Psychostimulants for Children: Are We Over or Under Dosing?

An estimated 3% to 10% of school children meet the DSM-V criteria for ADHD (Attention-Deficit/Hyperactivity Disorder), however, to be over-diagnosed, the rate of children inappropriately diagnosed with ADHD (false positives) would have to be larger than the number of children with ADHD who are under-identified and not diagnosed (false negatives). Accordingly, a number of investigators take the position that under-treatment with psychostimulants, especially in children and adolescence, will result in continued ADHD symptomatology including future Substance Use Disorder (SUD). However, other researchers and clinicians believe otherwise and espouse laudable arguments for caution and prolonged methamphetamine treatment. While there is ongoing controversy of the role of genetics and epigenetics linked to ADHD, it seems clear that a number of dopaminergic genes and their risk polymorphisms act as DNA antecedents impacted by epigenetic induced methylation. Our hypothesis and literature review suggest that one possible solution is to embrace non addictive interventions to induce global dopamine homeostasis.

Use of Integrative, Complementary, and Alternative Medicine in Children with Epilepsy: A Global Scoping Review.

(1) Background: Epilepsy is one of the most common chronic neurological disorders in childhood. Complementary and alternative medicine (CAM) use is highly prevalent in patients with epilepsy. Despite CAM's widespread and increasing popularity, its prevalence, forms, perceived benefits, and potential risks in pediatric epilepsy are rarely explored. (2) Methods: We performed a scoping review of the available literature on the use of CAM in pediatric epilepsy. (3) Results: Overall, global cross-sectional studies showed a variable degree of CAM usage among children with epilepsy, ranging from 13 to 44% in prevalence. Popular types of CAMs reported were supplements, cannabis products, aromatherapy, herbal remedies, dietary therapy, massage therapy, and prayer. Families often report that CAM is effective, although there are limited objective measures of this. Potential risks lie in the use of CAM, such as herbal remedies, and/or unregulated, contaminated, or unpurified products. Studies also underscored inadequate patient-physician discussions regarding CAM. (4) Conclusions: A better understanding of this topic would aid clinicians in guiding patients/families on the use of CAM. Further studies on the efficacy of the different types of CAM used, as well as potential side effects and drug interactions are needed.

Elsberg Syndrome with Mixed Presentation as Meningitis Retention Syndrome: A Pediatric Case Report and Comprehensive Review of the Literature.

Elsberg syndrome is a typically infectious syndrome that may cause acute or subacute bilateral lumbosacral radiculitis and sometimes lower spinal cord myelitis. Patients often present with various neurological symptoms involving the lower extremities, including numbness, weakness, and urinary disturbances such as retention. A 9-year-old girl with no significant past medical history presented with altered mental status, fever, urinary retention, and anuria and was found to have encephalomyelitis. An extensive diagnostic workup led to ruling out possible etiologies until identifying Elsberg syndrome. In this report, we describe a case of Elsberg syndrome caused by West Nile virus (WNV). To the best of our knowledge, this is the first reported case of its kind in the pediatric population. Utilizing PubMed and Web of Science databases, we reviewed the literature to describe the neurogenic control of the urinary system in correlation to a multitude of neurologic pathologies.

Thrombectomy of an Acute Ischemic Stroke in a Child with COVID-19 and MIS-C: Case Analysis and Literature Context.

We describe a very young child who developed an acute ischemic stroke from a LAO, while affected by COVID-19 and MIS-C, and whom we treated successfully with thrombectomy. We compare his clinical and imaging findings with those of the existing case reports, and we explore the multifactorial nature of such a neurovascular complication, particularly in the context of the most recent publications regarding the multifactorial endothelial derangements produced by the illness.

SYT1-Associated Neurodevelopmental Disorder: A Narrative Review.

Synaptic dysregulations often result in damaging effects on the central nervous system, resulting in a wide range of brain and neurodevelopment disorders that are caused by mutations disrupting synaptic proteins. SYT1, an identified synaptotagmin protein, plays an essential role in mediating the release of calcium-triggered neurotransmitters (NT) involved in regular synaptic vesicle exocytosis. Considering the significant role of SYT1 in the physiology of synaptic neurotransmission, dysfunction and degeneration of this protein can result in a severe neurological impairment. Genetic variants lead to a newly discovered rare disorder, known as SYT1-associated neurodevelopment disorder. In this review, we will discuss in depth the function of SYT1 in synapse and the underlying molecular mechanisms. We will highlight the genetic basis of SYT1-associated neurodevelopmental disorder along with known phenotypes, with possible interventions and direction of research.

SCN1B Genetic Variants: A Review of the Spectrum of Clinical Phenotypes and a Report of Early Myoclonic Encephalopathy.

Background: Pathogenic variants in SCN1B, the gene encoding voltage-gated sodium channel b1/b1B subunits are associated with a spectrum of epileptic disorders. This study describes a child with early myoclonic encephalopathy and a compound heterozygous variant in the SCN1B gene (p.Arg85Cys and c.3G>C/p.Met1), along with the child's clinical response to anti-seizure medications (ASMs) and the ketogenic diet. We reviewed the current clinical literature pertinent to SCN1B-related epilepsy. Methods: We described the evaluation and management of a patient with SCN1B-related developmental and epileptic encephalopathy (DEE). We used the Medline and Pubmed databases to review the various neurological manifestations associated with SCN1B genetic variants, and summarize the functional studies performed on SCN1B variants. Results: We identified 20 families and six individuals (including the index case described herein) reported to have SCN1B-related epilepsy. Individuals with monoallelic pathogenic variants in SCN1B often present with genetic epilepsy with febrile seizures plus (GEFS+), while those with biallelic pathogenic variants may present with developmental and epileptic encephalopathy (DEE). Individuals with DEE present with seizures of various semiologies (commonly myoclonic seizures) and status epilepticus at early infancy and are treated with various antiseizure medications. In our index case, adjunctive fenfluramine was started at 8 months of age at 0.2 mg/kg/day with gradual incremental increases to the final dose of 0.7 mg/kg/day over 5 weeks. Fenfluramine was effective in the treatment of seizures, resulting in a 50% reduction in myoclonic seizures, status epilepticus, and generalized tonic-clonic seizures, as well as a 70−90% reduction in focal seizures, with no significant adverse effects. Following the initiation of fenfluramine at eight months of age, there was also a 50% reduction in the rate of hospitalizations. Conclusions: SCN1B pathogenic variants cause epilepsy and neurodevelopmental impairment with variable expressivity and incomplete penetrance. The severity of disease is associated with the zygosity of the pathogenic variants. Biallelic variants in SCN1B can result in early myoclonic encephalopathy, and adjunctive treatment with fenfluramine may be an effective treatment for SCN1B-related DEE. Further research on the efficacy and safety of using newer ASMs, such as fenfluramine in patients under the age of 2 years is needed.

A Review of the Multi-Systemic Complications of a Ketogenic Diet in Children and Infants with Epilepsy.

Ketogenic diets (KDs) are highly effective in the treatment of epilepsy. However, numerous complications have been reported. During the initiation phase of the diet, common side effects include vomiting, hypoglycemia, metabolic acidosis and refusal of the diet. While on the diet, the side effects involve the following systems: gastrointestinal, hepatic, cardiovascular, renal, dermatological, hematologic and bone. Many of the common side effects can be tackled easily with careful monitoring including blood counts, liver enzymes, renal function tests, urinalysis, vitamin levels, mineral levels, lipid profiles, and serum carnitine levels. Some rare and serious side effects reported in the literature include pancreatitis, protein-losing enteropathy, prolonged QT interval, cardiomyopathy and changes in the basal ganglia. These serious complications may need more advanced work-up and immediate cessation of the diet. With appropriate monitoring and close follow-up to minimize adverse effects, KDs can be effective for patients with intractable epilepsy.

A review of fenfluramine for the treatment of Dravet syndrome patients.

INTRODUCTION: Dravet Syndrome (DS) is a rare epileptiform disorder typically presenting within the first year of life of a normally developing infant. It is characterized by several prolonged seizures that are often resistant to current anti-epileptic drug (AED) regimens. This paper outlines the history and clinical trials of the drug fenfluramine, a drug that when used in addition to AED regimens may provide hope to children affected by DS. BODY: Fenfluramine (3-trifulormethyl-N-ethylamphetamine) is an amphetamine derivative that primarily affects serotonin neurotransmitter levels. It was initially prescribed in the 1960s as an appetite suppressant marketed as a weight loss drug. However, it was removed from the markets due to its association with cardiac valvopathies. It continued to by studied in epilepsy by Gastaut in the 1980s in children with self-induced syncope and irretractable epilepsy. In 2012, Ceulemans et al. studied the use of fenfluramine in patients with DS. Following the success of that retrospective case study, Nabbout et al. and Legae et al. conducted two randomized control trials leading to the FDA approval of fenfluramine under its trade name Fintepla in 2020. DISCUSSION: The success of the randomized control trials suggests the addition of fenfluramine to current AED regimens may lead to better control of seizures in patients with DS. The side effects of fenfluramine prove to be manageable and the concern for valvopathies has not been reproducible with low dose fenfluramine.

Cannabidiol - A new fixture in childhood neurology.

This invited opinion article reviews current uses and controversies in vernacular and pharmacological cannabidiol use in pediatric neurologic disorders. Since the recent emergence of cannabidiol availability to the general public and recent Food and Drug Administration approval, it is important to highlight and expand understanding about CBD mechanism of action, long-term use, safety, and indications in children with neurological disorders.

Seizure frequency, quality of life, behavior, cognition, and sleep in pediatric patients enrolled in a prospective, open-label clinical study with cannabidiol.

OBJECTIVE: To evaluate the effects of oral pharmacological cannabidiol (CBD) on seizures, side effects, quality of life, behavior, mood, and sleep in children with drug-resistant epilepsy (DRE) during a phase II, prospective, open-label clinical study. METHODS: During a phase II expanded access program (EAP) study to evaluate the safety and efficacy of using cannabidiol (CBD) for the long-term treatment of children with drug-resistant epilepsy, secondary outcome measures were also performed, including quality of life (QOLCE), behavior (aberrant behavior checklist ABC), and sleep (children's sleep habit questionnaire, CSHQ). Participants between the ages of 2 and 16 years of age with drug-resistant epilepsy (n = 35) were included in this EAP. Primary outcomes included change in parent-recorded seizure frequency relative to baseline, as well as the safety and tolerability over the course of 24 months of CBD treatment. Secondary outcomes observed in the first 12 months included changes in child behavior, and cognitive function, and sleep quality. RESULTS: The median change in overall seizure frequency decreased from baseline (n = 33) by -61.3% ([n = 33], Inter Quartile Range (IQR): 43-88%) at month 3, -62.9% at month 6 ([n = 29], IQR: 48-92%), -74.7% at month 12 ([n = 29], IQR: 64-96%), and finally -83.7% ([n = 28], IQR: 68-100%) at the conclusion of 24 months of treatment. Seven (20%) of the 35 patients enrolled withdrew from treatment and observation by month 24: 2 failed inclusion criteria at baseline, 4 due to lack of treatment efficacy, and 1 was lost to follow-up. The 12-month recording of secondary measures revealed a significant improvement in Irritability (-39.4%, [n = 28], ABC), Hyperactivity (-45.4%, [n = 28], ABC), Cognition in Quality of Life (+14.2%, [n = 28], QOLCE), Behavioral function (+14.7%, [n = 28], QOLCE), General Health (+14.7%, [n = 28], QOLCE), Sleep duration (-33.9%, [n = 28], CSHQ), Daytime sleepiness (-23.8%, [n = 28], CSHQ), and nocturnal arousals (-36.2%, [n = 28], CSHQ). SIGNIFICANCE: The results of this phase II open-label study demonstrate that pharmacological CBD significantly reduces seizure frequency, and improves QOL, behavior deficits, and sleep disruption, in children with drug-resistant epilepsy. The results also suggest that CBD is efficacious in controlled seizures over a 2-year period in childhood DRE.

Psychoactive Drugs Like Cannabis -Induce Hypodopaminergic Anhedonia and Neuropsychological Dysfunction in Humans: Putative Induction of Dopamine Homeostasis via Coupling of Genetic Addiction Risk Severity (GARS) testing and Precision Pro-dopamine Regulation (KB220).

Many US states now embrace the medical and recreational use of Cannabis. Changes in the laws have heightened interest and encouraged research into both cannabinoid products and the potential harms of Cannabis use, addiction and intoxication. The major active ingredient of Cannabis sativa (marijuana), Δ9-tetrahydrocannabinol (THC) and it powerfully stimulates the type-1 cannabinoid (CB1) receptor. When used in the form of the plant marijuana, because of the many compounds that exist in the plant form they could inhibit the activity of the CB1 receptor thereby reducing many of the effects of THC. While this mechanism seems correct, in our opinion, Vallee., et al. incorrectly suggest that blocking CB1 receptors could open unforeseen approaches to the treatment of cannabis intoxication and addiction. We caution the scientific community that, other CB1 receptor blockers, such as, Rimonabant (SR141718) have been pulled off the market in Europe. In addition, CB1 receptor blockers were rejected by the FDA due to mood changes including suicide ideation. We argue that one issue facing the scientific community, has to do with the increasing legalization of Cannabis products in many states across America. We are in favor of some reform in terms of either decriminalization or restrictive legalization especially in control of legal limits of THC. Like other psychoactive compounds at high doses, it is our hypothesis that chronic use of these drugs including high THC content in its various forms (wax, smoke or vapor) resulting in brain reward dysfunction induces an imbalance of neurotransmission and subsequent hypodopaminergia and lead to aberrant substance and non-substance (behavioral) addictions. It is further proposed that in order to overcome THC and even other psychoactive drugs of abuse induced anhedonia the coupling of genetic risk testing and pro dopamine regulation is warranted.

Cannabidiol attenuates seizures and EEG abnormalities in Angelman syndrome model mice.

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by intellectual disability, lack of speech, ataxia, EEG abnormalities, and epilepsy. Seizures in individuals with AS are common, debilitating, and often drug resistant. Thus, there is an unmet need for better treatment options. Cannabidiol (CBD), a major phytocannabinoid constituent of cannabis, has shown antiseizure activity and behavioral benefits in preclinical and clinical studies for some disorders associated with epilepsy, suggesting that the same could be true for AS. Here, we show that acute CBD (100 mg/kg) treatment attenuated hyperthermia- and acoustically induced seizures in a mouse model of AS. However, neither acute CBD nor a 2-week-long course of CBD administered immediately after a kindling protocol could halt the proepileptogenic plasticity observed in AS model mice. CBD had a dose-dependent sedative effect but did not have an impact on motor performance. CBD abrogated the enhanced intracortical local field potential power, including the delta and theta rhythms observed in AS model mice, indicating that CBD administration could also help normalize the EEG deficits observed in individuals with AS. We believe our results provide critical preclinical evidence supporting CBD treatment of seizures and alleviation of EEG abnormalities in AS and will thus help guide the rational development of CBD as a treatment for AS.

Sustained somatostatin gene expression reverses kindling-induced increases in the number of dividing Type-1 neural stem cells in the hippocampi of behaviorally responsive rats.

Neurogenesis persists throughout life in the hippocampi of all mammals, including humans. In the healthy hippocampus, relatively quiescent Type-1 neural stem cells (NSCs) can give rise to more proliferative Type-2a neural progenitor cells (NPCs), which generate neuronal-committed Type-2b NPCs that mature into Type-3 neuroblasts. Many Type-3 neuroblasts survive and mature into functionally integrated granule neurons over several weeks. In kindling models of epilepsy, neurogenesis is drastically upregulated and many new neurons form aberrant connections that could support epileptogenesis and/or seizures. We have shown that sustained vector-mediated hippocampal somatostatin (SST) expression can both block epileptogenesis and reverse seizure susceptibility in fully kindled rats. Here we test whether adeno-associated virus (AAV) vector-mediated sustained SST expression modulates hippocampal neurogenesis and microglial activation in fully kindled rats. We found significantly more dividing Type-1 NSCs and a corresponding increased number of surviving new neurons in the hippocampi of kindled versus sham-kindled rats. Increased numbers of activated microglia were found in the granule cell layer and hilus of kindled rats at both time points. After intrahippocampal injection with either eGFP or SST-eGFP vector, we found similar numbers of dividing Type-1 NSCs and -2 NPCs and surviving BrdU+ neurons and glia in the hippocampi of kindled rats. Upon observed variability in responses to SST-eGFP (2/4 rats exhibited Grade 0 seizures in the test session), we conducted an additional experiment. We found significantly fewer dividing Type-1 NSCs in the hippocampi of SST-eGFP vector-treated responder rats (5/13 rats) relative to SST-eGFP vector-treated non-responders and eGFP vector-treated controls that exhibited high-grade seizures on the test session. The number of activated microglia was upregulated in the GCL and hilus of kindled rats, regardless of vector treatment. These data support the hypothesis that sustained SST expression exerts antiepileptic effects potentially through normalization of neurogenesis and suggests that abnormally high proliferating Type-1 NSC numbers may be a cellular mechanism of epilepsy.

Longitudinal evaluation of tumor microenvironment in rat focal brainstem glioma using diffusion and perfusion MRI.

BACKGROUND: Brainstem gliomas are aggressive and difficult to treat. Growth of these tumors may be characterized with MRI methods. PURPOSE: To visualize longitudinal changes in tumor volume, vascular leakiness, and tissue microstructure in an animal model of brainstem glioma. STUDY TYPE: Prospective animal model. ANIMAL MODEL: Male Sprague-Dawley rats (n = 9) were imaged with 9L gliosarcoma cells infused into the pontine reticular formation of the brainstem. The MRI tumor microenvironment was studied at 3 and 10 days postimplantation of tumor cells. FIELD STRENGTH/SEQUENCE: Diffusion tensor imaging (DTI) and dynamic contrast-enhanced (DCE)-MRI were performed at 4.7T using spin-echo multislice echo planar imaging and gradient echo multislice imaging, respectively. ASSESSMENT: Tumor leakiness was assessed by the forward volumetric transfer constant, Ktrans , estimated from DCE-MRI data. Tumor structure was evaluated with fractional anisotropy (FA) obtained from DTI. Tumor volumes, delineated by a T1 map, T2 -weighted image, FA, and DCE signal enhancement were compared. STATISTICAL TESTS: Changes in the assessed parameters within and across the groups (ie, rats 3 and 10 days post tumor cell implantation) were evaluated with Wilcoxon rank-sum tests. RESULTS: Day 3 tumors were visible mainly on contrast-enhanced images, while day 10 tumors were visible in both contrast-enhanced and diffusion-weighted images. Mean Ktrans at day 10 was 41% lower than at day 3 (P = 0.23). In day 10 tumors, FA was regionally lower in the tumor compared to normal tissue (P = 0.0004), and tumor volume, segmented based on FA map, was significantly smaller (P ≤ 0.05) than that obtained from other contrasts. DATA CONCLUSION: Contrast-enhanced MRI was found to be more sensitive in detecting early-stage tumor boundaries than other contrasts. Areas of the tumor outlined by DCE-MRI and DTI were significantly different. Over the observed period of tumor growth, average vessel leakiness decreased with tumor progression. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;49:1322-1332.

Temporal lobe epilepsy affects spatial organization of entorhinal cortex connectivity.

Evidence for structural connectivity patterns within the medial temporal lobe derives primarily from postmortem histological studies. In humans and nonhuman primates, the parahippocampal gyrus (PHg) is subdivided into parahippocampal (PHc) and perirhinal (PRc) cortices, which receive input from distinct cortical networks. Likewise, their efferent projections to the entorhinal cortex (ERc) are distinct. The PHc projects primarily to the medial ERc (M-ERc). The PRc projects primarily to the lateral portion of the ERc (L-ERc). Both M-ERc and L-ERc, via the perforant pathway, project to the dentate gyrus and hippocampal (HC) subfields. Until recently, these neural circuits could not be visualized in vivo. Diffusion tensor imaging algorithms have been developed to segment gray matter structures based on probabilistic connectivity patterns. However, these algorithms have not yet been applied to investigate connectivity in the temporal lobe or changes in connectivity architecture related to disease processes. In this study, this segmentation procedure was used to classify ERc gray matter based on PRc, ERc, and HC connectivity patterns in 7 patients with temporal lobe epilepsy (TLE) without hippocampal sclerosis (mean age, 14.86 ±â€¯3.34 years) and 7 healthy controls (mean age, 23.86 ±â€¯2.97 years). Within samples paired t-tests allowed for comparison of ERc connectivity between epileptogenic and contralateral hemispheres. In healthy controls, there were no significant within-group differences in surface area, volume, or cluster number of ERc connectivity-defined regions (CDR). Likewise, in line with histology results, ERc CDR in the control group were well-organized, uniform, and segregated via PRc/PHc afferent and HC efferent connections. Conversely, in TLE, there were significantly more PRc and HC CDR clusters in the epileptogenic than the contralateral hemisphere. The surface area of the PRc CDR was greater, and that of the HC CDRs was smaller, in the epileptogenic hemisphere as well. Further, there was no clear delineation between M-ERc and L-ERc connectivity with PRc, PHc or HC in TLE. These results suggest a breakdown of the spatial organization of PHg-ERc-HC connectivity in TLE. Whether this breakdown is the cause or result of epileptic activity remains an exciting research question.

Fast noninvasive functional diffuse optical tomography for brain imaging.

Advances in epilepsy studies have shown that specific changes in hemodynamics precede and accompany seizure onset and propagation. However, it has been challenging to noninvasively detect these changes in real time and in humans, due to the lack of fast functional neuroimaging tools. In this study, we present a functional diffuse optical tomography (DOT) method with the guidance of an anatomical human head atlas for 3-dimensionally mapping the brain in real time. Central to our DOT system is a human head interface coupled with a technique that can incorporate topological information of the brain surface into the DOT image reconstruction. The performance of the DOT system was tested by imaging motor tasks-involved brain activities on N = 6 subjects (3 epilepsy patients and 3 healthy controls). We observed diffuse areas of activations from the reconstructed [HbT] images of patients, relative to more focal activations for healthy subjects. Moreover, significant pretask hemodynamic activations were also seen in the motor cortex of patients, which indicated abnormal activities persistent in the brain of an epilepsy patient. This work demonstrates that fast functional DOT is a valuable tool for noninvasive 3-dimensional mapping of brain hemodynamics.

Stimulants Do Not Increase the Risk of Seizure-Related Hospitalizations in Children with Epilepsy.

OBJECTIVE: To evaluate the safety of stimulants in children with epilepsy. METHODS: In a retrospective cohort study based on Medicaid Analytic eXtract billing records from 26 U.S. states from 1999 to 2010, we identified incident stimulant use among children with epilepsy through outpatient encounter claims and pharmacy claims. We established a control group of nonusers and used frequency matching to generate index dates. We followed both cohorts for 12 months and calculated hazard ratios [HRs] of current and former use of stimulants versus no use on the outcome of seizure-related hospitalization using multivariate Cox proportional hazard models. RESULTS: We identified 18,166 stimulant users and 54,197 nonusers in children with epilepsy. The incidence of seizure-related hospitalization in current stimulant users, former users, and nonusers was 3.6, 3.5, and 4.3 per 100 patient-years. After adjustment for confounders, we found current and former use of stimulants did not increase seizure-related hospitalizations (HR 0.95, 95% confidence interval [CI]: 0.83, 1.09 and HR 0.99, 95% CI: 0.85, 1.15). Children with cerebral palsy, congenital nervous system anomalies, or intellectual disability did not have significantly higher HRs than those without the already mentioned comorbidities. CONCLUSION: This study has not identified any overall increase in the rate of seizure-related hospitalizations with the use of stimulants in children with epilepsy.

Trends in Antiepileptic Drug Use in Children and Adolescents With Epilepsy.

OBJECTIVE: We describe the trends in antiepileptic drug (AED) use in children and adolescents with epilepsy in the United States. METHODS: We undertook a cross-sectional study based on Medicaid Analytic eXtract data set from 26 US states. Children and adolescents aged three to 18 years with at least one year continuous Medicaid fee-for-service coverage after the second outpatient or the first inpatient diagnosis of epilepsy in each calendar year during 1999 to 2009 were included in the study; therefore, 11 cohorts were established. A patient was defined as being exposed to a specific AED if he or she had at least one-day supply of the AED during the 1-year follow-up period. The annual prevalence of AEDs was reported, stratified by gender and age. The trends in AED use were evaluated through linear regression. RESULTS: The sample sizes of the 11 cohorts ranged between 17,304 and 22,672. The annual prevalence of valproic acid use declined from 42.4% in 1999 to 26.5% in 2009, and the prevalence of carbamazepine use declined from 37.1% to 10.2%. Meanwhile, the prevalence of levetiracetam use increased from 5.1% to about 32.0% in 2009, and the prevalence of oxcarbazepine use increased from 1.3% to 19.1%. Since 2008, levetiracetam (29.6%) has replaced valproic acid (27.8%) as the most commonly used AED in children and adolescents with epilepsy. The prevalence of diazepam use increased from 11.6% to 28.1%. SIGNIFICANCE: Compared with first- and second-generation antiepileptic drugs, third-generation AEDs have fewer adverse side effects, resulting in increased patient treatment adherence. Equally important is the economic impact of these newer AEDs. This first-of-its-kind study underscores the need for large database studies that objectively assess the cost-effectiveness of third-generation AEDs versus first- and second-generation AEDs in the treatment of childhood epilepsy.

Detecting and characterizing high-frequency oscillations in epilepsy: a case study of big data analysis.

We develop a framework to uncover and analyse dynamical anomalies from massive, nonlinear and non-stationary time series data. The framework consists of three steps: preprocessing of massive datasets to eliminate erroneous data segments, application of the empirical mode decomposition and Hilbert transform paradigm to obtain the fundamental components embedded in the time series at distinct time scales, and statistical/scaling analysis of the components. As a case study, we apply our framework to detecting and characterizing high-frequency oscillations (HFOs) from a big database of rat electroencephalogram recordings. We find a striking phenomenon: HFOs exhibit on-off intermittency that can be quantified by algebraic scaling laws. Our framework can be generalized to big data-related problems in other fields such as large-scale sensor data and seismic data analysis.

The hippocampus: detailed assessment of normative two-dimensional measurements, signal intensity, and subfield conspicuity on routine 3T T2-weighted sequences.

PURPOSE: The hippocampus has a critical role in many common disease processes. Currently, routine 3 Tesla structural MRI is a mainstay of clinical diagnosis. The goal of our study is to evaluate the normal variability in size and/or conspicuity of the hippocampal subcomponents in routine clinical 3 Tesla high-resolution T2-weighted images to provide a basis for better defining pathological derangements. Additionally, we utilize diffusion data acquired from a 17.6 Tesla MRI of the hippocampus as a benchmark to better illustrate these subcomponents. METHODS: The hippocampus was retrospectively assessed on 104 clinically normal patients undergoing coronal T2-weighted imaging. The conspicuity of the majority of hippocampal subcomponents was assessed in each portion of the hippocampus. Additionally, easily applicable cross-sectional measurements and signal intensities were obtained to evaluate the range of normal, as well as inter- and intra-subject variability. RESULTS: The normal range of cross-sectional measurements of the hippocampal subcomponents was calculated. There was minimal side-to-side variability in cross-sectional measurements of hippocampal subcomponents (< 5%) with the exception of the subiculum (R>L by 8.3%) and the CA4/DG (R>L by 5.8%). The internal architecture showed high variability in visibility of subcomponents between different segments of the hippocampus. CONCLUSIONS: Confident clinical assessment of the hippocampus requires a thorough knowledge of hippocampal size and signal, but also the internal architecture expected to be seen. The data provided in this study will provide the reader with vital information necessary for distinguishing a normal from abnormal exam.