Diagnostic validity of epidermal nerve fiber densities in painful sensory neuropathies

Abstract

In this prospective study, intraepidermal nerve fiber densities (IENFD) and subepidermal nerve plexus densities (SENPD) were quantified by immunostaining in skin punch biopsies from the distal calf in 99 patients with clinical symptoms of painful sensory neuropathy and from 37 agematched healthy volunteers. The clinical diagnosis was based on history and abnormal thermal thresholds on quantitative sensory testing (QST). In patients with neuropathy, IENFD and SENPD were reduced to about 50% of controls. Elevated warm detection thresholds on QST correlated with IENFD but not with SENPD. Using receiver-operating characteristic (ROC) curve analysis of IENFD values, the diagnostic sensitivity for detecting neuropathy was 0.80 and the specificity 0.82. For SENPD, sensitivity was 0.81 and specificity 0.88. With ROC analysis of both IENFD and SENPD together, the diagnostic sensitivity was further improved to 0.92. The combined examination of IENFD and SENPD is a highly sensitive and specific diagnostic tool in patients suspected to suffer from painful sensory neuropathies but with normal values on clinical neurophysiological studies. Painful sensory neuropathies with exclusive or preferential involvement of small sensory nerve fibers of the A-delta and C types are commonly encountered in clinical practice. 32 Among the most prominent complaints of patients suffering from small-fiber neuropathy are burning pain and paresthesias, typically beginning distally in the feet and slowly progressing proximally in a length-dependent fashion. 12,21,37 Unless there is associated large-fiber involvement, patients display few abnormities on standard neurological examination and nerve conduction studies may remain within normal limits. The functional bedside tests most commonly used for the assessment of small fibers include the assessment of thermal detection and pain thresholds, which can be corroborated by quantitative sensory testing (QST), 13,32 and autonomic function tests, such as the quantitative sudomotor axon reflex test, 29,32 sympathetic skin response, 3 heart-rate variability, and other cardiovascular reflexes. 29 Further neurophysiological methods reflecting small-fiber function (e.g., laser-evoked sensory potentials) 16 are valuable additions but less frequently available in clinical practice.Morphological evaluation of the intraepidermal innervation in skin biopsies has proven to be both a useful 14,18,25,32,34 and reproducible method 7,25,40 for the diagnosis of small-fiber neuropathy and has now become a standard tool in the diagnostic evaluation of sensory neuropathies. 20,22 However, data on the sensitivity, the correlation with clinical symptoms and signs, 11,34,39 and the diagnostic validity of intraepidermal nerve fiber density (IENFD) examination have revealed variable results between studies. 4,25 This also applies to the correlation between skin biopsy findings and neurophysiological and psychophysical examinations, which have shown a wide range of findings in different studies. 10,14,23,30 -33,39,4...

Abnormal LDIflare but Normal Quantitative Sensory Testing and Dermal Nerve Fiber Density in Patients with Painful Diabetic Neuropathy

“…A recent study confirms the validity of assessing alterations in dermal NFD in thin sections and has specifically demonstrated a reduction in arteriolar innervation in patients with smallfiber neuropathy (23). Furthermore, the assessment of dermal NFD in addition to IENFD has been shown to improve the diagnostic sensitivity for detecting painful sensory neuropathy (24). Finally, functional defects in unmyelinated C-fibers may precede structural defects (25), which would be detected by an abnormal LDIflare but with no effect on NFD, as demonstrated in this study.…”

Three-dimensional Imaging of Nociceptive Intraepidermal Nerve Fibers in Human Skin Biopsies

“…At present, it is common practice for physicians to quantify intraepidermal nerve fiber densities, (IENFD) from skin punch biopsies, which can be used to diagnose small fiber neuropathies 3,[6][7][8] . Biopsies are taken from the distal leg (DL), 10 cm above the lateral malleolus, and the proximal thigh (PT), 20 cm below the anterior iliac spine 9 .…”

“…At present, it is standard practice to diagnose small fiber neuropathies using IENFD determined by PGP staining with brightfield microscopy 6 . Additionally, several research groups have used immunofluorescent protocols for PGP immunohistochemistry [7][8][9] . Small fiber neuropathy is commonly associated with neuropathic pain.…”

Epidermal nerve fibers

“…A series of reports showed the value of ENFs/mm in the diagnosis of painful small-fiber sensory polyneuropathy, especially in patients with few or no neurologic signs or test abnormalities. [12][13][14][15][16][17][18][19] Decreased ENFs/mm has also been shown to be characteristic of generalized sensorimotor neuropathies of various kinds. 7,13,15,[20][21][22][23][24][25][26][27] Consensus panels have accepted the assessment of ENFs as objective and valid indications of small sensory nerve fiber involvement in disease.…”