Small nerve fiber pathology in critical illness

Nicola Latronico, Massimiliano Filosto, Nazzareno Fagoni, Laura Gheza, Bruno Guarneri, Alice Todeschini, Raffaella Lombardi, Alessandro Padovani, Giuseppe Lauria, Nicola Latronico, Massimiliano Filosto, Nazzareno Fagoni, Laura Gheza, Bruno Guarneri, Alice Todeschini, Raffaella Lombardi, Alessandro Padovani, Giuseppe Lauria

Abstract

Background: Degeneration of intraepidermal nerve fibers (IENF) is a hallmark of small fiber neuropathy of different etiology, whose clinical picture is dominated by neuropathic pain. It is unknown if critical illness can affect IENF.

Methods: We enrolled 14 adult neurocritical care patients with prolonged intensive care unit (ICU) stay and artificial ventilation (≥ 3 days), and no previous history or risk factors for neuromuscular disease. All patients underwent neurological examination including evaluation of consciousness, sensory functions, muscle strength, nerve conduction study and needle electromyography, autonomic dysfunction using the finger wrinkling test, and skin biopsy for quantification of IENF and sweat gland innervation density during ICU stay and at follow-up visit. Development of infection, sepsis and multiple organ failure was recorded throughout the ICU stay.

Results: Of the 14 patients recruited, 13 (93%) had infections, sepsis or multiple organ failure. All had severe and non-length dependent loss of IENF. Sweat gland innervation was reduced in all except one patient. Of the 7 patients available for follow-up visit, three complained of diffuse sensory loss and burning pain, and another three showed clinical dysautonomia.

Conclusions: Small fiber pathology can develop in the acute phase of critical illness and may explain chronic sensory impairment and pain in neurocritical care survivors. Its impact on long term disability warrants further studies involving also non-neurologic critical care patients.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Skin biopsy.
Figure 1. Skin biopsy.
Bright field immunohistochemical studies (polyclonal anti-protein gene product 9.5 antibody; Ultraclone, Wellow, Isle of Wight, UK) in sections of skin biopsy taken at the proximal thigh (A) and distal site of the leg (B) with a sweat gland (C) in patient no. 7, and at the proximal thigh (D) and distal site of the leg (E) with a sweat gland (F) in a healthy subject. Arrows indicate intra-epidermal nerve fibers and arrowheads indicate dermal nerve bundles. The patient, with normal nerve conduction study findings and myopathy at needle electromyography, showed a severe depletion of intra-epidermal nerve fibers and a severe reduction in the density of dermal nerve bundles, whose staining was fragmented and weaker due to axonal degeneration. Sweat gland innervation was also markedly reduced. Original magnification 40x. Bar is 50 µm in all images.

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