What is the definition of highly active multiple sclerosis?

Definition of Highly Active Multiple Sclerosis

Highly active MS (HAMS) is most commonly defined as disease with ≥2 relapses in the prior year AND ≥1 gadolinium-enhancing lesion on baseline MRI, though no universally standardized definition currently exists across clinical practice and regulatory guidance 1, 2.

Core Diagnostic Criteria

The most widely accepted definition in clinical trials and practice includes:

• ≥2 clinical relapses in the 12 months prior to assessment
• ≥1 gadolinium-enhancing (Gd+) lesion on baseline brain MRI
• Often occurs despite treatment with disease-modifying therapy

This definition was utilized in major clinical trials including the SELECT study 2 and represents the most operationalized criteria for identifying patients requiring high-efficacy therapies.

Key Clinical and Radiological Features

Beyond the core criteria, HAMS is characterized by:

• Frequent relapses with incomplete recovery between episodes 3
• High MRI lesion burden with multiple new or enlarging T2 lesions 3
• Active inflammation demonstrated by contrast-enhancing lesions
• Poor prognostic indicators including:
  • Spinal cord lesions 4
  • Brainstem involvement 4
  • Presence of ≥4 paramagnetic rim lesions (PRL) 4
  • Early brain volume loss 5

Important Distinctions and Terminology Challenges

A critical caveat: The terminology surrounding activity-based MS subgroups remains inconsistent 1. Three overlapping but distinct categories are often conflated:

1. Active RRMS: Evidence of clinical or radiological disease activity
2. Highly Active RRMS (HARRMS): The ≥2 relapses + ≥1 Gd+ lesion definition described above
3. Rapidly Evolving Severe (RES) RRMS: More aggressive disease with rapid disability accumulation, often defined by ≥2 disabling relapses in one year with MRI activity 6

The most commonly endorsed definition among clinicians is the "Rush criteria" (53.9% agreement), though significant variation exists in practice 3.

Prognostic MRI Markers

Beyond the diagnostic Gd+ lesion requirement, additional MRI features predict worse outcomes in HAMS 4:

• New lesions in high-risk locations: Spinal cord and brainstem lesions strongly predict long-term disability
• Paramagnetic rim lesions: ≥4 PRL associated with greater disability accumulation 4
• Early brain atrophy: Present even in early disease and predicts long-term disability 5
• T1 hypointense lesions ("black holes"): Indicate irreversible tissue damage 5

Clinical Recognition

Brazilian neurologists surveyed identified the most important indicators as 3:

• Annualized relapse rate (37.4% cited as primary indicator)
• Number of Gd+ lesions on MRI (32.0%)
• Nearly all (98.1%) agreed that signs of high disease activity should influence therapeutic decisions toward high-efficacy treatments

Treatment Implications

Recognition of HAMS is critical because 7, 2:

• These patients are at significantly higher risk for disability progression
• Early intervention with high-efficacy therapies (natalizumab, ocrelizumab, alemtuzumab) is essential
• Delayed recognition represents a "lost opportunity" to prevent irreversible neurological damage 7
• Treatment efficacy in HAMS patients is similar to less active disease when appropriate therapies are used 2

Common Pitfalls

• Waiting too long to escalate therapy: The window for preventing irreversible damage is narrow 7
• Relying solely on clinical relapses: MRI activity (new T2 or Gd+ lesions) may occur without clinical symptoms and still indicates high disease activity 5
• Inconsistent application of criteria: The lack of standardized definitions leads to variable treatment access and delayed escalation 1