Páll Karlsson1, Simon Haroutounian2, Michael Polydefkis3, Jens R Nyengaard4, Troels S Jensen5. 1. 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. Electronic address: pkar@svf.au.dk. 2. Danish Pain Research Center, Aarhus University Hospital, Aarhus, Denmark; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA. 3. Department of Neurology, The Johns Hopkins Hospital, Baltimore, MD, USA. 4. Stereology and Electron Microscopy Laboratory and Centre for Stochastic Geometry and Advanced Bioimaging, Aarhus University Hospital, Aarhus, Denmark. 5. Danish Pain Research Center, Aarhus University Hospital, Aarhus, Denmark; Department of Neurology, Aarhus University Hospital, Aarhus, Denmark.
Abstract
OBJECTIVES: 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. MATERIALS AND METHODS: 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)). RESULTS: 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%. CONCLUSIONS: 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. IMPLICATIONS: Combining small fibre parameters may improve the diagnostic accuracy of DSP.
OBJECTIVES: 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. MATERIALS AND METHODS: 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)). RESULTS: 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%. CONCLUSIONS: 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. IMPLICATIONS: Combining small fibre parameters may improve the diagnostic accuracy of DSP.
Authors: Shannon M Smith; Robert H Dworkin; Dennis C Turk; Ralf Baron; Michael Polydefkis; Irene Tracey; David Borsook; Robert R Edwards; Richard E Harris; Tor D Wager; Lars Arendt-Nielsen; Laurie B Burke; Daniel B Carr; Amy Chappell; John T Farrar; Roy Freeman; Ian Gilron; Veeraindar Goli; Juergen Haeussler; Troels Jensen; Nathaniel P Katz; Jeffrey Kent; Ernest A Kopecky; David A Lee; William Maixner; John D Markman; Justin C McArthur; Michael P McDermott; Lav Parvathenani; Srinivasa N Raja; Bob A Rappaport; Andrew S C Rice; Michael C Rowbotham; Jeffrey K Tobias; Ajay D Wasan; James Witter Journal: J Pain Date: 2017-02-27 Impact factor: 5.820
Authors: Troels S Jensen; Pall Karlsson; Sandra S Gylfadottir; Signe T Andersen; David L Bennett; Hatice Tankisi; Nanna B Finnerup; Astrid J Terkelsen; Karolina Khan; Andreas C Themistocleous; Alexander G Kristensen; Mustapha Itani; Søren H Sindrup; Henning Andersen; Morten Charles; Eva L Feldman; Brian C Callaghan Journal: Brain Date: 2021-07-28 Impact factor: 13.501
Authors: Pall Karlsson; Sandra S Gylfadottir; Alexander G Kristensen; Juan D Ramirez; Pedro Cruz; Nhu Le; Pallai R Shillo; Solomon Tesfaye; Andrew S C Rice; Hatice Tankisi; Nanna B Finnerup; Jens R Nyengaard; Troels S Jensen; David L H Bennett; Andreas C Themistocleous Journal: Diabetologia Date: 2021-01-23 Impact factor: 10.122