Fampridine and real-life walking in multiple sclerosis: Low predictive value of clinical test for habitual short-term changes.

BACKGROUND: Fampridine improves walking speed in patients with multiple sclerosis (MS) in performance-based tests. The impact on habitual mobility and its correlation with clinical tests has not been analysed. OBJECTIVE: To investigate the association between clinical response criteria and habitual mobility in MS patients starting a fampridine treatment. METHODS: During a four-week baseline-to-treatment study, we assessed in 28 patients (median EDSS 4.75, range 4-6.5) walking tests as the Timed-25-Foot-Walk (T25FW) and mobility questionnaires at day 0, 14 (start of treatment) and 28. Habitual steps and distance per day, total activity and walking speed was measured by accelerometry over four weeks. Beside improvement in real-life mobility, we investigated if such measures differed between non-responders and responders defined by a 20% improvement in clinical tests. RESULTS: All clinical test, patient reported outcomes and total activity improved significantly (p<0.05). 46% improved (any change >0) in three of four real-life measures. Change of the T25FW predicted only an increase of distance per day. Subjective rating of patients performed better by predicting distance and walking speed changes correctly. CONCLUSION: Fampridine might improve walking in daily life of MS, but clinical tests are weak predictors. Accelerometry opens a new perspective on mobility measurment, but the current data do not show a consistent effect on non-performance based accelerometry outcomes.

Validating predictors of disease progression in a large cohort of primary-progressive multiple sclerosis based on a systematic literature review.

BACKGROUND: 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. OBJECTIVE: To analyse the impact of published predictors on EDSS disease progression in a large cohort of PPMS patients. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Onset of secondary progressive phase and long-term evolution of multiple sclerosis.

OBJECTIVES: To assess factors affecting the rate of conversion to secondary progressive (SP) multiple sclerosis (MS) and its subsequent evolution. METHODS: Among 806 patients with relapsing remitting (RR) onset MS from the London Ontario database, we used Kaplan-Meier, Cox regression and multiple logistic regression analyses to investigate the effect of baseline clinical and demographic features on (1) the probability of, and the time to, SP disease, (2) the time to bedbound status (Disability Status Scale (DSS 8)) from onset of progression. RESULTS: The risk of entering the SP phase increased proportionally with disease duration (OR=1.07 for each additional year; p<0.001). Shorter latency to SP was associated with shorter times to severe disability. The same association was found even when patients were grouped by number of total relapses before progression. However, the evolution of the SP phase was not influenced by the duration of the RR phase. Male sex (HR=1.41; p<0.001), older age at onset (age ≤20 and 21-30 vs >30 HR=0.52 (p<0.001), 0.65 (p<0.001), respectively) and high early relapse frequency (1-2 attacks vs ≥3 HR=0.63 (p<0.001), 0.75 (p=0.04), respectively) predicted significantly higher risk of SP MS and shorter latency to progression. Times to DSS 8 from onset of progression were significantly shorter among those with high early relapse frequency (≥3 attacks), and among those presenting with cerebellar and brainstem symptoms. CONCLUSIONS: The onset of SP MS is the dominant determinant of long-term prognosis, and its prevention is the most important target measure for treatment. Baseline clinical features of early relapse frequency and age at onset can be used to select groups at higher risk of developing severe disability based on the probability of their disease becoming progressive within a defined time period.

Prognostic risk estimates of patients with multiple sclerosis and their physicians: comparison to an online analytical risk counseling tool.

BACKGROUND: Prognostic counseling in multiple sclerosis (MS) is difficult because of the high variability of disease progression. Simultaneously, patients and physicians are increasingly confronted with making treatment decisions at an early stage, which requires taking individual prognoses into account to strike a good balance between benefits and harms of treatments. It is therefore important to understand how patients and physicians estimate prognostic risk, and whether and how these estimates can be improved. An online analytical processing (OLAP) tool based on pooled data from placebo cohorts of clinical trials offers short-term prognostic estimates that can be used for individual risk counseling. OBJECTIVE: The aim of this study was to clarify if personalized prognostic information as presented by the OLAP tool is considered useful and meaningful by patients. Furthermore, we used the OLAP tool to evaluate patients' and physicians' risk estimates. Within this evaluation process we assessed short-time prognostic risk estimates of patients with MS (final n = 110) and their physicians (n = 6) and compared them with the estimates of OLAP. RESULTS: Patients rated the OLAP tool as understandable and acceptable, but to be only of moderate interest. It turned out that patients, physicians, and the OLAP tool ranked patients similarly regarding their risk of disease progression. Both patients' and physicians' estimates correlated most strongly with those disease covariates that the OLAP tool's estimates also correlated with most strongly. Exposure to the OLAP tool did not change patients' risk estimates. CONCLUSION: While the OLAP tool was rated understandable and acceptable, it was only of modest interest and did not change patients' prognostic estimates. The results suggest, however, that patients had some idea regarding their prognosis and which factors were most important in this regard. Future work with OLAP should assess long-term prognostic estimates and clarify its usefulness for patients and physicians facing treatment decisions.

Early relapses, onset of progression, and late outcome in multiple sclerosis.

OBJECTIVES: To investigate the relationship among attacks in the first 2 years (early relapses), secondary progression (SP), and late disability in multiple sclerosis (MS). DESIGN: Cohort study with follow-up of 28 years. SETTING: Referral MS center. PATIENTS: Patients (N=730) with relapsing-remitting MS diagnosed according to Poser criteria, from the database of the London Multiple Sclerosis Clinic, London, Ontario, Canada. MAIN OUTCOME MEASURE: Long-term evolution of patients with high (≥ 3 attacks) and early (within the first 2 years of the disease) frequency of relapses. In the total SP population and in patients grouped by numbers of early relapses, we assessed the predictive effect of latency to progression (time to SP) on times to attain cane requirement (Disability Status Scale score of 6 [DSS 6]) and bedridden status (DSS 8). RESULTS: Among the group with frequent early relapses (n=158), outcomes were variable. Although 103 (65.2%) experienced rapid conversion to SP MS (median duration, 5 years) and rapidly attained DSS 6 and DSS 8 scores (7 and 17 years, respectively), the remainder (n=55) did not enter the SP phase, despite adverse early relapse features. Among the total SP population, longer latency to progression was associated with lower probability of attaining DSS 6 (odds ratio, 0.76 [95% CI, 0.69-0.84] and 0.44 [95% CI, 0.37-0.52] for 5- and 15-year latency, respectively) and longer times to severe disability. The same association between time to onset of SP and late outcomes was observed even in patients matched by number of early attacks. However, duration of the relapsing-remitting phase did not influence the times from SP onset to DSS levels. CONCLUSIONS: Our results indicate dissociation between early inflammatory attacks and onset of the SP phase and further question the validity of relapse frequency as a surrogate marker for late disability. Among the group with frequent early relapses, we observed a large variability of outcomes, ranging from one extreme to the opposite.

Placebo cohorts in phase-3 MS treatment trials - predictors for on-trial disease activity 1990-2010 based on a meta-analysis and individual case data.

BACKGROUND: Annualized relapse rates (ARR) in the placebo cohorts of phase-3 randomized controlled trials (RCT) of new treatments for relapsing remitting multiple sclerosis (RRMS) have decreased substantially during the last two decades. The causes of these changes are not clear. We consider a better understanding of this phenomenon essential for valuing the effects of new drugs and by designing new trials. OBJECTIVES: To identify predictive factors of on-study ARR in early and recent MS trials. METHODS: ARR, rate of relapse-free patients, trial start dates, baseline demographics, relapse definitions and the use of McDonald criteria were retrieved by literature research of the placebo cohorts from RRMS phase-3 trials. Predictors were estimated by univariate and multivariate regression analyses and random-effects meta-regression. In addition, regression models were calculated by the Sylvia Lawry Centre's (SLC), including individual case data from clinical trials performed until 2000. The most reliable meta-analytic results can be gained from pooled individual case data. In lack of this, random-effects meta-analyses are recommended. RESULTS: Data from 12 published and one unpublished trial show a decrease of ARR from 1988 to 2012 (adjR(2) = 0.807, p<0.0001). Regression models identified McDonald criteria followed by baseline mean age and the pre-study relapse rate as predictors of the ARR. The pooled individual case data (n = 505) confirmed a decrease of ARR over time. The pre-study relapse rate was the best predictor for on-study relapses. Lacking individual case data after implementation of the McDonald criteria excludes a direct comparison concerning McDonald criteria. CONCLUSION: Pre-study relapse rate was the best predictor for on-study relapse rate but failed to explain the decrease of the ARR over time alone. Higher age at baseline and the implementation of McDonald criteria were associated as well with a lowered relapse rate in the random-effects meta-regression. These findings need further clarification based on individual case data.

Association between walking speed and age in healthy, free-living individuals using mobile accelerometry--a cross-sectional study.

CONTEXT: Walking speed is a fundamental parameter of human motion and is increasingly considered as an important indicator of individuals' health status. OBJECTIVE: To evaluate the relationship of gait parameters, and demographic and physical characteristics in healthy men and women. DESIGN, SETTING, AND PARTICIPANTS: Recruitment of a subsample (n = 358) of male and female blood donors taking part in the Cambridge CardioResource study. Collection of demographic data, measurement of physical characteristics (height, weight and blood pressure) and assessment of 7-day, free-living activity parameters using accelerometry and a novel algorithm to measure walking speed. Participants were a median (interquartile range[IQR]) age of 49 (16) years; 45% women; and had a median (IQR) BMI of 26 (5.4). MAIN OUTCOME MEASURE: Walking speed. RESULTS: In this study, the hypothesis that walking speed declines with age was generated using an initial 'open' dataset. This was subsequently validated in a separate 'closed' dataset that showed a decrease of walking speed of -0.0037 m/s per year. This is equivalent to a difference of 1.2 minutes, when walking a distance of 1 km aged 20 compared to 60 years. Associations between walking speed and other participant characteristics (i.e. gender, BMI and blood pressure) were non-significant. BMI was negatively correlated with the number of walking and running steps and longest non-stop distance. CONCLUSION: This is the first study using accelerometry which shows an association between walking speed and age in free-living, healthy individuals. Absolute values of gait speed are comparable to published normal ranges in clinical settings. This study highlights the potential use of mobile accelerometry to assess gait parameters which may be indicative of future health outcomes in healthy individuals.

The natural history of multiple sclerosis: a geographically based study 10: relapses and long-term disability.

The relationship of relapses to long-term disability in multiple sclerosis is uncertain. Relapse reduction is a common therapeutic target but clinical trials have shown dissociation between relapse suppression and disability accumulation. We investigated relationships between relapses and disability progression for outcomes of requiring assistance to walk, being bedridden and dying from multiple sclerosis [Disability Status Scale 6, 8, 10] by analysing 28 000 patient-years of evolution in 806-bout onset patients from the London Ontario natural history cohort. Having previously shown no effect of relapse frequency among progressive multiple sclerosis subtypes, here we examined these measures in the pre-progressive or relapsing-remitting phase. Survival was compared among groups stratified by (i) early relapses--number of attacks during the first 2 years of multiple sclerosis; (ii) length of first inter-attack interval; (iii) interval between onset and Disability Status Scale 3 (moderate disability); (iv) number of attacks from the third year of disease up to onset of progression; and (v) during the entire relapsing-remitting phase. Early clinical features can predict hard disability outcomes. Frequent relapses in the first 2 years and shorter first inter-attack intervals predicted shorter times to reach hard disability endpoints. Attack frequencies, in the first 2 years, of 1 versus >or=3, gave differences of 7.6, 12.8 and 20.3 years in times from disease onset to Disability Status Scale 6, 8 and 10, respectively. Time to Disability Status Scale 3 highly and independently predicted time to Disability Status Scale 6, 8 and 10. In contrast, neither total number of relapsing-remitting phase attacks nor of relapses experienced during the relapsing-remitting phase after the second year up to onset of progression showed a deleterious effect on times from disease onset, from progression onset and from Disability Status Scale 3 to these hard endpoints. The failure of a regulatory mechanism tied to neurodegeneration is suggested. Relapse frequency beyond Year 2 does not appear to predict the key outcome of secondary progression or times to Disability Status Scale 6, 8 or 10, highlighting two distinct disease phases related to late outcome. These appear to be separated by a watershed within the relapsing-remitting phase, just a few years after clinical onset. Higher early relapse frequencies and shorter first inter-attack intervals herald more rapid deterioration via interaction with the neurodegeneration characterizing secondary progression. They increase the probability of its occurrence, its latency and influence--to a lesser degree--its slope. The prevention or delay of the progressive phase of the disease is implicated as a key therapeutic target in relapsing-remitting patients.

Prognosis of the individual course of disease: the elements of time, heterogeneity and precision.

There is no gold standard in monitoring disease activity for clinical trials in multiple sclerosis. Various outcome measures, including relapses, disability and magnetic resonance imaging (MRI) measures have been used to demonstrate the efficacy of the different available therapies for multiple sclerosis. Recently, the potential limitations of these measures have received increasing attention, and these have stimulated research into more appropriate and sensitive outcome measures for clinical trials. For example, it has been shown that widely-used MRI measures add little, if any, independent information to that provided by more clinically relevant measures such as relapses and disability. Similarly, the Expanded Disability status Scale (EDSS), which is the most widely-used measure of disability related to multiple sclerosis, is insufficiently sensitive to detect robust changes in disability over the timeframes usually used in clinical trials. An alternative to the EDSS is the Multiple Sclerosis Severity Score (MSSS), a severity scale which relates clinical disability to disease duration. The MSSS was originally developed from a database of nearly ten thousand patients from eleven European countries and Australia and has since been reproduced in an independent dataset of 1134 patients from the placebo arms of randomised clinical trials. Based on the MSSS score, disease severity can be defined, which shows stability over time and may provide evidence-based decision support for patient management. Another alternative to measure disability is the objective quantification of physical activity. There is evidence that recent developments in pervasive computing using tiny accelerometers may have the potential to increase the reliability and precision of motor assessment, especially in the mid-range of the EDSS. The outcome measures discussed have potential use as online tools for evidence-based decision support which are increasingly being used in medical research and clinical decision-making.