Pall Karlsson1,2, Sandra S Gylfadottir1,3, Alexander G Kristensen1,4, Juan D Ramirez5, Pedro Cruz6, Nhu Le7, Pallai R Shillo8, Solomon Tesfaye8, Andrew S C Rice9,10, Hatice Tankisi4, Nanna B Finnerup1,3, Jens R Nyengaard2, Troels S Jensen1,3, David L H Bennett5, Andreas C Themistocleous11. 1. Danish Pain Research Centre, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark. 2. Core Centre for Molecular Morphology, Section for Stereology for Microscopy, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark. 3. Department of Neurology, Aarhus University Hospital, Aarhus, Denmark. 4. Department of Clinical Neurophysiology, Aarhus University Hospital, Aarhus, Denmark. 5. Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. 6. Faculty of Medicine, Universidade de Coimbra, Coimbra, Portugal. 7. Radboud University Medical Centre, Nijmegen, the Netherlands. 8. Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK. 9. Pain Research Group, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital Campus, London, UK. 10. Pain Medicine, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK. 11. Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. andreas.themistocleous@ndcn.ox.ac.uk.
Abstract
AIMS/HYPOTHESIS: Distal diabetic sensorimotor polyneuropathy (DSP) is a common complication of diabetes with many patients showing a reduction of intraepidermal nerve fibre density (IENFD) from skin biopsy, a validated and sensitive diagnostic tool for the assessment of DSP. Axonal swelling ratio is a morphological quantification altered in DSP. It is, however, unclear if axonal swellings are related to diabetes or DSP. The aim of this study was to investigate how axonal swellings in cutaneous nerve fibres are related to type 2 diabetes mellitus, DSP and neuropathic pain in a well-defined cohort of patients diagnosed with type 2 diabetes. METHODS: A total of 249 participants, from the Pain in Neuropathy Study (UK) and the International Diabetic Neuropathy Consortium (Denmark), underwent a structured neurological examination, nerve conduction studies, quantitative sensory testing and skin biopsy. The study included four groups: healthy control study participants without diabetes (n = 45); participants with type 2 diabetes without DSP (DSP-; n = 31); and participants with evidence of DSP (DSP+; n = 173); the last were further separated into painless DSP+ (n = 74) and painful DSP+ (n = 99). Axonal swellings were defined as enlargements on epidermal-penetrating fibres exceeding 1.5 μm in diameter. Axonal swelling ratio is calculated by dividing the number of axonal swellings by the number of intraepidermal nerve fibres. RESULTS: Median (IQR) IENFD (fibres/mm) was: 6.7 (5.2-9.2) for healthy control participants; 6.2 (4.4-7.3) for DSP-; 1.3 (0.5-2.2) for painless DSP+; and 0.84 (0.4-1.6) for painful DSP+. Swelling ratios were calculated for all participants and those with IENFD > 1.0 fibre/mm. When only those participants with IENFD > 1.0 fibre/mm were included, the axonal swelling ratio was higher in participants with type 2 diabetes when compared with healthy control participants (p < 0.001); however, there was no difference between DSP- and painless DSP+ participants, or between painless DSP+ and painful DSP+ participants. The axonal swelling ratio correlated weakly with HbA1c (r = 0.16, p = 0.04), but did not correlate with the Toronto Clinical Scoring System (surrogate measure of DSP severity), BMI or type 2 diabetes duration. CONCLUSIONS/ INTERPRETATION: In individuals with type 2 diabetes where IENFD is >1.0 fibre/mm, axonal swelling ratio is related to type 2 diabetes but is not related to DSP or painful DSP. Axonal swellings may be an early marker of sensory nerve injury in type 2 diabetes.
AIMS/HYPOTHESIS: Distal diabetic sensorimotor polyneuropathy (DSP) is a common complication of diabetes with many patients showing a reduction of intraepidermal nerve fibre density (IENFD) from skin biopsy, a validated and sensitive diagnostic tool for the assessment of DSP. Axonal swelling ratio is a morphological quantification altered in DSP. It is, however, unclear if axonal swellings are related to diabetes or DSP. The aim of this study was to investigate how axonal swellings in cutaneous nerve fibres are related to type 2 diabetes mellitus, DSP and neuropathic pain in a well-defined cohort of patients diagnosed with type 2 diabetes. METHODS: A total of 249 participants, from the Pain in Neuropathy Study (UK) and the International Diabetic Neuropathy Consortium (Denmark), underwent a structured neurological examination, nerve conduction studies, quantitative sensory testing and skin biopsy. The study included four groups: healthy control study participants without diabetes (n = 45); participants with type 2 diabetes without DSP (DSP-; n = 31); and participants with evidence of DSP (DSP+; n = 173); the last were further separated into painless DSP+ (n = 74) and painful DSP+ (n = 99). Axonal swellings were defined as enlargements on epidermal-penetrating fibres exceeding 1.5 μm in diameter. Axonal swelling ratio is calculated by dividing the number of axonal swellings by the number of intraepidermal nerve fibres. RESULTS: Median (IQR) IENFD (fibres/mm) was: 6.7 (5.2-9.2) for healthy control participants; 6.2 (4.4-7.3) for DSP-; 1.3 (0.5-2.2) for painless DSP+; and 0.84 (0.4-1.6) for painful DSP+. Swelling ratios were calculated for all participants and those with IENFD > 1.0 fibre/mm. When only those participants with IENFD > 1.0 fibre/mm were included, the axonal swelling ratio was higher in participants with type 2 diabetes when compared with healthy control participants (p < 0.001); however, there was no difference between DSP- and painless DSP+ participants, or between painless DSP+ and painful DSP+ participants. The axonal swelling ratio correlated weakly with HbA1c (r = 0.16, p = 0.04), but did not correlate with the Toronto Clinical Scoring System (surrogate measure of DSP severity), BMI or type 2 diabetes duration. CONCLUSIONS/ INTERPRETATION: In individuals with type 2 diabetes where IENFD is >1.0 fibre/mm, axonal swelling ratio is related to type 2 diabetes but is not related to DSP or painful DSP. Axonal swellings may be an early marker of sensory nerve injury in type 2 diabetes.
Authors: Gigi J Ebenezer; Justin C McArthur; Diane Thomas; Beth Murinson; Peter Hauer; Michael Polydefkis; John W Griffin Journal: Brain Date: 2007-10 Impact factor: 13.501
Authors: Andreas C Themistocleous; Juan D Ramirez; Pallai R Shillo; Jonathan G Lees; Dinesh Selvarajah; Christine Orengo; Solomon Tesfaye; Andrew S C Rice; David L H Bennett Journal: Pain Date: 2016-05 Impact factor: 7.926
Authors: Nanna B Finnerup; Simon Haroutounian; Peter Kamerman; Ralf Baron; David L H Bennett; Didier Bouhassira; Giorgio Cruccu; Roy Freeman; Per Hansson; Turo Nurmikko; Srinivasa N Raja; Andrew S C Rice; Jordi Serra; Blair H Smith; Rolf-Detlef Treede; Troels S Jensen Journal: Pain Date: 2016-08 Impact factor: 7.926
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