Independent outdoor mobility of persons with multiple sclerosis – A systematic review

Background: Multiple sclerosis (MS) can manifest itself in many ways, all of which can affect the independent outdoor mobility of persons with MS (pwMS). In most studies, mobility of pwMS is defined by the ability to walk. However, mobility comprises more than walking alone. This systematic review provides an overview of the literature on several types of independent outdoor mobility of pwMS. We aimed to identify which specific factors may influence outdoor mobility and how the lives of pwMS may be affected by a reduced mobility. Methods: A systematic literature search was performed, using three databases (PubMed, PsychInfo and Web of Science). Studies had to describe a group of pwMS sclerosis and had to concern some type of mobility other than walking. Results: The 57 studies that fulfilled the criteria included in total 10,394 pwMS and in addition, 95,300 pwMS in separate prevalence study. These studies showed that pwMS as a group have a decreased fitness to drive, make use of a wheelchair or mobility scooter more often and have difficulties making use of public transport. Mobility problems especially occur in patients with cognitive problems, secondary progressive MS or high disability scores. Conclusions: The reduced mobility may prevent pwMS participating in society. However, few studies investigating interventions or rehabilitation options to improve mobility were found in the existing literature, highlighting an until now under recognised unmet need

Whole Exome Sequencing in Multi-Incident Families Identifies Novel Candidate Genes for Multiple Sclerosis

Multiple sclerosis (MS) is a degenerative disease of the central nervous system in which auto-immunity-induced demyelination occurs. MS is thought to be caused by a complex interplay of environmental and genetic risk factors. While most genetic studies have focused on identifying common genetic variants for MS through genome-wide association studies, the objective of the present study was to identify rare genetic variants contributing to MS susceptibility. We used whole exome sequencing (WES) followed by co-segregation analyses in nine multi-incident families with two to four affected individuals. WES was performed in 31 family members with and without MS. After applying a suite of selection criteria, co-segregation analyses for a number of rare variants selected from the WES results were performed, adding 24 family members. This approach resulted in 12 exonic rare variants that showed acceptable co-segregation with MS within the nine families, implicating the genes MBP, PLK1, MECP2, MTMR7, TOX3, CPT1A, SORCS1, TRIM66, ITPR3, TTC28, CACNA1F, and PRAM1. Of these, three genes (MBP, MECP2, and CPT1A) have been previously reported as carrying MS-related rare variants. Six additional genes (MTMR7, TOX3, SORCS1, ITPR3, TTC28, and PRAM1) have also been implicated in MS through common genetic variants. The proteins encoded by all twelve genes containing rare variants interact in a molecular framework that points to biological processes involved in (de-/re-)myelination and auto-immunity. Our approach provides clues to possible molecular mechanisms underlying MS that should be studied further in cellular and/or animal models

Fluoxetine in Progressive Multiple Sclerosis (FLUOX-PMS) : study protocol for a randomized controlled trial

Background: Currently available disease-modifying treatments acting by modifying the immune response are ineffective in progressive multiple sclerosis (MS), which is caused by a widespread axonal degeneration. Mechanisms suspected to be involved in this widespread axonal degeneration are reduced axonal energy metabolism, axonal glutamate toxicity, and reduced cerebral blood flow. Fluoxetine might theoretically reduce axonal degeneration in MS because it stimulates energy metabolism through enhancing glycogenolysis, stimulates the production of brain-derived neurotrophic factor, and dilates cerebral arterioles. The current document presents the protocol of a clinical trial to test the hypothesis that fluoxetine slows down the progressive phase of MS. Methods/Design: The FLUOX-PMS trial is a multi-center, randomized, controlled and double-blind clinical study. A total of 120 patients with the diagnosis of either secondary or primary progressive MS will be treated either by fluoxetine (40 mg daily) or placebo for a total period of 108 weeks. The primary endpoint is the time to confirmed disease progression defined as either at least a 20% increase in the timed 25-Foot Walk or at least a 20% increase in the 9-Hole Peg Test. Secondary endpoints include the Hauser ambulation index, cognitive changes, fatigue, magnetic resonance imaging of the brain, and in a small subgroup optical coherence tomography. Discussion: The FLUOX-PMS trial will gives us information as to whether fluoxetine has neuroprotective effects in patients with progressive MS

Tremor in multiple sclerosis

Tremor is estimated to occur in about 25 to 60 percent of patients with multiple sclerosis (MS). This symptom, which can be severely disabling and embarrassing for patients, is difficult to manage. Isoniazid in high doses, carbamazepine, propranolol and gluthetimide have been reported to provide some relief, but published evidence of effectiveness is very limited. Most trials were of small size and of short duration. Cannabinoids appear ineffective. Tremor reduction can be obtained with stereotactic thalamotomy or thalamic stimulation. However, the studies were small and information on long-term functional outcome is scarce. Physiotherapy, tremor reducing orthoses, and limb cooling can achieve some functional improvement. Tremor in MS remains a significant challenge and unmet need, requiring further basic and clinical research

Reduced Dual-Task Performance in MS Patients Is Further Decreased by Muscle Fatigue

Background. Multiple sclerosis (MS) can be accompanied by motor, cognitive, and sensory impairments. Additionally, MS patients often report fatigue as one of their most debilitating symptoms. It is, therefore, expected that MS patients will have difficulties in performing cognitive-motor dual tasks (DTs), especially in a fatiguing condition. Objective. To determine whether MS patients are more challenged by a DT than controls in a fatiguing and less-fatiguing condition and whether DT performance is associated with perceived fatigue. Methods. A group of 19 MS patients and 19 age-, sex-, and education-matched controls performed a cognitive task (2-choice reaction time task) separately or concurrent with a low-force or a high-force motor task (index finger abduction at 10% or 30% maximal voluntary contraction). Results. MS patients performed less well on a cognitive task than controls. Cognitive task performance under DT conditions decreased more for MS patients. Moreover, under high-force DT conditions, cognitive performance declined in both groups but to a larger degree for MS patients. Besides a decline in cognitive task performance, MS patients also showed a stronger decrease in motor performance under high-force DT conditions. DT costs were positively related to perceived fatigue as measured by questionnaires. Conclusions. Compared with controls, MS patients performed less well on DTs as demonstrated by a reduction in both cognitive and motor performances. This performance decrease was stronger under fatiguing conditions and was related to the sense of fatigue of MS patients. These data illustrate problems that MS patients may encounter in daily life because of their fatigue

Muscle Fatigability During a Sustained Index Finger Abduction and Depression Scores Are Associated With Perceived Fatigue in Patients With Relapsing-Remitting Multiple Sclerosis

Introduction. Fatigue is a common and debilitating symptom in patients with multiple sclerosis (MS). Self-reported levels of perceived fatigue are associated with both patient characteristics and clinical measures. Pilot analysis indicated that muscle fatigability combined with depression scores was highly associated with perceived fatigue in patients with MS. Studies that combine physiological and psychological constructs to explain MS-related fatigue are scarce. Therefore, the present study aimed to evaluate the robustness of the association between perceived fatigue, muscle fatigability, and depression scores in MS. Methods. Eighty-six patients with relapsing-remitting MS completed 2 fatigue questionnaires (Fatigue Severity Scale [FSS] and Modified Fatigue Impact Scale [MFIS]) and a depression questionnaire (Hospital Anxiety and Depression Scale [HADS]). Maximal index finger abduction force (maximum voluntary contraction [MVC]) was measured, as well as muscle fatigability during a 2-minutes sustained maximal contraction. Multivariable regression analyses were used to analyze the association between perceived fatigue, and muscle fatigability and depression scores. Results. Perceived fatigue was associated with depression, muscle fatigability, and, depending on the questionnaire, to sex or to MVC. The model explained 40% and 48% of the variation in perception of fatigue as indexed with FSS questionnaire (r(partial): HADS 0.45, muscle fatigability 0.45, MVC -0.14, sex 0.32), and MFIS physical questionnaire (r(partial): HADS 0.59, muscle fatigability 0.49, MVC -0.38), respectively. Conclusions. The found association accentuates the importance of including both physiological fatigability-related and psychological mood-related constructs in models to explain perceived fatigue in patients with MS. The model also directs future research toward applying effortful conditions and emphasizes the importance of assessing different constructs when evaluating rehabilitation strategies to reduce MS-related fatigue

Reduced Voluntary Activation During Brief and Sustained Contractions of a Hand Muscle in Secondary-Progressive Multiple Sclerosis Patients

Background. Secondary-progressive multiple sclerosis (SPMS) patients have structural cortical damage resulting in increased compensatory cortical activity during (submaximal) performance. However, functional effects of changed cortical output are difficult to measure. The interpolated-twitch technique allows for measurement of voluntary activation (VA) necessary for force production. This study aimed to determine VA, force, and muscle fatigue during brief and sustained contractions in SPMS patients. Because fatigue effects are not confined to the motor system, we additionally examined fatiguing effects on cognitive performance. Methods. Twenty-five SPMS and 25 sex-, age-, and education-matched participants performed brief (5 seconds) and sustained (2 minutes) maximal index finger abductions. To evaluate VA, double-pulse twitches were evoked before, during, and after contractions. Additionally, data were compared with data obtained in relapsing-remitting multiple sclerosis (RRMS) patients. Subjects also performed choice-reaction time tasks before and after the sustained contraction. Results. During brief contractions, VA (85% vs 94%, P = .004) and force (25 N vs 32 N, P = .011) were lower for SPMS patients than controls. During sustained contractions, VA (P = .001) was also lower, resulting in greater force decline (73% vs 63%, P <.001) and reduced peripheral fatigue (19% vs 50%, P <.001). Comparisons with RRMS resulted in lower VA, greater force decline, and greater estimated central fatigue in SPMS. SPMS patients were slower (P <.001) and made more errors (P <.001) than controls, but neither group reduced their performance after the sustained contraction. Conclusion. SPMS patients had lower VA than RRMS patients and controls. The importance of voluntary activation for muscle force and fatigability warrants targeted rehabilitation strategies

Progression in multiple sclerosis:Further evidence of an age dependent process

The relapsing-remitting phase and the progressive phase of multiple sclerosis (MS) seem to be the result of distinct pathophysiological processes. Previous research on the natural history of MS was largely focussed on relapses and disability scores. In this study we evaluated 438 patients with secondary or primary progressive MS. The influence of gender, initial disease course, onset manifestation and age at disease onset on age at progression and time to progression were evaluated with Kaplan-Meier survival analysis and Cox multivariate regression models. The analysis of these data showed that the initial disease course (SPMS or PPMS) had no influence on the age at progression. Gender had no influence on age at progression in PPMS and SPMS patients nor on time to progression in SPMS patients. PPMS patients with visual or brainstem/cerebellar onset had a significantly younger age at progression. SPMS patients with motor onset had a significantly higher age at progression and longer time to progression. Time to progression was significantly shorter in SPMS patients with higher age at disease onset. Our data give further support to the notion that progression in MS is an age dependent process independent of relapses. (c) 2007 Elsevier B.V. All rights reserved