Non‐motor involvement in amyotrophic lateral sclerosis: new insight from nerve and vessel analysis in skin biopsy

• Published in: Neuropathology and applied neurobiology 2017-02, Vol.43 (2), p.119-132
• Main Authors: Nolano, M., Provitera, V., Manganelli, F., Iodice, R., Caporaso, G., Stancanelli, A., Marinou, K., Lanzillo, B., Santoro, L., Mora, G.
• Format: Article
• Language: English
• Subjects: Adult; Aged; amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - pathology; autonomic nervous system; Autonomic Pathways - pathology; Biopsy; Blood Vessels - pathology; epidermal nerve fibres; Female; Humans; Male; Middle Aged; Nerve Degeneration - pathology; Sensory Receptor Cells - pathology; Skin - pathology; skin biopsy
• ISSN: 0305-1846; 1365-2990
• DOI: 10.1111/nan.12332

Aims To assess cutaneous sensory and autonomic nerves and the vascular bed in amyotrophic lateral sclerosis (ALS). Methods We enrolled 41 patients (M = 20, aged 63.5 ± 11.8 years), and 41 age‐ and gender‐matched healthy volunteers (M = 20, aged 63.5 ± 11.8 years). Disease severity and sensory and autonomic symptoms were scored using dedicated rating scales. Skin biopsies obtained from thigh, leg and fingertip were processed using indirect immunofluorescence. Intraepidermal nerve fibres, Meissner corpuscles (MCs), intrapapillary myelinated endings, cholinergic and noradrenergic pilomotor nerves and dermal vessels were quantified on confocal images. Intraepidermal nerve fibres, pilomotor nerves and vessels were also assessed on distal leg skin samples of 10 spinal cord injury patients to compare our findings with those of a chronic hypomobility condition. Results Compared to healthy controls skin biopsies showed: (i) non–length‐dependent loss of intraepidermal nerve fibres (P < 0.01) and loss of MCs (P < 0.01); (ii) reduced (P < 0.01) density of pilomotor nerves involving cholinergic and noradrenergic fibres and (iii) a reduced (P < 0.01) vascular bed. Autonomic nerve and dermal vessel densities were higher in patients with higher disease progression rate (P < 0.01). Moreover, we observed signs of nerve regeneration coexisting with nerve degeneration and increased complexity of the dermal vessels. In patients with posttraumatic spinal cord injury, the density of intraepidermal nerve fibres, pilomotor nerves and of the vascular bed did not differ from controls (P > 0.05). Conclusions We demonstrated a cutaneous sensory and autonomic denervation in ALS and a previously undescribed relationship between autonomic and vascular involvement that appeared to be linked to the disease progression rate. This beautifully illustrated study Nolano and colleagues explores the involvement of sensory and autonomic systems in amyotrophic lateral sclerosis (ALS) demonstrating cutaneous sensory and autonomic denervation and a novel relationship between autonomic and vascular involvement with a relationship to rapid disease progression.