Stages in the development of ALS. ALS is a disease that may have a preclinical and a clinical phase (see Appendix). The low frequency of ALS suggests an inherent susceptibility in patients who are destined to develop the disease at a particular point in life subsequent to a possible initiating event.'There is currently no clear-cut evidence of neuropathologic, neurophysiologic, or clinical abnormalities that would mark a patient as potentially susceptible to ALS during the susceptibility period. Initiating events may include severe electric shock exposure, which is a physical injury that is epidemiologically linked to the development of ALS, or dietary intake of particular substances that have, in isolated instances, been associated by case-control studies with the development of ALS. During the latent period of the development of the disease, there may be changes in motoneuron soma and dendritic size as the only neuropathologic features long before there is evidence of motoneuron loss or corticospinal tract degeneration. No clear-cut neurophysiologic signs have yet been described. 2 During the clinical period of the disease, there may be a presymptomatic period during which there are pathologic changes involving motoneuron size and loss as well as possible corticospinal tract degeneration. This hypothetical construct is based on pathologic~ tudies.~ Neurophysiologic changes during this time may include changes in single-fiber density, with variable changes in motor unit The clinical examination at this point is characterized by patient reports of possible functional changes and by possible abnormalities in isokinetic muscle testing at a time when normal isometric strength is present. 6 During the stage of disease spread from focal onset to more symmetric generalization, there will be changes in motoneuron size and loss as well as corticospinal tract degeneration. Motor unit counts and single fiber density abnormalities would be present, and EMG findings would be more clear-cut. Clinically, patients at this time are more consistent in their reports of abnormalities in function, which may not be clearly evident at clinical examination when employing manual muscle testing only. Patients show changes in isokinetic strength as well as early changes in isometric strength. 6 During the symptomatic phase of ALS, pathology would be more severe in regions where ALS had initially started and would become much more involved in regions to which the disease had spread. EMG findings would be clearly evident. Single-fiber density increases would be less apparent due to motor-unit dropout, and motor-unit counts would be significantly decreased in involved regions. Function would be more clearly abnormal. Manual muscle testing would be abnormal in addition to isometric muscle testing and isokinetic testing.