Natural history of multiple sclerosis: a unifying concept
Confavreux C and Vukusic S;
Commented by , 20 Feb 2006
Background
Multiple sclerosis (MS) is classically described in four distinct categories: Relapsing remitting, secondary progressive, primary progressive and progressive relapsing.
Acute focal inflammation characterizes the relapse in MS, whereas progression and accumulation of disability correlate with the diffuse and chronic axonal and neuronal loss. Although there are obvious histological similarities between progressive types of MS, they may have a different course and has been described as separate disease entities.
Aim
To determine whether MS represents one or several distinct diseases.
Methods
The authors used data from 1844 MS patients (The Lyon MS Cohort). Patients were categorized according to the classic criteria: Relapsing-remitting (RR=58%), secondary progressive (SP=27%), progressive relapsing (PR=6%) and primary progressive (PP=9%).
The statistical approach was t-test for quantitative data and Kaplan-Meyer test for survival data. Survival curves were compared using log-rank test.
Results
- There was similar age at disease onset for RR and SP cases.
- Initial symptoms, recovery from first relapse and time between the first two relapses were also similar in RR and SP cases.
- PP and PR cases were similar in their clinical characteristics.
- In the cases with a progressive course, median age of onset of the progressive phase was similar and the proportion of cases with superimposed relapses was almost the same.
- All progressive patients who started with a RR course and all patients with a PP course were similar with respect to time course of disability accumulation and age at assignment of disability landmarks.
Dr Blinkenberg's comments
The authors suggest that the clinical phenotype and course of MS is age dependent. RRMS is regarded as a preface to the final progressive disease course. Progressive disease from onset is viewed upon as "amputated" from the usual preceding relapsing remitting phase.
Interestingly it is shown that disability milestones and the time at which landmarks are reached in progressive types of MS, follow a predefined schedule that is not influenced by relapses.
In this way the authors argue for a unifying disease concept regarding PP and SPMS, which is in line with a recent study showing that the neuropathology of progressive MS is generally characterized by compartmentalized diffuse inflammation in the CNS (ref. 1).
The authors’ approach is interesting, although still not explaining the difference in clinical phenotype between PPMS and SPMS. And if the disease is truly age dependent and amnesic to prior clinical history, does it mean that treatment of RRMS is useless?
There is no evidence showing that treatment of the RR phase actually postpones the shift to secondary progressive and self-perpetuating disease, and for ethical reasons we will probably never gain this information from randomized controlled studies.
Prospective studies on disease course will hopefully show that time to progression in RRMS is prolonged in treated individuals, compared with historical data of untreated patients. Treatment of progressive disease has shown limited efficacy in SPMS using beta-interferon, although more convincing results have been obtained with mitoxantrone.
Still we have no efficacious treatment for PPMS, which in fact speak against the view, that progressive MS can be regarded as one disease entity.
Reference
1. Kutzelnigg A, Lucchinetti CF, Stadelmann C, Bruck W, et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 2005; 128; 2705-2712