Axonal Excitability Does Not Differ between Painful and Painless Diabetic or Chemotherapy-Induced Distal Symmetrical Polyneuropathy in a Multicenter Observational Study

Andreas C. Themistocleous*, Alexander G. Kristensen, Roma Sola, Sandra S. Gylfadottir, Kristine Bennedsgaard, Mustapha Itani, Thomas Krøigård, Lise Ventzel, Søren H. Sindrup, Troels S. Jensen, Hugh Bostock, Jordi Serra, Nanna B. Finnerup, Hatice Tankisi, David L.H. Bennett


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Objective: Axonal excitability reflects ion channel function, and it is proposed that this may be a biomarker in painful (vs painless) polyneuropathy. Our objective was to investigate the relationship between axonal excitability parameters and chronic neuropathic pain in deeply phenotyped cohorts with diabetic or chemotherapy-induced distal symmetrical polyneuropathy. Methods: Two hundred thirty-nine participants with diabetic polyneuropathy were recruited from sites in the UK and Denmark, and 39 participants who developed chemotherapy-induced polyneuropathy were recruited from Denmark. Participants were separated into those with probable or definite neuropathic pain and those without neuropathic pain. Axonal excitability of large myelinated fibers was measured with the threshold tracking technique. The stimulus site was the median nerve, and the recording sites were the index finger (sensory studies) and abductor pollicis brevis muscle (motor studies). Results: Participants with painless and painful polyneuropathy were well matched across clinical variables. Sensory and motor axonal excitability measures, including recovery cycle, threshold electrotonus, strength–duration time constant, and current–threshold relationship, did not show differences between participants with painful and painless diabetic polyneuropathy, and there were only minor changes for chemotherapy-induced polyneuropathy. Interpretation: Axonal excitability did not significantly differ between painful and painless diabetic or chemotherapy-induced polyneuropathy in a multicenter observational study. Threshold tracking assesses the excitability of myelinated axons; the majority of nociceptors are unmyelinated, and although there is some overlap of the "channelome" between these axonal populations, our results suggest that alternative measures such as microneurography are required to understand the relationship between sensory neuron excitability and neuropathic pain. ANN NEUROL 2022;91:506–520.

TidsskriftAnnals of Neurology
Udgave nummer4
Sider (fra-til)506-520
StatusUdgivet - apr. 2022

Bibliografisk note

Funding Information:
This project received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement 633491 (DOLORisk). D.L.H.B., A.C.T, N.B.F, and T.S.J are members of the DOLORisk consortium. Research reported in this publication is part of the IDNC research program, which is supported by a Novo Nordisk Foundation Challenge Program grant (NNF14OC0011633). A.C.T is supported by Academy of Medical Sciences Starter Grant SGL022\1086, and is an Honorary Senior Research Fellow and Carnegie‐Wits Diaspora Fellow at the Brain Function Research Group, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. For the purpose of Open Access, the authors have applied a CC BY public copyright license to any author‐accepted manuscript version arising from this submission. We thank the patients who took part in the study; the GPs and staff of the National Institute for Health Research Thames Valley Primary Care Research Network; the staff of the Oxford Centre for Diabetes, Endocrinology, and Metabolism; the Thames Valley Primary Care Research Network for assisting with recruitment; and Dr G. Baskozos, Nuffield Department of Clinical Neurosciences at University of Oxford, for providing assistance with the statistical analysis.


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