Current Evidence: Seizures in Extremely Low Gestational Age Newborns (ELGANs).

Extremely low gestational age newborns (ELGANs) are born at or below 28 weeks of gestational age. Despite improved obstetric care, the incidence of preterm birth continues to rise in advanced countries. Preterm birth remains a major cause of infant mortality, and for infants who survive, neonatal seizures are a significant predictor of later neurologic morbidity. However, little is known about risk factors for neonatal seizures in ELGANs. Understanding the association between neonatal seizures and the development of other neurologic disorders is important given the increasing prevalence of ELGANs. Identifying risk factors that contribute to the development of neonatal seizures in ELGANs may offer insights into novel mechanisms of epileptogenesis in the developing brain and improvements in the prevention or treatment of seizures in preterm infants, including ELGANs. In this literature review, we outline the limitations of epidemiologic studies of neonatal seizures in ELGANs and discuss risk factors for neonatal seizures.

Recent advances and future directions on small molecule VEGFR inhibitors in oncological conditions.

"A journey of mixed emotions" is a quote that best describes the progress chart of vascular endothelial growth factor receptor (VEGFR) inhibitors as cancer therapeutics in the last decade. Exhilarated with the Food and Drug Administration (FDA) approvals of numerous VEGFR inhibitors coupled with the annoyance of encountering the complications associated with their use, drug discovery enthusiasts are on their toes with an unswerving determination to enhance the rate of translation of VEGFR inhibitors from preclinical to clinical stage. The recently crafted armory of VEGFR inhibitors is a testament to their growing dominance over other antiangiogenic therapies for cancer treatment. This review perspicuously underscores the earnest attempts of the researchers to extract the antiproliferative potential of VEGFR inhibitors through the design of mechanistically diverse structural assemblages. Moreover, this review encompasses sections on structural/molecular properties and physiological functions of VEGFR, FDA-approved VEGFR inhibitors, and hurdles restricting the activity range/clinical applicability of VEGFR targeting antitumor agents. In addition, tactics to overcome the limitations of VEGFR inhibitors are discussed. A clear-cut viewpoint transmitted through this compilation can provide practical directions to push the cart of VEGFR inhibitors to advanced-stage clinical investigations in diverse malignancies.

Interrater reliability of interictal EEG waveforms in Lennox-Gastaut Syndrome.

OBJECTIVE: Identification of EEG waveforms is critical for diagnosing Lennox-Gastaut Syndrome (LGS) but is complicated by the progressive nature of the disease. Here, we assess the interrater reliability (IRR) among pediatric epileptologists for classifying EEG waveforms associated with LGS. METHODS: A novel automated algorithm was used to objectively identify epochs of EEG with transient high power, which were termed events of interest (EOIs). The algorithm was applied to EEG from 20 LGS subjects and 20 healthy controls during NREM sleep, and 1350 EOIs were identified. Three raters independently reviewed the EOIs within isolated 15-second EEG segments in a randomized, blinded fashion. For each EOI, the raters assigned a waveform label (spike and slow wave, generalized paroxysmal fast activity, seizure, spindle, vertex, muscle, artifact, nothing, or other) and indicated the perceived subject type (LGS or control). RESULTS: Labeling of subject type had 85% accuracy across all EOIs and an IRR of κ =0.790, suggesting that brief segments of EEG containing high-power waveforms can be reliably classified as pathological or normal. Waveform labels were less consistent, with κ =0.558, and the results were highly variable for different categories of waveforms. Label mismatches typically occurred when one reviewer selected "nothing," suggesting that reviewers had different thresholds for applying named labels. SIGNIFICANCE: Classification of EEG waveforms associated with LGS has weak IRR, due in part to varying thresholds applied during visual review. Computational methods to objectively define EEG biomarkers of LGS may improve IRR and aid clinical decision-making.

Small molecule tractable PARP inhibitors: Scaffold construction approaches, mechanistic insights and structure activity relationship.

Diverse drug design strategies viz. molecular hybridization, substituent installation, scaffold hopping, isosteric replacement, high-throughput screening, induction and separation of chirality, structure modifications of phytoconstituents and use of structural templates have been exhaustively leveraged in the last decade to load the chemical toolbox of PARP inhibitors. Resultantly, numerous promising scaffolds have been pinpointed that in turn have led to the resuscitation of the credence to PARP inhibitors as cancer therapeutics. This review briefly presents the physiological functions of PARPs, the pharmacokinetics, and pharmacodynamics, and the interaction profiles of FDA-approved PARP inhibitors. Comprehensively covered is the section on the drug design strategies employed by drug discovery enthusiasts for furnishing PARP inhibitors. The impact of structural variations in the template of designed scaffolds on enzymatic and cellular activity (structure-activity relationship studies) has been discussed. The insights gained through the biological evaluation such as profiling of physicochemical properties andin vitroADME properties, PK assessments, and high-dose pharmacology are covered.

Hyperventilation and Seizures: Not a New Sense: A Literature Review.

Hyperventilation and seizures have a long association in the clinical literature and were known to have a relationship long before the electroencephalogram (EEG) was used to record changes in brain activity. As the use of EEG recording progressed, hyperventilation was the first activation method used to assist with diagnosis of epilepsy. Along with slowing of brain activity, hyperventilation can activate epileptiform spiking activity in patients with epilepsy. Currently, hyperventilation is used in standard practice to assist with the diagnosis of epilepsy during EEG recording. Hyperventilation activates epileptiform spiking activity more often than seizures but can trigger clinical seizures in up to 50% of patients with generalized epilepsy. It is more likely to trigger events in children with absence seizures than adults, and it acts as a trigger in patients with focal epilepsy far less often. However, while some clinicians suggest that its diagnostic value is limited, especially in adults with focal epilepsies, others suggest that it is simple, safe, and an important diagnostic tool, even in these patients. This review presents the history of hyperventilation and seizures, its use in the clinical practice, and possible mechanisms involved.

Prudent tactics to sail the boat of PARP inhibitors as therapeutics for diverse malignancies.

INTRODUCTION: PARP inhibitors block the DNA-repairing mechanism of PARP and represent a promising class of anti-cancer therapy. The last decade has witnessed FDA approvals of several PARP inhibitors, with some undergoing advanced-stage clinical investigation. Medicinal chemists have invested much effort to expand the structure pool of PARP inhibitors. Issues associated with the use of PARP inhibitors that make their standing disconcerting in the pharmaceutical sector have been addressed via the design of new structural assemblages. AREA COVERED: In this review, the authors present a detailed account of the medicinal chemistry campaigns conducted in the recent past for the construction of PARP1/PARP2 inhibitors, PARP1 biased inhibitors, and PARP targeting bifunctional inhibitors as well as PARP targeting degraders (PROTACs). Limitations associated with FDA-approved PARP inhibitors and strategies to outwit the limitations are also discussed. EXPERT OPINION: The PARP inhibitory field has been rejuvenated with numerous tractable entries in the last decade. With numerous magic bullets in hand coupled with unfolded tactics to outwit the notoriety of cancer cells developing resistance toward PARP inhibitors, the dominance of PARP inhibitors as a sagacious option of targeted therapy is highly likely to be witnessed soon.

Paroxysmal hyperthermia, dysautonomia and rhabdomyolysis in a patient with Lesch-Nyhan syndrome.

Lesch-Nyhan syndrome is an x-linked genetic disorder of purine metabolism that results in the overproduction of uric acid and neurologic deficits manifesting as intellectual disability, dystonia, other movement disorders and self-mutilation. We describe a 12-year-old patient with a history of Lesch-Nyhan syndrome, G6PD deficiency and central diabetes insipidus and multiple admissions for fever, acute kidney injury and transaminitis in the setting of rhabdomyolysis. The patient's temperature dysregulation and dysautonomia is likely attributable to abnormal neurotransmitter release, particularly that of dopamine, in the central nervous system. Our patient presented similarly to that of a patient with neuroleptic malignant syndrome (NMS), with symptoms including altered mental status, fever, dysautonomia and renal failure, and laboratory findings including elevated serum creatinine kinase, leukocytosis, transaminitis, hypernatremia and metabolic acidosis. Similar to NMS, disruption of dopamine neurotransmission results in dysregulated sympathetic activity and hyperthermia.

Assessment and Treatment of Concussion in the Pediatric Population.

Traumatic brain injury (TBI) is common in children. The evaluation and management of children with TBI is based on the research performed in adults. There is a relative paucity of research in the literature involving children and many of the practice recommendations for this age are based on expert opinion in the absence of good research studies in both sports and non-sports-related injuries. The pediatric population is heterogeneous and the approach might be specific for infants, preschoolers, school age children, and adolescents. Children may also suffer from neurodevelopmental disabilities, making their evaluation even more challenging. Adult neurologists are often asked to see children due to increasing demands. This review will focus on specific issues related to TBI in children that might be useful to adult neurologists. Science, however, is evolving rapidly and physicians should make sure to remain up to date to offer evidence-based services to their patients.

The Assessment and Treatment of Sleep Abnormalities in Children and Adolescents with Autism Spectrum Disorder: A Review.

OBJECTIVE: To summarize causes, evaluation methods, and treatment of sleep disturbance in children and adolescents with autism spectrum disorder (ASD). METHODS: A narrative literature and synthesis approach was used. RESULTS/DISCUSSION: Sleep disturbances in this population are common and include insomnia, parasomnias, circadian rhythm disorders, and sleep-related movement disorders. Multiple factors may contribute to the higher rates of sleep disturbances in persons with ASD. Unfortunately, there are not evidence-based guidelines specific for the management of these sleep disorders in this population. There is also a lack of controlled clinical studies. Nevertheless, assessment of sleep problems using both subjective and objective methods are recommended to develop an individualized approach. Behavioural interventions are preferred first line treatment for insomnia. As adjunctive measures, pharmacotherapy may be warranted and choice should be guided based on accompanying symptoms. The most commonly used pharmacotherapy for sleep disturbance, primarily insomnia, include melatonin and alpha agonists. Not all currently used medications are approved for use for children and adolescents.

OBJECTIF: Résumer les causes, les méthodes d'évaluation et de traitement des troubles du sommeil chez les enfants et les adolescents souffrant du trouble du spectre de l'autisme (TSA). MÉTHODES: une littérature narrative et une approche de synthèse ont été utilisées. RÉSULTATS/DISCUSSION: les troubles du sommeil dans cette population sont communs et comprennent l'insomnie, la parasomnie, les perturbations du rythme circadien, et le trouble du mouvement lié au sommeil. De multiples facteurs peuvent contribuer aux taux élevés de troubles du sommeil chez les personnes souffrant du TSA. Malheureusement il n'existe pas de directives fondées sur des données probantes pour la prise en charge de ces troubles du sommeil dans cette population. Il manque également des études cliniques contrôlées. Néanmoins, l'évaluation des troubles de sommeil à l'aide de méthodes tant subjectives qu'objectives est recommandée pour développer une approche individualisée. Les interventions comportementales sont le traitement de première intention préféré pour l'insomnie. La pharmacothérapie des mesures d'appoint peut être justifiée et le choix devrait être basé sur les symptômes accompagnateurs. La pharmacothérapie la plus utilisée pour les troubles du sommeil, surtout l'insomnie, comprend la mélatonine et les alpha-agonistes. Les médicaments couramment en usage ne sont pas tous approuvés à utiliser pour les enfants et les adolescents.

Increasing ear pain and headache.

Visits to the family physician, a specialist, and the ED prompted us to look beyond the initial diagnosis of acute otitis media.

Alternative Approaches to Adenotonsillectomy and Continuous Positive Airway Pressure (CPAP) for the Management of Pediatric Obstructive Sleep Apnea (OSA): A Review.

Continuous positive airway pressure (CPAP) is considered first-line treatment in the management of pediatric patients without a surgically correctible cause of obstruction who have confirmed moderate-to-severe obstructive sleep apnea (OSA). The evidence supports its reduction on patient morbidity and positive influence on neurobehavioral outcome. Unfortunately, in clinical practice, many patients either refuse CPAP or cannot tolerate it. An update on alternative approaches to CPAP for the management of OSA is discussed in this review, supported by the findings of systematic reviews and recent clinical studies. Alternative approaches to CPAP and adenotonsillectomy for the management of OSA include weight management, positional therapy, pharmacotherapy, high-flow nasal cannula, and the use of orthodontic procedures, such as rapid maxillary expansion and mandibular advancement devices. Surgical procedures for the management of OSA include tongue-base reduction surgery, uvulopalatopharyngoplasty, lingual tonsillectomy, supraglottoplasty, tracheostomy, and hypoglossal nerve stimulation. It is expected that this review will provide an update on the evidence available regarding alternative treatment approaches to CPAP for clinicians who manage patients with pediatric OSA in daily clinical practice.

[Sleep in children: physiology and update of a literature review]. / Sueño en los ninos: fisiología y actualizacion de los últimos conocimientos.

Sleep is an active and cyclic physiological process that has a critical impact on health. Its functions are numerous: growth, development, learning, memory, synaptic efficiency, regulation of behavior, emotion, immune strengthening and cleaning time of neurotoxic substances. During the first years of life, there are a number of important changes in development, which lead to the expected pattern of sleep and wakefulness in adults. The sleep occupies a third of the adult's life. However, sleeping during the first months of life takes up more than 50% of time. This review of the topic will describe normal sleep patterns in childhood.

El sueño es un proceso fisiológico activo y cíclico que tiene efectos críticos en la salud. Sus funciones son numerosas: crecimiento, desarrollo, aprendizaje, memoria, eficiencia sináptica, regulación del comportamiento, emoción, fortalecimiento inmunológico y tiempo de limpieza de sustancias neurotóxicas. Durante los primeros años de vida hay una serie de cambios importantes en el desarrollo que conducen al patrón esperado de sueño y vigilia en los adultos. El sueño ocupa un tercio de la vida del adulto. Sin embargo, dormir durante los primeros meses de vida ocupa más del 50% del tiempo. Esta revisión del tema describirá los patrones normales de sueño en la infancia.

Sueño en los niños: fisiología y actualizacion de los últimos conocimientos / Sleep in children: physiology and update of a literature review

El sueño es un proceso fisiológico activo y cíclico que tiene efectos críticos en la salud. Sus funciones son numerosas: crecimiento, desarrollo, aprendizaje, memoria, eficiencia sináptica, regulación del comportamiento, emoción, fortalecimiento inmunológico y tiempo de limpieza de sustancias neurotóxicas. Durante los primeros años de vida hay una serie de cambios importantes en el desarrollo que conducen al patrón esperado de sueño y vigilia en los adultos. El sueño ocupa un tercio de la vida del adulto. Sin embargo, dormir durante los primeros meses de vida ocupa más del 50% del tiempo. Esta revisión del tema describirá los patrones normales de sueño en la infancia.

Sleep is an active and cyclic physiological process that has a critical impact on health. Its functions are numerous: growth, development, learning, memory, synaptic efficiency, regulation of behavior, emotion, immune strengthening and cleaning time of neurotoxic substances. During the first years of life, there are a number of important changes in development, which lead to the expected pattern of sleep and wakefulness in adults. The sleep occupies a third of the adult's life. However, sleeping during the first months of life takes up more than 50% of time. This review of the topic will describe normal sleep patterns in childhood.

Perspectives on the role of brain cellular players in cancer-associated brain metastasis: translational approach to understand molecular mechanism of tumor progression.

Brain metastasis is one of the leading causes of death among cancer patients. Cancer cells migrate to various sites and harbor different niche in the body which help cancer cells in their survival. The brain is one of the safest place where cancer cells are protected from immune cells. Breast, lung, and melanoma cancer cells have high propensity to migrate towards the brain. To enter the brain, cancer cells have to cross the blood brain barrier. Survival and finding new niche in the brain are directed by several mechanisms in which different cellular players take part such as astrocytes, microglia, Schwann cells, satellite cells, oligodendrocytes, and ependymal cells. Usually, cancer cells highjack the machinery of brain cellular players to survive in the brain environment. It has been shown that co-culture of M2 macrophage with cancer cells leads to increased proliferation and survival of cancer cells. One of the challenges of understanding brain metastasis is appropriate model system to understand dynamic interaction of cancer cells and brain cellular players. To meet this challenge, microfluidic-based devices are employed which can mimic the dynamic conditions as well as can be used for culturing human cells for personalized therapy. In this review, we have systematically reviewed the current status of the role of cellular players in brain metastasis along with explaining how translational approach of microfluidics can be employed for finding new drug target as well as biomarker for brain metastasis. Finally, we have also commented on the mechanism of action of drugs against brain metastasis.

Obstructive sleep apnea in infancy: a 7-year experience at a pediatric sleep center.

PURPOSE: To investigate the common indications for polysomnogram (PSG) associated co-morbid conditions, evaluation strategies, treatment options, and outcomes in a series of infants diagnosed with obstructive sleep apnea (OSA) by a PSG. METHODS: Retrospective chart review of infants who underwent PSG over a 7-year period was done. Infants with PSG diagnosed OSA were included in this study. RESULTS: A total of 97 infants (59 males, mean age 4.6 months, standard deviation 3.3 months) were diagnosed with OSA (AHI ≥ 1/hr) based on PSG. The most common indication for PSG in infants were excessive snoring (53%) followed by nocturnal desaturations (24%). Associated co-morbid conditions included gastro-esophageal reflux (30%), laryngomalacia (24%), and craniofacial abnormalities (16%). Genetic abnormalities were found in 53%, of which trisomy 21 was the most common. Surgical treatments were employed in 36% and oxygen therapy in 15%. Thirty-eight patients were followed up with a repeat sleep study after a median interval of 8 months (range 1-24 months), of whom 26/38 had resolution of symptoms. Twenty-seven patients (28%) were followed clinically after a mean interval of 5 months of intervention (range, 1-34.5 months), in whom the symptoms resolved in 23/27 patients. Seven patients were deceased at review. Causes of death included status epilepticus, respiratory failure, hepatic failure, kidney failure, or unknown causes. CONCLUSION: The etiologies of OSA in infants are different when compared to older children. PSG is feasible and a valuable tool in the diagnosis of OSA in infants and may help determine timely and appropriate evaluation and interventions. Clinical improvement in symptoms and resolution of PSG parameters were noted following medical and/or surgical interventions. Prospective studies need to be done to ascertain the long-term outcome of infants diagnosed with OSA to assess the benefits of early intervention on their neurocognitive development.