Exercise-based Therapy for Multiple Sclerosis Patients

Clinical manifestations of Multiple Sclerosis (MS) indicate the involvement of motor, sensory, visual, and autonomic systems as well as brain circuits implicated in cognition and emotion. Due to the complexity and the heterogeneity of the disease course and the clinical symptoms, the search for the appropriate personalized treatment and the disease management remains a challenging issue. Nowadays, it is increasingly recognized that MS treatment and care demand a multi-disciplinary approach, including non-pharmacological interventions, aimed to improve quality of life (QoL) and engagement in daily-life activities. Active-rehabilitation or exercise is currently considered as the form of non-medical interventions that best meets these requirements. In the context of MS, there is now general agreement on the positive effects of exercise for both relapsing remitting (RR) and progressive (P) MS patients. Significant effects have been described for cardiovascular functions, aerobic capacity, muscular strength and ambulatory performance. Even if clear conclusions cannot be drawn, other outcomes, like balance and depression seem to be positively influenced by exercise. Symptoms linked to autonomic dysfunction caused by sympathovagal imbalance, like altered heart rate variability (HRV) and correlating with the load of inflammation in MS may benefit from exercise, being the physical activity an important modulator of the peripheral nervous system. However, the DMT potential of exercise is still overlooked, since only few studies have investigated the influence of exercise on inflammation and neurodegeneration, the main pathogenic events in MS with unclear and, to some extent, contrasting data. This longitudinal study aims is designed to enrol at least 35 MS patients to perform a conventional 4 weeks rehabilitation program. Physical therapy will be performed for 6 days/week for 4 weeks and will consist of 3 hours of treatment. The rehabilitation program will be planned by a physician specialized in physical and rehabilitation medicine and will consist of both passive and active therapeutic exercises specifically aimed at restoring or maintaining muscular flexibility, range of motion, balance, coordination of movements, postural passages and transfers, and ambulation. According to the patient's disability status, different therapeutic exercises will be performed by qualified physiotherapists. Moreover, intensity of exercise will be tailored to the level of patient's disability. To avoid fatigue and to increase patient's tolerance to the exercises, compensative pauses will be included. Moreover, genotype analysis from peripheral blood cells will be performed to identify single nucleotide polymorphisms (SNPs) in coding regions and/or gene regulators (microRNA or proteins) involved in MS synaptic transmission alterations, like NGF, PDGF, which might correlate to clinical parameters described as both primary and secondary outcomes. Statistical analysis will be performed by IBM SPSS Statistics 15.0. Data will be tested for normality distribution through the Kolmogorov-Smirnov test. Differences between pre- and post-values will be analyzed using parametric Student's t-test for matched pairs, or if necessary, nonparametric Wilcoxon signed-rank test for matched pairs. Changes in categorical variables will be assessed by McNemar test. Correlation analysis will be performed by calculating Pearson or Spearman coefficients as appropriate. Data will be presented as the mean (standard deviation, sd) or median (25th- 75th percentile). The significance level is established at p\<0.05. Sample size calculation was performed according to the following criteria. Supposing that in MS patients the cytokine values in particular the TNF levels after exercise therapy decrease in a manner similar to that showed in the study by Hedegaard et al (2008), the investigators can estimate that the therapy will have a medium effect on TNF values, d=0.59, calculating a pre-mean value equal to 2611.2 (standard deviation, sd=1586.96) and post-exercise equal to 1249.1 (sd=1261.89), a correlation between pre-post values equals to -0.326. To detect as significant a moderate effect with a power of 95%, assuming a two-sided a=0.05 and applying a Wilcoxon signed-rank test for matched pairs, the investigators estimate a total number of 35 patients. The analysis was performed by G\*POWER v3.1.9.2.