Epilepsy Disorders Research Articles

ENHANCING VIGABATRIN DELIVERY TO THE BRAIN: THE POTENTIAL OF SOLID LIPID NANOPARTICLES

Vigabatrin is a powerful and helpful drug for treating epilepsy and other neurological disorders. Unfortunately, because it cannot effectively cross the blood-brain barrier, its therapeutic use has been restricted. brain-blood barrier. This hinders the ability of drugs such as vigabatrin to reach their intended target region in the brain effectively. Solid lipid nanoparticles (SLNs) provide a potential solution to this problem. They are biocompatible and biodegradable, making it easier for drugs to penetrate the BBB. The effectiveness of solid lipid nanoparticles and their potential to improve vigabatrin transport to the brain is covered in this article. Furthermore, the purpose of using Solid lipid nanoparticles as drug delivery systems and the potential applications of this technology in the treatment of neurological conditions.

De novo GRIN variants in M3 helix associated with neurological disorders control channel gating of NMDA receptor

N-methyl-d-aspartate receptors (NMDARs) are members of the glutamate receptor family and participate in excitatory postsynaptic transmission throughout the central nervous system. Genetic variants in GRIN genes encoding NMDAR subunits are associated with a spectrum of neurological disorders. The M3 transmembrane helices of the NMDAR couple directly to the agonist-binding domains and form a helical bundle crossing in the closed receptors that occludes the pore. The M3 functions as a transduction element whose conformational change couples ligand binding to opening of an ion conducting pore. In this study, we report the functional consequences of 48 de novo missense variants in GRIN1, GRIN2A, and GRIN2B that alter residues in the M3 transmembrane helix. These de novo variants were identified in children with neurological and neuropsychiatric disorders including epilepsy, developmental delay, intellectual disability, hypotonia and attention deficit hyperactivity disorder. All 48 variants in M3 for which comprehensive testing was completed produce a gain-of-function (28/48) compared to loss-of-function (9/48); 11 variants had an indeterminant phenotype. This supports the idea that a key structural feature of the M3 gate exists to stabilize the closed state so that agonist binding can drive channel opening. Given that most M3 variants enhance channel gating, we assessed the potency of FDA-approved NMDAR channel blockers on these variant receptors. These data provide new insight into the structure–function relationship of the NMDAR gate, and suggest that variants within the M3 transmembrane helix produce a gain-of-function.

The critical need to accelerate cerebral palsy research with consumer engagement, global networks, and adaptive designs.

The prevalence of cerebral palsy (CP) varies globally, with higher rates and burden of disease in low- and middle-income countries. CP is a lifelong condition with no cure, presenting diverse challenges such as motor impairment, epilepsy, and mental health disorders. Research progress has been made but more is needed, especially given consumer demands for faster advancements and improvements in the scientific evidence base for interventions. This paper explores three strategies to accelerate CP research: consumer engagement, global clinical trial networks, and adaptive designs. Consumer engagement involving individuals with lived experience enhances research outcomes. Global clinical trial networks provide efficiency through larger and more diverse participant pools. Adaptive designs, unlike traditional randomized controlled trials, allow real-time modifications based on interim analyses, potentially answering complex questions more efficiently. The establishment of a CP Global Clinical Trials Network, integrating consumer engagement, global collaboration, and adaptive designs, marks a paradigm shift. The Network aims to address consumer-set research priorities. While challenges like ethical considerations and capacity building exist, the potential benefits for consumers, clinicians, researchers, and funding bodies are substantial. This paper underscores the urgency of transforming CP research methodologies for quicker translation of novel treatments into clinical practice to improve quality of life for those with CP.

Novel deep learning framework for detection of epileptic seizures using EEG signals.

Epilepsy is a chronic neurological disorder characterized by abnormal electrical activity in the brain, often leading to recurrent seizures. With 50 million people worldwide affected by epilepsy, there is a pressing need for efficient and accurate methods to detect and diagnose seizures. Electroencephalogram (EEG) signals have emerged as a valuable tool in detecting epilepsy and other neurological disorders. Traditionally, the process of analyzing EEG signals for seizure detection has relied on manual inspection by experts, which is time-consuming, labor-intensive, and susceptible to human error. To address these limitations, researchers have turned to machine learning and deep learning techniques to automate the seizure detection process. In this work, we propose a novel method for epileptic seizure detection, leveraging the power of 1-D Convolutional layers in combination with Bidirectional Long Short-Term Memory (LSTM) and Gated Recurrent Unit (GRU) and Average pooling Layer as a single unit. This unit is repeatedly used in the proposed model to extract the features. The features are then passed to the Dense layers to predict the class of the EEG waveform. The performance of the proposed model is verified on the Bonn dataset. To assess the robustness and generalizability of our proposed architecture, we employ five-fold cross-validation. By dividing the dataset into five subsets and iteratively training and testing the model on different combinations of these subsets, we obtain robust performance measures, including accuracy, sensitivity, and specificity. Our proposed model achieves an accuracy of 99-100% for binary classifications into seizure and normal waveforms, 97.2%-99.2% accuracy for classifications into normal-interictal-seizure waveforms, 96.2%-98.4% accuracy for four class classification and accuracy of 95.81%-98% for five class classification. Our proposed models have achieved significant improvements in the performance metrics for the binary classifications and multiclass classifications. We demonstrate the effectiveness of the proposed architecture in accurately detecting epileptic seizures from EEG signals by using EEG signals of varying lengths. The results indicate its potential as a reliable and efficient tool for automated seizure detection, paving the way for improved diagnosis and management of epilepsy.

Familial occurrence of seizure disorders across MRI defined structural focal epilepsy etiology

BackgroundPrevious studies have established familial occurrence of epilepsy and seizure disorders and early age of epilepsy onset as predictors of genetic epilepsy, but have not evaluated the rate of their occurrence in patients with different epilepsy etiology. Our study determines the distribution of familial occurrence and age of epilepsy onset across structural focal epilepsy (FE) etiology in a large FE cohort. MethodsRecords of 1354 consecutive patients evaluated for epilepsy and seizure disorders in The Neurology Clinic, University Clinical Center of Serbia from 2008 to 2019 were screened for FE. Structural etiology, lobar diagnosis, familial occurrence, and age at epilepsy onset were determined. Patients with a. nonlesional focal epilepsy (NLFE), b. hippocampal sclerosis (HS) and c. congenital or perinatal etiology (CPE) were classified as NAFE, while patients with an identified acquired focal epilepsy (AFE) constituted the control group. ResultsWe identified 965 patients with FE, 329 (34.1 %) with NLFE, 213 (22.1 %) with HS, 174 (18.0 %) with CPE and 249 (25.8 %) with AFE. Familial occurrence was identified in 160 (16.6 %), 19.1 % of patients with NAFE and 9.2 % of AFE (p = 0.003). Patients with NAFE had a younger age of epilepsy onset (13 vs. 18 years, p < 0.001). The highest proportion of familial occurrence was found in patients with NLFE (23.7 %), while the youngest median age of epilepsy onset was identified in patients with HS (12 years) and CPE (11 years). ConclusionPatients with NAFE frequently have familial occurrence of epilepsy and have an earlier age of epilepsy onset than patients with AFE.

Neurological care for LGBT+ people.

Sexual and gender minority (LGBT+) people face unique health disparities that must be considered by health-care providers to ensure equitable and inclusive care. Although traditionally LGBT+ health has not been integrated into neurology training, sexual orientation and gender identity have direct relevance to neurological health, driven by both systemic and interpersonal factors. In this Review, we summarize the evidence for associations between sexual orientation and gender identity with the prevalence and outcomes of various neurological conditions, including neurodegenerative diseases, epilepsy, stroke and neurodevelopmental disorders, among others. We describe important clinical considerations pertaining to LGBT+ people and recommend language and practices to promote inclusive care, as well as highlight gaps in need of further research and possible strategies to minimize these, including systematic collection of sexual orientation and gender identity and use of inclusive language.

Epilepsy and childhood psychiatric disorders: a two-sample bidirectional Mendelian randomization study.

Observational studies have indicated that psychiatric disorders are the most common comorbidities in pediatric epilepsy. However, the existence and direction of a causal relationship between the two remains controversial. This study aims to investigate the association between common childhood psychiatric disorders and epilepsy using a two-sample, bidirectional Mendelian randomization (MR) approach. Genetic instruments were obtained from the most recent and largest genome-wide association studies (GWAS), including datasets for epilepsy (N_case = 29,994, N_control = 52,538), attention deficit hyperactivity disorder (ADHD) (N_case = 38,691, N_control = 186,843), autism spectrum disorder (ASD) (N_case = 18,381, N_control = 27,969), and Tourette syndrome (TS) (N_case = 4,819, N_control = 9488). MR analyses were conducted using the inverse variance weighted (IVW) method, weighted median method, and MR-Egger regression. No reliable evidence was found to suggest a causal effect of ADHD, ASD, or TS on epilepsy, nor was there any reliable evidence indicating that epilepsy increases the risk of these three psychiatric disorders. These findings remained consistent across various sensitivity analyses. Although observational studies have highlighted a high comorbidity rate between pediatric epilepsy and psychiatric disorders like ADHD and ASD, the MR analysis did not confirm a causal relationship between them. This suggests that previous studies might have been influenced by confounding biases or other biases, potentially overestimating the true relationship. A deeper understanding of the mechanisms underlying these comorbidities is crucial for refining the treatment of pediatric epilepsy.

Theta-frequency medial septal nucleus deep brain stimulation increases neurovascular activity in MK-801-treated mice.

Deep brain stimulation (DBS) has shown remarkable success treating neurological and psychiatric disorders including Parkinson's disease, essential tremor, dystonia, epilepsy, and obsessive-compulsive disorder. DBS is now being explored to improve cognitive and functional outcomes in other psychiatric conditions, such as those characterized by reduced N-methyl-D-aspartate (NMDA) function (i.e., schizophrenia). While DBS for movement disorders generally involves high-frequency (>100 Hz) stimulation, there is evidence that low-frequency stimulation may have beneficial and persisting effects when applied to cognitive brain networks. In this study, we utilize a novel technology, functional ultrasound imaging (fUSI), to characterize the cerebrovascular impact of medial septal nucleus (MSN) DBS under conditions of NMDA antagonism (pharmacologically using Dizocilpine [MK-801]) in anesthetized male mice. Imaging from a sagittal plane across a variety of brain regions within and outside of the septohippocampal circuit, we find that MSN theta-frequency (7.7 Hz) DBS increases hippocampal cerebral blood volume (CBV) during and after stimulation. This effect was not present using standard high-frequency stimulation parameters [i.e., gamma (100 Hz)]. These results indicate the MSN DBS increases circuit-specific hippocampal neurovascular activity in a frequency-dependent manner and does so in a way that continues beyond the period of electrical stimulation.

Genetic testing for unexplained epilepsy: A review of diagnostic approach, benefits, and referral algorithm

In the last several decades, advances in genetic testing have transformed the diagnostic and therapeutic approach to pediatric epilepsy. However, the interpretation of these genetic tests often requires expert analysis and counseling. For this reason, as our molecular understanding of the linkages between abnormal cerebral physiology and genetics has grown, so too has the field of clinical epilepsy genetics. Here we explore recent advances in genetic testing, describe the benefits of genetic testing in epilepsy, and provide a practice guideline for testing and referrals to specialized epilepsy genetics centers, highlighting the Epilepsy NeuroGenetics Initiative (ENGIN) Clinic and the Center for Epilepsy and Neurodevelopmental Disorders (ENDD) at the Children's Hospital of Philadelphia as an illustration of such a specialized center.

A binding site for phosphoinositides described by multiscale simulations explains their modulation of voltage-gated sodium channels

Voltage-gated sodium channels (Naᵥ) are membrane proteins which open to facilitate the inward flux of sodium ions into excitable cells. In response to stimuli, Naᵥ channels transition from the resting, closed state to an open, conductive state, before rapidly inactivating. Dysregulation of this functional cycle due to mutations causes diseases including epilepsy, pain conditions, and cardiac disorders, making Naᵥ channels a significant pharmacological target. Phosphoinositides are important lipid cofactors for ion channel function. The phosphoinositide PI(4,5)P2 decreases Naᵥ1.4 activity by increasing the difficulty of channel opening, accelerating fast inactivation and slowing recovery from fast inactivation. Using multiscale molecular dynamics simulations, we show that PI(4,5)P2 binds stably to inactivated Naᵥ at a conserved site within the DIV S4–S5 linker, which couples the voltage-sensing domain (VSD) to the pore. As the Naᵥ C-terminal domain is proposed to also bind here during recovery from inactivation, we hypothesize that PI(4,5)P2 prolongs inactivation by competitively binding to this site. In atomistic simulations, PI(4,5)P2 reduces the mobility of both the DIV S4–S5 linker and the DIII–IV linker, responsible for fast inactivation, slowing the conformational changes required for the channel to recover to the resting state. We further show that in a resting state Naᵥ model, phosphoinositides bind to VSD gating charges, which may anchor them and impede VSD activation. Our results provide a mechanism by which phosphoinositides alter the voltage dependence of activation and the rate of recovery from inactivation, an important step for the development of novel therapies to treat Naᵥ-related diseases.

A binding site for phosphoinositides described by multiscale simulations explains their modulation of voltage-gated sodium channels.

Voltage-gated sodium channels (Naᵥ) are membrane proteins which open to facilitate the inward flux of sodium ions into excitable cells. In response to stimuli, Naᵥ channels transition from the resting, closed state to an open, conductive state, before rapidly inactivating. Dysregulation of this functional cycle due to mutations causes diseases including epilepsy, pain conditions, and cardiac disorders, making Naᵥ channels a significant pharmacological target. Phosphoinositides are important lipid cofactors for ion channel function. The phosphoinositide PI(4,5)P2 decreases Naᵥ1.4 activity by increasing the difficulty of channel opening, accelerating fast inactivation and slowing recovery from fast inactivation. Using multiscale molecular dynamics simulations, we show that PI(4,5)P2 binds stably to inactivated Naᵥ at a conserved site within the DIV S4-S5 linker, which couples the voltage-sensing domain (VSD) to the pore. As the Naᵥ C-terminal domain is proposed to also bind here during recovery from inactivation, we hypothesize that PI(4,5)P2 prolongs inactivation by competitively binding to this site. In atomistic simulations, PI(4,5)P2 reduces the mobility of both the DIV S4-S5 linker and the DIII-IV linker, responsible for fast inactivation, slowing the conformational changes required for the channel to recover to the resting state. We further show that in a resting state Naᵥ model, phosphoinositides bind to VSD gating charges, which may anchor them and impede VSD activation. Our results provide a mechanism by which phosphoinositides alter the voltage dependence of activation and the rate of recovery from inactivation, an important step for the development of novel therapies to treat Naᵥ-related diseases.

Navigating the Digital Neurolandscape: Analyzing the Social Perception of and Sentiments Regarding Neurological Disorders through Topic Modeling and Unsupervised Research Using Twitter

Neurological disorders represent the primary cause of disability and the secondary cause of mortality globally. The incidence and prevalence of the most notable neurological disorders are growing rapidly. Considering their social and public perception by using different platforms like Twitter can have a huge impact on the patients, relatives, caregivers and professionals involved in the multidisciplinary management of neurological disorders. In this study, we collected and analyzed all tweets posted in English or Spanish, between 2007 and 2023, referring to headache disorders, dementia, epilepsy, multiple sclerosis, spinal cord injury or Parkinson’s disease using a search engine that has access to 100% of the publicly available tweets. The aim of our work was to deepen our understanding of the public perception of neurological disorders by addressing three major objectives: (1) analyzing the number and temporal evolution of both English and Spanish tweets discussing the most notable neurological disorders (dementias, Parkinson’s disease, multiple sclerosis, spinal cord injury, epilepsy and headache disorders); (2) determining the main thematic content of the Twitter posts and the interest they generated temporally by using topic modeling; and (3) analyzing the sentiments associated with the different topics that were previously collected. Our results show that dementias were, by far, the most common neurological disorders whose treatment was discussed on Twitter, and that the most discussed topics in the tweets included the impact of neurological diseases on patients and relatives, claims to increase public awareness, social support and research, activities to ameliorate disease development and existent/potential treatments or approaches to neurological disorders, with a significant number of the tweets showing negative emotions like fear, anger and sadness, and some also demonstrating positive emotions like joy. Thus, our study shows that not only is Twitter an important and active platform implicated in the dissemination and normalization of neurological disorders, but also that the number of tweets discussing these different entities is quite inequitable, and that a greater intervention and more accurate dissemination of information by different figures and professionals on social media could help to convey a better understanding of the current state, and to project the future state, of neurological diseases for the general public.

Glial KCNQ K+ channels control neuronal output by regulating GABA release from glia in C. elegans

KCNQs are voltage-gated K+ channels that control neuronal excitability and are mutated in epilepsy and autism spectrum disorder (ASD). KCNQs have been extensively studied in neurons, but their function in glia is unknown. Using voltage, calcium, and GABA imaging, optogenetics, and behavioral assays, we show here for the first time in Caenorhabditis elegans (C.elegans) that glial KCNQ channels control neuronal excitability by mediating GABA release from glia via regulation of the function of L-type voltage-gated Ca2+ channels. Further, we show that human KCNQ channels have the same role when expressed in nematode glia, underscoring conservation of function across species. Finally, we show that pathogenic loss-of-function and gain-of-function human KCNQ2 mutations alter glia-to-neuron GABA signaling in distinct ways and that the KCNQ channel opener retigabine exerts rescuing effects. This work identifies glial KCNQ channels as key regulators of neuronal excitability via control of GABA release from glia.

Patients’ and physicians’ awareness of clinical symptoms and disease severity in tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is a rare inherited disease with the potential to affect virtually every organ system. Clinical presentation is age- and partly sex-dependent and varies broadly with respect to disease manifestations including treatment-refractory epilepsy, intellectual disability and TSC-associated neuropsychiatric disorders, chronic kidney disease or progressive lung function decline. Given the complexity of this disease, multidisciplinary care in specialized TSC centres is recommended. We aimed to elucidate the state of knowledge of patients/caregivers and physicians on individual disease manifestations. We further examined whether the association to a TSC centre has an impact on the comprehensive consideration of potential disease manifestations. Therefore, a survey was performed in a cohort of German TSC patients and their physicians. Complete information was available for 94 patients with a median age of 18 years [range 1–55] and a sex distribution of 53.2% (male): 48.8% (female). Using almost identical questionnaires for patients/caregivers and their respective physician, there was a good correlation for disease assessments associated with relevant morbidity and mortality like epilepsy, renal angiomyolipoma, cardiac rhabdomyomas or intellectual disability. Correlation was moderate for several neuropsychiatric disorders and only poor for hypomelanotic macules, dental pits or retinal achromic patches. Estimation of overall disease severity using a numeric rating scale correlated highly significantly (Pearson correlation coefficient = 0.767; p < 0.001) between patients/caregivers and physicians. In general, physicians more likely quoted items as ‘unknown’ than patients (822 answers vs. 435 answers in the respective groups). Questionnaires completed by physicians who were associated with a specialized TSC centre declared a significantly lower proportion of items as unknown (mean 8.7% vs. 20.5%; p < 0.001). These findings indicate that patients treated by specialized TSC centres seem to obtain a more comprehensive surveillance. Furthermore, it shows that there were reasonable surveillance strategies in general and sufficient patient/caregiver interaction and education in the examined cohort. However, for the most prominent disease characteristics there was a good awareness within both the patients/caregivers and the physicians group.

Consanguinity, complex diseases and congenital disabilities in the Souss population (Southern Morocco): a cross-sectional survey

BackgroundSeveral studies showed that the perpetuation of consanguinity increases homozygosity and homogenizes the population's gene pool. This allows the expression of recessive deleterious mutations and increases the prevalence of genetic disorders and birth defects. Despite the reported negative health effects, consanguinity is still practiced in Morocco. This study aimed to evaluate the prevalence and socio-demographic determinants of consanguinity in the Souss region and to assess the association of this type of union with congenital disabilities and complex diseases. To meet this aim, a survey based on a cross-sectional approach was conducted between January 2019 and January 2020 among 520 randomly selected participants in the Souss region.ResultsThe findings revealed a high prevalence of consanguinity of 28.46%, with first-cousin unions accounting for 16.15% of all marriages. According to multivariate logistic regression analysis, early age at first marriage, men’s occupation, endogamy, and parental consanguinity were predictive factors for consanguineous unions in the study population. Moreover, the results revealed a significant association between consanguinity and the incidence of physical disabilities (OR = 3.753; [95% CI 1.398–10.074]), mental retardation (OR = 5.219; [95% CI 1.545–17.631]), deafness-mutism (OR = 4.262; [95% CI 1.004–18.089]) and cardiovascular diseases (OR = 2.167; [95% CI 1.036–4.530]). However, no significant association was found between consanguinity and diabetes, cancer, asthma, epilepsy, and psychiatric disorders.ConclusionOverall, our results suggest a high practice of consanguinity in the Souss population, associated with social, economic, and cultural factors. Consanguineous unions were associated with a high incidence of mental retardation, physical disabilities, deafness-mutism, and cardiovascular diseases. In this population, where marriage between relatives is highly preferred, awareness programs are not sufficient, and genetic studies on consanguinity-related diseases are necessary to provide specific premarital screening and thus increase the efficiency of genetic counseling.

Kv7 channel activation reduces brain endothelial cell permeability and prevents kainic acid-induced blood-brain barrier damage.

Ion channels in the blood-brain barrier (BBB) play a main role in controlling the interstitial fluid composition and cerebral blood flow, and their dysfunction contributes to the disruption of the BBB occurring in many neurological diseases such as epilepsy. In this study, using morphological and functional approaches, we evaluated the expression and role in the BBB of Kv7 channels, a family of voltage-gated potassium channels including five members (Kv7.1-5) that play a major role in the regulation of cell excitability and transmembrane flux of potassium ions. Immunofluorescence experiments showed that Kv7.1, Kv7.4, and Kv7.5 were expressed in rat brain microvessels (BMVs), as well as brain primary- and clonal (BEND-3) endothelial cells (ECs). Kv7.5 localized at the cell-to-cell junction sites, whereas Kv7.4 was also found in pericytes. The Kv7 activator retigabine increased transendothelial electrical resistance (TEER) in both primary ECs and BEND-3 cells; moreover, retigabine reduced paracellular dextran flux in BEND-3 cells. These effects were prevented by the selective Kv7 blocker XE-991. Exposure to retigabine also hyperpolarized cell membrane and increased tight junctions (TJs) integrity in BEND-3 cells. BMVs from rats treated with kainic acid (KA) showed a disruption of TJs and a selective reduction of Kv7.5 expression. In BEND-3 cells, retigabine prevented the increase of cell permeability and the reduction of TJs integrity induced by KA. Overall, these findings demonstrate that Kv7 channels are expressed in the BBB, where they modulate barrier properties both in physiological and pathological conditions.NEW & NOTEWORTHY This study describes for the first time the expression and the functional role of Kv7 potassium channels in the blood-brain barrier. We show that the opening of Kv7 channels reduces endothelial cell permeability both in physiological and pathological conditions via the hyperpolarization of cell membrane and the sealing of tight junctions. Therefore, activation of endothelial Kv7 channels might be a useful strategy to treat epilepsy and other neurological disorders characterized by blood-brain barrier dysfunction.

Temporal lobe epilepsy and interictal dysphoric disorder: a case report and literature review

Temporal lobe epilepsy and interictal dysphoric disorder: a case report and literature review

Clinical effectiveness of the psychological therapy Mental Health Intervention for Children with Epilepsy in addition to usual care compared with assessment-enhanced usual care alone: a multicentre, randomised controlled clinical trial in the UK

Mental health difficulties are common in children and young people with chronic health conditions, but many of those in need do not access evidence-based psychological treatments. The study aim was to evaluate the clinical effectiveness of integrated mental health treatment for children and young people with epilepsy, a common chronic health condition known to be associated with a particularly high rate of co-occurring mental health difficulties. We conducted a parallel group, multicentre, open-label, randomised controlled trial of participants aged 3-18 years, attending epilepsy clinics across England and Northern Ireland who met diagnostic criteria for a common mental health disorder. Participants were randomised (1:1; using an independent web-based system) to receive the Mental Health Intervention for Children with Epilepsy (MICE) in addition to usual care, or assessment-enhanced usual care alone (control). Children and young people in both groups received a full diagnostic mental health assessment. MICE was a modular psychological intervention designed to treat common mental health conditions in children and young people using evidence-based approaches such as cognitive behaviour therapy and behavioural parenting strategies. Usual care for mental health disorders varied by site but typically included referral to appropriate services. Participants, along with their caregivers, and clinicians were not masked to treatment allocation but statisticians were masked until the point of analysis. The primary outcome, analysed by modified intention-to-treat, was the parent-report Strengths and Difficulties Questionnaire (SDQ) at 6 months post-randomisation. The study is complete and registered with ISRCTN (57823197). 1401 young people were potentially deemed eligible for study inclusion. Following the exclusion of 531 young people, 870 participants were assessed for eligibility and completed the SDQ, and 480 caregivers provided consent for study inclusion between May 20, 2019, and Jan 31, 2022. Between Aug 28, 2019, and Feb 21, 2022, 334 participants (mean ages 10·5 years [SD 3·6] in the MICE group vs 10·3 [4·0] in control group at baseline) were randomly assigned to an intervention using minimisation balanced by age, primary mental health disorder, diagnosis of intellectual disability, and autistic spectrum disorder at baseline. 168 (50%) of the participants were female and 166 (50%) were male. 166 participants were randomly assigned to the MICE group and 168 were randomly assigned to the control group. At 6 months, the mean SDQ difficulties for the 148 participants in the MICE group was 17·6 (SD 6·3) and 19·6 (6·1) for the 148 participants in the control group. The adjusted effect of MICE was -1·7 (95% CI -2·8 to -0·5; p=0·0040; Cohen's d, 0·3). 14 (8%) patients in the MICE group experienced at least one serious adverse event compared with 24 (14%) in the control group. 68% percent of serious adverse events (50 events) were admission due to seizures. MICE was superior to assessment-enhanced usual care in improving symptoms of emotional and behavioural difficulties in young people with epilepsy and common mental health disorders. The trial therefore shows that mental health comorbidities can be effectively and safely treated by a variety of clinicians, utilising an integrated intervention across ages and in the context of intellectual disability and autism. The evidence from this trial suggests that such a model should be fully embedded in epilepsy services and serves as a model for other chronic health conditions in young people. UK National Institute for Health Research Programme Grants for Applied Research programme and Epilepsy Research UK Endeavour Project Grant.

Protocol for a scoping review of factors associated with disparities in clinical provision of deep brain stimulation

IntroductionDeep brain stimulation (DBS) can be used to treat several neurological and psychiatric conditions such as Parkinson’s disease, epilepsy and obsessive-compulsive disorder; however, limited work has been done to assess...

Pharmacokinetic Simulation Study: Exploring the Impact of Clinical Parameters on Lamotrigine for Different Patient Populations with Implications for Liver Function Assessment and Therapeutic Drug Monitoring

Lamotrigine, widely used for managing epilepsy and bipolar disorder, carries potential side effects, including severe anticonvulsant hypersensitivity syndrome (AHS) or drug rash with eosinophilia and systemic symptoms (DRESS), which may lead to hepatotoxicity. Patients with Type 2 Diabetes (TD2) and Non-Alcoholic Fatty Liver Disease (NAFLD) are identified as more susceptible to these adverse reactions. This exploratory analysis aims to identify clinical parameters influencing lamotrigine pharmacokinetics across diverse populations, shedding light on toxicity and therapeutic drug monitoring (TDM) considerations. Starting with a retrospective analysis of 41 lamotrigine-treated patients at Hospital Santo António reveals changes or deviations from normal levels in various blood parameters and significant correlations between these parameters. Serum level changes, including creatinine, albumin, gamma-glutamyl transferase, total bilirubin, and Vitamin B12, are observed, with strong negative correlations between Vitamin B12 and creatinine. Then, we used GastroPlus and DILIsym to explore the impact of clinical parameters on lamotrigine for different patient populations. We constructed a Physiologically Based Pharmacokinetic (PBPK) model for lamotrigine in GastroPlus, based on ADMET predictions and data from the literature, to simulate the pharmacokinetic variability of lamotrigine in different populations, and we visualized the impact of increasing lamotrigine dose on its plasma concentration–time profiles (200 mg, 400 mg, 600 mg, 1200 mg) and reduced bioavailability. At higher doses, it is possible that the saturation of metabolic pathways leads to the formation of toxic metabolites or intermediates. These metabolites may exert inhibitory effects on drug-metabolizing enzymes or disrupt normal physiological processes, thereby impeding the drug’s clearance and potentially lowering its bioavailability. In DILIsym, we investigated lamotrigine’s DILI potential for individuals with diabetes and NAFLD. The results demonstrated an increased risk, emphasizing the need for careful monitoring. This study underscores the importance of understanding lamotrigine’s pharmacokinetics for tailored treatment decisions, improved outcomes, and minimized adverse reactions.