Comorbidities in children with cerebral palsy: a single-centre cross-sectional hospital-based study from India.

OBJECTIVE: To describe the comorbidities in children with cerebral palsy (CP) and determine the characteristics associated with different impairments. DESIGN: Cross-sectional study. SETTING: Tertiary care referral centre in India. PATIENTS: Between April 2018 and May 2022, all children aged 2-18 years with a confirmed diagnosis of CP were enrolled by systematic random sampling. Data on antenatal, birth and postnatal risk factors, clinical evaluation and investigations (neuroimaging and genetic/metabolic workup) were recorded. MAIN OUTCOME MEASURES: Prevalence of the co-occurring impairments was determined using clinical evaluation or investigations as indicated. RESULTS: Of the 436 children screened, 384 participated (spastic CP=214 (55.7%) (spastic hemiplegic=52 (13.5%); spastic diplegia=70 (18.2%); spastic quadriplegia=92 (24%)), dyskinetic CP=58 (15.1%) and mixed CP=110 (28.6%)). A primary antenatal/perinatal/neonatal and postneonatal risk factor was identified in 32 (8.3%), 320 (83.3%) and 26 (6.8%) patients, respectively. Prevalent comorbidities (the test used) included visual impairment (clinical assessment and visual evoked potential)=357/383(93.2%), hearing impairment (brainstem-evoked response audiometry)=113 (30%), no understanding of any communication (MacArthur Communicative Development Inventory)=137 (36%), cognitive impairment (Vineland scale of social maturity)=341 (88.8%), severe gastrointestinal dysfunction (clinical evaluation/interview)=90 (23%), significant pain (non-communicating children's pain checklist)=230 (60%), epilepsy=245 (64%), drug-resistant epilepsy=163 (42.4%), sleep impairment (Children's Sleep Habits Questionnaire)=176/290(60.7%) and behavioural abnormalities (Childhood behaviour checklist)=165 (43%). Overall, hemiparetic and diplegic CP and Gross Motor Function Classification System ≤3 were predictive of lesser co-occurring impairment. CONCLUSION: CP children have a high burden of comorbidities, which increase with increasing functional impairment. This calls for urgent actions to prioritise opportunities to prevent risk factors associated with CP and organise existing resources to identify and manage co-occurring impairments. TRIAL REGISTRATION NUMBER: CTRI/2018/07/014819.

Literature search: Simple rules for confronting the unknown.

Literature search forms the foundation of most clinical decisions about patient management and is the starting point for all bedside/bench-side research. Despite being an essential tool in the armamentarium of all medical professionals and researchers, literature search remains a challenge, often resulting in frustration and waste of time (and resources). This article aims to provide a beginner's guide to information seekers for a step-wise approach to literature search on web-based databases.

New-onset seizure at high altitude among healthy males.

OBJECTIVES: The risk of developing new-onset seizure following ascent to high-altitude areas is currently unknown. We undertook a prospective study to quantify this risk. METHODS: The study was conducted at a tertiary care hospital in India between July 2015 and December 2017. It included apparently healthy males of age ≥18 years who ascended to an altitude of ≥ 2500 m and stayed there for > 30 continuous days. Individuals with a history of seizure in the past two years, those who had not undergone acclimatization protocol, and those who had a history of any chronic systemic illness were excluded. RESULTS: The 39,213 individuals included in the study together had 39,848.6 person-years of high-altitude exposure. New-onset seizure after ascent occurred in 41 of them, indicating a seizure incidence rate of 102.9 per 100,000 person-years (95% CI = 75.8-139.7). The incidence per 100,000 person-years (95% CI) at altitudes of 2,500-3,500 m, 3,500-5,800 m, and > 5,800 m was 82.3 (53.6-126.1), 134.6 (84.9-213.6), and 210.8 (52.8-841.4), respectively. Seizure was secondary to cerebral venous thrombosis in 12 (29.3%) individuals. No etiology could be determined in the remaining 29 (70.7%) individuals. CONCLUSIONS: Our findings suggest that when subjects living at sea level are exposed to high altitudes, they will be at a higher risk for new-onset seizure in the immediate few months of exposure, and that this risk increases with increasing altitude.

New-onset diabetic ketoacidosis with purpura fulminans in a child with COVID-19-related multisystem inflammatory syndrome.

BACKGROUND: Coronavirus disease 2019 (COVID 19) usually causes a mild illness among children. However, in a minority of children, it may be associated with the life-threatening multisystem inflammatory syndrome (MIS-C), or thrombotic microangiopathy, or sequelae like type-1 diabetes mellitus (T1DM). We describe a previously healthy, 12-year-old boy with new-onset T1DM with diabetic ketoacidosis (DKA) in the setting of MIS-C, with a course complicated by thrombotic microangiopathy. CASE PRESENTATION: The patient presented with four days history of fever, non-bilious vomiting, polyuria and polydipsia. On evaluation, he was noted to have diabetic ketoacidosis. Although Diabetic ketoacidosis with insulin and intravenous fluids, his hospital course was notable for shock requiring vasopressor, purpura fulminans with eschar formation, neurological manifestations (left hemiparesis due to right middle cerebral artery territory infarct, mononeuritis multiplex) and thrombotic microangiopathy. MIS-C-like illness secondary to COVID-19 was suspected due to diabetic ketoacidosis, thrombotic microangiopathy, elevated inflammatory markers, history of contact with COVID-19-infected individual and detectable COVID-19 IgG antibodies. He improved following management with methylprednisolone, intravenous immunoglobulin, low-molecular-weight heparin and aspirin, and was discharged on hospital day 48. CONCLUSION: MIS-C-like illness should be considered in children and adolescents presenting with complex multisystem involvement in this era of COVID 19. Management with immunomodulatory agents can be lifesaving.

Two Novel Compound Heterozygous ADGRG1/GPR56 Mutations Associated with Diffuse Cerebral Polymicrogyria.

Background Polymicrogyria (PMG) has environmental or genetic etiologies. We report a 8-year-old boy with diffuse PMG and two novel adhesion G protein-coupled receptor G1 ( ADGRG1 ) / G protein-coupled receptor 56 ( GPR56 ) mutations. Case Report The proband has intellectual disability, spastic quadriparesis, and intractable epilepsy without antenatal or perinatal insults. Brain magnetic resonance imaging revealed PMG involving fronto-polar, parietal and occipital lobes with decreasing antero-posterior gradient, and a thinned-out brain stem. Targeted exome sequencing identified two novel compound heterozygote ADGRG1/GPR56 mutations (c.C209T and c.1010dupT), and each parent carries one of these mutations. Subsequent pregnancy was terminated because the fetus had the same mutations. Conclusion The detected mutations expanded the genetic etiology of PMG and helped the family to avoid another child with this devastating condition.

Clinical and molecular spectrum associated with Polymerase-γ related disorders.

BACKGROUND: POLG pathogenic variants are the commonest single-gene cause of inherited mitochondrial disease. However, the data on clinicogenetic associations in POLG-related disorders are sparse. This study maps the clinicogenetic spectrum of POLG-related disorders in the pediatric population. METHODS: Individuals were recruited across 6 centers in India. Children diagnosed between January 2015 and August 2020 with pathogenic or likely pathogenic POLG variants and age of onset <15 years were eligible. Phenotypically, patients were categorized into Alpers-Huttenlocher syndrome; myocerebrohepatopathy syndrome; myoclonic epilepsy, myopathy, and sensory ataxia; ataxia-neuropathy spectrum; Leigh disease; and autosomal dominant / recessive progressive external ophthalmoplegia. RESULTS: A total of 3729 genetic reports and 4256 hospital records were screened. Twenty-two patients with pathogenic variants were included. Phenotypically, patients were classifiable into Alpers-Huttenlocher syndrome (8/22; 36.4%), progressive external ophthalmoplegia (8/22; 36.4%), Leigh disease (2/22; 9.1%), ataxia-neuropathy spectrum (2/22; 9.1%), and unclassified (2/22; 9.1%). The prominent clinical manifestations included developmental delay (n = 14; 63.7%), neuroregression (n = 14; 63.7%), encephalopathy (n = 11; 50%), epilepsy (n = 11; 50%), ophthalmoplegia (n = 8; 36.4%), and liver dysfunction (n = 8; 36.4%). Forty-four pathogenic variants were identified at 13 loci, and these were clustered at exonuclease (18/44; 40.9%), linker (13/44; 29.5%), polymerase (10/44; 22.7%), and N-terminal domains (3/44; 6.8%). Genotype-phenotype analysis suggested that serious outcomes including neuroregression (odds ratio [OR] 11, 95% CI 2.5, 41), epilepsy (OR 9, 95% CI 2.4, 39), encephalopathy (OR 5.7, 95% CI 1.4, 19), and hepatic dysfunction (OR 4.6, 95% CI 21.3, 15) were associated with at least 1 variant involving linker or polymerase domain. CONCLUSIONS: We describe the clinical subgroups and their associations with different POLG domains. These can aid in the development of follow-up and management strategies of presymptomatic individuals.

Intermittent versus daily regimen of prednisolone in ambulatory boys with Duchenne muscular dystrophy: A randomized, open-label trial.

INTRODUCTION/AIMS: Corticosteroids prolong ambulation and improve muscle power among boys with Duchenne muscular dystrophy (DMD). However, the optimal steroid regimen remains unclear. Hence, this study was undertaken to compare the efficacy of daily- versus intermittent-steroid regimens in ambulatory boys with DMD. METHODS: In this single-center, open-label randomized trial, 72 children were randomized to receive either daily prednisolone (0.75 mg/kg/day) or intermittent prednisolone (0.75 mg/kg/day, for first 10 days of every month). The primary outcome measure was the difference in average score on manual muscle testing (MMT) at baseline and after 6 mo of steroids. A difference of >0.2 was hypothesized to be significant. Secondary outcomes included changes in timed functions, muscular dystrophy-specific functional-rating scale score, peak torque, average power, and pulmonary function. RESULTS: In the intention-to-treat analysis, the mean (SD) change in MMT scores was 0.17 (0.15) and 0.08 (0.10) for the daily and intermittent steroid groups, respectively. The mean difference between the two interventions was 0.10 (95% confidence interval [CI] = 0.04-0.16; P = .003), which although significant was less than the predefined value of 0.2. Statistically significantly improvements were observed with daily-steroid regimen in the Gowers time (P = .01), nine-metre walk test (P = .02) and average power (P = .02) as compared to intermittent-steroid regimen. A total of 19/32 (52.8%) children in the daily-steroid group and 8/29 (27%) children in the intermittent-steroid group experienced some form of adverse effect (P = .02). DISCUSSION: Over a short-term period, the intermittent-steroid regimen was non-inferior to the daily-steroid regime in preserving muscle strength among children with DMD. However, better improvement of functional measures was observed with daily-steroid administration. The frequency of individual side effects was similar between the two groups.

Somatic mutations involving TSC 1 and TSC2 genes in two children with focal cortical dysplasia.

BACKGROUND: The role of PI3K/AKT/mTOR pathway hyperactivation in localized brain overgrowth is evolving. We describe two patients with focal cortical dysplasia (FCD) who demonstrated somatic mutations in TSC1 and TSC2 genes in the dysplastic brain tissue but not peripheral blood. METHODS: Paired whole-exome sequencing was performed on genomic DNA extracted from blood and excised brain tissue in two children with FCD who underwent excision of dysplastic tissue. RESULTS: Patient 1, a 14-year boy, had drug-resistant focal epilepsy with onset at 20 months. His brain MRI showed abnormalities suggestive of FCD in the left superior and middle frontal lobes. Patient 2 presented at the age of 10 years with pharmaco-resistant focal epilepsy (onset at six years). His MRI suggested FCD in the left insular lobe. Both patients underwent surgical excision of FCD, and excised tissues were pathologically confirmed to have type IIb FCD. For patient 1, a missense mutation (c.64C > T; p.Arg22Trp) was detected in the TSC1 gene in DNA of dysplastic brain tissue but not peripheral blood lymphocytes. Similarly, for patient 2, a frameshift mutation (c.4258_4261delCAGT; p.Ser1420GlyfsTer55) in the TSC2 gene was identified in the brain tissue but not blood. Both gene variants are likely pathogenic and cause mTOR pathway activation. CONCLUSION: Our report of TSC1/TSC2 somatic mutations in patients with non-syndromic FCD suggests that localized hyperactivation of the mTOR pathway can cause focal malformations during cortical development and presents pharmacological targets for precision therapy in FCD management.

Association of Child Neurology (AOCN) Consensus Statement on the Diagnosis and Management of Febrile Seizures.

JUSTIFICATION: Febrile seizures are quite common in children but there are controversies in many aspects of their diagnosis and management. METHODS: An expert group consisting of pediatric neurologists and pediatricians was constituted. The modified Delphi method was used to develop consensus on the issues of definitions and investigations. The writing group members reviewed the literature and identified the contentious issues under these subheadings. The questions were framed, pruned, and discussed among the writing group members. The final questions were circulated to all experts during the first round of Delphi consensus. The results of the first round were considered to have arrived at a consensus if more than 75% experts agreed. Contentious issues that reached a 50-75% agreement was discussed further in online meetings and subsequently voting was done over an online platform to arrive at a consensus. Three rounds of Delphi were conducted to arrive at final statements. RESULTS: The expert group arrived at a consensus on 52 statements. These statements pertain to definitions of febrile seizures, role of blood investigations, urine investigations, neuroimaging, electroencephalography (EEG), cerebrospinal fluid analysis and screening for micronutrient deficiency. In addition, role of rescue medications, intermittent anti-seizure medication and continuous prophylaxis, antipyretic medication and micronutrient supplementation have been covered. CONCLUSIONS: This consensus statement addresses various contentious issues pertaining to the diagnosis and management of febrile seizures. Adoption of these statements in office practice will improve and standardize the care of children with this disorder.

Effects of lockdown during corona pandemic on children with neurodevelopmental disorders-A questionnaire-based survey.

BACKGROUND: Lockdown due to Corona pandemic is an unprecedented event, which has had a profound impact on the lives of children across all ages. Its effects on children with Neurodevelopmental Disorders (NDD) has not been adequately studied. This study was performed in order to explore the effects of lockdown during the Corona pandemic on children with NDD and their parents. METHODS: The survey was conducted in three Indian tertiary-care hospitals wherein parents of children with NDD were requested to respond to an online questionnaire. The questions attempted to elicit various aspects of the children`s therapies and behavioural profiles as well as their parents` experiences during the pandemic related lockdown. RESULTS: 135/188 (71.8%) parents of children with Autism Spectrum Disorder (ASD)(n=104), Attention Deficit Hyperactivity Disorder (ADHD) (n=26) and Learning Disability (LD)(n=5) responded. Pre-lockdown, 133 (99%) children were receiving regular institution-based therapy, which ceased intra-lockdown. Mean cumulative home-based therapy duration significantly increased during lockdown (p=0.03). Parents reported significantly increased temper tantrums in children (p=0.02). They perceived that during lockdown, their children were bored and their interactions and speech worsened. Majority of parents reported worsening of own qualities of life, but felt confident of taking care of their children during lockdown. CONCLUSIONS: To conclude, children with NDD and their parents were significantly affected by Corona pandemicrelated lockdown. Institutional therapy discontinuation, behavioural deterioration (especially among ASD and ADHD) and parental stress were prominent challenges whereas parental motivation and reliance on homebased therapy were the positive highlights. The survey points to the role of regular parent-administered homebased therapy in children with NDD, especially to tide over similar unexpected adverse scenarios.

CNS autoimmunity in children: An unwanted wrinkle in a smooth narrative.

The emerging paradigm of childhood autoimmune neurological disorders has exploded in recent times due to reliable diagnostic methods and their ease of availability, well-defined diagnostic criteria, and universal awareness about these disorders. The most important aspect of these disorders is a considerable recovery in response to early targeted immunotherapy. If left untreated and/or ill-treated, these can lead to mortality or lifelong morbidity. Autoantibodies can target any part of the central nervous system (CNS), ranging from superficial structures like myelin to deep intracellular ion channels like voltage-gated potassium channels, resulting in contrasting and at times overlapping symptomatology. Though neuroimaging characteristics and serological tests confirm these disorders' diagnosis, it is essential to suspect them clinically and start management before the reports are available for minimizing morbidity and mortality. In the pediatric age group, several metabolic conditions, like mitochondrial disorders and enzyme deficiencies like HMG-CoA-lyase deficiency, can develop neuroimaging patterns similar to those seen in childhood CNS autoimmune disorders and may also show a favorable response to steroids in acute phases. Hence, the clinician must suspect and work up the index patient appropriately. Here, we briefly discuss the pathophysiology, clinical clues, and potential therapeutic targets related to pediatric CNS autoimmune disorders.

Development Assessment Scale for Indian Infants: A Systematic Review and Perspective on Dwindling Cutoffs.

The Developmental Assessment Scale for Indian Infants (DASII) remains the mainstay in India for diagnostic confirmation and validation of upcoming screening tools for development in infants and toddlers. This is an Indian adaptation of Bayley Scales of Infant Development which is the globally accepted gold standard. However, the DASII cutoff points used for categorizing development and distinguishing normal from abnormal development are not in agreement across different studies conducted over the last two decades in India. This is probably due to a lack of mention of cutoff points in the DASII manual and existing literature. The current systematic review summarizes the heterogeneity in literature for interpretation of DASII and its cutoff points. Also, a perspective on the ideal cutoff points is presented.

Efficacy of Ketogenic Diet, Modified Atkins Diet, and Low Glycemic Index Therapy Diet Among Children With Drug-Resistant Epilepsy: A Randomized Clinical Trial.

Importance: The ketogenic diet (KD) has been used successfully to treat children with drug-resistant epilepsy. Data assessing the efficacy of the modified Atkins diet (MAD) and low glycemic index therapy (LGIT) diet compared with the KD are scarce. Objective: To determine whether the MAD and LGIT diet are noninferior to the KD among children with drug-resistant epilepsy. Design, Setting, and Participants: One hundred seventy children aged between 1 and 15 years who had 4 or more seizures per month, had not responded to 2 or more antiseizure drugs, and had not been treated previously with the KD, MAD, or LGIT diet were enrolled between April 1, 2016, and August 20, 2017, at a tertiary care referral center in India. Exposures: Children were randomly assigned to receive the KD, MAD, or LGIT diet as additions to ongoing therapy with antiseizure drugs. Main Outcomes and Measures: Primary outcome was percentage change in seizure frequency after 24 weeks of dietary therapy in the MAD cohort compared with the KD cohort and in the LGIT diet cohort compared with the KD cohort. The trial was powered to assess noninferiority of the MAD and LGIT diet compared with the KD with a predefined, noninferiority margin of -15 percentage points. Intention-to-treat analysis was used. Results: One hundred fifty-eight children completed the trial: KD (n = 52), MAD (n = 52), and LGIT diet (n = 54). Intention-to-treat analysis showed that, after 24 weeks of intervention, the median (interquartile range [IQR]) change in seizure frequency (KD: -66%; IQR, -85% to -38%; MAD: -45%; IQR, -91% to -7%; and LGIT diet: -54%; IQR, -92% to -19%) was similar among the 3 arms (P = .39). The median difference, per intention-to-treat analysis, in seizure reduction between the KD and MAD arms was -21 percentage points (95% CI, -29 to -3 percentage points) and between the KD and LGIT arms was -12 percentage points (95% CI, -21 to 7 percentage points), with both breaching the noninferiority margin of -15 percentage points. Treatment-related adverse events were similar between the KD (31 of 55 [56.4%]) and MAD (33 of 58 [56.9%]) arms but were significantly less in the LGIT diet arm (19 of 57 [33.3%]). Conclusions and Relevance: Neither the MAD nor the LGIT diet met the noninferiority criteria. However, the results of this study for the LGIT diet showed a balance between seizure reduction and relatively fewer adverse events compared with the KD and MAD. These potential benefits suggest that the risk-benefit decision with regard to the 3 diet interventions needs to be individualized. Trial Registration: ClinicalTrials.gov Identifier: NCT02708030.

Vitamin-Responsive Movement Disorders in Children.

Movement disorders in childhood comprise a heterogeneous group of conditions that lead to impairment of voluntary movement, abnormal postures, or inserted involuntary movements. Movement disorders in children are frequently caused by metabolic disorders, both inherited and acquired. Many of these respond to vitamin supplementation. Examples include infantile tremor syndrome, biotinidase deficiency, biotin-thiamine-responsive basal ganglia disease, pyruvate dehydrogenase deficiency, aromatic amino acid decarboxylase deficiency, ataxia with vitamin E deficiency, abetalipoproteinemia, cerebral folate deficiency, and cobalamin metabolism defects. Recognition of these disorders by pediatricians and neurologists is imperative as they are easily treated by vitamin supplementation. In this review, we discuss vitamin-responsive movement disorders in children.

Non-Pharmacological and Non-Surgical Treatment of Refractory Childhood Epilepsy.

Nearly 20-40% of patients with epilepsy are likely to have drug resistant epilepsy (DRE). Add-on antiseizure drugs do not produce optimal seizure control in these patients. Among the non-pharmacological options, only resective surgery is curative. However, a large majority of patients are not candidates for resective epilepsy surgery. For these children with DRE, non-pharmacological non-surgery "palliative" options should be considered early than late. These include dietary therapies and neuromodulation. While there are numerous clinical trials supporting the efficacy of dietary therapies (viz ketogenic diet, modified Atkins diet and low glycemic index therapy), the evidence for neuromodulation is still evolving. Neuromodulation techniques include vagal nerve stimulation, deep brain stimulation, and transcranial magnetic stimulation. Each of the options, whether diet or neuromodulation, has its own advantages, disadvantages and adverse events profile. These have to be considered and discussed with the family before deciding the modality being chosen.

Novel RNASEH2C mutation in multiple members of a large family: insights into phenotypic spectrum of Aicardi-Goutières Syndrome.

BACKGROUND: Aicardi-Goutières syndrome (AGS) is a genetic inflammatory disorder that presents with early infantile encephalopathy. We report the clinical and molecular details of multiple members of a family with AGS secondary to a novel RNASEH2C mutation, highlighting the evolution of phenotypic abnormalities in AGS. METHODS: Between February 2018 and June 2019, a pedigree tree was constructed for 141 members of a family. The clinical and radiological details of 14 symptomatic children were chronicled and compared with the asymptomatic family members. Genetic analysis was performed on 23 individuals (six symptomatic). This involved whole exome sequencing for one patient and confirmation of the identified indel variant in other family members. RESULTS: The symptomatic children were diagnosed as AGS secondary to a novel indel variation in exon 2 of the RNASEH2C gene (chr11:65487843_65487846delinsGCCA). Clinically, between the ages of 2 and 6 months, the symptomatic children developed irritability (14/14), unexplained fever (9/14), chill blains (12/14), sleep irregularities (14/14) and developmental delay (14/14), with deterioration to vegetative state at a median (IQR) age of 10.5 months (9.25-11). In addition, chill blains were observed in 5/17 (29.4%) carrier individuals. Neuroimaging demonstrated a gradual progression of calcification involving basal ganglia, periventricular white matter and dentate nucleus. Three patients also demonstrated presence of subependymal germinolytic cysts. CONCLUSION: This report highlights a novel founder RNASEH2C mutation and the phenotypic evolution of AGS. In addition, we report chill blains in one-third of RNASEH2C mutation carriers. Neuroradiologically, the report illustrates novel MRI findings and demonstrates a progression pattern of disease. These findings will aid in earlier suspicion and diagnosis of AGS.