Background: Because motor manifestations of ALS begin focally and progress contiguously, the anatomic distribution of underlying lower motor neuron and upper motor neuron degeneration should correlate to onset.

Objectives: To assess the rostral–caudal distribution of lower motor neuron loss in relation to the region of clinical onset.

Methods: We evaluated 19 ALS postmortem nervous systems from patients whose motor manifestations had begun in different body regions. In each, we looked at four neuraxis levels: hypoglossal nucleus and cervical, thoracic, and lumbar spinal cord. We used light microscopy and devised a technique of particle counting that indexed lower motor neuron loss.

Results: The average overall loss of lower motor neurons in ALS nervous systems was 55%, and the range of loss had a normal distribution that ranged between 8% and 90%. The distribution of lower motor neuron loss was graded within the nervous system relative to onset (p = 0.02 by analysis of variance). In 14 of the 19 nervous systems, the regional lower motor neuron loss within the nervous systems was graded radially away from the region of onset. In 1, radial degeneration seemed likely but did not meet significance. In 2, radial degeneration was apparent but loss was greatest in a region different than that identified as the region of onset. In the remaining 2, lower motor neuron loss was minimal and not graded (both from patients whose motor manifestations had been predominantly upper motor neuron).

Conclusion: Lower motor neuron degeneration in ALS is a focal process that advances contiguously, summates over time, and creates graded loss. Stage of degeneration in the nervous system is a function of anatomic location.