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.

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.

Epilepsy and restless legs syndrome.

OBJECTIVE: Restless legs syndrome (RLS) is a common neurological movement disorder occurring in approximately 10% of the general population. The prevalence of moderately severe RLS is 2.7% overall (3.7% for women and 1.7% for men). Epilepsy is also a common neurological disorder with significant associated morbidity and impact on quality of life. We evaluated the severity and frequency of primary RLS in patients with localization-related temporal lobe epilepsy (TLE) and investigated the role of prodromal RLS symptoms as a warning sign and lateralizing indicator. METHODS: All epilepsy patients seen in the outpatient clinic were screened for movement disorders from 2005 to 2015. Ninety-eight consecutive patients with localization-related TLE (50 right TLE and 48 left TLE) who met inclusion criteria were seen in the outpatient clinic. The control group consisted of 50 individuals with no history or immediate family history of epilepsy. Each patient was evaluated with the International Restless Legs Study Group (IRLSSG) questionnaire, NIH RLS diagnostic criteria, ferritin level, and comprehensive sleep screening including polysomnography. Furthermore, patients with obstructive sleep apnea or a definite cause of secondary restless legs syndrome such as low serum ferritin or serum iron levels were also excluded from the study. RESULTS: There was a significant association between the type of epilepsy and whether or not patients had RLS χ2 (1)=10.17, p<.01, using the χ2 Goodness of Fit Test. Based on the odds ratio, the odds of patients having RLS were 4.60 times higher if they had right temporal epilepsy than if they had left temporal epilepsy, serving as a potential lateralizing indicator. A prodromal sensation of worsening RLS occurred in some patients providing the opportunity to intervene at an earlier stage in this subgroup. SIGNIFICANCE: We identified frequent moderate to severe RLS in patients with epilepsy. The frequency of RLS was much more common than would typically be seen in patients of similar age. The restlessness was typically described as moderately severe. The RLS symptoms were more common and somewhat more severe in the right TLE group than the left TLE group.

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.

Voxelized Model of Brain Infusion That Accounts for Small Feature Fissures: Comparison With Magnetic Resonance Tracer Studies.

Convection enhanced delivery (CED) is a promising novel technology to treat neural diseases, as it can transport macromolecular therapeutic agents greater distances through tissue by direct infusion. To minimize off-target delivery, our group has developed 3D computational transport models to predict infusion flow fields and tracer distributions based on magnetic resonance (MR) diffusion tensor imaging data sets. To improve the accuracy of our voxelized models, generalized anisotropy (GA), a scalar measure of a higher order diffusion tensor obtained from high angular resolution diffusion imaging (HARDI) was used to improve tissue segmentation within complex tissue regions of the hippocampus by capturing small feature fissures. Simulations were conducted to reveal the effect of these fissures and cerebrospinal fluid (CSF) boundaries on CED tracer diversion and mistargeting. Sensitivity analysis was also conducted to determine the effect of dorsal and ventral hippocampal infusion sites and tissue transport properties on drug delivery. Predicted CED tissue concentrations from this model are then compared with experimentally measured MR concentration profiles. This allowed for more quantitative comparison between model predictions and MR measurement. Simulations were able to capture infusate diversion into fissures and other CSF spaces which is a major source of CED mistargeting. Such knowledge is important for proper surgical planning.

In vivo imaging of epileptic foci in rats using a miniature probe integrating diffuse optical tomography and electroencephalographic source localization.

OBJECTIVE: The goal of this work is to establish a new dual-modal brain-mapping technique based on diffuse optical tomography (DOT) and electroencephalographic source localization (ESL) that can chronically/intracranially record optical/electroencephalography (EEG) data to precisely map seizures and localize the seizure-onset zone and associated epileptic brain network. METHODS: The dual-modal imaging system was employed to image seizures in an experimental acute bicuculline methiodide rat model of focal epilepsy. Depth information derived from DOT was used as constraint in ESL to enhance the image reconstruction. Groups of animals were compared based on localization of seizure foci, either at different positions or at different depths. RESULTS: This novel imaging technique successfully localized the seizure-onset zone in rat induced by bicuculline methiodide injected at a depth of 1, 2, and 3 mm, respectively. The results demonstrated that the incorporation of the depth information from DOT into the ESL image reconstruction resulted in more accurate and reliable ESL images. Although the ESL images showed a horizontal shift of the source localization, the DOT identified the seizure focus accurately. In one case, when the bicuculline methiodide (BMI) was injected at a site outside the field of view (FOV) of the DOT/ESL interface, ESL gave false-positive detection of the focus, while DOT showed negative detection. SIGNIFICANCE: This study represents the first to identify seizure-onset zone using implantable DOT. In addition, the combination of DOT/ESL has never been documented in neuroscience and epilepsy imaging. This technology will enable us to precisely measure the neural activity and hemodynamic response at exactly the same tissue site and at both cortical and subcortical levels.

Noninvasive real time tomographic imaging of epileptic foci and networks.

While brain imaging and electrophysiology play a central role in neuroscience research and in the evaluation of neurological disorders, a single noninvasive modality that offers both high spatial and temporal resolution is currently not available. Here we show in an acute epilepsy rat model that photoacoustic tomography (PAT) can noninvasively track seizure brain dynamics with both high spatial and temporal resolution, and at a depth that is clinically relevant. The noninvasive yet whole surface and depth capabilities of the PAT system allowed us to actually see what is happening during ictogenesis in terms of seizure onset and spread. Both seizure onset and propagation were tomographically detected at a spatial resolution of 150µm and a temporal resolution of 300ms, respectively. The current study lends support to the theory that seizure onset and spread involves a rich interplay between multiple cortical and subcortical brain areas during the onset and spread of epileptic seizures. Dynamical changes of vasculature during epileptiform events were also detected with high spatiotemporal resolution. Together, these findings suggest that PAT represents a powerful tool for noninvasively mapping seizure onset and propagation patterns, and the 'functional' connectivity within epileptic brain networks.

Phase shift in the 24-hour rhythm of hippocampal EEG spiking activity in a rat model of temporal lobe epilepsy.

For over a century epileptic seizures have been known to cluster at specific times of the day. Recent studies have suggested that the circadian regulatory system may become permanently altered in epilepsy, but little is known about how this affects neural activity and the daily pattern of seizures. To investigate, we tracked long-term changes in the rate of spontaneous hippocampal EEG spikes (SPKs) in a rat model of temporal lobe epilepsy. In healthy animals, SPKs oscillated with near 24-h period; however, after injury by status epilepticus, a persistent phase shift of ∼12 h emerged in animals that later went on to develop chronic spontaneous seizures. Additional measurements showed that global 24-h rhythms, including core body temperature and theta state transitions, did not phase shift. Instead, we hypothesized that locally impaired circadian input to the hippocampus might be responsible for the SPK phase shift. This was investigated with a biophysical computer model in which we showed that subtle changes in the relative strengths of circadian input could produce a phase shift in hippocampal neural activity. MRI provided evidence that the medial septum, a putative circadian relay center for the hippocampus, exhibits signs of damage and therefore could contribute to local circadian impairment. Our results suggest that balanced circadian input is critical to maintaining natural circadian phase in the hippocampus and that damage to circadian relay centers, such as the medial septum, may disrupt this balance. We conclude by discussing how abnormal circadian regulation may contribute to the daily rhythms of epileptic seizures and related cognitive dysfunction.

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.

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.

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.

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.

Detecting effective connectivity in networks of coupled neuronal oscillators.

The application of data-driven time series analysis techniques such as Granger causality, partial directed coherence and phase dynamics modeling to estimate effective connectivity in brain networks has recently gained significant prominence in the neuroscience community. While these techniques have been useful in determining causal interactions among different regions of brain networks, a thorough analysis of the comparative accuracy and robustness of these methods in identifying patterns of effective connectivity among brain networks is still lacking. In this paper, we systematically address this issue within the context of simple networks of coupled spiking neurons. Specifically, we develop a method to assess the ability of various effective connectivity measures to accurately determine the true effective connectivity of a given neuronal network. Our method is based on decision tree classifiers which are trained using several time series features that can be observed solely from experimentally recorded data. We show that the classifiers constructed in this work provide a general framework for determining whether a particular effective connectivity measure is likely to produce incorrect results when applied to a dataset.

Influence of needle insertion speed on backflow for convection-enhanced delivery.

Fluid flow back along the outer surface of a needle (backflow) can be a significant problem during the direct infusion of drugs into brain tissues for procedures such as convection-enhanced delivery (CED). This study evaluates the effects of needle insertion speed (0.2 and 1.8 mm/s) as well as needle diameter and flow rate on the extent of backflow and local damage to surrounding tissues. Infusion experiments were conducted on a transparent tissue phantom, 0.6% (w/v) agarose hydrogel, to visualize backflow. Needle insertion experiments were also performed to evaluate local damage at the needle tip and to back out the prestress in the surrounding media for speed conditions where localized damage was not excessive. Prestress values were then used in an analytical model of backflow. At the higher insertion speed (1.8 mm/s), local insertion damage was found to be reduced and backflow was decreased. The compressive prestress at the needle-tissue interface was estimated to be approximately constant (0.812 kPa), and backflow distances were similar regardless of needle gauge (22, 26, and 32 gauge). The analytical model underestimated backflow distances at low infusion flow rates and overestimated backflow at higher flow rates. At the lower insertion speed (0.2 mm/s), significant backflow was measured. This corresponded to an observed accumulation of material at the needle tip which produced a gap between the needle and the surrounding media. Local tissue damage was also evaluated in excised rat brain tissues, and insertion tests show similar rate-dependent accumulation of tissue at the needle tip at the lower insertion speed. These results indicate that local tissue damage and backflow may be avoided by using an appropriate insertion speed.

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.

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.

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.

Control of neural synchrony using channelrhodopsin-2: a computational study.

In this paper, we present an optical stimulation based approach to induce 1:1 in-phase synchrony in a network of coupled interneurons wherein each interneuron expresses the light sensitive protein channelrhodopsin-2 (ChR2). We begin with a transition rate model for the channel kinetics of ChR2 in response to light stimulation. We then define "functional optical time response curve (fOTRC)" as a measure of the response of a periodically firing interneuron (transfected with ChR2 ion channel) to a periodic light pulse stimulation. We specifically consider the case of unidirectionally coupled (UCI) network and propose an open loop control architecture that uses light as an actuation signal to induce 1:1 in-phase synchrony in the UCI network. Using general properties of the spike time response curves (STRCs) for Type-1 neuron model (Ermentrout, Neural Comput 8:979-1001, 1996) and fOTRC, we estimate the (open loop) optimal actuation signal parameters required to induce 1:1 in-phase synchrony. We then propose a closed loop controller architecture and a controller algorithm to robustly sustain stable 1:1 in-phase synchrony in the presence of unknown deviations in the network parameters. Finally, we test the performance of this closed-loop controller in a network of mutually coupled (MCI) interneurons.