Differential myelinated and unmyelinated sensory and autonomic skin nerve fiber involvement in patients with ophthalmic postherpetic neuralgia.

Andrea Truini,Lucio Santoro,Annamaria Stancanelli,Giuseppe Caporaso,Maija Haanpaa,Giorgio Cruccu,Antonella Biasiotta,Vincenzo Provitera,Maria Nolano

doi:10.3389/fnana.2015.00105

Abstract

Postherpetic neuralgia (PHN) is a common and exceptionally drug-resistant neuropathic pain condition. In this cross-sectional skin biopsy study, seeking information on the responsible pathophysiological mechanisms we assessed how ophthalmic PHN affects sensory and autonomic skin innervation. We took 2-mm supraorbital punch skin biopsies from the affected and unaffected sides in 10 patients with ophthalmic PHN. Using indirect immunofluorescence and a large panel of antibodies including protein gene product (PGP) 9.5 we quantified epidermal unmyelinated, dermal myelinated and autonomic nerve fibers. Although skin biopsy showed reduced epidermal and dermal myelinated fiber density in specimens from the affected side, the epidermal/dermal myelinated nerve fiber ratio was lower in the affected than in the unaffected side (p < 0.001), thus suggesting a predominant epidermal unmyelinated nerve fiber loss. Conversely, autonomic skin innervation was spared. Our study showing that ophthalmic PHN predominantly affects unmyelinated nerve fiber and spares autonomic nerve fiber might help to understand the pathophysiological mechanisms underlying this difficult-to-treat condition.

Highlights

Ophthalmic postherpetic neuralgia (PHN) is a disabling and extensively investigated neuropathic pain condition caused by herpes zoster and persisting or recurring for at least 3 months in areas supplied by the ophthalmic division of the trigeminal nerve (IHS Classification, 2013)
An approach based on immunofluorescence and confocal microscopy using double and triple immunostaining with an extensive panel of antibodies including the pan-neuronal marker protein gene product (PGP) 9.5, the basement membrane marker, collagen IV (ColIV), and antibodies for various myelinated and unmyelinated nerve fiber populations, has proved to provide distinct information on sensory and autonomic nerve fibers, and possibly assess skin innervation more accurately (Doppler et al, 2012; Nolano et al, 2013)
Confocal immunofluorescence analysis showed that skin innervation in the supraorbital punch skin biopsies from patients with PHN differed strikingly between the unaffected (Figures 2A,C,E) and affected sides (Figures 2B,D,F)

Summary

Introduction

Studies assessing cutaneous innervation in skin biopsy specimens have provided new insight into the mechanisms underlying neuropathic pain in several conditions (Sommer and Lauria, 2007). Epidermal innervation consists mainly of unmyelinated C-fiber terminals, with relatively few small myelinated Aδ-fibers that lose their myelin sheath and reach the epidermis as unmyelinated free nerve endings. An approach based on immunofluorescence and confocal microscopy using double and triple immunostaining with an extensive panel of antibodies including the pan-neuronal marker PGP 9.5, the basement membrane marker, collagen IV (ColIV), and antibodies for various myelinated and unmyelinated nerve fiber populations, has proved to provide distinct information on sensory and autonomic nerve fibers, and possibly assess skin innervation more accurately (Doppler et al, 2012; Nolano et al, 2013)

Methods

Results

Conclusion