is credited with the earliest descriptions of ALS and he believed that the sclerosis in the lateral columns of the spinal cord induced the loss of neurons in the anterior horns, thus prompting him to name the disease amyotrophic
lateral sclerosis and postulating primacy of the UMN. However, he did not discuss the wide variability of UMN and LMN involvement or the focality in early stages of the disease (he actually only examined 20 patients). Gowers,2
on the other hand, believed that UMN and LMN abnormalities were independent of one another. Most,3–6
but not all,7
neuropathologic and neurophysiology studies that have sought correlation between the UMN and LMN have found none, supporting Gowers’ view of UMN and LMN independence.
The debate resurfaced in the 1990s when Eisen and others8,9
postulated that ALS is a disease primarily of the corticomotor neuron, citing the phylogenetic and physiologic uniqueness of the human cortex and postulating an anterograde “dying forward” process in which the UMN recruits the LMN into the degenerative process, thus reformulating Charcot’s view of UMN primacy. This model was criticized because of contradicting neurophysiologic and neuropathologic observations,10
relative lack of testability,11
and lack of histologic corroboration.5
Chou and Norris countered by postulating primacy of the LMN and a retrograde or dying-back process triggered by the LMN.12
More recently, a principal role for the periphery, including skeletal muscle13
and neuromuscular junction,14
has been postulated.
Through most of these debates, the uniquely focal manner in which weakness appeared at the clinical onset of ALS and the contiguous outward spread was implied, but not explicitly addressed. Gowers2
made this clinical observation first, and, indeed, his original description of it is still the best:
… From the part [of the limb] first affected the disease spreads to other parts of the same limb. Before it has attained a considerable degree in one limb, it usually shows itself in the corresponding limb on the other side; often in the muscles corresponding to those in which it commenced ….
Here he describes onset of motor neuron degeneration in one precise region of the spinal neuraxis, rostral-caudal advancement, and then crossing to the contralateral side. Remarkably, he did this before UMN-LMN motor organization was formally elucidated by Sherrington and before the neural basis of nervous system function was discovered by Ramon y Cajal.
Most of the clinical literature on ALS focality is descriptive and does not actually analyze the phenomenon.15–18
did analyze it neuropathologically and neurophysiologically and proposed that interaction of multiple factors determines relative susceptibility and resistance for what may be fundamentally a generalized abnormality, thus shifting but not negating the observations of focality. Brooks,21
in the early 1990s, longitudinally tracked symptom accrual and showed anatomic contiguity, which suggested a role for axonal transport and transneuronal propagation; however, his method involved serial patient questionnaires and thus tracked functional rather than UMN and LMN anatomic changes. Munsat22
studied the natural history of ALS spread, noting linear uniform progression in different regions of the same patient, but marked variability between patients. Armon23
observed but did not directly analyze spread, which he hypothesized resulted from certain toxic subcellular components, involving acquired DNA mutations. In 2007, one of us performed a retrospective cross-sectional analysis of initial clinical motor deficits and showed that in early disease there is a linkage between UMN and LMN degeneration in terms of the innervated body region that first manifests motor deficits, but a dichotomy between them for relative severity of involvement and outward spread.24
This was supported by a postmortem study of the LMN, which found that the degree of motor neuron loss was related to the site of onset.25