Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies.

Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders exclusively or predominantly affecting the sensory and autonomic neurons. Due to the rarity of the diseases and findings based mainly on single case reports or small case series, knowledge about these disorders is limited. Here, we describe the molecular workup of a large international cohort of CIP/HSAN patients including patients from normally under-represented countries. We identify 80 previously unreported pathogenic or likely pathogenic variants in a total of 73 families in the >20 known CIP/HSAN-associated genes. The data expand the spectrum of disease-relevant alterations in CIP/HSAN, including novel variants in previously rarely recognized entities such as ATL3-, FLVCR1- and NGF-associated neuropathies and previously under-recognized mutation types such as larger deletions. In silico predictions, heterologous expression studies, segregation analyses and metabolic tests helped to overcome limitations of current variant classification schemes that often fail to categorize a variant as disease-related or benign. The study sheds light on the genetic causes and disease-relevant changes within individual genes in CIP/HSAN. This is becoming increasingly important with emerging clinical trials investigating subtype or gene-specific treatment strategies.

Clinical Profile and Treatment Outcomes of Hypermanganesemia with Dystonia 1 and 2 among 27 Indian Children.

Background: Hypermanganesemia with dystonia 1 and 2 (HMNDYT1 and 2) are rare, inherited disorders of manganese transport. Objectives: We aimed to describe clinical, laboratory features, and outcomes among children with HMNDYT. Methods: We conducted a retrospective multicenter study involving tertiary centers across India. We enrolled children between 1 month to 18 years of age with genetically confirmed/clinically probable HMNDYT. Clinical, laboratory profile, genetic testing, treatment details, and outcomes scored by treating physicians on a Likert scale were recorded. Results: We enrolled 27 children (19 girls). Fourteen harbored SLC30A10 mutations; nine had SLC39A14 mutations. The SLC39A14 cohort had lower median age at onset (1.3 [interquartile range (IQR), 0.7-5.5] years) versus SLC30A10 cohort (2.0 [IQR, 1.5-5.1] years). The most frequent neurological features were dystonia (100%; n = 27), gait abnormality (77.7%; n = 21), falls (66.7%; n = 18), and parkinsonism (59.3%; n = 16). Median serum manganese (Mn) levels among SLC39A14 (44.9 [IQR, 27.3-147.7] mcg/L) cohort were higher than SLC30A10 (29.4 [17.1-42.0] mcg/L); median hemoglobin was higher in SLC30A10 (16.3 [IQR, 15.2-17.5] g/dL) versus SLC39A14 cohort (12.5 [8.8-13.2] g/dL). Hepatic involvement and polycythaemia were observed exclusively in SLC30A10 variants. A total of 26/27 children underwent chelation with disodium calcium edetate. Nine demonstrated some improvement, three stabilized, two had marked improvement, and one had normalization. Children with SLC39A14 mutations had poorer response. Two children died and nine were lost to follow-up. Conclusions: We found female predominance. Children with SLC39A14 mutations presented at younger age and responded less favorably to chelation compared to SLC30A10 mutations. There is emerging need to better define management strategies, especially in low resource settings.

Correlation of Preoperative Functional Magnetic Resonance Imaging (fMRI) with Intraoperative Cortical Stimulation in Surgeries of Eloquent Brain Lesions.

Background: Direct Cortical Stimulation (DCS) represents the gold standard for mapping of eloquent brain cortex. However, DCS is an invasive and time-consuming procedure. fMRI has become a useful tool to delineate motor and sensory eloquent cortex from the areas of planned neurosurgical resection. In our study, we will be studying the reliability of preoperative imaging when compared with the intraoperative DCS. Objectives: The aim of this study was to assess the reliability of fMRI by comparing it with DCS. Methods and Materials: Thirty patients with eloquent cortex lesions were admitted. Preoperative fMRI sequences were loaded into a neuro-navigational system. Intraoperative motor mapping was done by DCS. The location of all cortical stimulated points was correlated with the cortical functional structures. Based on it, specificity, sensitivity, positive predictive value, negative predictive value of fMRI was calculated. Preoperative and postoperative Karnofsky score and MRC grading was then noted. Results: Concordance between fMRI and DCS was noted in 26 cases. Overall mean sensitivity, specificity, positive and negative predictive value of fMRI as compared to DCS was 95%, 92.48%, 85.56%, and 96.08%, respectively. Preoperative and Postoperative Karnofsky score stayed same in most of the cases [25/30]. Conclusions: DCS remains the gold standard for mapping eloquent cortex in-spite of its invasiveness, side effects such as seizures and cost concerns. Although fMRI cannot replace DCS, it can guide and increase the efficacy in resection, select high-risk patients for intraoperative monitoring, help in preoperative stratification of risk counseling and preservation of neurological status in eloquent brain lesions.

Leukocyte Phosphomannomutase and Phosphomannose Isomerase Activity in an Indian Cohort.

Advances in molecular sequencing technology has increased the diagnostic yield for Congenital disorder of glycosylation (CDG). However, novel variants or those of uncertain significance (vus) often pose a challenge and in such cases confirmed diagnosis can be warranted through enzyme analysis of these defects. We thus, aimed to optimize leukocyte-based enzyme assays for first two enzymes involved in N-glycosylation pathway i.e. Phosphomannomutase (PMM) and Phosphomannose isomerase (MPI). Study population comprised of 50 healthy non-alcoholic adults and 20 pediatric controls. Leukocyte enzyme activity was measured by monitoring the conversion of NADP to NADPH at 340 nm. The conditions were optimized and precision was assessed for both low and normal activity leukocyte controls. Enzyme activities for PMM and MPI in healthy individuals were measured in the range 1.6-3.9 and 7-20 nmol/min/mg protein respectively and did not vary with age and gender. The precision for both PMM and MPI showed %CV of 19.9 and 19.8 respectively. The enzyme activity in leukocyte pellet was found to be stable for up to 9 months when stored at -80 °C. The enzyme assays are optimized for PMM and MPI and can be used for evaluation of CDG patients in India.

Analytical Method Validation for Estimation of Neurotransmitters (Biogenic Monoamines) from Cerebrospinal Fluid Using High Performance Liquid Chromatography.

Biogenic amine neurotransmitters such as serotonin and dopamine are essential for signaling in both central and peripheral nervous system. Their metabolism is a multistep pathway and any defect in this results in alteration in metabolites of serotonin 5-Hydroxyindole acetic acid (5HIAA) and dopamine homovanillic acid (HVA) and 3-O-Methyl Dopa (3-OMD). Estimation of these metabolites in cerebrospinal fluid (CSF) assists in diagnosis of neurotransmitter defects. Their estimation is technically demanding and is currently available only in referral centers. We aimed to optimize a method for analysis of 5HIAA, HVA and 3-OMD. A high performance liquid chromatography (HPLC) method with electro chemical detector (ECD) was standardized for estimation. Analysis for method validation, reference range verification and clinical correlation was performed. Linearity obtained for 5-HIAA, HVA and 3-OMD was 65.35-2615.0 nmoles/l, 68.62-2745.0 nmoles/l and 236.5-4730.0 nmoles/l respectively. The coefficient of variation for internal quality controls ranged from 5 to 14% and the external proficiency testing samples (n = 16) were within peer group range. CSF metabolite levels of samples for reference range analysis overlapped with age matched ranges reported in literature. Among the 40 suspected patients analyzed for clinical testing four were found to have a neurotransmitter defect. These patients were then confirmed with molecular testing and clinical correlation. The method is validated and can be adapted in a clinical laboratory with analytical competence in HPLC.

Mobile media exposure and use in children aged zero to five years with diagnosed neurodevelopmental disability.

OBJECTIVE: The present study was conducted to determine the extent of exposure to and use of mobile devices by children (aged 0-60 months) with a diagnosed neurodevelopmental disability. DESIGN: A self-report survey-based design was employed. SETTING: Questionnaires were administered at a tertiary care hospital in Mumbai, India. PARTICIPANTS: The study included a convenience sample of 423 children with a neurodevelopmental disability (aged 0-60 months). The self-report survey was administered to the parents of the children. RESULTS: Analyses showed that 92.7% (n = 392) of all respondents have smartphones. 61% (n = 258) of the respondents stated that their children used mobile devices before 2 years of age. 58% (n = 246) of the parents gave children devices while feeding. A statistically significant difference was found in the mobile media usage between groups of children with different diagnoses (p < 0.001). Children diagnosed with ASD appeared to spend the largest amount of time on mobile media (m = 180.44 mins), as compared to children included with other diagnoses. Of the diagnosed children, only 13.4% (n = 57) of parents were informed about the possible negative effects of media use by their paediatricians. CONCLUSION: The results suggest premature mobile media habits, frequent use and lack of awareness about the effects of mobile media usage among children diagnosed with a neurodevelopmental disability. We suggest there is a need to update recommendations for caregivers on the use of mobile media by young children with disability.Implications for rehabilitationThe usage and consequences of mobile media use differ based on the type of neurodevelopmental disorder diagnosis. Parents of children with neurodevelopmental disorders often use mobile media as a distraction while engaging in various activities themselves, this information helps identify times at which mobile media might be purposefully used by parents as distractorsThere is an urgent need for clinical guidelines regarding mobile media usage among young children with neurodevelopmental disorders.

Normative Values for Auditory Brainstem Responses and Wave V Thresholds in Indian Neonates and Infants.

Click-evoked auditory-brainstem-response (ABR) is widely used for hearing screening in neonates and infants. However, their normative values are based on small studies. This retrospective study was done at a tertiary-care centre where click-ABR based screening is done in all newborns. ABR records (Nihon-Kohden machine, model MEB-9400K) of 420 healthy neonates (preterm 75; full-term 32) and infants (113) done over a period 4 years (2014-2018) were analysed retrospectively. Sick neonates and those with Wave V threshold > 40 dbnHL were excluded. Infants were divided into four groups based on post-conceptual age, Group A (75): 34-36 weeks; Group B (44): 37-40weeks; Group C (188):41 weeks-1 month; and Group D (113): 1-6months. The mean absolute latencies for wave I, wave III, and wave V varied from 1.45-1.56 milliseconds (ms), 4.14-4.37 ms, and 6.36-6.81 ms respectively. Interpeak latencies for I-V and I-III varied from 4.91 ms to 5.22 ms and 2.69 ms to 2.81 ms respectively. Older infants had lower absolute and interpeak latencies. Late preterm babies were not different from term babies suggesting early maturation of brainstem pathways.

Profile of Children With Tuberculosis in a Pediatric Intensive Care Unit in Mumbai.

OBJECTIVE: This study was done to analyze the profile of confirmed pediatric TB patients seen in an intensive care setting. METHODS: Data of all children admitted in our PICU with bacteriologically proven tuberculosis (smear, culture, poly-merase chain reaction, genotypic testing or Pyrosequencing) between January, 2007 and December, 2019 were retrieved. Drug resistance was classified as per World Health Organization definitions. RESULTS: 59 children (28 boys) met the inclusion criteria (median (IQR) age 8 (4,13) years). About a third (22/59) had past history of treatment with antituberculosis drugs. The indications for admission to PICU were monitoring and management of neurological status in 31 children, post procedure monitoring in 20 children and respiratory failure in 8 children. Severe ARDS was seen in 2 children. Out of 37 children with neuro-tuberculosis, 19 children had TB in additional sites, and 9 children died. Sample positivity rate for CSF culture was 66%. Drug sensitivity testing (DST) of positive culture was done in 35 cases and showed multidrug resistance in 4 children, pre-XDR (extreme drug resistance) in 10 and XDR in 5 children. CONCLUSION: Neurotuberculosis was the commonest reason for admission to PICU. Concerted efforts should be made to obtain samples for culture and drug sensitivity testing in critically ill children with tuberculosis.

Current practices in epilepsy monitoring units (EMU) in India.

AIM: As an initial step to develop guidelines for epilepsy monitoring units (EMUs) appropriate for developing countries, we inquired the existing practices in EMUs in India. METHODS: After checking for the content and face validity as well for clarity, we sent a 52-item online non-anonymized questionnaire to all the 52 EMUs in India. RESULTS: The questionnaire was completed by 51 of the 52 EMUs (98% response rate). The majority of the EMUs are located in major cities and 51% are located in non-governmental corporate hospitals. There are total of 122 prolonged video-EEG monitoring (PVEM) beds in India and 70% EMUs have ≤2 beds. Approximately two-thirds of the EMUs have defined protocols for pre-procedure consent and risk assessment, management of seizure clusters and status epilepticus, continuous observation of patients, and peri­ictal testing. Only one-third of the EMUs have protocols for management of post-ictal psychosis, anti-suffocation pillows, and protected environment within bathrooms. The waiting period for PVEM is more (49.9 ± 101 vs. 4.9 ± 10.9 days; p = 0.04) and mean cost for 3-day PVEM is less (INR 8311 ± 9021 vs. 30,371 ± 17,563; p <0.0001) in public as compared to private hospitals. There was a negative correlation between cost of PVEM and the waiting period (r=-0.386; p = 0.01). Safety practices are similar in public and private hospitals. CONCLUSIONS: Although practices in EMUs in India vary widely, they are comparable to those in developed countries. India has severe shortage of EMUs and long waiting lists for affordable PVEM.

Cerebrospinal Fluid Biogenic Monoamine Analysis for Diagnosis of Primary Neurotransmitter Disorders.

Biogenic amine neurotransmitters metabolism is a multistep pathway with pterin and pyridoxal phosphate (vitamin B6) as cofactors. A defect in biogenic amine and cofactor metabolism and vesicular transporters result in a primary neurotransmitter disorders. These are a well-recognized groups of inherited disorders and often present with features overlapping with other neurological conditions. Their diagnosis is made by analysis of biogenic amine metabolites in cerebrospinal fluid (CSF) and other body fluids and respective enzyme assays. Many of these disorders are treatable and deficits can be reverted by timely intervention. CSF biogenic amine or cofactor metabolite analysis is one of the primary indicators of a neurotransmitter disorder. In this paper, 3 cases are reported-2 of cofactor deficiency and 1 with enzyme deficiency wherein biogenic amine estimation has assisted in diagnosis.

'To reveal or to conceal'- Disclosure strategies in parents of children with epilepsy in India.

PURPOSE: Disclosure of epilepsy is a relevant but under-researched topic in epilepsy research. This study was done to assess the disclosure strategies in parents of CWE in a developing country with conservative culture. The study also assessed the influence of demographic factors and seizure characteristics on the choice of disclosure. Enablers and barriers behind disclosure and the consequences after disclosure were evaluated. METHODS: A cross-sectional analytical, self-report survey was done in 284 parents of CWE with the help of a semi-structured questionnaire over a 7-month period in the paediatric epilepsy clinic. Disclosure was considered present if epilepsy was revealed to two or more of the five target groups (extended family, school, friends, neighbours, and peers of children). Separate set of questions was given for reasons behind their choice and consequences after disclosure. For continuous variables, unpaired T test or Mann - Whitney U test between group and for categorized variables, Pearson's Chi square test or Fisher's exact test was used. RESULTS: 92.96 % of 284 subjects disclosed their child's epilepsy while 7.04% concealed. Demographic factors and seizure characteristics did not influence the disclosure choice. Most parents revealed to the extended family followed by teachers. Type of seizure was the commonest information revealed. The main reason behind disclosure was better acceptance of the child followed by safety while main barrier was considering epilepsy as private grief. 92.8% felt their children were better accepted after disclosure. CONCLUSION: Disclosure practices have improved in parents of CWE in India and well-being and safety of the child has overridden the fear of stigma and discrimination. This could be the first major step to bring epilepsy out of the shadows at national and global levels.

Prolonged Fever: An Atypical Presentation in MOG Antibody-Associated Disorders.

BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelinating disorders (MOGAD) are increasingly being recognized in the pediatric age group. Over time, unusual presentations have expanded the clinical presentation. We report 12 cases of MOGAD where prolonged fever (PF) was an important part of the symptom complex during the course of the illness. METHODS: After initial recognition of this atypical clinical presentation, more patients were recruited over 2 years and followed up prospectively. RESULTS: Eight of twelve patients had no clinical/imaging evidence of demyelination until much later in the course. Three clinical presentations recognized were fever of unknown origin (4 of 12), aseptic meningitis (4 of 12), and PF seen concurrently with established acute demyelination syndrome (4 of 12). Leukocytosis, raised inflammatory markers, and cerebrospinal fluid pleocytosis were almost universal. The first two presentations frequently caused diagnostic confusion, as MOGAD was not considered until several weeks after disease onset. The third group was more a therapeutic conundrum on how to manage the PF. Early seizures without encephalopathy were not uncommon and were probably independent of the later-appearing demyelination. CONCLUSIONS: This case series highlights PF as an important component of the pediatric MOGAD symptom complex. MOGAD could be considered in the differential diagnosis of these clinical presentations.

Paroxysmal Nonepileptic Events in a Pediatric Epilepsy Clinic.

AIMS: We aimed to study the frequency, age, and gender distribution of paroxysmal nonepileptic events (PNEs) in children referred to epilepsy clinic with the diagnosis of epilepsy. We also evaluated the therapeutic implications of correct diagnosis and co-existence of true epilepsy in this population. SETTINGS AND DESIGN: All new patients below 18 years attending the Pediatric epilepsy out-patient clinic of PD Hinduja hospital over 6 months were evaluated. MATERIALS AND METHODS: Patients with history of paroxysmal events characterized by abrupt changes in consciousness or behavior or movement were included. They were assessed on description of events aided by recorded videos. If the diagnosis was not confirmed by this preliminary evaluation, further investigations were advised. STATISTICAL ANALYSIS USED: Chi-square/Fisher's exact test was used to analyze differences between categorical variables and Kruskal-Wallis test between continuous variables. The data were analyzed by SAS University Edition. All significance tests were two-tailed with α <0.05. RESULTS: Two hundred new patients presenting with paroxysmal events were enrolled over 6 months. After diagnoses, 19% of these children had PNEs, 80% had epileptic events, and 1% remained undiagnosed. Common nonepileptic events seen were physiological in patients below 5 years and psychogenic in older children. Thirty-four percent of patients with PNEs were on anti-epileptic drugs (AEDs). After confirming nonepileptic attacks, only 2.6% patients needed AEDs for coexisting epilepsy which was statistically significant (P < 0.001) change in treatment. CONCLUSIONS: Epilepsy mimics are common in children and are often misdiagnosed causing undue stress. Correct diagnosis leads to a drastic change in management like withdrawal of drugs, commencing new treatment if needed, and appropriate referrals.

Establishing criteria for pediatric epilepsy surgery center levels of care: Report from the ILAE Pediatric Epilepsy Surgery Task Force.

Presurgical evaluation and surgery in the pediatric age group are unique in challenges related to caring for the very young, range of etiologies, choice of appropriate investigations, and surgical procedures. Accepted standards that define the criteria for levels of presurgical evaluation and epilepsy surgery care do not exist. Through a modified Delphi process involving 61 centers with experience in pediatric epilepsy surgery across 20 countries, including low-middle- to high-income countries, we established consensus for two levels of care. Levels were based on age, etiology, complexity of presurgical evaluation, and surgical procedure. Competencies were assigned to the levels of care relating to personnel, technology, and facilities. Criteria were established when consensus was reached (≥75% agreement). Level 1 care consists of children age 9 years and older, with discrete lesions including hippocampal sclerosis, undergoing lobectomy or lesionectomy, preferably on the cerebral convexity and not close to eloquent cortex, by a team including a pediatric epileptologist, pediatric neurosurgeon, and pediatric neuroradiologist with access to video-electroencephalography and 1.5-T magnetic resonance imaging (MRI). Level 2 care, also encompassing Level 1 care, occurs across the age span and range of etiologies (including tuberous sclerosis complex, Sturge-Weber syndrome, hypothalamic hamartoma) associated with MRI lesions that may be ill-defined, multilobar, hemispheric, or multifocal, and includes children with normal MRI or foci in/abutting eloquent cortex. Available Level 2 technologies includes 3-T MRI, other advanced magnetic resonance technology including functional MRI and diffusion tensor imaging (tractography), positron emission tomography and/or single photon emission computed tomography, source localization with electroencephalography or magnetoencephalography, and the ability to perform intra- or extraoperative invasive monitoring and functional mapping, by a large multidisciplinary team with pediatric expertise in epilepsy, neurophysiology, neuroradiology, epilepsy neurosurgery, neuropsychology, anesthesia, neurocritical care, psychiatry, and nursing. Levels of care will improve safety and outcomes for pediatric epilepsy surgery and provide standards for personnel and technology to achieve these levels.

Posterior Reversible Encephalopathy Syndrome: An Expanding Phenotype.

How to cite this article: Udani V. Posterior Reversible Encephalopathy Syndrome: An Expanding Phenotype. Indian J Crit Care Med 2020;24(12):1163-1164.

Association of Child Neurology-Indian Epilepsy Society Consensus Document on Parental Counseling of Children with Epilepsy.

When a child is diagnosed with epilepsy, counseling regarding the same is done by the treating doctor. Most parents are frightened and have poor knowledge about epilepsy. Therapeutic advice including drug dosage, administration and side effects takes up the major part of physician's time, thereby neglecting important issues like home seizure management, follow up and others. These lacunae in knowledge require systematic patient and family education. To address these issues, an expert group meeting of pediatric neurologists and epileptologists in India along with social workers/epilepsy educators, legal experts, parents, and teachers was held. The various aspects regarding parental counseling in children with epilepsy were discussed and a consensus document was formulated. Here authors present the group consensus statement on counseling parents and caregivers of children with epilepsy. This document is intended to help physicians and pediatricians counsel the families when a child is diagnosed with epilepsy.

Paroxysmal Asymmetric Dystonic Arm Posturing-A Less Recognized but Characteristic Manifestation of ATP1A3-related disease.

BACKGROUND: ATP1A3 mutations cause a wide clinical spectrum, and are one of the "commoner rare diseases". METHODS: Case series of four patients with ATP1A3 mutations. RESULTS: The patients displayed characteristic episodes of dystonic arm posturing, involving a dystonic, flexed arm held in front of the body or close to the body, but with the hand raised upwards. Other attacks manifested with arm extension, either beside the body or reaching upwards. Dystonic posturing occurred paroxysmally, with no neurological signs between attacks, or combined with other signs like chorea, ataxia, and hypotonia. CONCLUSIONS: While previous diagnostic criteria have not included paroxysmal or episodic dystonia, recent expert consensus has proposed to include alternating or paroxysmal dystonia as major feature calling for ATP1A3 genetic testing. Attacks of marked arm flexion posturing, either paroxysmal or as episodic exacerbation of mild pre-existent dystonia, are a characteristic clue to ATP1A3-related disease.