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Purpose Chemotherapy-induced peripheral neuropathy (CIPN) is an adverse event of cancer treatment that can affect sensory, motor, or autonomic nerves. Assessment of autonomic neuropathy is challenging, with limited available tools. Accordingly, it is not routinely assessed in chemotherapy-treated patients. In this study, we aimed to examine whether electrochemical skin conductance (ESC) via Sudoscan, a potential measure of autonomic function, associates with subjective and objective measures of CIPN severity and autonomic neuropathy. Methods A cross-sectional assessment of patients who completed neurotoxic chemotherapy 3–24 months prior was undertaken using CIPN patient-reported outcomes (EORTC-QLQ-CIPN20), clinically graded scale (NCI-CTCAE), neurological examination score (TNSc), autonomic outcome measure (SAS), and Sudoscan. Differences in CIPN severity between participants with or without ESC dysfunction were investigated. Linear regression analyses were used to identify whether ESC values could predict CIPN severity. Results A total of 130 participants were assessed, with 93 participants classified with CIPN according to the clinically graded scale (NCI-CTCAE/grade ≥ 1), while 49% demonstrated hands or feet ESC dysfunction (n = 46). Participants with ESC dysfunction did not significantly differ from those with no dysfunction on multiple CIPN severity measures (clinical-grade, patient-report, neurological examination), and no differences on the autonomic outcome measure (SAS) (all p > 0.0063). Linear regression analyses showed that CIPN could not be predicted by ESC values. Conclusions The inability of ESC values via Sudoscan to predict clinically-graded and patient-reported CIPN or autonomic dysfunction questions its clinical utility for chemotherapy-treated patients. The understanding of autonomic neuropathy with chemotherapy treatment remains limited and must be addressed to improve quality of life in cancer survivors.

The aim of this study was to investigate the reliability of subbasal corneal nerve plexus parameters of the inferior whorl compared with the central cornea with in vivo corneal confocal microscopy and to investigate the impact of inferior whorl pattern complexity on reproducibility.Subbasal corneal nerves of healthy controls (n = 10) and patients with chemotherapy-induced peripheral neuropathy (n = 10) were imaged with a laser scanning confocal microscope. Two masked, experienced observers and the original image taker were tasked with selecting representative images of the central cornea and inferior whorl for each participant. This was conducted on 2 occasions 1 week apart. Corneal nerve fiber length (CNFL) and fractal dimension (CNFrD) [central cornea: CNFL and CNFrD; inferior whorl region: inferior whorl length (IWL) and inferior whorl fractal dimension (IWFrD)] were analyzed. Intraclass correlation coefficient (ICC) was analyzed for interobserver and intraobserver reliability. Inferior whorl complexity was classified according to the ease of identification of the center point of convergence.Interobserver ICC was 0.992 for CNFL, 0.994 for CNFrD, 0.980 for IWL, and 0.954 for IWFrD. When analyzed by inferior whorl complexity, the interobserver reliability was similar for simple (0.987 for IWL; 0.960 for IWFrD) and complex patterns (0.967 for IWL; 0.949 for IWFrD). However, intraobserver ICC were reduced for complex (IWL 0.841-0.970; IWFrD 0.830-0.955) compared with simple patterns (IWL 0.931-0.970; IWFrD 0.921-0.969).Although the overall interobserver reliability was excellent for the central corneal and inferior whorl parameters, there was lower intraobserver reliability for the inferior whorl parameters for complex morphological patterns. To improve reliability, more sophisticated wide-field imaging of the inferior whorl may be needed.

Immune-mediated neuropathies such as chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) produce significant disability and often require maintenance treatment. There is a paucity of epidemiological data on these conditions in Australia.We undertook a prevalence study of CIDP and MMN in North Queensland and Tasmania, coinciding with a national census. Diagnoses were classified against the diagnostic criteria of the European Federation of Neurological Societies/Peripheral Nerve Society. Case ascertainment was undertaken via multiple methods, including survey of local neurologists across public and private clinics, search of neurophysiology, neurology and hospital databases, search of admitted hospital database collections using ICD codes and through immunoglobulin therapy prescription lists.The crude prevalence of CIDP was 5.00 per 100,000 (95% confidence interval [CI] 3.79-6.62) and the crude prevalence of MMN was 1.33 per 100,000 (95% CI 0.78-2.27). Prevalence was also investigated using National Blood Authority numbers of cases prescribed immunoglobulin therapy, indicating a CIDP prevalence of 5.72 per 100,000 (95% CI 4.41-7.43) and MMN prevalence of 1.94 per 100,000 (95% CI 1.24-3.03). There was no significant difference between these numbers and those calculated through access of patient records locally. There was no significant difference in prevalence between Tasmania and North Queensland for any category.This study updates the prevalence of CIDP and MMN in Australia. Understanding the distribution of CIDP and MMN patients and their need for treatment is essential for future resource planning and to enable monitoring and coordination of therapies such as immunoglobulin.

Purpose Chemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity of cancer treatment, with potential to significantly impact cancer survivors’ long-term quality of life. Patient reported outcome measures (PROMs) are increasingly utilised to evaluate CIPN. However, guidance remains lacking on how to identify fit for purpose PROMs with considerations necessarily differing when used in various research and in-clinic contexts. This study aimed to evaluate evidence about CIPN PROMs measurement properties and propose considerations to optimize CIPN PROM selection for each purpose. Methods A systematic review was conducted to identify literature assessing measurement properties of CIPN PROMs. These were evaluated against Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) criteria and International Society for Quality of Life minimum standards. Risk of Bias (RoB) was assessed using the COSMIN RoB checklist. Results Thirty-nine papers evaluating measurement properties of 13 PROMs were included. The European Organization for Research and Treatment of Cancer Quality of Life Chemotherapy-Induced Peripheral Neuropathy Questionnaire (QLQ-CIPN20) and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) were the most commonly investigated PROMs and had the most measurement properties meeting established criteria. Conclusion The use of the QLQ-CIPN20 and FACT/GOG-Ntx to assess CIPN in research settings has the most supporting evidence. However other considerations including study aims, endpoints and target population also factor into PROM selection and need to be considered more often when determining the most suitable outcome measure. Evidence of CIPN PROMs use in clinical practice is limited and their adoption to individual-patient level management requires more evaluation.

The excitability of motor and sensory axons of the main upper limb nerves were compared to characterise the differences between nerves and provide a guide for future studies in human diseases with median neuropathy at the wrist.Axonal excitability studies were undertaken on median and ulnar motor (APB and ADM) and sensory axons (D2 and D5) and the superficial radial axons (D1) using a threshold tracking technique.Compared to the median, ulnar motor axons had reduced early depolarising threshold electrotonus (TEd40(10-20 ms) p = 0.02) and superexcitability (p = 0.03). The ulnar sensory axons required a stronger stimulus (p = 0.02) and had a larger rheobase (p = 0.02) than median axons, but were otherwise comparable. The superficial radial axons were "fanned-in" compared to median, and to a lesser degree ulnar axons, with greater resting I/V slope. Mathematical modelling of the radial and median sensory axons suggested that a 15.1% reduction in conductances between nodal and internodal compartments accounted for 82% of this discrepancy.The excitability parameters of motor and sensory axons are most comparable between median and ulnar nerves.The present study demonstrates the feasibility of, and provides normative data for, axonal excitability recordings of the radial and ulnar nerves. We suggest the use of ulnar recordings as an alternative to the median nerve in the setting of compressive neuropathy at the wrist.

INTRODUCTION: Chemotherapy-induced peripheral neurotoxicity (CIPN) remains a significant toxicity in cancer survivors without preventative strategies or rehabilitation. Exercise and physical activity-based interventions have demonstrated promise in reducing existing CIPN symptoms and potentially preventing toxicity, however there is a significant gap in evidence due to the lack of quality clinical trials and appropriate outcome measures. AREAS COVERED: The authors systematically reviewed outcome measures in CIPN exercise and physical rehabilitation studies with expert panel consensus via the Peripheral Nerve Society Toxic Neuropathy Consortium to provide recommendations for future trials. Across 26 studies, 75 outcome measures were identified and grouped into 16 domains within three core areas - measures of manifestations of CIPN (e.g. symptoms/signs), measures of the impact of CIPN and other outcome measures. EXPERT OPINION: This article provides a conceptual framework for CIPN outcome measures and highlights the need for definition of a core outcome measures set. The authors provide recommendations for CIPN exercise and physical rehabilitation trial design and outcome measure selection. The development of a core outcome measure set will be critical in the search for neuroprotective and treatment approaches to support cancer survivors and to address the significant gap in the identification of effective rehabilitation and treatment options for CIPN.

Multiple pathological mechanisms are involved in the development of chemotherapy-induced peripheral neurotoxicity (CIPN). Recent work has provided insights into the molecular mechanisms underlying chemotherapy-induced axonal degeneration. This review integrates evidence from preclinical and clinical work on the onset, progression and outcome of axonal degeneration in CIPN. We review likely triggers of axonal degeneration in CIPN and highlight evidence of molecular pathways involved in axonal degeneration and their relevance to CIPN, including SARM1-mediated axon degeneration pathway. We identify potential clinical markers of axonal dysfunction to provide early identification of toxicity as well as present potential treatment strategies to intervene in axonal degeneration pathways. A greater understanding of axonal degeneration processes in CIPN will provide important information regarding the development and progression of axonal dysfunction more broadly and will hopefully assist in the development of successful interventions for CIPN and other neurodegenerative disorders.

Immune cell infiltration has been implicated in neurotoxic chemotherapy for cancer treatment. However, our understanding of immune processes is still incomplete and current methods of observing immune cells are time consuming or invasive. Corneal dendritic cells are potent antigen-presenting cells and can be imaged with in-vivo corneal confocal microscopy. Corneal dendritic cell densities and nerve parameters in patients treated with neurotoxic chemotherapy were investigated. Patients treated for cancer with oxaliplatin (n = 39) or paclitaxel (n = 48), 3 to 24 months prior to assessment were recruited along with 40 healthy controls. Immature (ImDC), mature (MDC) and total dendritic cell densities (TotalDC), and corneal nerve parameters were analyzed from in-vivo corneal confocal microscopy images. ImDC was increased in the oxaliplatin group (Median, Md = 22.7 cells/mm2) compared to healthy controls (Md = 10.1 cells/mm2, p = 0.001), but not in the paclitaxel group (Md = 10.6 cells/mm2). ImDC was also associated with higher oxaliplatin cumulative dose (r = 0.33, p = 0.04) and treatment cycles (r = 0.40, p = 0.01). There was no significant difference in MDC between the three groups (p > 0.05). Corneal nerve parameters were reduced in both oxaliplatin and paclitaxel groups compared to healthy controls (p

Background Chemotherapy-induced peripheral neuropathy (CIPN) is reported to affect up to 70 % of cancer survivors. Despite evidence that CIPN-related impairments often translate into balance and mobility deficits, the effects on stepping and quality of gait, well-documented risk factors for falls, are unclear. Aims (i) Establish choice-stepping reaction time (CSRT) performance in survivors with CIPN compared to young and older healthy controls and people with Parkinson’s disease; (ii) document walking stability; (iii) investigate relationships between stepping and gait data to objective and patient-reported outcomes. Methods 41 cancer survivors with CIPN (mean (SD) age: 60.8 (9.7) years) who were ≥3months post chemotherapy, performed tests of simple and inhibitory CSRT. Walking stability measures were derived from 3-D accelerometry data during the 6-minute walk test. CIPN was assessed using neurological grading and patient-reported outcome measures (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire in CIPN Questionnaire scale EORTC CIPN20). Results In both stepping tests, CIPN participants performed at the level of adults aged 10 years older and people with mild to moderate Parkinson’s disease. Mean (SD) total stepping response times in both CSRT (1160 (190) milliseconds) and inhibitory CSRT (1191 (164) milliseconds) tests were not associated with objective neurological grading but were correlated with increased difficulty feeling the ground. Participants with lower-limb vibration sensation deficit had slower and more variable CSRT times. There were no associations between walking stability and objective measures of CIPN, and limited correlations with the EORTC-CIPN20. Conclusions Cancer survivors with CIPN showed deficits in voluntary stepping responses and seemed to compensate for their sensory and motor deficits by walking slower to maintain stability. Objective and patient-reported outcomes of CIPN were correlated with slower and more variable stepping response times. Future studies should aim to identify the causes of the apparent premature decline in cognitive-motor function and develop remediating interventions.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a major dose-limiting side effect of many anti-cancer agents, including taxanes, platinums, vinca alkaloids, proteasome inhibitors, immunomodulatory drugs, and antibody–drug conjugates. The resultant symptoms often persist post treatment completion and continue to impact on long-term function and quality of life for cancer survivors. At present, dose reduction remains the only strategy to prevent severe neuropathy, often leading clinicians to the difficult decision of balancing maximal treatment exposure and minimal long-lasting side effects. This review examines the clinical presentations of CIPN with each class of neurotoxic treatment, describing signs, symptoms, and long-term outcomes. We provide an update on the proposed mechanisms of nerve damage and review current data on clinical and genetic risk factors contributing to CIPN development. We also examine recent areas of research in the treatment and prevention of CIPN, with specific focus on current clinical trials and consensus recommendations for CIPN management.

Background: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a major adverse effect of cancer treatment. However, its impact remains poorly understood. This study aimed to investigate the impact associated with CIPN on the lives of cancer survivors. Patients and Methods: A volunteer sample of 986 individuals who had received neurotoxic chemotherapy completed an anonymous, cross-sectional survey. Outcomes assessed included CIPN symptoms, pain, neuropathic pain, quality of life (QoL), physical activity, and comorbid health conditions via the Self-Administered Comorbidity Questionnaire. Results: Respondents had a mean age of 58 years (SD, 10.7), and 83.2% were female. Most were treated for breast (58.9%) or colorectal cancer (13.5%); had received docetaxel (32.7%), paclitaxel (31.6%), or oxaliplatin (12.5%); and had completed treatment 3.6 ± 3.5 years previously. We found that 76.5% of respondents reported current CIPN. Respondents reporting severe CIPN had poorer QoL, more comorbidities, and higher body mass index, and more often received multiple neurotoxic chemotherapies than those with mild CIPN. Respondents who completed the survey ≤1 year after completing chemotherapy did not differ in reported CIPN or pain compared with respondents who completed chemotherapy ≥6 years earlier. However, respondents who completed chemotherapy ≥6 years earlier reported better QoL. Multivariable linear regression analyses revealed predictors of CIPN severity as follows: F(7, 874) = 64.67; PR2 = 0.34, including pain (β = −0.36; PPPPP=.006), number of comorbid conditions (β = 0.07; P=.02), and body mass index (β = 0.07; P=.02). Conclusions: Respondents with a high CIPN symptom burden experienced poorer general health and QoL. Improvements in CIPN may be more likely soon after treatment. However, improvements in QoL may occur over time in those with chronic symptoms. CIPN seems to have lasting impacts on cancer survivors, and understanding risk factors is important to enable the design of further preventive and therapeutic management strategies.

INTRODUCTION/AIMS Clinically, the chemotherapeutic agent oxaliplatin can cause peripheral neuropathy, impaired balance, and muscle wastage. Using a preclinical model, we investigated whether exercise intervention could improve these adverse conditions. METHODS Mice were chronically treated with oxaliplatin alone or in conjunction with exercise. Behavioral studies, including mechanical allodynia, rotarod, open-field, and grip-strength tests, were performed. After euthanasia, multiple organs and four different muscle types were dissected and weighed. The cross-sectional area (CSA) of muscle fibers in the gastrocnemius muscle was assessed and gene expression analysis performed on the forelimb triceps muscle. RESULTS Oxaliplatin-treated mice displayed reduced weight gain, mechanical allodynia, and exploratory behavior deficits that were not significantly improved by exercise. Oxaliplatin-treated exercised mice showed modest evidence of reduced muscle wastage compared with mice treated with oxaliplatin alone, and exercised mice demonstrated evidence of a mild increase in CSA of muscle fibers. DISCUSSION Exercise intervention did not improve signs of peripheral neuropathy but moderately reduced the negative impact of oxaliplatin chemotherapy related to muscle morphology, suggesting the potential for exploring the impact of exercise on reducing oxaliplatin-induced neuromuscular toxicity in cancer patients.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect of neurotoxic cancer treatment, often impacting treatment tolerability and patient functioning. Factors predicting an individual’s vulnerability for developing CIPN remain ill-defined. However, patient characteristics may contribute to CIPN risk, with obesity being a prevalent patient comorbidity. This study was aimed at evaluate if being overweight (BMI ≥ 25 kg/m2) was associated with worse symptomatic, clinical, and functional CIPN following neurotoxic cancer treatment. Three hundred seventy-nine cancer survivors were assessed 5 (IQR 3–5) months post oxaliplatin or paclitaxel treatment via comprehensive patient-reported, clinical, and functional CIPN measures. Patients classified as overweight (BMI ≥ 25 kg/m2) were compared to those within the normal BMI range (< 25 kg/m2). Multilinear regression was conducted to evaluate the association between patient clinical factors and CIPN severity. Most patients reported CIPN symptoms (78%), with deficits evident on clinical examination. Overweight patients (n = 242, 63.8%) had significantly worse CIPN across symptomatic, objective clinical, and functional outcomes compared to those with a normal BMI (p < .05). In multivariate linear regression, older age (B = .088, 95%CI = .053–.122, p < .001), larger waist circumference (B = .030, 95%CI = .001–.059, p < .05), and larger BSA (B = 2.41, 95%CI = .34–04.48, p < .05) were associated with CIPN. Diabetes and BMI were significant on univariate analysis but not in the final models. Overweight patients represent a large proportion of cancer survivors who may be particularly impacted by CIPN, requiring closer monitoring and referral to supportive services. Accessible data such as a patient’s general and abdominal obesity status may aid in formulating personalized treatment. Identifying routinely measured patient characteristics which may contribute to an individual’s CIPN risk profile could assist with informing treatment decisions.

Platinum complexes remain frontline anticancer therapies, even after 50 years of usage in clinical applications. However, there is still a lack of methodology to robustly detect and quantify these complexes in biological fluids. We report here a fluorescent sensor array comprising six sensors that demonstrates progress toward the detection of platinum levels in chemotherapy patients. Linear discriminant analysis was performed to examine each multidimensional data set, and the array was able to discriminate platinum from other biologically relevant metals and heavy metals and separately able to differentiate and identify platinum complexes with different coordination environments with 100% accuracy. Finally, the array showed sensitivity to various cisplatin and oxaliplatin concentrations in human plasma and was able to discriminate between a cohort of 27 cancer patients at different stages of platinum treatment. We envisage that our array system could lead to a better understanding of blood platinum concentrations of chemotherapy patients and could inform the modification of dosage regimes to minimize dose-limiting side effects.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common dose-limiting toxicity of cancer treatment causing functional impairment and impacting quality of life. Effective prevention and treatment of CIPN are lacking, and CIPN risk factors remain ill-defined. Metabolic syndrome and associated conditions have emerged as potential risk factors, due to their high prevalence and independent association with nerve dysfunction. This systematic review aimed to investigate the association between these common metabolic-lifestyle factors and CIPN. Searches were undertaken using Medline, Embase, CINAHL, Scopus, and Web of Science databases, with additional studies identified from bibliographic references cited by original and review articles. Articles that analyzed metabolic-lifestyle risk factors associated with CIPN for patients treated with platinum- or taxane-based chemotherapy were included. Searches identified 6897 titles; 44 articles had full text review, with 26 studies included. Overall incidence of neuropathy ranged from 16.9 to 89.4%. Obesity had the most consistent patient-oriented evidence as a risk factor for CIPN, with moderate evidence suggesting diabetes did not increase CIPN incidence or severity. A limited number of studies supported an association with low physical activity and greater CIPN risk. Comorbidities and lifestyle factors, particularly obesity and low physical activity, may contribute to the development of CIPN. The implementation of sensitive outcome measures in large-scale clinical trials is required to further elucidate CIPN risk factors and evaluate if changes in lifestyle would improve long-term CIPN outcomes for cancer survivors. Better understanding of CIPN risk profiles may inform personalized medicine strategies and help elucidate pathophysiological mechanisms which could be targeted for neuroprotection.

Oxaliplatin chemotherapy produces acute changes in peripheral nerve excitability in humans by modulating voltage-gated Na+ channel activity. However, there are few animal studies of oxaliplatin-induced neuropathy that demonstrate similar changes in excitability. In the present study, we measured the excitability of motor and sensory caudal nerve in C57BL/6 mice after oxaliplatin injections either systemically (intraperitoneal) or locally (intramuscular at the base of the tail). As opposed to intraperitoneal administration of oxaliplatin, a single intramuscular injection of oxaliplatin produced changes in both motor and sensory axons. In motor axons, oxaliplatin caused a greater change in response to long-lasting depolarization and an upward shift in the recovery cycle, particularly at 24 h [depolarizing threshold electrotonus (TEd) 10-20 ms, P = 0.0095; TEd 90-100 ms, P = 0.0056) and 48 h (TEd 10-20 ms, P = 0.02; TEd 90-100 ms, P = 0.04) posttreatment. Oxaliplatin treatment also stimulated the production of afterdischarges in motor axons. These changes were transient and showed dose dependence. Mathematical modeling demonstrated that these changes could be accounted for by slowing inactivation of voltage-gated Na+ channels by 73.3% and reducing fast K+ conductance by 47% in motor axons. In sensory axons, oxaliplatin caused an increase in threshold, a reduction in peak amplitude, and greater threshold changes to strong hyperpolarizing currents on days 4 and 8. Thus, local administration of oxaliplatin produced clinically relevant changes in nerve excitability in mice and may provide an alternative approach for the study of acute oxaliplatin-induced neurotoxicity.NEW & NOTEWORTHY We present a novel mouse model of acute oxaliplatin-induced peripheral neurotoxicity that is comparable to clinical observations. Intramuscular injection of oxaliplatin produced acute changes in motor nerve excitability that were attributable to alterations in Na+ and K+ channel activity. Conversely, we were unable to show any significant changes in nerve excitability with systemic intraperitoneal injections of oxaliplatin. This study suggests that local intramuscular injection is a valid approach for modelling oxaliplatin-induced peripheral neuropathy in animals.

Cancer is a global health problem and is one of the leading causes of death worldwide. Pleasingly, the rate of survival has improved and continues in an upward trend mainly due to better diagnosis and treatment modalities. In particular, the development of anticancer drugs including cytotoxic chemotherapy, hormonal agents and targeted therapies have provided the most effective treatment options in combatting cancerous cells. However, the antineoplastic mechanisms of these drugs can also lead to undesirable systemic and ocular side effects resulting from cytotoxicity, inflammation and neurotoxicity. While survival rates are projected to increase with time, the number of patients presenting with these side effects that can substantially impact quality of life will also rise. The current paper reviews the ocular surface and adnexal side effects of anticancer drugs, the appropriate management and possible interactions between drugs for ocular surface pathology treatment and the anticancer drugs.

Peripheral neuropathy is a commonly reported adverse effect of oxaliplatin treatment, representing a significant limitation which may require discontinuation of effective therapy. The present study investigated the neuroprotective potential of riluzole in patients undergoing oxaliplatin treatment in a randomised-controlled trial comparing riluzole and placebo-control. Fifty-two patients (17 females, 58.1 ± 12.7 years) receiving oxaliplatin treatment were randomised into either a treatment (50 mg riluzole) or lactose placebo group. The primary outcome measure was the total neuropathy score-reduced (TNSr). Secondary outcome measures include nerve excitability measures, 9-hole pegboard and FACT-GOG NTX questionnaire. Patients were assessed at baseline, pre-cycle 10 or 12, 4-week and 12-week post-treatment. Both the treatment and placebo groups developed objective and patient reported evidence of neurotoxicity over the course of oxaliplatin treatment, although there were no significant differences across any parameters between the two groups. However, across follow-up assessments, the treatment group experienced greater neuropathy, represented by a higher TNSr score at 4-week post-chemotherapy of 8.3 ± 2.7 compared with 4.6 ± 3.6 (p = 0.032) which was sustained at 12-week post-treatment (p = 0.089). Similarly, patients in the treatment group reported worse symptoms with a FACT-GOG NTX score of 37.4 ± 10.2 compared with 43.3 ± 7.4 (p = 0.02) in the placebo group at 4-week post-treatment. This study is the first to provide an objective clinical investigation of riluzole in oxaliplatin-induced peripheral neuropathy employing both functional and neurophysiological measures. Although the recruitment target was not reached, the results do not show any benefit of riluzole in minimising neuropathy and may suggest that riluzole worsens neuropathy associated with oxaliplatin treatment.

In the context of increasing numbers of childhood cancer survivors (CCS), this study aimed to enhance understanding of the biophysical basis for long term chemotherapy induced peripheral neuropathy from different chemotherapy agents in CCS.Detailed cross-sectional neurophysiological examination, using median nerve axonal excitability studies, alongside clinical assessments, in 103 long term CCS (10.5 ± 0.6 years post-treatment).Cisplatin treated CCS (n = 16) demonstrated multiple sensory axonal excitability changes including increased threshold (P0.05), alterations in depolarising and hyperpolarising threshold electrotonus (P 0.05) and reduction in resting and minimum IV slope (P 0.01). Vincristine treated CCS (n = 73) were comparable to controls, except for prolonged distal motor latency (P = 0.001). No differences were seen in the non-neurotoxic chemotherapy group (n = 14). Abnormalities were more evident in the cisplatin subgroup with greater clinical neuropathy manifestations.Persistent long term changes in axonal biophysical properties vary with different chemotherapy agents, most evident after cisplatin exposure. Longitudinal studies of nerve function during chemotherapy treatment are required to further evaluate these differences and their mechanistic basis.This study provides a unique biophysical perspective for persistent cisplatin related neurotoxicity in children, previously under recognised.

Pharmacological strategies for chemotherapy-induced peripheral neurotoxicity (CIPN) are very limited. We systematically reviewed data on rehabilitation, exercise, physical therapy, and other physical non-pharmacological interventions and offered evidence-based recommendations for the prevention and treatment of CIPN. A literature search using PubMed, Web of Science and CINAHL was conducted from database inception until May 31st, 2021. 2791 records were title-abstract screened, 71 papers were full-text screened, 41 studies were included, 21 on prevention and 20 on treatment of CIPN. Treatment type, cancer type, chemotherapy compounds were heterogeneous, sample size was small (median: N = 34) and intention-to-treat analysis was lacking in 26/41 reports. Because of the methodological issues of included studies, the reviewed evidence should be considered as preliminary. Exercise, endurance, strength, balance, and sensorimotor training have been studied in low-to-moderate quality studies, while the evidence for other treatments is preliminary/inconclusive. We offer recommendation for the design of future trials on CIPN.

Background: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common complication of cancer treatment that produces functional disability. Increasingly, patient-reported outcome measures (PROMs) are used to assess CIPN, providing a broader symptom perspective than clinician-graded scales. Understanding when a reported change in CIPN symptoms meets the threshold for clinical significance is challenging. This study aimed to provide interpretation guidelines for validated CIPN PROMs, and thereby enable estimation of thresholds to identify clinically relevant symptoms. Methods: Patients commencing neurotoxic cancer treatments were assessed at 3 timepoints: baseline, midtreatment, and end-of-treatment. Trajectory of CIPN development was assessed by means of CIPN PROMs, EORTC Quality of Life – Chemotherapy-Induced Peripheral Neuropathy questionnaire (QLQ-CIPN20), and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group – Neurotoxicity questionnaire (FACT/GOG-NTX). Thresholds were estimated for CIPN PROMs using the NCI CTCAE sensory neuropathy scale as the clinical anchor by midtreatment and end-of-treatment. Patients were assigned to a clinical change group according to CIPN development: either no development; grade 1 neuropathy (minimally important difference [MID]); or grade 2 neuropathy (clinically important difference). Distribution-based estimates (SD, 0.5) were also evaluated as supportive evidence. Results: In total, 406 patients were recruited to the study, of whom 62% (n=199/320) developed CIPN by midtreatment and 80% (n=274/343) by end-of-treatment. Anchor-based MID estimates by midtreatment were 5.06 (95% CI, 4.26–5.86) for the QLQ-CIPN20 and 3.54 (95% CI, 2.87–4.20) for the FACT/GOG-NTX. End-of-treatment MIDs were estimated to be 7.32 (95% CI, 6.23–8.40) for the QLQ-CIPN20 and 4.84 (95% CI, 3.98–5.70) for the FACT/GOG-NTX. Distribution-based MID estimations yielded lower values than anchor-based methods, at 3.73 for the QLQ-CIPN20 and 2.64 for the FACT/GOG-NTX at midtreatment and 5.52 for the QLQ-CIPN20 and 3.64 for the FACT/GOG-NTX at end-of-treatment. Conclusions: Findings from the present series aid meaningful interpretation for commonly used validated CIPN PROMs and provide thresholds that serve as guidance on how to interpret score changes, which will be useful for design and evaluation of clinical trials and clinical practice.

Neurotoxic chemotherapy has been shown to be associated with reduced corneal nerves and ocular surface discomfort. Substance P is a neuropeptide expressed by sensory nerves including those in the densely innervated cornea. It is involved in both pain signaling and the regulation of epithelial and neural health. While its levels in tear fluids have been used as a neuropathic biomarker in diabetes, investigations of tear concentrations of substance P in chemotherapy-induced peripheral neuropathy have not been explored. The current cross-sectional study assessed substance P expression in tears of patients following neurotoxic chemotherapy treatment. Patients treated with paclitaxel (n = 35) or oxaliplatin (n = 30) 3-24 months prior to assessment were recruited along with healthy controls (n = 25). Flush tear collection, in-vivo corneal confocal microscopy and neurotoxicity assessments were also conducted. Enzyme-linked immunosorbent assays were used to measure substance P concentrations in collected tears, while total protein content (TPC) was measured with the bicinchoninic acid method (BCA). General linear models were used for statistical analysis. Substance P concentration was reduced in paclitaxel-treated patients [Median (Interquartile range, IQR): 1.11 (0.20-2.24) ng/ml)] compared to the oxaliplatin group [4.28 (1.01-10.73) ng/ml, p = 0.02]. Substance P expressed as a proportion of TPC was also lower in the paclitaxel group [0.00006 (0.00001-0.00010) %] compared to the oxaliplatin group [0.00018 (0.00008-0.00040) %, p = 0.005]. Substance P concentration and its percentage in TPC were also reduced in the paclitaxel group when compared to healthy controls [4.61 (1.35-18.51) ng/ml, p = 0.02; 0.00020 (0.00006-0.00060) %, p = 0.04, respectively]. Higher cumulative dose of paclitaxel was correlated with a reduction in substance P concentrations (r = -0.40, p = 0.037), however no associations were found with corneal nerve parameters or neuropathy severity (p 0.05). While these findings show evidence for the dysregulation of tear film substance P following paclitaxel treatment, longitudinal studies should be conducted to investigate how substance P levels in tears change during treatment.

Objective Gene silencing treatments for hereditary transthyretin amyloidosis (ATTRv) have recently been developed with dramatic improvements observed in patient outcomes. However, the optimal time to initiate treatment is not yet known. The aim of this study is to explore the pathophysiological progression of neuropathic features of ATTRv using nerve excitability and motor unit number estimation. Methods We prospectively recruited 14 symptomatic patients and 7 asymptomatic carriers and with varied TTR mutations and compared these to 21 healthy controls. Nerve excitability properties of ulnar motor and sensory axons, and ulnar-ADM motor unit number estimation was collected. Results ‘Fanning in’ of threshold electrotonus was observed in the motor axons of symptomatic ATTRv patients, suggestive of membrane depolarisation. Motor unit number estimation demonstrated a significant reduction in mean unit number between symptomatic and asymptomatic ATTRv patients (p =0.04), with declines seen according to FAP stage and PND score. Significantly increased hyperpolarising current/threshold gradients were seen in sensory axons between symptomatic ATTRv patients and healthy controls (p=0.002), suggesting that upregulation of inwardly rectifying conductance may underlie sensory symptoms and neuropathic pain in ATTRv amyloidosis. Conclusions These findings suggest that ulnar nerve excitability and motor unit number estimation could be used as a tool to identify early nerve disease in ATTRv and monitor progression.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a major dose-limiting side effect of many anti-cancer agents, including taxanes, platinums, vinca alkaloids, proteasome inhibitors, immunomodulatory drugs, and antibody-drug conjugates. The resultant symptoms often persist post treatment completion and continue to impact on long-term function and quality of life for cancer survivors. At present, dose reduction remains the only strategy to prevent severe neuropathy, often leading clinicians to the difficult decision of balancing maximal treatment exposure and minimal long-lasting side effects. This review examines the clinical presentations of CIPN with each class of neurotoxic treatment, describing signs, symptoms, and long-term outcomes. We provide an update on the proposed mechanisms of nerve damage and review current data on clinical and genetic risk factors contributing to CIPN development. We also examine recent areas of research in the treatment and prevention of CIPN, with specific focus on current clinical trials and consensus recommendations for CIPN management.

Background:Chemotherapy-induced peripheral neuropathy (CIPN) persists after treatment in up to 40% of cancer survivors and has been linked with increased balance deficits, disabilities, and fall occurrences. This study aimed to comprehensively assess the links between CIPN, balance deficits, and functional disability and to inform the development of clinical screening tools for patients at risk of these events.Patients and Methods:A total of 190 cancer survivors exposed to neurotoxic chemotherapies (age, 57 ± 13 years; average time from completion of neurotoxic therapy, 12 ± 11 months) attended a neurology research clinic for a single cross-sectional assessment of patient-reported and objective CIPN, standing balance in 4 conditions of increasing difficulty, and functional disability.Results:Most patients (68%) reported CIPN symptoms at assessment. Symptomatic patients displayed increased functional disability (F=39.4;PP2=0.46; patient-reported R2=0.49;P2=0.41; patient-reported R2=0.30;P2=0.46;P2=0.56;PConclusions:This study confirms links between increasing CIPN severity and increasing balance deficits and functional disability using comprehensive CIPN assessment methodology. The extent of balance deficits in patients with CIPN underscores the functional consequences of neurotoxicity. A 5-factor model provides a foundation for clinical screening tools to assess balance deficits and functional disability in patients exposed to neurotoxic chemotherapies.

Patient-reported outcomes (PRO) are becoming increasingly recognised as essential to comprehensively collect chemotherapy-induced peripheral neuropathy (CIPN) symptom information. This study aimed to evaluate the utility and feasibility of CIPN PRO assessment tools in a real-world clinical setting through investigation of the correlation of PRO with NCI-CTCAE assessments particularly in relation to cumulative dose of chemotherapy. Patients receiving oxaliplatin or paclitaxel chemotherapy in Sydney, Australia, completed a questionnaire containing standardised CIPN PRO assessments (EORTC CIPN-20, PRO-CTCAE) via tablet device. PRO assessment scores were correlated with NCI-CTCAE grade determined by nursing assessment and analysed with respect to cumulative dose of chemotherapy. There were 87 patients who completed a total of 145 questionnaires, 68 in patients receiving oxaliplatin and 77 in patients receiving paclitaxel. CIPN PRO scores were associated with NCI-CTCAE grade, for EORTC CIPN-20 (r2 = 0.19, p

Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) affects up to 40% of cancer survivors and is associated with functional deficits and an increased falls incidence. There are presently no strongly recommended treatment strategies for CIPN. The aim of this study was to evaluate the impact of a multimodal exercise intervention on CIPN symptoms and related functional deficits, as well as neurophysiologic parameters. Methods: All outcomes were assessed before and after an 8-week exercise intervention (3-weekly sessions) and preceding 8-week control period at baseline, pre-exercise and post-exercise. Outcome measures were objective and patient-reported CIPN, standing and dynamic balance, mobility, quality of life, and sensory and motor nerve excitability and conduction studies. Results: Twenty-nine cancer survivors (8 male, 21 female; mean age 61.6 ± 11.8 years) with CIPN symptoms affecting function completed all assessments. Objective and patient-reported CIPN, dynamic balance, standing balance in eyes open conditions, mobility and quality of life were improved from pre- to post-exercise (4.0 .21). No changes were observed in sensory or motor neurophysiologic parameters (p >.23). Conclusions: This study provides encouraging evidence of the rehabilitative potential of multimodal exercise for persisting CIPN in a post-treatment cohort. Large randomised controlled trials are justified to confirm observed benefits and determine the mechanisms and clinical significance.

ObjectiveThe aim of the study was to assess the utility of a novel amyotrophic lateral sclerosis (ALS) diagnostic index (ALSDI).MethodsA prospective multicenter study was undertaken on patients presenting with suspected ALS. The reference standard (Awaji criteria) was applied to all patients at recruitment. Patients were randomly assigned to a training (75%) and a test (25%) cohort. The ALSDI was developed in the training cohort and its diagnostic utility was subsequently assessed in the test cohort.ResultsA total of 407 patients were recruited, with 305 patients subsequently diagnosed with ALS and 102 with a non-ALS mimicking disorder. The ALSDI reliably differentiated ALS from neuromuscular disorders in the training cohort (area under the curve 0.92, 95% confidence interval 0.89–0.95), with ALSDI ≥4 exhibiting 81.6% sensitivity, 89.6% specificity, and 83.5% diagnostic accuracy. The ALSDI diagnostic utility was confirmed in the test cohort (area under the curve 0.90, 95% confidence interval 0.84–0.97), with ALSDI ≥4 exhibiting 83.3% sensitivity, 84% specificity, and 83.5% diagnostic accuracy. In addition, the diagnostic utility of the ALSDI was confirmed in patients who were Awaji negative at recruitment and in those exhibiting a predominantly lower motor neuron phenotype.ConclusionThe ALSDI reliably differentiates ALS from mimicking disorders at an early stage in the disease process.Classification of evidenceThis study provides Class I evidence that for patients with suspected ALS, the ALSDI distinguished ALS from neuromuscular mimicking disorders.

PURPOSE: Up to 40% of cancer patients treated with neurotoxic chemotherapies experience chemotherapy-induced peripheral neuropathy (CIPN). Currently, there is no gold standard assessment tool for CIPN and there is little information in the literature on patient preferences for such assessments. This study aims to address this gap by identifying the features of a CIPN assessment tool that cancer patients value. METHODS: An online discrete choice experiment (DCE) survey of neurotoxic chemotherapy-treated patients was implemented. Respondents completed 8 choice questions each. In each choice question, they chose between two hypothetical CIPN assessment tools, each described by six attributes: impact on quality of life; level of nerve damage detected; questionnaire length; physical tests involved; impact on clinic time; impact on care. RESULTS: The survey was completed by 117 respondents who had a range of cancers of which breast cancer was the most common. Respondents favoured an assessment tool that includes a physical test and that asks about impact on quality of life. Respondents were strongly opposed to clinicians, alone, deciding how the results of a CIPN assessment might influence their care especially their chemotherapy treatment. They were concerned about small changes in their CIPN, independent of clinical relevance. Respondents were willing to add half an hour to the usual clinic time to accommodate the CIPN assessment. CONCLUSION: The findings of this DCE will assist clinicians in choosing an assessment tool for CIPN that is satisfactory to both clinician and patient.

Background Paclitaxel treatment produces significant peripheral neuropathy, but the time course of neuropathy development and outcomes are unclear. Dose reduction is the only strategy to prevent neurotoxicity, however, the impact of dose-reduction on neuropathy outcomes remains unknown. This study aimed to prospectively evaluated neuropathy development from weekly paclitaxel treatment and evaluate the impact of dose-reduction on post-treatment neuropathy outcomes. Patients and Methods Breast cancer patients receiving paclitaxel (80mg/m2) weekly for 12-weeks were prospectively assessed using patient reported (Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity; FACTGOG-Ntx), clinical (Total Neuropathy Score clinical version; TNSc) and neurophysiological measures up to 12-months post completion. The impact of dose-reduction on post-treatment (3.6 ± 0.1 months) clinical and patient reported outcomes was evaluated in 105 weekly paclitaxel-treated patients. Results Significant neuropathy was present by 6-weeks across patient-reported, clinical, and objective neurophysiological assessments, increasing in prevalence and severity over the treatment course. Limited recovery occurred, with significant neuropathy being maintained up to 12 months (p Conclusion Weekly paclitaxel produces symptomatic and objective neuropathy early in the treatment course which can persist. Dose reduction does not necessarily lead to more favorable neuropathy outcomes, with individual risk factors likely important in addition to cumulative dose. Implications for Practice Weekly paclitaxel schedules are extensively used in breast cancer. Patients may develop symptomatic and objective neuropathy early in the treatment course, with these individuals requiring closer monitoring. Furthermore, neuropathy is a long-term sequela that may impact quality of life and require appropriate supportive services. Results suggest that dose reduction does not necessarily lead to better neuropathy outcomes. Understanding schedule-specific toxicity and risk factors for neuropathy will be critical to determining individualized treatment strategies and improving quality of life in breast cancer survivors.

Survival rates of cancer has improved with the development of anticancer drugs including systemic chemotherapeutic agents. However, long-lasting side effects could impact treated patients. Neurotoxic anticancer drugs are specific agents which cause chemotherapy-induced peripheral neuropathy (CIPN), a debilitating condition that severely deteriorates quality of life of cancer patients and survivors. The ocular surface is also prone to neurotoxicity but investigation into the effects of neurotoxic chemotherapy on the ocular surface has been more limited compared to other systemic etiologies such as diabetes. There is also no standardized protocol for CIPN diagnosis with an absence of a reliable, objective method of observing nerve damage structurally. As the cornea is the most densely innervated region of the body, researchers have started to focus on corneal neuropathic changes that are associated with neurotoxic chemotherapy treatment. In-vivo corneal confocal microscopy enables rapid and objective structural imaging of ocular surface microscopic structures such as corneal nerves, while esthesiometers provide means of functional assessment by examining corneal sensitivity. The current article explores the current guidelines and gaps in our knowledge of CIPN diagnosis and the potential role of in-vivo corneal confocal microscopy as a diagnostic or prognostic tool. Corneal neuropathic changes with neurotoxic anticancer drugs from animal research progressing through to human clinical studies are also discussed, with a focus on how these data inform our understanding of CIPN.

Chemotherapy-induced peripheral neuropathy (CIPN) is a highly prevalent and dose-limiting toxicity of many widely used chemotherapy regimens for the treatment of common cancers including lung, breast, prostate, gastrointestinal, and blood cancers. Symptoms include numbness, tingling, pain, and cramping in the hands and feet, as well as impaired balance and gait that collectively increase the risk of falls and compromise activities of daily living. Among the extremely limited treatment options for CIPN, exercise has emerged as a promising intervention based on a growing body of studies. Here, we review preclinical and clinical evidence on the use of exercise and related modalities for the prevention, treatment, and management of CIPN. We identified 2 studies in rodents plus 23 studies in humans, including 15 randomized studies (10 comparing exercise vs. non-exercise control), plus 19 pre-registered studies. The 10 randomized studies collectively suggest that exercise is beneficial for the treatment and prevention of CIPN with little to no side effects. However, these studies tend to be either rigorous yet small or large yet simple and exploratory, with no Phase III randomized studies published or pre-registered. Next, we discuss biological and psychosocial mechanisms by which exercise might exert its effects. We are optimistic for the trajectory of this work including seeking definitive answers to whether exercise is beneficial, what dose of exercise is needed, how it exerts its effects mechanistically, and how to best disseminate exercise to patients in the real world.

Chemotherapy-induced peripheral neuropathy (CIPN) is a highly prevalent, severe, and dose-limiting toxicity of several chemotherapy regimens for the treatment of multiple cancers including lung, breast, prostate, gastrointestinal, blood, and others. Patients with CIPN may experience numbness, tingling, pain, and cramping in the hands and feet, as well as problems with balance and gait that increase the risk of falls, reduce physical function, and hinder activities of daily living. At this point there are extremely limited treatment options for CIPN. Fortunately, a growing body of preliminary evidence suggests that exercise, physical therapy, and occupational therapy may help prevent, treat, and manage CIPN. Although there is not definitive evidence for the benefits of exercise on CIPN due to lack of Phase III randomized controlled trials, exercise is generally helpful in the cancer treatment continuum and poses low risk for patients with the help of a qualified professional. Therefore, we present clinical suggestions in the use of exercise for CIPN, including assessments of patient risk factors and other considerations. We conclude with an example exercise prescription that a qualified exercise professional can adapt for the specific needs, risks, and abilities of each individual patient.

IntroductionChemotherapy-induced peripheral neuropathy (CIPN) is a poorly understood side effect of many antineoplastic agents. Patients may experience sensory, motor and autonomic symptoms, negatively impacting quality of life. A gold-standard assessment methodology has yet to be determined, limiting efforts to identify effective agents to prevent or treat CIPN.Methods and analysisThis is a protocol of a systematic review of psychometric analyses of CIPN Clinician Reported Outcome Measures (ClinROM) and Patient-Reported Outcome Measures (PROM) among adults receiving, or who had previously received chemotherapy for cancer. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) quality ratings will be compared across studies and across ClinROMs and PROMs. Studies reporting psychometric proprieties of CIPN ClinROMs and/or PROMs among adults aged ≥18 years will be eligible for inclusion, with no restriction on language or year of publication. MEDLINE, Embase, CINAHL and APA PsycINFO databases will be searched from inception to 31 December 2021. Study characteristics, measurement properties of the ClinROMs and/or PROMs and the CIPN definitions will be extracted. The Synthesis Without Meta-analysis guideline will be used to guide data synthesis. The COSMIN Risk of Bias checklist will be used by two independent raters to assess methodological quality. Subgroup analyses by age, chemotherapy type, and study timing in relation to the delivery of chemotherapy will be carried out where data are available. An adapted version of Outcome Measures in Rheumatology filter 2.1 will be used to provide a best-evidence synthesis of CIPN ClinROMs and PROMs and to recommend a CIPN assessment tool for clinical and research settings.Ethics and disseminationEthical approval is not necessary to be obtained for this systematic review protocol. Results will be disseminated to clinicians and policy-makers by publication in a peer-reviewed journal and by presenting at relevant conferences.PROSPERO registration numberCRD42021278168.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect of neurotoxic cancer treatment, often impacting treatment tolerability and patient functioning. Factors predicting an individual's vulnerability for developing CIPN remain ill-defined. However, patient characteristics may contribute to CIPN risk, with obesity being a prevalent patient comorbidity. This study was aimed at evaluate if being overweight (BMI ≥ 25 kg/mThree hundred seventy-nine cancer survivors were assessed 5 (IQR 3-5) months post oxaliplatin or paclitaxel treatment via comprehensive patient-reported, clinical, and functional CIPN measures. Patients classified as overweight (BMI ≥ 25 kg/mMost patients reported CIPN symptoms (78%), with deficits evident on clinical examination. Overweight patients (n = 242, 63.8%) had significantly worse CIPN across symptomatic, objective clinical, and functional outcomes compared to those with a normal BMI (p.05). In multivariate linear regression, older age (B = .088, 95%CI = .053-.122, p.001), larger waist circumference (B = .030, 95%CI = .001-.059, p.05), and larger BSA (B = 2.41, 95%CI = .34-04.48, p.05) were associated with CIPN. Diabetes and BMI were significant on univariate analysis but not in the final models.Overweight patients represent a large proportion of cancer survivors who may be particularly impacted by CIPN, requiring closer monitoring and referral to supportive services. Accessible data such as a patient's general and abdominal obesity status may aid in formulating personalized treatment.Identifying routinely measured patient characteristics which may contribute to an individual's CIPN risk profile could assist with informing treatment decisions.

A syndrome of continuous muscle-fibre activity Authors: Isaacs H Year published: 1960 Number of times cited: 480 Six decades ago, Dr Hyam Isaacs reported a new clinical syndrome in the Journal of Neurology, Neurosurgery and Psychiatry .1 Isaacs used the term ‘syndrome of continuous muscle-fibre activity’ or the more descriptive ‘armadillo disease’ for the condition which now has become known as Isaacs syndrome or acquired autoimmune neuromyotonia. In his landmark series, Isaacs described a phenotype of progressive muscle stiffness, with widespread fasciculation leading to weakness. A key finding was continuous muscle activity on electromyography, occurring at rest and unaffected by local nerve blockade. The original report also detailed a number of unsuccessful treatment approaches, as well as an astonishing improvement produced by sodium diphenyl hydantoinate (phenytoin) treatment. Over the past 60 years, while we have learnt much more about the pathophysiology of Isaacs syndrome, there are still many elements that remain unresolved. A critical factor in understanding the Isaacs jigsaw puzzle came with the identification of the autoimmune basis for the disorder by the group led by John Newsom-Davis …

Introduction: The prevalence of early-onset type 2 diabetes (EOT2D; diagnosed with T2DM before 40 years old), has increased sharply in recent years. Peripheral neuropathy (DPN) is a common and debilitating complication associated with T2DM, and it is also common in EOT2D, even among adolescents. Nerve excitability studies (NES) examine nerve axonal ion channel function; and may allow early detection of axonal dysfunction. The aim of this study was to explore the differences in NES outcomes between a cohort with EOT2D and matched healthy controls. Method: Thirteen participants with EOT2D with no clinical evidence of DPN and 14 matched healthy control participants (HC) were included in the study. Nerve conduction studies (NCS) were used to assess amplitude, latency, and conduction velocity in sural (sensory) and peroneal (motor) nerves. Motor and sensory NES were conducted on the median nerve. NES parameters assessed included strength-duration time constant, threshold electrotonus (TE), current-threshold relationship and recovery cycle. HbA1c was measured. Independent sample t-tests were used to compare the group means ± standard deviations. Results: Participants with EOT2D (F:M 5:8, age 34.1±6.7yr, BMI 31.7±5.4kg∙m-2) differed from matched HC (F:M 6:8, age 32.5±5.1yr, BMI 29.6±4.4kg∙m-2) for HbA1c (EOT2D=6.8±1.0%, HC=5.2±0.3%, p Conclusion: Participants with EOT2D and no clinical evidence of DPN may demonstrate minor changes in sensory axonal function. Prospective studies are required to determine the clinical significance and progression of these changes. Disclosure Y. Gu: None. A.R. Harmer: None. S.M. Dennis: None. T. Li: None. H.C. Timmins: None. P. Loh: None. N. Garg: None. T. Dharmadasa: None. J. Wong: Advisory Panel; Self; Sanofi. Speaker’s Bureau; Self; AstraZeneca, Merck & Co., Inc. A. Gauld: None. P.A. Munoz: None. S.B. Park: None. Funding Diabetes Australia; Sydney Local Health District

Peripheral neuropathy is a commonly reported adverse effect of oxaliplatin treatment, representing a significant limitation which may require discontinuation of effective therapy. The present study investigated the neuroprotective potential of riluzole in patients undergoing oxaliplatin treatment in a randomised-controlled trial comparing riluzole and placebo-control.Fifty-two patients (17 females, 58.1 ± 12.7 years) receiving oxaliplatin treatment were randomised into either a treatment (50 mg riluzole) or lactose placebo group. The primary outcome measure was the total neuropathy score-reduced (TNSr). Secondary outcome measures include nerve excitability measures, 9-hole pegboard and FACT-GOG NTX questionnaire. Patients were assessed at baseline, pre-cycle 10 or 12, 4-week and 12-week post-treatment.Both the treatment and placebo groups developed objective and patient reported evidence of neurotoxicity over the course of oxaliplatin treatment, although there were no significant differences across any parameters between the two groups. However, across follow-up assessments, the treatment group experienced greater neuropathy, represented by a higher TNSr score at 4-week post-chemotherapy of 8.3 ± 2.7 compared with 4.6 ± 3.6 (p = 0.032) which was sustained at 12-week post-treatment (p = 0.089). Similarly, patients in the treatment group reported worse symptoms with a FACT-GOG NTX score of 37.4 ± 10.2 compared with 43.3 ± 7.4 (p = 0.02) in the placebo group at 4-week post-treatment.This study is the first to provide an objective clinical investigation of riluzole in oxaliplatin-induced peripheral neuropathy employing both functional and neurophysiological measures. Although the recruitment target was not reached, the results do not show any benefit of riluzole in minimising neuropathy and may suggest that riluzole worsens neuropathy associated with oxaliplatin treatment.