Peripheral neuropathy in ALS: phenotype association 

Introduction: The association between peripheral neuropathy (PNP) and amyotrophic lateral sclerosis (ALS) has been described before, present in about 15-20% of the ALS patients 1 . Severity is usually mild, the associated phenotype(s), cofounders, genotypes and pathogenesis are unknown. Methods: We prospectively applied our clinical protocol 2 (OnWebDuals project) to characterize phenotype-genotype and risk-factors, in a population of 339 consecutive ALS patients, followed in Lisbon. We characterized region-of-onset, sex, disease duration, weight-loss before disease-onset (>10%), diabetes, previous history of chemotherapy or other toxic agents, and SOD1 and C9orf72 mutations. The study cohort underwent standardized nerve conduction studies at first consultation, including 2 or more sensory nerves in lower limbs. Sensory nerve amplitude < mean+2.5SD (compared with age-matched controls) was accepted as indicating neuropathy. Patients were grouped in Group 1 (no PNP) and Group 2 (with PNP). Results: 29 patients (8.6%) were in G2. The proportion of men (169 G1 vs 22 G2, p=0.03) and mean age at disease onset (67.31±13.03SD G1 vs 61.00±13.44SD G2, p=0.02) were higher in G2. Disease duration (41.79±55.23SD G1 vs 32.38±36.57SD in G2, p=0.22) was similar between groups. Weight-loss was found in 51 patients G2 and 2 G1 (p=0.28), diabetes in 4 in G2 and 35 in G1 (p=0.76), previous chemotherapy in 7 patients G2 and 1 in G1 (p=0.52), and C9Orf72 mutation was positive in 1 G1 and in 17 in G2 (p=1). Three patients with SOD mutation were in G1. Bulbar and spinal-onset patients were equally distributed between groups (p=0.64 and 0.83). Respiratory-onset occurred in 4 patients in G2 (13.8%) and in 7 in G1 (2.3%) - p=0.009. Logistic regression confirmed that age (p=0.01), gender (p=0.03) and respiratory-onset (p=0.003, b=4.37), were independent predictors for PNP. Conclusions: PNP was found in 8.6% of our patients. In the group of patients with PNP, diabetes, weight-loss or C9orf72HRE mutation were not a risk-factor. However, PNP was more frequent in older men and, in particular, in patients with respiratory presentation. We speculate that peripheral hypoxia in vasa nervorum is associated with peripheral nerve injury in ALS. 1.      Pugdahl K, Fuglsang-Frederiksen A, De Carvalho M, et al. Generalised sensory system abnormalities in amyotrophic lateral sclerosis: A European multicentre study. J Neurol Neurosurg Psychiatry . 2007;78(7):746-749. doi:10.1136/jnnp.2006.098533. 2.      De Carvalho M, Ryczkowski A, Andersen P, et al. International Survey of ALS Experts about Critical Questions for Assessing Patients with ALS. Amyotroph Lateral Scler Front Degener . 2017;0(0):1-6. doi:10.1080/21678421.2017.1349150.