What characterizes disease activity in Multiple Sclerosis (MS)?

Disease Activity in Multiple Sclerosis

Disease activity in MS is characterized by clinical relapses, new or enlarging T2 lesions on MRI, gadolinium-enhancing lesions indicating active inflammation, and progressive disability accumulation—with MRI activity being far more sensitive than clinical relapses alone for detecting ongoing disease. 1

Clinical Markers of Disease Activity

Clinical relapses represent the most traditional marker of MS activity, defined as new neurological symptoms developing over several days in young adults (typically ages 20-30 years), including:

• Unilateral optic neuritis
• Partial myelitis
• Sensory disturbances
• Brainstem syndromes such as internuclear ophthalmoplegia 2

However, clinical assessments alone substantially underestimate true disease activity, as most inflammatory activity occurs asymptomatically. Early relapsing-remitting and secondary progressive MS demonstrate the highest rates of asymptomatic disease activity. 1

MRI Markers of Active Disease

Gadolinium-Enhancing Lesions (Most Sensitive for Acute Inflammation)

Gadolinium-DTPA enhancement is the gold standard for detecting active inflammation, as it indicates blood-brain barrier breakdown and acute inflammatory activity. 1

Key characteristics by MS subtype:

• Relapsing-remitting and secondary progressive MS: Approximately 80% of new lesions show gadolinium enhancement 1
• Benign MS: Only 33% of new lesions enhance 1
• Primary progressive MS: Only 5% of new lesions enhance 1, 3

Enhancement occurs in almost all new lesions during serial monthly scans in relapsing-remitting or secondary progressive patients; the few non-enhancing lesions are invariably small. 1

New or Enlarging T2 Lesions

New and enlarging T2 hyperintense lesions represent active disease and can provide sufficient information about subclinical activity when contrast is not used. 1 These lesions should be:

• Visible on both echoes (though may be more conspicuous on one)
• Minimum size of 3 pixels
• Compared to baseline scans using identical MRI protocols 1

Chronic T1 Hypointense Lesions ("Black Holes")

Chronic T1 hypointense lesions persisting longer than 6 months indicate focal neurodegeneration and irreversible tissue damage, representing a marker beyond acute inflammation. 1

Quantifying Disease Activity Burden

The MAGNIMS score stratifies early disease activity risk:

• Low score: No relapses AND <3 new T2 lesions (8.9% reached disability endpoint)
• Medium score: No relapses AND ≥3 new T2 lesions OR 1 relapse AND 0-2 new T2 lesions (23.7% reached disability endpoint; HR=1.94)
• High score: 1 relapse AND ≥3 new T2 lesions OR ≥2 relapses (27.3% reached disability endpoint; HR=2.47) 4

Within the low score category, absence of contrast-enhancing lesions further reduces risk (8.1% vs 15.4% with CELs present; HR=2.11). 4

Frequency and Variability of Activity

Disease activity varies dramatically between patients and within individual patients over time. Serial data from untreated patients over 6 months shows:

• Range of active lesions: 1 to 207 in relapsing-remitting patients
• Range of active lesions: 4 to 108 in secondary progressive patients 1

This extreme variability underscores why serial MRI monitoring is essential—single timepoint assessments cannot capture the dynamic nature of MS activity. 1

"Hidden" Disease Activity

Multiple indicators of disease activity are not captured by standard relapse and MRI monitoring:

• Cognitive impairment
• Brain atrophy (volume loss)
• Fatigue
• Silent progression (neurological decline without obvious relapses or new lesions) 5

Brain atrophy can be present even in early MS stages and correlates with long-term cognitive impairment and disability progression. 1 However, interpretation requires caution due to "pseudoatrophy" (excessive volume decrease in the first 6-12 months of anti-inflammatory treatment due to resolution of edema). 1

Practical Monitoring Approach

Brain MRI should be performed using:

• Same MRI system and identical imaging protocol as baseline
• Contrast-enhanced T1-weighted sequences to detect acute inflammation
• T2-weighted sequences to identify new/enlarging lesions 1

Spinal cord imaging adds limited value for routine monitoring because:

• Technical challenges reduce sensitivity for detecting activity
• Most spinal cord lesions are clinically symptomatic
• Strong correlation exists between brain and spinal cord lesion development 1

Clinical assessments measuring disability (EDSS) and recording relapses must always be performed in parallel with MRI, as imaging alone provides incomplete assessment. 1

Critical Pitfall

The absence of clinical relapses does NOT indicate absence of disease activity. Contrast-enhancing lesions and relapse rates correlate with subsequent disability, but this relationship is mediated through relapses—meaning CELs predict future relapses, which then predict disability. 6 Therefore, asymptomatic MRI activity requires therapeutic intervention to prevent future clinical deterioration, even when patients feel stable. 4, 5