Comorbidity Of Epilepsy Research Articles

Distinct comorbidity phenotypes among post-9/11 Veterans with epilepsy are linked to diverging outcomes and mortality risks.

To investigate phenotypes of comorbidity before and after an epilepsy diagnosis in a national cohort of post-9/11 Service Members and Veterans and explore phenotypic associations with mortality. Among a longitudinal cohort of Service Members and Veterans receiving care in the Veterans Health Administration (VHA) from 2002 to 2018, annual diagnoses for 26 conditions associated with epilepsy were collected over 5 years, ranging from 2 years prior to 2 years after the year of first epilepsy diagnosis. Latent class analysis (LCA) was used to identify probabilistic comorbidity phenotypes with distinct health trajectories. Descriptive statistics were used to describe the characteristics of each phenotype. Fine and Gray cause-specific survival models were used to measure mortality outcomes for each phenotype up to 2021. Six distinct phenotypes were identified: (1) relatively healthy, (2) post-traumatic stress disorder, (3) anxiety and depression, (4) chronic disease, (5) bipolar/substance use disorder, and (6) polytrauma. Accidents were the most common cause of death overall, followed by suicide/mental health and cancer, respectively. Each phenotype exhibited unique associations with mortality and cause of death, highlighting the differential impact of comorbidity patterns on patient outcomes. By delineating clinically meaningful epilepsy comorbidity phenotypes, this study offers a framework for clinicians to tailor interventions. Moreover, these data support systems of care that facilitate treatment of epilepsy and comorbidities within an interdisciplinary health team that allows continuity of care. Targeting treatment toward patients with epilepsy who present with specific heightened risks could help mitigate adverse outcomes and enhance overall patient care.

Emotional comorbidities in epilepsy result from seizure-induced corticosterone activity

People with epilepsy often have psychiatric comorbidities that can significantly impair their quality of life. We previously reported that repeated seizure activity persistently alters endocannabinoid (eCB) signaling in the amygdala which accounts for comorbid emotional dysregulation in rats, however, the mechanism by which these alterations in eCB signaling within the epileptic brain occur is unclear. Endocannabinoid signaling is influenced by corticosterone (CORT) to modulate cognitive and emotional processes and a hyperactive hypothalamic-pituitary-adrenal (HPA) axis occurs in both people with epilepsy and nonhuman animal models of epilepsy.We employed selective pharmacological tools and a variety of approaches including whole-cell patch-clamp electrophysiology, behavioural paradigms and biochemical assays in amygdala kindled adult male Long-Evans rats. We aimed to determine whether seizures induce hypersecretion of CORT and the role this plays in eCB system dysregulation, impaired fear memory, and anxiety-like behaviours associated with seizure activity.Plasma CORT levels were significantly and consistently elevated following seizures over the course of kindling. Pre-seizure administration with the CORT synthesis inhibitor metyrapone prevented this seizure-induced CORT increase, prevented amygdala anandamide downregulation, and synaptic alteration induced by seizure activity. Moreover, treatment with metyrapone or combined glucocorticoid receptor (GR)/mineralocorticoid receptor (MR) antagonists prior to each elicited seizure were equally effective in preventing chronically altered anxiety-like behaviour and fear memory responses.Inhibiting seizure-induced corticosterone synthesis, or directly blocking the effects of CORT at GR/MR prevents deleterious changes in emotional processing and could be a treatment option for emotional comorbidities in epilepsy.

Functional seizure semiology and classification in a public and private hospital

PurposeOur understanding of potential differences in seizure semiology among patients with functional seizures (FS), also known as psychogenic non-epileptic seizures (PNES), across socioeconomic contexts is currently limited. By examining the differences in seizure manifestations between different socioeconomic groups, we aim to enhance the understanding of how socioeconomic factors may influence FS presentation. This study aimed to describe FS semiology in patients from a private and public epilepsy monitoring units (EMUs) in Cape Town, South Africa. MethodsThe study included patients with FS confirmed through video-electroencephalography (video-EEG) and without comorbid epilepsy. For this retrospective case-control study, data on seizure semiology was gathered from digital patient records, beginning with the earliest available record for each hospital. ResultsA total of 305 patients from a private hospital and 67 patients from a public hospital were eligible for the study (N = 372). The private hospital tended to report more akinetic and subjective seizure types when compared to the public hospital. Additionally, patients at the public hospital had higher odds of reporting emotional seizure triggers (aOR=2.57, 95% CI [1.03, 6.37]), loss of consciousness or awareness (aOR=2.58, 95% CI [1.07, 6.24]), and rapid post-event recovery (aOR=6.01, 95% CI [2.52, 14.34]). At the same time, they were less likely to report both short (<30 s) (aOR=0.21, 95% CI [0.08, 0.55]) and long (>5 min) seizures (aOR=0.73, 95% CI [0.13, 0.56]), amnesia for the event (aOR=0.19, 95% CI [0.09, 0.43]), ictal aphasia (aOR=0.33, 95% CI [0.14, 0.76]) or falls and drop attacks (aOR=0.43, 95% CI [0.18, 0.996]), when compared to the private hospital patients. ConclusionWhile the seizure manifestations were largely consistent across the two socioeconomic cohorts of patients with FS, some subtle differences were observed and warrant further investigation.

Evaluating depression in Indonesian adolescents with epilepsy: Comprehensive validation and reliability assessment of the neurological disorders depression inventory-epilepsy for youth Indonesian version (NDDI-E-Y[ID]).

Epilepsy is a common chronic neurological disorder in pediatrics. Depression is an often underdetected comorbidity in childhood epilepsy. This study aimed to adapt the Neurological Disorders Depression Inventory-Epilepsy for Youth (NDDI-E-Y) to the Indonesian language and population, as well as to validate the Indonesian version of NDDI-E-Y (NDDI-E-Y[ID]). This three-stage study comprised instrument translation, cultural verification, and content validity testing (first stage), pilot testing (second stage), followed by concurrent validity and reliability testing (third stage) of the NDDI-E-Y(ID). Validation was done against the Centre for Epidemiologic Studies Depression Scale - Revised (CESD-R). Content validity, assessed by six experts, was quantified using the content validity index for items (I-CVI) and scale (S-CVI). Participants were adolescents aged 12-17 years diagnosed with any type of epilepsy who completed both instruments. Concurrent validity was evaluated using Spearman's correlation and reliability was measured using Cronbach's alpha. The first stage produced a culturally appropriate NDDI-E-Y(ID). Thirty healthy adolescents and 10 adolescents with epilepsy participated in the second stage. In the third stage, another group of 30 adolescents with epilepsy took part. We obtained I-CVI and S-CVI values averaging 1. The NDDI-E-Y(ID) showed a positive and significant correlation with CESD-R (Spearman's rho = 0.671, p < 0.001). A Cronbach's alpha of 0.928 reflected a high internal consistency. Based on the results, the NDDI-E-Y(ID) was found to be a valid and reliable screening instrument for detecting depression in youth with epilepsy. Depression is an under-recognized problem in youth with epilepsy. Currently available depression screening tools are in English, making it less suitable for detection purposes in Indonesia. This study developed and validated the Indonesian version of the NDDI-E-Y, a depression screening tool for youth with epilepsy.

Prevalence and predictors of psychiatric comorbidities in epilepsy: A cross-sectional study

Prevalence and predictors of psychiatric comorbidities in epilepsy: A cross-sectional study

Structural brain characteristics of epilepsy patients with comorbid migraine without aura

Migraine is a common bi-directional comorbidity of epilepsy, indicating potential complex interactions between the two conditions. However, no previous studies have used brain morphology analysis to assess possible interactions between epilepsy and migraine. Voxel-based morphometry (VBM), surface-based morphometry (SBM), and structural covariance networks (SCNs) can be used to detect morphological changes with high accuracy. We recruited 30 individuals with epilepsy and comorbid migraine without aura (EM), along with 20 healthy controls (HC) and 30 epilepsy controls (EC) without migraine. We used VBM, SBM, and SCN analysis to compare differences in gray matter volume, cortical thickness, and global level and local level graph theory indexes between the EM, EC, and HC groups to investigate structural brain changes in the EM patients. VBM analysis showed that the EM group had gray matter atrophy in the right temporal pole compared with the HC group (p < 0.001, false discovery rate correction [FDR]). Furthermore, the headache duration in the EM group was negatively correlated with the gray matter volume of the right temporal pole (p < 0.05). SBM analysis showed cortical atrophy in the left insula, left posterior cingulate gyrus, left postcentral gyrus, left middle temporal gyrus, and left fusiform gyrus in the EM compared with the HC group (p < 0.001, family wise error correction). We found a positive correlation between headache frequency and the cortical thickness of the left middle temporal gyrus (p < 0.05). SCN analysis revealed no differences in global parameters between the three groups. The area under the curve (AUC) of the nodal betweenness centrality in the right postcentral gyrus was lower in the EM group compared with the HC group (p < 0.001, FDR correction), and the AUC of the nodal degree in the right fusiform gyrus was lower in the EM group compared with the EC group (p < 0.001, FDR correction). We found clear differences in brain structure in the EM patients compared with the HC group. Accordingly, migraine episodes may influence brain structure in epilepsy patients. Conversely, abnormal brain structure may be an important factor in the development of epilepsy with comorbid migraine without aura. Further studies are needed to investigate the role of brain structure in individuals with epilepsy and comorbid migraine without aura.

Dysregulation of Neuropilin-2 Expression in Inhibitory Neurons Impairs Hippocampal Circuit Development and Enhances Risk for Autism-Related Behaviors and Seizures.

Dysregulation of development, migration, and function of interneurons, collectively termed interneuronopathies, have been proposed as a shared mechanism for autism spectrum disorders (ASDs) and childhood epilepsy. Neuropilin-2 (Nrp2), a candidate ASD gene, is a critical regulator of interneuron migration from the median ganglionic eminence (MGE) to the pallium, including the hippocampus. While clinical studies have identified Nrp2 polymorphisms in patients with ASD, whether selective dysregulation of Nrp2-dependent interneuron migration contributes to pathogenesis of ASD and enhances the risk for seizures has not been evaluated. We tested the hypothesis that the lack of Nrp2 in MGE-derived interneuron precursors disrupts the excitation/inhibition balance in hippocampal circuits, thus predisposing the network to seizures and behavioral patterns associated with ASD. Embryonic deletion of Nrp2 during the developmental period for migration of MGE derived interneuron precursors (iCKO) significantly reduced parvalbumin, neuropeptide Y, and somatostatin positive neurons in the hippocampal CA1. Consequently, when compared to controls, the frequency of inhibitory synaptic currents in CA1 pyramidal cells was reduced while frequency of excitatory synaptic currents was increased in iCKO mice. Although passive and active membrane properties of CA1 pyramidal cells were unchanged, iCKO mice showed enhanced susceptibility to chemically evoked seizures. Moreover, iCKO mice exhibited selective behavioral deficits in both preference for social novelty and goal-directed learning, which are consistent with ASD-like phenotype. Together, our findings show that disruption of developmental Nrp2 regulation of interneuron circuit establishment, produces ASD-like behaviors and enhanced risk for epilepsy. These results support the developmental interneuronopathy hypothesis of ASD epilepsy comorbidity.

Psychiatric Comorbidity in Children and Youth with Epilepsy

Introduction: Psychiatric comorbidities of epilepsy are common. Yet psychiatric disorders are often under-prevented, under-diagnosed, and under-treated. Objectives: to assess the prevalence of different psychiatric disorders in children and adolescents with epilepsy and to determine associated risk factors. Methods: This is a descriptive and analytical cross-sectional study of patients treated for a psychiatric disorder comorbid with epilepsy, conducted in the Child Psychiatry Department at Ar-Razi Hospital in Salé, Morocco, from January 1st to December 31st, 2022.Data were collected using a questionnaire concerning the socio-demographic and clinical characteristics of our patients. Psychiatric disorders were assessed using the diagnostic criteria of the DSM-5 psychiatric manual. Results: Our study included 70 patients followed for epilepsy comorbid with a psychiatric disorder. The most common psychiatric comorbidities were intellectual development disorder, autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). 72.9% suffered from a single psychiatric comorbidity, while 27.1% had two or more. Several sociodemographic and clinical factors were associated with different psychiatric disorders. Gender was associated with conduct and behavior disorders, with males predominating (p=0.043), while age was significantly associated with psychosis (p=0.047). Mood disorders were associated with the type of epilepsy. Seizure recurrence was associated with behavioral and anxiety disorders. Conclusion: The co-morbidity of psychiatric disorders and epilepsy in children and adolescents is common, underscoring the importance of early detection for improved management.

Imbalance between hippocampal projection cell and parvalbumin interneuron architecture increases epileptic susceptibility in mouse model of methyl CpG binding protein 2 duplication syndrome.

Methyl CpG-binding protein 2 (MECP2) duplication syndrome is a rare X-linked genomic disorder affecting predominantly males, which is usually manifested as epilepsy and autism spectrum disorder (ASD) comorbidity. The transgenic line MeCP2Tg1 was used for mimicking MECP2 duplication syndrome and showed autism-epilepsy co-occurrence. Previous works suggested that the excitatory/inhibitory (E/I) imbalance is a potential common mechanism for both epilepsy and ASD. The projection neurons and parvalbumin (PV) interneurons account for the majority of E/I balance in the hippocampus. Therefore, we explored how structural changes of projection and PV+ neurons occur in the hippocampus of MeCP2Tg1 mice and whether these morphological changes contribute to epilepsy susceptibility. We used the interneuron Designer receptors exclusively activated by designer drugs mouse model to inhibit inhibitory neurons in the hippocampus to verify the epilepsy susceptibility of MeCP2Tg1 (FVB, an inbred strain named as sensitivity to Friend leukemia virus) mice. Electroencephalograms were recorded for the definition of seizure. We performed retro-orbital injection of virus in MeCP2Tg1 (FVB):CaMKIIα-Cre (C57BL/6) mice or MeCP2Tg1:PV-Cre (C57BL/6) mice and their littermate controls to specifically label projection and PV+ neurons for structural analysis. Epilepsy susceptibility was increased in MeCP2Tg1 mice. There was a reduced number of PV neurons and reduced dendritic complexity in the hippocampus of MeCP2Tg1 mice. The dendritic complexity in MeCP2Tg1 mice was increased compared to wild-type mice, and total dendritic spine density in dentate gyrus of MeCP2Tg1 mice was also increased. Total dendritic spine density was increased in CA1 of MeCP2Tg1 mice. Overexpression of MeCP2 may disrupt crucial signaling pathways, resulting in decreased dendritic complexity of PV interneurons and increased dendritic spine density of projection neurons. This reciprocal modulation of excitatory and inhibitory neuronal structures associated with MeCP2 implies its significance as a potential target in the development of epilepsy and offers a novel perspective on the co-occurrence of autism and epilepsy.

Increased susceptibility to kainate-induced seizures in a mouse model of tuberous sclerosis complex: Importance of sex and circadian cycle.

Comorbidity of epilepsy and autism in tuberous sclerosis complex 2 (TSC2) is very frequent, but the link between these conditions is still poorly understood. To study neurological problems related to autism, the scientific community has been using an animal model of TSC2, Tsc2+/- mice. However, it is still unknown whether this model has the propensity to exhibit increased seizure susceptibility. Further, the importance of sex and/or the circadian cycle in this biological process has never been addressed. This research aimed to determine whether male and female Tsc2+/- mice have altered seizure susceptibility at light and dark phases. We assessed seizure susceptibility and progression in a Tsc2+/- mouse model using the chemical convulsant kainic acid (KA), a potent agonist of the AMPA/kainate class of glutamate receptors. Both male and female animals at adult age were evaluated during non-active and active periods. Seizure severity was determined by integrating individual scores per mouse according to a modified Racine scale. Locomotor behavior was monitored during control and after KA administration. We found increased seizure susceptibility in Tsc2+/- mice with a significant influence of sex and circadian cycle on seizure onset, progression, and behavioral outcomes. While, compared to controls, Tsc2+/- males overall exhibited higher susceptibility independently of circadian cycle, Tsc2+/- females were more susceptible during the dark and post-ovulatory phase. Interestingly, sexual dimorphisms related to KA susceptibility were always reported during light phase independently of the genetic background, with females being the most vulnerable. The enhanced susceptibility in the Tsc2 mouse model suggests that other neurological alterations, beside brain lesions, may be involved in seizure occurrence for TSC. Importantly, our work highlighted the importance of considering biological sex and circadian cycle for further studies of TSC-related epilepsy research. Tuberous sclerosis complex (TSC) is a rare genetic disorder. It causes brain lesions and is linked to epilepsy, intellectual disability, and autism. We wanted to investigate epilepsy in this model. We found that these mice have more induced seizures than control animals. Our results show that these mice can be used in future epilepsy research for this disorder. We also found that sex and time of day can influence the results. This must be considered in this type of research.

In-hospital outcomes in people with autism and epilepsy – A population-based study

Autism is a common comorbid diagnosis in those with epilepsy. Understanding the health needs and outcomes in patients with this dual diagnosis is important for optimizing healthcare outcomes. We compared hospital-level variables amongst patients with co-occurring autism and epilepsy, to those with epilepsy alone. Non-elective hospital admissions amongst patients with epilepsy alone and co-occurring autism and epilepsy were identified in the 2003–14 National Inpatient Sample (NIS) using previously validated ICD-9-CM case definitions. One patient with co-occurring epilepsy and autism was matched to three epilepsy patients for age and sex. Multinomial logistic regressions were performed to examine outcomes of interest. Compared to those with epilepsy alone (n = 27,762), patients with autism and epilepsy (n = 9254) had a higher odds of transfer to another facility (OR = 1.09, p = 0.048), in-hospital mortality (OR = 1.36, p = 0.011), longer mean length of stay (5.63 days vs. 5.12 days, p < 0.0001), and septicemia (4.21 % vs. 3.08 %, p < 0.0001). Distributions of demographics, insurance type, socioeconomic status, and comorbidities significantly differed between both groups. Our findings demonstrate that patients with comorbid autism and epilepsy are a unique population with health outcomes significantly differing from those with epilepsy alone. Given the effect that dual diagnosis has on hospital trajectory, focused treatment plans must be adopted to optimize care and hospital outcomes in these patients.

Vagus Nerve Stimulation Therapy in Epilepsy: An Overview of Technical and Surgical Method, Patient Selection, and Treatment Outcomes.

Epilepsy affects over 65 million people worldwide. One-third of people with epilepsy do not respond to medication and may benefit from surgery. Vagus nerve stimulation (VNS) is the first neuromodulation therapy for the treatment of drug-resistant epilepsy. This method is used in combination with anti-seizure medications in adults and in the pediatric population. VNS has also been demonstrated to have benefits for some epilepsy comorbidities, such as depression, and can be used in combination with other neuromodulation therapies in epilepsy. The authors present an overview of VNS physiology, patient selection, surgery and risks, neuromodulation therapy, and application to epilepsy comorbidities.

Hypothalamic-Pituitary-Adrenal Axis Dysfunction Elevates SUDEP Risk in a Sex-Specific Manner.

Epilepsy is often comorbid with psychiatric illnesses, including anxiety and depression. Despite the high incidence of psychiatric comorbidities in people with epilepsy, few studies address the underlying mechanisms. Stress can trigger epilepsy and depression. Evidence from human and animal studies supports that hypothalamic-pituitary-adrenal (HPA) axis dysfunction may contribute to both disorders and their comorbidity ( Kanner, 2003). Here, we investigate if HPA axis dysfunction may influence epilepsy outcomes and psychiatric comorbidities. We generated a novel mouse model (Kcc2/Crh KO mice) lacking the K+/Cl- cotransporter, KCC2, in corticotropin-releasing hormone (CRH) neurons, which exhibit stress- and seizure-induced HPA axis hyperactivation ( Melon et al., 2018). We used the Kcc2/Crh KO mice to examine the impact on epilepsy outcomes, including seizure frequency/burden, comorbid behavioral deficits, and sudden unexpected death in epilepsy (SUDEP) risk. We found sex differences in HPA axis dysfunction's effect on chronically epileptic KCC2/Crh KO mice seizure burden, vulnerability to comorbid behavioral deficits, and SUDEP. Suppressing HPA axis hyperexcitability in this model using pharmacological or chemogenetic approaches decreased SUDEP incidence, suggesting that HPA axis dysfunction may contribute to SUDEP. Altered neuroendocrine markers were present in SUDEP cases compared with people with epilepsy or individuals without epilepsy. Together, these findings implicate HPA axis dysfunction in the pathophysiological mechanisms contributing to psychiatric comorbidities in epilepsy and SUDEP.

Children with ADHD and EEG abnormalities at baseline assessment, risk of epileptic seizures and maintenance on methylphenidate three years later

PurposeThis study aimed to assess the incidence of EEG abnormalities (EEG-ab) in children diagnosed with ADHD, investigate the risk of epileptic seizures (SZ) and maintenance on methylphenidate (MPH) over a three-year period.MethodsA total of 517 ADHD children aged 6–14 years were included. Baseline assessments included the identification of EEG-ab, ADHD inattentive subtype (ADHD-I), comorbid epilepsy, the use of antiepileptic drugs (AEDs) and the use of MPH. At the 3-year follow-up, assessments included the presence of EEG-ab, maintenance on MPH, AED usage, SZ risk in cases with EEG-epileptiform abnormalities (EEG-epi-ab), compared with control ADHD cases without EEG-epi-ab matched for age and gender.ResultsEEG-ab were identified in 273 (52.8%) cases. No statistically significant differences were observed between the EEG-ab and EEG-non-ab groups in terms of age, gender, ADHD-I type or initial use of MPH. EEG non-epileptiform abnormalities (EEG-non-epi-ab) were found in 234 out of 478 (49%) cases without EEG-epi-ab. Notably, EEG-non-epi-ab occurred more frequently in the group of 39 cases with EEG-epi-ab (30/39 (76.9%) vs. 9/39, (21.3%), a subset selected for 3-year follow-up. At 3-year-follow-up no statistically significant difference was found in maintenance on MPH in ADHD cases with and without EEG-epi-ab. Nobody of ADHD cases without comorbid epilepsy or with comorbid epilepsy with achieved SZ freedom developed new SZ. Only 3 children with drug resistant epilepsy experienced SZs, without increase in SZ frequency. The disappearance rate of EEG-epi-ab was higher than that EEG-non-epi-ab (71.8% vs. 33.3%).ConclusionsChildren with and without EEG-ab exhibited similar patterns of MPH use (initial use, positive response, and maintenance on MPH). The presence of comorbid epilepsy and EEG-ab, with or without EEG-epi-ab, was not associated with an increased risk of SZ despite the use of MPH.

Behavioral comorbidities treatment by fecal microbiota transplantation in canine epilepsy: a pilot study of a novel therapeutic approach.

Anxiety and cognitive dysfunction are frequent, difficult to treat and burdensome comorbidities in human and canine epilepsy. Fecal microbiota transplantation (FMT) has been shown to modulate behavior in rodent models by altering the gastrointestinal microbiota (GIM). This study aims to investigate the beneficial effects of FMT on behavioral comorbidities in a canine translational model of epilepsy. Nine dogs with drug-resistant epilepsy (DRE) and behavioral comorbidities were recruited. The fecal donor had epilepsy with unremarkable behavior, which exhibited a complete response to phenobarbital, resulting in it being seizure-free long term. FMTs were performed three times, two weeks apart, and the dogs had follow-up visits at three and six months after FMTs. Comprehensive behavioral analysis, including formerly validated questionnaires and behavioral tests for attention deficit hyperactivity disorder (ADHD)- and fear- and anxiety-like behavior, as well as cognitive dysfunction, were conducted, followed by objective computational analysis. Blood samples were taken for the analysis of antiseizure drug (ASD) concentrations, hematology, and biochemistry. Urine neurotransmitter concentrations were measured. Fecal samples were subjected to analysis using shallow DNA shotgun sequencing, real-time polymerase chain reaction (qPCR)-based Dysbiosis Index (DI) assessment, and short-chain fatty acid (SCFA) quantification. Following FMT, the patients showed improvement in ADHD-like behavior, fear- and anxiety-like behavior, and quality of life. The excitatory neurotransmitters aspartate and glutamate were decreased, while the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and GABA/glutamate ratio were increased compared to baseline. Only minor taxonomic changes were observed, with a decrease in Firmicutes and a Blautia_A species, while a Ruminococcus species increased. Functional gene analysis, SCFA concentration, blood parameters, and ASD concentrations remained unchanged. Behavioral comorbidities in canine IE could be alleviated by FMT. This study highlights FMT's potential as a novel approach to improving behavioral comorbidities and enhancing the quality of life in canine patients with epilepsy.

The 2017 and 2022 ILAE epilepsy classification systems identify needs and opportunities in care: A paediatric hospital-based study

ObjectivesThere is a paucity of studies reporting the epilepsy spectrum using the 2017 and 2022 ILAE classification systems in everyday clinical practice. To identify gaps and opportunities in care we evaluated a hospital-based cohort applying these epilepsy classification systems, including aetiology and co-morbidity, and the utility of molecular genetic diagnosis to identify available precision therapies. MethodsCross sectional retrospective study of all children with epilepsy (≤16 years) attending University Hospital Galway (2017–2022). Data collection and analysis of each case was standardised to ensure a systematic approach and application of the recent ILAE categorisation and terminology (2017 and 2022). Ethics approval was obtained. ResultsAmong 356 children, epilepsy was classified as focal (46.1 %), generalised (38.8 %), combined (6.2 %), and unknown (9 %). Epilepsy syndrome was determined in 145/356 (40.7 %), comprising 24 different syndromes, most commonly SeLECTS (9 %), CAE (7 %), JAE (6.2 %) and IESS (5.9 %). New aetiology-specific syndromes were identified (e.g. CDKL5-DEE). Molecular diagnosis was confirmed in 19.9 % (n = 71) which encompassed monogenic (13.8 %) and chromosomopathy/CNV (6.2 %). There was an additional 35.7 % (n = 127) of patients who had a presumed genetic aetiology of epilepsy. Remaining aetiology included structural (18.8 %, n = 67), infectious (2 %, n = 7), metabolic (1.7 %, n = 6) and unknown (30.3 %, n = 108). Encephalopathy categorisation was determined in 182 patients (DE in 38.8 %; DEE in a further 11.8 %) associated with a range of co-morbidities categorised as global delay (29.2 %, n = 104), severe neurological impairment (16.3 %, n = 58), and ASD (14.6 %, n = 52). Molecular-based “precision therapy” was deemed available in 21/356 (5.9 %) patients, with “molecular precision” approach utilised in 13/356 (3.7 %), and some benefit noted in 6/356 (1.7 %) of overall cohort or 6/71 (8.5 %) of the molecular cohort. ConclusionApplying the latest ILAE epilepsy classification systems allow comparison across settings and identifies a major neuro-developmental co-morbidity rate and a large genetic aetiology. We identified very few meaningful molecular-based disease modifying “precision therapies”. There is a monumental gap between aetiological identification, and impact of meaningful therapies, thus the new 2017/2022 classification clearly identifies the major challenges in the provision of routine epilepsy care.

Prevalence and associated factors of psychiatric comorbidities in epilepsy in the Casablanca-Settat region of Morocco: A cross-sectional study.

To determine the estimated prevalence of anxiety, depression, and anxiety-depression syndrome (ADS) and to identify the associated factors in Moroccan people with epilepsy (PWE). A cross-sectional study was conducted among adult PWE (June 2021-December 2022) in the Casablanca-Settat region. PWE were interviewed by completing a questionnaire collecting sociodemographic and clinical data. Anxiety and depression were assessed by the Hospital Anxiety and Depression Scale (HADS). Out of 21 points, a score ≥8 is in favor of considerable anxiety/depression symptoms and a sum of the two scores ≥15 indicates the presence of ADS. Data were analyzed using Statistical Package for Social Sciences (SPSS) 21.0. p-values ≤0.05 were considered statistically significant and logistic regression was performed to determine the associated factors. Among 294 PWE, the median age was 39 years (interquartile range [IQR]: 25.75-54.00). The median anxiety, depression, and ADS scores were 8 (IQR: 5.00-10.00), 7 (IQR: 4.00-10.00), and 15 (IQR: 10.00-20.00), respectively. Anxiety, depression, and ADS were revealed in 51.4%, 44.9%, and 51.0% of PWE, respectively. Depression was the only predictor for anxiety (aOR = 24.20; 95%CI: 12.45-47.01). Antiseizure polytherapy (aOR = 3.35; 95%CI: 1.72-6.54) and anxiety (aOR = 24.04; 95%CI: 12.12-47.67) were the factors associated with depression. The risk of ADS was increased by female gender (aOR = 2.83; 95%CI: 1.68-4.78), antiseizure polytherapy (aOR = 2.75; 95%CI: 1.62-4.65), structural epilepsy (aOR = 1.73; 95%CI: 1.01-2.94), and the presence of concomitant conditions with epilepsy (aOR = 1.96; 95%CI: 1.16-3.31). Our study reports high psychiatric comorbidity prevalence in epilepsy, which supports the bidirectional link hypothesis. Associated factors found are important in the prognosis and prevention. The neural mechanisms underlying epilepsy tend to expose PWE to psychiatric disorders. Our study aims to quantify the rate of psychiatric comorbidities and their predictive factors in Moroccan PWE. The estimated prevalences of significant symptoms of anxiety, depression, and ADS were 51.4%, 44.9%, and 51.0%, respectively. Depression was the predictor of anxiety. Antiseizure polymedication and anxiety were the associated factors with depression. The risk of SAD was increased by female gender, antiseizure polymedication, structural epilepsy, and concomitant diseases with epilepsy. Our results are important for considering the psychiatric aspect of PWE and improving their care and quality of life.

Ficus platyphylla alleviates seizure severity and neurobehavioral comorbidities in pentylenetetrazole–kindled rats via modulation of oxidative stress

PTZ kindling induces oxidative stress, neuronal cell degeneration, and neurobehavioral alterations in rodents that mimic neuropsychiatric comorbidities of epilepsy, which could be initiated or aggravated by some antiepileptic drugs. Here, we investigated the effects of the methanol extract of Ficus platyphylla (FP) on severity scores for seizures, neuronal cell degeneration, and neurobehavioral alterations in rats kindled with pentylenetetrazole (PTZ) and probed the involvement of oxidative stress in these ameliorative effects of FP. FP (50 and 100 mg/kg, p.o.) ameliorated seizure severity, neuronal cell degeneration, depressive behaviors, cognitive dysfunctions, and oxidative stress in rats kindled with PTZ (42.5 mg/kg, i.p.). The findings from this study give additional insights into the potential values of FP in the treatment of persistent epilepsy and major neuropsychiatric comorbidities via modulation of oxidative stress.

Common Ground: We Can Comprehensively Treat Pediatric Epilepsy and Psychiatric Comorbidities

Epilepsy and psychiatric illness have been long studied and today are better accepted as co-occurring than as discrete illnesses that are independent even if associated. Common pathophysiology may not be easily explained, but clearly exists given the significant overrepresentation of psychiatric illness among individuals with epilepsy. Conditions like autism spectrum disorder, anxiety, depression, and attention deficit hyperactivity disorder are prevalent in pediatric epilepsy much more than expected, even in the context of chronic neurologic disease. The interplay between pediatric epilepsy and neuropsychiatric symptoms represents a complex clinical circumstance that is not well subtended by the chasm-like division of labor between psychiatrists and neurologists. The unfortunate result is that children and families often experience care that is fractured and at worst, counterproductive for their quality of life. A neuropsychiatric paradigm is essential to address epilepsy and its intrinsic psychiatric symptoms. Practical strategies will be discussed to address this challenge.

Neuronal Mitochondrial Calcium Uniporter (MCU) Deficiency Is Neuroprotective in Hyperexcitability by Modulation of Metabolic Pathways and ROS Balance.

Epilepsy is one of the most common neurological disorders in the world. Common epileptic drugs generally affect ion channels or neurotransmitters and prevent the emergence of seizures. However, up to a third of the patients suffer from drug-resistant epilepsy, and there is an urgent need to develop new therapeutic strategies that go beyond acute antiepileptic (antiseizure) therapies towards therapeutics that also might have effects on chronic epilepsy comorbidities such as cognitive decline and depression. The mitochondrial calcium uniporter (MCU) mediates rapid mitochondrial Ca2+ transport through the inner mitochondrial membrane. Ca2+ influx is essential for mitochondrial functions, but longer elevations of intracellular Ca2+ levels are closely associated with seizure-induced neuronal damage, which are underlying mechanisms of cognitive decline and depression. Using neuronal-specific MCU knockout mice (MCU-/-ΔN), we demonstrate that neuronal MCU deficiency reduced hippocampal excitability in vivo. Furthermore, in vitro analyses of hippocampal glioneuronal cells reveal no change in total Ca2+ levels but differences in intracellular Ca2+ handling. MCU-/-ΔN reduces ROS production, declines metabolic fluxes, and consequently prevents glioneuronal cell death. This effect was also observed under pathological conditions, such as the low magnesium culture model of seizure-like activity or excitotoxic glutamate stimulation, whereby MCU-/-ΔN reduces ROS levels and suppresses Ca2+ overload seen in WT cells. This study highlights the importance of MCU at the interface of Ca2+ handling and metabolism as a mediator of stress-related mitochondrial dysfunction, which indicates the modulation of MCU as a potential target for future antiepileptogenic therapy.