Neurocognitive outcomes in survivors of childhood acute lymphoblastic leukemia: Experience from a tertiary care center in India.

BACKGROUND: Data of neurocognitive deficits in survivors of acute lymphoblastic leukemia (ALL) is scarce from low middle-income countries (LMICs), and is influenced by biological and cultural variations. The objective of this study was to assess the prevalence and spectrum of neurocognitive deficits in a cohort of survivors from India. PROCEDURE: Seventy survivors of childhood ALL were evaluated for neurocognitive deficits by the Indian adaptation of Wechsler Intelligence Scale for Children - Fourth Edition (WISC-IVINDIA ). The prevalence of neurocognitive deficits was calculated based on the full-scale intelligence quotient (FSIQ), and scores in discrete domains like verbal comprehension, perceptual reasoning, working memory, and processing speed were calculated and compared to demographics, treatment, and sociocultural factors. RESULTS: The mean (SD) current age and time since diagnosis was 10.5 (±3.2) years and 5 (±2.8) years, respectively. The mean FSIQ was 86.1 ± 20.5, with significant neurocognitive deficit (FSIQ <90) being prevalent in 50% (95% CI: 38%-62%) of the cohort. The proportion of survivors with deficits in individual domains of verbal comprehension, perceptual reasoning, working memory, and processing speed were 49%, 50%, 47%, and 44%, respectively. The odds of having neurocognitive deficits were higher when a child belonged to lower socioeconomic strata (OR 5.7, p = .004), parents with lower education attainment (OR 4.3, p = .041), and whose birth order was higher (OR 20.1, p = .005). Age at diagnosis/assessment, chemotherapy received, or dose of radiotherapy did not have a direct impact on neurocognition. CONCLUSIONS AND RELEVANCE: Rates of neurocognitive deficits are higher in survivors in LMICs, with socioeconomic variables contributing more than the direct neurotoxic effects of treatment.

Mutation Spectrum of Tuberous Sclerosis Complex Patients in Indian Population.

Tuberous sclerosis complex (TSC) is a multiorgan disorder characterized by formation of hamartomas and broad phenotypic spectrum including seizures, mental retardation, renal dysfunction, skin manifestations and brain tubers. It is inherited in an autosomal dominant pattern, caused due to mutation in either TSC1 or TSC2 genes. Seizures are one of the major presenting symptoms of TSC that helps in early diagnosis. The present study describes the mutation spectrum in TSC1 and TSC2 genes in TSC patients and their association with neurocognitive-behavioral phenotypes. Ninety-eight TSC patients were enrolled for TSC genetic testing after detailed clinical and neurobehavioral assessment. Large genomic rearrangement testing was performed by multiplex ligation-dependent probe amplification (MLPA) technique for all cases and Sanger sequencing was performed for MLPA negative cases. Large rearrangements were identified in approximately 1% in TSC1 and 14.3% in TSC2 genes. The present study observed the presence of duplications in two (2%) cases, both involving TSC2/PKD1 contiguous genes which to the best of our knowledge is reported for the first time. 8.1% of small variants were identified in the TSC1 gene and 85.7% in TSC2 gene, out of which 23 were novel variations and no variants were found in six (6.1%) cases. This study provides a representative picture of the distribution of variants in the TSC1 and TSC2 genes in Indian population along with the detailed assessment of neurological symptoms. This is the largest cohort study from India providing an overview of comprehensive clinical and molecular spectrum.

Decoding of novel missense TSC2 gene variants using in-silico methods.

BACKGROUND: Mutations in TSC1 or TSC2 gene cause tuberous sclerosis complex (TSC), an autosomal dominant disorder characterized by the formation of non-malignant hamartomas in multiple vital organs. TSC1 and TSC2 gene products form TSC heterodimer that senses specific cell growth conditions to control mTORC1 signalling. METHODS: In the present study 98 TSC patients were tested for variants in TSC1 and TSC2 genes and 14 novel missense variations were identified. The pathogenecity of these novel variations was determined by applying different bioinformatics tools involving computer aided protein modeling. RESULTS: Protein modelling could be done only for ten variants which were within the functional part of the protein. Homology modeling is the most reliable method for structure prediction of a protein. Since no sequence homology structure was available for the tuberin protein, three dimensional structure was modeled by a combination of homology modeling and the predictive fold recognition and threading method using Phyre2 threading server. The best template structures for model building of the TSC1 interacting domain, tuberin domain and GAP domain are the crystal structures of clathrin adaptor core protein, Rap1GAP catalytic domain and Ser/Thr kinase Tor protein respectively. CONCLUSIONS: In this study, an attempt has been made to assess the impact of each novel missense variant based on their TSC1-TSC2 hydrophobic interactions and its effect on protein function.

Developmental Status of Children Operated for Esophageal Atresia with or without Tracheoesophageal Fistula Along with Maternal Stress, Their Quality of life, and Coping Abilities at AIIMS, New Delhi.

INTRODUCTION: Esophageal atresia with or without tracheoesophageal fistula (EA with or without TEF) is one of the neonatal surgical emergencies requiring surgical intervention in the early neonatal period, influencing the developmental outcome in the operated children. This study was aimed to assess the developmental status of children operated for EA with or without TEF along with maternal stress, their quality of life (QOL), and coping abilities. MATERIALS AND METHODS: A descriptive cross-sectional survey was conducted on 51 children aged up to 5 years after EA with or without TEF repair and their mothers' in a tertiary care facility. The tools used were, namely, demographic datasheet of child and mother, anthropometry assessment, Developmental Assessment Scale for Indian Infants, and modified Vineland Social Maturity Scale for the developmental evaluation, Child Behavior Checklist (1.5-5 years) caregiver report form, Parental Stress Scale, WHOQOL BREF, and Coping Strategies Checklist. RESULTS: The majority of children had low weight (47.1%) and height (31.4%), for reference age. The overall and social developmental delay was observed in 40.7 and 37.5% of children, respectively, and few children (7.4%) had behavioral problems in the borderline range. Among the mothers, 47% had moderate stress and relatively poor QOL in environmental (60.1 ± 18.9) and psychological (60.8 ± 18.8) domains. The most commonly used coping strategy by the mothers was an emotional outlet (29.4%). CONCLUSION: Developmental delay was present in children operated for EA with or without TEF caused significant stress among mothers, affecting their QOL for which the emotional outlet was the most commonly used coping strategy.

Hospital Based Psychosocial Support Program for Children with ALL and their Families: A Comprehensive Triad's Perspective.

OBJECTIVES: To elucidate potential target areas of intervention and mechanisms for implementation of intervention for children with cancer during the treatment phase. METHODS: Focused group discussion (FGDs) served as a primary source of providing phenomenal perspectives to explore the key objective. Eight focus groups of 45-60 min each were held with 5-9 members in each discussion. The participants were either patients, their caregivers or health care providers. The focus group audio recordings were professionally transcribed after all identifiers were removed. Employing a constructivist paradigm with a phenomenological approach, also known as emergent-systematic focus group design the study reported on families' experiences of childhood cancer as construction of objective reality. Investigator triangulation method was adopted to ensure trustworthiness. RESULTS: Using constant comparison analysis, multistage process analysis was done which resulted in 849 codes, 32 subthemes, 20 themes and 5 domains. A total of 64 participants participated: 4 FGDs with parents of children with ALL (n = 31); 1 FGD with professionals working in the field of cancer (n = 10) and 3 FGDs with children with ALL (n = 23). Participant's mean age at the time of study was 10 y (+3.3) for children; 37 y (+4.93) for caregivers and 35 y (+3.5) for professionals. The number of participants and their age range at study varied slightly between the eight focus groups. CONCLUSIONS: Caregivers presented care burden and compromised aspects of Quality of life (QOL). An effective and culturally sensitive psychosocial support for patients and their families during and post treatment, in addition to medical therapy, is strongly recommended.

Endoscope-assisted (with robotic guidance and using a hybrid technique) interhemispheric transcallosal hemispherotomy: a comparative study with open hemispherotomy to evaluate efficacy, complications, and outcome.

OBJECTIVEEndoscope-assisted hemispherotomy (EH) has emerged as a good alternative option for hemispheric pathologies with drug-resistant epilepsy.METHODSThis was a prospective observational study. Parameters measured included primary outcome measures (frequency, severity of seizures) and secondary outcomes (cognition, behavior, and quality of life). Blood loss, operating time, complications, and hospital stay were also taken into account. A comparison was made between the open hemispherotomy (OH) and endoscopic techniques performed by the senior author.RESULTSOf 59 cases (42 males), 27 underwent OH (8 periinsular, the rest vertical) and 32 received EH. The mean age was 8.65 ± 5.41 years (EH: 8.6 ± 5.3 years; OH: 8.6 ± 5.7 years). Seizure frequency per day was 7 ± 5.9 (EH: 7.3 ± 4.6; OH: 15.0 ± 6.2). Duration of disease (years since first episode) was 3.92 ± 1.24 years (EH: 5.2 ± 4.3; OH: 5.8 ± 4.5 years). Number of antiepileptic drugs per patient was 3.9 ± 1.2 (EH: 4.2 ± 1.2; OH: 3.8 ± 0.98). Values for the foregoing variables are expressed as the mean ± SD. Pathologies included the following: postinfarct encephalomalacia in 19 (EH: 11); Rasmussen's syndrome in 14 (EH: 7); hemimegalencephaly in 12 (EH: 7); hemispheric cortical dysplasia in 7 (EH: 4); postencephalitis sequelae in 6 (EH: 2); and Sturge-Weber syndrome in 1 (EH: 1). The mean follow-up was 40.16 ± 17.3 months. Thirty-nine of 49 (79.6%) had favorable outcomes (International League Against Epilepsy class I and II): in EH the total was 19/23 (82.6%) and in OH it was 20/26 (76.9%). There was no difference in the primary outcome between EH and OH (p = 0.15). Significant improvement was seen in the behavioral/quality of life performance, but not in IQ scores in both EH and OH (p < 0.01, no intergroup difference). Blood loss (p = 0.02) and hospital stay (p = 0.049) were less in EH.CONCLUSIONSEH was as effective as the open procedure in terms of primary and secondary outcomes. It also resulted in less blood loss and a shorter postoperative hospital stay.

Does surgery help in reducing stigma associated with drug refractory epilepsy in children?

INTRODUCTION: Epilepsy has several comorbidities and associated stigma. Stigma associated with epilepsy is well known and prevalent worldwide. Surgical treatment is an established treatment for drug refractory epilepsy. Following surgery in children, it is possible that the stigma may reduce, but such an effect has not been studied earlier. MATERIALS AND METHODS: Analysis of prospectively collected data was performed for pediatric patients at a single tertiary center for treating epilepsy. Child stigma scale, as described by Austin et al., was used to evaluate stigma both pre- and postoperatively. Analysis was done using Paired t test. RESULTS: In this study, following surgery, there was significant reduction of stigma (P<0.001). This was proportional to the reduction in seizures, though there were 9 (30%) patients, who due to persistent neurodisability did not have any reduction of stigma despite having good seizure outcome. CONCLUSION: Surgery in drug-resistant epilepsy helps in reducing stigma. Seizure reduction is probably not the only factor responsible for a change in stigma outcome.

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.

Surgery for Drug-Resistant Epilepsy in Children.

BACKGROUND: Neurosurgical treatment may improve seizures in children and adolescents with drug-resistant epilepsy, but additional data are needed from randomized trials. METHODS: In this single-center trial, we randomly assigned 116 patients who were 18 years of age or younger with drug-resistant epilepsy to undergo brain surgery appropriate to the underlying cause of epilepsy along with appropriate medical therapy (surgery group, 57 patients) or to receive medical therapy alone (medical-therapy group, 59 patients). The patients in the medical-therapy group were assigned to a waiting list for surgery. The primary outcome was freedom from seizures at 12 months. Secondary outcomes were the score on the Hague Seizure Severity scale, the Binet-Kamat intelligence quotient, the social quotient on the Vineland Social Maturity Scale, and scores on the Child Behavior Checklist and the Pediatric Quality of Life Inventory. RESULTS: At 12 months, freedom from seizures occurred in 44 patients (77%) in the surgery group and in 4 (7%) in the medical-therapy group (P<0.001). Between-group differences in the change from baseline to 12 months significantly favored surgery with respect to the score on the Hague Seizure Severity scale (difference, 19.4; 95% confidence interval [CI], 15.8 to 23.1; P<0.001), on the Child Behavior Checklist (difference, 13.1; 95% CI, 10.7 to 15.6; P<0.001), on the Pediatric Quality of Life Inventory (difference, 21.9; 95% CI, 16.4 to 27.6; P<0.001), and on the Vineland Social Maturity Scale (difference, 4.7; 95% CI, 0.4 to 9.1; P=0.03), but not on the Binet-Kamat intelligence quotient (difference, 2.5; 95% CI, -0.1 to 5.1; P=0.06). Serious adverse events occurred in 19 patients (33%) in the surgery group, including hemiparesis in 15 (26%). CONCLUSIONS: In this single-center trial, children and adolescents with drug-resistant epilepsy who had undergone epilepsy surgery had a significantly higher rate of freedom from seizures and better scores with respect to behavior and quality of life than did those who continued medical therapy alone at 12 months. Surgery resulted in anticipated neurologic deficits related to the region of brain resection. (Funded by the Indian Council of Medical Research and others; Clinical Trial Registry-India number, CTRI/2010/091/000525 .).

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.

Prevalence of celiac disease in Indian children with Down syndrome and its clinical and laboratory predictors.

OBJECTIVE: To study the prevalence of celiac disease in Indian children with Down syndrome and evaluate its clinical and laboratory predictors. METHODS: Prevalence of celiac disease (CD) was assessed in 100 patients with Down syndrome (DS) attending pediatric genetic clinic at All India Institute of Medical Sciences,in a prospective observational study, based on the characteristic symptomatology, positive indirect immunofluorescence anti endomyseal antibody(anti EMA) test and duodenal histology based on adapted Marsh criteria. Clinical and laboratory features were compared in children having both CD and DS and those with DS alone. RESULTS: Anti EMA was positive in 7 out of 100 patients screened for CD; 6 in whom the duodenal biopsy could be done showed histopathological features consistent with celiac disease. Amongst various clinical features evaluated as possible risk factors; pallor reached statistical significance (OR = 7.04 95%CI 1.08-45.7). In addition anemia (Hb <11 g%) was significantly associated with CD (p = 0.06). CONCLUSIONS: The present results showed a high prevalence of CD in DS children in a tertiary hospital in India and low hemoglobin to be an important risk factor. The authors recommend that all Indian children with Down syndrome, particularly those with anemia should be screened for celiac disease.

The bidirectional cavopulmonary (Glenn) shunt without cardiopulmonary bypass: is it a safe option?

OBJECTIVES: The bidirectional cavopulmonary (Glenn) shunt is a commonly performed procedure for a variety of cyanotic congenital heart diseases that lead eventually to a single ventricle repair. It is usually performed under cardiopulmonary bypass with its associated adverse effects and costs. We report our results of bidirectional Glenn operation done without cardiopulmonary bypass. METHODS: Between January 2002 and July 2003, 37 patients with complex cyanotic congenital heart defects underwent bidirectional Glenn operation by a single surgeon at our center. Of these, 22 patients had the procedure performed without cardiopulmonary bypass. Age of the patients ranged from 7 months to 11 years (mean 3.11+/-2.38 years). The procedures were done with temporary clamping of the superior vena cava. Four patients had bilateral Glenn procedure done and one had additional right pulmonary artery-plasty done. All the patients underwent complete neurological examination, CT scan of head and developmental quotient/intelligence quotient test both preoperatively as well as postoperatively. RESULTS: There was no operative mortality in our patients. Mean follow-up was 17.18+/-5.28 months. The mean internal jugular venous pressure on clamping the superior vena cava was 34.04+/-10.15 mmHg, and the mean clamp time was 6.85+/-1.52 min. There was no hemodynamic instability during any of the procedures and oxygen saturation was maintained at more than 65-70% throughout the procedure. The mean intensive care unit stay was 1.27+/-0.45 days. There were no neurological complications in any patient as assessed clinically and by CT scan of the head. None of the patients showed deterioration of developmental quotient/intelligence quotient score during follow-up evaluation. CONCLUSIONS: Our results show that in selected patients, bidirectional Glenn operation without cardiopulmonary bypass is a safe procedure. It avoids cardiopulmonary bypass related problems and is economical, with excellent results.