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.

Subcutaneous IGF-1 is not beneficial in 2-year ALS trial.

BACKGROUND: Previous human clinical trials of insulin-like growth factor type I (IGF-1) in amyotrophic lateral sclerosis (ALS) have been inconsistent. This phase III, randomized, double-blind, placebo-controlled study was undertaken to address whether IGF-1 benefited patients with ALS. METHODS: A total of 330 patients from 20 medical centers were randomized to receive 0.05 mg/kg body weight of human recombinant IGF-1 given subcutaneously twice daily or placebo for 2 years. The primary outcome measure was change in their manual muscle testing score. Secondary outcome measures included tracheostomy-free survival and rate of change in the revised ALS functional rating scale. Intention to treat analysis was used. RESULTS: There was no difference between treatment groups in the primary or secondary outcome measures after the 2-year treatment period. CONCLUSIONS: Insulin-like growth factor type I does not provide benefit for patients with amyotrophic lateral sclerosis.

Diffusion tensor imaging in amyotrophic lateral sclerosis: volumetric analysis of the corticospinal tract.

BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) allows direct visualization and volumetric analysis of the corticospinal tract (CST). The purpose of this study was to determine whether color maps and fiber tracking derived from DTI data are valuable in detecting and quantifying CST degeneration in patients with amyotrophic lateral sclerosis (ALS). METHODS: Sixteen patients with ALS with clinical signs of upper motor neuron (UMN) involvement and 17 healthy subjects were studied with the use of DTI. Disease severity was determined by means of the ALS Functional Rating Scale-Revised (ALSFRS-R) and an UMN involvement score. DTI was acquired with a 12-direction, single-shot, spin-echo echo-planar sequence. The CST from the lower pons to the corona radiata at the level of the corpus callosum on 4 contiguous coronal sections was manually segmented by using color maps generated from the DTI data. The left and right CST volumes were measured separately and normalized to the total intracranial volume. Normalized CST volumes were compared between patients with ALS and healthy subjects. RESULTS: The CST volumes of patients with ALS were significantly reduced (P < .01, unpaired t test) compared with healthy subjects, in both affected and nonaffected hemispheres. No significant correlation was found between CST volumes and any of the clinical parameters, including disease duration, ALSFRS-R, or UMN involvement score. CONCLUSION: This study shows that volumetric analysis by using DTI-based color maps is valuable in detecting and monitoring structural degeneration of the CST. This will lead to objective and quantitative assessment of axonal degeneration in ALS.

Cognitive functioning in sporadic amyotrophic lateral sclerosis: a six month longitudinal study.

OBJECTIVE: To observe changes in cognition over six months in subjects with recently diagnosed sporadic amyotrophic lateral sclerosis (ALS). METHODS: The study used a between-group and within-group longitudinal design. Nineteen ALS subjects and eight matched caregivers were recruited to participate in baseline neuropsychological assessments that were repeated six months later. Between group comparisons for these variables were undertaken at baseline and six months later. Within group/across time comparisons for these variables were carried out for both groups. Individual analyses for the neuropsychological variables using z scores were done for the ALS subjects using their baseline performance as the basis for comparison with their six month performance. RESULTS: The between-group and within-group comparisons did not show significant differences in cognitive function over time. In individual analyses, however, seven of 19 ALS subjects (36.84%) developed abnormal neuropsychological performance over six months. CONCLUSIONS: Early in the disease course, over one third of the ALS subjects developed cognitive deficits over six months. These findings support the hypothesis that cognitive deficits in ALS become more prominent over time.

Venous thrombosis in an ALS population over four years.

We conducted a retrospective chart review of all ALS patients seen at our institution over four years to determine the incidence of venous thromboembolism and to identify risk factors in this population. Events occurred in 13 of 438 patients (2.97%), yielding an annual incidence rate of 33.1 events per 1,000 patients (95% CI 17.5-55.3). ALS patients have a risk of venous thromboembolism that is higher than the general population but lower than the population of patients with acute stroke or spinal cord injury. Immobility was significantly associated with increased risk of venous thrombosis (RR = 4.96; 95% CI 1.39-17.78).

Evolution of temporal lobe hypoperfusion in transient global amnesia: a serial single photon emission computed tomography study.

Previous functional neuroimaging studies performed during transient global amnesia (TGA) have not answered the central question regarding the etiology of TGA, namely: whether the observed hypoperfusion in the mesial temporal lobe structures reflects a primarily ischemic process or whether it represents a secondary phenomenon resulting from locally decreased metabolism. The authors performed Tc 99-m-bicisate brain single photon-emission computed tomography (SPECT) scanning in a 66-year-old man during an episode of TGA, 24 hours after the episode and 3 months after the episode. To the authors' knowledge, this is the only reported study in which a follow-up SPECT scan was performed within 24 hours. The initial study showed bilateral mesial temporal lobe hypoperfusion that partially resolved after 24 hours and returned to normal at 3 months. Resolution of the SPECT scan abnormalities correlated well with resolution of the memory loss. These findings agree with previously reported SPECT, positron-emission tomography (PET), and diffusion magnetic resonance imaging (MRI) studies that indicate the mesial temporal lobe structures as the major site of pathology in TGA. The authors suggest that a process causing decreased local metabolism, such as cortical spreading depression, constitutes the primary pathophysiologic mechanism in this case.

Proximal diabetic neuropathy presenting with respiratory weakness.

A patient is described with proximal diabetic neuropathy presenting with respiratory weakness. A 50 year old man developed progressive shortness of breath over 2 months. He also had weakness of hip flexion. Phrenic nerve responses were absent, and spontaneous activity was seen in the intercostal and lumbar paraspinal muscles with long duration neurogenic MUPs and reduced recruitment in the diaphragm. Without treatment, the patient began to improve with resolution of his proximal leg weakness and breathing difficulties. Proximal diabetic neuropathy is another cause of neuromuscular respiratory weakness.

Compression and entrapment neuropathies of the lower extremity.

Injury to a peripheral nerve from pressure placed on it causes a compression neuropathy. There are particular anatomic sites where individual nerves are most vulnerable. The authors describe the physiology and structural anatomy of peripheral nerves, the pathophysiology of nerve entrapment, and the classification of peripheral nerve injury. Specific compression and entrapment neuropathies of the lower extremity are described in detail.

Direct muscle stimulation in acute quadriplegic myopathy.

We have previously found that muscle is electrically inexcitable in severe acute quadriplegic myopathy (AQM). In contrast, muscle retains normal electrical excitability in peripheral neuropathy. To study the relationship between muscle electrical excitability and all types of flaccid weakness occurring in the intensive care unit, we identified 14 critically ill, weak patients and measured the amplitude of compound muscle action potentials (CMAPs) obtained with direct muscle stimulation (dmCMAP) and with nerve stimulation (neCMAP). In 11 of 14 patients dmCMAP amplitudes were reduced and the ratio of the neCMAP amplitude to the dmCMAP amplitude (nerve/muscle ratio) was indicative of loss of muscle electrical excitability. In 2 other patients, the nerve/muscle ratio indicated neuropathy. Direct muscle stimulation may allow differentiation of AQM from neuropathy even in comatose or encephalopathic critically ill patients. AQM may be more common than has previously been appreciated.

Unusual presentation of cis-platinum neuropathy.

Symptoms and signs of cis-diamminedichloroplatinum II (DDP) neuropathy usually develop during treatment and stabilize or improve when DDP is stopped. We report three patients whose symptoms began 3 to 8 weeks after the last dose of DDP and progressed over 1 or 2 months to moderate-marked disability. The clinical picture in each was consistent with DDP neuropathy, and no other cause could be identified. Two of the patients improved over 8 and 27 months to become asymptomatic; the other died 2 months after presentation. It is important to recognize that DDP neuropathy can present after treatment has been discontinued since the clinical picture mimics the paraneoplastic dorsal root ganglionitis, which has a different prognosis.