Association of electrochemical skin conductance with neuropathy in chemotherapy-treated patients

Participants who completed neurotoxic chemotherapy (including taxanes, platinum-based agents, bortezomib, vinca alkaloids and thalidomide) were recruited cross-sectionally from Sydney, Australia, between June 2017 and March 2020. Participants who were aged ≥ 18 years and 3–24 months post-treatment were eligible. The study was approved by Sydney Local Health District (RPAH zone) Human Research Ethics Committee, with informed consent obtained from each participant.

Clinical data (age, height, chemotherapy type, cancer diagnosis and stage) were retrieved from medical records. Participants’ weight was assessed during their study visit. Body mass index (BMI) was calculated as kg/m².

ESC was evaluated by assessing sweat gland function using the Sudoscan device (Impeto Medical, Paris, France) [23]. Participants placed their palms (hands) and soles (feet) onto the electrodes in a standing position for 2–3 min. A direct current of ≤ 4 V was applied through the electrodes by chronoamperometry which generated a current relative to the chloride ions extracted from the skin through the mechanism of reverse iontophoresis [23‐27]. The ESC values were quantified in microSiemens (µS) based on the reaction between chloride ions from the sweat glands and the direct current generated from the electrodes [23]. The electrodes were sterilised before each test, and the test was repeated twice for both the hands and feet, with the average ESC value taken separately for the hands and feet. Average ESC values were categorised as no dysfunction (≥ 60 μS) or dysfunction (< 60 μS), as in prior studies [24, 26]. Participants were classified with ESC dysfunction if they had dysfunction in the hands, feet, or both.

CIPN severity was assessed using the Total Neuropathy Score-clinical version (TNSc©, Johns Hopkins University), a composite tool of six domains including upper and lower limb pin-prick sensory and vibration sensibility, deep tendon reflexes, strength assessment and patient-reported sensory and motor symptoms [28, 29]. Each domain was graded between 0 ‘normal’ and 4 ‘severe’, with a total score ranging from 0 ‘no neuropathy’ to 24 ‘severe neuropathy’; Researchers completed training to ensure reliability across assessors. Researchers graded CIPN severity via the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) sensory neuropathy subscale Version 4.0 categorised: Grade 0 ‘no symptoms’, Grade 1 ‘asymptomatic, not interfering with daily function’, Grade 2 ‘moderate symptoms, limiting daily function’, Grade 3 ‘severe symptoms, limiting daily function and self-care’, and Grade 4 ‘disabling’[30]. Nerve conduction studies (NCS) were undertaken to record maximal amplitude of lower limb tibial and sural nerves, using methodology as reported in previous studies [31].

The European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire-Core (EORTC-QLQ-CIPN-20) is a 20-item validated questionnaire assessing motor, sensory and autonomic peripheral neuropathy symptoms, rating each item on a 4-point Likert scale from 1 ‘not at all’ to 4 ‘very much’, converted to a 0–100 scale, with higher scores indicating more severe CIPN [32]. The Survey of Autonomic Symptoms (SAS) questionnaire is an 11-item questionnaire to measure autonomic symptoms based on two scores: total number of symptoms (SAS symptom score), and total impact score (SAS impact score) graded from 1 ‘least severe’ to 5 ‘most severe’ for each reported symptom [33]. Questions assessing the following autonomic symptom domains were grouped: sudomotor, gastrointestinal, vasomotor, orthostatic, and urinary function. The total number of symptoms is calculated as the sum of total reported symptoms, whilst the total impact score is the sum of the total burden from each reported symptom. The SAS domains have been well-validated with other measures of autonomic function, displaying strong correlations with Autonomic Symptom Profile (ASP) domains and QSART measurements [33]. Male specific questions (Question 20 EORTC-QLQ-CIPN20; question 12 SAS) were omitted from analysis. The Pain Numeric Rating Scale (PNRS) was utilised to assess the worst neuropathic pain that participants have experienced in the last 24 h prior to testing. The scale ranges from 0 to 10, with ‘0’ representing ‘no pain at all’ and 10 representing ‘the worst pain possible’ [34].

All analyses were conducted using SPSS Statistics Software V27 (IBM; Armonk, NY, USA) and followed the STROBE statement for observational studies [35]. Normality of data was assessed using the Shapiro–Wilk test. Normally distributed data (p > 0.05) were presented as mean ± standard deviation (SD), while non-normally distributed data (p < 0.05) were presented as medians and interquartile range (IQR). Independent sample t tests or Mann–Whitney U tests were used for normally and non-normally distributed data, respectively, to explore mean differences between clinical, neurophysiological and CIPN outcome measure scores of the two cohorts (participants with ESC dysfunction vs. no-ESC dysfunction). The associations between ESC values via Sudoscan, clinical characteristics, CIPN, pain and autonomic outcome measures were calculated using Pearson’s or Spearman’s correlation coefficients for normally and non-normally distributed data, respectively. Where specified, the Bonferroni correction was applied, modifying the significance level from p < 0.05 to p < 0.0063 due to the number of contrasts. Finally, we examined the ability of ESC values and clinical characteristics to predict patient scores on CIPN severity and autonomic outcome measures using linear regression. The independent variables were age, sex, BMI, hand ESC and feet ESC. Dependent variables were scores of patient-reported outcome measure (EORTC-QLQ-CIPN20), neurological examination score (TNSc), sural and tibial amplitudes, and sudomotor dysfunction of the autonomic outcome measure (SAS). The independent variables of the model were checked for multicollinearity. Linear regression was bootstrapped to account for non-normal distribution of the residuals and to produce robust confidence intervals.

A total of 130 neurotoxic chemotherapy-treated participants were assessed cross-sectionally at a median of 6.0 (3.0–12.0) months post-treatment completion. Of these, 67% were female (n = 87), and the median age at the time of assessment was 58.6 years (47.6–66.5) (Table 1). The most common cancer types were breast (33%, n = 43) and gynaecological (21%, n = 27). The most common chemotherapy types were taxanes (61%, n = 79) and platinum-based (24%, n = 31). Clinical and demographic information is displayed in Table 1.

Overall, 28% of participants (n = 37) had no CIPN symptoms (Grade-0) at the time of assessment using a clinically graded scale (NCI-CTCAE), while 72% (n = 93) were graded with CIPN symptoms of any severity (Grade ≥ 1), while 23% were classified with mild CIPN (Grade-1; n = 30), 42% with moderate (Grade-2, n = 54), and 7% with severe CIPN (Grade-3, n = 9). Using the neurological examination score (TNSc), the median score of the cohort was 3.5 (2.0–6.0) (out of 24). From the TNSc score, 62% had reduced pinprick sensation (score ≥ 1, n = 81), 22% had reduced vibration sensation (score ≥ 1, n = 29), 73% had abnormal tendon reflexes (score ≥ 1, n = 95) and none had reduced ankle plantar flexor strength (score = 0, n = 130). Also, 17% (n = 22) reported some nerve pain (≥ 1/10) in the 24 h prior to the study visit. Based on the patient-reported autonomic neuropathy outcome measure (SAS), completed by 81 participants, 52% reported having sudomotor dysfunction (n = 42), 45% reported vasomotor dysfunction (n = 36), 36% reported orthostatic dysfunction (n = 29), 28% reported gastrointestinal dysfunction (n = 20) and 11% reported urinary dysfunction (n = 9).

Participants with CIPN were older (p < 0.001) and had significantly greater CIPN severity score on multiple CIPN outcome measures versus those without CIPN (Table 2), including the patient-reported outcome (EORTC-QLQ-CIPN20; p < 0.001), clinically graded scale (NCI-CTCAE; p < 0.001) and neurological examination scores (TNSc; p < 0.001). Sural and tibial amplitudes were significantly reduced in participants with CIPN compared to those without CIPN (all p < 0.002) (Table 2). In patients with CIPN, higher scores on the patient-reported outcome measure (EORTC-QLQ-CIPN20) correlated with higher autonomic outcome measure (SAS) symptom score (r = 0.48) and total impact score (r = 0.47) (both p < 0.001). However, despite this, there was no significant difference in the autonomic outcome measure (SAS) domain scores between patients with and without CIPN (all p > 0.0063) (Table 2). ESC values via Sudoscan, including average hand ESC and feet ESC, were also not statistically different between participants with or without CIPN (all p > 0.0063) (Table 2).

Of the 93 participants with CIPN, 49% (n = 46) had any ESC dysfunction, while 51% (n = 47) had no dysfunction, and 39% (n = 36) experienced ESC dysfunction in their hands, 30% (n = 28) experienced ESC dysfunction in their feet, while 19% (n = 18) had dysfunction in both their hands and feet. There were no significant correlations between clinical, neurophysiological, or autonomic outcome measures with ESC values for either hands or feet (all p > 0.0063) (Table 3), including the patient-reported outcome measure (EORTC-QLQ-CIPN20) and the neurological examination score (TNSc) (Fig. 1).

CIPN severity from patient-reported outcome (EORTC-QLQ-CIPN20), clinically graded scale (NCI-CTCAE) and neurological examination score (TNSc) were not significantly different between participants with and without ESC dysfunction (all p > 0.0063) (Table 4). Neurophysiological measurements did not significantly differ between participants with and without ESC dysfunction (p > 0.0063). None of the individual items or total scores of the autonomic outcome measure were different between participants with and without ESC dysfunction (p > 0.0063) (Table 4).

Linear regression analyses revealed that age was a significant predictor of all clinically graded and patient-reported CIPN severity measures, including the patient-reported outcome (EORTC-QLQ-CIPN20, p = 0.002) and the neurological examination score (TNSc, p = 0.001), but not of patient-reported sudomotor function (p > 0.05) (Table 5). Sex was a predictor of sural amplitudes (p = 0.001), while BMI was a predictor of tibial amplitudes (p = 0.003) (Table 5). Neither hand ESC nor feet ESC values could predict CIPN severity with any measures, including the sudomotor dysfunction sub-scale of the autonomic outcome measure (all p > 0.05) (Table 5).