Elsevier

The Lancet

Volume 369, Issue 9578, 16ā€“22 June 2007, Pages 2031-2041
The Lancet

Seminar
Amyotrophic lateral sclerosis

https://doi.org/10.1016/S0140-6736(07)60944-1Get rights and content

Summary

Amyotrophic lateral sclerosis (known in the UK as motor neuron disease) is a devastating illness with uncertain pathogenesis. In this Seminar, we review its natural history, clinical features, diagnostic criteria, variant and mimic syndromes, genetic forms, and epidemiology. Several hypotheses about causes of the disorder are discussed, such as excitotoxicity and oxidant stress, and we review past and present putative disease-modifying treatments. Disease-management strategies, from telling the patient about their illness to end-of-life decisions and palliative care, are presented. We review options for control of the main symptoms of amyotrophic lateral sclerosisā€”including dysphagia, dysarthria, respiratory distress, pain, and psychological disordersā€”and care in the terminal phase. The need for good psychosocial and spiritual care of patients and families is emphasised. We conclude with an overview of some current major issues and future prospects, ranging from the search for disease markers to challenging developments such as stem-cell and gene therapy.

Section snippets

Natural history

Amyotrophic lateral sclerosis is one of the major neurodegenerative diseases alongside Alzheimer's disease and Parkinson's disease. It is a progressive disorder that involves degeneration of the motor system at all levels. Involvement of other elements of the nervous system has been described, particularly at post mortem, but motor-system involvement is most important in relation to clinical features noted during life. Overlap with other neurodegenerative diseases is sometimes seen; some

Diagnostic criteria, clinical rating scales, and quality-of-life measurement

The El Escorial diagnostic criteria for amyotrophic lateral sclerosis were developed in the late 1980s16 and have subsequently been revised.17 Panel 1 shows the essential features of the revised criteria. Although intended as an aid to research and slightly more restrictive than the burden of proof usually applied in clinical practice, these criteria do provide a structured approach to assessment of people suspected of having amyotrophic lateral sclerosis, which can enhance objectivity in

Causal and pathogenetic hypotheses

Many causal and pathogenetic hypotheses for amyotrophic lateral sclerosis have been proposed over the years, ranging from heavy-metal toxic effects27 to environmental and occupational exposures.28 Despite extensive research, the disorder remains poorly understood in terms of a unifying causal hypothesis and, indeed, might turn out to be a common end-stage phenotype of diverse causes. Current work focuses largely on excitotoxicity and oxidant stress. Viral hypotheses drawing from the role of

Disease-modifying treatments

Many putative disease-modifying strategies for amyotrophic lateral sclerosis have been tested in clinical trials (table 2),29, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 but only one drug (riluzole) has so far been licensed. One of the actions of riluzole is as a glutamate-release inhibitor acting on sodium channels.60 In this context, riluzole has similar pharmacological properties to lamotrigine. It prolongs the lifespan of patients with amyotrophic lateral sclerosis

Diagnostic markers and markers of disease progression

Although there is still no strongly effective disease-modifying treatment for amyotrophic lateral sclerosis, the flow of potential drugs continues. Thus, a methodology that permits rapid testing of new potential treatments, including markers of disease progression, is needed. Spirometry is an important measure that can be used to assess rate of progression in clinical trials of amyotrophic lateral sclerosis, but the reliability of this test is uncertain particularly in patients with prominent

The way forward

Because of the shortage of satisfactory disease-modifying treatments, early diagnosis of amyotrophic lateral sclerosis has traditionally not been imperative. It will, however, be increasingly important for any attempts to develop more effective treatments. Encouragingly, findings of high-throughput technologies have shown potential proteomic and metabolic targets that might be used as disease-specific biomarkers. Such indicators could provide opportunities for early diagnosis and surrogate

Search strategy and selection criteria

The literature search was aimed at finding papers relevant to this Seminar dating back to 2000. Medline and Embase were used as the basis of this search. Papers relating to amyotrophic lateral sclerosis were sought with the terms: ā€œALSā€, ā€œMNDā€, ā€œamyotrophic lateral sclerosisā€, ā€œmotor neuron(e) diseaseā€, and ā€œmotorneuron diseaseā€. Papers on motor neuron disease identified with this strategy were further selected for relevance by seeking those containing the following terms: ā€œepidemiologyā€,

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