Quantitative pathology of cutaneous nerve terminal degeneration in the human skin

Abstract

Pathological diagnosis of neuropathy has traditionally depended on ultrastructural examinations of nerve biopsy specimens, particularly for sensory neuropathies affecting unmyelinated and small-myelinated nociceptive nerves. These sensory nerves terminate in the epidermis of the skin, and the pathology of neuropathy usually begins from nerve terminals. We investigated the feasibility of diagnosing small-fiber sensory neuropathy by evaluating cutaneous innervation. Skin biopsy specimens of 3-mm in diameter were obtained from the distal leg and the distal forearm of 55 healthy controls and 35 patients with sensory neuropathy. In the healthy controls, conventional intraepidermal nerve fiber densities (IENF densities) as measured using the image analysis system in the distal forearm and in the distal leg were correlated (r=0.55, P<0.0001), with significantly higher values in the distal forearm than in the distal leg (17.07±6.51 vs 12.92±5.33 fibers/mm, P<0.001). Compared to IENF densities of healthy controls, these values of neuropathic patients were significantly reduced in the distal forearm (5.82±6.50 fibers/mm, P<0.01) and in the distal leg (2.40±2.30, P<0.001). We further explored the possibility of quantifying skin innervation by counting "ocular intraepidermal nerve fiber density" (ocular nerve fiber den-sity) with no aid of an image analysis system. This was based on the fact that the epidermal length on specifically defined sections was very close to the predicted epidermal length of 3 mm, the diameter of skin punches (P=0.14). Ocular nerve fiber densities were significantly correlated with IENF densities as measured by the image analysis system (r=0.99, P<0.0001). Dermal nerve fibers of neuropathic patients either disappeared or became degenerated. These findings were consistent with the notion of early terminal degeneration in neuropathy, and will facilitate quantitative interpretation of epidermal innervation in human neuropathy.

Intraepidermal nerve fibre density at wrist level in diabetic and non‐diabetic patients

“…Comparative studies on IENFD in the upper extremity are sparse. Based on skin biopsies from the distal forearm, a significantly reduced IENFD was demonstrated in patients with neuropathy compared with healthy control subjects [7]. However, the aetiologies behind the neuropathy were mixed, with only five out of 35 because of diabetes.…”

Skin nerve pathology: Biomarkers of premanifest and manifest amyloid neuropathy

“…After the genetic confirmation of TTR mutations, enrolled subjects underwent clinical evaluations, including clinical symptoms, neurological examinations, and laboratory tests, such as nerve conduction studies, quantitative sensory testing, autonomic function tests, and skin biopsies, for the quantitation of epidermal and sudomotor innervation, and amyloid depositions followed established protocols …”

Sudomotor innervation in transthyretin amyloid neuropathy: Pathology and functional correlates

“…PGP 9.5 is a general marker of neurons and peripheral nerve fibers. 17,31 The reduction of PGP 9.5 1 sudomotor nerves reflects sudomotor nerve degeneration as shown at the electron microscopic level. 6 This suggests that PGP 9.5 may serve as a structural marker of sudomotor nerves and VIP serves as a functional marker of sudomotor nerves because of its coexistence with cholinergic sympathetic innervation 10,32 and modulation of cholinergic responses of sweat glands.…”

“…Skin biopsy was performed by following established procedures after informed consent had been obtained. 16,17 A 3mm diameter skin punch was taken from the distal leg 10cm proximal to the lateral malleolus under local anesthesia with 2% lidocaine. All patients tolerated the procedure with no obvious discomfort.…”