Morphometry of dermal nerve fibers in human skin

Neuromuscular Diseases Unit, IRCCS Foundation, Carlo Besta Neurological Institute, Via Celoria, 11, 20133, Milan, Italy.
Neurology (Impact Factor: 8.29). 07/2011; 77(3):242-9. DOI: 10.1212/WNL.0b013e318225ab51
Source: PubMed


We aimed to assess the innervation density of dermal nerves in human skin biopsies by bright-field immunohistochemistry.
The size of dermal area where nerve length was quantified was validated in 30 skin biopsy sections (5 controls and 5 patients with small-fiber neuropathy [SFN]). It was obtained dividing an area of 200-μm depth from the dermal-epidermal junction into 4 equal portions. The length of dermal nerves (DNFL) was measured into 150 sections (25 controls and 25 patients with SFN) and values per millimeter of epidermis (DNFL/mm) and dermal area (DNFL/mm2) were obtained. Age- and gender-matched normative values of intraepidermal nerve fiber (IENF) density were used as gold standard to calculate the performance of dermal nerve morphometry.
Patients showed significantly lower DNFL (1.96 mm ± 0.96 SD), DNFL/mm (0.65 ± 0.29 SD), and DNFL/mm2 (3.75 ± 1.7 SD) than controls (DNFL 3.52 mm ± 1.31 SD, 5th percentile 2.05; DNFL/mm 1.25 ± 0.39, 5th percentile 0.71; DNFL/mm2 7.07 ± 2.41 SD, 5th percentile 3.95). Sensitivity, specificity, and percentage of individuals correctly classified were 75.8%, 73.9%, and 74.8% for DNFL, 75%, 80%, and 77.7% for DNFL/mm, and 75.8%, 80.2%, and 78.1% for DNFL/mm2. Receiver operator characteristic area analysis confirmed the excellent discrimination (0.8-0.9) between patients and controls. Dermal nerve morphometry significantly correlated with IENF density. Spearman rank correlation demonstrated good agreement for interobserver analysis (0.87-0.89), and between DNFL and IENF densities (0.71-0.73; p < 0.0001).
We provided a reliable method to quantify the innervation density of dermal nerves that might improve the diagnostic yield of skin biopsy.

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Available from: Giuseppe Lauria, May 19, 2014
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    • "Several studies have demonstrated a correlation between IENFD, dNFLD and/or eNFLD; one showed that a combination of IENFD and dermal NFLD increases diagnostic specificity and sensitivity in diagnosing small fibre neuropathy [1,23,38]. In the present study, a higher diagnostic sensitivity and specificity were obtained by combining the determined values of both IENFD and epidermal NFLD, thus allowing a better differentiation between DSP and healthy controls. "
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    ABSTRACT: Quantification of intraepidermal nerve fibre density (IENFD) is an important small fibre measure in distal symmetric polyneuropathies (DSP), but quantitative evaluation of additional structural and functional factors may help in elucidating the underlying mechanisms, and in improving the diagnostic accuracy in DSP. The literature reports a weak or moderate relationship between IENFD and spontaneous and evoked pain in neuropathies, but the relationship between functional and structural small fibre parameters in patients with DSP is unclear. The objectives of the current study, therefore, were to determine morphological and functional parameters related to small nerve fibres in subjects with distal symmetric polyneuropathy (DSP) and healthy controls, and to characterize the interplay among these parameters in these two groups.
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    • "Indeed, in about 12% of patients with complaints of SFN, IENF density can be normal (Devigili et al., 2008). We have recently standardized a new method to determine the innervation of the dermis in human skin by measuring the overall length of the fibers, that proved to be reliable in terms of diagnostic yield in patients with pure SFN (Lauria et al., 2011). Other studies are warranted to demonstrate that dermal nerve morphometry can increase the value of skin biopsy in diagnosing patients with neuropathy. "
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    ABSTRACT: Starting from the original studies of the 19th century, this review covers some of the advances achieved over the last 15 years since skin biopsy has become a diagnostic tool for neurologists. In a relatively short period of time, focused works demonstrated the correlation between the loss of intraepidermal nerve fibers (IENF) and symptoms and signs of small fiber neuropathy (SFN), and provided standardized protocols for nerve morphometry as well as normative reference values to be used in clinical practice. This contributed to the definition of the diagnostic criteria for SFN that is now recognized as a distinct nosologic entity. The relationship between IENF degeneration and neuropathic pain led to the recent discovery that SFN can be caused by mutations in sodium channels, providing evidence for a new diagnostic approach to the etiology of the disease in patients. The presence of myelinated nerve fibers in the dermis prompted studies focused on demyelinating neuropathies of genetic and immune-mediated origin. Specific changes in dermal myelinated nerves have been described suggesting a potential role for skin biopsy also in these fields. Finally, studies on the sequence of events occurring after nerve degeneration in experimental models and patients with chronic neuropathies allowed to understand better the ability of skin nerves to regenerate and the reasons for its failure, providing important hints for the use of skin biopsy as an outcome measure in clinical practice and neuroprotective trials.
    Full-text · Article · Dec 2012 · Journal of the Peripheral Nervous System
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    • "This compares well to data on reliability of vision [11] [14]. Notably, applying the same criteria to objective measures of neuropathic damage, such as intraepidermal nerve fiber density, reveals that they are by no means methodologically superior to the subjective methods of QST [12] [13] [17] [25]. Thus, the data that we presented are representative for sensory assessment in general and not specific for this particular method [8]. "

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