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

Emotional, behavioral and cognitive profile, and quality of life of Indian children and adolescents with type 1 diabetes

Background and Aims: The psychological stress associated with type 1 diabetes (T1D) may be higher in children from developing world due to limited health resources. The aims of the study were to assess the quality of life (QoL), emotional well-being, behavioral, and cognitive profile of children/adolescents with T1D diagnosed at least 6 months prior. Materials and Methods: Forty-nine children with T1D, aged 6−18 years were assessed using DAWN Youth QoL questionnaire, WHO-5 Well-Being Index, Child Behavior Checklist (CBCL), and Malin′s Intelligence Scale for Indian children (MISIC). The association of the scores was studied with age, gender, socioeconomic status (SES), frequency of hypoglycemia, HbA1c, and age of onset and duration of T1D. Results: The mean (standard deviation (SD)) for DAWN QoL, WHO-5, CBCL, and MISIC scores was 24.7 (16.7), 74.6 (19.4), 52.6 (8.8), and 96.0 (11.2), respectively. The significant associations noted were: Elevated HbA1c with poorer emotional well-being; higher negative impact on ′symptoms of disease′ and ′future prospects′ sub-areas of QoL; shorter duration of disease with more behavioral issues; lower maternal education with more ′withdrawn/depressed′ behaviors and ′worry about future prospects′; and lower SES with lower MISIC scores. Earlier onset (age <5 years) was associated with fewer behavioral problems and less negative impact on QoL. Conclusion: Children with recent diagnosis, older age at onset, lower maternal educational level, elevated HbA1c, or belonging to lower SES were identified to have higher prevalence of various psychological and cognitive problems. In resource-limited settings, these children should be prioritized for behavioral and cognitive evaluation

Late effects of treatment in survivors of childhood cancers: A single-centre experience

Background & objectives: With improved survival of childhood cancer patients, the number of long-term cancer survivors is increasing. Some studies have assessed the long-term morbidity after childhood cancer treatment in the developing countries. This study was conducted to assess the spectrum of late effects of cancer treatment in paediatric cancer survivors. Methods: Evaluation of the first 300 patients who completed five years of follow up in the after treatment completion clinic was done. Details of primary diagnosis, treatment received and current clinical status were noted. The spectrum of late effects was ascertained by appropriate investigations. Results: Haematological malignancies comprised 25 per cent of total cases. Most common primary diagnosis comprised acute lymphoblastic leukaemia, retinoblastoma and Hodgkin's lymphoma. The median age at evaluation and follow up was 14 and 8.5 yr, respectively. Twenty three per cent (69) of the survivors had a minimal disability (growth retardation or underweight), 13 per cent (39) had moderate disabilities needing medical attention (hepatitis B surface antigen positive, myocardial dysfunction, azoospermia and hypothyroidism), while two per cent had major/life-threatening disabilities (mental retardation, liver disease and mortality). Eleven patients relapsed on follow up, of those five patients expired. Two second malignancies were recorded during the period of follow up. Interpretation & conclusions: Late effects were of concern; however, severe disability (Grade 3-5) was seen in only two per cent survivors. Lifelong follow up of childhood cancer survivors is required to assess cancer-related morbidity, occurrence of a secondary neoplasm, to facilitate timely diagnosis and to implement remedial or preventive interventions to optimize health outcomes. Awareness towards the existence of late effects of cancer therapy is required among parents, patients and health professionals

Long-term follow-up of retinoblastoma survivors: Experience from India

Background: Retinoblastoma (Rb) is the most common primary intraocular tumor of infancy and childhood. Survivors' ocular and visual problems and increased risk for subsequent malignancy are well documented, but data on long-term health status of Rb survivors are limited, this being particularly true for India. Methodology: Children who had completed treatment for Rb at least 2 years ago before and were under follow-up at the after cancer treatment clinic were evaluated. Results: In our series of 213 patients, the median age was 29 months, there was a male preponderance, and majority had unilateral disease. Enucleation was done in almost three-fourth and 3% underwent bilateral enucleation. Majority of the patients received chemotherapy, and few received radiation. Growth was affected in about one-third and majority were those who had received radiation. Diminished vision was noticed in about one-sixth. Orbital hypoplasia and contracted socket were seen in 14.1% cases. 2.7% were hearing impaired. About one-sixth had a global intelligence delay. Second neoplasms were seen in 0.01%. No other abnormalities were seen. Conclusions: Common late effects in our Rb survivors include diminished vision in the salvage eye, intellectual disability, and contracted socket; there is a need for timely institution of prosthesis to avoid late effects such as hypoplasia, contracted sockets, and better cosmesis and enhanced self-esteem. Second neoplasm is a concern. Lifelong follow-up and counseling of a healthy lifestyle are needed for Rb survivors

Follow-up of high risk neonates

The improvement in perinatal care has led to increase in survival as well as reduction of morbidity in sick newborns. These babies need to be followed up regularly to assess growth and neurodevelopmental outcome and for early stimulation and rehabilitation. We present a protocol describing the various components of a follow up program, and services

Growth and neurosensory outcomes of preterm very low birth weight infants at 18 months of corrected age

Objective: To determine the growth and neurosensory outcomes of infants with birth weight ≤1,500 g or gestation ≤32 wks at 18 months corrected age. This prospective cohort study was conducted at a Level III neonatal unit in India. The neonates with birth weight ≤1,500 g or gestation ≤32 wks were included in the study. Methods: The infants were followed up at 3,6,9,12 and 18 months corrected age. Weight, length and head circumference were plotted on WHO multisite growth reference study (MGRS) charts. Neurological examination was conducted by Amiel-Tison method, hearing was evaluated with brainstem auditory evoked responses, vision assessed with Teller acuity cards, and development assessed with Developmental Assessment Scales for Indian Infants II. Results: During the period from July 2006 through June 2007, there were 141 neonates born at gestation ≤32 wks or birth weight ≤1,500 g. Seven infants had major malformations, 30 died before discharge, 36 had residence >20 km and parents of four had refused consent. The remaining 64 neonates were enrolled for follow up. The mean gestation and birth weight were 31(2.4) wks and 1208 (365) g respectively. There were 38 (59%) small for gestation infants. Fifty-five infants completed 18 months follow up for growth outcomes. Seventeen (30.9%; 95% CI 18.3% to 43.5%) infants were undernourished, 28(50.9%; 95% CI 37.3% to 64.6%) were stunted, 8(14.5%; 95% CI 0 to 24) were wasted and 14(25.4%; 95% CI 13.6% to 37.3%) had microcephaly. Infants with birth weight &#60; 1,000 g (n = 17) were significantly more affected. Ten (58.8%; p &#60; 0.01) were undernourished, 13(76.5%; p &#60;  0.01) were stunted and 10(58.8%; p &#60; 0.01) had microcephaly. Complete formal neurological evaluation for development, hearing and vision was done in 31 infants. Six of these 31 (19.3%; 95% CI 4.6% to 34.1%) infants had one or more major disabilities. These included cerebral palsy (n = 3), developmental delay (development quotient &#60; 70, n = 3), and deafness (n = 3). Conclusions: Very low birth weight infants are at a high risk of neurosensory disability and growth failure. There is a need to create a nation-wide database of these infants for neurodevelopment and growth outcomes

Spectrum of MECP2 mutations in Indian females with Rett Syndrome - a large cohort study

Aim: This study aimed to characterize MECP2 gene variants in Indian female patients with classical Rett syndrome (RTT).Methods: Seventy-two patients fulfilling the revised diagnostic criteria of classical RTT were enrolled and exons 2-4 of MECP2 gene were analyzed by Sanger sequencing followed by quantitative analysis using MLPA. Bioinformatic analysis was done using different software packages to predict the effect of sequence variations on the function of the MeCP2 protein.Results: A heterogeneous spectrum of MECP2 sequence variants including 13 novel variants was identified with a detection rate of 98.6%. The majority of the variants were distributed in the functional domain of MECP2 with most missense variants clustered in methyl binding domain and truncating variants in interdomain and transcription repression domain of MECP2. Genotype-phenotype correlations revealed that patients carrying early truncating variants presented with a more severe phenotype.Conclusion: RTT is a childhood neurodevelopmental disorder primarily affecting females. It is caused by mutations in the Methyl-CpG-Binding Protein 2 gene (MECP2 ), an important regulator of gene expression, located at Xq28. Variants in MECP2 can be identified in 95%-97% of individuals with Classical RTT using a combination of molecular techniques. This large cohort study from India showed the highest detection rate of MECP2 variants in classical RTT patients, emphasizing the importance of using diagnostic criteria and having a multidisciplinary team in the assessment of RTT patients, which can further help provide diagnostic testing, genetic counseling, and prenatal testing

Development and validation of DSM-5 based diagnostic tool for children with Autism Spectrum Disorder.

Diagnostic and Statistical Manual of mental disorder-IV (DSM-IV) TR based INCLEN Diagnostic Tool for Autism Spectrum Disorder (INDT-ASD) is an established instrument for the diagnosis of ASD in Indian subcontinent and low-middle income countries (LMIC). The introduction of DSM-5 necessitated revision of existing INDT-ASD tool to incorporate the DSM-5 related changes. This study was undertaken to develop and validate the DSM-5 based All India Institute of Medical Sciences (AIIMS)-Modified-INDT-ASD Tool. The modifications were done using Delphi method and included: (a) rearrangement of questions from the previous tool; and (b) addition of new questions on sensory symptoms. The modified tool was validated against DSM-5 diagnostic criteria. In addition, receiver operating characteristic (ROC) curves were used to determine the cut-off for total score as compared to Childhood Autism Rating Scale (CARS) score to grade the severity of ASD. Two-hundred-twenty-five children (159 boys, median age = 47months) were enrolled. The modified tool demonstrated sensitivity of 98.4% and specificity of 91.7% to diagnose ASD. A score ≥14 on the tool was suggestive of severe ASD (CARS>36.5) with a sensitivity and specificity of 80% and 80.7% respectively [Area under the curve = 0.89]. AIIMS-Modified-INDT-ASD Tool is a simple and structured instrument based on DSM-5 criteria which can facilitate diagnosis of ASD with acceptable diagnostic accuracy