Cross-Sectional Examination of the Associations Between Symptoms, Community Integration, and Mental Health in Multiple Sclerosis.

OBJECTIVE: To determine the frequency and severity of 8 symptoms in persons with multiple sclerosis (MS) and to examine the association between these symptoms and community integration and mental health. DESIGN: Cross-sectional survey that assessed 8 symptoms (pain, fatigue, imbalance, numbness, weakness, shortness of breath, vision loss, and memory loss), disease progression (self-report version of the Expanded Disability Status Scale), community integration, and mental health. SETTING: Community. PARTICIPANTS: Adults with self-reported MS who responded to a mailed survey (N=180). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The presence and intensity of symptoms were measured with a symptoms checklist. Community integration was assessed with the Community Integration Questionnaire, and mental health was measured by the Mental Health Index of the Medical Outcomes Study 36-Item Short-Form Health Survey. RESULTS: The average number of symptoms reported was 5.07±2.18. The most common symptoms (fatigue, weakness, and imbalance) were also rated as the most severe. Not all symptoms were associated with level of disease progression or with MS subtype. Symptoms related to mobility were more likely to be associated with these variables. The 8 symptoms as a whole accounted for significant amounts of variance (range, 13%-21%) in measures of community integration and mental health, with specific symptoms making differential independent contributions to these measures. CONCLUSIONS: This study demonstrates that most individuals with MS report a number of bothersome symptoms. Type of MS or level of progression does not tell the whole story regarding the impact of symptoms.

Improved physical fitness correlates with improved cognition in multiple sclerosis.

OBJECTIVE: To determine whether there is an association between improvements in objective measures of physical fitness and performance on cognitive tests in people with multiple sclerosis (MS). DESIGN: Post hoc correlational analysis in which people demonstrating physical improvement were compared with those not demonstrating physical improvement. SETTING: Individuals with MS residing in the community. PARTICIPANTS: Adults with clinically confirmed MS (N=88) who participated in a controlled trial of a telephone-based health promotion intervention, chose to work on exercise, and completed the pre- and postintervention assessments. INTERVENTIONS: Participants were measured for strength (isokinetic dynamometer), aerobic fitness (bicycle ergometer), and cognition (Paced Auditory Serial Addition Test [PASAT], Trail Making Test [TMT]) at baseline and 12 weeks later. Change in fitness was calculated by subtracting each participant's baseline score from the outcome score, and then transforming the difference to a z score. Individuals with a z score ≥1 on any fitness measure were placed in the physically improved group (n=25). All others were in the physically not improved group (n=57). MAIN OUTCOME MEASURES TMT, PASAT RESULTS: After controlling for covariates (age, sex, ethnicity, education, disease activity, MS type), there was a significant group-by-time interaction, suggesting that cognitive functioning changed over time based on level of fitness. Participants in the physically improved group demonstrated improved performance on measures of executive functioning after 12 weeks of exercise. CONCLUSIONS: The results of this study lend support to the hypothesis that change in fitness is associated with improved executive functioning in people with MS.

A PROMIS fatigue short form for use by individuals who have multiple sclerosis.

PURPOSE: To derive from the Patient Reported Outcomes Measurement Information System (PROMIS) fatigue item bank, a short form for individuals with multiple sclerosis (MS), the PROMIS-Fatigue(MS). METHODS: A panel of 37 clinicians and 46 individuals with MS ranked the relevance of PROMIS fatigue items to persons with MS. Eight items were selected for the PROMIS-Fatigue(MS) that maximized relevance rankings, content coverage, and item discrimination. The PROMIS-Fatigue(MS) and an existing, 7-item PROMIS fatigue short form (PROMIS-Fatigue(SFv1.0)) were administered to a new sample of 231 individuals with MS. Known groups and content validity were assessed. RESULTS: Scores from the short forms were highly correlated (r = 0.92). Discriminant validity of the PROMIS-Fatigue(MS) scores was supported in known groups comparisons. Scores of neither short form exhibited an advantage in quantitative analyses. The PROMIS-Fatigue(MS) targeted more of the content included in participants' responses to open-ended questions than did the PROMIS-Fatigue(SFv1.0). CONCLUSIONS: The PROMIS-Fatigue(MS) was derived to have content validity in MS samples. The validity of the measure was further supported by the ability of PROMIS-Fatigue(MS) items to discriminate among groups expected to differ in levels of fatigue. We recommend its use in measuring the fatigue of individuals with MS.

Exercise training and cognition in multiple sclerosis: The GET Smart trial protocol.

BACKGROUND AND OBJECTIVES: Multiple sclerosis (MS) causes cognitive impairment in approximately 50% of cases. Disease modifying medications and cognitive rehabilitation produce only small positive effects on cognition in MS. Converging animal and human research suggests that aerobic exercise may improve cognition in people with MS, but definitive trials are lacking. We describe the design of the GET Smart study, a randomized controlled trial comparing the effects of aerobic exercise versus stretching and toning on cognition in MS. METHODS: The study is a single-blind, parallel group randomized (1:1) controlled trial that compares aerobic exercise training with an active control group consisting of stretching and toning exercises for improving cognition. Participants are nondepressed, ambulatory, non-exercising adults with MS aged 18-54 years who have below average cognitive processing speed. Both treatments were designed to generate equivalent outcome expectancies and entailed supervised, progressive exercise programs, 3 times per week for up to 40 min over a 6 month period. PROJECTED PATIENT OUTCOMES: The primary hypothesis is that the aerobic training group will demonstrate significantly greater cognitive processing speed compared with the control group at the end of the treatment phase (6 months) as measured by a composite of the Paced Auditory Serial Additon Test and the oral Symbol-Digit Modalities Test using intent-to treat analyses. Secondary outcomes are neuropsychological functioning and cardiorespiratory fitness as well as participant reported outcomes such as depression, sleep, and fatigue. Study findings will inform future research, patient education, clinical care and policymaking. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02106052.

Hematopoietic stem cell transplantation for multiple sclerosis: collaboration of the CIBMTR and EBMT to facilitate international clinical studies.

Clinical investigation of autologous hematopoietic stem cell transplantation (HSCT) as therapy for multiple sclerosis (MS) has been ongoing for over a decade. While several phase II studies have been finalized or are in progress, no definitive prospective randomized studies comparing HSCT versus alternative therapies for MS have been completed. In this conference report of North American and European experts who are involved in the care of MS patients, including neurologists and HSCT physicians, and representatives of the Center for International Blood and Marrow Transplant Research (CIBMTR) and European Group for Blood and Marrow Transplantation (EBMT), we (1) critically review progress to date in HSCT for MS; (2) describe current registry based projects including long-term follow-up studies in HSCT for MS and harmonization of the MS disease-specific research forms that will be used in future by both databases; (3) discuss challenges in study design for a prospective randomized clinical trial of HSCT versus alternative therapy for MS such as feasibility, and the importance of multidisciplinary clinical teams, need for a large sample size and duration of observation required for outcomes assessment; and (4) address future directions in HSCT therapy for MS. To undertake a definitive multicenter clinical trial in autologous HSCT for MS, it will be important to begin well in advance to assemble the team, evaluate proposals for study design, and consider options for the infrastructure and logistical support that will be needed. International collaboration, including partnership with the CIBMTR and EBMT, may be desirable and may in fact be critical for successful completion of a definitive comparative study.

Efficacy of paroxetine in treating major depressive disorder in persons with multiple sclerosis.

OBJECTIVE: The objective of this study was to evaluate the efficacy of paroxetine in treating major depressive disorder (MDD) in persons with multiple sclerosis (MS). METHOD: In this double-blind trial, 42 participants with MS and MDD were randomly assigned to one of two parallel 12-week treatment arms: paroxetine or placebo. The participants started at an initial dose of 10 mg/day paroxetine or placebo, titrated up to 40 mg daily based on symptoms response and side effects. The primary outcome measure was the Hamilton Rating Scale for Depression (HAM-D). Secondary outcomes included fatigue, anxiety and self-reported quality of life. RESULTS: Intent-to-treat analyses revealed that both groups improved from pretreatment to posttreatment. Although the treatment group improved more than the control group on most measures, few differences were statistically significant. For the primary outcome, 57.1% of participants in the treatment arm had at least a 50% reduction in HAM-D score, compared with 40% in the control group (nonsignificant). Treatment effects were greater among the participants who completed the study; 78.6% of completers had a treatment response compared with 42.1% of controls (P=.073). CONCLUSION: Although paroxetine may not be efficacious for all persons with MS and MDD, it appears to benefit some individuals.

The efficacy of telephone counseling for health promotion in people with multiple sclerosis: a randomized controlled trial.

OBJECTIVE: To determine if motivational interviewing-based telephone counseling increases health promotion activities and improves other health outcomes in people with multiple sclerosis (MS). DESIGN: Randomized controlled trial with wait-list controls and single-blinded outcome assessments conducted at baseline and at 12 weeks. SETTING: MS research and training center in the Pacific Northwest. PARTICIPANTS: Community-residing persons (N=130) with physician confirmed MS aged 18 or older who were able to walk unassisted at least 90 m (300 ft). INTERVENTION: A single in-person motivational interview followed by 5 scheduled telephone counseling sessions to facilitate improvement in 1 of 6 health promotion areas: exercise, fatigue management, communication and/or social support, anxiety and/or stress management, and reducing alcohol or other drug use. MAIN OUTCOME MEASURES: Health Promotion Lifestyle Profile II plus fatigue impact, subjective health, and objective measures of strength, fitness, and cognition. Intent-to-treat analyses of change scores were analyzed using nonparametric tests. RESULTS: Seventy persons were randomized to treatment and 60 to the control condition. The treatment group reported significantly greater improvement in health promotion activities, including physical activity, spiritual growth, and stress management as well as in fatigue impact and mental health compared with controls. In addition, the exerciser subgroup showed greater improvement than controls in self-selected walking speed. CONCLUSIONS: A less intensive, more accessible approach to health promotion based on telephone counseling and motivational interviewing shows promise and merits further study.

The electromyographer's guide to the motor unit.

This article's purpose is to explain the anatomicophysiologic basis for observations and measurements made by the electromyographer. An electromyographer may be trained in the techniques of electromyography without understanding the anatomicophysiology, and valuable interpretive subtleties may be missed. This article is an attempt to provide that background (ie, the link among anatomy, physiology, and electrodiagnostic findings). It is hoped that with a fuller understanding of the anatomicophysiologic basis of clinical electromyography, subtle observations can be made which will allow a more sophisticated level of interpretation of electromyography results. Such interpretations should improve the electromyographer's capacity to provide useful information to a referring physician and hence, improve the management of a patient.

Brain pathology of a patient 7years after autologous hematopoietic stem cell transplantation for multiple sclerosis.

Aggressive immunosuppression followed by autologous hematopoietic stem cell transplantation (aHSCT) can be an effective treatment for severe multiple sclerosis (MS), but not all stages of disease may benefit equally. The case of a 49-year-old woman with advanced secondary-progressive MS whose clinical course was not improved by aHSCT and who seven years after transplantation succumbed to complications of severe MS disease-related disability is presented. Autopsy findings of ongoing neurodegeneration despite only rare infiltrating T-lymphocytes illustrate that late MS disease may not represent a suitable disease stage for aHSCT.

Project Extension for Community Healthcare Outcomes (ECHO) in Multiple Sclerosis: Increasing Clinician Capacity.

BACKGROUND: A pilot program using the Project Extension for Community Healthcare Outcomes (ECHO) model was conducted for multiple sclerosis (MS) clinicians in the Pacific Northwest. The pilot was a collaboration between the National Multiple Sclerosis Society and faculty at the University of Washington. The goal was to determine the feasibility of using this telehealth model to increase the capacity and capability of clinicians in rural areas to treat people with MS. METHODS: Thirteen practice sites with 24 clinicians were recruited to participate. Videoconferencing was used to conduct weekly sessions consisting of brief didactics followed by case consultations. RESULTS: Most participants completing the outcome survey (10 of 15) indicated that they were more confident in treating patients with MS. They were satisfied with the training, felt better able to care for their patients, and had made changes in their treatment based on the case consultations and didactic content. They valued the case studies and case-based didactics and learned from each other as well as from the team. CONCLUSIONS: The pilot MS Project ECHO warrants further investigation regarding its potential effect on access to MS care delivery for underserved populations.

High-dose immunosuppressive therapy and autologous HCT for relapsing-remitting MS.

OBJECTIVE: To evaluate the safety, efficacy, and durability of multiple sclerosis (MS) disease stabilization after high-dose immunosuppressive therapy (HDIT) and autologous hematopoietic cell transplantation (HCT). METHODS: High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis (HALT-MS) is a phase II clinical trial of HDIT/HCT for patients with relapsing-remitting (RR) MS who experienced relapses with disability progression (Expanded Disability Status Scale [EDSS] 3.0-5.5) while on MS disease-modifying therapy. The primary endpoint was event-free survival (EFS), defined as survival without death or disease activity from any one of: disability progression, relapse, or new lesions on MRI. Participants were evaluated through 5 years posttransplant. Toxicities were reported using the National Cancer Institute Common Terminology Criteria for Adverse Events (AE). RESULTS: Twenty-five participants were evaluated for transplant and 24 participants underwent HDIT/HCT. Median follow-up was 62 months (range 12-72). EFS was 69.2% (90% confidence interval [CI] 50.2-82.1). Progression-free survival, clinical relapse-free survival, and MRI activity-free survival were 91.3% (90% CI 74.7%-97.2%), 86.9% (90% CI 69.5%-94.7%), and 86.3% (90% CI 68.1%-94.5%), respectively. AE due to HDIT/HCT were consistent with expected toxicities and there were no significant late neurologic adverse effects noted. Improvements were noted in neurologic disability with a median change in EDSS of -0.5 (interquartile range -1.5 to 0.0; p = 0.001) among participants who survived and completed the study. CONCLUSION: HDIT/HCT without maintenance therapy was effective for inducing long-term sustained remissions of active RRMS at 5 years. CLINICALTRIALSGOV IDENTIFIER: NCT00288626. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that participants with RRMS experienced sustained remissions with toxicities as expected from HDIT/HCT.

Double trouble in hereditary neuropathy: concomitant mutations in the PMP-22 gene and another gene produce novel phenotypes.

BACKGROUND: Mutations in the peripheral myelin protein 22 (PMP-22) gene are the most common cause of Charcot-Marie-Tooth neuropathy and may rarely occur in combination with other neurogenetic diseases. OBJECTIVE: To characterize 3 families having a mutation in PMP-22 in addition to another neurogenetic disease mutation. DESIGN: Clinical, electrophysiologic, and genetic evaluations were made of 3 families with more than 1 genetic neuromuscular disease. SETTING AND PATIENTS: Family members were evaluated in neurogenetic and muscular dystrophy clinics in a university medical center setting. RESULTS: Three unusual families were found: (1) 2 young brothers each having a PMP-22 duplication and a missense mutation in the GJB1 (Connexin-32) gene; (2) a 32-year-old woman having a PMP-22 duplication and a 1000-fold CTG repeat expansion in the DMPK gene (DM1 myotonic dystrophy); and (3) a 39-year-old man with a PMP-22 deletion and a missense mutation in the ABCD1 gene (adrenomyeloneuropathy). The mutations were "additive," causing a more severe phenotype than expected with each individual disease and coinciding with the important impact of each gene on peripheral nerve function. CONCLUSIONS: Individuals having 2 separate mutations in neuromuscular disease-related genes may develop unusually severe phenotypes. Neurologists should be alert to this possibility.

Satisfaction with, and the beneficial side effects of, hypnotic analgesia.

Case study research suggests that hypnosis treatment may provide benefits that are not necessarily the target of specific suggestions. To better understand satisfaction with and the beneficial "side effects" of hypnosis treatment, questions inquiring about treatment satisfaction and treatment benefits were administered to a group of 30 patients with chronic pain who had participated in a case series of hypnotic analgesia treatment. The results confirmed the authors' clinical experience and showed that most participants reported satisfaction with hypnosis treatment even when the targeted symptom (in this case, pain intensity) did not decrease substantially. Study participants also reported a variety of both symptom-related and nonsymptom-related benefits from hypnosis treatment, including decreased pain, increased perceived control over pain, increased sense of relaxation and well-being, and decreased perceived stress, although no single benefit was noted by a majority of participants.

Use of Neurofeedback to Enhance Response to Hypnotic Analgesia in Individuals With Multiple Sclerosis.

This proof of principle study examined the potential benefits of EEG neurofeedback for increasing responsiveness to self-hypnosis training for chronic pain management. The study comprised 20 individuals with multiple sclerosis (MS) who received 5 sessions of self-hypnosis training--1 face-to-face session and 4 prerecorded sessions. Participants were randomly assigned to have the prerecorded sessions preceded by either (a) EEG biofeedback (neurofeedback) training to increase left anterior theta power (NF-HYP) or (b) a relaxation control condition (RLX-HYP). Eighteen participants completed all treatment sessions and assessments. NF-HYP participants reported greater reductions in pain than RLX-HYP participants. The findings provide support for the potential treatment-enhancing effects of neurofeedback on hypnotic analgesia and also suggest that effective hypnosis treatment can be provided very efficiently.

An Empirical Investigation of a Biopsychosocial Model of Pain in Multiple Sclerosis.

OBJECTIVES: Pain is a significant problem for many individuals with multiple sclerosis (MS). Pain is often associated with other MS symptoms (eg, physical, sensorimotor, cognitive declines), and both pain and MS symptoms are hypothesized to contribute to psychosocial problems (eg, depression), other symptoms (eg, fatigue, sleep disturbance), and functional impairments (eg, pain interference). On the basis of a biopsychosocial model, we sought to: (1) examine the associations between pain, MS symptoms, depression, psychosocial, and functional variables and (2) identify possible risk and protective factors associated with pain in MS. MATERIALS AND METHODS: A cross-sectional survey was completed by 424 individuals with MS. Pain, MS symptoms, demographics, MS diagnostic factors, and psychosocial and functional variables were assessed. Data were analyzed by structural equation models. RESULTS: Participants were predominantly white (92%), middle-aged (mean=50.7 y), and female (80%). Results indicated that pain severity and depression accounted for >50% of the variance in pain interference. Although pain contributed minimally to fatigue and sleep quality, depression and MS symptoms predicted 49% of the variance in fatigue, and depression was largely responsible for the 40% of predicted variance in sleep quality. Identified risk factors for pain were low educational attainment and lack of a committed/marital relationship, even while controlling for diagnostic and other key demographic variables. DISCUSSION: Results highlight the importance of targeting interventions toward improving coping skills and social support within the context of pain and MS. Research is needed to determine whether effectively targeting depression in MS results in improvements of other critical psychosocial and physical functioning domains.

Fatigue and psychiatric illness in a large community sample of persons with multiple sclerosis.

BACKGROUND: Fatigue and depression are among the most common and disabling symptoms in multiple sclerosis (MS), but the nature and extent of the relationships between fatigue and psychiatric disorders in MS patients remain poorly understood. METHODS: A mail survey was completed by 739 members of the King County (WA) MS Association. Fatigue was evaluated by questions from the Modified Fatigue Impact Scale (MFIS), depressive symptoms by the Center for Epidemiologic Studies Depression Scale (CES-D), substance-use disorders from the PRIME-MD. Information on demographics, employment and characteristics of MS was also collected. Logistic regression was used to identify covariates significantly associated with disabling fatigue. Receiver operating characteristic (ROC) curve analysis evaluated the sensitivity and specificity of fatigue for depression. RESULTS: Twenty-five percent of this community-dwelling sample reported that their activities were often or almost always limited by fatigue. Seventy-six percent of subjects with disabling fatigue had significant depressive symptoms (CES-D >16), compared with 31% of those without disabling fatigue. Depression was strongly associated with fatigue, after controlling for age, gender, marital status, and severity, course and duration of illness. In logistic regression analysis, subjects with clinically significant depressive symptoms (CES-D >16) were much more likely to report disabling fatigue: OR = 6.24 (4.16, 9.35). Anxiety and substance-use disorders did not have the same strong associations with fatigue. Fatigue was highly sensitive and specific for clinically significant depressive symptoms. CONCLUSIONS: Disabling fatigue is strongly associated with clinically significant depressive symptoms. Patients who report disabling fatigue should be screened for depression.

Exercise and rehabilitation for individuals with multiple sclerosis.

It is the coexistence of physical and cognitive impairments, together with emotional and social issues in a disease with an uncertain course, that makes MS rehabilitation unique and challenging. Inpatient rehabilitation improves functional independence but has only limited success improving the level of neurologic impairment. Benefits are usually not long lasting. Severely disabled people derive equal or more benefit than those who are less disabled, but cognitive problems and ataxia tend to be refractory. There is now good evidence that exercise can improve fitness and function for those with mild MS and helps to maintain function for those with moderate to severe disability. Therapy can be performed over 6 to 15 weeks in outpatient or home-based settings or as a weekly day program lasting several months. Several different forms of exercise have been investigated. For most individuals, aerobic exercise that incorporates a degree of balance training and socialization is recommended. Time constraints, access, impairment level, personal preferences, motivations, and funding sources influence the prescription for exercise and other components of rehabilitation. Just as immunomodulatory drugs must be taken on a continual basis and be adjusted as the disease progresses, so should rehabilitation be viewed as an ongoing process to maintain and restore maximum function and QOL.

Modafinil to treat fatigue in amyotrophic lateral sclerosis: an open label pilot study.

An open label trial of modafinil was conducted to determine whether it would be tolerated and effective in treating fatigue for people with amyotrophic lateral sclerosis (ALS). Fifteen patients with ALS were treated for two weeks with either 200 mg or 400 mg of modafinil. Reported side effects of the medication were mild and included diarrhea, headache, nervousness, and insomnia. Side effects did not result in any study dropouts. Following treatment, mean scores on the Fatigue Severity Scale (FSS) decreased from 51.3 (SD 9.2) to 42.8 (SD 10.2). On the Epworth Sleepiness Scale (ESS), mean scores decreased from 8.2 (SD 2.0) to 4.5 (SD 2.4). Reductions in both the FSS and the ESS were significant at p < 0.001. Mean scores on the self-report version of the Functional Independence Measure (FIM-SR) increased from 115.2 (SD 5.6) to 118.1 (SD 5.4), with p < 0.01. This pilot study suggests that modafinil is well-tolerated and may reduce symptoms of fatigue in ALS. Further blinded, controlled studies of modafinil in larger numbers of ALS patients are warranted.

Hypnotic analgesia for chronic pain in persons with disabilities: a case series.

Thirty-three adults with chronic pain and a disability were treated with hypnotic analgesia. Analyses showed significant pre- to posttreatment changes in average pain intensity that was maintained at 3-month follow-up. Significant changes were also found in pain unpleasantness and perceived control over pain but not in pain interference or depressive symptoms. Hypnotizability, concentration of treatment (e.g., daily vs. up to weekly), and initial response to treatment were not significantly associated with treatment outcome. However, treatment-outcome expectancy assessed after the first session showed a moderate association with treatment outcome. The findings support the use of hypnotic analgesia for the treatment of pain in persons with disabilities for some patients but not the use of pretreatment measures of hypnotizability or treatment-outcome expectancy for screening patients for treatment.

Pain affects depression through anxiety, fatigue, and sleep in multiple sclerosis.

OBJECTIVE: Over a quarter million individuals in the United States have multiple sclerosis (MS). Chronic pain and depression are disproportionately high in this population. The purpose of this study was to examine the relationship between chronic pain and depression in MS and to examine potentially meditational effects of anxiety, fatigue, and sleep. METHOD: We used cross-sectional data from self-reported instruments measuring multiple symptoms and quality of life indicators in this study. We used structural equation modeling to model direct and indirect effects of pain on depression in a sample of 1,245 community-dwelling individuals with MS. Pain interference, depression, fatigue, and sleep disturbance were modeled as latent variables with 2 to 3 indicators each. The model controlled for age, sex, disability status (Expanded Disability Status Scale), and social support. RESULTS: A model with indirect effects of pain on depression had adequate fit and accounted for nearly 80% of the variance in depression. The effects of chronic pain on depression were almost completely mediated by fatigue, anxiety, and sleep disturbance. Higher pain was associated with greater fatigue, anxiety, and sleep disturbance, which in turn were associated with higher levels of depression. The largest mediating effect was through fatigue. Additional analyses excluded items with common content and suggested that the meditational effects observed were not attributable to content overlap across scales. CONCLUSION: Individuals living with MS who report high levels of chronic pain and depressive symptoms may benefit from treatment approaches that can address sleep, fatigue, and anxiety.