It is estimated that neuropathic pruritus, i.e. pruritus caused by disorders of the somatosensory system, accounts for approximately 8% of cases of chronic pruritus, while other possible causes include dermatological, systemic, psychogenic or multifactorial conditions, or may arise from unknown causes [
1]. The assessment of the intraepidermal nerve fiber density (IENFD) allows the morphological quantification of the unmyelinated C-fibers crossing the basement membrane of the epidermis. This diagnostic tool has gained interest in recent years in the diagnostics of neuropathic pruritus, since, next to central processes, a dysfunction of the small unmyelinated C-fibers plays a central role in neuropathic pruritus [
2]. In addition to pure itch, damage to these nerve fibers can lead to positive and negative neurological symptoms that are generally more pronounced distally. Interestingly, different cutaneous C fiber subgroups and mediators are responsible for various subjective qualities of chronic pruritus [
3]. Mechano-insensitive C fibers (CMi fibers) utilize H
1 receptors to mediate histamine-induced pruritus through the ion channel TRPV1 (transient receptor potential channel V1) and phospholipase‐β3 generating a more pure itching, while mechano- and heat-sensitive (CMH) C fibers mediate pruritus, burning and thermal pain through the activation of TRPV1 receptors [
4]. The aim of this review is to present the methodological aspects of the quantification of IENFD, as well as its diagnostic and therapeutic relevance for the clinical practice. Additionally, a brief case report is presented to demonstrate the role of this diagnostic tool in the management of patients with chronic neuropathic pruritus.
When to Assess the Intraepidermal Nerve Fiber Density?
A reduced IENFD can be found in small-fiber neuropathy of different origins, with pruritus as the leading symptom. This reinforces the pathophysiological concept that the genesis of pruritus originates from unmyelinated nerve endings in the epidermis and at the dermoepidermal junction [
2].
A detailed medical history is essential for the diagnosis and further differentiation of neuropathic pruritus. In neuropathic pruritus, pathological processes causing itch may arise from different levels of the somatosensory system from the periphery to conditions of the central nervous system [
5], leading to a multitude of possible clinical presentations. Depending on the pathophysiological mechanisms, patients may present a localized (e.g., in compression syndromes such as brachioradial pruritus and burning mouth syndrome) or generalized (e.g., in a generalized small-fiber neuropathy) pruritic condition [
6,
7]. Typical for neuropathic pruritus is the report of sensory symptoms such as burning, itching, stinging and even pain by the affected patients. Additionally, the application of ice packs or cold water often relieves the itching, while warmth may worsen the symptoms [
2].
Comorbidities associated with small-fiber neuropathy should be thoroughly assessed, especially its chronological association with the onset of pruritus. Metabolic diseases often induce small fiber neuropathy, for which diabetes mellitus represents the most common cause. Pruritus arising from diabetes mellitus typically begins at the feet and lower legs or at the torso [
8]. Adjusting the postprandial glucose levels generally provide relief from the pruritus [
9]. Other commonly associated diseases include neurological syndromes. Compression syndromes, such as brachioradial pruritus (compression of the root ganglia or spinal nerve C3–C6) and notalgia paresthetica (compression of the dorsal rami Th2–Th6) are associated with a reduced IENFD and thus to localized pruritus in the affected dermatomes. Other localized neuropathic syndromes leading to small-fiber neuropathy and pruritus include postherpetic neuralgia, vulvodynia or burning mouth syndrome [
6]. Moreover, skin diseases have been linked to an impairment of small-fibers. In sensitive skin, a condition in which paraesthesias occur in apparently normal skin mostly at the face, a reduced IENFD could be demonstrated [
10] and thus a neuropathic involvement is speculated [
11]. Prurigo nodularis, in which itching hyperkeratotic nodules develop due to chronic scratching, is associated with a reduced IENFD regardless of the underlying pruritic disease [
12]. Interestingly, with improvement of the prurigo condition, the IENFD may normalize [
13].
Many other diseases are associated with small-fiber neuropathy without, however, necessarily causing itch. These include metabolic (e.g., vitamin B12 deficiency), neurological (e.g., inflammatory demyelinating diseases) immunological (e.g., rheumatoid arthritis, lupus erythematodes, M. Sjögren), infectious (e.g., hepatitis C, HIV), paraneoplastic and drug-induced (e.g., antibiotics, antiretroviral drugs, alcohol) conditions [
2,
14].
When the detailed clinical history provides hints of a small-fiber neuropathy as the cause for pruritus, the measurement of IENFD is the gold standard for the objectification and quantification of the neuropathy [
15].