Reply to: Age at disability milestones in multiple sclerosis and history of multiple sclerosis: a unifying concept
The European Database for Multiple Sclerosis (EDMUS) Coordinating Center and Service de Neurologie A INSERM U 433, Hôpital Neurologique, Hospices Civils de Lyon, Lyon, France
Correspondence to: Prof. Christian Confavreux, Service de Neurologie A, Hôpital Neurologique Pierre Wertheimer, 59 boulevard Pinel, 69677 Lyon-Bron Cedex, France E-mail: christian.confavreux{at}chu-lyon.fr
We thank Dr Goodin for his interest in our recently published articles (Confavreux and Vukusic, 2006a, b). First of all, our objective in both papers, as in the two previous ones (Confavreux et al., 2000
, 2003), was to study the mechanisms underlying the natural history of multiple sclerosis (MS). This is why the database was locked in April 1997, at a time when the patients of the Lyon cohort had essentially not been given currently acknowledged disease-modifying therapies. Consequently, the data referred to in the four articles are exactly the same. The difference appearing in the duration of the disease course is artificial. Disease duration is 11 years in the original paper (Confavreux et al., 2000) because of the rounding off of the figure which, in fact, is 11.3 years when deciles are included, as mentioned in the more recent articles (Confavreux and Vukusic, 2006a, b). This being said, the follow-up of the initial 1844 patients of the Lyon MS cohort keeps going on. Furthermore, any new patient seen in our department of neurology is included in the cohort, which contains over 4500 patients to date.
Dr Goodin is right when stating that the younger the age at onset of MS, the younger the age at reaching the disability milestones and that the age at onset of MS is younger in cases with an exacerbating–remitting initial course (median = 29 years) compared with cases with a progressive initial course (median = 40 years). Therefore, we agree with Dr Goodin that age at onset of MS is a confounding factor when cases with an exacerbating–remitting onset are compared with cases with a progressive onset according to the time course of disability accumulation. In our study devoted to the time to disability landmarks (Confavreux et al., 2003), we have adjusted for age at onset of MS in the multivariate statistical analysis. We have thus shown that, when taking onset of MS as reference time, the time to reach disability landmarks was all the more longer since the age at onset of MS was younger. It was also longer in cases with an exacerbating–remitting initial course compared with cases with a progressive initial course. In contrast, when the time of assignment to a disability status score (DSS) of 4 or 6 of irreversible disability was taken as reference time, neither the age at onset of MS nor the initial course, be it exacerbating–remitting or progressive, was influential on the time to subsequent disability levels. Therefore, both factors significantly influence the time from onset of MS to reach a DSS score of 4, but not the subsequent progression of irreversible disability.
Addressing the issue of ‘age at’ time of assignment of irreversible disability landmarks is totally different from that of the ‘time to’ reach these milestones. Indeed, this does not make sense to use age at disease onset as an adjustment variable when studying age at disability landmarks as outcome criteria. The former is, by essence, included in the latter. Furthermore, considering a given patient with onset of MS at an age of X, this patient will not reach disability landmarks at an age younger than X. Therefore, there is no satisfactory adjustment according to the age at onset of the disease for the statistical analysis of age at disability landmarks. Adjustment techniques to be used in the statistical analyses with respect to age at onset of the disease cannot be the same when addressing the issue of ‘time to’ and that of ‘age at’ disability landmarks.
It must also be understood that both above-mentioned parameters are interacting, that is, the observation according to which the younger the age at onset of MS, the younger the age at reaching disability milestones, is true for the cases with an exacerbating–remitting onset and the cases with a progressive onset as well. Furthermore, there is a wide range of ages at onset of MS in both settings (see Confavreux and Vukusic, 2006b, Fig. 1A and B). It is therefore inappropriate to follow Dr Goodin's suggestion of comparing a subgroup of late-onset exacerbating–remitting cases with the entire group of progressive-onset cases. Only comparable data ought to be compared, either the entire groups of patients with different initial courses of MS (exacerbating–remitting versus progressive) or subgroups of both populations selected on the basis of a similar category of age at onset of MS. The latter approach leads to multiple comparisons and opens the path to type I and type II errors.
For these various reasons, we decided in our study (Confavreux and Vukusic, 2006a, b) to focus on the comparison of the entire groups of patients classified according to the onset of MS, be it exacerbating–remitting or progressive. Through this approach, the time course of disability accumulation from assignment of a given disability score onwards and the age at reaching disability landmarks were essentially similar in our 1562 patients with an exacerbating–remitting initial course and the 282 patients with a progressive initial course of the disease (see Confavreux and Vukusic, 2006b, Table 4). Furthermore, age at onset of the progressive phase was similar in the cases with secondary progression and in the cases with primary progression (see Confavreux and Vukusic, 2006b, Fig. 1B). These results do not mean that all the patients reach the course landmarks (onset of the relapsing–remitting phase, and onset of progression) or the disability landmarks at a similar age, but at an age with a similar distribution, whether the initial course of the disease is exacerbating–remitting or progressive. Taken altogether, these results suggest that both the clinical phenotype and the disability accumulation in MS might just be age-dependent. They provide robust support for a unifying concept of the disease.
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Confavreux C and Vukusic S. (2006) Age at disability milestones in multiple sclerosis. Brain 129:595–605.
Confavreux C and Vukusic S. (2006) Natural history of multiple sclerosis: a unifying concept. Brain 129:606–16.
Confavreux C, Vukusic S, Moreau T, Adeleine P. (2000) Relapses and progression of disability in multiple sclerosis. New Engl J Med 343:1430–8.
Confavreux C, Vukusic S, Adeleine P. (2003) Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain 126:770–82.
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