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An orally administered, fixed‐dose coformulation of sodium phenylbutyrate‐taurursodiol (PB‐TURSO) significantly slowed functional decline in a randomized, placebo‐controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long‐term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB‐TURSO or placebo. Participants completing the 6‐month (24‐week) randomized phase were eligible to receive PB‐TURSO in the open‐label extension. An all‐cause mortality analysis (35‐month maximum follow‐up post‐randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of follow‐up of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB‐TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34‐0.92; P = .023). Initiation of PB‐TURSO treatment at baseline resulted in a 6.5‐month longer median survival as compared with placebo. Combined with results from CENTAUR, these results suggest that PB‐TURSO has both functional and survival benefits in ALS.

Quantitative measures of disease severity are essential outcome measures for clinical trials. The slow progression of disease in primary lateral sclerosis (PLS) requires clinical measures that are sensitive to changes occurring within the time frame of a clinical trial. Proposed clinical outcome measures include the PLS functional rating scale (PLSFRS), burden scores derived from clinical examination findings, and quantitative measures of motor performance. The PLSFRS has good inter-rater reliability and showed greater longitudinal change over 6- and 12-months compared to the revised ALS functional rating scale. Examination-based upper motor neuron burden (UMNB) scales also have good reliability, and longitudinal studies are in process. Quantitative measures of strength, dexterity, gait, and speech have the potential to provide objective and precise measures of clinical change, but have been the least studied in persons with PLS.

BACKGROUND: Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known. METHODS: In this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate–taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization. RESULTS: A total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate–taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was −1.24 points per month with the active drug and −1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal. CONCLUSIONS: Sodium phenylbutyrate–taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate–taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR Clinicaltrials.gov number, NCT03127514.)

Primary lateral sclerosis (PLS) is a condition that most neurologists will never personally diagnose. For the estimated several thousand people living with PLS globally, while it may not be life-sh...

Introduction: Improved outcome measures are essential to efficiently screen the growing number of potential amyotrophic lateral sclerosis (ALS) therapies. Methods: This longitudinal study of 100 (70 male) participants with ALS compared Accurate Test of Limb Isometric Strength (ATLIS), using a fixed, wireless load cell, with ALS Functional Rating Scale-Revised (ALSFRS-R) and vital capacity (VC). Results: Participants enrolled at 5 U.S. sites. Data were analyzed from 66 participants with complete ATLIS, ALSFRS-R, and VC data over at least 3 visits. Change in ATLIS was less variable both within- and among-person than change in ALSFRS-R or VC. Additionally, participants who had normal ALSFRS-R arm and leg function averaged 12 to 32% below expected strength values measured by ATLIS. Conclusions: ATLIS was more sensitive to change than ALSFRS-R or VC and could decrease sample size requirements by approximately one-third. The ability of ATLIS to detect prefunctional change has potential value in early trials. Muscle Nerve 56: 710–715, 2017

Introduction RNS60 is a novel immune-modulatory agent that has shown neuroprotective effects in amytrophic lateral sclerosis (ALS) preclinical models. RNS60 is administered by weekly intravenous infusion and daily nebulization. The objective of this pilot open-label trial was to test the feasibility, safety, and tolerability of long-term RNS60 administration in ALS patients. Methods The planned treatment duration was 23 weeks and the primary outcomes were safety and tolerability. Secondary outcomes included PBR28 positron emission tomography (PET) imaging and plasma biomarkers of inflammation. Results Sixteen participants with ALS received RNS60 and 13 (81%) completed 23 weeks of RNS60 treatment. There were no serious adverse events and no participants withdrew from the trial due to drug-related adverse events. There were no significant changes in the biomarkers. Discussion Long-term RNS60 administration was safe and well-tolerated. A large, multicenter, phase II trial of RNS60 is currently enrolling participants to test the effects of RNS60 on ALS biomarkers and disease progression. Muscle Nerve 59:303-308, 2019.

Objective:Amyotrophic lateral sclerosis (ALS) progresses at different rates between patients, making clinical trial design difficult and dependent on large cohorts of patients. Currently, there are few data showing whether the left and right limbs progress at the same or different rates. This study addresses rates of decline in specific muscle groups of patients with ALS and assesses whether there is a relationship between left and right muscles in the same patient, regardless of overall progression.Methods:A large cohort of patients was used to assess decline in muscle strength in right and left limbs over time using 2 different methods: The Tufts Quantitative Neuromuscular Exam and Accurate Test of Limb Isometric Strength protocol. Then advanced linear regression statistical methods were applied to assess progression rates in each limb.Results:This report shows that linearized progression models can predict general slopes of decline with good accuracy. Critically, the data demonstrate that while overall decline is variable, there is a high degree of correlation between left and right muscle decline in ALS. This implies that irrespective of which muscle starts declining soonest or latest, their rates of decline following onset are more consistent.Conclusions:First, this study demonstrates a high degree of power when using unilateral treatment approaches to detect a slowing in disease progression in smaller groups of patients, thus allowing for paired statistical tests. These findings will be useful in transplantation trials that use muscle decline to track disease progression in ALS. Second, these findings discuss methods, such as tactical selection of muscle groups, which can improve the power efficiency of all ALS clinical trials.

summary scores created from normalized data con-trols for these differences, reduces variance andminimizes the chance of finding false-positiveresults, as fewer variables are analyzed. 27,28 Summary scores are routinely used to analyzeTQNE data. The 20 raw MVIC values are first con-verted to z-scores based on a population mean andstandard deviation for each muscle group derivedfrom a natural history ALS data bank. Two re-gional megascores are then calculated by averagingthe 10 individual leg z-scores (megaleg) and the 10individual arm z-scores (megaarm). This methodplaces all muscles on a ‘‘common yardstick,’’ thusallowing each muscle, regardless of size, to contrib-ute equally to the megascore. Disease progressioncan then be expressed as the slope of the mega-score over time (megaslope). 29 Unfortunately, megascore values are expressedas z-scores and, thus, clinical interpretation is diffi-cult. In addition, megaslope analysis can be mis-leading, because the slopes are often very small frac-tions. Therefore, clinically insignificant changes canresult in a several-fold change in slope (e.g., the dif-ference between a megaslope of 0.001 and a meg-aslope of 0.0001 is not clinically detectable,although, statistically, the difference is tenfold).An improved method for summarizing TQNEdata is to convert raw MVIC values to percent of pre-dicted normal (PPN).

The objective of the study was to establish the safety and pharmacodynamics of escalating dosages of sodium phenylbutyrate (NaPB) in participants with ALS. Transcription dysregulation may play a role in the pathogenesis of ALS. Sodium phenylbutyrate, a histone deacetylase inhibitor, improves transcription and post-transcriptional pathways, promoting cell survival in a mouse model of motor neuron disease. Forty research participants at eight sites enrolled in an open-label study. Study medication was increased from 9 to 21 g/day. The primary outcome measure was tolerability. Secondary outcome measures included adverse events, blood histone acetylation levels, and NaPB blood levels at each dosage. Twenty-six participants completed the 20-week treatment phase. NaPB was safe and tolerable. No study deaths or clinically relevant laboratory changes occurred with NaPB treatment. Histone acetylation was decreased by approximately 50% in blood buffy-coat specimens at screening and was significantly increased after NaPB administration. Blood levels of NaPB and the primary metabolite, phenylacetate, increased with dosage. While the majority of subjects tolerated higher dosages of NaPB, the lowest dose (9 g/day), was therapeutically efficient in improving histone acetylation levels.

Haley SM, Andres PL, Coster WJ, Kosinski M, Ni P, Jette AM. Short-form Activity Measure for Post-Acute Care. Arch Phys Med Rehabil 2004;85:649–660. Objective To develop a comprehensive set of short forms using item response theory (IRT) and item pooling procedures for the purpose of monitoring postacute care functional recovery. Design Prospective study. Setting Six postacute health care networks in the greater Boston area, including inpatient acute rehabilitation, transitional care units, home care, and outpatient services. Participants A convenience sample of 485 adult volunteers who were currently receiving skilled rehabilitation services. Interventions Not applicable. Main outcome measures We developed a set of 6 short forms across 3 activity domains from new items and items from existing postacute care instruments. Results Inpatient- and community-based short forms were developed for each of 3 activity domains: physical & movement, applied cognition, and personal care & instrumental. Items were selected for inclusion on the short forms to maximize content coverage and information value of items across the range of content and to minimize ceiling and floor effects. We were able to match the distribution of sample scores with very good item precision for 1 of the constructs (physical & movement); the other 2 domains (personal care & instrumental, applied cognition) were more challenging because of the variability in patient recovery and ceiling effects. Conclusions ITR methods and item pooling procedures were valuable in developing paired sets of short-form instruments for inpatient and community rehabilitation that provided estimates of functioning along a common metric for use across postacute care settings.

Current functional assessment instruments in stroke rehabilitation are often setting-specific and lack precision, breadth, and/or feasibility. Computer adaptive testing (CAT) offers a promising potential solution by providing a quick, yet precise, measure of function that can be used across a broad range of patient abilities and in multiple settings. CAT technology yields a precise score by selecting very few relevant items from a large and diverse item pool based on each individual’s responses. We demonstrate the potential usefulness of a CAT assessment model with a cross-sectional sample of persons with stroke from multiple rehabilitation settings.

Objective A major challenge in the development of a comprehensive measurement system to evaluate effectiveness across a broad range of postacute care settings is the stability and consistency of outcomes measures across respondents and settings. The objective of this study was to investigate the test-retest and subject-proxy reliability of activity scores for use in a new postacute care outcome instrument using an interview format across different care settings. Design Twenty-five subjects were randomly selected from a larger study of 485 individuals and were interviewed on two occasions within 1 to 4 days to assess self-reported test-retest reliability of summary scores of the Activity Measure-Post-Acute Care item pool. Proxy reliability was tested by interviewing the primary physical or occupational therapist or family member using an identical questionnaire in addition to the subject in 45 patients. Results Test-retest and subject-proxy reliability was acceptable for the three domains of the activity construct: physical and movement, personal and instrumental, and applied cognition with intraclass correlation coefficients of the summary scores of each of the three domains ranging between 0.91 and 0.97 for test-retest and 0.68 and 0.90 for subject-proxy. Conclusions Reliability is adequate to justify use of these activity scales across respondents and settings.

Background and Purpose. The purpose of this study was to determine the level of muscle force associated with ability to walk in the community without assistance, in the community with assistance, or at home only in individuals with amyotrophic lateral sclerosis (ALS). Subjects and Methods. Percentage of predicted maximal muscle force (%PMF) of lower-extremity muscles was determined, and walking ability was categorized in 118 patients with ALS during periodic visits to the Neuromuscular Research Unit. Data were derived from consecutive visits in which subjects demonstrated declines in walking ability. Means for %PMF of each muscle group and a limb average were calculated at each consecutive visit. Results. The mean lower-extremity average %PMF was: (1) 54.01% (SD=12.76%) for subjects who walked independently in the community and 50.19% (SD=14.38%) during the next visit when these same subjects required assistance in the community (difference=3.82%, 95% confidence interval [CI][=] 2.45−5.19);(2) 37.52% (SD=15.17%) during the last visit that subjects walked with assistance in the community and 32.18% (SD=13.83%) during the next visit when they walked only at home (difference=5.33%, 95% CI=3.61–7.06); and (3) 19.12% (SD=9.08%) during the visit when subjects were last able to ambulate at home versus 13.70% (SD=7.36%) when they became unable to walk (difference=5.42%, 95% CI=2.97−7.96). Conclusion and Discussion. The findings suggest there are required levels of lower-extremity muscle force for various categories of walking ability. Variations in forces within and between categories of walking ability, however, indicate the complexity of this relationship.

Effective clinical trials in neuromuscular research require accurate and sensitive methods to quantitate disease progression. The purpose of this study was to concurrently compare manual muscle testing (MMT), maximal voluntary isometric contraction (MVIC), and a functional scale (the ALS Score). Twenty patients with ALS were tested ten times at monthly intervals using each of the three methods. High inter-rater reliability for each of the three methods was demonstrated. All three methods demonstrated a decline over the testing period. However, MMT and the ALS Score were less sensitive to early change. A wide variation of percent of normal MVIC was demonstrated within each MMT grade and extensive overlap between MMT grades was observed. MVIC is the method of choice in studying patients in the early stages of ALS and in studies conducted over a short period of time.

The Accurate Test of Limb Isometric Strength (ATLIS) device can reliably measure the strength of 12 muscle groups using a fixed load cell. The purpose of this study was to analyze ATLIS data from healthy adults to calculate an individual's predicted strength scores.ATLIS data were collected from 432 healthy adults. Linear regression models were developed to predict each muscle group's strength. The R-squared statistic assessed variability accounted for by the models.Simple main effects models stratified by gender were used to establish regression equations for each muscle using factors of age, weight, and height.Normalizing raw strength scores controls for biometric factors, thus enabling meaningful comparisons between subjects and allowing each muscle to contribute equally to a summary score. Normalized scores are easily interpreted for broad clinical uses, and derived summary scores establish individuals' disease progression rates using a common scale, allowing for more efficient clinical trials.

Strength measures with reduced variability and higher sensitivity could improve efficiency in clinical trials of amyotrophic lateral sclerosis (ALS). The Accurate Test of Limb Isometric Strength (ATLIS) was developed to precisely and conveniently measure force in 12 muscle groups. In this study we evaluate the reliability and validity of the ATLIS testing protocol.Twenty healthy adults and 10 patients with ALS were tested twice by the same or by different evaluators to determine test-retest and interrater reliability. Twenty healthy adults were examined using ATLIS and a well-validated strength testing protocol (TQNE) to assess criterion-based validity.Mean absolute variation between tests was 8.6%, and intraclass correlation coefficients for each muscle group were high (range 0.82-0.99). The Pearson correlation coefficient of mean ATLIS and TQNE scores was 0.90. A subject survey demonstrated high user acceptance of ATLIS.ATLIS is convenient for patients and evaluators, produces precise strength measurements, and is easily moved between examining rooms.

Objective To examine whether the range of disability in the medically complex and postsurgical populations receiving rehabilitation is adequately sampled by the new Activity Measure--Post-Acute Care (AM-PAC), and to assess whether computer adaptive testing (CAT) can derive valid patient scores using fewer questions. Design Observational study of 158 subjects (mean age 67.2 yrs) receiving skilled rehabilitation services in inpatient (acute rehabilitation hospitals, skilled nursing facility units) and community (home health services, outpatient departments) settings for recent-onset or worsening disability from medical (excluding neurological) and surgical (excluding orthopedic) conditions. Measures were interviewer-administered activity questions (all patients) and physical functioning portion of the SF-36 (outpatients) and standardized chart items (11 Functional Independence Measure (FIM), 19 Standardized Outcome and Assessment Information Set (OASIS) items, and 22 Minimum Data Set (MDS) items). Rasch modeling analyzed all data and the relationship between person ability estimates and average item difficulty. CAT assessed the ability to derive accurate patient scores using a sample of questions. Results The 163-item activity item pool covered the range of physical movement and personal and instrumental activities. CAT analysis showed comparable scores between estimates using 10 items or the total item pool. Conclusion The AM-PAC can assess a broad range of function in patients with complex medical illness. CAT achieves valid patient scores using fewer questions.

Coster WJ, Haley SM, Ludlow LH, Andres PL, Ni PS. Development of an applied cognition scale to measure rehabilitation outcomes. Objective To examine the structure and content coverage of an item pool of new items based on the Activity categories from the International Classification of Functioning, Disability and Health and items from existing instruments to measure the applied cognition dimension of function. Design Prospective study. Setting Four postacute care rehabilitation settings (inpatient, transitional care, home care, outpatient) in an urban-suburban area of northeast United States. Participants Convenience sample of 477 patients (mean age, 62.7y) receiving rehabilitation services for neurologic, orthopedic, or complex medical conditions. Interventions Not applicable. Main outcome measures Participants were administered applied cognition items from the new Activity Measure for Post-Acute Care, the Medical Outcomes Study 8-Item Short-Form Health Survey, and an additional setting-specific measure: the FIM instrument (inpatient rehabilitation); the Minimum Data Set (skilled nursing facility); the Minimum Data Set–Post Acute Care (postacute settings); or the Outcome Assessment and Information Set (home care). Rasch (partial-credit model) analyses were conducted to examine item fit, item coverage, scale unidimensionality, and category difficulty estimates. Results The majority of items (46/59) could be located along a single continuum. Relatively few people were performing at the lower end of the difficulty scale, and about 25% were at ceiling. Conclusions The proposed definition of applied cognition dimension provides a useful guide for item development to measure this dimension. Further work is needed to determine how best to measure function in this domain for people at the upper and lower ends of the continuum.

Haley SM, Coster WJ, Andres PL, Kosinski M, Ni P. Score comparability of short forms and computerized adaptive testing: simulation study with the Activity Measure for Post-Acute Care. Arch Phys Med Rehabil 2004;85:661–666. Objective To compare simulated short-form and computerized adaptive testing (CAT) scores to scores obtained from complete item sets for each of the 3 domains of the Activity Measure for Post-Acute Care (AM-PAC). Design Prospective study. Setting Six postacute health care networks in the greater Boston metropolitan area, including inpatient acute rehabilitation, transitional care units, home care, and outpatient services. Participants A convenience sample of 485 adult volunteers who were receiving skilled rehabilitation services. Interventions Not applicable. Main outcome measures Inpatient and community-based short forms and CAT applications were developed for each of 3 activity domains (physical & mobility, personal care & instrumental, applied cognition) using item pools constructed from new items and items from existing postacute care instruments. Results Simulated CAT scores correlated highly with score estimates from the total item pool in each domain (4- and 6-item CAT r range, .90–.95; 10-item CAT r range, .96–.98). Scores on the 10-item short forms constructed for inpatient and community settings also provided good estimates of the AM-PAC item pool scores for the physical & movement and personal care & instrumental domains, but were less consistent in the applied cognition domain. Confidence intervals around individual scores were greater in the short forms than for the CATs. Conclusions Accurate scoring estimates for AM-PAC domains can be obtained with either the setting-specific short forms or the CATs. The strong relationship between CAT and item pool scores can be attributed to the CAT's ability to select specific items to match individual responses. The CAT may have additional advantages over short forms in practicality, efficiency, and the potential for providing more precise scoring estimates for individuals.

Objective The objective of this study was to evaluate the payment implications of substituting the Minimum Data Set-Post Acute Care (MDS-PAC) for the FIM trade mark instrument for use in the planned prospective payment system (PPS) for inpatient rehabilitation hospitals. FIM trade mark is a trademark of the Uniform Data System for Medical Rehabilitation, a division of UB Foundation Activites, Inc. Research design We used a prospective cross-sectional design using consecutive sampling. Subjects We studied all Medicare admissions with stays of 3 days or more over a 2-month period to 50 inpatient rehabilitation hospitals in 22 states. Measurements and methods Each participating institution completed both the FIM and the MDS-PAC assessments on all participants. Items from the MDS-PAC were combined and translated to create "FIM-like" items. We assessed agreement of classification into prospective payment cells using FIM assessment data and also using MDS-PAC data. Statistical adjustments were applied to improve the level of agreement. Results The mean differences between the FIM motor and cognitive scales and their MDS-PAC translations were 2.4 (mean = 45) and 0.0 (mean = 28), respectively, with scale correlations of.85 and.84. Weighted kappas on individual items ranged from.32 to.64. There were substantial hospital-specific differences in scoring. Payment cell classification using FIM data agreed with that using MDS-PAC data only 56% of the time. Twenty percent of the facilities experienced revenue shifts larger than 10%. Conclusion Despite better item-level agreement than previously observed, poor payment cell agreement and substantial revenue shifts indicated that the MDS-PAC should not be substituted for the FIM trade mark instrument in the rehabilitation hospital PPS.

Background Rehabilitation outcome measures routinely include content on performance of daily activities; however, the conceptual basis for item selection is rarely specified. These instruments differ significantly in format, number, and specificity of daily activity items and in the measurement dimensions and type of scale used to specify levels of performance. We propose that a requirement for upper limb and hand skills underlies many activities of daily living (ADL) and instrumental activities of daily living (IADL) items in current instruments, and that items selected based on this definition can be placed along a single functional continuum. Objective To examine the dimensional structure and content coverage of a Personal Care and Instrumental Activities item set and to examine the comparability of items from existing instruments and a set of new items as measures of this domain. Methods Participants (N = 477) from 3 different disability groups and 4 settings representing the continuum of postacute rehabilitation care were administered the newly developed Activity Measure for Post-Acute Care (AM-PAC), the SF-8, and an additional setting-specific measure: FIM (in-patient rehabilitation); MDS (skilled nursing facility); MDS-PAC (postacute settings); OASIS (home care); or PF-10 (outpatient clinic). Rasch (partial-credit model) analyses were conducted on a set of 62 items covering the Personal Care and Instrumental domain to examine item fit, item functioning, and category difficulty estimates and unidimensionality. Results After removing 6 misfitting items, the remaining 56 items fit acceptably along the hypothesized continuum. Analyses yielded different difficulty estimates for the maximum score (eg, "Independent performance") for items with comparable content from different instruments. Items showed little differential item functioning across age, diagnosis, or severity groups, and 92% of the participants fit the model. Conclusions ADL and IADL items from existing rehabilitation outcomes instruments that depend on skilled upper limb and hand use can be located along a single continuum, along with the new personal care and instrumental items of the AM-PAC addressing gaps in content. Results support the validity of the proposed definition of the Personal Care and Instrumental Activities dimension of function as a guide for future development of rehabilitation outcome instruments, such as linked, setting-specific short forms and computerized adaptive testing approaches.

Background Efforts to evaluate the effectiveness of a broad range of postacute care services have been hindered by the lack of conceptually sound and comprehensive measures of outcomes. It is critical to determine a common underlying structure before employing current methods of item equating across outcome instruments for future item banking and computer-adaptive testing applications. Objective To investigate the factor structure, reliability, and scale properties of items underlying the Activity domains of the International Classification of Functioning, Disability and Health (ICF) for use in postacute care outcome measurement. Methods We developed a 41-item Activity Measure for Postacute Care (AM-PAC) that assessed an individual's execution of discrete daily tasks in his or her own environment across major content domains as defined by the ICF. We evaluated the reliability and discriminant validity of the prototype AM-PAC in 477 individuals in active rehabilitation programs across 4 rehabilitation settings using factor analyses, tests of item scaling, internal consistency reliability analyses, Rasch item response theory modeling, residual component analysis, and modified parallel analysis. Results Results from an initial exploratory factor analysis produced 3 distinct, interpretable factors that accounted for 72% of the variance: Applied Cognition (44%), Personal Care & Instrumental Activities (19%), and Physical & Movement Activities (9%); these 3 activity factors were verified by a confirmatory factor analysis. Scaling assumptions were met for each factor in the total sample and across diagnostic groups. Internal consistency reliability was high for the total sample (Cronbach alpha = 0.92 to 0.94), and for specific diagnostic groups (Cronbach alpha = 0.90 to 0.95). Rasch scaling, residual factor, differential item functioning, and modified parallel analyses supported the unidimensionality and goodness of fit of each unique activity domain. Conclusions This 3-factor model of the AM-PAC can form the conceptual basis for common-item equating and computer-adaptive applications, leading to a comprehensive system of outcome instruments for postacute care settings.

Objective: To examine the relation between lower extremity muscle force production and functional ambulation in patients with amyotrophic lateral sclerosis (ALS). Design: Retrospective analysis of data collected from 1979 to 1995. Patients: Two hundred forty ALS patients referred to the New England Medical Center Neuromuscular Research Unit. Main Outcome Measures: Muscle force production during a maximum, voluntary isometric contraction of ankle dorsiflexors, knee flexors, knee extensors, hip flexors, and hip extensors was calculated as percent predicted maximal force (PPMF). Functional ambulation status was classified as unable, home, or community. Results: The probability of community ambulation compared with home increased with progressively higher PPMF for all muscle groups. Subjects with knee flexion strength greater than 75% PPMF were 395 times more likely to ambulate in the community. Subjects with hip extension strength over 50% PPMF showed improved chance of ambulation at home. Conclusion: Lower extremity PPMF is a critical factor determining functional ambulation in patients with ALS. Knee flexors play an important role in community ambulation while the hip extensors are important for home ambulation.

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.

Evidence that thyrotropin-releasing hormone (TRH) has prominent trophic effects on the motor system led to several negative therapeutic trials in amyotrophic lateral sclerosis, a disease of the motor system. Since TRH crosses the blood-brain barrier poorly, if at all, we postulated that the negative parenteral clinical trials could be a result of insufficient drug-receptor interaction. We thus carried out a blinded, placebo-controlled, crossover study of intrathecal TRH in 36 patients by delivery through an implanted, constant infusion pump achieving a steady-state CSF level comparable with that shown to be effective in tissue culture experiments. Utilizing a quantitative measurement technique to assess motor unit loss, we did not observe any alteration of the progressive course during 6 months on TRH and 6 months on saline placebo. However, the implanted pump delivery system proved to be safe, reliable, and well tolerated.

A battery of electrophysiologic tests was developed to assess the relative degree of lower and upper motor neuron (spasticity) deficit in a group of ALS patients enrolled in a therapeutic trial. Test results were correlated with strength in the tibialis anterior muscle as determined by measurement of maximum voluntary isometric contraction (MVIC), using strain gauge tensiometers, and were also correlated with a clinical spasticity rating scale. Patients were tested every 6 to 8 weeks over more than 1 year. Compound muscle action potential amplitude (CMAPa) from tibialis anterior correlated best with MVIC and also showed a strong linear correlation with time, as did MVIC. Other tests correlated poorly with MVIC on the average, although individual patients did show high correlations. In those patients where correlation between CMAPa and MVIC was low, MVIC did not show a high linear correlation with time and was also highly variable. This study suggests that the addition of CMAPa should be considered in ALS therapeutic trials if MVIC is not available. In addition, CMAPa can be useful in study samples where MVIC deterioration is not linear over time or is highly variable.

Background: There is a known connection between physical injury and disability and emotional distress. Several investigators have shown a relationship between trauma, depression, and poor outcomes. The literature on trauma and depression is limited with regard to clarifying the relationship between the degree of injury and depression and the relationship between physical function of patients with less severe injuries and depression. Methods: One hundred and sixty-one patients who presented to our orthopaedic trauma services were enrolled in the study and interviewed. We obtained information about patient demographics and administered several self-reported outcome measures: the Beck Depression Inventory (BDI), the Short Musculoskeletal Function Assessment (SMFA), and the Physical Function-10 (PF-10) subset of the Short Form-36 (SF-36). We documented the nature and severity of the injury or injuries and calculated correlations between the outcome measures and the BDI. Injury-specific factors such as the AO Fracture Classification, the Abbreviated Injury Scale (AIS), the Injury Severity Score (ISS), and the Gustilo and Anderson grade of open fractures were also examined. Results: Fifty-five percent of the patients had minimal depression, as measured with the BDI; 28% had moderate depression; 13% had moderate-to-severe depression; and 3.7% had severe depression. When the somatic elements of the BDI were removed, the prevalence of moderate, moderate-to-severe, or severe depression was 26%. The SMFA scores had a strong negative correlation with the BDI (–0.75; p < 0.001). Of the injury-specific factors, only open factures were found to have an impact on the presence of depression, with an odds ratio of 4.58 (95% confidence ratio, 1.57 to 12.35). Conclusions: The prevalence of clinically relevant depression approached 45% in a diverse cohort of orthopaedic trauma patients. Global disability is strongly correlated with depression. The presence of an open fracture may also increase the risk of depression. Level of Evidence: Prognostic Level II. See Instructions to Authors for a complete description of levels of evidence.

We analyzed the natural history of amyotrophic lateral sclerosis in 277 patients. Our goal was to develop a better understanding of the clinical disease and thus improve the design of therapeutic trials. The Tufts Quantitative Neuromuscular Exam (TQNE) was used as the primary assessment instrument. Our analysis suggested that although more observations are desirable, six monthly TQNEs were adequate to establish the rate of disease progression. We observed a spectrum of deterioration rates without definable subgroups. The striking linearity of deterioration was confirmed. We found a high correlation between deterioration rates in arm and leg strength for individual patients, but a wide range between different patients. Sex and the age at clinical onset did not affect the deterioration rate. As compared with patients without a positive family history, those with other affected family members had a slower loss in arm but not leg strength. We propose that natural history controls can be used effectively in the design of ALS therapeutic trials.

Several criteria must be met in developing a test battery forr ALS. First, the test items should be designed to answer the specific questions being asked. If questions involve the amount and rate of deterioration, then the test items should generate interval data and show evidence that they reflect change in the disease itself. Second, the reliability of the test items should be carefully determined. Are the variances due to testing errors such as inconsistent positioning or changes in verbal instructions; or do they reflect human performance variation? Third, the test items must be sensitive to small changes, and one must be able to test the very strong as well as the severely debilitated patient. The TQNE was designed to measure degree of disease progression in ALS. The major portion of the protocol consists of isometric force measurement using an electronic strain gauge. Other quantitative segments include tests of pulmonary function, speech rates, and timed activities. Using z-score transformations, we have summarized these test items into five megascores: pulmonary function, bulbar function, timed hand activities, arm strength, and leg strength. Megascores have been used to characterize the natural history of the disease and to judge therapeutic efficacy. Quantitative methods to measure deficit in neuromuscular disease lag far behind other technologic advances in medical research. Future advances in the measurement of neuromuscular deficit depend on the commitment of researchers to invest the time and resources necessary to develop more sensitive and reliable testing techniques.

Summary Background Mutations in SOD1 cause 13% of familial amyotrophic lateral sclerosis. In the SOD1 Gly93Ala rat model of amyotrophic lateral sclerosis, the antisense oligonucleotide ISIS 333611 delivered to CSF decreased SOD1 mRNA and protein concentrations in spinal cord tissue and prolonged survival. We aimed to assess the safety, tolerability, and pharmacokinetics of ISIS 333611 after intrathecal administration in patients with SOD1 -related familial amyotrophic lateral sclerosis. Methods In this randomised, placebo-controlled, phase 1 trial, we delivered ISIS 333611 by intrathecal infusion using an external pump over 11·5 h at increasing doses (0·15 mg, 0·50 mg, 1·50 mg, 3·00 mg) to four cohorts of eight patients with SOD1 -positive amyotrophic lateral sclerosis (six patients assigned to ISIS 333611, two to placebo in each cohort). We did the randomisation with a web-based system, assigning patients in blocks of four. Patients and investigators were masked to treatment assignment. Participants were allowed to re-enrol in subsequent cohorts. Our primary objective was to assess the safety and tolerability of ISIS 333611. Assessments were done during infusion and over 28 days after infusion. This study was registered with Clinicaltrials.gov, number NCT01041222. Findings Seven of eight (88%) patients in the placebo group versus 20 of 24 (83%) in the ISIS 333611 group had adverse events. The most common events were post-lumbar puncture syndrome (3/8 [38%] vs 8/24 [33%]), back pain (4/8 [50%] vs 4/24 [17%]), and nausea (0/8 [0%] vs 3/24 [13%]). We recorded no dose-limiting toxic effects or any safety or tolerability concerns related to ISIS 333611. No serious adverse events occurred in patients given ISIS 333611. Re-enrolment and re-treatment were also well tolerated. Interpretation This trial is the first clinical study of intrathecal delivery of an antisense oligonucleotide. ISIS 333611 was well tolerated when administered as an intrathecal infusion. Antisense oligonucleotides delivered to the CNS might be a feasible treatment for neurological disorders. Funding The ALS Association, Muscular Dystrophy Association, Isis Pharmaceuticals.

Reliable measurements are needed to document the natural history of ALS and to determine therapeutic efficacy. We have devised a standardized protocol that generates interval data sensitive to change-the Tufts Quantitative Neuromuscular Exam (TQNE). The TQNE consists of the following four major categories: pulmonary function, oropharyngeal function, timed functional activities, and isometric strength using an electronic strain gauge. The 29-item exam takes about 1 hour to administer and has excellent test-retest reliability.

Using a quantitative, reliable, sensitive and valid measurement technique, we analyzed the rate and pattern of motor deterioration in 50 strictly defined ALS patients for up to 67 months. We observed that the rate of motoneuron loss was linear and symmetric. Bulbar function deteriorated more slowly than respiratory, arm, and leg function. The loss of leg strength was slower than in the arm. No correlation was observed between age at onset and rate of deterioration, or with different regions of onset. Arm strength changed more slowly in women, but other functions showed no male-female differences. These data should prove useful in the design of clinical trials and in generating testable hypotheses of the etiology of this disease.

Four patients with inclusion body myositis were treated with 150 rad of total body irradiation given in 5 weeks. One patient responded subjectively and transiently, but no patient showed clear benefit. This treatment is not recommended for inclusion body myositis.

The Tufts Quantitative Neuromuscular Exam (TQNE) consists of 28 items that were designed to measure voluntary motor deficit in amyotrophic lateral sclerosis (ALS) and related diseases. Individual raw data were converted to Z scores for standardization and then grouped into five megascores with statistical and clinical relevance. The derived megascores were Mega 1, pulmonary function; Mega 2, bulbar function; Mega 3, timed hand activities; Mega 4, isometric arm strength; and Mega 5, isometric leg strength. Megascores should enhance the usefulness of testing in therapeutic trials and in analyzing the natural history of ALS and related diseases.