Elevated lactate and alkalosis in chronic human brain infarction observed by 1H and 31P MR spectroscopic imaging.

The goal of this study was to investigate lactate and pH distributions in subacutely and chronically infarcted human brains. Magnetic resonance spectroscopic imaging (MRSI) was used to map spatial distributions of 1H and 31P metabolites in 11 nonhemorrhagic subacute to chronic cerebral infarction patients and 11 controls. All six infarcts containing lactate were alkalotic (pHi = 7.20 +/- 0.04 vs. 7.05 +/- 0.01 contralateral, p less than 0.01). This finding of elevated lactate and alkalosis in chronic infarctions does not support the presence of chronic ischemia; however, it is consistent with the presence of phagocytic cells, gliosis, altered buffering mechanisms, and/or luxury perfusion. Total 1H and 31P metabolites were markedly reduced (about 50% on average) in subacute and chronic brain infarctions (p less than 0.01), and N-acetyl aspartate (NAA) was reduced more (approximately 75%) than other metabolites (p less than 0.01). Because NAA is localized in neurons, selective NAA reduction is consistent with pathological findings of a greater loss of neurons than glial cells in chronic infarctions.

Effect of recombinant human insulin-like growth factor-I on progression of ALS. A placebo-controlled study. The North America ALS/IGF-I Study Group.

The objective of this study was to investigate the safety and efficacy of recombinant human insulinlike growth factor-I (rhIGF-I) in the treatment of sporadic ALS. A double-blind, placebo-controlled, randomized study of 266 patients was conducted at eight centers in North America. Placebo or rhIGF-I (0.05 mg/kg/day or 0.10 mg/kg/day) was administered for 9 months. The primary outcome measure was disease symptom progression, assessed by the rate of change (per patient slope) in the Appel ALS rating scale total score. The Sickness Impact Profile (SIP), a patient-perceived, health-related quality of life assessment, was a secondary outcome variable. Progression of functional impairment in patients receiving high-dose (0.10 mg/kg/day) rhIGF-I was 26% slower than in patients receiving placebo (p = 0.01). The high-dose treatment group was less likely to terminate the study due to protocol-defined markers of disease symptom progression, and members in this group exhibited a slower decline in quality of life, as assessed by the SIP. Patients receiving 0.05 mg/kg/day of rhIGF-I exhibited trends similar to those associated with high-dose treatment, suggesting a dose-dependent response. The incidence of clinically significant adverse experiences was comparable among the three treatment groups. Recombinant human insulin-like growth factor-I slowed the progression of functional impairment and the decline in health-related quality of life in patients with ALS with no medically important adverse effects.

Placebo-controlled trial of gabapentin in patients with amyotrophic lateral sclerosis. WALS Study Group. Western Amyotrophic Lateral Sclerosis Study Group.

We designed a phase II trial to evaluate the efficacy of gabapentin in slowing the rate of decline in muscle strength of patients with amyotrophic lateral sclerosis (ALS) and to assess safety and tolerability. Gabapentin (800 mg) or placebo was administered t.i.d. in a randomized, double-blinded, placebo-controlled, trial for 6 months. We enrolled 152 patients at eight sites in the United States. The primary outcome measure was the slope of the arm megascore, the average maximum voluntary isometric strength from eight arm muscles standardized against a reference ALS population. A secondary outcome measure was forced vital capacity. Slopes of arm megascores for patients on gabapentin were compared with slopes of those taking placebo using a two-way ANOVA. We observed a nonstatistically significant trend (p = 0.057-0.08) toward slower decline of arm strength in patients taking gabapentin compared with those taking placebo (mean difference 24%, median 37%). We observed no treatment effect on forced vital capacity. Gabapentin was well tolerated by patients with ALS. These results suggest that further studies of gabapentin in ALS are warranted.

Phase III randomized trial of gabapentin in patients with amyotrophic lateral sclerosis.

BACKGROUND: Preclinical and clinical studies of gabapentin in patients with ALS led the authors to undertake a phase III randomized clinical trial. METHODS: Patients were randomly assigned, in a double-blinded fashion, to receive oral gabapentin 3,600 mg or placebo daily for 9 months. The primary outcome measure was the average rate of decline in isometric arm muscle strength for those with two or more evaluations. RESULTS: Two hundred four patients enrolled, 196 had two or more evaluations, and 128 patients completed the study. The mean rate of decline of the arm muscle strength was not significantly different between the groups. Moreover, there was no beneficial effect upon the rate of decline of other secondary measures (vital capacity, survival, ALS functional rating scale, timed walking) nor was there any symptomatic benefit. In fact, analysis of the combined data from the phase II and III trials revealed a significantly more rapid decline of forced vital capacity in patients treated with gabapentin. CONCLUSION: These data provide no evidence of a beneficial effect of gabapentin on disease progression or symptoms in patients with ALS.

Blunted pressor and intramuscular metabolic responses to voluntary isometric exercise in multiple sclerosis.

To test the hypothesis that a lower mean arterial pressure (MAP) response during voluntary isometric exercise in multiple sclerosis (MS) is related to a dampened muscle metabolic signal, 9 MS and 11 control subjects performed an isometric dorsiflexor contraction at 30% maximal voluntary contraction until target failure (endurance time). We made continuous and noninvasive measurements of heart rate and MAP (Finapres) and of intramuscular pH and P(i) (phosphorus magnetic resonance spectroscopy) in a subset of 6 MS and 10 control subjects. Endurance times and change in heart rate were similar in MS and control subjects. The decrease in pH and increase in P(i) were less throughout exercise in MS compared with control subjects, as was the change in MAP response. Differences in muscle strength accounted for some of the difference in MAP response between groups. Cardiovascular responses during Valsalva and cold pressor tests were similar in MS and control subjects, suggesting that the blunted MAP response during exercise in MS was not due to a generalized dysautonomia. The dampened metabolic response in MS subjects was not explained by inadequate central muscle activation. These data suggest that the blunted pressor response to exercise in MS subjects may be largely appropriate to a blunted muscle metabolic response and differences in contracting muscle mass.

Mechanical ventilation in amyotrophic lateral sclerosis: a cross-cultural perspective.

Mechanical ventilation is known to be an effective means of relieving symptoms of chronic hypoventilation and prolonging life in patients with amyotrophic lateral sclerosis (ALS). Various methods of mechanical ventilation are available to patients with ALS. However, attitudes towards mechanical ventilation in ALS vary widely across different cultures, and even within a given medical system. This article describes differences and similarities between a North American, a European and a Japanese approach, based on the respective medical and cultural traditions. The common goal is to provide optimal palliative care to patients with ALS.

Quality of life for ventilator-dependent ALS patients and their caregivers.

Seven ventilator-dependent ALS patients and eleven caregivers were interviewed in order to assess the impact of ventilator-dependence on patients and their families. The ALS Care Database questionnaires were administered with special attention to components derived from the Health Status Survey (SF-12) and ALS Quality-of-Life Index (ALSQLI) as well as the ALS Patient Caregiver Form. Six patients had difficulty communicating and one patient was totally unable to communicate. Patients had maximal limitation of daily activities as measured by The ALS QLI, yet a self-reported satisfactory quality-of-life. Caregivers were heavily burdened and their outside activities were severely limited.

A placebo-controlled trial of gabapentin in spinal muscular atrophy.

OBJECTIVE: To evaluate the efficacy of gabapentin in increasing muscle strength of patients with spinal muscular atrophy (SMA). BACKGROUND: Preclinical data in experimental models of motor neuron disease suggest a neuroprotective effect of gabapentin. METHODS: Gabapentin (1200 mg), or placebo, was administered three times daily in a randomized, double-blind trial for 12 months. The primary outcome measure was the average percent change from baseline, based on the measurement of strength in four muscles (elbow flexion and hand grip bilaterally) for each patient. Drug efficacy was examined by comparing the percent change in strength for patients on drug vs. placebo. Secondary efficacy variables included: forced vital capacity (FVC), SMA functional rating scale (SMAFRS), and mini-Sickness Impact Profile (SIP). RESULTS: Eighty-four patients, with type II or III SMA, were enrolled at eight sites across the United States. There were no differences in baseline features. There was no difference between the placebo and drug groups in any outcome measure. CONCLUSIONS: This study demonstrates the feasibility of this trial design and provides data for the design of future clinical trials in SMA.

Cost effectiveness of recombinant human insulin-like growth factor I therapy in patients with ALS.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal, degenerative neuromuscular disease characterised by a progressive loss of voluntary motor activity. Recombinant human insulin-like growth factor I (rhIGF-I) has been shown to be useful in treating ALS. The purpose of this study was to examine the cost effectiveness of rhIGF-I therapy in patients who have ALS. DESIGN: We performed a cost-effectiveness analysis from the societal perspective on 177 patients who received treatment with rhIGF-I or placebo in a North American randomised clinical trial. We estimated the incremental cost-effectiveness ratio of rhIGF-I using resource utilisation and functional status measurements from the clinical trial. Costs were estimated from 1996 US Medicare reimbursement schedules. Utility weights were elicited from ALS healthcare providers using the standard gamble technique. MAIN OUTCOME MEASURES AND RESULTS: The overall cost per quality-adjusted life-year (QALY) gained for rhIGF-I therapy compared with placebo was $US67,440. For the subgroups of patients who were progressing rapidly or were in earlier stages of disease at enrolment, rhIGF-I cost $US52,823 and $US43,197 per QALY gained, respectively. CONCLUSIONS: Treatment with rhIGF-I is most cost effective in ALS patients who are either in earlier stages of the disease or progressing rapidly. The cost effectiveness of rhIGF-I therapy compares favourably with treatments for other chronic progressive diseases.

Reduced NAA in motor and non-motor brain regions in amyotrophic lateral sclerosis: a cross-sectional and longitudinal study.

OBJECTIVES: After replication of previous findings we aimed to: 1) determine if previously reported (1)H MRSI differences between ALS patients and control subjects are limited to the motor cortex; and 2) determine the longitudinal metabolic changes corresponding to varying levels of diagnostic certainty. METHODS: Twenty-one patients with possible/suspected ALS, 24 patients with probable/definite ALS and 17 control subjects underwent multislice (1)H MRSI co-registered with tissue-segmented MRI to obtain concentrations of the brain metabolites N-acetylaspartate (NAA), creatine, and choline in the left and right motor cortex and in gray matter and white matter of non-motor regions in the brain. RESULTS: In the more affected hemisphere, reductions in the ratios, NAA/Cho and NAA/Cre+Cho were observed both within (12.6% and 9.5% respectively) and outside (9.2% and 7.3% respectively) the motor cortex in probable/definite ALS. However, these reductions were significantly greater within the motor cortex (P<0.05 for NAA/Cho and P<0.005 for NAA/Cre+Cho). Longitudinal changes in NAA were observed at three months within the motor cortex of both possible/suspected ALS patients (P<0.005) and at nine months outside the motor cortex of probable/definite patients (P<0.005). However, there was no clear pattern of progressive change over time. CONCLUSIONS: NAA ratios are reduced in the motor cortex and outside the motor cortex in ALS, suggesting widespread neuronal injury. Longitudinal changes of NAA are not reliable, suggesting that NAA may not be a useful surrogate marker for treatment trials.

Placebo-controlled phase I/II studies of minocycline in amyotrophic lateral sclerosis.

Two double-blind, randomized, placebo-controlled feasibility trials of minocycline in ALS were conducted. In Trial 1, 19 subjects received 200 mg/day or placebo for 6 months; there were no significant differences in adverse events (AE). In Trial 2, 23 subjects received up to 400 mg/day in an 8-month crossover trial. The mean tolerated dose was 387 mg/day, there was a trend toward more gastrointestinal AE (p = 0.057), and blood urea nitrogen and liver enzymes became elevated (p < 0.05). Using these data, the authors have designed and launched a phase III trial.

Measurement of health-related quality of life in patients with amyotrophic lateral sclerosis in clinical trials of new therapies.

OBJECTIVES: Recent trials of amyotrophic lateral sclerosis (ALS) therapies have included the Sickness Impact Profile (SIP) to evaluate health-related quality of life (HQL). The purpose of this study was to assess the feasibility, psychometric properties, and interpretation of the Sickness Impact Profile in this setting. METHODS: The Sickness Impact Profile was administered at baseline, 3, 6, and 9 months during a double-blind, placebo-controlled study of recombinant human insulin-like growth factor I. The frequency of missing Sickness Impact Profile data and administration time were recorded. Patients' scores on the Appel ALS (AALS) Rating Scale were used to identify a stable subgroup for reliability testing and clinically distinct groups for validity testing. Internal consistency reliability and reproducibility were evaluated using Cronbach's alpha and intraclass correlation coefficients, respectively. Analysis of variance (ANOVA) models and t tests were used to assess validity. Effect sizes and the responsiveness index were used to assess responsiveness. RESULTS: At baseline, 259 (97%) patients completed a 30-minute Sickness Impact Profile interview. At subsequent assessments, response rates ranged from 92% to 97% and mean administration times ranged from 25 to 27 minutes. The overall Sickness Impact Profile score demonstrated alpha reliability and 3-month stability coefficients of 0.94 and 0.80, respectively. Baseline overall Sickness Impact Profile scores discriminated between patients in the two AALS-defined groups with a mean of 13.0+/-7.8 and 24.0+/-11.7 in the better and worse AALS groups, respectively. Similarly, mean overall SIP change scores discriminated patients progressing at different rates (slow to moderate = 4.00+/-7.97; rapid = 10.74+/-8.76). With few exceptions, dimension and category scores met similar criteria. Responsiveness statistics for the physical and overall Sickness Impact Profile scores were lower at 3 months and higher at 6 and 9 months. CONCLUSIONS: The feasibility, psychometric, and interpretive findings support the validity of the Sickness Impact Profile for assessing outcomes of amyotrophic lateral sclerosis and its treatment. Based on these findings, we recommend including the Sickness Impact Profile in future amyotrophic lateral sclerosis clinical trials.

Reanalysis of multislice (1)H MRSI in amyotrophic lateral sclerosis.

The goal of this work was to reexamine previously published (1) brain spectroscopy data of abnormal metabolite ratios in amyotrophic lateral sclerosis (ALS). Toward this goal, (1)H MR spectroscopic imaging data from 10 ALS and nine control subjects were reanalyzed using improved data analysis techniques, including automated curve fitting and tissue-volume correction. In the motor cortex of ALS, N-acetyl aspartate (NAA) was 23% (P = 0.004) lower than in controls, and in the posterior internal capsule of ALS choline compounds (Cho) were 20% (P = 0.02) higher. This demonstrates that the metabolite ratio changes in ALS were due to NAA loss in the motor cortex (as expected) and Cho increase in the posterior internal capsule (not expected). Magn Reson Med 45:513-516, 2001.