Diagnosis and Management of Global Development Delay: Consensus Guidelines of Growth, Development and Behavioral Pediatrics Chapter, Neurology Chapter and Neurodevelopment Pediatrics Chapter of the Indian Academy of Pediatrics

Justification: Global developmental delay (GDD) is a relatively common neurodevelopmental disorder; however, paucity of published literature and absence of uniform guidelines increases the complexity of clinical management of this condition. Hence, there is a need of practical guidelines for the pediatrician on the diagnosis and management of GDD, summarizing the available evidence, and filling in the gaps in existing knowledge and practices. Process: Seven subcommittees of subject experts comprising of writing and expert group from among members of Indian Academy of Pediatrics (IAP) and its chapters of Neurology, Neurodevelopment Pediatrics and Growth Development and Behavioral Pediatrics were constituted, who reviewed literature, developed key questions and prepared the first draft on guidelines after multiple rounds of discussion. The guidelines were then discussed by the whole group in an online meeting. The points of contention were discussed and a general consensus was arrived at, after which final guidelines were drafted by the writing group and approved by all contributors. The guidelines were then approved by the Executive Board of IAP. Guidelines: GDD is defined as significant delay (at least 2 standard deviations below the mean with standardized developmental tests) in at least two developmental domains in children under 5 years of age; however, children whose delay can be explained primarily by motor issues or severe uncorrected visual/ hearing impairment are excluded. Severity of GDD can be classified as mild, moderate, severe and profound on adaptive functioning. For all children, in addition to routine surveillance, developmental screening using standardized tools should be done at 9-12 months,18-24 months, and at school entry; whereas, for high risk infants, it should be done 6-monthly till 24 months and yearly till 5 years of age; in addition to once at school entry. All children, especially those diagnosed with GDD, should be screened for ASD at 18-24 months, and if screen negative, again at 3 years of age. It is recommended that investigations should always follow a careful history and examination to plan targeted testing and, vision and hearing screening should be done in all cases prior to standardized tests of development. Neuroimaging, preferably magnetic resonance imaging of the brain, should be obtained when specific clinical indicators are present. Biochemical and metabolic investigations should be targeted towards identifying treatable conditions and genetic tests are recommended in presence of clinical suspicion of a genetic syndrome and/or in the absence of a clear etiology. Multidisciplinary intervention should be initiated soon after the delay is recognized even before a formal diagnosis is made, and early intervention for high risk infants should start in the nursery with developmentally supportive care. Detailed structured counselling of family regarding the diagnosis, etiology, comorbidities, investigations, management, prognosis and follow-up is recommended. Regular targeted follow-up should be done, preferably in consultation with a team of experts led by a developmental pediatrician/ pediatric neurologist.

Indian Academy of Pediatrics (IAP) Task Force Recommendations for Incorporating Nurturing Care for Early Childhood Development (NC-ECD) in Medical Education in India

Background: The World Health Organization (WHO) recommends promotion of nurturing care for early childhood development (NCECD) by focusing on five essential components viz., good health, adequate nutrition, promotion of early childhood learning, responsive caregiving, and safety and security. Indian medical graduates and pediatricians are the keys to successful delivery and propagation of NC-ECD in the community. Their training therefore needs to include skills and knowledge needed to promote and practice ECD. Objective: To evaluate the existing undergraduate (UG) and postgraduate (PG) curricula of pediatrics for components related to early childhood development, assess gaps in the training essential to practice and promote ECD, and suggest recommendations to incorporate NC-ECD in the UG and PG curricula. Process: Indian Academy of Pediatrics created a task force to review the UG/PG medical curricula, consisting of experts from pediatrics and medical education. The task force deliberated on 20 March, 2021 and identified the gaps in current curricula and provided suggestions to strengthen it. The recommendations of the task force are presented here. Recommendations: Taskforce identified that the UG/PG medical curricula are lacking training for propagating early childhood learning, responsive caregiving, caregiver support, and ensuring safety and security of children. The taskforce provided a list of competencies related to ECD that need to be included in both UG and PG curriculum. NC-ECD should also be included in topics for integrated teaching. Postgraduates also need to be exposed to hands-on-training at anganwadis, creches, and in domestic setting.

Children’s Color Trail Test for Objective Assessment of Attention in Children with Attention Deficit Hyperactivity Disorder: A Diagnostic Accuracy Study

Objective: To compare the Children’s Color Trail Test scores in children with and withoutAttention Deficit Hyperactivity Disorder to assess its diagnostic performance in assessingattention-deficit. Methods: 50 children with Attention Deficit Hyperactivity Disorder(diagnosed as per Diagnostic and Statistical Manual, 5th edition) and 50 age- and sex-matched children underwent Test 1 and Test 2 of the Children’s Color Trail Test. A ReceiverOperating Characteristics curve was constructed for the diagnostic accuracy of Children’sColor Trail Test in Attention Deficit Hyperactivity Disorder. Results: The Receiver OperatingCharacteristics curve showed a score ≤32 for Children’s Color Trail Test 1 [AUC: 0.8 (0.71 to0.87); P<0.001] and score ≤40 for Children’s Color Trail Test 2 [AUC: 0.85 (0.77 to 0.92);P<0.001] as the best cut-off for diagnosing Attention Deficit Hyperactivity Disorder.Conclusion: Children’s Color Trail Test is a promising tool for diagnosing attention deficit,and could be used in settings where parent or teacher reports are not available

Autism Spectrum Disorders and Celiac Disease: Is there an Association?

We included 150 children aged 2-12 years with Autism SpectrumDisorders and normal serum total IgA levels, and screened themfor celiac disease using anti-tissue transglutaminase IgA levels.All the children were screen negative, suggesting lack ofpositive association between Autism Spectrum Disorders andCeliac disease.

Diagnostic Accuracy of International Epidemiology Network (INCLEN) Diagnostic Tool for Autism Spectrum Disorder (INDT-ASD) in Comparison with Diagnostic and Statistical Manual of Mental Dis- orders-5 (DSM-5)

Objective: To compare the diagnostic accuracy of INCLEN Diagnostic Tool for AutismSpectrum Disorder (INDT-ASD) against Diagnostic and Statistical Manual of MentalDisorders – 5 (DSM-5) for the diagnosis of Autism Spectrum Disorder (ASD). Methods: 118children aged 2-9 years with symptoms suggestive of ASD were assessed by INDT-ASDand DSM-Vby trained personnel. ASD diagnosis by INDT-ASD was compared against theexpert’s DSM-5 diagnosis. Results: INDT-ASD had a sensitivity and specificity of 100% and75%, respectively against DSM-5 for the diagnosis of ASD; specificity for Autistic Disorderwas 87%. Conclusion: The INDT-ASD has a good sensitivity and specificity against DSM-5,and can continue to be used for the diagnosis of ASD even after the adoption of DSM-5criteria

Neurodevelopmental Status of Children Aged 6-30 Months with Congenital Heart Disease.

Background: Children with congenital heart diseases (CHD) are considered to be at high-risk for neurodevelopmental delay, but scant Indian data are available. Objective: To evaluate the neurodevelopmental status of children with CHD. Methods: We enrolled consecutive children aged 6-30 months with echocardiographically-confirmed CHD between June 2013 and January 2014. Children with clinically recognizable genetic syndromes or disorders; visual and/or hearing deficits, and microcephaly; and post-cardiac surgery children were excluded. Development was assessed by Developmental Assessment Scale for Indian Infants (DASII) and Developmental delay defined as Development Quotient (DQ) <70 in either the mental or motor scale. Results: 75 children (53 males) with CHD were enrolled. Acyanotic CHD was seen in 51 children (VSD in 47%), and Tetralogy of Fallot was the commonest cyanotic CHD (25%). Developmental delay was seen in 25% of these children, more in the motor domain (48%) than in mental (12%). Mean motor and mental DQ in acyanotic CHD was 77 and 84, respectively; and 65 and 85, respectively in cyanotic CHD. Mean motor DQ was significantly less than mental DQ in both acyanotic and cyanotic CHD children (P=0.048). Conclusion: Children with CHD are at an increased risk for developmental delay. Periodic surveillance, screening and evaluation should be instituted in them for early identification and appropriate interventions to enhance later academic, behavioral, psycho-social and adaptive function.

Ophelia Syndrome: Hodgkin Lymphoma with Limbic Encephalitis.

Background: Limbic encephalitis, an immune-mediated encephalitis, results from inflammation in the medial temporal lobes. The paraneoplastic form is rare in pediatric population, and frequently precedes tumor diagnosis. Case characteristics: A 9-year-old boy receiving chemotherapy for Hodgkin lymphoma, developed headache, temporal lobe seizures, anxiety, hallucinations, short-term memory loss and autonomic disturbances. Magnetic resonance imaging of brain showed features suggestive of limbic encephalitis. Electro-encephalography showed diffuse slowing with no epileptiform discharges. Outcome: We diagnosed paraneoplastic form of limbic encephalitis. Treatment with steroids and intravenous immunoglobulin failed, and the child died 4 weeks after onset of symptoms. Message: Limbic encephalitis should be kept as differential diagnosis in a child with sub-acutely evolving neuropsychiatric symptoms.

Benign Infantile Seizures.

Background: Benign infantile seizures are a common form of idiopathic seizures in infants, but infrequently reported. Case characteristics: Four cases identified over a 9-month period. Observation: All had a cluster of focal seizures, normal development and no abnormality on hematological and biochemical work-up. Outcome: No recurrence of seizures over a follow-up of 5 to 9 months. Message: Identification of this syndrome has important therapeutic and prognostic implications.

Identification of a Novel TAZ Gene Mutation in a Family With X-Linked Dilated Cardiomyopathy Barth Syndrome

Abstract Mutations in the tafazzin (TAZ) gene on chromosome Xq28 are responsible for the Barth syndrome (BTHS) phenotype resulting in a loss of function in the protein tafazzin involved in the transacylation of cardiolipin, an essential mitochondrial phospholipid. TAZ gene was investigated in the proband in our study, who died of dilated cardiomyopathy at 8 months of age, and his family by sequencing to identify the genetic cause of BTHS. Molecular analysis revealed a novel mutation in exon 5 (c.520T>G) of the TAZ gene. This novel mutation c.520T>G, pW174G, was also found in female carriers (mother and grandmother of proband) in the family. Bioinformatic analysis was carried out to examine the effect of mutation in the gene and confirmed the deleterious effect of this single mutation to the protein structure. Protein modeling and 3-dimensional structure of TAZ protein demonstrated the significantly visible changes in mutated protein leading to BTHS phenotype. Prenatal diagnosis in a subsequent pregnancy showed a carrier female, and pregnancy was continued. Child is doing well at 1 year of age.

INCLEN Diagnostic Tool for Neuromotor Impairments (INDT-NMI) for Primary Care Physician: Development and Validation.

Objectives: To develop and validate a diagnostic tool for use by primary care physicians for diagnosing neuro-motor impairment among 2-9 year old children in primary care settings. Study design: Modified Delphi technique involving national (n=49) and international (n=6) experts was used for development of INDT-NMI. The tool was then validated through a cross sectional study. Setting: Neurology specialty clinics of three tertiary care pediatric centers in New Delhi, India. Participants: 454 children aged 2-9 years [mean (SD) age: 60.4 (23.7) mo], selected through systematic random sampling, underwent assessment for identification and classification of neuromotor impairments (NMI). Intervention: All study subjects were first administered INDTNMI (candidate test) by a trained physician followed by expert assessment for NMI and other neurodevelopment disorders (NDD) by team of two pediatric neurologists (Gold standard). Results: According to expert evaluation, 171 (37.8%) children had neuromotor impairments. There were four categories of subjects: NMI alone (n=66); NMI+other NDDs (n=105); Other NDDs without NMI (n=225) and ‘Normal’ group (n=58). Using expert evaluation as gold standard, overall sensitivity of the INDTNMI was 75.4% and specificity was 86.8%. INDT-NMI helped graduate physicians to correctly classify 86.6% (112/129) children with NMI into different types (cerebral palsy, neuromotor diseases and other NMI). Graduate physicians assigned 40 children (8.8%) as ‘indeterminate’, 38 (95%) of whom had either NDD and/or NMI and thus merited referral. Misclassification of NMI occurred in those with mild changes in muscle tone, dystonia, or ataxia and associated NDDs. Conclusion: Graduate primary care physicians with a structured short training can administer the new tool and diagnose NMI in 2-9 year old children with high validity. INDT-NMI requires further evaluation in actual primary care settings.

Atypical Manifestations of Dengue Fever.

We reviewed case records of 40 in-patients (22 boys) with serologically confirmed dengue fever between 1st October and 30th November, 2013. Severe dengue was seen in 30, out of which 12 (30%) had compensated shock. Splenomegaly (6,15%) and encephalopathy (4,10%) were the commonest atypical features. Atypical manifestations of dengue fever were more common than that reported in the past.

Health-related Quality of Life in Children with Cerebral Palsy and Their Families.

Objective: To determine the health-related quality of life in children with cerebral palsy and their families. Methods: One hundred children (3-10 years of age) receiving regular rehabilitation therapy for cerebral palsy for last 1 year at a Child Development Centrer were enrolled and the Lifestyle assessment questionnaire – cerebral palsy was administered to the parents. Results: 9% had good, 24% had mildly-affected, 37% had moderately-affected and 30% had severely-affected healthrelated quality of life. The physical independence, mobility and social integration dimensions were much more severely affected than the clinical burden, economic burden and schooling dimensions. Conclusion: Health-related quality of child is affected in most children with cerebral palsy.

INCLEN Diagnostic Tool for Autism Spectrum Disorder (INDT-ASD): Development and Validation.

Objective: To develop and validate INCLEN Diagnostic Tool for Autism Spectrum Disorder (INDT-ASD). Design: Diagnostic test evaluation by cross sectional design Setting: Four tertiary pediatric neurology centers in Delhi and Thiruvanthapuram, India. Methods: Children aged 2-9 years were enrolled in the study. INDT-ASD and Childhood Autism Rating Scale (CARS) were administered in a randomly decided sequence by trained psychologist, followed by an expert evaluation by DSM-IV TR diagnostic criteria (gold standard). Main outcome measures: Psychometric parameters of diagnostic accuracy, validity (construct, criterion and convergent) and internal consistency. Results: 154 children (110 boys, mean age 64.2 mo) were enrolled. The overall diagnostic accuracy (AUC=0.97, 95% CI 0.93, 0.99; P<0.001) and validity (sensitivity 98%, specificity 95%, positive predictive value 91%, negative predictive value 99%) of INDT-ASD for Autism spectrum disorder were high, taking expert diagnosis using DSM-IV-TR as gold standard. The concordance rate between the INDT-ASD and expert diagnosis for ‘ASD group’ was 82.52% [Cohen’s κ=0.89; 95% CI (0.82, 0.97); P=0.001]. The internal consistency of INDT-ASD was 0.96. The convergent validity with CARS (r = 0.73, P= 0.001) and divergent validity with Binet-Kamat Test of intelligence (r = -0.37; P=0.004) were significantly high. INDT-ASD has a 4-factor structure explaining 85.3% of the variance. Conclusion: INDT-ASD has high diagnostic accuracy, adequate content validity, good internal consistency high criterion validity and high to moderate convergent validity and 4-factor construct validity for diagnosis of Autistm spectrum disorder.

Attention Deficit Hyperactivity Disorder in Adolescent School Children.

The prevalence of Attention deficit hyperactivity disorder was estimated in 500 adolescents using Conners’ parents and teachers rating scales. Thirty six (7.2%) adolescents had positive scores on both the scales. The parents and teachers also completed a Diagnostic and Statistical Manual-IV based questionnaire which showed good agreement with Conners’ rating scales.

Intellectual Disability in Indian Children: Experience with a Stratified Approach for Etiological Diagnosis.

Objective: To study the clinico-etiological profile of children with intellectual disability using an algorithmic approach. Design: Cross-sectional study. Setting: Tertiary care centre in Northern India. Participants: Consecutive children aged 3 months to 12 years, presenting with intellectual disability, confirmed by Developmental Assessment Scale for Indian Infants, Binet Kulshreshtha Test and Vineland Social Maturity Scale. Method: All children were assessed on an internally validated structured proforma. A targeted approach included thyroid function tests, Brainstem evoked response audiometry, electroencephalogram, neuroimaging and metabolic screen done as a pre-decided schema. Genetic tests included karyotyping, molecular studies for Fragile X, Multiplex Ligation Dependent Probe Amplification and Array Comparative Genomic Hybridisation. Results: Data of 101 children (median age 22 months) was analyzed. The etiological yield was 82.1% with genetic causes being the most common (61.4%) followed by perinatal acquired (20.4%), CNS malformations (12%), external prenatal (3.6%), and postnatal acquired (2.4%). Mild delay was seen in 11.7%, moderate in 21.7%, severe in 30.6% and profound in 35.6%. Conclusion: It is possible to ascertain the diagnosis in most of the cases of intellectual disability using a judicious and sequential battery of tests.

Recurrent Headache in Pediatric Outpatients at a Public Hospital in Delhi.

This observational, descriptive study was conducted to study the clinical profile of children presenting with recurrent headaches to the general pediatric services of a tertiary-care, public hospital in northern India. 43 children, 3-18 year old (23 females, median age 10 years), were enrolled between April, 2011 to January, 2012. History, clinical examination (including fundus evaluation and detailed ophthalmological evaluation) and follow-up were done using a structured proforma. Headache diagnosis was made on the basis of International Classification of Headache Disorders, 2nd edition (ICHD-II). Headache disability and severity were assessed by pedMIDAS, and Visual analog scale and Faces scale, respectively. 26 patients (60.5%) had headache with migraine features (20, migraine without aura), 11 (25.6%) had Tension type headache (TTH), and 4 (9.3%) children had nonspecific headache. Stress was the commonest (42.3%) trigger identified by children with migraine. No patient in the study had an ophthalmological problem as cause of headache. 69.2% of migraine patients and 36% of TTH patients had been suffering from it for 1-2 years before reporting to the hospital. Majority of children with recurrent headache present late for medical attention. Ophthalmological problems are an infrequent cause of recurrent headache in these children.

Ages and Stages Questionnaire as a Screening Tool for Developmental Delay in Indian Children.

Objective: To evaluate the ability of ‘Ages and Stages Questionnaire’, a parent completed developmental screening questionnaire to detect developmental delay in Indian children. Design: Cross-sectional study. Setting: Child Development Clinic of a tertiary care center located in Northern India Participants and Methods: 200 children, 50 each in the age groups of 4±1, 10±1, 18±1 and 24±1 months were recruited (20 high risks and 30 low risks in each age group). The Ages and Stages Questionnaire (ASQ) was translated into Hindi and administered to the parents, followed by standardized development assessment using Developmental Assessment Scale for Indian Infants (DASII). Results: 102 (51%) children failed on ASQ and 90 (45%) children failed on DASII. The overall sensitivity of ASQ for detecting developmental delay was 83.3% and specificity was 75.4%. The sensitivity was best for the 24-months questionnaire (94.7%) and specificity was best for the 4-month questionnaire (86.4%). The sensitivity of ASQ was much higher in the high risk group (92.3%) as compared to the low risk group (60%). Conclusion: ASQ has strong test characteristics for detecting developmental delay in Indian children, especially in high risk cases. It may be easily converted into other Indian languages and used widely for developmental screening.

Add-on Lamotrigine in Pediatric Epilepsy in India.

Lamotrigine is a newer antiepileptic drug useful as oral adjunctive therapy in refractory epilepsy. Indian data on use of lamotrigine is limited. This study was conducted to evaluate add-on lamotrigine in Indian children with epilepsy. Twenty children (median age 90 months) receiving lamotrigine as add-on therapy for mean 26.7 (19.1) months, were followed for a median period of 7.9 (6-10) months. Follow-up was done every two weeks. The most common seizures types were either generalized tonic-clonic (6, 30%) or myoclonic (8, 40%). The average dose used was 3.86 mg/kg/day (with concomitant valproate). Good response (>50% reduction) or complete seizure control was seen in 72% patients. Side effects were seen in 27.5% patients and were ‘mild’ in more than half of these. Lamotrigine was stopped in two patients due to adverse reactions, which resolved on stopping the drug. Lamotrigine was observed to be an effective, add-on, broad-spectrum antiepileptic with ‘mild’ side effects in Indian children.

Iron Deficiency in Indian Children with Attention Deficit Hyperactivity Disorder.

A case control study was conducted at the Child Development and Early Intervention Clinic to determine the body iron status of children with ADHD, and study the correlation between the body iron status and ADHD symptoms. Serum ferritin was measured in newly diagnosed cases with ADHD and compared with that of controls. Correlation was studied between serum ferritin levels and the severity of ADHD symptoms as determined by Conners’ Rating Scale. Serum ferritin was found to be significantly lower in children with ADHD (6.04 ± 3.85 ng/ mL) as compared to controls (48.96 ± 41.64 ng/mL, P value<0.001). There was a significant negative correlation between serum ferritin levels and oppositional subscore on Conners’ Rating Scale.