoms

• Relapsing-remitting MS (RRMS) presents with discrete neurological episodes lasting at least 24 hours, including unilateral optic neuritis, partial myelitis, sensory disturbances, or brainstem syndromes like internuclear ophthalmoplegia developing over several days. 2, 3
• Common attack symptoms include numbness, tingling, weakness, vision loss, gait impairment, incoordination, imbalance, and bladder dysfunction, with stability between attacks. 4
• Primary progressive MS (PPMS) shows insidious neurological deterioration from onset without relapses or remissions, affecting 10-15% of MS patients. 5
• An attack requires objective clinical findings on examination—subjective historical reports alone are insufficient for diagnosis. 2

Defining an Attack

• An attack must last at least 24 hours and represent true neurological dysfunction, not pseudoattacks from fever or infection. 2
• Single paroxysmal episodes (e.g., one tonic spasm) do not constitute a relapse, but multiple episodes over 24 hours do. 2
• Separate attacks must be separated by at least 30 days from onset of the first event to onset of the second event. 2

Diagnostic Criteria Framework

MRI Requirements (Most Critical)

MRI is the most sensitive and specific paraclinical test for MS diagnosis. 1

Dissemination in Space (DIS) requires lesions in at least two of these locations: 1

• Periventricular
• Cortical/juxtacortical
• Infratentorial
• Spinal cord

Dissemination in Time (DIT) is demonstrated by: 1

• Both gadolinium-enhancing and non-enhancing lesions on a single MRI, OR
• A new T2 or gadolinium-enhancing lesion on follow-up MRI compared with baseline

Cerebrospinal Fluid Analysis

• CSF showing oligoclonal bands (detected by isoelectric focusing) that differ from serum bands, or elevated IgG index, supports the diagnosis. 1
• CSF analysis is particularly valuable when clinical presentation is atypical or MRI findings don't fully meet diagnostic criteria. 1
• The traditional Tibbling & Link IgG index and CSF isoelectrofocusing for oligoclonal bands remain standard laboratory tests. 6

Visual Evoked Potentials

• VEPs showing delay with well-preserved waveform provide additional diagnostic support. 1
• VEPs are most useful when MRI abnormalities are few (as in PPMS with progressive myelopathy) or when MRI findings have less specificity (in older individuals with microvascular disease risk factors). 2, 1

Diagnostic Classification

Following evaluation, classify patients as: MS, "possible MS" (at risk but equivocal evaluation), or "not MS." 1

The outdated terms "clinically definite," "laboratory-supported definite MS," "clinically probable MS," and "laboratory-supported probable MS" are no longer recommended. 2, 1

Clinical Phenotypes

Four Main Types

• Relapsing-Remitting MS (RRMS): Clearly defined relapses with full or partial recovery, no progression between attacks, typically in younger patients. 5
• Secondary Progressive MS (SPMS): Initial relapsing-remitting course followed by progressive deterioration for at least 6 months, with or without superimposed relapses. 5
• Primary Progressive MS (PPMS): Progressive deterioration from onset without relapses or remissions. 5
• Clinically Isolated Syndrome (CIS): First clinical episode suggestive of MS but not yet meeting full MS criteria. 5

MRI Activity Patterns

• RRMS shows higher inflammatory activity with approximately 80% of new lesions showing gadolinium enhancement. 5
• PPMS shows less inflammatory activity with only about 5% of new lesions showing gadolinium enhancement. 5

Critical Diagnostic Pitfalls

When to Apply Criteria with Caution

• Exercise caution in patients with atypical presentations including dementia, epilepsy, or aphasia. 1
• In older individuals, MRI findings may have less specificity due to microvascular ischemic disease. 2, 1
• A positive test for an MS "mimic" does not automatically exclude MS—clinical judgment remains essential. 4

Role of Biopsy

• Biopsy is rarely needed but can confirm inflammatory demyelination; however, it cannot alone establish an MS diagnosis. 1

Exclusion of Alternative Diagnoses

Excluding other explanations for clinical features is essential before diagnosing MS. 2

Testing for MS mimics includes: 7

• Aquaporin-4 (AQP4) antibodies for neuromyelitis optica spectrum disorder
• Myelin oligodendrocyte glycoprotein (MOG) antibodies for MOG-antibody disease

These biomarker-defined entities have reduced MS misdiagnosis rates. 7

Treatment Implications

FDA-Approved Disease-Modifying Therapies

• For relapsing forms of MS (including CIS, RRMS, and active SPMS): Interferon beta-1a and fingolimod are approved options. 8, 9
• Fingolimod is approved for patients 10 years of age and older. 9
• Nine classes of DMTs are available for relapsing-remitting MS and secondary progressive MS with activity, reducing annualized relapse rates by 29-68% compared with placebo or active comparators. 3