title: Structural and functional characterization of nerve fibres in polyneuropathy and healthy subjects.
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.
  
  
  
  17 patients with painful DSP (≥4 on 0-10 numerical rating scale) and with symptoms and signs of small fibre abnormality (with or without large fibre involvement) and 19 healthy control subjects underwent comprehensive functional and structural small fibre assessments that included quantitative sensory testing, response to 30min topical application of 10% capsaicin and analysis of skin biopsy samples taken from the distal leg (IENFD, epidermal and dermal nerve fibre length densities (eNFLD, dNFLD) using global spatial sampling and axonal swelling ratios (swellings/IENFD and swellings/NFLD)).
  
  
  
  DSP patients had reduced sensitivity to cold (median -11.07°C vs. -2.60, P≤0.001) and heat (median 46.7 vs. 37.70, P≤0.001), diminished neurovascular (median 184 vs. 278 mean flux on laser Doppler, P=0.0003) and pain response to topical capsaicin (median 10 vs. 35 on 0-100 VAS, P=0.0002), and lower IENFD, eNFLD and dNFLD values combined with increased swelling ratios (all P<0.001) compared to healthy controls. The correlation between structural and functional parameters was poor in DSP patients, compared with healthy controls. In healthy controls eNFLD and dNFLD, IENFD and eNFLD, IENFD and dNFLD all correlated well with each other (r=0.81; P≤0.001, r=0.58; P=0.009, r=0.60; P=0.007, respectively). In DSP, on the other hand, only eNFLD and dNFLD showed significant correlation (r=0.53, P=0.03). A diagnostic approach of combined IENFD and eNFLD utilization increased DSP diagnostic sensitivity from 82.0% to 100% and specificity from 84.0% to 89.5%.
  
  
  
  This study presents a rigorous comparison between functional and morphological parameters, including parameters such as eNFDL and dNFLD that have not been previously evaluated in this context. The correlation pattern between functional and structural small fibre parameters is different in patients with DSP when compared to healthy controls. The findings suggest a more direct relationship between structure and function of nerve fibres in healthy controls compared to DSP. Furthermore, the findings suggest that combining IENFD with measurement of NFLD improves the diagnostic sensitivity and specificity of DSP.
  
  
  
  Combining small fibre parameters may improve the diagnostic accuracy of DSP.
authors.affiliation: Danish Pain Research Center, Aarhus University Hospital, Aarhus, Denmark.|Stereology and Electron Microscopy Laboratory and Centre for Stochastic Geometry and Advanced Bioimaging, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Páll
authors.initials: P
authors.lastname: Karlsson
authors.affiliation: Danish Pain Research Center, Aarhus University Hospital, Aarhus, Denmark.|Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Haroutounian
authors.affiliation: Department of Neurology, The Johns Hopkins Hospital, Baltimore, MD, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Polydefkis
authors.affiliation: Stereology and Electron Microscopy Laboratory and Centre for Stochastic Geometry and Advanced Bioimaging, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Jens R
authors.initials: JR
authors.lastname: Nyengaard
authors.affiliation: Danish Pain Research Center, Aarhus University Hospital, Aarhus, Denmark.|Department of Neurology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Troels S
authors.initials: TS
authors.lastname: Jensen
mesh_terms: D016022:Case-Control Studies; D004817:Epidermis; D064368:Healthy Volunteers; D006801:Humans; D009412:Nerve Fibers; D010523:Peripheral Nervous System Diseases; D011115:Polyneuropathies / Q000473:pathology*
keywords: Global spatial sampling; IENFD; Nerve fibre length density; Polyneuropathy; Skin biopsy