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Implications of ALS focality

Rostral–caudal distribution of lower motor neuron loss postmortem

From the Section of Neurology (J.R.), Virginia Mason Medical Center, Seattle; Neurogenomics Laboratory (J.R., P.L., Y.F.), Benaroya Research Institute at Virginia Mason, Seattle, WA; and California Pacific Medical Center (D.H.M.), San Francisco, CA.

Address correspondence and reprint requests to Dr. Ravits, Neurogenomics Laboratory, Benaroya Research Institute at Virginia Mason, 1201 Ninth Avenue, Seattle, WA 98101 jravits{at}benaroyaresearch.org

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.

See also page 1571

Supplemental data at www.neurology.org

Supported by grants from the National Institute of Neurological Diseases and Stroke (NS051738), Juniper Foundation, Moyer Foundation, and Benaroya Foundation.

Disclosure: The authors report no conflicts of interest.

Presented in part at the 58th Annual Meeting of the American Academy of Neurology, San Diego, CA, April 1–8, 2006.

Received December 21, 2005. Accepted in final form January 30, 2007.

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Focality of upper and lower motor neuron degeneration at the clinical onset of ALS

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