Neurodevelopmental disorders in children aged 2-9 years: Population-based burden estimates across five regions in India.

BACKGROUND: Neurodevelopmental disorders (NDDs) compromise the development and attainment of full social and economic potential at individual, family, community, and country levels. Paucity of data on NDDs slows down policy and programmatic action in most developing countries despite perceived high burden. METHODS AND FINDINGS: We assessed 3,964 children (with almost equal number of boys and girls distributed in 2-<6 and 6-9 year age categories) identified from five geographically diverse populations in India using cluster sampling technique (probability proportionate to population size). These were from the North-Central, i.e., Palwal (N = 998; all rural, 16.4% non-Hindu, 25.3% from scheduled caste/tribe [SC-ST] [these are considered underserved communities who are eligible for affirmative action]); North, i.e., Kangra (N = 997; 91.6% rural, 3.7% non-Hindu, 25.3% SC-ST); East, i.e., Dhenkanal (N = 981; 89.8% rural, 1.2% non-Hindu, 38.0% SC-ST); South, i.e., Hyderabad (N = 495; all urban, 25.7% non-Hindu, 27.3% SC-ST) and West, i.e., North Goa (N = 493; 68.0% rural, 11.4% non-Hindu, 18.5% SC-ST). All children were assessed for vision impairment (VI), epilepsy (Epi), neuromotor impairments including cerebral palsy (NMI-CP), hearing impairment (HI), speech and language disorders, autism spectrum disorders (ASDs), and intellectual disability (ID). Furthermore, 6-9-year-old children were also assessed for attention deficit hyperactivity disorder (ADHD) and learning disorders (LDs). We standardized sample characteristics as per Census of India 2011 to arrive at district level and all-sites-pooled estimates. Site-specific prevalence of any of seven NDDs in 2-<6 year olds ranged from 2.9% (95% CI 1.6-5.5) to 18.7% (95% CI 14.7-23.6), and for any of nine NDDs in the 6-9-year-old children, from 6.5% (95% CI 4.6-9.1) to 18.5% (95% CI 15.3-22.3). Two or more NDDs were present in 0.4% (95% CI 0.1-1.7) to 4.3% (95% CI 2.2-8.2) in the younger age category and 0.7% (95% CI 0.2-2.0) to 5.3% (95% CI 3.3-8.2) in the older age category. All-site-pooled estimates for NDDs were 9.2% (95% CI 7.5-11.2) and 13.6% (95% CI 11.3-16.2) in children of 2-<6 and 6-9 year age categories, respectively, without significant difference according to gender, rural/urban residence, or religion; almost one-fifth of these children had more than one NDD. The pooled estimates for prevalence increased by up to three percentage points when these were adjusted for national rates of stunting or low birth weight (LBW). HI, ID, speech and language disorders, Epi, and LDs were the common NDDs across sites. Upon risk modelling, noninstitutional delivery, history of perinatal asphyxia, neonatal illness, postnatal neurological/brain infections, stunting, LBW/prematurity, and older age category (6-9 year) were significantly associated with NDDs. The study sample was underrepresentative of stunting and LBW and had a 15.6% refusal. These factors could be contributing to underestimation of the true NDD burden in our population. CONCLUSIONS: The study identifies NDDs in children aged 2-9 years as a significant public health burden for India. HI was higher than and ASD prevalence comparable to the published global literature. Most risk factors of NDDs were modifiable and amenable to public health interventions.

Intranasal versus intravenous lorazepam for control of acute seizures in children: a randomized open-label study.

PURPOSE: Intravenous lorazepam is considered the drug of first choice for control of acute convulsive seizures. However, resource or personnel constraints necessitate the study of alternative routes and medications. This study compared the efficacy and adverse effects of intranasal versus intravenous lorazepam in children aged 6-14 years who presented with acute seizures. METHODS: This was a randomized open-label study conducted at an Indian hospital from August 2008 to April 2009. One hundred forty-one consecutive children aged 6-14 years who presented convulsing to the emergency room were included. After stabilization, the children were randomized to receive either intravenous or intranasal lorazepam (0.1 mg/kg, maximum 4 mg). The primary outcome measure was clinical seizure remission within 10 min of drug administration. The study was registered with clinicaltrials.gov (NCT00735527). KEY FINDINGS: Seventy patients were randomized to receive intravenous and 71 to receive intranasal lorazepam. The patients in the two groups were comparable at baseline. Clinical seizure remission within 10 min of drug administration was found in 80% of the intravenous group as compared to 83.1% of intranasal group. The lower limit of 95% confidence interval for effect size was approximately -9.7%, with an a priori cutoff for noninferiority of -10%. SIGNIFICANCE: Intranasal administration of lorazepam is not found to be inferior to intravenous administration for termination of acute convulsive seizures in children.

Fourth ventricular hamartoma presenting with status epilepticus treated with emergency surgery in an infant.

A 4-week-old infant presented with hemifacial spasms noticed from the 4th day after delivery. These progressed in severity, with generalization every 3-4 h. On admission, the infant went into refractory status epilepticus and had to be electively ventilated and taken for surgery on a semi-emergency basis. MRI showed a fourth ventricular hamartoma and video EEG showed spikes that were synchronous with the facial 'twitches' with generalization. Following the first surgery, the infant had an initial complete recovery, but developed recurrence of facial twitches after 2 weeks. Repeat MRI showed a small residual tumor which was re-operated and completely excised (at 8 weeks). Following this, the patient had complete recovery from seizures (5-year follow-up). This is the youngest patient reported presenting with status epilepticus with a fourth ventricular hamartoma operated successfully.

Cyclin-dependent kinase-like 5 (CDKL5) mutation screening in Rett syndrome and related disorders.

Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting females almost exclusively and is characterized by a wide spectrum of clinical manifestations. Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene have been found in up to 95% of classical RTT cases and a lesser proportion of atypical cases. Recently, mutations in another X-linked gene, CDKL5 (cyclin-dependent kinase-like 5) have been found to cause atypical RTT, in particular the early onset seizure (Hanefeld variant) and one female with autism. In this study we screened several cohorts of children for CDKL5 mutations, totaling 316 patients, including individuals with a clinical diagnosis of RTT but who were negative for MECP2 mutations (n=102), males with X-linked mental retardation (n=9), patients with West syndrome (n=52), patients with autism (n=59), patients with epileptic encephalopathy (n=33), patients with Aicardi syndrome (n=7) and other patients with intellectual disability with or without seizures (n=54). In all, seven polymorphic variations and four de novo mutations (c.586C>T [p.S196L]; c.58G>C [p.G20R]; c.2504delC [p.P835fs]; deletion of exons 1-3) were identified, and in all instances of the latter the clinical phenotype was that of an epileptic encephalopathy. These results suggest that pathogenic CDKL5 mutations are unlikely to be identified in the absence of severe early-onset seizures and highlight the importance of screening for large intragenic and whole gene deletions.

Evaluation of the immunogenicity and safety of an indigenously developed DTwP-Hib tetravalent combination vaccine (Shan 4) with EasyFourTM in Indian infants administered per EPI schedule: a phase III trial.

The study was planned to assess and compare immunogenicity and safety of an indigenous DTPw-Hib combination vaccine (Shan 4) with EasyFour, the available DTwP-Hib vaccine in India. Overall 210 healthy infants, six to eight weeks of age, were randomized to receive three doses of either Shan 4 or EasyFour at 6, 10 and 14 weeks of age. Antibodies were analyzed prior to and four to six weeks post third vaccine dose. Solicited and unsolicited local and systemic events in the follow up period after each dose were recorded. Post vaccination 100% of the infants in Shan 4 and EasyFour groups had seroprotective concentrations of Anti PRP-T IgG antibodies, IgG anti-diphtheria toxoid antibodies and IgG anti-tetanus toxoid antibodies. Following third dose of vaccination 86.99% subjects in the Shan 4 group and 73.85% subjects in the EasyFour group seroconverted for anti-pertussis antibody titres. Two Serious Adverse Events (SAE s) were reported during the course of the study, all unrelated to the respective vaccine administered. Most commonly reported adverse events in both the groups were pain at injection site, mild fever (<103°F) and minor swelling at injection site. The study proved that Shan 4 was safe and immunogenic compared to the available licensed vaccine.

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.

Cystic white-matter changes in childhood Wilson's disease.

Altered signals in magnetic resonance imaging are present in most symptomatic patients with neurologic manifestations of Wilson's disease. The changes primarily involve the basal ganglia, but they can be diverse and can involve a host of other structures. We describe a 12-year-old boy with Wilson's disease who manifested prominent white-matter cystic changes. These changes can cause diagnostic confusion, and may also present prognostic implications.

De novo ABCD1 gene mutation in an Indian patient with adrenoleukodystrophy.

A large number of ABCD1 gene mutations have been reported all over the world, but not previously in India. We report on the first known patient with childhood cerebral adrenoleukodystrophy and a de novo 3' splice-site mutation in this gene. Magnetic resonance imaging of the brain revealed large, confluent, hyperintense areas in the bilateral cerebral white matter, predominantly parieto-occipital, with extensions into posterior regions that led to breakdown of the blood-brain barrier. An increased level of very long chain fatty acids was also consistent with the biochemical defect for adrenoleukodystrophy. Sequencing of the ABCD1 gene of this patient identified a 3' splice-site mutation in the intervening sequence 4 (-2a > g). We did not find any mutation in the gene of the proband's mother, which confirms its de novo occurrence.

Failure of prophylactic zinc in Wilson disease.

Early institution of prophylactic therapy of asymptomatic Wilson disease patients can prevent the expression of the disease. Zinc is currently preferred therapy for presymptomatic patients. We report onset of symptomatic disease in a presymptomatic patient and deterioration of biochemical parameters in another, despite appropriate zinc therapy.

Congenital myopathies: a clinicopathological study of 25 cases.

OBJECTIVE: Congenital myopathies are rare. Through this article, the authors want to present a clinicopathological analysis of 25 new cases. MATERIALS AND METHODS: The clinical data of patients who were diagnosed with congenital myopathy between 2001 and 2006 was retrieved. Muscle biopsies were processed for H&E staining, enzyme histochemistry, and immunohistochemistry. Biopsies were also processed for ultrastructural analysis. RESULTS: During a period of 6 years, 1.12% of the muscle biopsies were diagnosed as congenital myopathies. The most common congenital myopathy was central core disease followed by nemaline rod myopathy and multi-mini core disease. Clinically, they have variable features. The final diagnosis was made with the help of enzyme histochemistry and ultrastructural features. CONCLUSION: This study emphasizes the importance of enzyme histochemistry and electron microscopic examination in the diagnosis of congenital myopathies especially in the absence of genetic studies.

Consensus Statement of the Indian Academy of Pediatrics on Evaluation and Management of Attention Deficit Hyperactivity Disorder.

JUSTIFICATION: Attention-Deficit/Hyperactivity Disorder (ADHD) is highly prevalent in children worldwide. Management of ADHD requires a systematic, multidisciplinary approach and therefore evidence-based, standardized national guidelines are essential. PROCESS: A meeting for formulation of national consensus guidelines on neurodevelopmental disorders was organized by Indian Academy of Pediatrics in Mumbai, on 18th and 19th December, 2015. The invited experts included Pediatricians, Developmental Pediatricians, Pediatric Neurologists, Psychiatrists, Remedial Educators and Clinical Psychologists. The participants framed guidelines after extensive discussions. OBJECTIVE: To provide consensus guidelines on evaluation and management of ADHD in children in India. RECOMMENDATIONS: ADHD is a chronic condition and thus education of patients, families, and teachers regarding the diagnosis is an integral part of management. Involvement of patient the and the family in the management program is extremely vital. Management of ADHD centers on the achievement of target outcomes, which are chosen in collaboration with the child, parents, and school personnel. Coexisting conditions must be treated concurrently with ADHD. Modalities of management of ADHD include behavioral interventions, medications, and educational interventions. These modalities can be implemented individually or in combination.

Intranasal midazolam vs rectal diazepam in acute childhood seizures.

One hundred eighty-eight seizure episodes in 46 children were randomly assigned to receive treatment with rectal diazepam and intranasal midazolam with doses of 0.3 mg/kg body weight and 0.2 mg/kg body weight, respectively. Efficacy of the drugs was assessed by drug administration time and seizure cessation time. Heart rate, blood pressure, respiratory rate, and oxygen saturation were measured before and after 5, 10, and 30 minutes following administration of the drugs in both groups. Mean time from arrival of doctor to drug administration was 68.3 +/- 55.12 seconds in the diazepam group and 50.6 +/- 14.1 seconds in the midazolam group (P = 0.002). Mean time from drug administration to cessation of seizure was significantly less in the midazolam group than the diazepam group (P = 0.005). Mean heart rate and blood pressure did not vary significantly between the two drug groups. However, mean respiratory rate and oxygen saturation differed significantly between the two drug groups at 5, 10, and 30 minutes after drug administration. Intranasal midazolam is preferable to rectal diazepam in the treatment of acute seizures in children. Its administration is easy, it has rapid onset of action, has no significant effect on respiration and oxygen saturation, and is socially acceptable.

West syndrome and other infantile epileptic encephalopathies--Indian hospital experience.

Children with infantile epileptic encephalopathies comprising 3.5% of the Pediatric Neurology Clinic registrations in a tertiary care hospital were retrospectively analyzed. Data were retrieved from case records and analyzed for seizure semiology, prenatal and perinatal insults, developmental status and relevant investigations. The various therapeutic modalities and their influence on spasm frequency, long-term development and final seizure status were compared. The two primary outcome variables analyzed included final seizure status and developmental outcome. Of the 94 infantile epileptic encephalopathies, West syndrome was the commonest (55.3%), of which two thirds were symptomatic. Etiological factors were prenatal in 66.6% and perinatal in 33.3%. The initial response to ACTH was good in 54.5% with subsequent relapse in 27.8% and for prednisolone was 52.9 and 44.4%, respectively, compared to 25.3% spasms control with conventional antiepileptic drugs. Disease category of infantile epileptic encephalopathies evolved in 4, i.e. early myoclonic encephalopathy to West syndrome 1, early infantile epileptic encephalopathy to West syndrome 1, West syndrome to Lennox-Gastaut syndrome 2. Psychomotor retardation was seen in 88.2%, with 16.1% having normal development at onset of spasms. Microcephaly was associated with delayed development but did not influence final seizure outcome. Final seizure outcome was poor in children with delayed development at onset (adjusted odds ratio [OR] = 4), delay in diagnosis >12 months (OR = 2.27) and in children with Lennox-Gastaut syndrome (OR = 4.75). ACTH/prednisolone and antiepileptic treatment versus antiepileptics alone showed a good final seizure response in 36.6% versus 20%. Development on follow up was delayed in children with initial psychomotor retardation (OR = 23.4) and abnormal electroencephalogram (OR = 7.46). Perinatal factors constituted one third of symptomatic West syndrome. The use of ACTH/corticosteroids resulted in good initial spasm control though final seizure outcome and development were unaffected. Prednisolone had similar response to ACTH in spasm control but higher subsequent relapse rate. Vigabatrin was useful though often unaffordable. The identification of a neurometabolic etiology, though uncommon, has significant therapy implications. Delay in diagnosis was common and negatively influenced final seizure outcome.

Hypothalamic hamartoma, gelastic epilepsy, precocious puberty--a diffuse cerebral dysgenesis.

Childhood epileptic syndrome characterized by early onset gelastic seizures, hypothalamic hamartoma and precocious puberty is well recognized though rare. We report association of agenesis of corpus callosum, Dandy-Walker complex and heterotopic gray matter with this childhood epileptic syndrome which is hitherto an unreported association. The child showed a satisfactory response to gonadotropin releasing hormone agonist.