The epidemiology and treatment of ALS: Focus on the heterogeneity of the disease and critical appraisal of therapeutic trials

Abstract

Effective treatments for amyotrophic lateral sclerosis (ALS) have remained elusive. Only riluzole, a drug thought to affect glutamate metabolism, improves survival albeit to modest extent. Explanations for the negative results of therapeutic trials include a likely heterogeneity, both in disease susceptibility and pathogenic mechanisms, and faulty methodology of clinical trials. Further understanding of these factors will lead to improvements in patient stratification, and in the design of future clinical trials.

Screening for cognitive and behavioural impairment in amyotrophic lateral sclerosis: Frequency of abnormality and effect on survival

“…If there were a progressive deterioration of cognition over time, this could be due to the spread of pathology from motor regions to other regions, through prion-like spread, as has recently been proposed [63]. However, the finding that some patients have cognitive impairment at presentation while others remain cognitively normal throughout disease would be more consistent with ALS being a heterogeneous disease [38,64].…”

NOX2 As a Target for Drug Development: Indications, Possible Complications, and Progress

“…ALS is relatively rare, with a reported incidence of 1-2 per 100,000 per year. However, during the 1990s, clusters of cases were seen in Japan, Micronesia, and Indonesia with a local incidence at least 50 times higher than that seen worldwide (18). The average life expectancy of ALS patients ranges from 2 to 10 years after diagnosis.…”

Challenges in the Understanding and Treatment of Amyotrophic Lateral Sclerosis/Motor Neuron Disease

“…In the absence of widespread acceptance of diagnostic criteria for specific disease subtypes, there have been a number of clinical phenotypes described [11,37,48,[56][57][58][59]. These phenotypic descriptions, with variable disease progression, severity, and survival often fit into the basic diagnostic criteria of ALS/MND, although they do not necessarily obey the more classically described patterns of regional spread involving upper and lower motor neuron pathology.…”

“…Our inability to find effective therapeutics that fundamentally alter the disease course of ALS/MND is often attributed to this heterogeneity of the patient population; thus, there is a need for better diagnostic definitions that will allow for the prognostically relevant categorizations of the disease [3][4][5][7][8][9][10][11]. Our difficulty in identifying reliable biomarkers of disease progression and therapeutic benefit further confound this challenge [4,[12][13][14].…”

“…The disease-modifying effect of such supportive care is significant and often results in improvement of both survival and function, which can exceed the treatment effect that was sought in many of our recent clinical trials [25][26][27][28][29][30][31][32][33][34]. The use of such treatment strategies introduces an important prognostic variable that is not consistently considered in clinical trial design and thus confounds our ability to detect efficacious therapies [11,35].…”