Classification of Multiple Sclerosis
Multiple sclerosis (MS) is classified into four main clinical phenotypes based on disease course patterns: relapsing-remitting MS, secondary progressive MS, primary progressive MS, and clinically isolated syndrome. 1
Main MS Phenotypes
1. Relapsing-Remitting MS (RRMS)
- Characterized by clearly defined relapses (attacks) with full or partial recovery, without disease progression between attacks 1
- Most common initial presentation, affecting approximately 85-90% of MS patients at onset 2
- Typically presents in younger patients (20s-30s) 1
- Shows higher inflammatory activity on MRI with more gadolinium-enhancing lesions (about 80% of new lesions show enhancement) 1
2. Secondary Progressive MS (SPMS)
- Follows an initial relapsing-remitting course with subsequent progressive deterioration for at least six months, with or without superimposed relapses 1
- Approximately two-thirds of RRMS patients eventually transition to SPMS 1, 3
- Transition is often gradual and difficult to precisely identify clinically 3
- Characterized by steady accumulation of disability independent of relapses 3
- Further subcategorized as active (with relapses or new MRI activity) or non-active 2
3. Primary Progressive MS (PPMS)
- Progressive deterioration from disease onset without relapses or remissions 1
- Affects approximately 10-15% of MS patients 1, 4
- Typically presents with gradual worsening of neurological function, often beginning with spinal cord symptoms 4
- Shows less inflammatory activity on MRI (only about 5% of new lesions show gadolinium enhancement) 1
- Generally poorer response to disease-modifying therapies compared to relapsing forms 4
4. Clinically Isolated Syndrome (CIS)
- First clinical episode with features suggestive of MS but not yet meeting full criteria for MS diagnosis 2
- Added to classification systems in more recent guidelines 2
- May or may not progress to definite MS 1
Modern Classification Refinements
Activity Status
- All forms of MS should be subcategorized as either active or non-active 2
- Activity is defined by:
- Clinical relapses and/or
- New T2 or gadolinium-enhancing lesions on MRI over a specified period (typically at least one year) 2
Progression Status
- Progressive forms (PPMS and SPMS) should be further classified as:
- With progression: evidence of disability worsening over time independent of relapses
- Without progression: stable disability over a specified period 2
Terminology Clarification
- "Worsening" describes disease advancement for any reason (including relapses)
- "Disease progression" should be reserved for true progression in progressive forms of MS 2
- The term "benign MS" (minimal disability after ≥10 years) should be used with caution as the disease course can worsen at any time 1, 2
Historical Classifications (Now Obsolete)
- Progressive-Relapsing MS: term previously used for primary progressive MS patients who later developed relapses 5
- Relapsing-Progressive MS: previously used when early course combined both relapses and progression 5
- These terms have been eliminated in current classification systems 2, 5
Emerging Concepts in MS Classification
- Recent evidence suggests MS may be better considered as a continuum rather than distinct categories 6
- Disease course reflects the relative contributions of:
- Focal inflammation (predominant in relapsing forms)
- Widespread inflammation and neurodegeneration (predominant in progressive forms)
- Failure of compensatory mechanisms like neuroplasticity and remyelination 6
- Aging increases neural susceptibility to injury and decreases resilience, contributing to progression 6
Treatment Implications of Classification
- FDA-approved treatments for MS are often specific to certain phenotypes:
- Primary progressive MS has historically had fewer treatment options 8, 4
Understanding the correct classification of MS is essential for appropriate treatment selection, accurate prognosis, clinical trial design, and effective communication among healthcare providers 2, 6.