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Background: Exercise may have beneficial effects on both well-being and walking ability in multiple sclerosis (MS). Exercise is shown to be neuroprotective in rodents and may also enhance cognitive function in humans. It may, therefore, be particularly useful for MS patients with pronounced neurodegeneration. Objective: To investigate the potential of standardized exercise as a therapeutic intervention for progressive MS, in a randomized-controlled pilot trial. Methods: Patients with progressive MS and moderate disability (Expanded Disability Status Scale (EDSS) of 4-6) were randomized to one of three exercise interventions (arm ergometry, rowing, bicycle ergometry) for 8-10 weeks or a waitlist control group. We analyzed the drop-out rate as a measure of feasibility. The primary endpoint of the study was aerobic fitness. Secondary endpoints were walking ability, cognitive function as measured by a neuropsychological test battery, depression and fatigue. Results: A total of 42 patients completed the trial (10.6% drop-out rate). Significant improvements were seen in aerobic fitness. In addition, exercise improved walking ability, depressive symptoms, fatigue and several domains of cognitive function. Conclusion: This study indicated that aerobic training is feasible and could be beneficial for patients with progressive MS. Larger exercise studies are needed to confirm the effect on cognition. Trial Registration: ISRCTN (trial number 76467492) http://isrctn.org

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Patient self-report health measures have received increasing recognition as supplementary outcome parameters in multiple sclerosis (MS). Given the high prevalence of cognitive problems in this population, reliability and validity of self-report instruments in patient groups with cognitive impairment is essential, especially when using such scales longitudinally. A sample of 80 MS patients with cognitive dysfunction according to Symbol Digit Modalities Test (SDMT) score and 107 unimpaired patients were included in the analyses. Data was available from the Hamburg Quality of Life Questionnaire in Multiple Sclerosis (HAQUAMS), the Hospital Anxiety and Depression Scale (HADS), clinical rating scores [Expanded Disability Status Scale (EDSS) and FS (Functional Status) scales, CAMBS (Cambridge MS Basic Score)] and objective tests of upper and lower limb function [Timed 8 Meter Walk (T8) and Nine Hole Peg Test (9HPT)). Both self-report questionnaires showed satisfactory internal consistencies and retest reliability. Pattern and magnitude of correlations with other health status measures supported the validity of both instruments. However, there was a marked discrepancy between subjective and objective measures of cognitive function. Cognitively impaired patients furthermore showed significantly higher depression and anxiety as well as lower quality of life (QoL). The report provides evidence that QoL and affective symptomatology can be reliably assessed in MS patients with cognitive dysfunction. The common pattern of poor correlation between self-rated and objective cognitive function thus appears to be a result of the patients' (adaptive or maladaptive) coping mechanisms rather than being due to inaccurate measurement.

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Objective: Depression and fatigue are among the most common symptoms of multiple sclerosis (MS). These symptoms frequently co-occur and partially overlap in MS but their underlying biological substrates are unclear. In this study, we examined the relative role of cytokines and hypothalamic-pituitary-adrenal (HPA) axis activity for depression and fatigue in patients with relapsing-remitting MS (RRMS).Methods: HPA axis function and frequency of stimulated cytokine (IFNγ and TNFα) producing T cells was measured cross-sectionally in 44 female patients with RRMS. All subjects completed a neurological exam, the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) and self-report questionnaires. Results: Ten patients met diagnostic criteria for MDD. MS patients with comorbid MDDshowed normal morning but elevated evening salivary cortisol levels resulting in a flattened slope. While higher frequency of cytokine producing CD8+ T cells was also seen in MS patients with MDD, these markers were more closely associated with fatigue than depression. Conclusions:This study supports a role of HPA axis hyperactivity for major depression in MS. In addition, inflammatory and neuroendocrine factors may differentially mediate fatigue and depressive symptoms.

Quality of life (QoL) is discussed as an additional outcome measure in multiple sclerosis (MS). However, few questionnaires assessing disease specific QoL in MS have been published. On the basis of the literature and interviews with clinicians and MS patients, we have developed a disease specific QoL instrument and validated it in a broad range of patients with MS. In this study, a heterogeneous sample of n = 237 MS patients completed the newly developed Hamburg Quality of Life Questionnaire in Multiple Sclerosis (HAQUAMS, in German language) and a battery of already validated questionnaires. They further underwent neurological scoring and objective tests. By these means, we investigated its validity, appropriateness, internal consistency, and retest reliability. Internal consistency and retest coefficients were high and satisfied psychometric standards. Convergent and discriminant validity was supported by direction, magnitude and pattern of correlations with other health measures. HAQUAMS subscales and its total score distinguished between patient groups of varied disease severity, cognitive impairment, and affective symptomatology. No floor or ceiling effects were found in either of the HAQUAMS subscales. The HAQUAMS is a reliable, valid and appropriate instrument for QoL assessment in multiple sclerosis. Data of responsiveness are currently being obtained.

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