Acute Encephalitis Syndrome in Children and Adolescents: A Five-Year Descriptive Study From South India.

OBJECTIVE: Acute encephalitis syndrome (AES) in children results in significant neurocognitive deficits or mortality. It is pertinent to study the AES patterns periodically to identify the changes in the etiological trends and outcomes. Our objective was to find the etiological agents of AES, mode of diagnosis, treatment given, and outcomes. METHODS: We reviewed the electronic records of children aged 1 month to 15 years who were admitted with AES in our centre from January 2015 to December 2019. We analyzed the the clinical, laboratory, and radiological profile of these children and adolescents in relation to their outcome. Poor outcome was defined as death, discharge against medical advice with neurological deficits, or Glasgow Outcome Score Extended (GOS-E) d≤ 5 at the time of discharge. RESULTS: Among 250 patients admitted with AES during the study period, a definitive etiological diagnosis was established in 56.4% of children (30.4% viral, 22% bacterial). Scrub typhus (11.2%) and dengue (9%) were the two most common underlying illnesses. Serology helped in clinching the diagnosis in 30% of children. A surge in AES cases in the post-monsoon season was observed in our cohort. Third-generation cephalosporin drugs (85.7%) and acyclovir (77.7%) were the most commonly used empiric antimicrobial drugs. About one-third of children (n = 80) had a poor outcome. GCS ≤ 8 at presentation and requirement for invasive ventilation were found to be significant predictors of poor outcome. CONCLUSION: A definitive diagnosis was obtained in about half of the children with AES. Viral (30.4%) and rickettsial infections (22%) were the common etiologies identified. Poor outcome was observed in 32% of patients.

KCTD7-related progressive myoclonic epilepsy: Report of 42 cases and review of literature.

OBJECTIVE: KCTD7-related progressive myoclonic epilepsy (PME) is a rare autosomal-recessive disorder. This study aimed to describe the clinical details and genetic variants in a large international cohort. METHODS: Families with molecularly confirmed diagnoses of KCTD7-related PME were identified through international collaboration. Furthermore, a systematic review was done to identify previously reported cases. Salient demographic, epilepsy, treatment, genetic testing, electroencephalographic (EEG), and imaging-related variables were collected and summarized. RESULTS: Forty-two patients (36 families) were included. The median age at first seizure was 14 months (interquartile range = 11.75-22.5). Myoclonic seizures were frequently the first seizure type noted (n = 18, 43.9%). EEG and brain magnetic resonance imaging findings were variable. Many patients exhibited delayed development with subsequent progressive regression (n = 16, 38.1%). Twenty-one cases with genetic testing available (55%) had previously reported variants in KCTD7, and 17 cases (45%) had novel variants in KCTD7 gene. Six patients died in the cohort (age range = 1.5-21 years). The systematic review identified 23 eligible studies and further identified 59 previously reported cases of KCTD7-related disorders from the literature. The phenotype for the majority of the reported cases was consistent with a PME (n = 52, 88%). Other reported phenotypes in the literature included opsoclonus myoclonus ataxia syndrome (n = 2), myoclonus dystonia (n = 2), and neuronal ceroid lipofuscinosis (n = 3). Eight published cases died over time (14%, age range = 3-18 years). SIGNIFICANCE: This study cohort and systematic review consolidated the phenotypic spectrum and natural history of KCTD7-related disorders. Early onset drug-resistant epilepsy, relentless neuroregression, and severe neurological sequalae were common. Better understanding of the natural history may help future clinical trials.

The barriers, facilitators and association of vaccine certificates on COVID-19 vaccine uptake: a scoping review.

BACKGROUND: Globally, COVID-19 vaccines have proven to be instrumental for promoting population health by reducing illness from SARS-CoV-2. Vaccine certificates emerged as a potentially promising solution for encouraging vaccination and facilitating the safe reopening of society, however, they were controversial due to criticisms of infringing upon individual rights. While there is extensive literature describing the ethical, legal, and public health implications of vaccine certificates, there is currently a gap in knowledge about the association of vaccine certificates on vaccine uptake during the COVID-19 pandemic and barriers and facilitators to their use. OBJECTIVES: The objectives of this scoping review are to (i) describe the existing literature on the association of vaccine certificates on the rates of COVID-19 vaccine uptake across several countries and (ii) describe the intrinsic and extrinsic barriers or facilitators that moderate this relationship. METHODS: We conducted a scoping review based on PRISMA Extension for Scoping Reviews (PRSIMA-ScR) guidelines. We searched three bibliographic databases (APA PsychInfo, Embase Classic + Embase, OVID-Medline) and preprint severs during the first week of July 2023. Three reviewers independently screened the studies based on pre-specified eligibility criteria and performed quality assessments of the primary literature and data extraction. RESULTS: Sixteen studies met the inclusion criteria. 14 or these were surveys and 2 were modelling studies. The majority documented that vaccine certificates were significantly associated with increased rates of COVID-19 vaccine uptake (n = 12), motivated by factors such as travel/employer requirements, influence from the government/peers, and trust in the safety, efficacy, and science behind COVID-19 vaccines. Three studies had non-significant or mixed findings. Only one study found a significant decrease in COVID-19 vaccine uptake, motivated by pervasive distrust in the QR code-based system of digital vaccine certificates in Russia. Quality of survey studies was generally high. CONCLUSION: Our findings provide insights into the existing literature on vaccine certificates association with vaccine uptake in several different jurisdictions and barriers and facilitators to their uptake. This information can be used to guide future examinations of the implementation of vaccine certificates and more effective implementations.

Landscape of genetic infantile epileptic spasms syndrome-A multicenter cohort of 124 children from India.

OBJECTIVE: Literature on the genotypic spectrum of Infantile Epileptic Spasms Syndrome (IESS) in children is scarce in developing countries. This multicentre collaboration evaluated the genotypic and phenotypic landscape of genetic IESS in Indian children. METHODS: Between January 2021 and June 2022, this cross-sectional study was conducted at six centers in India. Children with genetically confirmed IESS, without definite structural-genetic and structural-metabolic etiology, were recruited and underwent detailed in-person assessment for phenotypic characterization. The multicentric data on the genotypic and phenotypic characteristics of genetic IESS were collated and analyzed. RESULTS: Of 124 probands (60% boys, history of consanguinity in 15%) with genetic IESS, 105 had single gene disorders (104 nuclear and one mitochondrial), including one with concurrent triple repeat disorder (fragile X syndrome), and 19 had chromosomal disorders. Of 105 single gene disorders, 51 individual genes (92 variants including 25 novel) were identified. Nearly 85% of children with monogenic nuclear disorders had autosomal inheritance (dominant-55.2%, recessive-14.2%), while the rest had X-linked inheritance. Underlying chromosomal disorders included trisomy 21 (n = 14), Xq28 duplication (n = 2), and others (n = 3). Trisomy 21 (n = 14), ALDH7A1 (n = 10), SCN2A (n = 7), CDKL5 (n = 6), ALG13 (n = 5), KCNQ2 (n = 4), STXBP1 (n = 4), SCN1A (n = 4), NTRK2 (n = 4), and WWOX (n = 4) were the dominant single gene causes of genetic IESS. The median age at the onset of epileptic spasms (ES) and establishment of genetic diagnosis was 5 and 12 months, respectively. Pre-existing developmental delay (94.3%), early age at onset of ES (<6 months; 86.2%), central hypotonia (81.4%), facial dysmorphism (70.1%), microcephaly (77.4%), movement disorders (45.9%) and autistic features (42.7%) were remarkable clinical findings. Seizures other than epileptic spasms were observed in 83 children (66.9%). Pre-existing epilepsy syndrome was identified in 21 (16.9%). Nearly 60% had an initial response to hormonal therapy. SIGNIFICANCE: Our study highlights a heterogenous genetic landscape and phenotypic pleiotropy in children with genetic IESS.

Adult-onset leukodystrophies: a practical guide, recent treatment updates, and future directions.

Adult-onset leukodystrophies though individually rare are not uncommon. This group includes several disorders with isolated adult presentations, as well as several childhood leukodystrophies with attenuated phenotypes that present at a later age. Misdiagnoses often occur due to the clinical and radiological overlap with common acquired disorders such as infectious, immune, inflammatory, vascular, metabolic, and toxic etiologies. Increased prevalence of non-specific white matter changes in adult population poses challenges during diagnostic considerations. Clinico-radiological spectrum and molecular landscape of adult-onset leukodystrophies have not been completely elucidated at this time. Diagnostic approach is less well-standardized when compared to the childhood counterpart. Absence of family history and reduced penetrance in certain disorders frequently create a dilemma. Comprehensive evaluation and molecular confirmation when available helps in prognostication, early initiation of treatment in certain disorders, enrollment in clinical trials, and provides valuable information for the family for reproductive counseling. In this review article, we aimed to formulate an approach to adult-onset leukodystrophies that will be useful in routine practice, discuss common adult-onset leukodystrophies with usual and unusual presentations, neuroimaging findings, recent advances in treatment, acquired mimics, and provide an algorithm for comprehensive clinical, radiological, and genetic evaluation that will facilitate early diagnosis and consider active treatment options when available. A high index of suspicion, awareness of the clinico-radiological presentations, and comprehensive genetic evaluation are paramount because treatment options are available for several disorders when diagnosed early in the disease course.

Clinico-Etiological Spectrum and Functional Outcomes of Children with Pre-Status Dystonicus and Status Dystonicus (SD): A Descriptive Study.

Background: Status dystonicus (SD) is a life-threatening movement disorder emergency characterized by increasingly frequent and severe episodes of generalized dystonia, requiring urgent hospital admission. The diverse clinico-etiological spectrum, high risk of recurrence, and residual disabilities complicate functional outcomes. Aim: We aim to describe the clinico-etiological spectrum, radiology, therapeutic options, and follow-up of patients with pre-status dystonicus (pre-SD) and SD. Methodology: A cross-sectional retrospective study was carried out in a tertiary care referral center. The clinical, laboratory, and radiology data of all patients aged less than 18 years with pre-SD and SD from January 2010 to December 2020 were collected. The Dystonia Severity Assessment Plan (DSAP) scale for grading severity and the modified Rankin Scale (mRS) for assessing outcome were used at the last follow-up visit. Results: Twenty-eight patients (male:female: 2.1:1) experiencing 33 episodes of acute dystonia exacerbation were identified. The median age at the onset of dystonia and SD presentation was 8.71 (range: 0.25-15.75) and 9.12 (range: 1-16.75) years, respectively. Four patients experienced more than one episode of SD. The etiological spectrum of SD includes metabolic (Wilson's disease-13, L-aromatic amino acid decarboxylase deficiency-one, and Gaucher's disease-one), genetic (neurodegeneration with brain iron accumulation-three and KMT2B and THAP 1 gene-related-one each), structural-three, post-encephalitic sequelae (PES)-four, and immune-mediated (anti-NMDA receptor encephalitis-one). Five patients had pre-SD (DSAP grade 3), and 23 patients had established SD (DSAP grade 4-17 and DSAP grade 5-six). The Rapid escalation of chelation therapy precipitated SD in 11 patients with Wilson's disease. Febrile illness or pneumonia precipitated SD in nine patients. Twenty-three episodes of SD required midazolam infusion in addition to anti-dystonic medications. The median duration of hospital stay was 10 days (range: 3-29). Twenty-three patients had resolution of SD but residual dystonia persisted, while two patients had no residual dystonia at follow-up. Three patients succumbed owing to refractory SD and its complications. Conclusion: Early identification of triggers, etiology, and appropriate management are essential to calm the dystonic storm.

Use of artificial intelligence in the detection of primary prostate cancer in multiparametric MRI with its clinical outcomes: a protocol for a systematic review and meta-analysis.

INTRODUCTION: Multiparametric MRI (mpMRI) has transformed the prostate cancer diagnostic pathway, allowing for improved risk stratification and more targeted subsequent management. However, concerns exist over the interobserver variability of images and the applicability of this model long term, especially considering the current shortage of radiologists and the growing ageing population. Artificial intelligence (AI) is being integrated into clinical practice to support diagnostic and therapeutic imaging analysis to overcome these concerns. The following report details a protocol for a systematic review and meta-analysis investigating the accuracy of AI in predicting primary prostate cancer on mpMRI. METHODS AND ANALYSIS: A systematic search will be performed using PubMed, MEDLINE, Embase and Cochrane databases. All relevant articles published between January 2016 and February 2023 will be eligible for inclusion. To be included, articles must use AI to study MRI prostate images to detect prostate cancer. All included articles will be in full-text, reporting original data and written in English. The protocol follows the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 checklist. The QUADAS-2 score will assess the quality and risk of bias across selected studies. ETHICS AND DISSEMINATION: Ethical approval will not be required for this systematic review. Findings will be disseminated through peer-reviewed publications and presentations at both national and international conferences. PROSPERO REGISTRATION NUMBER: CRD42021293745.

Childhood Neurological Disorders With Hyperhomocystinemia: A Case-Based Review.

Hyperhomocysteinemia is a rare neurometabolic syndrome with diverse manifestations in the pediatric age group, thereby posing a diagnostic challenge. Biochemical testing is imperative to guide plan of evaluation, which may include appropriate genetic testing, in inherited disorders. Through this case-based approach, we demonstrate the heterogeneity of clinical presentation, biochemical and genetic evaluation, and treatment strategies that may reverse this condition among children.

Exploration of clinical and genetic findings in Ataxia-Telangiectasia (AT) patients from the Indian subcontinent.

BACKGROUND: Ataxia-Telangiectasia (AT) is a rare autosomal recessive neurodegenerative disorder. It is caused by mutations in the Ataxia-Telangiectasia mutated (ATM) gene, which codes for protein ATM serine/threonine kinase. OBJECTIVE: We aim to describe the clinical and radiological findings in children and adolescents of 20 molecularly confirmed cases of AT. We aim to correlate these findings with the genotype identified among them. METHODS: This retrospective study included 20 patients diagnosed clinically and genetically with AT over 10 years. The clinical, radiological and laboratory data were extracted from the hospital's electronic medical records. Molecular testing was done using next generation sequencing and Sanger sequencing. In silico predictions were performed for the variants identified by applying Cryp-Skip, Splice site prediction by Neural Network, Mutation Taster and Hope prediction tool. RESULTS: Consanguinity was documented in nearly half of the patients. Telangiectasia was absent in 10%. Microcephaly was seen in 40% cases. The incidence of malignancy in our study population was low. Molecular testing done in the 18 families (20 patients) identified 23 variants of which ten were novel. Biallelic homozygous variants were noted in 13 families and compound heterozygous in 5 families. Out of the 13 families who were homozygous, 8 families (61.5%) (9 patients) have history of consanguinity. In silico prediction of novel missense variants, NM_000051.4 (ATM_v201): c.2702T > C showed disruption of the α-helix of ATM protein and NM_000051.4 (ATM_v201): c.6679C > G is expected to disturb the rigidity of protein structure in the FAT domain. The four novel splice site variants and two intronic variants result in exon skipping as predicted by Cryp-Skip. CONCLUSIONS: AT should be confirmed by molecular testing in young-onset cerebellar ataxia, even without telangiectasia. Awareness of this rare disease will facilitate study of larger cohorts from Indian population to characterize variants and determine its prevalence in this population.

Clustering of Juvenile Canavan disease in an Indian community due to population bottleneck and isolation: genomic signatures of a founder event.

Mild/juvenile Canavan disease (M/JCD) is less frequently reported in the literature and little is known about its pathogenetic mechanisms. We report a comprehensive investigation into the pathogenetic mechanism of a novel NM_000049.4(ASPA):c.526G>A variant in two families. The families belong to Telugu Devanga Chettiar community (TDC) from southern India. TDC has a complex history of migration from their historical origin centuries ago with high endogamy. TDC probably has the highest clustering M/JCD recorded historically (around 24 cases). The pathogenic variant was shown to cause non-classical splicing defect resulting in two different transcripts. The splicing aberration, a loss of function mechanism coupled with a milder missense effect can explain the milder phenotype compared to the infantile-onset CD. The high clustering of an extremely rare form of neurodegenerative disorder with reduced fitness, led us to speculate the possibility of a founder event. Genotyping array of TDC and multiple distinct populations of Indian origin for several population genetic parameters was performed. It yielded robust signatures of a founder event in TDC, such as a high fixation index, increased runs of homozygosity and identity-by-descent in the absence of consanguinity; a large haplotype with high linkage disequilibrium among markers comprising the pathogenic variant; a robust population structure; mutation dating, estimating the age of the potential founder of TDC at around 375 years; possibly a high carrier rate in TDC. This study has not only focused its attention on natural history and pathogenetics but also paves way for carrier screening programs in TDC and future therapeutic studies.

Management of Children and Adolescents with Wilson Disease and Neurological Worsening Following D-Penicillamine Therapy: A Single Centre Experience.

Background: Most centers in developing countries prefer chelation therapy with D-penicillamine for the management of Wilson's disease (WD) because of its easy availability and affordability. Neurological worsening following treatment with D-penicillamine is not uncommon. However, there is a paucity of Indian data on the incidence of neurological worsening in children and adolescents with WD following chelation therapy. Our study objectives were to identify the prevalence of neurological worsening in children and adolescents with WD following chelation with D-penicillamine therapy and to describe the management options and outcomes in these patients. Materials and Methods: In this retrospective chart review, children and adolescents with an established diagnosis of WD from 2010 to 2020 were identified from the hospital electronic database. Among these patients, data of children and adolescents with neurological worsening following D-penicillamine therapy were extracted and analyzed. Results: Neurological worsening was observed in 27/122 (22.1%) children and adolescents with WD on chelation therapy with D-penicillamine. Fifteen patients with neurological worsening following D-penicillamine therapy were managed with zinc monotherapy. Four patients were managed with a combination therapy of zinc and trientine. Five patients were treated with trientine monotherapy. Re-challenging with D-penicillamine at a lower dose followed by a slow dose escalation was attempted in three patients. Gradual clinical and functional status improvement was observed in 24 cases while one patient succumbed to pneumonia. Conclusion: Children and adolescents with WD who had neurological worsening on D-penicillamine therapy may be managed with trientine. Zinc monotherapy with copper restricted diet was also found to be effective in non-affordable patients.

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.

First reported cases with Xia-Gibbs syndrome from India harboring novel variants in AHDC1.

We report here two girls from different Indian families identified with novel variants in the AT Hook DNA Binding Motif Containing 1 gene (AHDC1) causing Xia-Gibbs syndrome. The diagnosis was made by clinical exome in both cases. Inconsistent dysmorphic features such as dolichocephaly in the first patient and brachycephaly in the second were observed. Prominent jaw and gelastic seizures were other features of patient 1. Thus, this syndrome, with developmental delay, poor expressive language and overlapping clinical phenotype requires the utility of next generation sequencing for diagnostic confirmation.

Utility of Chromosomal Microarray in Children with Unexplained Developmental Delay/Intellectual Disability.

ObjectiveTo evaluate the chromosomal microarray (CMA) yield among children who presented with global developmental delay/intellectual disability (GDD/ID) with/without co-occurring conditions. Methods: The pathogenic copy number variation (pCNVs) findings on CMA of all children who presented with unexplained GDD/ID were categorized based on the clinical features. The karyotype results were compared with CMA. Results: The overall pCNV yield in children presenting with GDD/ID with or without comorbid conditions constituted 20.9%. Among the 17 pCNVs, 13 were losses and four were gains. Cardiac defect was the only co-morbidity in our study that demonstrated statistically significant prediction for pCNV (odds ratio 6.13, p value- 0.031). Six children who were karyotyped prior to CMA testing showed a structural abnormality. Conclusions: In our study, 20.9% of children with GDD/ID showed pCNVs on CMA. Cardiac defect alongside GDD/ID, emerged as the single strongest phenotype associated with pCNVs. CMA also provided vital information in previously karyotyped patients.