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Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal motor neuron disease. We carried out two randomized, double-blind, placebo-controlled, multi-centre, multi-national studies with xaliproden (a drug with neurotrophic effect) to assess drug efficacy and safety at two doses. Patients with clinically probable or definite ALS of more than 6 months and less than 5 years duration were randomly assigned to placebo, 1 mg or 2 mg xaliproden orally once daily as monotherapy in Study 1 (n=867); or to the same regimen with addition of riluzole 50 mg bid background therapy in Study 2 (n=1210 patients). The two primary endpoints were defined as: 1. Time to death, tracheostomy, or permanent assisted ventilation (DTP), and 2. Time to vital capacity (VC)<50% or DTP before (log-rank test) and after adjustment using a Cox proportional hazard model for prespecified prognostic factors. Secondary endpoints were rates of change of various functional measures. In Study 1, primary outcome measures did not reach statistical significance. For the 2 mg group, for time to VC<50% analysis (without DTP) a significant 30% RRR was obtained (95% confidence interval [CI]: 8.46, P=0.009). In Study 2, no significant results were obtained. However, there was a trend in favour of add-on 1 mg dose xaliproden vs. placebo (RRR 15% [-6.31, ns] for time to VC<50%; RRR 12% [CI: -6.27, ns] for time to VC<50% or DTP). Adjusted RR ratios were consistently more favourable for the xaliproden groups. Tolerability was good, and dose-dependent side effects were largely associated with the serotonergic properties of xaliproden. An effect of xaliproden on functional parameters, especially VC, was noted. Although this effect did not reach statistical significance, xaliproden had a small effect on clinically noteworthy aspects of disease progression in ALS.

The cortical silent period (C-SP) was elicited by transcranial magnetic stimulation in 25 normal subjects and 19 patients with amyotrophic lateral sclerosis (ALS). The inhibitory (S-X) period was highly stimulus intensity (SI)-dependent (mean r2 = 0.89 for both normals and patients with ALS). The range of the C-SP (difference between maximum and minimum S-X intervals) was age-dependent for normals (r2 = 0.701, P < 0.001) but not patients with ALS. Means, maximums and ranges for the C-SP were not significantly different between normal and ALS groups and thresholds to cortical stimulation were also comparable. There was a significant, linear, relation between the maximum C-SP and disease duration of ALS (P = 0.002). The maximum C-SP was shorter early in the disease. It is hypothesized that the reduced inhibition early in the course of ALS might reflect glutamate-induced corticomotoneuronal excitotoxicity.

The ALS symposium in Vancouver was the first of its kind in Canada and was a contribution from both American and Canadian investigators. The main points presented were (1) a definition of what is truly ALS, in the clinical and pathological sense, based on what is called "classical" ALS: (2) how neurons may be cultured to provide a valuable experimental tool; (3) the significance of lipid abnormalities in ALS and the characterization of the ALS-like syndromes produced by hexosaminidase A deficiency; (4) the possible role of autoimmune disease as it may accompany classical ALS and nerve growth factor derived from skeletal muscle; (5) the western Pacific form of ALS as it has been intensely studied and has given rise to two hypotheses on pathogenesis: mineral toxicity caused by secondary hyperparathyroidism and poisoning through ingestion of the cycad seed, and (6) the possible abiotropic interaction of one or many environmental toxins over a lifetime with the aging nervous system, depleting it of its frail reserve of neurons.