Natural history of cutaneous innervation following herpes zoster

Abstract

As part of a comprehensive study of the natural history of herpes zoster (HZ), 57 of 94 subjects in a cohort at elevated risk for post-herpetic neuralgia (PHN) consented to collection of 3-mm skin punch biopsies from affected, mirror-image, and distant control skin at baseline and followup visits. As cutaneous innervation is reduced in longstanding severe PHN, we tested the hypothesis that development of PHN is correlated with severity of initial neural injury and/or a failure of neural recovery. Quantitative analysis using single-label PGP9.5 immunofluorescence microscopy showed epidermal profiles were reduced in zoster skin by approximately 40% at study entry compared to control and mirror skin. The density of the subepidermal plexus was approximately 15% lower in zoster skin. Mirror skin was not denervated compared to control skin. Although not significant at all visits, correlations between epidermal nerve fiber density in HZ skin and thermal sensation, allodynia, capsaicin response, and average daily pain all associated more severe abnormalities with lower epidermal innervation. There was limited evidence that the initial neural injury was more severe in the 15 eventual PHN subjects. Overall, pain and pain-related disability resolved the fastest. Sensory abnormalities and symptom aggravation by focal capsaicin application showed partial and selective recovery over 6months. In contrast, cutaneous innervation showed no recovery at all by 6months, conclusive evidence that resolution of pain and allodynia does not require cutaneous reinnervation. A much longer period of observation is needed to determine if zoster-affected skin is ever reinnervated.

Increased Density of Cutaneous Nerve Fibres in the Affected Dermatomes After Herpes Zoster Therapy

“…This is the first study to assess the evolution of nerve injury in HZ evaluating data from the acute stage by examining immunostained nerve fibres fragments in corresponding positions. In this aspect our findings are different from the study by Petersen et al (10), who did not find any trace of nerve regeneration at 6 months. However, their study population was older than ours (only patients over 50 years old were included) and older subjects reportedly have lower densities of intraepidermal nerves (13).…”

“…Our findings are in agreement with Petersen et al (10), who at 6 months still could not observe any evidence of nerve regeneration in the epidermis.…”

“…They observed that the presence of PHN strongly correlated with loss of cutaneous sensory nerve terminals. Petersen et al (10), in a natural history study of cutaneous innervation, following HZ with serial skin biopsies and PGP 9.5 immunofluorescence, have shown that reinnervation of the affected skin in HZ is not evident at 6 months after the rash onset, and resolution of pain and allodynia does not require cutaneous reinnervation.…”

Taxane induced neuropathy in patients affected by breast cancer: Literature review

“…A similar reduction of epidermal nerve fibers (ENFs) is also present in other diseases characterized by neuropathy, such as diabetes [29] and post-herpetic nevralgia [30]. In these cases, the diagnosis is only possible with a skin biopsy [31,32]; furthermore, neuropathy is characterized by a long persistence, when the symptoms last more than 3 months after the end of chemotherapy, due to a greater loss of ENFs.…”

Cytokine-Related and Histological Biomarkers for Neuropathic Pain Assessment

“…The IENF density was not different between patients with inflammatory and non-inflammatory poly neuropathy and between patients with and without NP; in all groups, the IENF density was lower in the distal skin sample, which reflects neuropathy [65]. In patients with PHN IENF density at the site of maximum pain was lower compared to a skin area with less pain and also compared to normal skin [66]. In our cohort of patients with PHN we also found a reduction in IENF density in the affected skin area, however, without correlation with pain intensity [Üçeyler N In patients with SFN the IENF density is also reduced (Figure 2) [60,61,67], however, the degree of fiber loss does not correlate with the presence or the intensity of pain: patients with complete fiber loss may have severe pain or no pain at all and vice versa.…”