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.

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.

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.

L-asparginase administration reduces white blood cell count and prevents tumor lysis syndrome in children with hyperleukocytic acute lymphoblastic leukemia.

BACKGROUND: The management of hyperleukocytosis currently involves intensive supportive care for preventing tumor lysis syndrome (TLS)-associated metabolic abnormalities as well as cytoreduction procedures to reduce the white blood cell (WBC) count. These procedures are often equipment-intensive and may not be practised in developing countries with limited resources. Hence, it is not clear what would be the most effective strategy to manage hyperleukocytosis and prevent TLS. PROCEDURE: All children ≤12 years, diagnosed with acute lymphoblastic leukemia (ALL) and hyperleukocytosis (WBC count >100 × 10(9)/l) were administered L-asparginase (L-asp, 6,000 U/m(2), i.m.) along with standard supportive care consisting of hydration, oral allopurinol administration and alkalization. The complete blood counts and biochemical parameters were monitored for 72 h. After 48 h, if the WBC count was >100 × 10(9)/l, a repeat dose of L-asp was administered. RESULTS: Twenty-one children (9 boys and 12 girls) with hyperleukocytic ALL were treated with L-asp. The median age of the children was 5.3 years (range 2-11 years). The median initial WBC count was 249 × 10(9)/l (range 151-476 × 10(9)/l). Twenty children received only one dose of L-asp. The mean reduction in WBC count achieved by treatment was 15.7, 42.0, 61.0, 76.4, 85.5 and 90.8% at 12, 24, 36, 48, 60 and 72 h, respectively. None of the patients developed TLS. CONCLUSIONS: Chemical cytoreduction by administering L-asp is an effective means of managing hyperleukocytosis and preventing TLS.

A unique association of unilateral idiopathic calcinosis cutis with ipsilateral porokeratotic eccrine ostial and dermal duct nevus.

An 11-year-old boy presented with complaints of multiple skin-colored hard lumps on the right side of his body and progressive deformity of the right leg of 7-years duration. His parents had also noticed multiple asymptomatic pits over his right arm, palms, and soles since childhood. Examination revealed skin-colored nontender nodules on the right half of his body and shortening of his right leg. The multiple hyperpigmented pits over the right arm, palm, and sole raised diagnostic difficulties, but histopathologic, radiologic, and biochemical investigations confirmed the features of idiopathic calcinosis cutis and porokeratotic eccrine ostial and dermal duct nevus. Unilateral idiopathic calcinosis cutis has not been previously reported in the literature, and the association with ipsilateral porokeratotic eccrine ostial and dermal duct nevus makes this case unique. Diagnostic difficulties and limited options for treatment make this case interesting academically.

Propranolol for infantile hemangioma (PINCH): an open-label trial to assess the efficacy of propranolol for treating infantile hemangiomas and for determining the decline in heart rate to predict response to propranolol.

BACKGROUND: Propranolol has emerged as front-line therapy for infantile hemangiomas (IHs). However, a well-defined protocol for administering and predicting response to propranolol is unavailable. METHODS: In this open-label trial, 31 children with IH (median age=5 mo; range,1 mo to 9 y) were administered propranolol (2 mg/kg/d) for a median duration of 28 weeks (12 to 50 wk). They were compared with 14 historical controls with IH who did not receive any treatment. An image-based scoring system was used to assess involution. RESULTS: Propranolol (28/31, 90.3%) produced better and faster response compared with control treatment (4/14, 28.6%). With propranolol, 65% to 80% involution was obtained in the first 8 weeks, with an additional 2% to 10% involution until 20 weeks. After 20 weeks, the changes in IH were insignificant. Response was more pronounced among infants ≤6 months of age who attained a peak involution score of 1.86, suggesting >80% involution of IH. The similar score in the cohort aged 6 to 36 months was 3.31. The heart rate (HR) decline after propranolol treatment was significantly higher among patients whose hemangioma responded to propranolol than in those who did not respond (P=0.0006). Decline in HR by >20%, 2 weeks after propranolol administration, was predictive of IH involution (relative risk=0.11; 95% confidence interval, 0.02-0.51; P=0.036). CONCLUSIONS: Propranolol is efficacious in patients with IH. The most pronounced response is seen in the first 8 weeks and in infants aged 6 months or younger. A decline in HR >20% is an early marker of response to propranolol.

Immunosuppressive therapy in adults with aplastic anaemia: single-institution experience from India.

OBJECTIVE: To determine overall survival and factors predicting survival after immunosuppressive therapy in patients with acquired aplastic anaemia. DESIGN: Retrospective. SETTING: Tertiary care hospital. PATIENTS: 120 adults diagnosed as having acquired aplastic anaemia between 1 January 1996 and 31 December 2009. INTERVENTIONS: Anti-thymocyte globulin (ATG) followed by ciclosporin was administered to all patients for 15-18 months as the initial treatment. Haematological response was assessed 6 months after ATG administration and 6-monthly thereafter. Platelets were transfused if levels were <10 × 10(3)/l and for symptomatic bleeding. Transfusions of red blood cells were given for haemoglobin levels <70 g/l or symptomatic anaemia. Febrile neutropenia was managed with antibiotics, with the addition of antifungal agents after 3-4 days of unresponsive fever. Granulocyte colony-stimulating factor was administered at a dose of 5 µg/kg/day (maximum 300 µg/day) subcutaneously for infective episodes. PRIMARY OUTCOME: overall survival. Secondary outcome: response to immunosuppressive therapy, failure-free survival, relapse and clonal evolutions. The response and relapse criteria were defined in accordance with the British Council for Standards in Haematology guidelines. RESULTS: Overall response at 6 months after initiation of treatment was 85.8% (103/120). Overall survival at 76 months was 83.4%. Overall survival correlated with presence of response (complete response or partial response) at 6 months after ATG administration (HR=0.021, 95% CI 0.006 to 0.079, p<0.001). The occurrence of infectious complications adversely affected the overall survival (HR=5.71, 95% CI 1.22 to 26.77, p=0.027). Six patients relapsed. There were no deaths or adverse events 12 months after treatment among responders. CONCLUSIONS: In our study, overall survival was 83.4% at a median follow-up of 76 months. The two variables that significantly affected overall survival were response to therapy at 6 months and occurrence of infectious complications.

Translating technology into patient care: Smartphone applications in pediatric health care.

The latest generations of smartphones are increasingly viewed as handheld computers rather than as phones and the applications on these phones are becoming increasingly popular among the medical professionals. A large number of health care applications are available across various smartphone platforms. At times it may be difficult to identify most appropriate and reliable application for use at the point of care. In this review, we have tried to identify the applications relevant to Pediatrics and Childcare which when used at the point of care might be helpful in improving patient care.

A study to determine the prevalence of pulmonary arterial hypertension in children with Down syndrome and congenital heart disease.

BACKGROUND: Down syndrome (DS) is a common chromosomal abnormality associated with congenital heart disease (CHD). These cardiac abnormalities are known to be associated with pulmonary arterial hypertension (PAH). METHODS: The aim of this study was to assess the prevalence of PAH in DS children with CHD and to compare it with PAH prevalence in non-syndromic children with CHD. It was a cross-sectional study including all children presenting to Cardiology Department at a tertiary care center between Jan 2007 and Dec 2010. RESULTS: Thirty-five DS children with CHD were compared with 38 non-syndromic children with CHD. Atrioventricular septal defect (AVSD, 13/35) was the commonest CHD among DS children while isolated VSD (26/38) accounted for maximum cases in non-syndromic CHD. PAH was more prevalent among DS children with CHD (18/42) than among the control group (7/38, p = 0.038). In addition, 14/19 patients with AVSD in the entire cohort developed PAH. CONCLUSION: DS children with CHD have a higher predisposition to develop PAH, and the likelihood is highest with underlying AVSD.

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.

Complete remission and long-term survival in a child with relapsed medulloblastoma with extensive osteosclerotic bony metastasis with a novel metronomic chemobiological approach.

Extraneural metastases in medulloblastoma are rare. We report a boy with medulloblastoma who was initially treated with gross total excision of primary tumor followed by radiotherapy. Six years later, he developed disseminated osteosclerotic bony relapse associated with bone marrow involvement. He was successfully salvaged with metronomic low-dose cyclophosphamide, etoposide, and zoledronic acid. In patients with medulloblastoma and bone pain, metastases to bone should be excluded, and medulloblastoma should be considered while investigating osteosclerotic bone lesions. Furthermore, metronomic chemotherapy should be considered in this setting until better therapeutic modalities emerge.

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.

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.

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.

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.

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.

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.

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.