Associations between onset age and disability in multiple sclerosis patients studied using MSSS and a progression model
Introduction
The mechanisms that determine the variable rate of accumulation of disability in multiple sclerosis (MS) patients remain unclear (Dean and Kurtzke, 1971, Kurtzke, 1975, Kurtzke, 1983, Weinshenker et al., 1989, Confavreux et al., 2003, Hensiek et al., 2003). While many factors have been examined, male gender and older age at MS onset are among few variables consistently associated with increased disability. Interestingly, the association between onset age and disability may not be linear (Confavreux and Vukusic, 2006). Thus, in patients with onset ages less than 30 years (up to 19 years and 20–29 years) an Extended Disability Severity Scale (EDSS) score of 7 was reached after a median duration of 33 years in both groups. However, in those with onset ages of 30–39, 40–49 and over 50 years, the corresponding times progressively fell (25 years, 22 years and 17 years respectively) suggesting two relationships between onset age and disability; a younger group in whom increasing age is not associated with more disability and an older onset group in whom age is linked with more disability (Confavreux and Vukusic, 2006). However, because of the relatively large age spans it is unclear at which interval of onset ages this apparent change occurs.
We now further explore the relationship between onset age and disability. Such studies require a reliable measure of disability and as EDSS is based on an ordinal scale and related to MS duration, models such as Multiple Sclerosis Severity Scale (MSSS) have been developed (Roxburgh et al., 2005). This score is derived from an algorithm relating EDSS to the distribution of disability in patients with similar durations. Importantly, the algorithm is based on data from one patient group (Roxburgh et al., 2005). We described recently, an alternative, cross-sectional EDSS-based approach (progression model) in patients recruited in north west England before disease-modifying therapy (Ramachandran et al., 2012). This model uses time from symptoms onset until a single measure of EDSS to define outcome; patients taking more than the median time to reach an EDSS are slow progressors (implying better outcome) and those taking the median or less are fast progressors (implying worse outcome). Our present aim was firstly to determine if the relationship between disability and onset age was linear throughout the range of ages found in our patients, secondly, if the relationship was not linear, define onset ages associated with a change in the relationship and thirdly, because gender determines disability, identify whether the relationship between onset age and disability in the total group were similar in female patients only. We used MSSS and the progression model to assess disability; the continuous variable MSSS allowed comparison of median values in groups defined by different onset ages while the progression model allowed comparison of proportions of fast and slow progressors in these groups.
Section snippets
Patients
We studied 500 unrelated Northern European Caucasians with relapse onset MS (Poser criteria) recruited in Neurology clinics in Stoke-on-Trent and Liverpool with written informed consent and Ethics Committee approval. This cross-sectional study is based on cases recruited between 1995 and 2009 (Partridge et al., 2004, Ramachandran et al., 2012). A single EDSS was determined during the first available stable period at least 1 month from the previous relapse and before use of disease modifying
MSSS and onset age
Simple linear regression analysis demonstrated in relapse onset patients (MS onset age 15.0–54.9 years), that MSSS (dependent variable) was significantly associated (p<0.001) with onset age. However, while significant, the association was weak (r=0.3) showing the extent of variability explained by the model was modest.
Discussion
The mechanisms that determine how gender and onset age influence the rate of accumulation of disability in MS patients are poorly understood. Indeed, studying the pathological processes that determine this phenotype is not helped by difficulties in quantitatively assessing disability; its relationship with EDSS is ordinal and strongly determined by duration (Confavreux et al., 2003). Thus, irreversible disability levels of 4, 6 and 7 (EDSS) are reached after median MS durations of 8, 20 and 30
Conflict of interest
Authors confirm that there are no conflicts of interest relevant to this work and preparation of this manuscript.
Role of the funding source
This work was not supported by any external source of funding.
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