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We performed a randomized, double-blind phase I clinical trial for six months on the effects of oral L-serine in patients with ALS. The protocol called for enrollment of patients with a diagnosis of probable or definite ALS, age 18-85 years, disease duration of less than three years and forced vital capacity (FVC) ≥ 60%. Patients were randomly assigned to four different oral twice-daily dose regimens (0.5, 2.5, 7.5, or 15 g/dose). Blood, urine and CSF samples, ALS Functional Rating Scale-Revised (ALSFRS-R) scores and forced vital capacity (FVC) were obtained throughout the trial. Disease progression was compared with matched historical placebo controls from five previous ALS therapeutic trials. Of 20 patients enrolled, one withdrew before receiving study drug and two withdrew with gastro-intestinal problems. Three patients died during the trial. L-serine was generally well tolerated by the patients and L-serine did not appear to accelerate functional decline of patients as measured by slope of their ALSFRS-R scores. Based on this small study, L-serine appears to be generally safe for patients with ALS.

Although the cyanobacteria/BMAA hypothesis of the cause of ALS and other age-related neurodegenerative diseases remains to be proven, it is not too early to ask whether treatment would be possible if the hypothesis were correct. This paper reviews the possible ways that chronic BMAA neurotoxicity could be prevented or treated.

We report the establishment of an in vivo model using the fruit fly Drosophila melanogaster to investigate the toxic effects of L-BMAA. We found that dietary intake of BMAA reduced the lifespan as well as the neurological functions of flies. Furthermore, we have developed an HPLC method to reliably detect both free and protein-bound BMAA in fly tissue extracts.

Veterans of the 1990-1991 Gulf War have been reported to have an increased incidence of amyotrophic lateral sclerosis (ALS) compared to personnel who were not deployed. An excess of ALS cases was diagnosed in Gulf War veterans younger than 45 years of age. Increased ALS among Gulf War veterans appears to be an outbreak time-limited to the decade following the Gulf War. Seeking to identify biologically plausible environmental exposures, we have focused on inhalation of cyanobacteria and cyanotoxins carried by dust in the Gulf region, particularly Qatar. Cyanobacterial crusts and mats are widespread in the deserts of Qatar, occupying up to 56% of the available area in some microhabitats. These cyanobacterial crusts, which help bind the desert sands, are dormant throughout most of the year, but during brief spring rains actively photosynthesize. When disturbed by vehicular traffic or other military activities, the dried crusts and mats can produce significant dust. Using HPLC/FD, an amino acid analyzer, UPLC/MS, and triple quadrupole LC/MS/MS we find that the dried crusts and mats contain neurotoxic cyanobacterial toxins, including beta-N-methylamino-L-alanine (BMAA) and 2,4 diaminobutyric acid (DAB). If dust containing cyanobacteria is inhaled, significant exposure to BMAA and other cyanotoxins may occur. We suggest that inhalation of BMAA, DAB, and other aerosolized cyanotoxins may constitute a significant risk factor for the development of ALS and other neurodegenerative diseases.

Cognitive impairment in patients with amyotrophic lateral sclerosis (ALS) is well documented, but behavioral abnormalities are not well defined. The Frontal Systems Behavior Scale (FrSBe) was used to assess changes in apathy, disinhibition, and executive dysfunction in 45 patients with ALS. Results suggest a high incidence of behavioral change, most notably in apathy associated with the onset of the disease and independent of mood. Apathy and verbal fluency were correlated, lending further support to the hypothesis that an underlying continuum exists between ALS and frontotemporal dementia (FTD), which is characterized predominantly by behavioral disturbance. The FrsBe is useful for detecting behavioral change and abnormalities in patients with ALS.

The time is now ripe for the ALS community in the United States to set up a national ALS Study Group. NIH and other granting agencies should fund a program to set up and run the ALS Study Group for five years renewable. This program should result in a competitive request for applications. The benefits likely to derive from a national ALS Study Group would include cheaper and more cost-effective clinical therapeutic trials, the development of better techniques for pilot trials, an increased number of potential new drugs brought from bench to bedside for ALS trials, increased research on biological and surrogate markers of disease, and increased physician-initiated research.

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 VC50% 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 VC50%; RRR 12% [CI: -6.27, ns] for time to VC50% 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.

(2003). Psychosocial factors and cognition in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders: Vol. 4, No. 4, pp. 217-224.

In the aftermath of World War II, U.S. Army physicians in Guam found an unusual paralytic disease among the indigenous Chamorro people of Guam and nearby islands in the Pacific Ocean. Some villager...

Dear Sir,We reported the results of a phase I study of hyperbaric oxygen therapy (HBOT) in amyotrophic lateral sclerosis (ALS) in this journal in 2004 [1]. Although that report described a pilot st...

A number of facts about ALS are unquestionable. We need more effective drugs to treat the disease. The disease is remarkably variable in its site of involvement and rate of progression from patienttopatient.Ifadrugarrestedprogressionofthedisease,or even reversed it, we would only need one patient to prove this. Unfortunately, current expectations are for the discovery of drugs that only slow the progression. Until now, clinical trials of a drug that has laboratory features suggesting a likely effect on motor neuron death have proceeded along the classical path: phase 1 clinical trials designed to show that the drug is safe; phase 2 trials in ALS patients who show some possible clinical benefit; and phase 3 double blind, randomized, placebo controlledtrialsthatinvolve300patientspertreatmentarm,oreven more, and cost at least $20 million, the cost depending on the amount ofdata collected.Unfortunately,although todate many trials have been undertaken, only those involving Riluzole have unequivocally proved the positive effect of the drug. 1‐3 There has been much research into ways of speeding the process of identifying new drugs for ALS. Recent work has been devoted to trials in murine models of ALS, and in the rapid screening of potential drugs in motor neuron-like cultures. The question of the use of placebo controlled trials in ALS and in other lethaldiseases continues tobe a topicfordiscussion. From thepatient’spoint ofview, if thereisa drugthatmight producea benefit, he wants it now and does not want a trial involving a placebo. This attitude is counter-intuitive in that an unstudied drug is of untried efficacy, and cannot be classed as a therapy. However, patients with ALS are not interested in scientific proof that a drug works, but rather whether they can live longer. This is as true in ALS as it is for cancer and AIDS. Physicians looking after these dire diseases are among the most caring of our profession, and often have the same psychological drive to treat the patient to the exclusion of finding out if the drug actually helps or even hurts the patient. The latter is always possible. For instance, in the Regeneron high dose CNTF trial, patients treated with theactivedrugdeteriorated fasterthanthosetreated with the placebo. 4 For a number of years after that trial was published, the clamor for avoidance of placebo-controlled trials was muted, though we are now back in an era when ALS patients try to obtain every drug that is even suggested to be worthy of trial. Munsat and colleagues showed that Z-scores of data from a populationofALSpatientsdecreasedlinearly,andthattherewas a similar trend in individual patients.5 The implication of their work was that therapeutic trials in ALS could be designed to compare an active treatment group with a database from patients in an observational, natural history study. This would greatly reduce the cost the trial, and avoid some patients having to take a placebo. Unfortunately, this has not proved to be the case. Comparison of the placebo groups in the various controlled ALS trials in the last decade has shown significant differences, presumably derived from different inclusion and exclusion criteria, and the demographic details of the patients. Alternative trial designs allow the patient to act as his own control.Across-overdesigninALSiscomplicatedbythefactthat the patient is more advanced by the time of the cross-over. This might be avoided by collecting data during a natural history phase preceding an active treatment phase. However, this presupposesthatdiseaseprogressionislinearinbothphases,witha similar slope ofdeterioration on thecriticalmeasure,andso still needs a placebo arm if the placebo response is to be avoided. In this issue of the Journal, Bryan et al. revisit the question of the elimination of a placebo arm in ALS trials. 6 Based on data fromtheplacebogroupinthenegativelowdoseCNTFtrial, 7 the authors compare the rate of deterioration during the 3 month ‘‘lead-in’’ or natural history phase with that during the 6-month treatment phase. The authors report that the rate of decrease in FVC was significantly faster in the placebo phase than in the preceding natural history phase, casting doubt on the underlying theory of this type of study. Moreover, there was no correlation between the two phases of the study for the slopes of the leg and FVC megascores. There was a small but significant correlation between the deterioration in the two phases in the arm scores, indicating a smaller variation in the arm data, a fact previously reported. 8 The authors suggest that comparison with natural history database controls might allow exploratory trials to rule out ineffective treatments. They recommend the use of arm strength measurements in such trials. However, they indicate that double-blind placebo controlled trials are still needed to prove drug efficacy and to study safety of potential drugs for ALS, a point I have previously advocated.9 Until we have more effective drugs for the treatment of ALS, trial design will remain an important area of discussion. 3,10‐11