How can transition to adult care be best orchestrated for adolescents with epilepsy?

Objective evidence is limited for the value of transition programs for youth with chronic illness moving from pediatric to adult care; however, such programs intuitively "make sense". We describe the strengths and weaknesses of a variety of transition programs from around the world for adolescents with epilepsy. Consequences of poorly organized transition beyond suboptimal seizure control may include an increased risk of sudden unexpected death in epilepsy (SUDEP), poor psychological and social outcome, and inadequate management of comorbidities. The content of transition programs for those with normal intelligence differs from those with intellectual disability, but both groups may benefit from an emphasis on sporting activities. Concerns that may interfere with optimal transition include lack of nursing or social work services, limited numbers of adult neurologists/epileptologists confident in the treatment of complex pediatric epilepsy problems, institutional financial support, and time constraints for pediatric and adult physicians who treat epilepsy and the provision of multidisciplinary care. Successful programs eventually need to rely on a several adult physicians, nurses, and other key healthcare providers and use novel approaches to complex care. More research is needed to document the value and effectiveness of transition programs for youth with epilepsy to persuade institutions and healthcare professionals to support these ventures.

Cortical atrophy and hypofibrinogenemia due to FGG and TBCD mutations in a single family: a case report.

BACKGROUND: Blended phenotypes or co-occurrence of independent phenotypically distinct conditions are extremely rare and are due to coincidence of multiple pathogenic mutations, especially due to consanguinity. Hereditary fibrinogen deficiencies result from mutations in the genes FGA, FGB, and FGG, encoding the three different polypeptide chains that comprise fibrinogen. Neurodevelopmental abnormalities have not been associated with fibrinogen deficiencies. In this study, we report an unusual patient with a combination of two independently inherited genetic conditions; fibrinogen deficiency and early onset cortical atrophy. CASE PRESENTATION: The study describes a male child from consanguineous family presented with hypofibrinogenemia, diffuse cortical atrophy, microcephaly, hypertonia and axonal motor neuropathy. Through a combination of homozygosity mapping and exome sequencing, we identified bi-allelic pathogenic mutations in two genes: a homozygous novel truncating mutation in FGG (c.554del; p.Lys185Argfs*14) and a homozygous missense mutation in TBCD (c.1423G > A;p.Ala475Thr). Loss of function mutations in FGG have been associated with fibrinogen deficiency, while the c.1423G > A mutation in TBCD causes a novel syndrome of neurodegeneration and early onset encephalopathy. CONCLUSIONS: Our study highlights the importance of homozygosity mapping and exome sequencing in molecular prenatal diagnosis, especially when multiple gene mutations are responsible for the phenotype.

The Indian Academy of Pediatrics and Directorate General of Health Services, Government of India White Paper on Transition of Care for Youth with Special Health Care Needs.

Over the years, survival of children with chronic diseases has significantly improved and a large proportion of them now are entering into adulthood. Transition of Care (ToC) of such patients with having childhood onset of chronic diseases to the adult health care system is well organized in developed countries, although it is an emerging concept in India. In situations where the systems for ToC are not in place, such cases are fraught with unsatisfactory health outcomes. With proper ToC in place, these patients are likely to receive uninterrupted care by the adult care physicians and hence reach their full potential. This document highlights the need, rationale and way forward for ToC of youth with special health care needs (YSHCN) across the country. It also describes the standard operating procedures to develop the ToC at a hospital level for clinicians and administrators.

Acute Ischemic Stroke in Children - Should We Thrombolyze?

Ischemic stroke is a major cause of acute neurological symptoms in children with significant long-term neurological sequelae. Unlike in the adult population, the clinical presentation of strokes in children may not be stereotyped. Hence, many other differential diagnostic possibilities might have to be considered in the emergency setting. Due to this heterogeneous presentation and the resultant clinical dilemma in the early detection, acute thrombolysis even now remains as a very rarely tried therapeutic option in children. Many case reports over these years have shown consistently good results of acute intravenous thrombolysis in children with tissue plasminogen activator (tPA) administered within the time frame. There are also some recent reports of endovascular interventions. However, unlike in the adult population, class 1 clinical studies and good Randomized controlled trials (RCT) are yet to emerge in children. The absence of age-appropriate safety and outcome data for the commonly used thrombolytic agents in children is another major roadblock for developing clinical guidelines and recommendations for this age group. The ambitious Thrombolysis in Pediatric Stroke (TIPS) trial had to be terminated prematurely due to poor patient enrolment. This review critically looks at the current status of the acute management of ischemic strokes in children with a specific emphasis on thrombolytic therapy. Until we have better evidence-based guidelines for this age group, it will be prudent to develop robust institutional pathways to provide this important intervention for all eligible children with acute strokes.

Functional Categorization of Disease Genes Based on Spectral Graph Theory and Integrated Biological Knowledge.

Interaction of multiple genetic variants is a major challenge in the development of effective treatment strategies for complex disorders. Identifying the most promising genes enhances the understanding of the underlying mechanisms of the disease, which, in turn leads to better diagnostic and therapeutic predictions. Categorizing the disease genes into meaningful groups even helps in analyzing the correlated phenotypes which will further improve the power of detecting disease-associated variants. Since experimental approaches are time consuming and expensive, computational methods offer an accurate and efficient alternative for analyzing gene-disease associations from vast amount of publicly available genomic information. Integration of biological knowledge encoded in genes are necessary for identifying significant groups of functionally similar genes and for the sufficient biological elucidation of patterns classified by these clusters. The aim of the work is to identify gene clusters by utilizing diverse genomic information instead of using a single class of biological data in isolation and using efficient feature selection methods and edge pruning techniques for performance improvement. An optimized and streamlined procedure is proposed based on spectral clustering for automatic detection of gene communities through a combination of weighted knowledge fusion, threshold-based edge detection and entropy-based eigenvector subset selection. The proposed approach is applied to produce communities of genes related to Autism Spectrum Disorder and is compared with standard clustering solutions.

Two South Indian Children with KCNT1-Related Malignant Migrating Focal Seizures of Infancy - Clinical Characteristics and Outcome of Targeted Treatment with Quinidine.

KCNT1 gene encodes a sodium-gated potassium channel subunit that plays an important role in regulating excitability in neurons. Quinidine is a partial antagonist of this channel. We report the clinical characteristics of two south Indian children with KCNT1-related epileptic encephalopathy. Both of them had very high seizure burden which were resistant to antiepileptic and dietary therapy. Pharmacological response to quinidine in these children is described. Case 1 had 30% reduction in seizure burden at 20 mg/kg/day and 80% reduction at 36 mg/kg/day; case 2 had 30% reduction at 20 mg/kg/day. Serial electrocardiography was used to monitor the cardiotoxicity. Serum quinidine levels were not measured due to nonavailability. A critical review on the current status of targeted treatment of KCNT1-related epileptic encephalopathies with quinidine is attempted.

Mineralizing Angiopathy of Lenticulostriate Arteries with Infantile Basal Ganglia Infarct Following Minor Head Trauma: A Case Series.

Acute arterial ischemic stroke after minor head trauma has been reported in the past, mostly in infants. Most of these affected children had basal ganglia infarct on imaging. Investigations for other etiologies of stroke were noncontributory in most of the cases. Thin-slice computed tomography scan may show mineralizing angiopathy of lenticulostriate arteries. We report a clinical series of four infants who presented with the classical features of this distinct clinico-radiological entity. Clinical characteristics and risk factors at the time of stroke were described in detail. The long-term outcome on standard antiplatelet therapy is reported. None of the children had stroke recurrence during follow-up. The current literature on this clinico-radiological syndrome is reviewed in detail. In the typical cases, extensive etiological workup may not be warranted.

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.

Juvenile Behçet's disease: highlighting neuropsychiatric manifestations and putative genetic mechanisms.

Behçet's disease is a multisystem inflammatory disorder of unknown etiology. We report a 12-year-old boy who presented with features of raised intracranial tension and seizures and was found to have cerebral venous sinus thrombosis on evaluation. Behçet's disease was diagnosed based on occurrence of recurrent oral and genital ulcers in the past and characteristic skin lesions subsequently. He also showed significant personality changes including multiple attempts of deliberate self-harm. Pedigree analysis revealed that six family members spanning three generations had recurrent oral ulcers and three members satisfied the criteria for Behçet's disease. Clinical features varied amongst the family members and there was suggestion of genetic anticipation. The index case was carrying HLA-B37/B7 and the mother was carrying B37/B40. Our report sheds light on the genetics of Behçet's disease. Unusual features were early age of onset, cerebral venous sinus thrombosis, significant personality changes and strong family history with phenotypic heterogeneity.

Multidimensional knowledge-based framework is an essential step in the categorization of gene sets in complex disorders.

In complex disorders, collaborative role of several genes accounts for the multitude of symptoms and the discovery of molecular mechanisms requires proper understanding of pertinent genes. Majority of the recent techniques utilize either single information or consolidate the independent outlook from multiple knowledge sources for assisting the discovery of candidate genes. In any case, given that various sorts of heterogeneous sources are possibly significant for quality gene prioritization, every source bearing data not conveyed by another, we assert that a perfect strategy ought to give approaches to observe among them in a genuine integrative style that catches the degree of each, instead of utilizing a straightforward mix of sources. We propose a flexible approach that empowers multi-source information reconciliation for quality gene prioritization that augments the complementary nature of various learning sources so as to utilize the maximum information of aggregated data. To illustrate the proposed approach, we took Autism Spectrum Disorder (ASD) as a case study and validated the framework on benchmark studies. We observed that the combined ranking based on integrated knowledge reduces the false positive observations and boosts the performance when compared with individual rankings. The clinical phenotype validation for ASD shows that there is a significant linkage between top positioned genes and endophenotypes of ASD. Categorization of genes based on endophenotype associations by this method will be useful for further hypothesis generation leading to clinical and translational analysis. This approach may also be useful in other complex neurological and psychiatric disorders with a strong genetic component.

Epilepsy, antiepileptic drugs and educational problems.

Epilepsy is a chronic disorder that significantly affects learning and behavior. Children with epilepsy are particularly vulnerable to educational problems and resultant academic underachievement. Co-morbidities like cognitive and behavioral problems contribute significantly for the problems at school. Both epilepsy and neuropsychological deficits may occur as different clinical manifestations of a common etiological process. Ongoing seizures themselves adversely affect the developing brain. Furthermore, psychosocial issues also contribute significantly to the problems at school. The effect of antiepileptic drugs is double edged in this setting. They may reduce the seizure burden and thus improve the cognitive function. However, these drugs also significantly affect the learning process. The treating pediatrician should be equipped to comprehensively address all these factors for an optimal outcome. Recent onset of educational problems in a child with epilepsy deserves immediate and aggressive evaluation and management.

Clinical Characteristics and Follow-up of South Indian Children with Autoimmune Encephalopathy.

OBJECTIVE: To describe the clinical characteristics of a cohort of south Indian children with probable autoimmune encephalopathy from a tertiary care academic hospital and to compare this data with the existing literature. METHODS: Patients with encephalopathy plus one or more of neuropsychiatric symptoms, seizures, movement disorder or cognitive dysfunction were identified. Common infectious causes were excluded. Clinical characteristics, investigations, management and outcome were analyzed. RESULTS: Thirteen patients were included in the study; 12 were females (92.3 %) and mean age was 9.6 y. Most common presentation was behavior change (13 patients) followed by seizures (11 patients). Three patients showed lymphocytic pleocytosis in CSF and one patient had oligoclonal bands. Initial MRI was normal in all patients except in one. Most common EEG abnormality was mild background slowing. Only one child had ovarian tumor. S.NMDA receptor antibody was positive in 10 patients (83 %), and all of them received immunotherapy. Six out of 13 children were followed up for more than 1 y (mean - 21 mo). Recurrence was noted in 4 out of 6 patients (66 %). On last follow-up, good recovery was seen in 2 children (33 %), moderate disability in 3 (50 %) and severe disability in 1 (16 %). CONCLUSIONS: The clinical characteristics and outcome of one of the largest single center cohort of Indian children with autoimmune encephalopathy is reported. Autoimmune encephalopathy should be considered as a differential diagnosis in the acute and subacute encephalopathies of childhood and treating pediatrician should be aware of this entity.

Educational problems with underlying neuropsychological impairment are common in children with Benign Epilepsy of Childhood with Centrotemporal Spikes (BECTS).

INTRODUCTION: Benign Epilepsy of Childhood with Centrotemporal Spikes (BECTS) is one of the most common childhood epilepsies with a good prognosis regarding the seizure and neuropsychological outcomes. However, recent reports indicate the presence of neuropsychological problems in a significant percentage of children with BECTS. Our study was aimed to examine the educational performance and neuropsychological functions along with clinical and electrographic characteristics in a cohort of children with BECTS. METHODS: We identified a cohort of children with BECTS by screening medical and EEG recordings of patients attending our institute. Data were collected with a standard protocol. Their educational performance was evaluated by an interview with the parents. Neuropsychological and language tests were administered to children who had educational problems. Statistical analysis was done using the chi2-test. RESULTS: Fifty children (29 boys and 21 girls; mean age of onset of epilepsy 7.84+/-2.87 years) who met the criteria for BECTS were included in this study. Atypical seizure characteristics for BECTS were observed in 26 (52%) children. EEG showed typical centrotemporal spike and wave discharges in all children, 42% of them had a tangential dipole in the frontocentral region. An additional extra-rolandic focus in the EEG was found in seven children (14%). Educational problems were identified in 27 children (54%); 19 of them had neuropsychological or language impairment (p=0.003). We found a statistically significant correlation between the occurrence of educational problems and the absence of a tangential dipole in the EEG (p<0.001). Abnormal language function had a significant correlation with atypical seizure semiology (p=0.021). CONCLUSION: This study shows that a significant number of children with BECTS have neuropsychological impairment and educational problems.

Finger tapping activates spikes in benign epilepsy with centro-temporal spikes.

A case of benign epilepsy with centro-temporal spikes (BECT) is reported, in whom tapping of fingures activated typical spikes.

Jordans' anomaly.

A case of Jordans' Anomaly of leucocytes is reported in a young boy with congenital ichthyosis and hepatosplenomegaly. Cytoplasmic vacuoles were seen in granulocytes, monocytes and lymphocytes of the patient and his father. Serum triglyceride was found elevated in the child but not in the father. Ultrasonogram of the patient's liver showed features suggestive of fatty change, thus pointing to a possible abnormality of systemic triglyceride storage.