Fifty-four multiple sclerosis (MS) patients were randomly assigned to exercise (EX) or nonexercise (NEX) groups. Before and after 15 weeks of aerobic training, aspects of fitness including maximal aerobic capacity (VO2max), isometric strength, body composition, and blood lipids were measured. Daily activities, mood, fatigue, and disease status were measured by the Profile of Mood States (POMS), Sickness Impact Profile (SIP), Fatigue Severity Scale (FSS), and neurological examination. Training consisted of 3 x 40-minute sessions per week of combined arm and leg ergometry. Expanded Disability Status Scale (EDSS) scores were unchanged, except for improved bowel and bladder function in the EX group. Compared with baseline, the EX group demonstrated significant increases in VO2max, upper and lower extremity strength, and significant decreases in skinfolds, triglyceride, and very-low-density lipoprotein (VLDL). For the EX group, POMS depression and anger scores were significantly reduced at weeks 5 and 10, and fatigue was reduced at week 10. The EX group improved significantly on all components of the physical dimension of the SIP and showed significant improvements for social interaction, emotional behavior, home management, total SIP score, and recreation and past times. No changes were observed for EX or NEX groups on the FSS. Exercise training resulted in improved fitness and had a positive impact on factors related to quality of life.

Chronic Fatigue Syndrome (CFS) is characterized by debilitating fatigue, often accompanied by widespread muscle pain that meets criteria for Fibromyalgia Syndrome (FMS). Symptoms become markedly worse after exercise. Previous studies implicated dysregulation of the sympathetic nervous system (SNS), and immune system (IS) in CFS and FMS. We recently demonstrated that Acid Sensing Ion Channel (likely ASIC3), purinergic type 2X receptors (likely P2X4 and P2X5), and the transient receptor potential vanilloid type 1 (TRPV1) are molecular receptors in mouse sensory neurons detecting metabolites that cause acute muscle pain and possibly muscle fatigue. These molecular receptors are found on human leukocytes along with SNS and IS genes. Real-time, quantitative PCR showed that 19 CFS patients had lower expression of β-2 adrenergic receptors but otherwise did not differ from 16 controls before exercise. After a sustained moderate exercise test, CFS patients showed greater increases than controls in gene expression for metabolite detecting receptors ASIC3, P2X4 and P2X5, for SNS receptors α-2A, β-1, β-2 and COMT, and IS genes for IL10 and TLR4 lasting from 0.5-48 hours (P< .05). These increases were also seen in the CFS subgroup with comorbid FMS and were highly correlated with symptoms of physical fatigue, mental fatigue and pain. These new findings suggest dysregulation of metabolite detecting receptors as well as SNS and IS in CFS and CFS-FMS.Perspective-Muscle fatigue and pain are major symptoms of CFS. Following moderate exercise, CFS and CFS-FMS patients show enhanced gene expression for receptors detecting muscle metabolites and for SNS and IS, which correlate with these symptoms. These findings suggest possible new causes, points for intervention and objective biomarkers for these disorders.

For many years, patients with multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system, have been advised to avoid exercise. MS is believed to be autoimmune in origin, mediated by activated T cells which penetrate the blood-brain barrier and attack myelin. The pathophysiology, with respect to function is an impairment of saltatory conduction, specifically, slowing of conduction speed and/or conduction block. Symptoms can temporarily worsen on exposure to heat or during physical exercise. Exercise programmes must be designed to activate working muscles but avoid overload that results in conduction block. Fatigue, often severe, affects about 85% of MS patients and, along with motor and sensory symptoms, results in decreased mobility and reduced quality of life. Physical activity and recreation are reduced in patients with MS. Before developing recommendations, physical activity patterns and the physical effects of MS should be assessed in individual patients. Patients may then be functionally classified. Physical activity can also be classified in a pyramid structure, with the most basic functions forming the base and the most integrated functions on top. The muscular fitness pyramid progresses through passive range of motion, active resistive, specific strengthening and integrated strength exercises Overall physical activity may be increased according to functional level by performing activities of daily living, incorporating inefficiencies into daily living, pursuing more active recreation and eventually developing a structured exercise programme. The importance of the proper exercise environment, balance and coordination issues and factors related to adherence are discussed.

Davis SL, Wilson TE, White AT, Frohman EM. Thermoregulation in multiple sclerosis. J Appl Physiol 109: 1531-1537. First published July 29, 2010 doi:10.1152/japplphysiol.00460.2010.-Multiple sclerosis (MS) is a progressive neurological disorder that disrupts axonal myelin in the central nervous system. Demyelination produces alterations in saltatory conduction, slowed conduction velocity, and a predisposition to conduction block. An estimated 60 -80% of MS patients experience temporary worsening of clinical signs and neurological symptoms with heat exposure. Additionally, MS may produce impaired neural control of autonomic and endocrine functions. This review focuses on five main themes regarding the current understanding of thermoregulatory dysfunction in MS: 1) heat sensitivity; 2) central regulation of body temperature; 3) thermoregulatory effector responses; 4) heat-induced fatigue; and 5) countermeasures to improve or maintain function during thermal stress. Heat sensitivity in MS is related to the detrimental effects of increased temperature on action potential propagation in demyelinated axons, resulting in conduction slowing and/or block, which can be quantitatively characterized using precise measurements of ocular movements. MS lesions can also occur in areas of the brain responsible for the control and regulation of body temperature and thermoregulatory effector responses, resulting in impaired neural control of sudomotor pathways or neural-induced changes in eccrine sweat glands, as evidenced by observations of reduced sweating responses in MS patients. Fatigue during thermal stress is common in MS and results in decreased motor function and increased symptomatology likely due to impairments in central conduction. Although not comprehensive, some evidence exists concerning treatments (cooling, precooling, and pharmacological) for the MS patient to preserve function and decrease symptom worsening during heat stress. demyelination; core temperature; sweating; skin blood flow; fatigue MULTIPLE SCLEROSIS (MS) is a disabling progressive neurological disorder affecting ϳ400,000 individuals in the United States. The pathophysiology of MS results in a disruption or loss of axonal myelin in the central nervous system (CNS), leading to the formation of scar tissue (sclerosis). MS is thought to involve a number of autoimmune injury cascades that appear to be dependent on the interaction of complex epigenetic and environmental factors. Immune responses in individuals with MS are skewed toward a proinflammatory state, resulting in inflammation, demyelination, and ultimately loss of axons and disorganization of normal tissue architecture within the CNS (23). Demyelination is associated with corresponding changes in axonal physiology, including a loss of saltatory properties of electrical conduction, reduction in conduction velocity, and a predisposition to conduction block. These pathophysiological mechanisms underlie the myriad of symptoms (Table 1) in individuals with MS and are contingent on the neuroanatomic l...

Objectives To determine mRNA expression differences in genes involved in signaling and modulating sensory fatigue, and muscle pain in patients with Chronic Fatigue Syndrome (CFS) and Fibromyalgia Syndrome (FM) at baseline, and following moderate exercise. Design Forty eight Patients with CFS-only, or CFS with comorbid FM, 18 Patients with FM that did not meet criteria for CFS, and 49 healthy Controls underwent moderate exercise (25 minutes at 70% maximum age predicted heart-rate). Visual-analogue measures of fatigue and pain were taken before, during, and after exercise. Blood samples were taken before, and 0.5, 8, 24, and 48 hours after exercise. Leukocytes were immediately isolated from blood, number coded for blind processing and analyses, and flash frozen. Using real-time, quantitative PCR, the amount of mRNA for 13 genes (relative to control genes) involved in sensory, adrenergic, and immune functions was compared between groups at baseline, and following exercise. Changes in amounts of mRNA were correlated with behavioral measures, and functional clinical assessments. Results No gene expression changes occurred following exercise in Controls. In 71% of CFS patients, moderate exercise increased most sensory and adrenergic receptor’s and one cytokine gene’s transcription for 48 hours. These post-exercise increases correlated with behavioral measures of fatigue and pain. In contrast, for the other 29% of CFS patients, adrenergic α-2A receptor’s transcription was decreased at all time points after exercise; other genes were not altered. History of orthostatic intolerance was significantly more common in the α-2A decrease subgroup. FM only patients showed no post-exercise alterations in gene expression, but their pre-exercise baseline mRNA for two sensory ion channels and one cytokine were significantly higher than Controls. Conclusions At least two subgroups of CFS patients can be identified by gene expression changes following exercise. The larger subgroup showed increases in mRNA for sensory and adrenergic receptors and a cytokine. The smaller subgroup contained most of the CFS patients with orthostatic intolerance, showed no post-exercise increases in any gene, and was defined by decreases in mRNA for α-2A. FM only patients can be identified by baseline increases in 3 genes. Post-exercise increases for 4 genes meet published criteria as an objective biomarker for CFS, and could be useful in guiding treatment selection for different subgroups.

We examined whether treatment with daclizumab, a humanized monoclonal antibody specific for the interleukin-2 receptor alpha chain, was safe and efficacious in relapsing-remitting and secondary progressive multiple sclerosis patients. Nineteen ambulatory patients with clinically active disease were treated for 5 to 25 months. Seventeen patients were not responding to other immunotherapies. Daclizumab was generally well tolerated. Sustained clinical improvement (10 patients) or stabilization (9 patients) was observed. Daclizumab treatment produced significant reduction in magnetic resonance imaging activity.

Chronic fatigue syndrome (CFS) patients often report symptom flare (SF) for >24 h after moderate exercise (post-ex). We hypothesized that SF is linked to increases in circulating cytokines and CD40 Ligand (CD40L). In 19 CFS patients and 17 controls, mental and physical fatigue and pain symptom ratings were obtained together with serum for 11 cytokines and CD40L before and at 0.5, 8, 24, and 48 h post-ex. Before exercise, CFS had lower CD40L (p < .05) but similar cytokines versus controls. In subgroups based on SF at 48 h, high SF patients (n = 11) increased in IL-1β, IL-12, IL-6, IL-8, IL-10, and IL-13 (p < .05) 8 h post-ex. Low SF patients (n = 8) showed post-ex decreases in IL-10, IL-13, and CD40L, and controls decreased in IL-10, CD40L, and TNFα (p < .05). Thus, in CFS, cytokine activity may vary directly with SF, which may explain prior inconsistent findings.

Objective Chronic fatigue syndrome (CFS) and multiple sclerosis (MS) are characterized by debilitating fatigue, yet evaluation of this symptom is subjective. We examined metabolite-detecting, adrenergic, and immune gene expression (mRNA) in patients with CFS (n=22) vs. MS (n=20) vs. healthy controls (n=23) and determined their relationship to fatigue and pain before and after exercise. Methods Blood samples and fatigue and pain ratings were obtained at baseline and 0.5, 8, 24, and 48 hours following sustained moderate exercise. Leukocyte mRNA of 4 metabolite-detecting receptors (ASIC3, P2X4, P2X5, TRPV1), 4 adrenergic (α-2a, β-1, β-2 receptors, COMT) and 5 immune markers (CD14, TLR4, IL-6, IL-10, LTa) was examined using quantitative PCR. Results CFS patients had greater post-exercise increases in fatigue and pain (10–29 pts above baseline, p<.001) and greater mRNA increases in P2X4, TRPV1, CD14 and all adrenergic receptors than controls (1.3 ± .14 to 3.4 ± .90 fold increase above baseline, p=.04 – .005). CFS patients with co-morbid fibromyalgia (n=18) also showed greater increases in ASIC3 and P2X5 (p<.05). MS patients had greater post-exercise increases than controls in β-1 and β-2 adrenergic receptor expression (1.4 ± .27 and 1.3 ± .06 fold increase, respectively, p=.02 and <.001) and greater decreases in TLR4 (p=.02). In MS, IL-10 and TLR4 decreases correlated with higher fatigue scores. Conclusion Post-exercise mRNA increases in metabolite-detecting receptors were unique to CFS patients while both MS and CFS showed abnormal increases in adrenergic receptors. Among MS patients, greater fatigue was correlated with blunted immune marker expression.