Scalable Transdiagnostic Early Assessment of Mental Health (STREAM): a study protocol.

INTRODUCTION: Early childhood development forms the foundations for functioning later in life. Thus, accurate monitoring of developmental trajectories is critical. However, such monitoring often relies on time-intensive assessments which necessitate administration by skilled professionals. This difficulty is exacerbated in low-resource settings where such professionals are predominantly concentrated in urban and often private clinics, making them inaccessible to many. This geographic and economic inaccessibility contributes to a significant 'detection gap' where many children who might benefit from support remain undetected. The Scalable Transdiagnostic Early Assessment of Mental Health (STREAM) project aims to bridge this gap by developing an open-source, scalable, tablet-based platform administered by non-specialist workers to assess motor, social and cognitive developmental status. The goal is to deploy STREAM through public health initiatives, maximising opportunities for effective early interventions. METHODS AND ANALYSIS: The STREAM project will enrol and assess 4000 children aged 0-6 years from Malawi (n=2000) and India (n=2000). It integrates three established developmental assessment tools measuring motor, social and cognitive functioning using gamified tasks, observation checklists, parent-report and audio-video recordings. Domain scores for motor, social and cognitive functioning will be developed and assessed for their validity and reliability. These domain scores will then be used to construct age-adjusted developmental reference curves. ETHICS AND DISSEMINATION: Ethical approval has been obtained from local review boards at each site (India: Sangath Institutional Review Board; All India Institute of Medical Science (AIIMS) Ethics Committee; Indian Council of Medical Research-Health Ministry Screening Committee; Malawi: College of Medicine Research and Ethics Committee; Malawi Ministry of Health-Blantyre District Health Office). The study adheres to Good Clinical Practice standards and the ethical guidelines of the 6th (2008) Declaration of Helsinki. Findings from STREAM will be disseminated to participating families, healthcare professionals, policymakers, educators and researchers, at local, national and international levels through meetings, academic journals and conferences.

Efficacy of verbal suggestion, verbal suggestion with a tuning fork, and verbal suggestion with a cotton swab for inducing the paroxysmal event during video-EEG recording in children with suspected psychogenic nonepileptic seizures.

INTRODUCTION: Video-electroencephalogram (EEG) with suggestion is widely considered the gold standard for diagnosing psychogenic nonepileptic seizures (PNES). However, ethical concerns and uncertainties persist regarding the most minimally invasive and least deceptive suggestion approach. MATERIALS AND METHODS: In an open-label randomized controlled trial, we evaluated the effectiveness of three suggestion methods (verbal suggestion, verbal suggestion with a tuning fork, and verbal suggestion with a cotton swab) during short-term video-EEG (STVEEG) recordings to induce PNES in children aged 5-18 years. If the paroxysmal event couldn't be elicited with the assigned method, alternative techniques were employed. RESULTS: Out of 97 initially screened children, 75 were enrolled, with 25 in each group. The efficacy of all three suggestion methods was comparable in reproducing paroxysmal events (success rate of 16/25, 17/25 and 17/25 in verbal suggestion only, verbal suggestion with tuning fork and sterile cotton swab group respectively, p = 0.83) and the time required for induction (median of 2, 3 and 3 min respectively, p = 0.21). After trying alternative methods, 20 %, 12 %, and 12 % more patients in these three groups, respectively, were able to reproduce the paroxysmal event, with the differences not reaching statistical significance (p = 0.74). The assigned induction method or the success/failure of event reproduction did not significantly impact clinical outcomes at 12 weeks, and none of the patients in whom PNES could not be reproduced during STVEEG were later found to have an organic cause. Only the presence of psychiatric comorbidity independently predicted successful event reproduction during STVEEG, with statistical significance even after adjusting for other variables (p = 0.03). CONCLUSION: The efficacy of verbal suggestion alone in inducing paroxysmal nonepileptic seizures is on par with using a tuning fork or cotton swab in conjunction with verbal suggestion during STVEEG.

Novel Therapeutic Strategies of Non-Invasive Brain Stimulation and Nanomedicine in Pediatric Cerebral Palsy Patients.

Infantile central palsy (CP) is caused due to damage to the immature developing brain usually before birth, leading to altered topography and biochemical milieu. CP is a life-limiting disorder, which causes changes in sensory, motor, cognitive, and behavioral functioning. Understanding its pathophysiology is complex, and current therapeutic modalities, oral medication, surgical treatment, physical therapy, and rehabilitation provide minimal relief. As the brain is plastic, it has an inherent capacity to adapt to altered activity; thus, non-invasive brain stimulation (NIBS) strategies, like repetitive transcranial magnetic stimulation, which can modulate the neuronal activity and its function, may lead to recovery in CP patients. Further, in recent years, nanomedicine has shown a promising approach in pre-clinical studies for the treatment of central nervous system disorder because it can cross the blood-brain barrier, improve penetration, and provide sustained release of the drug. The review focuses on the principles and mechanisms of various NIBS techniques used in CP. We have also contemplated the effect of rehabilitation and nanomedicine in CP children, which will definitely lead to advancing our diagnostic as well as therapeutic abilities, in a vulnerable group of little ones.

Evaluation of Infantile Brachial Plexopathy Using 3T MRI and High-Resolution Ultrasound: Experience From a Tertiary Care Centre.

BACKGROUND: Currently, clinical assessment is the main tool for the evaluation of brachial plexus injury, complemented by electrophysiologic studies (EPS), and imaging studies whenever available. Imaging plays an important role as it enables the differentiation of pre-ganglionic and postganglionic injuries, and adds objectivity to presurgical evaluation. OBJECTIVES: The primary objective was to evaluate the utility of magnetic resonance imaging (MRI) and high-resolution ultrasonography (USG) in the localization and characterization of brachial plexus injury in infants. MATERIALS AND METHODS: In this prospective study, 34 infants with signs and symptoms of brachial plexus injury were evaluated by clinical examination, EPS, MRI, and USG. Imaging findings were correlated with intraoperative findings in infants who underwent surgical management. The association between EPS and MRI findings, and USG and MRI findings were assessed using Fisher's exact test. Semi-quantitative subjective analysis of various MRI sequences was done as well. RESULTS: The most common findings of preganglionic injury and postganglionic injury, in our study, were pseudomeningocele and nerve thickening, respectively. MRI detection of injuries had a significant association with EPS findings. All MRI-detected injuries had a muscle power of grade 3 or less. muscle. Three-dimensional (3D) short tau inversion recovery (STIR) sequence was found to be superior for detecting postganglionic injuries (P < 0.05). CONCLUSION: Imaging studies enable localization of the site of injury, determining the extent, and nature/morphology of injury. The gamut of findings obtained from MRI is far wider compared to that from USG. USG can be used as the first-line screening investigation.

NDUFV1-Related Mitochondrial Complex-1 Disorders: A Retrospective Case Series and Literature Review.

BACKGROUND: Pathogenic variants in the NDUFV1 gene disrupt mitochondrial complex I, leading to neuroregression with leukoencephalopathy and basal ganglia involvement on neuroimaging. This study aims to provide a concise review on NDUFV1-related disorders while adding the largest cohort from a single center to the existing literature. METHODS: We retrospectively collected genetically proven cases of NDUFV1 pathogenic variants from our center over the last decade and explored reported instances in existing literature. Magnetic resonance imaging (MRI) patterns observed in these patients were split into three types-Leigh (putamen, basal ganglia, thalamus, and brainstem involvement), mitochondrial leukodystrophy (ML) (cerebral white matter involvement with cystic cavitations), and mixed (both). RESULTS: Analysis included 44 children (seven from our center and 37 from literature). The most prevalent comorbidities were hypertonia, ocular abnormalities, feeding issues, and hypotonia at onset. Children with the Leigh-type MRI pattern exhibited significantly higher rates of breathing difficulties, whereas those with a mixed phenotype had a higher prevalence of dystonia. The c.1156C>T variant in exon 8 of the NDUFV1 gene was the most common variant among individuals of Asian ethnicity and is predominantly associated with irritability and dystonia. Seizures and Leigh pattern of MRI of the brain was found to be less commonly associated with this variant. Higher rate of mortality was observed in children with Leigh-type pattern on brain MRI and those who did not receive mitochondrial cocktail. CONCLUSIONS: MRI phenotyping might help predict outcome. Appropriate and timely treatment with mitochondrial cocktail may reduce the probability of death and may positively impact the long-term outcomes, regardless of the genetic variant or age of onset.

Prevalence of Sensory Processing Deficits in Children with Spastic Cerebral Palsy - An Indian Caregiver's Perspective.

This study aims to analyze the prevalence and patterns of sensory processing deficits (SPD) in Indian children with spastic cerebral palsy (CP) using child sensory profile-2 (CSP-2) caregiver questionnaire. The authors surveyed 230 caregivers of children aged 3 to 14 y with spastic CP, using CSP-2. The difference in prevalence and distribution of SPDs among the CP subtypes and Gross Motor Function Classification System (GMFCS) levels was done. Overall prevalence of "Definite" (>2 SD) SPDs was 83%. Forty-seven percent had definite SPDs in more than one sensory subsection. Prevalence of definite SPDs was similar among the spastic CP subtypes. "Conduct" domain had more affection among hemiplegics and quadriplegics. "Avoiding" pattern was observed more in quadriplegics and "Seeking" pattern was observed less in diplegics. Severe GMFCS levels had more definite sensory processing deficits. SPDs are highly prevalent in children with spastic CP with unique patterns of affection among the spastic CP subtypes.

Disseminated phaeohyphomycosis due to Cladophialophora bantiana in an immunocompetent child.

A 3-year-old boy presented with acute headache, vomiting and right focal clonic seizures without history of fever, joint pain or altered sensorium. Neuroimaging showed multifocal contrast enhancing lesions with significant perilesional edema. CECT chest and abdomen showed multiple variable sized nodules in the lungs and hypodense lesion in liver with mesenteric lymphadenopathy. There was persistent eosinophilia with maximum upto 35 %. Liver biopsy and brain biopsy revealed Cladophialophora bantiana. He was treated with IV liposomal amphotericin and voriconazole for 6 weeks with repeat neuroimaging showing more than 50 % resolution of the intracranial lesions. He was transitioned to oral combination of flucytosine and voriconazole. At 14 months follow-up, he remained symptom free with complete radiological resolution of the lesions and no eosinophilia. High suspicion, an aggressive approach in obtaining microbiological diagnosis and timely combination antifungal therapy may give satisfactory outcome without surgery.

Efficacy of daily versus intermittent low glycemic index therapy diet in children with drug-resistant epilepsy: A randomized controlled trial.

INTRODUCTION: The predominant reason for the discontinuation of low glycemic index therapy (LGIT) in children with epilepsy is the dietary restrictions imposed therein. This trial intended to compare the efficacy of daily and intermittent LGIT in children with drug-resistant epilepsy (DRE). METHODS: This study was performed between February 2018 and January 2019 to compare the efficacy of daily and intermittent LGIT in children aged 1-15 years with DRE following 24 weeks of dietary therapy. Compliance, the difficulty faced by caregivers, adverse effects, impact on behaviour, and social quotient in both arms were compared. Children in the intermittent LGIT arm received a liberalized diet for two days every week (Saturday and Sunday), which also allowed medium glycemic index foods. Carbohydrate calories were allowed up to 20% of the total caloric requirement in the liberalized diet, as compared to only 10% in standard LGIT. RESULTS: Out of 132 children randomized (66 in each group), 122 completed 24 weeks follow up. Mean weekly seizure frequency reduction at 24 weeks in the intermittent LGIT group was comparable with that of the daily LGIT group in both intention-to-treat (ITT) and per-protocol analysis (-50.95%± 22.34% vs -47.16%± 23.41%, p=0.36 in ITT and -53.88%±20.54% vs -49.20%±21.87%, p=0.23) in per-protocol analysis for intermittent and daily LGIT group respectively). The proportion with ≥50% reduction in seizure frequency was also comparable between both groups (p=0.73 and 0.56 in ITT and per protocol analysis respectively). The proportion of patients with adverse events and satisfactory compliance rate also had a trend towards favoring intermittent LGIT (p=0.06 and 0.51, respectively), while caregiver difficulty was lower with intermittent LGIT (p=0.001). CONCLUSIONS: Intermittent LGIT is comparable to daily LGIT in terms of seizure frequency reduction after 24 weeks of dietary therapy. TRIAL REGISTRATION: ClinicalTrials.gov (Registration number- NCT03464487, https://clinicaltrials.gov/ct2/show/NCT03464487).

Locked down-locked in: experiences of families of young children with autism spectrum disorders in Delhi, India.

Introduction: The onset of the COVID-19 pandemic and subsequent lockdowns in March 2020 disrupted the lives of families across India. The lockdown related restrictions brought forth a multitude of challenges including loss of employment, social isolation, school closures and financial burdens. Specifically, it also resulted in the restriction of health-care services for children with neurodevelopmental disabilities. Methods: This qualitative study was conducted as a part of a larger trial in India to understand the experiences of families of young children with autism during the pandemic. In-depth interviews were carried out with 14 caregivers residing in New Delhi, India. Results: Our findings identified pandemic and lockdown's universal impacts on family life and financial stability stemming from job loss, business closure, and salary deductions, affecting quality of life of families. Furthermore, COVID-19 pandemic's impact on autistic children was evident through limited access to essential services and financial challenges related service interruptions even after resumption of services. The lockdown's novelty also affected children's behavior, with both challenging behavioral changes and positive impacts. Primary caregivers, predominantly mothers, assumed additional responsibilities in household tasks, schooling, and therapy administration. While some these experiences were universally experienced, a few of these improved outcomes for autistic children. Despite challenges, parents expressed gratitude for their family's safety and well-being during the difficult time. Discussions: These findings inform service provision for vulnerable families and offer implications for designing interventions such as credit schemes for families, guidance and resources for establishing and maintaining routines of children with autism, adopting flexible and adaptable approaches to service delivery, and special provisions for children with autism to be able to maintain their routines outside of home. Furthermore, the study highlights the need for comprehensive support, including educational resources and stress management counselling to empower parents in supporting essential care and routines for their children during such unprecedented times.

Whole genome sequencing followed by functional analysis of genomic deletion encompassing ERCC8 and NDUFAF2 genes in a non-consanguineous Indian family reveals dysfunctional mitochondrial bioenergetics leading to infant mortality.

Genomic investigations on an infant who presented with a putative mitochondrial disorder led to identification of compound heterozygous deletion with an overlapping region of ∼142 kb encompassing two nuclear encoded genes namely ERCC8 and NDUFAF2. Investigations on fetal-derived fibroblast culture demonstrated impaired bioenergetics and mitochondrial dysfunction, which explains the phenotype and observed infant mortality in the present study. The genetic findings from this study extended the utility of whole-genome sequencing as it led to development of a MLPA-based assay for carrier screening in the extended family and the prenatal testing aiding in the birth of two healthy children.

Rare paediatric disorders in Indian healthcare settings with focus on neuromuscular disorders: Diagnostic and management challenges.

Rare diseases form the bulk of the financial expenditure of any developing or developed economy. Among the various rare diseases, paediatric neuromuscular disorders form a major portion, with a worldwide survey estimating a prevalence of 1 in 3500 individuals. In a lower middle-income country (LMIC) like India, malnutrition still accounts for most of the under-5 mortality. However, the economic burden of rare paediatric neuromuscular disorders cannot be underestimated. The treating physician should have a basic understanding of how to approach a child presenting with weakness and how to utilise the available tests which are affordable in an LMIC setting. History and examination still form the core, and with new diagnostic methods like nextgeneration sequencing, more and more rare disorders are getting diagnosed. It is important for the treating physician to know about basic supportive care, recent advancements, and available treatment options for these conditions. With exciting new treatment options being available for these disorders, the perception of these diseases as being not treatable is gradually changing. This review aims to be of guidance to clinicians from an LMIC setting like India and to empower them to manage such rare paediatric neuromuscular disorders.

Child Neurology: Allgrove Syndrome: An Intriguing Etiology of Motor Neuron Disease in Children

Motor neuron diseases are a rare group of neurodegenerative disorders with considerable phenotypic heterogeneity and a multitude of etiologies in the pediatric population. In this study, we report 2 unrelated adolescents (a boy and a girl) who presented with 4-6 years of progressive difficulty in walking, thinning of limbs, and gradually progressive darkening of the skin. Examination revealed generalized hyperpigmentation of skin and features suggestive of motor neuron involvement such as tongue atrophy, wasting of distal extremities, and brisk deep tendon reflexes. On detailed exploration for systemic involvement, history of dysphagia, inability to produce tears, and Addisonian crises were evident. An etiologic diagnosis of Allgrove syndrome, which is characterized by a triad of achalasia, alacrimia, and adrenal insufficiency was considered. Next-generation sequencing revealed pathogenic variants in the AAAS gene, confirming the diagnosis. Steroid replacement therapy was initiated along with relevant multidisciplinary referrals. The disease stabilized in the boy and a significant improvement was noted in the girl. These cases highlight the value of non-neurologic cues in navigating the etiologic complexities of motor neuron diseases in children and adolescents. It is imperative for neurologists to develop awareness of the diverse neurologic manifestations associated with Allgrove syndrome because they are often the first to be approached. A multidisciplinary team of experts including neurologists, endocrinologists, gastroenterologists, ophthalmologists, and dermatologists is essential for planning comprehensive care for these patients.