Tejaswi Kandula

Clinical Characteristics and Functional Motor Outcomes of Enterovirus 71 Neurological Disease in Children

IMPORTANCE Enterovirus 71 (EV71) causes a spectrum of neurological complications with significant morbidity and mortality. Further understanding of the characteristics of EV71-related neurological disease, factors related to outcome, and potential responsiveness to treatments is important in developing therapeutic guidelines. OBJECTIVE To further characterize EV71-related neurological disease and neurological outcome in children. DESIGN, SETTING, AND PARTICIPANTS Prospective 2-hospital (The Sydney Childrens Hospitals Network) inpatient study of 61 children with enterovirus-related neurological disease during a 2013 outbreak of EV71 in Sydney, Australia. The dates of our analysis were January 1, to June 30, 2013. MAIN OUTCOMES AND MEASURES Clinical, neuroimaging, laboratory, and pathological characteristics, together with treatment administered and functional motor outcomes, were assessed. RESULTS Among 61 patients, there were 4 precipitous deaths (7%), despite resuscitation at presentation. Among 57 surviving patients, the age range was 0.3 to 5.2 years (median age, 1.5 years), and 36 (63%) were male. Fever (100% [57 of 57]), myoclonic jerks (86% [49 of 57]), ataxia (54% [29 of 54]), and vomiting (54% [29 of 54]) were common initial clinical manifestations. In 57 surviving patients, EV71 neurological disease included encephalomyelitis in 23 (40%), brainstem encephalitis in 20 (35%), encephalitis in 6 (11%), acute flaccid paralysis in 4 (7%), and autonomic dysregulation with pulmonary edema in 4 (7%). Enterovirus RNA was more commonly identified in feces (42 of 44 [95%]), rectal swabs (35 of 37 [95%]), and throat swabs (33 of 39 [85%]) rather than in cerebrospinal fluid (10 of 41 [24%]). Magnetic resonance imaging revealed characteristic increased T2-weighted signal in the dorsal pons and spinal cord. All 4 patients with pulmonary edema (severe disease) demonstrated dorsal brainstem restricted diffusion (odds ratio, 2; 95% CI, 1-4; P = .001). Brainstem or motor dysfunction had resolved in 44 of 57 (77%) at 2 months and in 51 of 57 (90%) at 12 months. Focal paresis was evident in 23 of 57 (40%) at presentation and was the most common persisting clinical and functional problem at 12 months (observed in 5 of 6 patients), with 1 patient also requiring invasive ventilation. Patients initially seen with acute flaccid paralysis or pulmonary edema had significantly greater frequencies of motor dysfunction at follow-up compared with patients initially seen with other syndromes (odds ratio, 15; 95% CI, 3-79; P < .001). CONCLUSIONS AND RELEVANCE Enterovirus 71 may cause serious neurological disease in young patients. The distinct clinicoradiological syndromes, predominantly within the spinal cord and brainstem, enable rapid recognition within evolving outbreaks. Long-term functional neurological morbidity is associated with paresis linked to involvement of gray matter in the brainstem or spinal cord.

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.

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.

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

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.

Integrating exome sequencing into a diagnostic pathway for epileptic encephalopathy: Evidence of clinical utility and cost effectiveness

Epileptic encephalopathies are a devastating group of neurological conditions in which etiological diagnosis can alter management and clinical outcome. Exome sequencing and gene panel testing can improve diagnostic yield but there is no cost‐effectiveness analysis of their use or consensus on how to best integrate these tests into clinical diagnostic pathways.

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.

Cobalamin E defect, a rare inborn error of vitamin B12 metabolism: Value of early diagnosis and treatment

Cobalamin and its metabolites play a crucial role in DNA synthesis and cellular energy metabolism. Disorders of cobalamin metabolism are rare, autosomal recessive, conditions that present with neurological dysfunction of varying severity. We report a child with cobalamin E defect presenting in early infancy with vertical nystagmus, developmental delay, deceleration in head growth, status epilepticus and leukoencephalopathy, with only mild haematological abnormalities. Resolution of seizures and subsequent improvement in development and head growth was observed following early treatment with parenteral hydroxocobalamin, betaine, folate and methionine, emphasising the importance of early diagnosis and treatment in these conditions.

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 &mgr;V; 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.

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

Objective 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. Methods 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). Results 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. Conclusions The provision of written information can reduce the degree of pain and anxiety experienced during electrodiagnostic testing. Significance 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.

Multimodal quantitative examination of nerve function in colorectal cancer patients prior to chemotherapy: Baseline Nerve Function in Colorectal Cancer

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