Phase II screening trial of lithium carbonate in amyotrophic lateral sclerosis: examining a more efficient trial design.

OBJECTIVE: To use a historical placebo control design to determine whether lithium carbonate slows progression of amyotrophic lateral sclerosis (ALS). METHODS: A phase II trial was conducted at 10 sites in the Western ALS Study Group using similar dosages (300-450 mg/day), target blood levels (0.3-0.8 mEq/L), outcome measures, and trial duration (13 months) as the positive trial. However, taking riluzole was not a requirement for study entry. Placebo outcomes in patients matched for baseline features from a large database of recent clinical trials, showing stable rates of decline over the past 9 years, were used as historical controls. RESULTS: The mean rate of decline of the ALS Functional Rating Scale-Revised was greater in 107 patients taking lithium carbonate (-1.20/month, 95% confidence interval [CI] -1.41 to -0.98) than that in 249 control patients (-1.01/month, 95% CI -1.11 to -0.92, p = 0.04). There were no differences in secondary outcome measures (forced vital capacity, time to failure, and quality of life), but there were more adverse events in the treated group. CONCLUSIONS: The lack of therapeutic benefit and safety concerns, taken together with similar results from 2 other recent trials, weighs against the use of lithium carbonate in patients with ALS. The absence of drift over time and the availability of a large database of patients for selecting a matched historical control group suggest that use of historical controls may result in more efficient phase II trials for screening putative ALS therapeutic agents. CLASSIFICATION OF EVIDENCE: This study provided Class IV evidence that lithium carbonate does not slow the rate of decline of function in patients with ALS over 13 months.

The ALSSQOL: balancing physical and nonphysical factors in assessing quality of life in ALS.

BACKGROUND: There is no generally accepted instrument for measuring quality of life (QOL) in patients with ALS. Current instruments are either too heavily weighted toward strength and physical function or useful for the evaluation of individuals but of less utility in assessing large samples. OBJECTIVE: To develop and evaluate the psychometric properties of an ALS-specific QOL instrument (the ALSSQOL) that would reflect overall QOL as assessed by the patient and would be valid and reliable across large samples. METHODS: The ALSSQOL is based on the McGill Quality of Life Questionnaire (MQOL), modified by changes in format and by adding questions on religiousness and spirituality, items derived from interviews with ALS patients, and items identified from open-ended questions administered during the MQOL. The psychometric properties of the ALSSQOL were assessed by a prospective multicenter study in which participants completed the ALSSQOL, other instruments measuring overall QOL, and instruments assessing religiousness, spirituality, and psychological distress. RESULTS: A 59-item ALSSQOL was developed; 342 patients evaluated its psychometric properties. Completion time averaged 15 minutes. Forty-six items loaded on six factors. The ALSSQOL demonstrated concurrent, convergent, and discriminant validity for the overall instrument and convergent validity for its subscales. Analysis of individual items permitted insight into variables of clinical importance. CONCLUSIONS: This new ALS-specific quality of life instrument is a practical tool for the assessment of overall quality of life in individuals with ALS and appears to be valid and useful across large samples. Validation studies of a shortened version are now under way.

Electrophysiologic endpoint measures in a multicenter ALS drug trial.

We report the analysis of a battery of secondary electrophysiologic measurements to assess the progression of amyotrophic lateral sclerosis (ALS) in a two center, six month, double-blind, three arm trial comparing branched chain amino acids to L-threonine with pyridoxal 5-phosphate to placebo. The endpoint measurements were chosen to separately assess the effects of lower motor neuron loss and collateral reinnervation. For tests of inter-center reliability, we found no differences that could not be readily explained by variations in electrophysiologic testing techniques. Since the drug study was negative for the primary endpoint measure (muscle strength), we combined data from both centers and the three treatment arms. For measures of progression, all measures changed in the expected direction during the 6 months of the trial. We conclude that a battery of electrophysiologic measures can be used in a multicenter ALS drug trial to provide information on changes in lower motor neuron numbers and the effects of collateral reinnervation.

The use of "clinic room" presentation as an educational tool in the ambulatory care setting.

OBJECTIVE: To evaluate the utility of "clinic room" case presentation in the ambulatory care setting. BACKGROUND: Neurology is increasingly an outpatient specialty. The transition from ward to clinic presents challenges for student and resident education. Interaction between attending physician and trainee is limited by busy patient schedules. New educational strategies must be developed to address the particular challenges of the outpatient clinic. One strategy to increase the quality and length of attending-trainee interaction is case presentation in the patient's presence. METHODS: The authors randomized 100 patients seen in an academic neuromuscular clinic to presentation in a conference room or clinic room. In the latter, all interaction between the trainee and attending occurred in the patient's presence. The attending recorded the time spent with the trainee and patient. The patient was asked to complete a survey and provide certain demographic information. RESULTS: The two groups were similar demographically. Time spent by the attending physician was similar between the two settings. Although there was no difference in patient satisfaction, those randomized to clinic room presentation were significantly more likely (p < 0.002) to feel their questions were answered adequately. There were trends toward these patients feeling less embarrassed, feeling that they were treated respectfully, and feeling that adequate time was spent with them. CONCLUSIONS: Although clinic room presentation does not save attending time, it allows for a more dynamic and intensive interaction among teacher, student, and patient.

Randomized trial of azathioprine or prednisone for initial immunosuppressive treatment of myasthenia gravis.

Ten patients with myasthenia gravis were randomized to azathioprine or prednisone as the initial immunomodulating drug and followed for over one year. Of five patients randomized to azathioprine, two had idiosyncratic reactions and were immediately crossed over to prednisone. Two patients completed one year on azathioprine with little or no change in level of function and were crossed over to prednisone and showed greater improvement. The fifth patient on azathioprine had a satisfactory improvement and continued on it during the second year. All patients initially randomized to prednisone improved, but the degree varied among patients. The side effects of azathioprine were idiosyncratic reactions. The side effects of prednisone were manageable.

The economic impact of ALS.

ALS is a progressive degenerative neuromuscular disease for which there is no known cause, treatment, or cure. The steady disease progression of muscle weakness eventually causes paralysis, disabling the patient. Day-to-day patient care and management most frequently fall to family members. The resultant financial burden can be enormous. We review financial issues related to the diagnosis, management of disease progression, and issues of life support. Cost-effective solutions are discussed. It is believed the key to reduction of costs is education of the health care community, patients and families, and third-party payers.

Individuals with amyotrophic lateral sclerosis are in caloric balance despite losses in mass.

The purpose of this study was to quantify body composition changes during amyotrophic lateral sclerosis (ALS) progression and to determine whether these subjects were losing or maintaining the energy stored in their bodies. The body composition of 12 males in the early stages of ALS and 6 age-matched controls was measured twice over a 6-month period using dual X-ray absorptiometry. During the study period the control group did not change. The ALS group lost an average of 2 kg of lean mass while gaining 0.55 kg of fat mass, resulting in a 1.45 kg loss in total body mass. When the changes in mass were converted to their energy equivalents, the ALS subjects lost an average of 1800 kcal of energy stored in lean mass but gained 4900 kcal in fat mass, resulting in a net increase of 3100 kcal stored. In conclusion, a small increase in fat mass can successfully compensate for the energy lost in lean mass from disease progression. Therefore, it is possible to preserve the amount of energy stored in the body of ALS patients, even when there are significant losses in lean and overall body mass. Consequently, a moderate loss of body mass should be expected and even encouraged among this patient population.

Motor unit number estimation, isometric strength, and electromyographic measures in amyotrophic lateral sclerosis.

Pathologic progression in amyotrophic lateral sclerosis (ALS) results from motor neuron death, while the clinical expression also reflects the compensatory effects of collateral reinnervation consequent to lower motor neuron loss. In a cross-sectional study of ALS subjects, we made comparisons between motor unit number estimation (MUNE) values and several measures reflecting collateral reinnervation, including isometric strength, compound muscle action potential (CMAP) amplitude, surface motor unit action potential (S-MUAP) amplitude, fiber density (FD), macro-EMG potential amplitude, turns-to-amplitude (T/A) ratio, and amplitude and recruitment pattern of low threshold voluntary motor units in elbow flexor muscles. Before comparisons were made, test-retest reproducibility of these measures was assessed in ALS subjects, and is highest for isometric strength, and lower but similar for EMG measures. When the effects of multiple comparisons are considered, borderline significant correlations are found between MUNE values and isometric strength. Neither MUNE values nor isometric strength are significantly correlated with macro-EMG amplitude, FD, T/A ratio, or amplitude and recruitment rate of low threshold voluntary motor units. There are significant correlations of CMAP and S-MUAP with MUNE values, but these are statistical artifacts with no independent interpretation. We conclude that collateral reinnervation prevents isometric strength and EMG measures from accurately reflecting lower motor neuron death in ALS. MUNE measurements are better suited to provide insight into the true natural history of the disease process and may be clinically useful to follow progression and response in drug trials.