Spreading in ALS: The relative impact of upper and lower motor neuron involvement

Abstract

Objective: To investigate disease spread in amyotrophic lateral sclerosis (ALS), and determine the influence of lower (LMN) and upper motor neuron (UMN) involvement. Methods: We assessed disease spread in ALS in 1376 consecutively studied patients, from five European centers, applying an agreed proforma to assess LMN and UMN signs. We defined the pattern of disease onset and progression from predominant UMN or lower motor neuron (LMN) dysfunction in bulbar, upper limbs, lower limbs, and thoracic regions Non-linear regression analysis was applied to fit the data to a model that described the relation between two random variables, graphically represented by an inverse exponential curve. We analyzed the probability, rate of spread, and both combined (area under the curve). Results: We found that progression was more likely and quicker to or from the region of onset to close spinal regions. When the disease had a limb onset, bulbar motor neurons were more resistant. Furthermore, in the same time frame more patients progressed from bulbar to lower limbs than vice-versa, whether predominantly UMN or LMN involvement. Patients with initial thoracic involvement had a higher probability for rapid change. The presence of predominant UMN signs was associated with a faster caudal progression. Interpretation: Contiguous progression was leading pattern, and predominant UMN involvement is important in shortening the time for cranialcaudal spread. Our results can best be fitted to a model of independent LMN and UMN degeneration, with regional progression of LMN degeneration mostly by contiguity. UMN lesion causes an acceleration of rostral-caudal LMN loss.

Brain metabolic differences between pure bulbar and pure spinal ALS: a 2-[18F]FDG-PET study

“…Namely, PB patients showed a relative hypometabolism as compared to PS ones in such regions. This finding seems in agreement with a study investigating disease spreading in ALS through the assessment of clinical evidence of upper and lower motor neuron signs [ 15 ]. The authors suggested that when the disease had a limb onset, bulbar neurons were more resistant to be involved as compared with other spinal regions.…”

Unraveling the Heterogeneity of ALS—A Call to Redefine Patient Stratification for Better Outcomes in Clinical Trials

“…Early bulbar involvement was less likely if the primary region of onset was in a limb. Contrary to the findings of Maranzano et al [ 83 ] this spreading pattern was found to be independent of the primary involvement of UMN and LMN [ 84 ].…”

Use of hip- versus wrist-based actigraphy for assessing functional decline and disease progression in patients with motor neuron disease

“…Of interest, we found that decreased activity scores were detected in the wrist before patients reported reduced function in fine-motor skills (as inferred through a change in the fine-motor domain subscores of the ALSFRS-R). This outcome agrees with the common hypothesis that spread in MND (particularly in the spine) generally occurs within an affected region before moving to adjacent regions [ 17 , 18 ] and may infer potential use for limb-based actigraphy as an early, low-burden, marker for predicting the spread of disability in affected regions before this is apparent to the patient. To better understand the variable impact of device positioning, and the implications for biomarker development, it would be prudent to assess the impact of multiple device positions on the individual and their relation to various activity metrics and differing disease presentations.…”