Objectives: Our first objective was to explore the value of estimating 95% confidence intervals (CIs) of epidermal nerve fibers (ENFs)/mm for number of sections to be evaluated and for confidently judging normality or abnormality. Our second objective was to introduce a new continuous measure combining nerve conduction and ENFs/mm. Methods:The 95% CI studies were performed on 1, 1-2, 1-3 ---1-10 serial skip sections of 3-mm punch biopsies of leg and thigh of 67 healthy subjects and 23 patients with diabetes mellitus.Results: Variability of differences of ENFs/mm counts (and 95% CIs) from evaluation of 1, 1-2, 1-3 ---1-9 compared with 1-10 serial skip sections decreased progressively without a break point with increasing numbers of sections evaluated. Estimating 95% CIs as sections are evaluated can be used to judge how many sections are needed for adequate evaluation, i.e., only a few when counts and 95% CIs are well within the range of normality or abnormality and more when values are borderline. Also provided is a methodology to combine results of nerve conduction and ENFs/mm as continuous measures of normality or abnormality.Conclusion: Estimating 95% CIs of ENFs/mm is useful to judge how many sections should be evaluated to confidently declare counts to be normal or abnormal. Also introduced is a continuous measure of both large-fiber (nerve conduction) and small-fiber (ENFs/mm) normal structures/functions spanning the range of normality and abnormality for use in therapeutic trials. Neurology Enumeration of nerve endings in skin has been used to study differences among species, 1,2 development, maturation and aging, 3,4 and disease. 5,6 Light microscopic analysis of immune-stained intraepidermal nerve fibers (ENFs) and reference values were introduced to serve as objective and spatial indications of painful and small-fiber sensory polyneuropathy, "possibly useful for therapeutic trials." [7][8][9] The technique of biopsy was found to be acceptable to patients, and the estimation of ENFs/mm had high intraobserver and interobserver reproducibility.8 A somewhat different approach using punch skin biopsy, a blister technique with immunofluorescence and confocal microscopy, was also described (reviewed in Kennedy and Wendelschafer-Crabb 10 and Kennedy et al. 11). 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.
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