Quantitative pathology of cutaneous nerve terminal degeneration in the human skin

Pathological diagnosis of neuropathy has traditionally depended on ultrastr uctural examinations of nerve biopsy specimens, particularly for sensory ne uropathies affecting unmyelinated and small-myelinated nociceptive nerves. These sensory nerves terminate in the epidermis of the skin, and the pathol ogy of neuropathy usually begins from nerve terminals. We investigated the feasibility of diagnosing small-fiber sensory neuropathy by evaluating cuta neous 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 pa tients with sensory neuropathy. In the healthy controls, conventional intra epidermal nerve fiber densities (JENF densities) as measured using the imag e analysis system in the distal forearm and in the distal leg were correlat ed (r=0.55, P<0.0001), with significantly higher values in the distal forea rm 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 neuropath ic patients were significantly reduced in the distal forearm (5.82+/-6.50 f ibers/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 "ocula r intraepidermal nerve fiber density" (ocular nerve fiber density) with no aid of an image analysis system. This was based on the fact that the epider mal 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 ne rve fiber densities were significantly correlated with IENF densities as me asured by the image analysis system (r=0.99, P<0.0001). Dermal nerve fibers of neuropathic patients either disappeared or became degenerated. These fi ndings were consistent with the notion of early terminal degeneration in ne uropathy, and will facilitate quantitative interpretation of epidermal inne rvation in human neuropathy.