Prospective assessment of vincristine-induced peripheral neuropathy in paediatric acute lymphoblastic leukemia.

OBJECTIVE: Vincristine is a mainstay treatment for paediatric cancers, particularly acute lymphoblastic leukemia (ALL), with common toxicity including vincristine-induced peripheral neuropathy (VIPN). The present study comprehensively assessed VIPN outcomes in patients receiving vincristine treatment for ALL. METHODS: Children diagnosed with ALL commencing vincristine treatment were prospectively evaluated (baseline, post-induction, pre-reinduction, post-reinduction, follow-up). VIPN was examined clinically using the Balis sensory/motor scale, neurophysiologically using axonal excitability techniques and quality-of-life using Pediatric Quality of Life Inventory. RESULTS: Thirty-one patients were recruited to this study (age = 6.8 ± 4.4; 61.3% female). Incidence of motor VIPN (motor Balis grade > 0) symptoms were higher than sensory VIPN (sensory Balis grade > 0) at post-induction (92.0% vs 36.0%) and post-reinduction (81.8% vs 22.7%) vincristine treatment. Neurophysiological assessment also demonstrated greater change in motor axonal excitability parameters compared to sensory parameters including changes in depolarising threshold electrotonus (P < 0.0125), superexcitability and subexcitability parameters (all P < 0.0125). Follow-up assessment demonstrated persisting VIPN symptoms with reduced quality-of-life scores compared to baseline. CONCLUSIONS: Clinical and neurophysiological evaluation of VIPN suggests vincristine produces a motor-prominent sensorimotor neuropathy in children which persisted at follow-up. SIGNIFICANCE: VIPN signs and symptoms develop early in the treatment course, in line with axonal excitability profiles. Early detection of significant nerve changes may support timely implementation of neuroprotection strategies.

Chemotherapy-Induced Peripheral Neuropathy in Long-term Survivors of Childhood Cancer: Clinical, Neurophysiological, Functional, and Patient-Reported Outcomes.

Importance: In light of the excellent long-term survival of childhood cancer patients, it is imperative to screen for factors affecting health, function, and quality of life in long-term survivors. Objective: To comprehensively assess chemotherapy-induced peripheral neuropathy in childhood cancer survivors to define disease burden and functional effect and to inform screening recommendations. Design, Setting, and Participants: In this cross-sectional observational study, cancer survivors who were treated with chemotherapy for extracranial malignancy before age 17 years were recruited consecutively between April 2015 and December 2016 from a single tertiary hospital-based comprehensive cancer survivorship clinic and compared with healthy age-matched controls. Investigators were blinded to the type of chemotherapy. A total of 169 patients met inclusion criteria, of whom 48 (28.4%) were unable to be contacted or declined participation. Exposures: Chemotherapy agents known to be toxic to peripheral nerves. Main Outcomes and Measures: The clinical peripheral neurological assessment using the Total Neuropathy Score was compared between recipients of different neurotoxic chemotherapy agents and control participants and was correlated with neurophysiological, functional, and patient-reported outcome measures. Results: Of the 121 childhood cancer survivors included in this study, 65 (53.7%) were male, and the cohort underwent neurotoxicity assessments at a median (range) age of 16 (7-47) years, a median (range) 8.5 (1.5-29) years after treatment completion. Vinca alkaloids and platinum compounds were the main neurotoxic agents. Clinical abnormalities consistent with peripheral neuropathy were common, seen in 53 of 100 participants (53.0%) treated with neurotoxic chemotherapy (mean Total Neuropathy Score increase, 2.1; 95% CI, 1.4-2.9; P < .001), and were associated with lower limb predominant sensory axonal neuropathy (mean amplitude reduction, 5.8 µV; 95% CI, 2.8-8.8; P < .001). Functional deficits were seen in manual dexterity, distal sensation, and balance. Patient-reported outcomes demonstrating reduction in global quality of life and physical functioning were associated with the Total Neuropathy Score. Cisplatin produced long-term neurotoxicity more frequently than vinca alkaloids. Conclusions and Relevance: Clinical abnormalities attributable to peripheral neuropathy were common in childhood cancer survivors and persisted long term, with concurrent deficits in patient-reported outcomes. Both the type of neurotoxic agent and a targeted clinical neurological assessment are important considerations when screening survivors for long-term neuropathy. Further development of peripheral neuropathy-specific pediatric assessment tools will aid research into neuroprotective and rehabilitative strategies.

Multimodal quantitative examination of nerve function in colorectal cancer patients prior to chemotherapy.

INTRODUCTION: Given recent findings of subclinical sensory deficits in colorectal cancer patients before oxaliplatin treatment, in the current study we aimed to identify evidence of subclinical peripheral neuropathy on multimodal testing before chemotherapy commencement. METHODS: Clinical, functional, and neurophysiological assessments were undertaken in 93 colorectal cancer patients before chemotherapy. RESULTS: There was no neurophysiological evidence of neuropathy, with 92 of 93 sural sensory values within normative reference values for age and no significant abnormalities detected in nerve conduction or nerve excitability studies. Clinical neurological assessment revealed 75.9% of patients with no signs or symptoms, 10.3% with reduction in distal vibration or pinprick sensitivity, and 6.9% with reduction in ankle reflexes only. There was no difference in manual dexterity (using the 9-hole peg-board test) compared with normative data. DISCUSSION: The present study has established a low likelihood of significant distal symmetrical polyneuropathy in colorectal cancer patients before initiation of chemotherapy. Muscle Nerve 57: 615-621, 2018.

Neurophysiological and clinical outcomes in chemotherapy-induced neuropathy in cancer.

Chemotherapy induced peripheral neuropathy (CIPN) is a significant toxicity of cancer treatment, with the potential to affect long-term function and quality of life in cancer survivors. There remains a lack of consensus around optimal assessment techniques. While current approaches to CIPN assessment are focused on clinical grading scales, it is becoming increasingly evident that a more comprehensive multimodal assessment package is necessary to accurately characterise the impact of CIPN as well as gauge the utility of neuroprotective mechanisms. Neurophysiological techniques provide objective biomarkers and may enable early detection of toxicity while patient reported outcomes are necessary to determine the significance of symptoms to individual patients. In addition to providing an objective assessment, clinical neurophysiological techniques provide important insights into the contributory pathophysiological mechanisms of CIPN with different chemotherapy agents. There is a paucity of implementation of these techniques in the clinical trial setting. The present Review aims to facilitate the use of neurophysiological studies as part of comprehensive assessment packages for the monitoring of CIPN by summarising current understanding of neurophysiological changes that underlie the development of neuropathy, clinical presentations and patient reported outcomes as well as advantages and limitations of current techniques for the neurophysiological assessment of CIPN.

Pediatric chemotherapy induced peripheral neuropathy: A systematic review of current knowledge.

BACKGROUND: The dramatic increase in the number of childhood cancer survivors over the last 60years has made monitoring and minimising long term side effects of cancer treatment increasingly important. Chemotherapy induced peripheral neuropathy (CIPN) has been described with many commonly used chemotherapy agents. This article provides a critical overview of pediatric CIPN, its incidence, clinical manifestations, late effects, and recent advances in understanding of risk factors and pharmacogenomics as well as evaluating current assessment strategies and treatment approaches. METHODS: Neurotoxicity data was systematically collated from Medline, Embase and Pubmed and analysed for quality, relevance and originality in three stages prior to inclusion. Quality scoring was done using the QUALSYST assessment tool. RESULTS: A total of 61 studies met inclusion criteria. Peripheral neuropathy is common and may be long lasting with characteristics specific to each chemotherapy agent. There is significant variability in reported incidence and natural history, related to challenges in clinical assessment and diagnosis. Emerging risk factors for CIPN include treatment factors such as dose, duration and concurrent medication and patient factors such as age and inherited susceptibilities. Recent identification of individual genetic variations has advanced understanding of pathomechanisms and may direct future treatment approaches. CONCLUSION: While these studies guide suggestions for current clinical practice, further systematic research with development of strategies for amelioration and prevention of CIPN is necessary. Standardised assessment protocols and objective outcomes measures of CIPN applicable to patients of different ages are critical to enabling the development of novel treatments and facilitation of future clinical trials and treatment individualisation.

Asparagine Synthetase Deficiency causes reduced proliferation of cells under conditions of limited asparagine.

Asparagine Synthetase Deficiency is a recently described cause of profound intellectual disability, marked progressive cerebral atrophy and variable seizure disorder. To date there has been limited functional data explaining the underlying pathophysiology. We report a new case with compound heterozygous mutations in the ASNS gene (NM_183356.3:c. [866G>C]; [1010C>T]). Both variants alter evolutionarily conserved amino acids and were predicted to be pathogenic based on in silico protein modelling that suggests disruption of the critical ATP binding site of the ASNS enzyme. In patient fibroblasts, ASNS expression as well as protein and mRNA stability are not affected by these variants. However, there is markedly reduced proliferation of patient fibroblasts when cultured in asparagine-limited growth medium, compared to parental and wild type fibroblasts. Restricting asparagine replicates the physiology within the blood-brain-barrier, with limited transfer of dietary derived asparagine, resulting in reliance of neuronal cells on intracellular asparagine synthesis by the ASNS enzyme. These functional studies offer insight into the underlying pathophysiology of the dramatic progressive cerebral atrophy associated with Asparagine Synthetase Deficiency.

Isolated ventriculomegaly on prenatal ultrasound: what does fetal MRI add?

INTRODUCTION: Cerebral ventriculomegaly is one of the most commonly detected fetal anomalies at the midtrimester ultrasound. Current evidence suggests that magnetic resonance imaging (MRI) is indicated when the isolated ventriculomegaly (IVM) on ultrasound is severe (>15 mm), but there is less agreement when IVM is mild or moderate (10-15 mm). The current study aimed to determine the frequency and nature of additional findings on MRI in IVM and their relationship to the severity of VM and gestational age. METHODS: Data were gathered prospectively from all pregnant women with ultrasound-diagnosed IVM referred for MRI between November 2006 and February 2013. Cases with IVM and no other suspected cranial abnormality on a tertiary ultrasound performed at our institution, at or after 20 weeks gestation, were included. RESULTS: Of the 59 fetuses with unilateral or bilateral IVM, additional findings were seen on MRI in 10 cases (17%) and half of these findings were identified in fetuses with mild IVM. Five of 40 (12.5%) fetuses with mild IVM had additional findings and 3/5 (60%) were potentially clinically significant. No additional abnormalities were identified in fetuses less than or equal to 24 weeks gestation with mild or moderate IVM. There was no statistically significant relationship between gestational age and additional findings on MRI in mild IVM. Callosal and septum pellucidum lesions, periventricular abnormalities and malformations of cortical development accounted for all of the significant additional findings. CONCLUSION: This study helps to inform referral of pregnant women with a fetus who has IVM for prenatal MRI.