Abstract
BackgroundThough intra-epidermal nerve fiber density (IENFD) is considered the gold standard for diagnosis of small fiber sensory neuropathy (SFSN), we aimed to determine if novel threshold values derived from standard tests of small or large fiber function could serve as diagnostic alternatives.MethodsSeventy-four consecutive patients with painful polyneuropathy and normal nerve conduction studies (NCS) were defined as SFSN cases or controls by distal IENFD <5.4 and ≥5.4 fibers/mm, respectively. Diagnostic performance of small fiber [cooling (CDT) and heat perception (HP) thresholds, axon reflex-mediated neurogenic vasodilatation] and large fiber function tests [vibration perception thresholds (VPT) and sural nerve conduction parameters] were determined by receiver operating-characteristic (ROC) curve analyses.ResultsThe 26(35%) SFSN cases had mean IENFD 3.3±1.7 fibers/mm and the 48(65%) controls 9.9±2.9 fibers/mm. Male gender (p = 0.02) and older age (p = 0.02) were associated with SFSN cases compared to controls. VPT were higher and CDT lower in SFSN cases, but the largest magnitude of differences was observed for sural nerve amplitude. It had the greatest area under the ROC curve (0.75) compared to all other tests (p<0.001 for all comparisons) and the optimal threshold value of ≤12 µV defined SFSN cases with 80% sensitivity and 72% specificity.ConclusionIn patients presenting with polyneuropathy manifestations and normal NCS, though small fiber function tests were intuitively considered the best alternative measures to predict reduced IENFD, their diagnostic performance was poor. Instead, novel threshold values within the normal range for large fiber tests should be considered as an alternative strategy to select subjects for skin biopsy in diagnostic protocols for SFSN.
Highlights
Small fiber sensory neuropathy (SFSN) is an axonal neuropathy involving mainly thinly myelinated (Ad) and unmyelinated (C) fibers [1,2]
small fiber sensory neuropathy (SFSN) is suspected in the situation in which patients present with normal nerve conduction studies (NCS) and vibration perception thresholds (VPT), and diagnosis requires specialized approaches compared to the classical evaluation of polyneuropathy [4]
We aimed to determine in a group of patients presenting with polyneuropathy symptoms, but with normal large fiber function tests, whether small fiber tests of quantitative thermal sensory thresholds (QST) and laser Doppler flare imaging (LDI) or large fiber sural nerve electrophysiological tests could serve as proxy measures for intra-epidermal nerve fiber density (IENFD) for the diagnosis of SFSN
Summary
Small fiber sensory neuropathy (SFSN) is an axonal neuropathy involving mainly thinly myelinated (Ad) and unmyelinated (C) fibers [1,2]. Intra-epidermal nerve fiber density (IENFD) obtained from skin punch biopsy specimens has become widely accepted as one of the most accurate diagnostic methods for SFSN [4,5] and has become the gold standard for confirmatory diagnosis of SFSN in a clinical guideline. Large fiber sensory tests such as sural nerve electrophysiological parameters may have diagnostic performance for SFSN if alternative threshold values to those published for healthy populations are considered. Though intra-epidermal nerve fiber density (IENFD) is considered the gold standard for diagnosis of small fiber sensory neuropathy (SFSN), we aimed to determine if novel threshold values derived from standard tests of small or large fiber function could serve as diagnostic alternatives
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