Chemotherapy-induced peripheral neuropathy in children - translation from adults, assessment strategies, disease burden, functional impact and neurophysiological insights

This thesis examined chemotherapy-induced peripheral neuropathy (CIPN) in childhood cancer survivors (CCS). CIPN assessment strategies in adults and systematic review of paediatric literature informed development of appropriate paediatric assessment protocols. Neurophysiological maturational profiles of peripheral nerves in normally developing children were elucidated using specialised axonal excitability studies. Finally, a large cross-sectional study comprehensively evaluated CIPN related long term disease burden, functional impact and peripheral nerve biophysical changes following exposure to neurotoxic chemotherapy. Neurotoxicity assessments in adult patients highlighted the importance of multimodal testing and standardised assessment packages for coherent, clinically meaningful results. Systematic review of paediatric literature demonstrated significant variability in reported rates of CIPN. There was some evidence that it can be long lasting with persistent functional deficits. Significant gaps in our knowledge of CIPN from commonly used paediatric chemotherapy agents, such as vincristine and cisplatin, were evident. Normal control studies demonstrated a stereotyped pattern of axonal maturation through childhood, adolescence and young adulthood enabling interpretation of neurophysiological changes in CCS. Cross-sectional assessment of 121 CCS revealed that clinical evidence of peripheral neuropathy was common, associated with reduction in lower limb sensory nerve amplitudes and concurrent deficits in manual dexterity, balance, distal sensation and quality of life. Long term neurotoxicity was more frequently associated with cisplatin treatment. A directed clinical assessment was identified as a good screening tool for peripheral neuropathy. Finally, axonal excitability studies demonstrated widespread changes in peripheral nerve biophysical properties in cisplatin-treated CCS, once again highlighting the greater neurotoxicity profile of cisplatin. In conclusion, paediatric CIPN assessment can be challenging and requires specialised, age-appropriate assessment strategies. Long term peripheral nerve abnormalities are common in CCS and different chemotherapy agents have different degrees of neurotoxicity. Protocols and control data established through this thesis will facilitate longitudinal studies essential for elucidating natural history and pathophysiology of CIPN and future translational research into neuroprotective strategies

The provision of written information and its effect on levels of pain and anxiety during electrodiagnostic studies: A randomised controlled trial

<div><p>Objective</p><p>The provision of written information is a low-cost and readily available intervention that has been found to reduce pain and anxiety in a variety of clinical settings. The current study was undertaken to determine if information provision may improve patients’ experience during conventional electrodiagnostic studies.</p><p>Methods</p><p>128 participants were recruited from a tertiary teaching hospital who were referred for electrodiagnostic studies. They were randomized into 2 groups where the intervention group was provided with written information about the electrodiagnostic testing. Patients were invited to complete a questionnaire that included pain and anxiety using a visual analogue scale (VAS) following the testing. All participants underwent nerve conduction studies (NCS) whilst a subset also underwent subsequent needle electromyography (EMG).</p><p>Results</p><p>Those who received information had a statistically significant lower perception of anxiety during NCS, whilst only females who received information had a statistically significant lower perception of pain to both NCS and EMG.</p><p>Conclusions</p><p>The provision of written information can reduce the degree of pain and anxiety experienced during electrodiagnostic testing.</p><p>Significance</p><p>Improving patient comfort and tolerability during electrodiagnostic testing may have practical implications towards more reliable and accurate results obtained from such investigations that may in turn improve patient diagnosis and management.</p></div

There was a significant difference observed in the effect of information provision on pain perceived during NCS in females but not in males.

<p>There was a significant difference observed in the effect of information provision on pain perceived during NCS in females but not in males.</p

Flowchart of inclusion and exclusion criteria to achieve final cohort.

<p>Flowchart of inclusion and exclusion criteria to achieve final cohort.</p

There were no significant differences observed in the effect of information provision on the level of anxiety perceived during needle EMG testing.

<p>There were no significant differences observed in the effect of information provision on the level of anxiety perceived during needle EMG testing.</p

There was a significant difference observed in the effect of information provision on pain perceived during needle EMG testing in females but not in males.

<p>There was a significant difference observed in the effect of information provision on pain perceived during needle EMG testing in females but not in males.</p

There was a significant difference observed in the effect of information provision on the level of anxiety perceived during NCS compared to those that were not provided with information.

<p>There was a significant difference observed in the effect of information provision on the level of anxiety perceived during NCS compared to those that were not provided with information.</p

Baseline characteristics of study population.

<p>Baseline characteristics of study population.</p

A De Novo Mutation in the Sodium-Activated Potassium Channel KCNT2 Alters Ion Selectivity and Causes Epileptic Encephalopathy

Summary: Early infantile epileptic encephalopathies (EOEE) are a debilitating spectrum of disorders associated with cognitive impairments. We present a clinical report of a KCNT2 mutation in an EOEE patient. The de novo heterozygous variant Phe240Leu SLICK was identified by exome sequencing and confirmed by Sanger sequencing. Phe240Leu rSlick and hSLICK channels were electrophysiologically, heterologously characterized to reveal three significant alterations to channel function. First, [Cl−]i sensitivity was reversed in Phe240Leu channels. Second, predominantly K+-selective WT channels were made to favor Na+ over K+ by Phe240Leu. Third, and consequent to altered ion selectivity, Phe240Leu channels had larger inward conductance. Further, rSlick channels induced membrane hyperexcitability when expressed in primary neurons, resembling the cellular seizure phenotype. Taken together, our results confirm that Phe240Leu is a “change-of-function” KCNT2 mutation, demonstrating unusual altered selectivity in KNa channels. These findings establish pathogenicity of the Phe240Leu KCNT2 mutation in the reported EOEE patient. : Gururaj et al. report a KCNT2 mutation in a patient with epileptic encephalopathy and employ electrophysiological analyses to establish channel properties that could underlie epileptogenesis: namely, inhibition by high [Cl−]i and loss of exclusive selectivity to K+. Furthermore, primary neurons expressing Ph240Leu display a hyperexcitable phenotype. Keywords: seizures, epileptic encephalopathy, ion channels, potassium channels, Slick, KCNT2, selectivity, Xenopus oocytes, Slack, KCNT

CSF neopterin, quinolinic acid and kynurenine/tryptophan ratio are biomarkers of active neuroinflammationResearch in context

Summary: Background: Defining the presence of acute and chronic brain inflammation remains a challenge to clinicians due to the heterogeneity of clinical presentations and aetiologies. However, defining the presence of neuroinflammation, and monitoring the effects of therapy is important given its reversible and potentially damaging nature. We investigated the utility of CSF metabolites in the diagnosis of primary neuroinflammatory disorders such as encephalitis and explored the potential pathogenic role of inflammation in epilepsy. Methods: Cerebrospinal fluid (CSF) collected from 341 paediatric patients (169 males, median age 5.8 years, range 0.1–17.1) were examined. The patients were separated into a primary inflammatory disorder group (n = 90) and epilepsy group (n = 80), who were compared with three control groups including neurogenetic and structural (n = 76), neurodevelopmental disorders, psychiatric and functional neurological disorders (n = 63), and headache (n = 32). Findings: There were statistically significant increases of CSF neopterin, kynurenine, quinolinic acid and kynurenine/tryptophan ratio (KYN/TRP) in the inflammation group compared to all control groups (all p < 0.0003). As biomarkers, at thresholds with 95% specificity, CSF neopterin had the best sensitivity for defining neuroinflammation (82%, CI 73–89), then quinolinic acid (57%, CI 47–67), KYN/TRP ratio (47%, CI 36–56) and kynurenine (37%, CI 28–48). CSF pleocytosis had sensitivity of 53%, CI 42–64). The area under the receiver operating characteristic curve (ROC AUC) of CSF neopterin (94.4% CI 91.0–97.7%) was superior to that of CSF pleocytosis (84.9% CI 79.5–90.4%) (p = 0.005). CSF kynurenic acid/kynurenine ratio (KYNA/KYN) was statistically decreased in the epilepsy group compared to all control groups (all p ≤ 0.0003), which was evident in most epilepsy subgroups. Interpretation: Here we show that CSF neopterin, kynurenine, quinolinic acid and KYN/TRP are useful diagnostic and monitoring biomarkers of neuroinflammation. These findings provide biological insights into the role of inflammatory metabolism in neurological disorders and provide diagnostic and therapeutic opportunities for improved management of neurological diseases. Funding: Financial support for the study was granted by Dale NHMRC Investigator grant APP1193648, University of Sydney, Petre Foundation, Cerebral Palsy Alliance and Department of Biochemistry at the Children’s Hospital at Westmead. Prof Guillemin is funded by NHMRC Investigator grant APP 1176660 and Macquarie University