The natural history of multiple sclerosis: a geographically based study IX. Observations on the progressive phase of the disease

University of Oxford, Oxford, England, United Kingdom
Brain (Impact Factor: 9.2). 04/2006; 129(Pt 3):584-94. DOI: 10.1093/brain/awh721
Source: PubMed


The clinical features of relapses and progression largely define multiple sclerosis phenotypes. A relapsing course is followed by chronic progression in some 80% of cases within 2 decades. The relationship between these phases and long-term outcome remains uncertain. We have analysed these clinical features within a well-studied natural history cohort with mean follow-up of 25 years. For the entire cohort, median times to reach Disability Status Scale (DSS) 6, 8 and 10 were 12.7, 20.6 and 43.9 years, respectively. Among 824 attack-onset patients, the great majority entered a progressive phase with a mean time to progression of 10.4 years. The effects of relapses often cloud the clinical onset of progression. However, there are circumstances where onset of progression is early, relatively discrete and identifiable at DSS of 2 or less. Three subgroups allow for clarity of outcome comparison and they are (i) cases of primary progressive (PP) disease, (ii) attack-onset disease where only a single attack has occurred before onset of progression (SAP) and (iii) secondary progressive (SP) disease where recovery from relapses allows recognition of the earliest clinical stages when progression begins. Here we compare survival curves in these three groups. Among cohorts of SAP (n = 140), PP (n = 219) and SP (n = 146) where progression was stratified by DSS at its onset, there was no difference in time to DSS 6, 8 and 10. These findings demonstrate that the progressive course is independent of relapses either preceding the onset of relapse-free progression or subsequent to it. Among SAP patients, the degree of recovery from the single defining exacerbation had no significant effect on outcome. The site of the original attack was not usually where progression began. The relatively stereotyped nature of the progressive phase seen in all progressive phenotypes suggests regional and/or functional differential susceptibility to a process that appears degenerative in nature. The highly prevalent distal corticospinal tract dysfunction in progressive disease and the pathologically demonstrated selective axonal loss seen in this tract raises the possibility of a dying back central axonopathy, at least in part independent of plaque location or burden. Despite considerable individual variation, the progressive course of disability seen in groups of PP, SAP and SP-DSS2 is similarly stereotyped in quality and pace and may entail mechanisms common to all forms of progressive multiple sclerosis. The possibility that this is the primary process in some cases must be considered.

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    • "At least in primary progressive MS a change in EDSS scores is not predictive for the further disease course [5] and sustained progression over a few months is not predictive for long term disability [4]. Nevertheless, EDSS landmarks as the need for a walking aid are typical endpoints in natural cohort studies [6] [7] [8]. They cannot be used for individual patient monitoring as they only occur in the latter and mostly progressive disease course, when immunotherapy does not seem to influence the further accumulation of disability [9]. "
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    ABSTRACT: Background: Mobility assessment in Multiple Sclerosis (MS) is crucial for trials and individual patient counseling. Up to now, standard tests as the Timed 25-Foot Walk (T25FW) are restricted by floor effects in mildly disabled patients. The 3-meter Timed Tandem Walk (TTW) as a possibly more sensitive measure has not been investigated yet. Objective: To investigate sensitivity and specificity of the TTW and T25FW to detect mild clinical impairment in a large cohort of MS patients. Methods: We extracted T25FW, TTW and EDSS from our UMC patient database (2009-2012). After randomization into an explorative (n = 497) and validation (n = 228) cohort, we calculated change rates and performed ROC analyses of gait tests and EDSS including Functional System Scores. Results: Between disability stages of EDSS 0-2.5 and EDSS 3.0-4.0, the mean TTW difference was 4s (T25FW = 0.9s). The accuracy to separate between EDSS groups was moderate but identical for both tests (ROC-AUC T25FW = 0.79, TTW = 0.80, p = 0.4). TTW had a higher sensitivity and specificity to differentiate between asymptomatic and symptomatic patients concerning FS motor/cerebellar scores (ROC-AUC T25FW = 0.71, TTW = 0.75, p < 0.05). All hypotheses could be validated in the second cohort. Conclusion: A 3-m Timed Tandem Walk is a standardized test that is easy to implement to detect impairment of the motor or cerebellar system in fully ambulatory MS patients. Based on the complex-task character, TTW is a potential new outcome measure for MS mobility in mildly disabled patients and can act as easily accessible and significant additional information in patient counseling.
    Journal of the Neurological Sciences 08/2014; DOI:10.1016/j.jns.2014.08.001 · 2.47 Impact Factor
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    • "This has been described in other studies as well [24]. Other similarities include mean age of onset as 31 years, a female preponderance which is similar to other regional countries [22] [25] [15] but lower in western studies [26] [27]. Most patients in presented with sensory (63%) visual (45%) and weakness (43%) symptoms as initial presentations, which is different from other Middle Eastern data [12–14,16]. "
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    • "We identified a total of 3 prospective studies and reports from another 5 retrospective cohorts.[1], [5], [15]–[17], [20]–[26] The available data about predictors of disease progression in PPMS were very heterogeneous and included rarely information about what would allow a statistically meaningful meta-analytic synthesis. For the majority of the predictors only a subset of studies reported results. "
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    ABSTRACT: New agents with neuroprotective or neuroregenerative potential might be explored in primary-progressive Multiple Sclerosis (PPMS) - the MS disease course with leading neurodegenerative pathology. Identification of patients with a high short-term risk for progression may minimize study duration and sample size. Cohort studies reported several variables as predictors of EDSS disability progression but findings were partially contradictory. To analyse the impact of published predictors on EDSS disease progression in a large cohort of PPMS patients. A systematic literature research was performed to identify predictors for disease progression in PPMS. Individual case data from the Sylvia Lawry Centre (SLC) and the Hamburg MS patient database (HAPIMS) was pooled for a retrospective validation of these predictors on the annualized EDSS change. The systematic literature analysis revealed heterogeneous data from 3 prospective and 5 retrospective natural history cohort studies. Age at onset, gender, type of first symptoms and early EDSS changes were available for validation. Our pooled cohort of 597 PPMS patients (54% female) had a mean follow-up of 4.4 years and mean change of EDSS of 0.35 per year based on 2503 EDSS assessments. There was no significant association between the investigated variables and the EDSS-change. None of the analysed variables were predictive for the disease progression measured by the annualized EDSS change. Whether PPMS is still unpredictable or our results may be due to limitations of cohort assessments or selection of predictors cannot be answered. Large systematic prospective studies with new endpoints are needed.
    PLoS ONE 03/2014; 9(3):e92761. DOI:10.1371/journal.pone.0092761 · 3.23 Impact Factor
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