The value of skin biopsy with recording of intraepidermal nerve fiber density and quantitative sensory testing in the assessment of small fiber involvement in patients with different causes of polyneuropathy

Abstract

The primary aim of our study was to demonstrate how the diagnostic characteristics of skin biopsy used to evaluate small fiber involvement in patients with different causes of polyneuropathy are intrinsically related to the method used to establish the reference values (cut-off values). We also investigated intraepidermal nerve fiber (IENF) density and abnormalities in quantitative sensory testing (QST) in patients with different causes of polyneuropathy and signs of small fiber involvement. A total of 210 patients with symptoms and signs of polyneuropathy were entered into the study. All patients underwent neurological examination, nerve conduction studies, QST on the thigh and distal part of the calf with detection of warm and cold perception thresholds, and skin biopsy with assessment of IENF density. Cut-off values for IENF density were established from our reference material using Z-scores (calculated from multiple regression analysis), fifth percentile, and receiver operating characteristic (ROC) analysis. Of the patients participating in the study, 65 had an established diagnosis of diabetes mellitus, 70 were classified with idiopathic polyneuropathy, and 75 had other possible causes of polyneuropathy. Forty-five patients met the criteria for small fiber polyneuropathy (SFN), and the remaining 165 had also involvement of large nerve fibers. Of the total patient cohort, 84 (40%) had reduced IENF density based on the Z-score, and 106 patients (50%) had at least one abnormality based on QST. In the SFN group, skin biopsy showed a sensitivity of 31% and a specificity of 98% when reference values were presented with Z-scores. When the fifth percentile was used as the cut-off value (6.7 fibers/mm), sensitivity was 35% and specificity 95%. Applying the ROC analysis with a chosen sensitivity of 78% and specificity of 64%, we had a cut-off point of 10.3 fibers/mm. We conclude that skin biopsy with assessment of IENF is a useful method for investigating patients with SFN. The diagnostic value of the test, however, depends upon on the approach used to estimate the reference values.

Sensory, psychological, and metabolic dysfunction in HIV-associated peripheral neuropathy: A cross-sectional deep profiling study

“…For IENFD, data for patients with small fibre neuropathies vs healthy controls from Nebuchennykh et al [46] were used. This calculation revealed a minimum sample size of 16 was required per group for a power of >0.8 (power 0.816; difference in means 4.7; standard deviation 4.5; α = 0.05).…”

Utility of Skin Biopsy to Evaluate Peripheral Neuropathy

“…Sensitivity (percentage of true positives) has ranged from 45% to 90% [7••, 32] and specificity (percentage of true negatives) from 95% to 97% [7••] using the lower fifth percentile as a cutoff. In one study, sensitivity was lower in patients with SFSN (35%) than in those with a mixed pattern of small and large fiber involvement (49%) [32]. The sensitivity for SFSN was even lower in symptomatic patients with a normal neurologic examination than in those who had clinical signs as well as symptoms [7••, 34].…”

“…Using the fifth percentile as a cutoff, any ENFD equal or below this value indicates neuropathy. In different studies, the fifth percentile of the thigh has varied from 6.7 (unpublished observation) to 8 fibers/mm [31], and the fifth percentile of the calf has ranged from 5 to 6.7 fibers/ mm [31,32]. An early study of normative values for ENFD did not reveal any relation to age or gender, but a recent analysis of 188 healthy volunteers (97 women, 91 men) indicated that the mean ENFD gradually diminishes with increasing age [16].…”

“…Application of ROC analysis to skin biopsy provides a way to select sensitivity and specificity at a given threshold. In general, for diagnostic purposes, it seems appropriate to select a low threshold with a corresponding high specificity (and lower sensitivity), regardless of whether it is based on the fifth percentile or ROC analysis [32].…”

Submaksimal Uyarımla Elde Edilen İki Tepeli Ortodromik Duysal Yanıtların Hastalık Süreçlerine Yönelik Elektrofizyolojik İncelemelerde Kullanılması

“…Diyabetik a¤r›l› distal simetrik nöropatinin ön planda ince sinir liflerini tuttu¤u iddias› çeflitli dönemlerde bu liflerin fonksiyonlar›n› ortaya koymay› amaçlayan yöntemlerin gelifltirilmesi çabalar›na yol açm›flt›r. Bu yöntemler aras›nda Kantitatif Duysal Test (KDT), otonom sinir sistemine yönelik testler ve epidermal sinir biyopsi yöntemleri say›labilir (20). Çift tepeli duysal yan›tlara iliflkin ilk hipotezler bu aç›dan umut verici görünmekle birlikte daha sonra yap›lan çal›flmalar çift tepeli yan›tlar›n kökenine iliflkin de¤iflik bilgiler sa¤lam›flt›r.…”