Potential Metabolite Biomarkers of Multiple Sclerosis from Multiple Biofluids.

Multiple sclerosis (MS) is a chronic and progressive neurological disorder without a cure, but early intervention can slow disease progression and improve the quality of life for MS patients. Obtaining an accurate diagnosis for MS is an arduous and error-prone task that requires a combination of a detailed medical history, a comprehensive neurological exam, clinical tests such as magnetic resonance imaging, and the exclusion of other possible diseases. A simple and definitive biofluid test for MS does not exist, but is highly desirable. To address this need, we employed NMR-based metabolomics to identify potentially unique metabolite biomarkers of MS from a cohort of age and sex-matched samples of cerebrospinal fluid (CSF), serum, and urine from 206 progressive MS (PMS) patients, 46 relapsing-remitting MS (RRMS) patients, and 99 healthy volunteers without a MS diagnosis. We identified 32 metabolites in CSF that varied between the control and PMS patients. Utilizing patient-matched serum samples, we were able to further identify 31 serum metabolites that may serve as biomarkers for PMS patients. Lastly, we identified 14 urine metabolites associated with PMS. All potential biomarkers are associated with metabolic processes linked to the pathology of MS, such as demyelination and neuronal damage. Four metabolites with identical profiles across all three biofluids were discovered, which demonstrate their potential value as cross-biofluid markers of PMS. We further present a case for using metabolic profiles from PMS patients to delineate biomarkers of RRMS. Specifically, three metabolites exhibited a variation from healthy volunteers without MS through RRMS and PMS patients. The consistency of metabolite changes across multiple biofluids, combined with the reliability of a receiver operating characteristic classification, may provide a rapid diagnostic test for MS.

Multiple sclerosis alters the mechanical work performed on the body's center of mass during gait.

Patients with multiple sclerosis (MS) have less-coordinated movements of the center of mass resulting in greater mechanical work. The purpose of this study was to quantify the work performed on the body's center of mass by patients with MS. It was hypothesized that patients with MS would perform greater negative work during initial double support and less positive work in terminal double support. Results revealed that patients with MS perform less negative work in single support and early terminal double support and less positive work in the terminal double support period. However, summed over the entire stance phase, patients with MS and healthy controls performed similar amounts of positive and negative work on the body's center of mass. The altered work throughout different periods in the stance phase may be indicative of a failure to capitalize on passive elastic energy mechanisms and increased reliance upon more active work generation to sustain gait.

Gait mechanics are different between healthy controls and patients with multiple sclerosis.

Multiple sclerosis (MS) causes severe gait problems in relatively young individuals, yet there have been limited studies to quantitatively identify the specific gait parameters that are affected. The purpose of this study was to define any differences in biomechanical gait parameters between patients with MS and healthy controls. A total of 31 MS patients and 31 healthy controls were evaluated: joint torques and joint powers were calculated at the ankle, knee, and hip during the stance phase of gait. The self-selected walking velocity was used as a covariate in the analysis to ensure that group differences were not due to differences in walking velocity between the MS and healthy control groups. Reduced angular range, less joint torque, and reduced joint power were seen in patients with MS. We also found significant correlations between biomechanical gait parameters and EDSS score, which provides a clinical rating of disease severity. Our findings provide a quantitative assessment of the gait mechanics employed in patients with MS. The altered lower extremity mechanics observed in patients with MS reflect both a neurological and strength deficit compared with healthy controls during walking.

Persons with multiple sclerosis show altered joint kinetics during walking after participating in elliptical exercise.

Patients with multiple sclerosis (MS) experience abnormal gait patterns and reduced physical activity. The purpose of this study was to determine if an elliptical exercise intervention for patients with MS would change joint kinetics during gait toward healthy control values. Gait analysis was performed on patients with MS (n = 24) before and after completion of 15 sessions of supervised exercise. Joint torques and powers were calculated, while also using walking velocity as a covariate, to determine the effects of elliptical exercise on lower extremity joint kinetics during gait. Results show that elliptical exercise significantly altered joint torques at the ankle and hip and joint powers at the ankle during stance. The change in joint power at the ankle indicates that, after training, patients with MS employed a walking strategy that is more similar to that of healthy young adults. These results support the use of elliptical exercise as a gait training tool for patients with MS.

Is there a relationship between fatigue questionnaires and gait mechanics in persons with multiple sclerosis?

OBJECTIVE: To evaluate reported fatigue levels and gait deficits in patients with multiple sclerosis (MS) to determine the relationships that may exist between fatigue in patients with MS and alterations in gait mechanics. DESIGN: Cross-sectional. SETTING: Biomechanics laboratory. PARTICIPANTS: Subjects with MS (n=32) and age- and sex-matched controls (n=30). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Fatigue Severity Scale (FSS), Modified Fatigue Index Scale (MFIS), and 36-Item Short Form Health Survey (SF-36) to assess fatigue and general health. Biomechanical gait analysis was performed to measure peak joint torques and powers in the sagittal plane at the ankle, knee, and hip. Correlations were performed between fatigue measures and degree of deficit within each patient with MS for each joint torque and power measure. RESULTS: FSS score significantly correlated with deficits in ankle power generation at late stance and walking velocity. MFIS score significantly correlated with deficits in peak knee extensor torque and knee power absorption at early stance. SF-36 subscale scores correlated with several joint torque and power variables. CONCLUSIONS: Subjective fatigue rating scale scores alone should not be used as an indicator of motor disability or disease progression as it affects walking performance of patients with MS.

Interferons in the Treatment of Multiple Sclerosis: A Clinical Efficacy, Safety, and Tolerability Update.

Interferon beta (IFNß) was the first disease-modifying therapy available to treat multiple sclerosis (MS), providing patients with a treatment that resulted in reduced relapse rates and delays in the onset of disability. Four IFNß drugs are currently approved to treat relapsing forms of MS: subcutaneous (SC) IFNß-1b, SC IFNß-1a, intramuscular IFNß-1a, and, most recently, SC peginterferon beta-1a. Peginterferon beta-1a has an extended half-life and requires less frequent administration than other available treatments (once every 2 weeks vs every other day, 3 times per week, or weekly). Large randomized controlled clinical trials have confirmed the efficacy of interferons for the treatment of relapsing MS. The most frequent adverse events in patients receiving IFNs include injection site reactions and flu-like symptoms. Patient education and mitigation strategies are key to managing these adverse events and supporting therapy adherence. With fewer injections needed, peginterferon beta-1a is associated with less frequent discomfort, which may translate to improved adherence, a major factor in treatment efficacy. Because the available interferon therapies differ in administration route and frequency of injection, switching among these therapies may be a viable option for patients who experience issues with tolerability. Although a variety of disease-modifying therapies are now available to treat relapsing MS, the efficacy and long-term safety profile of interferons make them an important first-line option for treatment.

Nurses' perspective on approaches to limit flu-like symptoms during interferon therapy for multiple sclerosis.

BACKGROUND: Several interferon beta (IFNß) formulations are approved for first-line use as disease-modifying therapies to treat patients with multiple sclerosis (MS). Systemic post-injection reactions, often termed flu-like symptoms (FLS), occur in approximately half of all patients treated with IFNßs and can affect adherence to therapy. These symptoms, which include pyrexia, chills, malaise, myalgia, and headaches, usually resolve within 24 hours or persist intermittently following each injection. Because FLS, which usually occur early in the treatment course and diminish over time, are a primary cause of nonadherence to IFNß therapy, it is important to employ strategies that can attenuate these side effects. METHODS: To identify interventions effective in limiting FLS, a panel of United States-based nurses with expertise in MS patient care was convened and a literature review completed. RESULTS: Panel consensus was reached on specific interventions that can attenuate FLS. These prevention and mitigation strategies include dose titration, analgesia, and optimal injection timing, as well as other techniques that panel members have found useful in their clinical practice experience. CONCLUSIONS: These measures, in addition to effective patient education, will help to reduce the incidence of FLS secondary to IFNß therapy, improve patient medication adherence, and positively affect long-term clinical outcomes.

Supervised resistance training results in changes in postural control in patients with multiple sclerosis.

Postural disturbances are one of the first reported symptoms in patients with Multiple Sclerosis (MS). The purpose of this study was to investigate the effect of supervised resistance training on postural control in MS patients. Postural control was assessed using amount of sway variability [Root Mean Square (RMS)] and temporal structure of sway variability [Lyapunov Exponent (LyE)] from 15 MS patients. Posture was evaluated before and after completion of three months of resistance training. There were significant differences between MS patients pretraining and healthy controls for both LyE (p = .000) and RMS (p = .002), but no differences between groups after training. There was a significant decrease in RMS (p = .025) and a significant increase in LyE (p = .049) for MS patients pre- to posttraining. The findings suggested that postural control of MS patients could be affected by a supervised resistance training intervention.

Gait variability measures reveal differences between multiple sclerosis patients and healthy controls.

UNLABELLED: The purpose of this study was to determine the differences in gait variability between patients with multiple sclerosis (MS) and healthy controls during walking at a self-selected pace. METHODS: Kinematics were collected during three minutes of treadmill walking for 10 patients with MS and 10 healthy controls. The Coefficient of Variation (CoV), the Approximate Entropy (ApEn) and the Detrended Fluctuation Analysis (DFA) were used to investigate the fluctuations present in stride length and step width from continuous strides. RESULTS: ApEn revealed that patients with MS had significantly lower values than healthy controls for stride length (p < .001) and step width (p < .001). CONCLUSIONS: ApEn results revealed that the natural fluctuations present during gait in the stride length and step width time series are more regular and repeatable in patients with MS. These changes implied that patients with MS may exhibit reduced capacity to adapt and respond to perturbations during gait.

A brief neuropsychological battery for use in the chronic heart failure population.

BACKGROUND: Cognitive impairment is a recognized consequence of heart failure; however, there are no neuropsychological batteries with documented psychometric data in the chronic heart failure population. AIMS: To document the psychometric properties of a brief neuropsychological battery in a chronic heart failure sample. METHODS: The Repeatable Battery for the Assessment of Neuropsychological Status, Trail Making Test Part A and Part B, and letter fluency was administered to a sample of individuals with chronic heart failure. RESULTS: Eighty individuals with stable heart failure participated in this study. Individuals with chronic heart failure scored significantly lower than expected age and education adjusted norms in the domains of attention (p < 0.001), memory (p < 0.001), language (p < 0.001), executive function (p < 0.001), and psychomotor speed (p = 0.02). Scores on the tests of memory and executive function correlated to functional status (r = 0.28, p = 0.02 and r = 0.29, p = 0.03, respectively). Acceptable convergent validity and test-retest reliability were documented for this battery. CONCLUSION: The neuropsychological battery had adequate reliability and validity in individuals with chronic heart failure.

Postural control strategy during standing is altered in patients with multiple sclerosis.

Disturbances in balance are one of the first reported symptoms of Multiple Sclerosis (MS), yet limited research has been performed to classify the postural control deficits in this population. This study investigated the variability present in the sway patterns during quiet standing in patients with MS (PwMS) and healthy controls. Subjects were assessed (eyes open, closed) standing on a force platform. Variability of the sway patterns was quantified using a measure of amount of variability (root mean square; RMS) and two measures of temporal structure of variability (Lyapunov Exponent - LyE; Approximate Entropy - ApEn). RMS results revealed significantly higher amount of variability in the sway patterns of PwMS. PwMS also exhibit increased regularity (decreased ApEn) and decreased divergence (decreased LyE) during standing compared to healthy controls. Removing vision resulted in significantly decreased divergence (decreased LyE) in the MS subject group. These changes in the temporal structure correspond well with the theoretical model of the optimal movement variability hypothesis and the results support using variability measures to understand the mechanisms that underline postural control in PwMS and possibly other neurodegenerative disease pathologies.

Elliptical exercise improves fatigue ratings and quality of life in patients with multiple sclerosis.

Fatigue, reduced quality of life (QOL), and lower physical activity levels are commonly reported in patients with multiple sclerosis (MS). This study evaluated the effects of elliptical exercise on fatigue and QOL reports in patients with MS. Patients with MS (n = 26) completed the Fatigue Severity Scale (FSS), the Modified Fatigue Impact Scale (MFIS), and the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) before and after completing 15 elliptical exercise training sessions. Changes in fatigue and QOL were assessed based on any changes in the fatigue and SF-36 questionnaires, and correlations between changes in each of the scales were made to determine whether a relationship was present between the fatigue and QOL measures. Results showed significant improvement in FSS, MFIS, and five SF-36 subscales as a result of elliptical exercise. The change in FSS correlated with change in two of the SF-36 subscales. Elliptical exercise for patients with MS results in significant improvements in both fatigue and QOL. These findings indicate that regular elliptical exercise could be a part of inpatient and outpatient MS rehabilitation programs.

Multiple sclerosis affects the frequency content in the vertical ground reaction forces during walking.

BACKGROUND: Multiple sclerosis is a progressive neurological disease that results in a high incident of gait disturbance. Exploring the frequency content of the ground reaction forces generated during walking may provide additional insights to gait in patients with multiple sclerosis that could lead to specific tools for differential diagnosis. The purpose of this study was to investigate differences in the frequency content of these forces in an effort to contribute to improved clinical management of this disease. METHODS: Eighteen patients and eighteen healthy controls walked across a 10 meter long walkway. The anterior-posterior and vertical ground reaction forces generated during the stance phase of gait were evaluated in the frequency domain using fast Fourier transformation. T-tests were utilized for comparison of median frequency, the 99.5% frequency, and the frequency bandwidth between patients and healthy controls and also for comparisons between patients with mild and moderate severity. FINDINGS: Patients with multiple sclerosis had significantly lower 99.5% frequency (P=0.006) and median frequency (P<0.001) in the vertical ground reaction force. No differences were found in the anterior-posterior reaction force frequency content. There were no differences between patients with mild and moderate severity. INTERPRETATION: The lower frequency content suggests lesser vertical oscillation of the center of gravity. Lack of differences between severities may suggest presence of differences prior to currently established diagnosis timelines. Analysis of the frequency content may potentially serve to provide earlier diagnostic assessment of this debilitating disease.

Improvement in strength following resistance training in MS patients despite varied disability levels.

Strength and endurance data from 67 participants with multiple sclerosis (MS) were compared before, during and after a 6-month program of standardized resistance training. The hypothesis was that a standardized, structured resistance training exercise program improves strength in MS patients with different levels of disability. The range of EDSS scores was 1-8: (40% - EDSS of 1-4.5), (35% - EDSS of 5-7) (25% - EDSS of 7.5 or higher). This unique study evaluated patients with differing levels of disability for a change in strength and endurance following a 6-month training program. Data were analyzed by repeat measures and analysis of variables using Proc GLM in SAS to account for variability between subjects, and within subjects, due to repeated measures at 3 time points. Each treatment was blocked by disability class. Every within-treatment analysis was significant. Each exercise showed significant improvement in strength for participants, despite disability levels. Increases in strength followed parallel improvement pathways, at all disability levels. All but one treatment displayed highly significant improvement (p-value < 0.0001). The results demonstrated that all individuals with MS, despite disability levels, show parallel improvement in strength and endurance. This study supports the use of exercise, including resistance programs, for all MS patients.

A randomized open label study of pain medications (naproxen, acetaminophen and ibuprofen) for controlling side effects during initiation of IFN beta-1a therapy and during its ongoing use for relapsing-remitting multiple sclerosis.

Multiple sclerosis (MS) patients initiating IFN beta-1a, Avonex, therapy (Group 1, n = 30) or experiencing side effects after 6 months on therapy (Group 2, n = 30) were randomized for 5 weeks open label adjunct therapy to naproxen (Aleve), acetaminophen (Tylenol) or ibuprofen (Advil). Our hypothesis was that non-prescription pain medications are effective in decreasing or alleviating the side effects associated with IFN beta-1a therapy. Contrary to the hypothesis, most patients in both groups continued to report side effects on all pain medications. After 5 weeks, headache, fever, chills and injection site pain were low in < or = 50% of patients. Moderate to significant fatigue, muscle or joint pain continued in most patients. As a quality of life measure, the Modified Fatigue Impact Scale (mFIS) improved for Group 1 on naproxen or ibuprofen with greatest improvement in physical subset (P = 0.002 for naproxen and P<0.01 for ibuprofen). Total mFIS for Group 1 on acetaminophen improved (P = 0.04) due to improved cognitive subset rather than physical subset. Group 2, with side effects initially, reported less significant fatigue (severity 5-10) but more moderate fatigue (severity 2-4) at study end for all three medications. All medications improved cognitive subset (P = 0.05). Physical mFIS subset did not improve for Group 2 on acetaminophen, but did with naproxen (P = 0.05) or ibuprofen (P = 0.03). Naproxen and ibuprofen were more effective than acetaminophen in minimizing physical side effects of IFN beta-1a. None of the three pain medications tested were as effective as hypothesized for minimizing fatigue or muscle and joint pain.

Discordant functional and inflammatory parameters in multiple sclerosis patients after autologous haematopoietic stem cell transplantation.

This article describes outcomes in four patients with advanced multiple sclerosis up to two years after autologous haematopoietic stem cell transplantation using a total-body irradiation-based preparative regimen. MRI and CSF analyses demonstrated clear suppression of the inflammatory processes. The results demonstrate however, a dissociation of inflammation parameters and functional disability findings raising questions about optimal future stem cell transplantation strategies for this disease.