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In dealing with a disease like amyotrophic lateral sclerosis (ALS) that has no fully known cause and no cure, clinical trials are becoming the sole vehicle of hope to identify effective treatments. The World Federation of Neurology Committee of Motor Neuron Disease has published revised diagnostic criteria for ALS and guidelines on the design and conduct of clinical trials in ALS. These criteria and guidelines are helpful since we have no diagnostic or surrogate markers in ALS. Given this, clinical trialists must rely on currently available measurement techniques, including survival rate, neuromuscular assessments, clinimetrics, and quality of life (QoL). Survival has been used in several clinical trials, such as riluzole, SR57746A, and new brain-derived neurotrophic factor (BDNF) trials, but this has inherent problems. Tufts quantitative neuromuscular evaluation (TQNE), including the maximal voluntary isometric muscle contraction (MVIC), expresses a direct clinical feature of ALS; however, it has not been able to demonstrate positive results in trials, such as ciliary neurotrophic factor (CNTF), BDNF, and gabapentin. The use of TQNE remains important, though in investigator-driven trials. Among all measurement techniques, forced or slow vital capacity and ALS functional rating scale (ALSFRS) appear the most universally accepted evaluation techniques in ALS trials. For QoL measurements, only generic QoL instruments have been available until recently. Now ALS-specific QoL tools, such as the ALS assessment questionnaire-40 (ALSAQ-40), have just been introduced.
The use of objective quantitative measurements of lower motor neuron and upper motor neuron functions are imperative to directing the focus of clinical trials in ALS. Motor unit number estimate (MUNE) has been developed by 2 fundamentally different concepts and methodologies: statistical methods and multipoint stimulation methods. Although there are pros and cons for these 2 techniques, the importance of these measurement techniques in clinical trials must be emphasized. For measuring upper motor neuron function, we introduce the use of 2 novel methods. One is magnetic resonance spectroscopy imaging (MRSI), demonstrating a relative or absolute amount of N-acetyl aspartate, analyzing the anatomical neuronal (neurons and neuritis) tissue in the brain; the other is transcranial magnetic stimulation (TMS), analyzing electrophysiological excitability and descending tract integrity. Further studies of these 2 techniques are absolutely essential to establish the reliability and validity in assessing the disease evolution in ALS. In the near future, we should be able to measure ALS more objectively than before for identifying therapeutic agents for this disease.
Mitsumoto H. Can We Measure ALS? Arch Neurol. 2000;57(8):1237–1238. doi:
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