Intraepidermal Nerve Fiber Density: Diagnostic and Therapeutic Relevance in the Management of Chronic Pruritus: a Review

Manuel P Pereira, Sebastian Mühl, Esther M Pogatzki-Zahn, Konstantin Agelopoulos, Sonja Ständer, Manuel P Pereira, Sebastian Mühl, Esther M Pogatzki-Zahn, Konstantin Agelopoulos, Sonja Ständer

Abstract

In recent years, measurement of the intraepidermal nerve fiber (IENF) density has gained relevance in the diagnostics of chronic pruritus. This method allows the objectification and quantification of a small-fiber neuropathy, which may manifest clinically with pruritus, pain or dysesthetic sensory symptoms, such as burning, stinging and tingling sensations or numbness. Upon suspicion of a small-fiber neuropathy as a cause for chronic pruritus, targeted diagnostic procedures are essential for the early detection of the neuroanatomical changes. After a punch biopsy of the lower leg, the obtained tissue undergoes an immunofluorescence staining process with a primary antibody against the protein gene product 9.5. The IENFs can thus be detected and are quantified according to pre-determined guidelines based on an international consensus. In addition to morphological changes, functional impairment of small-fibers can be assessed using quantitative sensory testing by assessing detection and pain thresholds of various thermal and mechanic modalities. This method, however, is time-consuming and requires a specialized investigator, and thus it is not routinely used in the diagnostic investigation of chronic pruritus. Diagnosing a small-fiber neuropathy underlying chronic pruritus has therapeutic relevance. If possible, the underlying cause of the neuropathy should be treated. Alternatively, symptomatic therapy options include topical (capsaicin) and systemic (anticonvulsants and/or antidepressants) agents. Chronification processes may lead to refractory pruritus, and thus treatment should be initiated as soon as possible. The aim of this review is to present and discuss the measurement of the IENF density as a diagnostic tool and its role in the management of patients with chronic pruritus. A brief case report is presented to better illustrate the role of this diagnostic method in the clinical setting.

Keywords: Anticonvulsants; Capsaicin; Case report; Chronic pruritus; Corneal confocal microscopy; Intraepidermal nerve fiber density; Neuropathic pruritus; Quantitative sensory testing; Review; Small fiber neuropathy.

Figures

Fig. 1
Fig. 1
PGP 9.5 intraepidermal nerve fibers. a Example of PGP 9.5 intraepidermal nerve fibers (red arrows). b Only single intraepidermal nerve fibers crossing the dermoepidermal junction (arrowhead) are taken into account. Secondary branching (asterisks) or c fragments (white arrow) are not counted. Magnification: ×200, scale bar 100 µm in (a); ×400, scale bar 100 µm in (b, c). PGP 9.5 protein gene product 9.5
Fig. 2
Fig. 2
Brief case report: application of an 8% capsaicin patch. To better illustrate the role of the measurement of the intraepidermal nerve fiber density in the management of neuropathic pruritus, we present a brief case report. Informed consent was obtained from the patient for being included in the study. Medical history: A 45-year-old female presented with localized pruritus at the upper back between the scapulae. In addition to itch, the patient reported a tingling and stinging sensation. These sensory symptoms were of moderate intensity (5–6/10 in the visual analogue scale), but could become very intense during attacks (up to 9/10 in the visual analogue scale). Skin status: Upon examination of the skin, discrete erythematous lesions, likely due to scrubbing and scratching, could be observed in an otherwise normal skin. The dermographism was white. Intraepidermal nerve fiber density: Skin biopsies were taken at the back both in a lesional and a non-lesional area: lesional skin probe: 2.41 fibers/mm (strongly reduced IENFD) and non-lesional skin probe: 14.30 fibers/mm (normal IENFD). Diagnose: Notalgia paraesthetica. Previous therapies: A treatment with antihistamines did not alleviate the symptoms. The patient did not tolerate pregabalin due to nausea and dizziness. Gabapentin (up to 900 mg/day) as well as paroxetine (20 mg/day) showed no effect. Proposed treatment: Due to the localized sensory symptoms, an 8% capsaicin patch was applied in the affected area. The skin condition of the affected area is shown before (a) and after (b) application of the patch. A long-lasting itch relief is expected with this treatment. However, the application of the capsaicin patch may be repeated every 3 months or at longer intervals, if needed. Additionally, a prescription for a capsaicin cream in rising concentrations (0.025, 0.05 and 0.075%) was given to the patient to be used in case of itch recurrence

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Source: PubMed

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