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

Abstract

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 chemotherapyinduced 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

Diagnostic Accuracy of Perception Threshold Tracking in the Detection of Small Fiber Damage in Type 1 Diabetes

“…Recently, a large multicentre study reported no difference in axonal excitability when comparing those with painless to those with painful diabetic peripheral neuropathy, concluding that electrophysiological measures targeting the small nerves are needed to rule out axonal excitability changes in painful diabetic peripheral neuropathy [42]. One such method is microneurography, which is capable of assessing the function of small cutaneous C-fibres, and have previously associated increased spontaneous activity of cutaneous C-fibres with painful diabetic peripheral neuropathy [43,44].…”

The test–retest reliability of large and small fiber nerve excitability testing with threshold tracking

“…In 2017, shorter versions of the motor (TRONDOLM) and sensory (TRONDOLS) TROND protocols were introduced for clinical and research settings that the time ensured for the excitability testing experiments might be limited. These shorter protocols were used in a few recent studies ( Bennedsgaard et al, 2020a , Bennedsgaard et al, 2020b , Kristensen et al, 2021 , Themistocleous et al, 2022 ). However, like the traditional TROND protocols, the test–retest reliability of these protocols has never been investigated.…”

“…These protocols have been used in a few recent studies ( Bennedsgaard et al, 2020a , Bennedsgaard et al, 2020b , Kristensen et al, 2021 : Themistocleous et al, 2022 ) but their reliability has yet to be assessed.…”

“…A more comprehensive description of the nerve excitability testing methods employed in this study can be found in previously published literature ( Kristensen et al, 2021 , Themistocleous et al, 2022 ). The international guidelines have been followed for the methodology of all sensory and motor excitability tests ( Kiernan et al, 2020 ).…”

Big data, big consortia, and pain: UK Biobank, PAINSTORM, and DOLORisk

“…Patient partners contributed directly to the consensus meeting and to the development of the PAINSTORM protocol and both of these are very similar to those in DOLORisk (Table 1). Based on 119 ) makes way for microneurography 102,122 ; CPM was omitted as our data from the DOLORisk project suggest that an improved CPM protocol, to be applied and validated in the context of neuropathy, is required 52 ; EEG was not included because as yet the technology for undertaking this at scale is not available; and some participants will take part in imaging studies of the brain, the spinal cord, and the peripheral nervous system. Genetic analysis is likely to include technology advances in both sequencing and analysis for much more comprehensive genomic assessment such as whole genome sequencing.…”