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ObjectiveTo evaluate whether eculizumab helps patients with anti–acetylcholine receptor–positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension.MethodsPatients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study.ResultsA total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1–4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected.ConclusionEculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population.ClinicalTrials.gov IdentifierREGAIN, NCT01997229; REGAIN open-label extension, NCT02301624.Classification of EvidenceThis study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo.

Introduction While animal models of exercise and PD have pushed the field forward, few studies have addressed exercise-induced neuroplasticity in human PD. Method As a first step toward promoting greater international collaboration on exercise-induced neuroplasticity in human PD, we present data on 8 human PD studies (published between 2008 and 2015) with 144 adults with PD of varying disease severity (Hoehn and Yahr stage 1 to stage 3), using various experimental (e.g., randomized controlled trial) and quasi-experimental designs on the effects of cognitive and physical activity on brain structure or function in PD. We focus on plasticity mechanisms of intervention-induced increases in maximal corticomotor excitability, exercise-induced changes in voxel-based gray matter volume changes and increases in exercise-induced serum levels of brain derived neurotrophic factor (BDNF). Finally, we provide a future perspective for promoting international, collaborative research on exercise-induced neuroplasticity in human PD. Conclusion An emerging body of evidence suggests exercise triggers several plasticity related events in the human PD brain including corticomotor excitation, increases and decreases in gray matter volume and changes in BDNF levels.

Evaluate the safety and tolerability of resistance and endurance exercise in ALS participants as measured by their ability to complete this six-month study.Participants were randomized to Resistance, Endurance, or Stretching/Range of Motion (SROM the exercise regimen prescribed for most ALS patients) exercises. All exercises were performed at home with an individualized regimen designed by a physical therapist trained in ALS management. Primary outcome measures were tolerability of the exercises at 24 weeks defined by 50% of participants completing at least 50% of the prescribed exercise regimen. Secondary outcome measures included the ALSFRS-R, pulmonary FVC, and other measures of ALS function.At 12 and 24 weeks, all three exercise regimens were tolerated according to our pre-specified criteria. Compliance to the prescribed exercise regimen was the highest in the resistance and SROM arms of the study. All three forms of exercise were considered safe as there were no differences in the rates of disease progression among groups. There were no differences in the secondary outcome measures and feasibility for evaluating these measures was successful. In a post-hoc analysis, there was a trend towards fewer falls in the Resistance and Endurance groups.This study demonstrates that SROM, resistance, and endurance exercise are all safe to be performed with the specified regimen without any worsening of outcomes as related to ALS function. All three forms of exercise were tolerated with resistance and SROM exercises showing the highest compliance over the 24 week-period.

Objective To determine the validity of the 6-minute walk test (6MWT) as an outcome measure to evaluate walking capacity in ambulatory patients with amyotrophic lateral sclerosis (ALS). Design Observational study. Setting Multidisciplinary ALS clinic at an academic medical center. Participants Patients with ALS (N=186) who ambulate without (stage I) or with (stage II) an assistive device. Interventions Not applicable. Main Outcome Measure Walking distance obtained from the 6MWT. Results Participants performed the 6MWT, 25-foot walk test (25FWT), Timed Up and Go (TUG) test, lower extremity maximum voluntary isometric contraction (MVIC), ALS Functional Rating Scale-Revised (ALSFRS-R), and forced vital capacity (FVC). Walking capacity was reduced to 66% predicted of healthy subjects (75.2%±22% in stage I; 42.6%±22% in stage II). The 6MWT correlated with all other outcome measures in ambulatory patients with ALS (25FWT: r=−.74, P≤.0001; TUG test: r=−.80, P≤.0001; MVIC: r=.64, P≤.0001; percent predicted FVC: r=.25, P≤.0007; ALSFRS-R: r=.52, P≤.0001; ALSFRS-R gross motor subscore: r=.71, P≤.0001). When ambulatory patients with ALS were stratified by stage of ambulation, the 6MWT was associated with all other outcome measures in stage I (25FWT: r=−.56, P≤.0001; TUG test: r=−.66, P≤.0001; MVIC: r=.51, P≤.0001; percent predicted FVC: r=.40, P≤.02; ALSFRS-R: r=.52, P≤.0001; ALSFRS-R gross motor subscore: r=.61, P≤.0001). In stage II, the 6MWT correlated with the 25FWT (r=−.83, P≤.0001), TUG test (r=−.77, P≤.0001), MVIC (r=.47, P≤.0001), and ALSFRS gross motor subscore (r=.61, P≤.0001), but not with percent predicted FVC (r=.09, P≤.513) or ALSFRS-R (r=.21, P≤.141). Conclusions The 6MWT is a valid measure of walking capacity of ambulatory patients with ALS that is associated with measures of lower extremity muscle strength and function in both stages of ambulation. The discordance between the 6MWT with the ALSFRS-R and percent predicted FVC in stage II ambulatory patients with ALS indicates that the 6MWT is an independent measure of ambulatory function in both stages of ambulation. The 6MWT may provide a quantitative, simple, and inexpensive outcome measure of walking capacity for early stage clinical trials in ambulatory patients with ALS.

Objective To assess vestibular deficits in response to disequilibrium in ambulatory individuals with amyotrophic lateral sclerosis (ambALS). Design All participants completed standard protocols for the Sensory Organization Test (SOT) by computerized dynamic posturography. Setting Multidisciplinary amyotrophic lateral sclerosis clinic at an academic medical center. Participants Study participants (N=34) consisted of ambALS (n=19) and healthy controls (HC) (n=15). Interventions Not applicable. Main Outcome Measures Equilibrium scores (ESs) obtained from averaged sway amplitude in condition 5 (ES5) and condition 6 (ES6) of the SOT. Results In conditions of altered somatosensory information with vision absent or vision sway-referenced, the mean ± SD scores for ambALS (ES5=51.4±22.5; ES6=50.8±22.1) were lower than those for HC (ES5=65.4±11.7, P ≤.03; ES6=58.9±12.5, P >.05). Seven ambALS (37%) experienced a total of 19 falls during the sway-referenced support test conditions. There were no falls in the HC. Conclusions Nearly 37% of ambALS with normal clinical balance testing have decreased ability to use the vestibular input and required increased reliance on visual input for postural orientation to sustain equilibrium. The mechanism of this alteration in sensory preference is not completely clear. Extrapyramidal involvement early in ALS may be indicated.

Increasing physical activity, as part of an active lifestyle, is an important health goal for individuals with Parkinson's disease (PD). Exercise can positively impact health related quality of life. Given this, how can we promote physically active lifestyles among PD patients (most of whom are sedentary)? Here we suggest that health care professionals could significantly expand their impact by collaborating with PD patients and their spouses (or caregivers) as partners-in-care. We outline reasons why partners-in-care approaches are important in PD, including the need to increase social capital, which deals with issues of trust and the value of social networks in linking members of a community. We then present results of a qualitative study involving partners-in-care exercise beliefs among 19 PD patients and spouses, and conclude with our perspective on future benefits of this approach.

Sanjak M, Bravver E, Bockenek WL, Norton J, Brooks BR. Supported treadmill ambulation for amyotrophic lateral sclerosis: a pilot study. Objectives: To determine the feasibility, tolerability, safety, and exercise treatment-effect size of repetitive rhythmic exercise mediated by supported treadmill ambulation training (STAT) for patients with amyotrophic lateral sclerosis (ALS). Design: Interventional with repeated-measures design. Setting: Multidisciplinary ALS clinic at academic medical center. Participants: Convenience sample of patients with ALS (N=9) who were ambulatory with assistive devices (Sinaki-Mulder stages II–III). Interventions: Repetitive rhythmic exercise-STAT (30min total; 5min of exercise intercalated with 5min of rest) performed 3 times a week for 8 weeks. Main Outcome Measure: ALS Functional Rating Scale-Revised (ALSFRS-R), percentage of predicted vital capacity (VC), total lower-extremities manual muscle test (MMT), rate of perceived exertion (RPE), Fatigue Severity Scale (FSS), and maximum voluntary isometric contraction (MVIC) in 10 lower and 10 upper extremities. Gait performance, which included walking distance, speed, steps, and stride length, was evaluated during treadmill and ground 6-minute walk tests (6MWTs) and 25-foot walk test (25FWT). Results: Feasibility issues decreased screened participants by 4 patients (31%). Nine patients were enrolled, but 6 patients (67%) completed the study and 3 (23% of original cohort; 33% of enrolled cohort) could not complete the exercise intervention because of non–ALS-related medical problems. Tolerability of the intervention measures during the treadmill 6MWT showed improvement in RPE ( P ≤.05) and FSS score ( P ≥.05). Safety measures (ALSFRS-R, VC, MMT) showed no decrease and showed statistical improvement in ALSFRS-R score ( P ≤.05) during the study interval. Exercise treatment-effect size showed variable improvements. Gait speed, distance, and stride length during the treadmill 6MWT improved significantly ( P ≤.05) after 4 weeks and improvements were maintained after 8 weeks compared with baseline. Walking distance during the ground 6MWT increased significantly after 4 weeks and was maintained after 8 weeks compared with baseline ( P ≤.05). Walking speed during the 25FWT and lower-extremity MVIC improved, but were not statistically significant. Conclusions: Repetitive rhythmic exercise-STAT is feasible, tolerated, and safe for patients with ALS. Repetitive rhythmic exercise-STAT treatment-effect size across a number of ALS-related measures was consistent with improved work capacity and gait function in patients with ALS who are dependent on assistive devices for ambulation. Repetitive rhythmic exercise-STAT should be evaluated further in larger studies to determine the stability of this improved function in relation to the rate of progression of the underlying ALS.

Currently, ALS clinical trials require large sample size and the participation of many clinical evaluators to perform the outcome measure. High variability due to testers, instruments, or patients performance errors may result in systematic bias or random error leading to erroneous or uninterpretable results. Consequently, a quality control system that aims to produce high quality data in terms of reproducibility and accuracy to ensure reliability of the primary outcome measure is essential. In this paper we report our experience in preparing and executing a prospective quality control system that was implemented in conjunction with a large multicenter, multinational randomized placebo-controlled phase III clinical trial in ALS. We have shown that a prospective quality control system is highly effective to ensure inter- and intra-rater reliability of vital capacity as a primary outcome measure during the entire trial.

Ward AL, Sanjak M, Duffy K, Bravver E, Williams N, Nichols M, Brooks BR. Power wheelchair prescription, utilization, satisfaction, and cost for patients with amyotrophic lateral sclerosis: preliminary data for evidence-based guidelines. Objectives To determine the features most frequently selected in a power wheelchair (PWC), level of satisfaction with the selections, and how often the PWC features are used by patients diagnosed with amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Design Internally generated questionnaire. Setting An ALS/Muscular Dystrophy Association center. Participants Convenience sample of current patients (N=45) of our clinic with ALS/MND who are PWC users (men, n=27; women, n=18; age range, 27–85y). Intervention Self-administered survey. Main Outcome Measure Thirty-two patients completed a 31-question survey investigating patients' patterns of selection, satisfaction, and frequency of PWC use; technical and psychometric influences; and other aspects of decision-making processes that patients experience before, during, and after acquiring a PWC. Results Ninety percent of respondents received their evaluations at a multidisciplinary ALS clinic, 1 via the Department of Veterans Affairs, and 1 was unknown. Sixty-six percent of patients thought the chair evaluation was timed correctly, and 19% wished they had started sooner. Forty-five percent of people were able to walk a few steps, and 55% were able to stand when their chairs arrived. When they first received the chair, 79% were satisfied with the overall comfort of the chair, and 86% were satisfied with the ease of use; currently, 69% are satisfied with the overall comfort, and 72% are satisfied with ease of use. There was a statistically significant difference in how patients used their wheelchair features initially and currently in terms of seat elevate and attendant control, but not tilt, recline, and elevating leg rests. The average cost for the power chairs was $26,404 (range, $19,376–$34,311), and the average cost a month is $917. Overall, 88% of respondents said they would get the same type of chair with the same features again, and 81% felt that the chair was a good value for the cost. Conclusions We obtained first-hand knowledge from 32 patients with ALS/MND who are current PWC users on their use and satisfaction with their PWCs from initial to current use. Based on this survey, patients with ALS/MND seen for their wheelchair evaluation with experienced clinicians exhibit high use and satisfaction with their PWCs.

Motor fatigue, during 30 seconds of maximum voluntary isometric contraction (MVIC) was simultaneously evaluated by the decline in mechanical force output, and from the compression in the power spectrum obtained from surface electromyogram (sEMG). Measurements were performed in patients diagnosed with amyotrophic lateral sclerosis (ALS) and normal control (NC) in two muscle groups, elbow flexors (EF) and ankle dorsiflexors (DF). The decline in force output, as a manifestation of mechanical fatigue, was digitally calculated online by partitioning the force versus time curve to determine the percent of MVIC reduction over a 30 sec period and was expressed as force fatigue index (FFI). The compression in the sEMG power spectrum, as a manifestation of myoelectrical fatigue, was tracked by calculating the median frequency shift (MFS) from the first 5 sec to the last 5 sec of the 30 sec MVIC using digital Fast Fourier Transformation. In ALS patients, the significantly higher reduction in mechanical force output during the 30 sec MVIC (higher FFI) was accompanied with significantly less compression in the sEMG power spectrum (less MFS) as compared to NC (P < or =0.005) in the two muscle groups. This dissociation between the mechanical and myoelectrical manifestation of muscle fatigue in ALS indicates that a reduction in muscle fiber conduction velocity (MFCV) may be a contributing peripheral factor in the pathogenesis of muscle fatigue in ALS. Alterations in motor unit functionality, especially in type II fast motor unit muscle fibers, and structural damage in denervated muscle fibers may contribute to the lower MFCV during motor fatigue in ALS patients.

Motor fatigue is a common complaint in patients with amyotrophic lateral sclerosis (ALS), but is often excluded, unlike weakness, from the clinical assessment of these patients. This could be due to the complexity and often painful assessment techniques of this motor deficit. This study examines the feasibility of quantitative assessment of motor fatigue by modifying presently available force measurements. The relationship between weakness and fatigue in ALS patients was also examined. Fifty-four ALS patients and 39 normal control subjects performed 30 s of sustained maximal voluntary isometric contraction (MVIC) of elbow flexors (EF), knee extensors (NE), and ankle dorsiflexors (DF), using a computerized force measurement system and standardized testing procedures. Fatigue index (FI) was digitally calculated, from the force-time curve, as the percentage of MVIC unable to be sustained over the 30-s period. Fatigue was greater in ALS patients than in normal control (mean=23% vs. 15%) in all muscles including muscles that were not clearly weak. Weakness and fatigue were poorly correlated in ALS patients and may be independent measures of the pathogeneses of ALS.

Amyotrophic lateral sclerosis (ALS) is a lethal, progressive neurodegenerative disease characterized by loss of motor neurons.1 Patients with ALS lose function in the limbs, speech, swallowing, and breathing muscles. The cause of the disease is still not known for most patients. Approximately 25,000 people in the United States have ALS, and 5,000 people are diagnosed with ALS annually in the United States.1 Most patients die from respiratory failure 2 to 5 years after onset of symptoms. Cognitive dysfunction is seen in 20% to 50% of patients.2 The disease burden for patients and caregivers is enormous. The average cost of care has been estimated at $50,000 per patient per year.3 The authors would like to thank all the ALS Measure Development Work Group members for their contributions and work that supported the development of this manuscript: Robert G. Miller, MD (neurology); Benjamin Rix Brooks, MD (neurology); Steven Ringel, MD (neurology); Hiroshi Mitsumoto, MD (neurology); Carlayne Jackson, MD (neurology); Christen Shoesmith, MD, BSc (neurology); Edward Kasarskis, MD, PhD (neurology); Robert C. Basner, MD (pulmonology); Nicholas Procaccini, MD (gastroenterology); Gregory Carter, MD (physical medicine and rehabilitation); Dallas Forshew, RN, BSN (nursing); Mohammed Sanjak, PhD, PT, MBA (physical therapy/occupational therapy); Pat Casey, MS, CRCC (physical therapy/occupational therapy); Bob Osborne, RN (hospice/palliative care); Valerie Cwik, MD (Muscular Dystrophy Association); Christine Jasch, OTR/L (patient representative); Fredrik Tolin, MD, MBA (Humana); Rebecca J. Swain-Eng, MS, CAE (AAN staff); Gina Gjorvad (AAN staff); Rebecca Kresowik (methodologist); Richard Dubinsky, MD (facilitator); Joel Kaufman, MD (facilitator); Adam Cohen, MD (facilitator); Christopher Bever, MD (AAN QMR); Eric Cheng, MD, MS (AAN QMR). The authors would also like to thank the Muscular Dystrophy Association for their support in the development of the measures.

ALS/MND therapeutics will require juxtaposition in the patient of 1. primary treatments to mitigate the underlying pathogenesis of ALS/MND, 2. adjuvant treatments to stop propagating events trying to maximize survival, strength and function, and 3. symptomatic treatments to minimize symptoms and complications resulting from ALS/MND (Figure 1). Little attention has been paid to the strategies to develop mosaic therapeutic approaches in ALS/MND and how to evaluate efŽciently the potential efŽcacy and safety of mosaic therapies.

To compare muscular fatigue and postural stability of surgeons before and after laparoscopic and robotic surgery.The design of this study is Class II. A consecutive cohort of patients presenting at an academic tertiary-care center for scheduled gynecologic surgery was used. Routine surgical care was examined with testing of surgeon fatigue and postural measures before and after the procedure. Motor fatigue was measured using a quantitative grip dynamometer, and postural stability was measured using a nondominant, single-leg stance. A subjective fatigue score was recorded following surgery.Primary surgeons completed testing before and after 56 surgeries. A trend toward decline in postural stability was observed more in the laparoscopy group than in the robotic group (P=.29). The fatigue index and subjective fatigue scores were not significantly different.Similar changes in postural stability and muscular strength were observed following laparoscopic and robotic surgery. The optimal measurement tool to capture surgical fatigue remains elusive. Fatigue differences may have been more pronounced if surgical procedure degree of difficulty had been more consistent between groups.

Introduction - Inflammatory myopathy is a treatable cause of worsening in the spectrum of neurological conditions that may develop during the course of HTLV-1 infection. Material and methods - To investigate the cause of subacute worsening in the strength of a 46-y-old black male with HTLV-1 associated myelopathy we performed electrodiagnostic examination and a muscle biopsy which was studied with histochemistry, immunocytochemistry and electron microscopy. Serial measurements of isometric muscle strength were performed during the course of corticosteroid treatment. Results - The muscle biopsy showed evidence of denervation atrophy and prominent inflammatory changes with autoaggressive features. Lymphocyte typing showed a predominance of CD8 + T cells. The patient had sustained, marked improvement in strength, especially of the upper extremities, with oral, high single-dose, alternate-day prednisone therapy. Conclusion - A muscle biopsy should be considered in all patients with HTLV-1 associated weakness, especially when electromyography indicates possible coexisting primary muscle involvement and/or serum creatine kinase levels are elevated. HTLV-1-associated polymyositis can be successfully treated with corticosteroids.

Selection of maximum voluntary isometric contractions(MVIC) as a measure of motor strength and to be used as asurrogate outcome measure in ALS clinical trials should,ideally, be preceded by a rigorous theoretical and empiricalanalysis of the intrinsic and extrinsic determinants of thismeasure. These determinants, which include neural, mechani-cal, and architectural factors, will ultimately determine thesuitability of this measure in terms of its internal and externalvalidity, sensitivity, speci”city, and ease of standardization. Itshould be simple to perform in a way that will ensure accu-racy and reliability, to achieve the desired statistical power.

Objective: To determine the test–retest reliability of strength and fatigue measurements in patients with MS and in healthy control subjects, and to examine associations among motor fatigue, strength, and ambulatory impairment in MS patients.Background: Motor fatigue, defined as the loss of the maximal capacity to generate force during exercise, and weakness are common in patients with MS. Method:— Twenty ambulatory MS patients and 20 age- and sex-matched healthy control subjects participated in the study. Test–retest reliability was assessed in two identical testing sessions, separated by 3 to 5 days. Maximal voluntary isometric strength was determined by fixed myometry of seven muscle groups on each side. Motor fatigue was assessed using three exercise protocols: sustained maximal contractions (static fatigue), repetitive maximal contractions, and walking as far as 500 m. Four analysis models for static fatigue were examined for their test–retest reliability and their ability to discriminate between normal fatigue and pathologic fatigue from MS.Results: Test–retest reliability in MS patients was excellent for isometric strength and very good for static fatigue. Test–retest reliability was lower for exercise protocols that involved repetitive contractions or ambulation. Compared with healthy control subjects, MS patients were weak in lower extremity muscles, but upper extremity strength was relatively preserved. Fatigue was greater in MS patients, even in muscles that were not clearly weak. There were no significant associations between strength and fatigue in any of the muscles tested. A fatigue analysis model based on the area under the force-versus-time curve gave the best combination of reliability and sensitivity to detect differences between MS patients and healthy control subjects.Conclusions: Strength and motor fatigue can be measured reliably in patients with MS. MS patients experience more fatigue than healthy control subjects during sustained contractions, repetitive contractions, and ambulation. Motor fatigue appears to be distinct from weakness because the degree of fatigue was not associated with the degree of weakness in individual muscles. Quantitative assessment of strength and fatigue may be useful to monitor changes in motor function over time in MS patients.

ALS is a motor neuron disease defined as a progressive, neurological disorder, resulting from variable and combined degeneration of upper and lower motor neurons. The heterogeneity of clinical involvement early in the course of the disease makes it difficult to diagnose, as well as to identify one unique outcome measure to quantify neurological changes in the course of the disease. Since clinical evidence of upper and lower motor neuron degeneration must exist in four anatomical regions (bulbar, cervical, thoracic, and lumbosacral), outcome measures should assess these regions. The WFN Airline House recommendations specify the purpose, properties, and the preferred parameters which serve as outcome measures in ALS clinical trials. The purpose of this document is to serve as a review of these outcome measures in terms of their advantages, disadvantages, sensitivity, reliability, and other characteristics, as well as their proper performance in ALS clinical trials. Generally these outcome measures are allocated to four areas: respiratory function, muscle strength, general function, and bulbar function. Our review leads us to believe that respiratory function and strength provide the most useful information, both for research and clinical purposes, and are essential as outcome measures. Inclusion of bulbar and general function parameters in trial design may increase the possibility of identifying a beneficial effect of therapeutic intervention. It is essential to note that the guidelines and recommendations put forth are intended to provide initial evaluation and critique of the proper employment and performance of these outcome measures in ALS clinical trials, based on the available literature and our experience.

Objective: To validate 6MWT with outcome measures frequently used to evaluate motor performance in ALS which include the ALS Functional Rating Scale-Revised(ALSFRS-R), Quantitative Muscle Test(QMT), forced vital capacity(FVC), 4-step stair climbing(SC), 25-foot walk test(25FWT), and timed-up-and-go(TUG), and number of falls(F). Background Evaluation of motor impairments in ALS patient is necessary for clinical decision making, natural history, and efficacy of therapeutics. The recent surge in therapeutics with potential to improve rather than reduce progression of motor function in ALS may require a sensitive and meaningful functional outcome measure. 6MWT is being increasingly used in a variety of neurodegenerative motor system diseases including spinal muscular atrophy(Neurology 2010;74(10):833-838) and ALS(Arch Phys Med Rehabil 2010;91(12):1920-1929). Design/Methods: Distance during the 6MWT, ALSFRS-R, FVC, 25FWT, TUG, F, and QMT of bilateral hip, knee flexors and extensors, and ankle dorsiflexors were evaluated in 56 ambulatory ALS patients following standard procedures. TUG was evaluated as the time it took the patient to stand up from standard chair, walk 3 meters, and return to the chair. SC and 25FWT were evaluated as the time it took the patients to go up and down 4 steps and walk 25 foot respectively. Pearson9s correlations were used to test for linear relationships between the outcome measures. Results: 6MWT distance significantly correlated with ALSFRS-R total score(r=.49;p≤0.002), QMT(r=.58;p≤0.02), SC(r=-.57; p≤ 0.001), 25FWT(r =-.51;p≤ 0.005), and TUG(r =-.65;p≤ 0.001), but did not correlate with FVC(r=.18 p≤ 0.16). In addition, 6MWT significantlly correlated with number of falls, F(r=.42;p≤ 0.002)experienced by ALS patients. Conclusions: 6MWT correlates with other outcome measures that quantify lower extremity motor deficit in ALS, but does not correlate with FVC. 6MWT is a robust outcome measure expanding the dynamic range of treatment measurement in ambulatory ALS patients early in the disease. 6MWT correlates with the number of falls which is a meaningful safety-related outcome measure for ALS patients. Supported by: Carolinas ALS Research Fund, Pinstripes Fund, Carolinas Healthcare Foundation, Muscular Dystrophy Association/ALS Division. Disclosure: Dr. Sanjak has nothing to disclose. Dr. Langford has nothing to disclose. Dr. Holsten has nothing to disclose. Dr. Bockenek has nothing to disclose. Dr. Bravver has nothing to disclose. Dr. Desai has nothing to disclose. Dr. Bockenek has nothing to disclose. Dr. Williams has nothing to disclose. Ms. Russo has received personal compensation for activities with Serono, TEVA and Biogen as a consultant. Dr. Brooks has received personal compensation for activities with Avanir Pharmaceuticals, Bayer Healthcare Pharmaceuticals, Biogen Idec, Genentech, Inc., and Teva Neuroscience. Dr. Brooks has received research support from Avanir Pharmaceuticals, Biogen Idec, NINDS, Novartis, and Teva Neuroscience.

Objective: Report on initial choice, modification and accountability of ALS–performance measures in an ALS Clinic at a major medical center affiliated with a state-based medical school. Background AAN–ALS Guidelines(1999) were not formally deployed on a per–clinic basis, but were evaluated in a subset of clinics participating in the ALS CARE Database. A formal analysis between 1999–2004 indicated that guideline adherence increased from 3–31% to 9–43%[Ann Neurol 2009;65 (suppl):S24–S28]. Despite increased adherence to the AAN–ALS Guidelines, there is a 57–91% gap in patient care depending on the specific recommendation. In order to increase adherence to the AAN–ALS Guidelines(2009), we implemented a formal TJC–DSC process to develop per-patient performance measures to allow prospective assessment of guideline adherence according to the TJC–DSC protocol currently in place for heart disease, diabetes and stroke. Design/Methods: ALS–performance measures need to be developed from 80 primary(nearly 200 secondary)recommendations from the AAN–ALS Guidelines(2009). Based on the TJC–DSC protocol, ALS–performance measures identifying 1)cognitive function(Mini-Mental State Examination). 2)depression(Patient Health Questionaire), 3)falls(number of falls since last clinic visit) and 4)dispersal of care plans to MDs(faxed completed encounter reports) were chosen initially by the working group. Results: During the first 6 months, we identified that number of falls was more effective in identifying patients at risk for falls than the Hendrich II Falls Scale. Number of falls became an audit-established measure to be completed at each clinic visit when 5)respiratory management checklist became the new auditable measure. Provider monthly accountability (mean±standard deviation%] improved for all measures between the first and second 6-month intervals: 1)cognition(50±23%; 90±7%), 2)depression(95±6%; 92±8%), 3)falls(98±3%; 98±3%), 4)dispersal of care plan(90±8%; 91±7%), 5)respiratory management(99±1%;initiated in second 6 months). Conclusions: The process of implementation of AAN–ALS Guidelines-specific ALS–performance measures was initiated for 5/80 primary(200 secondary)recommendations. Accountability measures indicate that providers still need training to achieve 100% adherence. Patient acceptance and adherence accountability measures are being developed. Supported by: Carolinas ALS Research Fund, Pinstripes Fund, Muscular Dystrophy Association. Disclosure: Dr. Brooks has received personal compensation for activities with Avanir Pharmaceuticals, Bayer Healthcare Pharmaceuticals, Biogen Idec, Genentech, Inc., and Teva Neuroscience. Dr. Brooks has received research support from Avanir Pharmaceuticals, Biogen Idec, NINDS, Novartis, and Teva Neuroscience. Dr. Williams has nothing to disclose. Dr. Bravver has nothing to disclose. Dr. Desai has nothing to disclose. Dr. Wright has nothing to disclose. Dr. Sanjak has nothing to disclose. Dr. Bockenek has nothing to disclose. Dr. Nichols has nothing to disclose. Ms. Russo has received personal compensation for activities with Serono, TEVA and Biogen as a consultant. Dr. Smith has nothing to disclose. Dr. Blythe has nothing to disclose. Dr. Lindblom has nothing to disclose. Dr. Pacicco has nothing to disclose. Dr. Smrcina has nothing to disclose. Dr. Ward has nothing to disclose. Dr. Langford has nothing to disclose. Dr. Fischer has nothing to disclose. Dr. O9Neill has nothing to disclose. Dr. Henderson has nothing to disclose. Dr. Holsten has nothing to disclose. Dr. Frumkin has nothing to disclose. Dr. Walgren has nothing to disclose. Dr. Corey has nothing to disclose. Dr. Oplinger has nothing to disclose. Dr. Price has nothing to disclose. Dr. Fortier has nothing to disclose.

For over a century, the clinical and pathological essentials of motor neuron degeneration have been described [1]. Yet to this date, no cogent, easily applied quantiative description of the course of motor neuron degeneration has been forthcoming [2]. A complete understanding of the clinical features of motor neuron disease, both in the individual and within a group of affected individuals, is necessary for the optimal conduct of therapeutic trials. Precise endpoints are required to permit statistical planning of clinical trials, which will include determination of sample size, trial duration, and mode of analysis. In this chapter we will review the strategies to be applied when determining the best measures of change in individual patients or groups of patients with motor neuron disease over different time periods. We will also analyze the different statistical needs of individual case studies and parallel placebo-controlled case studies.

The general, systemic, and specific neuromuscular adaptation to physical exercise and training in healthy individuals is reviewed with application to individuals with neuromuscular disease in general and ALS in particular. A pilot study utilizing patients with ALS suggests the cardiopulmonary response to acute exercise is similar to normal individuals. However, a case study of a training response suggests the success of neuromuscular adaptation will be dependent upon the degree of motor neuron involvement.

Lennon et al. (J. Appl. Physiol. 55: 489–495, 1983) have recently reported a large loss of muscle total carnitine (TC) after 40 min of moderate exercise. These authors have also suggested that elevations in plasma esterified carnitine (EC) were due to the release of these carnitine esters from muscle during exercise. After 10 male subjects underwent 90 min of cycle egometry we found no alteration in muscle TC from preexercise values. Plasma EC progressively increased above resting values during exercise and remained elevated above rest at 0.75 and 1.5 h into recovery. Elevations of plasma EC were largely due to a decrement in free carnitine (FC) in both conditions. Immediately postexercise the urinary fractional reabsorbsion of EC and FC were similar to that at rest. These results suggest that a net loss of TC from exercising muscle does not occur. As in other conditions marked by falling insulin concentrations, elevations in plasma EC could result from an exchange of carnitine with the hepatic carnitine pool.

We sought to determine if chronic endurance training would increase mitochondrial respiration or protein content in rat diaphragm muscle. To this end, 20 male Wistar rats were randomly assigned to control (C) or an 8-week endurance training (T) group, n = 10 per group. At the end of T, VO2 max was 13% greater in T (83.3 vs 73.8 ml X kg-1 X min-1) and peak max power output was 32% greater (2.63 vs 1.98 kg X m X min-1). Mitochondrial specific activities of pyruvate-malate and cytochrome oxidase (expressed per mg mitochondrial protein) in both plantaris and diaphragm were similar in C and T rats, as were ADP/O and respiratory control ratios. When expressed per gram wet weight, whole muscle homogenate oxygen uptake (pyruvate + malate) and cytochrome oxidase activity increased 36 and 23%, respectively (P less than 0.05) in plantaris from T rats but did not change in diaphragm. Control oxidative capacity and mitochondrial protein content in the diaphragm were ca. 2-fold those in control plantaris. Plantaris mitochondrial protein content increased ca. 50% with T while the diaphragm was unaffected. We conclude that: plantaris muscle oxidative capacity adapts to training by increasing mitochondrial protein content, since there was no evidence for functional improvement of existing mitochondria, and in the face of a substantial training effect in whole animal and plantaris, the T stimulus was not sufficient to induce mitochondrial protein changes in the diaphragm. This finding is the result of either a 'pre-adaptation' secondary to the diaphragm's high chronic activity, or a sub-threshold increase in diaphragm recruitment during the exercise conditions studied.

Physical work capacity in 35 ALS patients and 6 untrained controls was evaluated during progressive bicycle ergometry. In the ALS patients, maximum oxygen consumption (VO2max) and work capacity (Wmax) drop in relation to the decrease in ALS functional score. However, the oxygen cost (ml O2/kpm) of submaximal exercise was significantly increased. Prolonged submaximal exercise tests in six ALS patients and six matched untrained controls indicated that the exercise-induced increase in plasma free fatty acids, beta-hydroxybutyrate, esterified carnitine, and muscle esterified carnitine was significantly retarded in ALS patients.