癫痫共患病的研究进展

Background: Developmental delay and intellectual disability (DD/ID) are frequently accompanied by epilepsy, and growing evidence implicates variants in voltage-gated calcium channel genes in their pathogenesis. This study aimed to investigate the association of polymorphisms in CACNA1A, CACNA1C, and CACNA1H with DD/ID and epilepsy comorbidity in Korean children. Methods: We retrospectively analyzed 141 pediatric patients diagnosed with DD/ID who underwent whole-exome sequencing (WES) and were not found to have pathogenic monogenic variants. Nine single-nucleotide polymorphisms (SNPs) across CACNA1A, CACNA1C, and CACNA1H were selected based on functional annotation scores and prior literature. Genotype data were extracted from WES variant files, and allele and genotype frequencies were compared with control data from the gnomAD East Asian population and the Korean Reference Genome Database (KRGDB). Subgroup analyses were performed according to epilepsy comorbidity. Results: The CACNA1A rs16023 variant showed a significantly higher B allele frequency in DD/ID patients than in both control datasets and was also associated with epilepsy comorbidity. Genotype distribution analysis revealed that the BB genotype of rs16023 was more frequent in patients with epilepsy. Conclusions: The CACNA1A rs16023 variant may contribute to genetic susceptibility to DD/ID and epilepsy in Korean children, potentially through regulatory mechanisms. These findings support the relevance of calcium channel genes in neurodevelopmental disorders and highlight the importance of integrating functional annotation in variant prioritization.

Objective: Epilepsy and sleep-related breathing disorders (SBD) are among the most prevalent conditions in neurology. This study aimed to compare sleep parameters in patients with primary snoring-epilepsy (PrS-E) and severe obstructive sleep apnea syndrome-epilepsy (OSAS-E). Additionally, the study sought to assess the mutual effects of treatments administered in each clinical area on the other. Materials and Methods: Patients who were subjected to follow-up in the sleep laboratory and epilepsy outpatient clinic between 2006 and 2022 were analysed retrospectively, following approval from ethics committe. The demographic data, medical history, characteristics of epileptic seizures, electroencephalograms (EEGs) and antiseizure drugs (ASD) before and after SBD treatment were compared. The effect on sleep structure and respiratory issues of lowering the dose of ASD after SBD treatment was also assessed. Results: The study included 28 patients with PrS-E and 28 patients with severe OSAS-E. Focal onset impaired awareness focal to bilateral tonic-clonic seizures were found to be more prevalent in both groups. Following treatment for SBD, there was a decline in seizure severity and frequency, a resolution of EEG pathologies, or a decrease ASDs in both groups. The reduction in ASDs and treatment for SBD resulted in an improvement in sleep structure, a reduction in body mass index, snoring, and Epworth Sleepiness Scale. Conclusion: Treating SBDs can lead to a reduction in the dosage of ASD, improved sleep structure, and decreased snoring. This study demonstrated mutual benefits in the management of both epilepsy and SBDs. SBD symptoms should be investigated in epilepsy patients, and the presence of epileptic seizures should be considered in patients with SBD.

BACKGROUND Temporal lobe epilepsy (TLE) and major depressive disorder (MDD) are prevalent and complex neurological disorders that affect individuals globally. Clinical and epidemiological studies indicate a significant comorbidity between TLE and MDD; however, the shared molecular mechanisms underlying this relationship remain unclear. This study aims to explore the common key genes associated with TLE and MDD through a systematic analysis of gene expression profiles, elucidate their underlying molecular pathological mechanisms, and evaluate the potential applications of these genes in diagnostic and therapeutic contexts. METHODS Brain tissue gene expression data for TLE and MDD were obtained from the GEO database. Differentially expressed genes (DEGs), weighted gene co-expression network analysis (WGCNA), functional enrichment, and protein-protein interaction (PPI) network construction were performed to identify shared gene modules. LASSO and random forest (RF) machine learning models were used to select diagnostic candidate genes, validated through ROC curve analysis. Immune infiltration analysis explored the immune involvement of key genes, while single-cell sequencing confirmed gene expression across cell types. Potential therapeutic drugs were identified using a drug database. RESULTS A total of 372 DEGs were identified as either up- or down-regulated between TLE and MDD, with WGCNA revealing nine shared gene modules. Seven hub genes, including HTR7 and CDHR2, demonstrated strong ROC performance. Immune infiltration analysis revealed changes in immune cell populations linked to key genes, confirmed by single-cell sequencing. Upadacitinib was identified as a potential therapeutic drug targeting these genes. CONCLUSION This study identified shared gene expression profiles between TLE and MDD, emphasizing immune pathway-related molecular mechanisms. Immune infiltration analysis and single-cell sequencing underscored the significance of immune regulation in their comorbidity, while drug prediction highlights candidates for precision medicine, establishing a foundation for future research and therapeutic strategies.

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The article is aimed to determine the specific features of common neurological diseases, migraine and epilepsy comorbidity, correct selection of drugs and increasing the effectiveness of treatment in cases where migraine and epilepsy are comorbid. A total of 60 (100%) patients were recruited during the study. 30 of them (the main group) were diagnosed with migraine and epilepsy and were prescribed lamotrigine, and 30 patients (the control group) were diagnosed with migraine and epilepsy and were prescribed convulex. The clinical course of migraine, the level of cognitive disorders, the quality of life of patients, and the level of limitation of daily work were studied in patients of both groups.

The bidirectional relationship between epilepsy and depression illustrates shared neurobiological mechanisms of neuroinflammation, hypothalamic–pituitary–adrenal axis dysregulation, and glutamatergic dysfunction. Depression is present in 20–55% of people with epilepsy, far greater than in the general population, while depression doubles epilepsy risk 2.5-fold, indicating shared pathophysiology. Neuroinflammatory mediators (interleukin-6, tumor necrosis factor alpha, high-mobility group box 1) establish a vicious cycle: seizures exacerbate inflammation and mood disruption, and stress lowers seizure thresholds. Hippocampal damage and cortisol toxicity also link these disorders, with early life stress imprinting lifelong risk via epigenetic alteration. Genetic studies identify pleiotropic genes (brain-derived neurotrophic factor) that regulate synaptic plasticity, serotonin activity, and immune responses. New treatments target shared pathways: ketamine and AMPAkines normalize glutamate tone; mGluR5 antagonists attenuate hyperexcitability and inflammation; DNA methyltransferase inhibitors reverse aberrant DNA methylation; and probiotics manipulate the gut–brain axis by boosting neuroprotective metabolites like butyrate. Despite challenges—transient effects, precision dosing, and blood–brain barrier penetration—these advances constitute a paradigm shift toward mechanistic repair rather than symptom management. The way forward includes clustered regularly interspaced short palindromic repeats (CRISPR)-based epigenome editing, biomarker-led therapies, and combination approaches (e.g., ketamine and probiotics). Such comorbidity needs to be managed holistically through integrated neuropsychiatry care, offering hope to patients with treatment-refractory symptoms.

Background: Epilepsy is a chronic neurological disorder frequently influenced by systemic inflammation, nutritional status, and comorbid conditions, which may worsen seizure outcomes. Given the increasing recognition of these factors in disease progression, this study aimed to investigate the relationship between the Modified Charlson Comorbidity Index (mCCI), inflammatory hematological parameters, and the prognostic nutritional index (PNI) with seizure frequency and clinical prognosis in patients with epilepsy. Methods: A total of 159 participants were enrolled between January 2021 and January 2023, including 53 healthy controls (mean age: 44 ± 14.2 years; female: 21, male: 32), 53 epilepsy patients without comorbidity (mean age: 33 ± 12.5 years; female: 28, male: 25), and 53 epilepsy patients with comorbidities (mean age: 56.2 ± 13.8 years; female: 22, male: 31). The participants were divided into three groups: 53 patients with isolated epilepsy, 53 patients with epilepsy and comorbid conditions, and 53 healthy individuals with no known diseases, matched for age and sex with the patient groups, who presented for routine check-ups. The mCCI was calculated for patients with comorbid epilepsy. Inflammatory hematological parameters and the PNI were assessed in all participants using previously obtained complete blood count data. Results: Inflammatory markers such as white blood cell count, neutrophil count, C-reactive protein (CRP), platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and mean platelet distribution width (PDW) were significantly higher in epilepsy patients with comorbidities compared to other groups. Epilepsy patients with comorbidities had a higher seizure frequency compared to those without comorbidities (75.5% vs. 54.7%, p < 0.001). The PNI was lowest in epilepsy patients with comorbidities, showing a significant difference between all groups (p < 0.001). High comorbidity burden increased seizure risk by 4.56 times (95% CI: 1.30–16.01), each unit increase in the SII raised the risk by 1.13 times (95% CI: 1.08–1.19), and each unit decrease in the PNI increased the risk by 1.14 times (OR = 0.88, p < 0.001). Cerebrovascular disease and hemiplegia were also significant risk factors, increasing seizure risk by 4.15 and 4.48 times, respectively. Conclusions: Our study demonstrates that inflammatory hematological parameters, particularly SII and MCCI scores, are elevated in epilepsy patients and further increase with comorbidities. These markers are strongly associated with seizure occurrence, highlighting the prognostic significance of systemic inflammation and comorbidity burden in epilepsy. Given the frequent observation of low PNI values in patients with comorbid conditions, which may reflect compromised nutritional status, and given associations suggest a role in poor clinical outcomes, comprehensive management is essential. Monitoring the PNI and SII may help stratify high-risk patients for targeted nutritional and anti-inflammatory interventions.

A bidirectional comorbidity exists between depression and epilepsy such that patients with epilepsy are at higher risk for developing depression, and vice versa. Each of these conditions individually can be complicated by behavioral effects that worsen quality of life, but less is known about these interactions within the comorbidity of depression and epilepsy. The SwLo rat has been selectively bred for depression-relevant behaviors and exhibits enhanced limbic seizure susceptibility. This study sought to characterize the effects of novelty and stress on the SwLo rodent model of this comorbidity. It was hypothesized that SwLo rats would exhibit altered responses to novelty, reflected in hyperactivity-, anxiety-, sensation seeking-, and/or compulsive behaviors, and that this would be exacerbated with stress. Compared to the SwHi rat (their depression- and epilepsy-resistant counterparts), SwLo rats showed increased entries in all areas of the Open Field Test and spent significantly more time in the light compartment of the Light-Dark Box. SwLo rats also had a significantly higher number of rearing behaviors in the inner squares of the Open Field Test, the closed arms of the Elevated Plus Maze, and both areas of the Light-Dark Box. They demonstrated increased Nestlet shredding but showed no difference in a marble burying task or in latency to consume food in a novelty suppressed feeding task. Interestingly, restraint stress showed little effect on these behaviors, despite increasing corticosterone levels. Combined, these results suggest an increase in exploratory sensation seeking and hypervigilant information-gathering behaviors in the SwLo rat that are not dependent on corticosterone levels. This shows the utility of this model for studying behavioral effects of comorbid depression and epilepsy and allows for their use in identifying underlying mechanisms or screening treatment strategies for this complex comorbidity.

The neuropilin receptors and their secreted semaphorin ligands play key roles in brain circuit development by regulating numerous crucial neuronal processes, including the maturation of synapses and migration of GABAergic interneurons. Consistent with its developmental roles, the neuropilin 2 ( Nrp2 ) locus contains polymorphisms in patients with autism spectrum disorder (ASD). Nrp2-deficient mice show autism-like behavioral deficits and propensity to develop seizures. In order to determine the pathophysiology in Nrp2 deficiency, we examined the hippocampal numbers of interneuron subtypes and inhibitory regulation of hippocampal CA1 pyramidal neurons in mice lacking one or both copies of Nrp2 . Immunostaining for interneuron subtypes revealed that Nrp2 −/− mice have a reduced number of parvalbumin, somatostatin, and neuropeptide Y cells, mainly in CA1. Whole-cell recordings identified reduced firing and hyperpolarized shift in resting membrane potential in CA1 pyramidal neurons from Nrp2 +/− and Nrp2 −/− mice compared to age-matched wild-type controls indicating decrease in intrinsic excitability. Simultaneously, the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) are reduced in Nrp2-deficient mice. A convulsive dose of kainic acid evoked electrographic and behavioral seizures with significantly shorter latency, longer duration, and higher severity in Nrp2 −/− compared to Nrp2 +/+ animals. Finally, Nrp2 +/− and Nrp2 −/− but not Nrp2 +/+ , mice have impaired cognitive flexibility demonstrated by reward-based reversal learning, a task associated with hippocampal circuit function. Together these data demonstrate a broad reduction in interneuron subtypes and compromised inhibition in CA1 of Nrp2 −/− mice, which could contribute to the heightened seizure susceptibility and behavioral deficits consistent with an ASD/epilepsy phenotype.

Background and Objectives Persons with epilepsy (PwE) have a higher risk of developing psychiatric comorbidities compared with the general population. There is limited knowledge about the prevalence of multiple psychiatric conditions in PwE. We summarize the current evidence on the prevalence of multipsychiatric comorbidities in PwE compared with persons without epilepsy. Methods A systematic review of multipsychiatric comorbidities in PwE compared with persons without epilepsy was performed, and the results were reported using the Preferred Reporting Items of Systematic Reviews and Meta-analyses reporting standards. The search was conducted from January 1945 to June 2023 in Ovid MEDLINE. Embase, and PsycINFO, using the search terms related to “epilepsy,” “psychiatric comorbidity,” and “multimorbidity,” combined with psychiatric disorders. Abstracts were reviewed in duplicate, and data were independently extracted using standard proforma. Data describing multipsychiatric comorbidities in PwE compared with persons without epilepsy were recorded. Descriptive statistics and, when feasible, meta-analyses are presented. The risk of bias of the studies was assessed using the Newcastle-Ottawa Scale and the International League Against Epilepsy tool. Results A total of 12,841 records were identified from the systematic database search, and 15 studies met the eligibility criteria. All included studies were deemed high-quality in risk of bias according to both tools. The prevalence of multipsychiatric comorbidity was greater in persons with compared with those without epilepsy. The pooled prevalence of concomitant depression and anxiety disorder in PwE in 2 population-based studies was 15 of 163 (9.2%), which was significantly higher than 250 of 10,551 (2.4%) in patients without epilepsy (odds ratio [OR] 3.7, 95% CI 2.1–6.5, p-value <0.001, I2 = 0%, Cochran Q p-value for heterogeneity = 0.84). In 2 hospital-based studies, the prevalence of concomitant depression and attention-deficit/hyperactivity disorder in PwE (14/97, 14.4%) was significantly higher than in patients without epilepsy (5/126, 3.9%), with an OR 5.2 (95% CI 1.8–15.0, p-value = 0.002, I2 = 0%, Cochran Q p-value for heterogeneity = 0.79). Discussion PwE experience elevated levels of multipsychiatric comorbidity compared with those without epilepsy. However, very few studies have empirically evaluated the extent of multipsychiatric comorbidity in PwE compared with persons without epilepsy nor their associations and consequences to prognosis in PwE.

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While it is known that epilepsy often co-occurs with psychiatric disorders, few studies have examined nonpsychiatric comorbidity. We analyzed 2021 and 2022 National Health Interview Survey Sample Adult data. Compared with adults with no epilepsy, the 1.2% of US adults (about 3.0 million) with active epilepsy had a higher prevalence of nearly all 21 conditions examined and were more likely to have 4 or more co-occurring chronic conditions. Health care and social service providers can promote healthy behaviors and preventive screening for common comorbidities, improve access to care, and refer people with epilepsy to evidence-based self-management programs.

Highlights • Combinations of anti-seizure medications (ASM) are common practice in people with epilepsy.• Risks for polytherapy, including psychiatric problems, have not been fully explored in Africa.• ASM combination in epilepsy may be associated with mental health comorbidity.• Longitudinal studies may clarify the relationship between polytherapy and mental health comorbidity.• Capacity building among healthcare workers on appropriate ASM combinations may be helpful.

BACKGROUND Psychiatric comorbidity is a double burden among people with epilepsy. Since people with epilepsy are more vulnerable to psychiatric illnesses. So, the implementation of an appropriate intervention to minimize the double burden of comorbidity is very important. Therefore, this systematic review and meta-analysis aimed to assess the prevalence and associated factors of psychiatric comorbidity among people with epilepsy in Ethiopia. METHODS This systematic review and meta-analysis followed the Preferred Reporting Item Review and Meta-analysis (PRISMA) guideline. Searching databases were PubMed, PsycINFO, Web of Science, Cochrane Library, Google Scholar, and HINARI.The quality of the included articles was assessed using the Newcastle-Ottawa Scale (NOS). The pooled meta-logistic regression was computed to estimate the pooled prevalence and the risk factors with a 95% CI. RESULTS The pooled prevalence of psychiatric comorbidity in people with epilepsy was 34.69 % (95 % CI: 29.27, 40.10). Frequent seizures (POR = 2.94: 95 % CI: 1.08, 8.00) and a history of divorce (POR = 2.00: 95 % CI: 1.09, 3.81) were associated factors of psychiatric comorbidity in people with epilepsy. CONCLUSIONS This systematic review and meta-analysis revealed that the pooled prevalence of psychiatric comorbidity among people with epilepsy was found to be higher compared with the general population. Therefore, among people with epilepsy, parallel psychiatric evaluation is very important along with neurological evaluation.

Highlights • The ideal screener for ADHD is validated & translated into the family’s language.• The Strengths & Difficulties Questionnaire screens for ADHD symptoms in 40 languages.• ADHD signs include inattentive symptoms and hyperactivity symptoms over 6 months.• Methylphenidate, amphetamine, & atomoxetine are used safely in epilepsy patients.• Psychiatry should evaluate patients without response to first line agents for ADHD.

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PURPOSE Prevalence of psychiatric disorders in people with epilepsy is high. However, diagnostic validity and information about the nature of the seizure disorders are often poor in population-based studies. In a well validated and classified patient sample, we investigated psychiatric comorbidity according to clinical characteristics. METHOD Participants in The Trøndelag Health Study (HUNT) with ≥ 2 diagnostic epilepsy codes during 1987-2019 were identified. Medical records were reviewed, and epilepsy was validated and classified according to ILAE. Psychiatric comorbidity was defined by ICD-codes. RESULTS In 448 individuals with epilepsy, 35% had at least one psychiatric disorder (anxiety and related disorders 23%, mood disorders 15%, substance abuse and personality disorders 7%, and psychosis 3%). Comorbidity was significantly higher in women than in men (p = 0.007). The prevalence of psychiatric disorders was 37% in both focal and generalized epilepsy. In focal epilepsy, it was significantly lower when etiology was structural (p = 0.011), whereas it was higher when the cause was unknown (p = 0.024). Comorbidity prevalence was 35% both in patients achieving seizure freedom and in those with active epilepsy but 38% among 73 patients with epilepsy resolved. CONCLUSION Just over one third of people with epilepsy had psychiatric comorbidities. The prevalence was equal in focal and generalized epilepsy but was significantly higher in focal epilepsy of unknown cause compared to lesional epilepsy. Comorbidity was independent of seizure control at last follow-up but was slightly more common in those with resolved epilepsy, often having non-acquired genetic etiologies possibly linked to neuropsychiatric susceptibility.

BACKGROUND Several studies implicate brain-derived neurotrophic factor (BDNF) in the pathophysiology of epilepsy. In particular, preclinical data suggest that lower serum BDNF is a biomarker of epilepsy severity and psychiatric comorbidities. We tested this prediction in clinical epilepsy cohorts. METHODS Patients with epilepsy were recruited from 4 epilepsy centers in France and serum BDNF was quantified. Clinical characteristics including epilepsy duration, classification, localization, etiology, seizure frequency and drug resistance were documented. Presence of individual anti-seizure medications (ASM) was noted. Screening for depression and anxiety symptoms was carried out in all patients using the NDDI-E and the GAD-7 scales. In patients with positive screening for anxiety and/or depression, detailed psychiatric testing was performed including the Mini International Neuropsychiatric Interview (MINI), STAI-Y, Holmes Rahe Stressful Events Scale and Beck Depression Interview. Descriptive analysis was applied. Spearman's test and Pearson's co-efficient were used to assess the association between BDNF level and continuous variables. For discrete variables, comparison of means (Student's t-test, Mann-Whitney u-test) was used to compare mean BDNF serum level between groups. Multivariate analysis was performed using a regression model. RESULTS No significant correlation was found between serum BDNF level and clinical features of epilepsy or measures of depression. The main group-level finding was that presence of any ASM at was associated with increased BDNF; this effect was particularly significant for valproate and perampanel. CONCLUSION Presence of ASM affects serum BDNF levels in patients with epilepsy. Future studies exploring BDNF as a possible biomarker of epilepsy severity and/or psychiatric comorbidity must control for ASM effects.

OBJECTIVE This study aimed to explore the association between epilepsy and cognitive impairment, and to determine factors associated with cognitive impairment in older people with epilepsy. METHODS People with epilepsy and controls aged ≥50 years were recruited and their global and domain-specific cognitive functions were evaluated by a comprehensive neuropsychological battery. Clinical characteristics were obtained from medical records. Analysis of covariance was used to examine the difference of cognition between two groups, after adjusting for age, gender, education years, hypertension, diabetes, and heart disease. A multiple linear regression model was used to explore the potential impact factors of cognitive functions among people with epilepsy. RESULTS This study recruited 90 people with epilepsy and 110 controls. The proportion of cognitive impairment among older adults with epilepsy was 62.2%, which was significantly higher than controls (25.5%, p<0.001). People with epilepsy performed worse on global cognition (p<0.001), especially in domains of memory (p<0.001), executive function (p<0.001), language (p<0.001), and attention (p=0.031). Among older adults with epilepsy, age was negatively correlated with the scores of memory (β=-0.303, p=0.029), executive function (β=-0.354, p=0.008), and attention (β=-0.558, p<0.001). Females performed better on executive function (β=-0.350, p=0.002) than males. Education years had a positive correlation with global cognition (β=0.314, p=0.004). Number of anti-seizure medications was also negatively correlated with scores of spatial construction function (β=-0.272, p=0.019). SIGNIFICANCE Our results indicated that cognitive impairment was a major comorbidity of epilepsy. Number of anti-seizure medications is suggested as a potential risk factor of impaired cognition in older people with epilepsy.

ANK3 is a leading bipolar disorder (BD) candidate gene in humans and provides a unique opportunity for studying epilepsy-BD comorbidity. Previous studies showed that deletion of Ank3-1b , a BD-associated variant of Ank3 in mice leads to increased firing threshold and diminished action potential dynamic range of parvalbumin (PV) interneurons and absence epilepsy, thus providing a biological mechanism linking epilepsy and BD. To explore the behavioral overlap of these disorders, we characterized behavioral patterns of Ank3-1b KO mice during overnight home-cage activity and examined network activity during these behaviors using paired video and EEG recordings. Since PV interneurons contribute to the generation of high-frequency gamma oscillations, we anticipated changes in the power of neocortical EEG signals in the gamma frequency range (> 25 Hz) during behavioral states related to human BD symptoms, including abnormal sleep, hyperactivity, and repetitive behaviors. Ank3-1b KO mice exhibited an overall increase in slow gamma (~25-45 Hz) power compared to controls, and slow gamma power correlated with seizure phenotype severity across behaviors. During sleep, increased slow gamma power correlated with decreased time spent in the rapid eye movement (REM) stage of sleep. Seizures were more common during REM sleep compared to non-REM (NREM) sleep. We also found that Ank3-1b KO mice were hyperactive and exhibited a repetitive behavior phenotype that co-occurred with increased slow gamma power. Our results identify a novel EEG biomarker associating Ank3 genetic variation with BD and epilepsy and suggest modulation of gamma oscillations as a potential therapeutic target.

OBJECTIVE This study aimed to examine the psychiatric diagnoses, parenting attitudes, family functioning among children and adolescents with epilepsy, coping styles of their mothers, and psychiatric symptoms of their mothers and fathers. METHODS Forty children and adolescents between the ages of 8 and 18 with epilepsy and 40 healthy controls were included in the study. The clinical interview and other measurements were used to assess psychiatric disorders and familial factors. RESULTS At least one psychiatric disorder was diagnosed in 65% of children and adolescents with epilepsy. It was determined that the mothers and fathers in the epilepsy group had higher anxiety and depression scores than the control group, and the fathers' hostility scores were also higher. The Family Assessment Device (FAD) (problem-solving and affective responsiveness), Coping Strategies Scale (COPE) (mental disengagement and substance use), and Parent Attitude Scale (PAS) (strictness/supervision) subtest scores of the epilepsy group were higher than the control group. CONCLUSION Psychiatric comorbidities, especially depression, anxiety disorders, and attention deficit hyperactivity disorder, are more common in children and adolescents with epilepsy. The mental health of parents, parent-child relationships, family functioning, and parental coping styles were adversely affected in families with children with epilepsy. It is essential to evaluate psychiatric comorbidity and family factors in children with epilepsy and to create a treatment plan for problem areas.

This study aims to determine the contribution of comorbidities to excess psychogenic nonepileptic seizures (PNES) mortality.

No abstract available

OBJECTIVE The present study aimed to explore the mechanisms underlying the comorbidity of epilepsy and migraine, identify potential common targets for drug intervention, and provide insight into new avenues for disease prevention and treatment using an integrated bioinformatic and network pharmacology approach. METHODS Disease targets in epilepsy and migraine were screened using the DisGeNET database to identify intersecting gene targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEEG) enrichment analyses were then performed using the WebGestalt database. Furthermore, the STRING database was used to construct a protein-protein interaction (PPI) network, and Cytoscape software was used to analyze the protein molecular signals at the intersection of epilepsy and migraine. The Drugbank database was used to identify common targets for antiepileptic drugs in epilepsy and migraine to further analyze the disease-gene-target-drug interaction network. Finally, molecular docking simulations were performed to verify the hypothesis that migraine and epilepsy share common diseases and drug targets. RESULTS A total of 178 common targets for epilepsy and migraine were identified using the DisGeNET database, and the 24 genes most related to the diseases were screened using the Score_gda gene scoring system. GO enrichment analysis indicated that common targets were mainly enriched in biological processes and molecular functions, including membrane potential regulation, inorganic ion transmembrane transport, axonal signaling, and ion channel activity. KEGG pathway enrichment analysis indicated that the mechanism of action might be related to neuroactive ligand receptors, AGE-RAGE, cAMP, and VEGF signaling pathways. The PPI network construction and analysis results showed that the PPI grid had 23 central nodes and 24 connected edges, with an average node degree of 2.09 and an average clustering coefficient of 0.384. The 10 genes with potentially important roles in epilepsy and migraine were CACNA1A, KCNQ2, KCNA1, SCN1A, PRRT2, SCN8A, KCNQ3, SCN2A, GRIN2A, and GABRG2. Drugbank database results indicated that antiepileptic drugs, including lamotrigine, topiramate, valproic acid, carbamazepine, gabapentin, and perampanel, also had common targets with migraine. The three most important targets exhibited strong binding affinity with drugs in the molecular docking simulations. CONCLUSION Our systematic and comprehensive analyses of disease-gene-target-drug interaction networks identified several biological processes and molecular functions common to migraine and epilepsy, most of which were related to neuroactive ligand-receptor interactions. These data provide a new theoretical basis and reference for the clinical treatment of comorbid epilepsy and migraine and may aid in the development of novel pharmacological strategies.

No abstract available

The present study aimed to examine the prevalence of dyscalculia, dyslexia, and their comorbidity rates in a large population‐based sample of children with idiopathic epilepsy (N = 2282) and a comparison sample of typically developing schoolchildren (N = 2371).

The aim was to determine school performance and psychiatric comorbidity in children with childhood absence epilepsy (CAE). We reviewed the medical records in children with ICD-10 codes for idiopathic generalized epilepsy before 18 years of age, and pediatric neurologists confirmed the International League Against Epilepsy criteria for CAE were met. Control groups were the general pediatric population or children with non-neurological chronic disease. Outcomes were from nationwide and population-based registers on school performance and psychiatric comorbidity. We compared the mean grade point average using linear regression and estimated hazard ratios (HR) using Cox regression for the other outcomes. Analyses were adjusted for the child's sex, and year of birth, and parental highest education, receipt of cash benefits or early disability pension. We included 114 children with CAE with a median age at onset of 5.9 years (interquartile range = 4.5-7.3 years). Compared with both population controls and non-neurological chronically ill children, children with CAE had increased hazard of special needs education (HR = 2.7, 95% confidence interval (CI) = 1.8-4.1, p < 0.0001), lower grade point average at 9th grade by 1.7 grade points (95% CI = -2.5 to -1.0, p < 0.001), increased ADHD medicine use (HR = 4.4, 95% CI = 2.7-7.2, p < 0.001), increased sleep medicine use (HR 2.7, 95% CI = 1.7-4.3, p < 0.001), and increased psychiatry visits (HR = 2.1; 95% CI = 1.1-4.0; p = 0.03). In conclusion, children with CAE have increased psychiatric comorbidity and a considerable proportion of these children receive special needs education in primary/secondary school, albeit insufficient to normalize their considerably lower grade point average in the 9th grade.

Epilepsy and migraine are among the most prevalent neurological disorders. By being comorbid, the presence of one disorder increases the likelihood of the other. Although several similar clinical features of epilepsy and migraine have been observed as early as the 19th century, only in recent years have researchers engaged in finding a common pathogenic mechanism between them. In this study, the epilepsy–migraine comorbidity rat model was generated, and the pathophysiological basis of epilepsy–migraine comorbidity was examined. Male rats were divided into four groups: control, migraine, epilepsy, epilepsy–migraine comorbidity. After establishing the models, the amount of scratching and the pain threshold of the rats were observed. Western blot and immunofluorescence staining were used to detect the protein expression levels of TLR4 and GABAARα1 in the temporal cortex, hippocampus, trigeminal ganglion, and medullary dorsal horn. Subsequently, co-immunoprecipitation of GABAARα1 and TLR4 was performed. Then, the rats were divided into three groups: comorbidity, comorbidity + TAK-242, and comorbidity + muscimol. After drug intervention, the seizure latency, seizure level, amount of scratching, and pain threshold were observed. Western blot was used to detect the protein expression levels of TLR4 and GABAARα1 in the temporal cortex, hippocampus, trigeminal ganglion, and medullary dorsal horn. Our results demonstrate that the seizure attacks in comorbidity and epilepsy groups performed severely, and the comorbidity and migraine groups displayed a remarkable increase in the amount of head-scratching and a noticeable decrease in the facial mechanical withdrawal threshold. Further analysis revealed considerably increased Toll-like receptor 4 (TLR4), associated with reduced γ-aminobutyric acid type A receptor α1 (GABAARα1) and microglia enhanced in the epilepsy–migraine comorbidity rat. Additionally, co-immunoprecipitation proved GABAARα1 binding TLR4. Following muscimol to activate GABAARα1, seizure attacks and migraine-like behavior were rescued. GABAARα1 level increment was accompanied by the decline of TLR4, while TAK-242, the inhibitor of TLR4, only decreased TLR4 without affecting GABAARα1 expression. It also ameliorated the migraine-like behavior with no impact on seizure activity. We propose that GABAARα1 binding and negatively regulating TLR4 contribute to epilepsy–migraine comorbidity; TLR4 is a critical intermediate link in epilepsy–migraine comorbidity; immune-induced neuroinflammation in microglia may be involved in migraine and epilepsy–migraine comorbidity.

PURPOSE This study aimed to evaluate the relationship between status epilepticus (SE) and cardiorespiratory comorbidity in patients with epilepsy. METHODS We conducted a population-based study using cloud-based aggregated electronic medical records from >53 million patients in the US (Explorys, IBM Watson; January 1999 to November 2020). During the study period, we identified patients with epilepsy with SE. Patients with a history of cardiac arrest, anoxic encephalopathy, and/or cerebrovascular disease were excluded. We reported the prevalences and prevalence ratios of cardiorespiratory and medical comorbidities using age- and sex-adjusted standardization. RESULTS We identified 494,790 patients with epilepsy and 19,190 had SE. Cardiovascular and respiratory diseases were statistically significantly more prevalent in patients with epilepsy with SE than in those without SE (adjusted prevalence ratio (APR) 1.13, prevalence 68.7% [95% confidence interval (CI): 67.6-69.9] vs 60.9% [95% CI: 60.7-61.1]) and (APR 1.25, 73.1% [95% CI: 71.8-74.3] vs 58.4% [95% CI: 58.1-58.6]), respectively. Aspiration pneumonia (APR 3.12, 0.47% [95% CI: 0.37-0.57] vs 0.15% [95% CI: 0.14-0.16]) and acute respiratory distress syndrome (APR 2.40, 0.47% [95% CI: 0.37-0.57] vs 0.20% [95% CI: 0.18-0.21]) were more prevalent in patients with epilepsy with SE. Common cardiovascular risk factors such as diabetes mellitus (APR 1.13, 17.1% [95% CI: 16.5-17.6] vs 15.1% [95% CI: 1.50-15.2]) and hypertension (APR 1.28, 10.6% [95% CI: 10.2-11.0] vs 8.31% [95% CI: 8.23-8.39]) were also more common in patients with epilepsy with SE. CONCLUSION In this population-based study, patients with epilepsy with SE had a statistically significantly higher prevalence of cardiorespiratory comorbidities than in those without SE.

Objective: The bio-psycho-social factors affecting the quality of life in patients with epilepsy can be numerous but are often overlooked. The behavioral side effects of anti-seizure medications can be one such potential factor. The aim of the study is to address the effect of the number of anti-seizure medications on the development of psychiatric comorbidity and quality of life in patients with adequate seizure control. Materials and Methods: The study recruited 100 participants with generalized tonic-clonic seizures from a tertiary care center in North India, who were seizure-free from the last 1 month. The study participants were divided into two groups based on whether they were on monotherapy or polytherapy. The two groups were matched for their socio-demographic and clinical profile. We assessed for psychiatric comorbidity in each group using Mini International Neuropsychiatric Interview. All the study participants were given Hindi translated version of quality of life in the epilepsy-31 questionnaire for objective assessment of the quality of life. Results: The patients receiving anti-epileptic polytherapy had significantly higher prevalence of psychiatric comorbidity than patients on monotherapy. Furthermore, the patients on polytherapy scored significantly less on the cognitive domain of quality of life as well as the overall quality of life domain in the epilepsy-31 questionnaire. Conclusion: The patients with epilepsy must be evaluated for psychiatric comorbidity and side effect profile of anti-seizure medications to improve the quality of life. This is particularly more important for patients who are on anti-epileptic polytherapy even if the seizure control is adequate.

The co-occurrence of psychiatric disorders in people with epilepsy (PWE) is not well documented or studied. Anxiety and depressive disorders are the most frequent comorbid disorders in PWE. In this paper, we characterized the rates of multiple psychiatric disorder comorbidity by reanalyzing data from a study sample of PWE. A total of 96 outpatient PWE completed the self-report symptom scale, and were diagnosed using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) Axis I disorders (SCID-I). For analyses, patients were assigned to a comprehensive diagnostic group of anxiety and depressive disorders. In order to determine comorbidity across psychiatric diagnoses for the DSM-IV categories, Pearson’s chi-squared test (χ2) was used. In the study sample, eight patients (8.3% of the study sample, n = 96) had comorbid major depressive disorder and anxiety disorder. When looking at comorbidity of each diagnosis separately, it was determined that 50% of individuals with an anxiety disorder had comorbid Major Depressive Disorder (MDD) and 38% patients with MDD had comorbid anxiety disorder. This finding encourages a more systematic reporting of psychiatric prevalence data in epilepsy, especially taking into account the high ratio of multiple comorbid anxiety and depressive disorders in PWE.

Vagus nerve stimulation (VNS) has been widely used in the clinical treatment of epilepsy, while its effects on comorbidities in epilepsy remain incompletely elucidated. This study aimed to evaluate the impact of VNS on comorbidities and quality of life in adult patients with epilepsy. A longitudinal, multicenter cohort study was conducted from 2021 to 2024 among adult patients with epilepsy who underwent VNS implantation. We enrolled 128 participants from 83 hospitals. The inclusion criteria were patients over 18 years old, diagnosed with epilepsy according to the 2014 International League Against Epilepsy guidelines, and having complete data from at least two follow-up visits. Standard assessment tools, including diagnosis according to International Classification of Diseases, 10th Edition (ICD-10), Neurological Disorders Depression Inventory for Epilepsy (NDDI-E), Generalized Anxiexy Disorde-7 (GAD-7), Pittsburgh Sleep Quality Index (PSQI), and Quality of Life in Epilepsy-31 (QOLIE-31) were used to evaluate comorbidities and quality of life. Statistical analysis was performed using SPSS 26.0. The major clinical measurements were changes in the scales above before and after VNS implantation during follow-up. Generalized estimation model was applied to illustrate the effect over time an its relation to seizure control. A total of 113 participants met the inclusion criteria. Baseline characteristics were comparable between the comorbidity and non-comorbidity groups in terms of gender, seizure onset, age at VNS implantation, seizure types, or the number of antiseizure medications used. Significant improvements were observed from the implantation to the end of follow-up. The PSQI score decreased from 5.43 ± 3.60 to 4.44 ± 3.14 (P < 0.01), indicating better sleep quality. Depressive symptoms (NDDI-E) and anxiety symptoms (GAD-7) decreased significantly, with scores dropping from 6.49 ± 4.67 to 4.83 ± 4.37 (P < 0.01) and from 7.15 ± 5.06 to 4.95 ± 3.69 (P < 0.01), respectively. The QOLIE-31 score increased from 54.40 ± 15.70 to 61.33 ± 16.19 (P < 0.01), suggesting improved quality of life. Further analysis indicated that in the early second postoperative follow-up (1 month after implantation), the scales had already improved significantly (P < 0.001 for PSQI and QOLIE-31, P = 0.006 for NDDI-E and GAD-7). We did not find any statistically significant difference between patients with comorbidity and those without on the efficacy of any scales in this study. The efficacy of VNS on the four scales above was related to follow-up time, with a slightly rebound at the last two follow-ups. The NDDI-E as well as the GAD-7 scores were related to better seizure control according to the GEE model. Higher stimulation currents over 1 mA did not improve the efficacy of VNS on the comorbid conditions. VNS implantation significantly improved sleep quality, mental health, and overall quality of life in adult patients with epilepsy. Such effects could be observed shortly after the implantation and were mostly long-lasting. Further research is needed to validate its long-term effects.

Epilepsy is one of the common clinical disorders with comorbid anxiety and depression that severely affects their quality of life and increases their suicidality, while screening for anxiety and depression currently lacks objective identifiers. This study aimed to analyze the characteristics of the electroencephalogram (EEG) power spectrum in patients with epilepsy with comorbid anxiety and depression, utilizing resting EEG data. Resting EEG data were collected under standard conditions from two groups: patients with epilepsy comorbid with anxiety and depression (n = 42) and patients without comorbidities (n = 45). EEG power was calculated using data processing with EEGLAB and MATLAB. This study compared the absolute and relative powers of the δ, θ, α, β, and γ frequency bands, as well as the values of (δ + θ)/(α + β), between the two groups. Additionally, the correlation between the EEG power of each frequency band and anxiety and depression scores was analyzed. 1) Among individuals with epilepsy comorbid with anxiety and depression, lower absolute power of δ, α, and θ at specific sites was observed (P < 0.05), along with lower relative power of θ at certain sites (P < 0.05). Conversely, higher relative power of β and γ at specific sites was noted in those with comorbidities (P < 0.05). 2) There was no statistically significant difference in the values of (δ + θ)/(α + β) between the two groups (P > 0.05). 3) Depression scores exhibited a negative correlation with θ absolute power at the T3 and T4 sites (P < 0.05), while showing a positive correlation with β relative power at the C4 and T6 sites (P < 0.05). Anxiety scores displayed a positive correlation with β relative power at the F4, C3, C4 and T6 sites and γ relative power at F8 site (P < 0.05). The findings suggest that comorbid anxiety and depression may impact resting EEG power spectra in individuals with epilepsy, particularly in regions exhibiting altered network connectivity. Furthermore, a positive correlation was observed between anxiety and depression scores and β relative power in the right central and right posterior temporal regions, indicating potential screening utility.

No abstract available

Objective This study aims to investigate the association of comorbid depression and anxiety with cognitive function in older adults with epilepsy. Methods A cross-sectional analysis was conducted on 406 older adults (≥65 years) diagnosed with epilepsy between January 2019 and December 2020. Depressive and anxious symptoms were measured using the Hospital Anxiety and Depression Scale (HADS), while cognitive impairment was assessed with the Montreal Cognitive Assessment Test (MoCA). Multivariate linear regression models were used to examine associations between cognitive impairment and anxiety/depression symptoms, adjusting for potential confounders. Results Of the 406 adults, 218 (53.7%) showed cognitive impairment. Adults with depression (70.2% vs. 51.0%, P<0.01) or anxiety (66.7% vs. 48.8%, P<0.01) had a significantly higher prevalence of cognitive impairment compared to those without these conditions. Multivariate linear regression analysis revealed significant associations between cognitive impairment and depression (β=-1.77, 95% CI: -2.67, -0.87; P<0.01) and anxiety (β=-2.18, 95% CI: -2.95, -1.42; P<0.01). Conclusion Anxiety and depression are significantly associated with cognitive impairment in older adults with epilepsy. Early screening and management of these psychiatric conditions are essential to reduce cognitive decline and enhance patient outcomes.

OBJECTIVE Epileptic seizures (ES) and functional seizures (FS) commonly coexist. People with both conditions (ES + FS) report different contributing factors to quality of life (QOL) compared to people with ES only. However, a distinct core outcome set (COS) for measuring QOL among people with ES + FS does not exist. METHODS We analyzed cross-sectional data from an existing Delphi consensus study that defined a QOL COS for adults with self-reported epilepsy with or without comorbid FS. Participants assigned importance rankings via a 9-point Likert scale to 248 QOL outcomes. A potential COS inclusion list was identified via established consensus thresholds. Differences in QOL priorities between those with and without comorbid FS were evaluated by Wilcoxon rank-sum tests. RESULTS Of 291 adults with epilepsy, 269 had ES and 22 had ES + FS. People with ES + FS assigned critical importance to more QOL outcomes across a wider range of domains, particularly in functional, psychiatric, and healthcare utilization areas. 38 QOL outcomes were rated as critically important for potential inclusion in a COS for people with ES + FS. There were differences in QOL priorities between groups, with people with ES + FS assigning higher importance to having questions on "having thoughts of suicide" and items related to high-acuity, frequent, and prolonged encounters with the healthcare system. SIGNIFICANCE Measuring QOL in people with ES + FS, who assigned greater importance to suicidal ideation and healthcare utilization items, requires an overlapping but distinct COS when compared to people with ES.

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.

Background Comorbid mental health conditions are common in people with epilepsy and have a significant negative impact on important epilepsy outcomes, although the evidence is mostly from high-income countries. This systematic review aimed to synthesise evidence on the association between comorbid mental health conditions and quality of life and functioning among people with epilepsy living in low- and middle income countries (LMICs). Methods We searched PubMed, EMBASE, CINAHL, Global Index medicus (GID) and PsycINFO databases from their dates of inception to January 2022. Only quantiative observational studies were included. Meta-analysis was conducted for studies that reported the same kind of quality of life and functioning outcome. Cohen’s d was calculated from the mean difference in quality-of-life score between people with epilepsy who did and did not have a comorbid depression or anxiety condition. The protocol was registered with PROSPERO: CRD42020161487. Results The search strategy identified a total of 2,101 articles, from which 33 full text articles were included. Depression was the most common comorbid mental health condition (33 studies), followed by anxiety (16 studies). Meta-analysis was conducted on 19 studies reporting quality of life measured with the same instrument. A large standardized mean effect size (ES) in quality of life score was found (pooled ES = −1.16, 95% confidence interval (CI) − 1.70, − 0.63) between those participants with comorbid depression compared to non-depressed participants. There was significant heterogeneity between studies (I 2  = 97.6%, p < 0.001). The median ES (IQR) was − 1.20 (− 1.40, (− 0.64)). An intermediate standard effect size for anxiety on quality of life was also observed (pooled ES = −0.64, 95% CI − 1.14, − 0.13). There was only one study reporting on functioning in relation to comorbid mental health conditions. Conclusion Comorbid depression in people with epilepsy in LMICs is associated with poor quality of life although this evidence is based on highly heterogeneous studies. These findings support calls to integrate mental health care into services for people with epilepsy in LMICs. Future studies should use prospective designs in which the change in quality of life in relation to mental health or public health interventions across time can be measured.

BACKGROUND Around 25% of people with Intellectual Disability (PwID) have comorbid epilepsy with seizures in up to two-thirds being drug-resistant. Little is known of the general characteristics and prescribing practices to this population. AIM Describe and compare characteristics of two cohorts of PwID and epilepsy in two different countries to inform clinical practice better. METHOD An explorative, retrospective, case-note review in a specialist ID community service in England and in an expert center for PwID and epilepsy in the Netherlands was conducted. Information on ID severity, medical/behavioral/psychiatric/neurodevelopmental/genetic comorbidities, psychotropic, and antiepileptic drugs (AEDs) for each cohort was collected. FINDINGS The English cohort consisted of 167 people (98 males; age range 18-73 years; mild/moderate ID- 35%) and the Dutch cohort of 189 people (111 males; age range 18-85 years; mild/moderate ID - 51%). The two cohorts were comparable in their baseline characteristics. The Dutch had higher rates of physical comorbidity, but less mental or behavioral disorders and were more likely to be on anti-psychotic medication. The mean dosages between three most common AEDs prescribed were similar. The most frequently prescribed drug in both centers is valproate. Three-quarters of the Dutch were on three or more AEDs compared to a third in the English cohort. CONCLUSIONS Structured description of the characteristics, differences, and commonalities of PwID, treatment, and services of both countries is presented. This is the first real-world study to reveal unique characteristics of managing epilepsy for a complex ID population. In particular, it highlights the considerable comorbid psychiatric burden and psychotropic prescribing.

Abstract People with epilepsy are at risk of premature death, of which sudden unexpected death in epilepsy (SUDEP), sudden cardiac death (SCD) and sudden arrhythmic death syndrome (SADS) are the primary, partly overlapping, clinical scenarios. We discuss the epidemiologies, risk factors and pathophysiological mechanisms for these sudden death events. We reviewed the existing evidence on sudden death in epilepsy. Classification of sudden death depends on the presence of autopsy and expertise of the clinician determining aetiology. The definitions of SUDEP, SCD and SADS lead to substantial openings for overlap. Seizure-induced arrhythmias constitute a minority of SUDEP cases. Comorbid cardiovascular conditions are the primary determinants of increased SCD risk in chronic epilepsy. Genetic mutations overlap between the states, yet whether these are causative, associated or incidentally present is often unclear. Risk stratification for sudden death in people with epilepsy requires a multidisciplinary approach, including a review of clinical history, toxicological analysis and complete autopsy with histologic and, preferably, genetic examination. We recommend pursuing genetic testing of relatives of people with epilepsy who died suddenly, mainly if a post-mortem genetic test contained a Class IV/V (pathogenic/likely pathogenic) gene variant. Further research may allow more precise differentiation of SUDEP, SCD and SADS and the development of algorithms for risk stratification and preventative strategies.

OBJECTIVE Knowledge about multimorbidity and types of multiple chronic conditions (CC) in people with epilepsy (PWE) seen in an outpatient care setting is lacking. We aim to examine the distribution of multimorbidity and describe the contributing comorbidity of somatic and psychiatric CC in adult PWE in relation to age (≤25; 26-64; ≥65 years), sex (female; male), type of epilepsy (Idiopathic; Structural; Developmental & Epileptic Encephalopathy [DEE]), resistance to treatment (yes; no), and duration of epilepsy (as per 4 quartiles). METHODS In this observational retrospective cohort study, we assessed 330 adult PWE seen in an epilepsy outpatient clinic. The prevalence of multimorbidity was estimated according to the presence of one or more somatic or psychiatric comorbid CC. We estimated the multimorbidity prevalence within each group and assessed for statistically significant differences. RESULTS Nearly 80% of PWE seen in an outpatient setting were multimorbid. Over two thirds of participants had a somatic CC and over two fifths a psychiatric CC. These conditions did not occur randomly but varied in relation to age, type of epilepsy, and resistance to treatment. Almost all older adults with epilepsy were multimorbid due to common somatic CC. Neurodevelopmental disorders were often seen in the young adults with epilepsy, people with drug-resistant epilepsy, and/or DEE. The most common chronic comorbid conditions in PWE included depression, anxiety, and insomnia. There appeared to be no influence on the prevalence of multimorbidity in epilepsy based on sex, drug resistance, or duration of epilepsy. CONCLUSION This is the first study of multimorbidity in adult PWE seen in an outpatient setting and its distribution according to patient and epilepsy characteristics. The findings provide insights into the burden of chronic disease in PWE seen in tertiary care and call for adequate identification and response to patient's needs by health professionals.

Background Epilepsy is a multifactorial disease characterized by spontaneous, recurrent seizures and a growing incidence of comorbid conditions such as anxiety, depression, cognitive dysfunction, and sudden unexpected death. Patients with epilepsy often experience cognitive impairment or dysfunction that can negatively affect their quality of life. There is limited research on cognitive dysfunction assessed through the Montreal Cognitive Assessment (MoCA) in the Amhara region, although the MoCA is considered superior to the Mini-Mental State Examination (MMSE). Therefore, this study aimed to assess cognitive dysfunction and identify factors associated with it in patients with epilepsy who were receiving follow-up care at referral hospitals in the Amhara region. Materials and methods A multicenter, institutional-based cross-sectional study was conducted among patients with epilepsy who were receiving follow-up care at randomly selected referral hospitals in the Amhara region from January 2024 to July 2024. A total of 355 participants were recruited for the study using a systematic random sampling technique, achieving a response rate of 98%. Cognitive dysfunction was measured using the MoCA. Data were entered with EpiData version 4.7 and then exported into SPSS version 26 for analysis. Multivariable logistic regression analysis was conducted, and a p-value of ≤0.05 was considered statistically significant. The results are presented in text and tables. Results The majority of the participants were women (52.1%). The mean age of the study participants was 31 (± 5.4) years. The prevalence of cognitive dysfunction was 29% (95% CI: 25.8, 34.5). Multivariable logistic regression analysis revealed that several factors were statistically significantly associated with cognitive dysfunction. Factors associated with cognitive dysfunction included being a rural resident (adjusted odds ratios (AOR) = 1.21; 95% CI: 1.29, 1.43), having a medical illness (AOR = 2.5; 95% CI: 2.1, 9.1), experiencing generalized seizures (AOR = 1.3; 95% CI: 1.08, 3.1), having a seizure frequency of daily to every other day (AOR = 2; 95% CI: 1.5, 9.2), experiencing seizures for more than 30 years (AOR = 1.5; 95% CI: 1.7, 7.6), and using a combination of anti-seizure drugs (AOR = 2.5; 95% CI: 1.2, 6.2). Conclusions and recommendations In this study, a significant proportion of patients with epilepsy receiving follow-up care experienced cognitive dysfunction. Neuropsychological assessment should be emphasized in patients with epilepsy at diagnosis and early follow-up phases of the condition.

Background: Comorbid conditions in epileptic patients depend on many factors like etiology, type of epileptic syndromes, social and environmental factors, which may differ from one region to another, which encourages us to do this study in Sudan, which is one of the low-income countries. Limited information is available regarding this in our region. Methods: This is a hospital-based, prospective, descriptive, and cross-sectional study aimed at determining the common medical, neurological, psychological, and cognitive comorbidities. Data were obtained by interviewing 115 epileptic patients attending the outpatient clinic of the Academic Charity Teaching Hospital and the National Center for Neurological Science using a questionnaire from November 2019 to March 2020. Results: Out of 115 patients, 52.2% (60/115) were females. The duration of epilepsy ranged from 1 year to 37 years. A high rate of unemployment (72.2%) and a low level of education (36.5%) were observed among epileptic patients in Sudan. The number of comorbidities ranged from one (58.3%) to four (0.9%). Neurological comorbidities (67%) were the commonest, followed by medical (32.2%), psychological (26.1%), and lastly cognitive comorbidities (13%). The most prevalent comorbidities were migraine (33.7%), hypertension (27%), depression (50%), and impaired memory (13%). Conclusion: This study sheds light on important prognostic factors in epileptic patients, which have not been previously analyzed in other research, particularly in Sudan. It introduces a new perspective on the condition, paving the way for further contributions in future studies.

AIM To characterize the nature and prevalence of comorbid conditions, as well as the extent of exposure to concomitant medications other than antiseizure medications (ASMs), in a large cohort of adults with epilepsy. MATERIALS AND METHODS This was a prospective, non-interventional, single-center study involving consecutive patients receiving care at a university epilepsy clinic. Demographic data, epilepsy characteristics, comorbid conditions, and medication use were retrieved from medical records during two consecutive clinical visits. Comorbidities were categorized according to the ICD-10, while medications were classified using the Anatomical Therapeutic Chemical classification system. RESULTS The final cohort included 517 patients (60 % female; median age: 35 years; SD ± 12). Focal epilepsy was present in 64 % of patients, and 58 % were drug-resistant. Comorbidities were observed in 48 % of patients, and 41 % received at least one non-ASM medication. Patients with comorbidities or concomitant medications were older, had a later epilepsy onset, and more frequently presented with focal and drug-resistant epilepsy. The most common comorbidity categories (ICD-10) were mental and behavioral disorders (22 %), endocrine/metabolic diseases (18 %), and circulatory system disorders (13 %). Frequently used non-ASMs included selective serotonin reuptake inhibitors (7 %), antipsychotics (7 %), and thyroid preparations (7 %). Comorbidities and comedication were significantly more common in drug-resistant cases (p = 0.007), focal epilepsy (p < 0.001), and with increasing age (rho = 0.310, p < 0.001). Notably, 73 % of patients on non-ASMs were also treated with enzyme-inducing or enzyme-inhibiting ASMs, posing a potential risk of drug interactions. CONCLUSIONS This study demonstrates that nearly half of adults with epilepsy present with comorbid conditions and that more than 40% require concomitant non-ASM medications. Mental and behavioral, endocrine/metabolic, and circulatory disorders were the most frequent comorbidities, while antidepressants, antipsychotics, and thyroid preparations were the most commonly prescribed medications. Both comorbidities and comedications were more prevalent in patients with focal and drug-resistant epilepsy and in older individuals. These results underscore the importance of systematically assessing comorbid conditions and non-ASM use in clinical practice to optimize treatment and minimize the risk of drug interactions.

BACKGROUND Migraine and epilepsy are distinct neurological disorders that co-occur as comorbid conditions as well. Despite their clinical differences, these disorders exhibit some overlapping symptoms and share underlying pathophysiological mechanisms driven by a common genetic contribution. AIM The current study aimed to explore the genetic predisposition associated with epilepsy, migraine, and their comorbidity in both familial and sporadic cases. METHODS Whole exome sequencing carried out in 191 individuals, comprising familial and sporadic cases diagnosed with migraine (n = 63), epilepsy (n = 62), and comorbid (n = 39) involving unaffected first-degree relatives (n = 16) and healthy controls (n = 11). Variant interpretation was performed in accordance with the American College of Medical Genetics and Genomics (ACMG) guidelines. Segregation analysis was carried out by Sanger sequencing. RESULTS Clinically relevant pathogenic and likely pathogenic variants were observed in the genes associated with ion channel functioning and neurotransmitter regulation in migraine as well as in epilepsy. Apart from these, variations in other genes regulating glucose transport, synaptic organization and signaling were also identified. In the epilepsy group, variants were detected in sodium channel genes (SCN1A, SCN1B, SCN2A), G protein-coupled receptor (ADGRV1), GLUT-1, and GABA transporters (SLC2A1, SLC6A1), synaptic transporter (STXBP1), and others (ICK, EFHC1, SETD1B, and DEPDC5). In the migraine group, genes including ion channel encoding gene (SCN9A, ATP1A2), GABA receptor-encoding gene (GABRA5) were noted. In individuals with migraine and epilepsy comorbidity alterations were observed in ion channel encoding gene (SCN1A, KCNMA1, and KIF1A) and other gene (COL4A1) highlighting that ion channel genes are common genetic markers shared by all three disorders. CONCLUSION The identified variants predominantly involve genes encoding sodium, potassium, and GABA receptors that result in ion channel dysfunction and neurotransmitter imbalance. These findings highlight shared molecular pathways contributing to the pathogenesis of epilepsy, migraine, and their comorbidity. The convergence of genetic factors suggests potential avenues for the development of unified therapeutic strategies.

Epilepsy is a significant neurological disorder caused by sudden, excessive electrical discharges in the brain neurons. It is more prevalent in children and individuals under 20 years of age. Children with epilepsy are particularly vulnerable to mental health issues due to comorbid conditions like attention deficit disorder, hyperactivity, and learning disabilities, making them more susceptible to anxiety and depression. This narrative review aims to assess the prevalence of mental disorders in children and teenagers with epilepsy. The review examines studies from PubMed, Google Scholar, Medline, Scientific Information Database, Cumulative Index to Nursing and Allied Health Literature (CI-NAHL), Scopus, Elsevier, Iran Doc, and Magiran published between 2015 and 2022, focusing on the last five years. The search involved keywords such as "Epilepsy", "Children and Teenagers", "Mental Disorders", "Anxiety", and "Depression", along with various combinations and Boolean operators. The results of this narrative review indicate a high prevalence of mental disorders among children and teenagers with epilepsy. Among these, anxiety disorders were the most common, followed by depression, attention deficit disorder, and hyperactivity. Other disorders, such as phobias and obsessive-compulsive disorder, were less prevalent but still notable. Given that epilepsy impacts all aspects of a child’s life, including psychological and social functions, leading to decreased efficiency and productivity, early detection and prevention of these mental health issues are crucial to improving the overall well-being and quality of life of these children.

This article provides an overview of the current state of the problem regarding the comorbidity of multiple sclerosis (MS) and epileptic seizures (ES). Epilepsy occurs in patients with MS 3–6 times more often than in the general population; however, its prevalence and clinical manifestations are variable. The pathogenetic link between the two conditions is bidirectional: demyelination and gray matter atrophy in MS contribute to epileptogenesis, while epileptic activity itself can exacerbate neurodegeneration. The clinical manifestations of ES in MS are heterogeneous and can include both focal and generalized seizures, which often serve as the first manifestation of the demyelinating disease. Electroencephalography and cerebral magnetic-resonance imaging play a crucial role in diagnosis, revealing focal activity and structural changes in the cortex. Treatment requires a comprehensive approach, whereby some disease-modifying therapies for MS and antiepileptic drugs can have a mutually positive influence. Conclusion. The comorbidity of multiple sclerosis and epilepsy is a complex problem due to shared pathogenetic mechanisms and mutual aggravating influence. Diagnosing epileptic seizures in MS can be challenging due to the variable clinical picture and non-specific changes on electroencephalogram. Given the high risk of developing epilepsy in this patient category and its potential impact on the progression of disability, neurologists need to maintain a high index of diagnostic suspicion. Further research in this area should be devoted to optimal treatment strategies aimed at both conditions simultaneously.

Background/Objectives: Our understanding of the transdiagnostic factors that influence health-related quality of life (HRQOL) in individuals with neurodivergent conditions is very sparse and highly siloed by diagnosis labels. Research on transdiagnostic predictors of HRQOL across neurodevelopmental conditions is needed to enable care models that address shared needs of neurodivergent individuals beyond diagnostic boundaries. Our objective was to identify transdiagnostic factors associated with HRQOL in children with autism, epilepsy, or comorbid autism/epilepsy. Methods: This cross-sectional study included 37 autistic and/or epileptic children (mean age = 9.2; SD = 3.9; boys = 28). Parents provided sociodemographic information and completed the following measures: Social Communication Questionnaire (measure of severity of autistic symptoms); Parenting Stress Index, Fourth Edition; Pediatric Quality of Life Inventory; and the Behavioral Assessment System for Children, Third Edition. Child intellectual functioning was measured using age-appropriate scales: the Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition: Canadian or the Wechsler Intelligence Scale for Children-Fifth Edition: Canadian. Results: Higher autistic symptom severity (OR = 0.851 95% CI: 0.732–0.988, p = 0.034) and parenting stress (OR = 0.687 95% CI: 0.493–0.959, p = 0.027) were associated with poorer HRQOL. Full Scale IQ and adaptive skills showed trend level associations with HRQOL. Sociodemographic factors including maternal education, child sex, and child age as well as child diagnosis were not associated with HRQOL. Conclusions: In this transdiagnostic sample of children, autism symptom severity and parenting stress were shared predictors of HRQOL. Interventions targeting child autistic symptoms and parents’ levels of stress could result in improved HRQOL in neurodivergent populations.

Background Stress is among the most common comorbid conditions with epilepsy and a strong factor in the pathophysiology of seizures. An imbalance in neuronal circuits causes recurrent unprovoked seizures in epilepsy. Dysregulation of BDNF/VEGF expression, oxidative stress, increased levels of neuroinflammatory cytokines, and increased expression of apoptotic genes contribute to the underlying cause of the seizure. Objectives Chrysophanol, an anthraquinone, has broad-spectrum therapeutic potential. This study evaluated the neuroprotective effect of chrysophanol with underlying pathways in PTZ-induced epilepsy with stress as a comorbid condition. Methods Male mice were given 35 mg/kg of PTZ every other day to induce seizures. In addition, they were exposed to 120 min of daily restraint stress for 21 days to induce stress. Chrysophanol (0.1, 1, 10 mg/kg) was administered to the mice 30 min before the PTZ in the acute study. The most effective dose (10 mg/kg) was proceeded for the chronic epilepsy model. Following this, various tests were conducted, including behavioral assessments for memory impairment and stress, analysis of antioxidant levels, histopathological and immunohistochemistry examinations, measurement of cortisol levels using ELISA, and gene expression analysis using RT-PCR. Results Chrysophanol demonstrated a notable decrease in both the intensity and frequency of seizures. Additionally, it effectively boosted the levels of important antioxidants such as GSH, GST, and CAT, while simultaneously reducing the levels of MDA and Nitric oxide. The histopathological analysis also showed improvement in overall morphology and survival of neurons. Chrysophanol treatment effectively showed an increase in the expression of BCL-2, and Nrf-2 with a decrease in BAX expression confirmed by immunohistochemistry. Dysregulation of vascular permeability factor, production of inflammatory cytokines, and apoptotic gene expression was successfully reversed after chrysophanol treatment analyzed through RT-PCR. Cortisol concentration was decreased in treatment groups analyzed through Enzyme-linked immunoassay. Molecular docking of chrysophanol with different proteins declared the binding affinity of the ligands with the target sites of proteins. Conclusion In conclusion, chrysophanol demonstrated remarkable neuroprotective and antiepileptic effects at a dose of 10 mg/kg in stress-exacerbated PTZ-induced epilepsy following the TLR4/NFκB -Nrf2/HO-1 and BDNF/VEGF pathways.

Purpose of the Review Intracranial neurostimulation is a well-established treatment of neurologic conditions such as drug-resistant epilepsy (DRE) and movement disorders, and there is emerging evidence for using deep brain stimulation to treat obsessive-compulsive disorder (OCD) and depression. Nearly all published reports of intracranial neurostimulation have focused on implanting a single device to treat a single condition. The purpose of this review was to educate neurology clinicians on the background literature informing dual treatment of 2 comorbid neuropsychiatric conditions epilepsy and OCD, discuss ethical and logistical challenges to dual neuropsychiatric treatment with a single device, and demonstrate the promise and pitfalls of this approach through discussion of the first-in-human closed-looped responsive neurostimulator (RNS) implanted to treat both DRE (on-label) and OCD (off-label). Recent Findings We report the first implantation of an intracranial closed-loop neurostimulation device (the RNS system) with the primary goal of treating DRE and a secondary exploratory goal of managing treatment-refractory OCD. The RNS system detects electrophysiologic activity and delivers electrical stimulation through 1 or 2 electrodes implanted into a patient's seizure-onset zones (SOZs). In this case report, we describe a patient with treatment-refractory epilepsy and OCD where the first lead was implanted in the right superior temporal gyrus to target the most active SOZ based on stereotactic EEG (sEEG) recordings and semiology. The second lead was implanted to target the right anterior peri-insular region (a secondary SOZ on sEEG) with the distal-most contacts in the right nucleus accumbens, a putative target for OCD neurostimulation treatment. The RNS system was programmed to detect and record the unique electrophysiologic signature of both the patient's seizures and compulsions and then deliver tailored electrical pulses to disrupt the pathologic circuitry. Summary Dual treatment of refractory focal epilepsy and OCD with an intracranial closed-loop neurostimulation device is feasible, safe, and potentially effective. However, there are logistical challenges and ethical considerations to this novel approach to treatment, which require complex care coordination by a large multidisciplinary team.

Despite the recognition of Sudden Unexpected Death in Epilepsy (SUDEP) and other risks of premature mortality in people with epilepsy (PWE), mortality in older PWE remains an understudied entity. This review provides a comprehensive overview of the multifaceted causes of premature mortality in older adults with epilepsy and emphasizes the need for targeted interventions to reduce mortality and enhance the quality of life in this vulnerable population. It underscores the heightened prevalence of epilepsy among older adults and the interplay of intrinsic and extrinsic factors contributing to their mortality. Further, this paper delves into the nuances of diagnosing SUDEP in older adults and the underestimation of its incidence due to misclassification and lack of standardized protocols. Factors such as frailty, comorbidities, and the bidirectional relationship between epilepsy and conditions such as dementia and stroke further compound the mortality risks. Key factors, including status epilepticus, comorbid conditions (such as cardiovascular diseases, cerebrovascular events, and neurodegenerative disorders), and external causes like accidents, falls, and suicide, are discussed. It also examines the implications of anti‐seizure medications, particularly polypharmacy, and their adverse effects on this population. Future directions include implementing enhanced diagnostic protocols, developing treatment plans, and integrating real‐time monitoring technologies to reduce the risk of sudden death and multifaceted premature mortality in this patient population. Increasing awareness among healthcare providers and families about the risks and management of epilepsy in older adults, along with fostering collaborative research efforts, is essential to improve mortality outcomes.

The article presents theses of the resolution of the Interdisciplinary Council of Experts in Psychiatry and Neurology (Moscow, 2024) on the issue of comorbid anxiety disorders (AD) in patients with neurological pathologies. The authors highlight the high prevalence of comorbid ADs and their significant negative impact on the course of underlying diseases, such as epilepsy, pain syndromes and post-stroke conditions. Modern approaches to the diagnosis and treatment of ADs in this group of patients are discussed. Special attention is given to the role of etifoxine as an effective anxiolytic in the comprehensive therapy of ADs. Etifoxine, due to its dual mechanism of action on GABA receptors, demonstrates high efficacy in reducing anxiety and has neuroprotective, neurotrophic, neuroplastic, analgesic, and anti-inflammatory properties, making it an important tool in the treatment of comorbid ADs in patients with neurological pathologies. The article also reviews recently published data confirming its efficacy and favourable safety profile compared to traditional benzodiazepines and other anxiolytic drugs.

Anxiety is characterized as an overwhelming sense of worry or fear for the future, while epilepsy is a chronic neurological condition. Both anxiety and epilepsy are prevalent conditions that impact individuals globally and are associated with diminished function and life quality. This review article explains about the treatment, etiology, pathophysiology, current advances and neurological relationship between anxiety and epilepsy. Previous research suggests that anxiety disorders are widespread and clinically relevant comorbid diseases in epilepsy patients because anxiety can cause seizures or seizures may cause anxiety. To treat anxiety and epilepsy, a thorough, multidisciplinary clinical assessment is required. Medication, lifestyle modifications, and psychotherapy are also required.

Introduction Epilepsy and Migraine are the chronic disorders with recurrent neurological dysfunction associated with headache and autonomic, abdominal and psychotic features. In some patients it may be difficult to differentiate between migraine and the seizure episodes. Both are having comorbid symptoms and occurrence. Migraine patients can develop seizure and epileptics can have migraine attacks. Epileptologists proposed the hyperexcitability of the altered brain tissue, as the cause of seizure and migraine headache occurrence and vice versa. Enhanced hyperexcitability of cortical neurons and diminished threshold are the pathophysiological mechanisms enumerated in these conditions. Low magnesium in brain and the altered neurotransmitters are responsible for increased cortical excitability. Both the environmental as well as the genetic factors might cause these changes.

Psychogenic non-epileptic seizures (PNES) resemble epileptic seizures (ES) but lack the associated brain electrical disruptions. Their underlying mechanism remains elusive, even though cognitive deficits are commonly reported in both ES and PNES patients. This preliminary cross-sectional study compared attention and executive functions in 20 patients with ES (ES group) and 18 with PNES or comorbid PNES and ES (PNES group) using the Stroop task and attentional network task (ANT). Both groups exhibited a significant Stroop effect, with no significant differences between them. In the ANT assessment, the ES group had significantly slower reaction times (RTs) in non-tone conditions compared to in-tone conditions (P < 0.05). Meanwhile, the PNES group displayed no significant difference in RTs between these conditions, indicating a more pronounced alerting effect in the ES compared to PNES group. No significant disparities emerged in executive control and orientation between the groups. The findings underscore differences in attentional processing between these groups, emphasizing the clinical significance of understanding these cognitive deficits for accurate diagnosis and tailored neuropsychological rehabilitation.

Epilepsy is a major neurological illness among the elderly, with the highest prevalence rates reported in those aged over 65 years, particularly rising in those over 80. Challenges in treating epilepsy in older individuals include age-related changes in pharmacokinetics, polypharmacy due to comorbid conditions, and heightened vulnerability to adverse drug reactions. Stroke, trauma, and intracranial neoplasms are the acquired causes for epilepsy, also considered as predominant etiological factors. It is challenging to identify suitable antiseizure medications (ASMs) with lesser chances of cognitive side effects, a low chance of drug interactions, and favourable pharmacokinetic profiles. Lacosamide has emerged as a feasible, well-accepted treatment option for elderly patients. It offers various benefits, including a low threat of cognitive impairment and low potential for drug–drug interactions. Lacosamide is considered easier to tolerate and can be acclimatised to each case's requirements compared to older antiseizure medications such as carbamazepine, phenytoin, and valproate. This positions lacosamide as an viable therapeutic option for managing epilepsy in old age, which improves overall quality of life. Purpose: This review provides a scientific evaluation of epilepsy management in the elderly, elucidating the complexities of age-related pharmacokinetic changes, polypharmacy, and comorbidities, while highlighting the clinical efficacy and tolerability of lacosamide, which has a low risk of cognitive adverse effects and a low potential for drug-drug interactions.

A bstract A seizure disorder is one of the most common comorbid neurologic conditions that may be present in children. Providing perioperative care for these children may be required during elective, urgent, or emergent procedures unrelated to their primary seizure disorder or during surgical procedures aimed at lessening their seizure burden when pharmacologic therapy is ineffective. Regardless of the surgical procedure, perioperative care requires a staged approach with specific considerations during the preoperative evaluation, intraoperative care, and the postoperative period related to the primary seizure disorder or other associated comorbid conditions. This educational review outlines the perioperative care of infants and children with an underlying seizure disorder with a focus on preoperative preparation including perioperative dosing of anti-epileptic drugs, intraoperative care including the impact of commonly administered anesthetic agents on the seizure foci, choice of intraoperative medications and neuromuscular blocking agents, as well as a review of issues that may be encountered during postoperative care including strategies for pain management.

Apart from seizure freedom, the presence of comorbidities related to neurological, cardiovascular, or psychiatric disorders is the largest determinant of a reduced health‐related quality of life in people with epilepsy (PwE). However, comorbidities are often underrecognized and undertreated, and clinical management of comorbid conditions can be challenging. The focus of a comprehensive treatment regimen should maximize seizure control while optimizing clinical management of treatable comorbidities to improve a person's quality of life and overall health. A panel of four European epileptologists with expertise in their respective fields of epilepsy‐related comorbidities combined the latest available scientific evidence with clinical expertise and collaborated to provide consensus practical advice to improve the identification and management of comorbidities in PwE. This review provides a critical evaluation for the diagnosis and management of sleep–wake disorders, cardiovascular diseases, cognitive dysfunction, and depression in PwE. Whenever possible, clinical data have been provided. The PubMed database was the main search source for the literature review. The deleterious pathophysiological processes underlying neurological, cardiovascular, or psychiatric comorbidities in PwE interact with the processes responsible for generating seizures to increase cerebral and physiological dysfunction. This can increase the likelihood of developing drug‐resistant epilepsy; therefore, early identification of comorbidities and intervention is imperative. The practical evidence‐based advice presented in this article may help clinical neurologists and other specialist physicians responsible for the care and management of PwE.

BACKGROUND Pediatric stroke, which is unique in that it represents a static insult to a developing brain, often leads to long-term neurological disability. Neuroplasticity in infants and children influences neurophysiologic recovery patterns after stroke; therefore outcomes depend on several factors including the timing and location of stroke and the presence of comorbid conditions. METHODS In this review, we discuss the unique implications of stroke occurring in the fetal, perinatal, and childhood/adolescent time periods. First, we highlight the impact of the developmental stage of the brain at the time of insult on the motor, sensory, cognitive, speech, and behavioral domains. Next, we consider the influence of location of stroke on the presence and severity of motor and nonmotor outcomes. Finally, we discuss the impact of associated conditions on long-term outcomes and risk for stroke recurrence. RESULTS Hemiparesis is common after stroke at any age, although the severity of impairment differs by age group. Risk of epilepsy is elevated in all age groups compared with those without stroke. Outcomes in other domains vary by age, although several studies suggest worse cognitive outcomes when stroke occurs in early childhood compared with fetal and later childhood epochs. Conditions such as congenital heart disease, sickle cell disease, and moyamoya increase the risk of stroke and leave patients differentially vulnerable to neurodevelopmental delay, stroke recurrence, silent infarcts, and cognitive impairment. CONCLUSIONS A comprehensive understanding of the interplay of various factors is essential in guiding the clinical care of patients with pediatric stroke.

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INTRODUCTION Adults with Juvenile myoclonic epilepsy (JME) are at increased risk for psychiatric comorbidities, personality traits, and abnormality in executive function. But studies on adolescents and their impact on quality of life are scarce in the literature. MATERIALS AND METHODS This cross-sectional study was performed between August 2019 and October 2022 to compare the prevalence of psychiatric comorbidities in adolescents with JME and age and gender-matched healthy controls. After completing DSM-5 Structured Clinical Interview (SCID-5) initially in all patients, we measured the severity of individual psychiatric problems like anxiety, depression, and somatic symptoms by using an appropriate psychometric scale. We also measured both groups' intelligence quotient (IQ), executive function, and quality of life. RESULTS One hundred patients with JME (14.3 ± 2.5 years, 48 boys) and 100 controls were enrolled. Psychiatric disorders were observed in 46% of JME and 6% of controls (p < 0.01). Psychiatric comorbidities noted in the patients with JME were: somatic symptom and related disorders(n = 14), anxiety (n = 13), adjustment disorders (n = 12), depression (n = 11), oppositional defiant disorder (n = 6), conduct disorder (n = 5), anorexia nervosa (n = 3), narcissistic (n = 3), histrionic (n = 1), substance-related disorder (n = 1), borderline (n = 2) and antisocial personality disorder (n = 2). The prevalence of depressive disorders, anxiety disorders, adjustment disorders, somatic symptoms, related disorders, and any personality disorder was significantly more in the JME group (p < 0.01 for all). Female gender, higher Epilepsy Stigma Scale score, and lower Epilepsy Outcome Expectancy Scale were significantly associated with depressive disorders (p = 0.04, 0.03, 0.03 respectively). Similarly, for anxiety, only female gender and lower Epilepsy Outcome Expectancy Scale were significant associated factors (p = 0.03, 0.02 respectively). CONCLUSIONS Psychiatric disorders like anxiety, depression, and personality disorders are more frequent in adolescents with JME than in controls.

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Background People with epilepsy (PWE) having comorbid psychiatric conditions may be at greater risk of death. We aimed to determine the association between psychiatric disorders and all-cause mortality among PWE after adjustment for somatic comorbidities. Methods Based on data from the National Health Insurance Fund, a Cox survival analysis was done within a retrospective open cohort of all PWE (≥12 years) in Lithuania between January 2014 and June 2020. Cox models comparing mortality between PWE with or without psychiatric comorbidities were adjusted for sex, age, hospitalizations, and the epilepsy-specific comorbidity index. Results Of 47,964 PWE (age Md = 49, IQR = 34–62 years, 60.3% male, follow-up Md = 4.4, IQR = 2.1–6.1 years), 10,290 (21.5%) died during the study. The diagnosis of any psychiatric disorder (n = 26,137, 54.5%) was associated with increased mortality when adjusted for only sex and age (HR = 1.13, 95% CI = 1.09 to 1.18). After including the epilepsy-specific comorbidity index, the number of hospitalizations and hospital days in the analysis, only self-harm (HR = 1.55, 95% CI = 1.40 to 1.71) and substance use disorders (HR = 1.39 95% CI = 1.32 to 1.47), but not any psychiatric comorbidities (HR = 0.92 95% CI = 0.88 to 0.96) were related to elevated all-cause mortality. Mood, anxiety and behavioral disorders were associated with lower odds of mortality; however, they were rarely documented. Conclusions Our results suggest that psychiatric comorbidities increase all-cause mortality among PWE through their association with coexisting somatic conditions as only substance use disorders and self-harm were independently related to elevated all-cause mortality. Future clinical interview-based studies should explore the relationship between mortality in epilepsy and psychiatric comorbidities while adjusting for somatic comorbidities.

Background Drug-resistant epilepsy (DRE) is a chronic neurological disorder with somatic impacts and an increased risk of psychiatric comorbidities and cognitive impairment. Previous studies suggested that genomic variants could contribute to the high interindividual variability in epilepsy and in its treatment response, but it remains unclear. Here, we aimed to perform genome-wide association study (GWAS), leverage the enrichment analysis of the genomic variants, and provide the potential molecular signature profiles. Moreover, we investigated the potential role of molecular signature profiles, as exemplified by tryptophan catabolites (TRYCATs), in DRE patients. Methods We used data from the Taiwan Biobank to perform a GWAS and identified enrichment pathways through the functional database Reactome. To validate the results, we enrolled community-dwelling controls and DRE patients. The levels of TRYCATs were determined using liquid chromatography–tandem mass spectrometry. In addition, we compared the levels of TRYCATs between the controls and DRE patients at baseline and after 6-month multivitamin supplementation. Seizure frequency was defined as the number of episodes per 28 days in DRE patients. Results Using GWAS and enrichment analysis of genomic data, we obtained candidate genes implicated in mechanisms and molecular signature profiles against epilepsy, such as the TRYCATs pathway. To validate the molecular signature from enrichment analysis, we further examined whether the TRYCATs pathway was associated with the pathophysiology of epilepsy and treatment outcome in DRE patients. We found that DRE patients had significantly lower levels of TRYCATs (tryptophan, serotonin, 3-indole acetic acid, 3-indoleperopionic acid, kynurenine, and kynurenic acid) than the controls. Additionally, changes in the balance of the TRYCATs pathway were noted in DRE patients treated with 6-month multivitamin supplementation. Furthermore, the change levels of TRYCATs were correlated with seizure frequency in the DRE patients during multivitamin supplementation. Conclusion The TRYCATs pathway plays an important role in the pathophysiology of epilepsy and is involved in the multivitamin-mediated physiological alterations in DRE patients. Therefore, the balance of TRYCATs might be a new biomarker and therapeutic strategy for epilepsy.

BACKGROUND Children with epilepsy are at increased risk for reduced health-related quality of life (HRQoL), due to the combined impact of seizures, comorbidities (somatic, psychiatric, neurologic, neurodevelopmental), social limitations. However, validated tools in different languages for HRQoL in pediatric epilepsies remain limited. AIM To explore HRQoL in children/adolescents with epilepsy, focusing on epilepsy-related factors, social difficulties, and overall well-being, after linguistic validation of the Italian Pediatric Quality of Life Inventory Epilepsy Module (PedsQL-EM). METHODS The sample included 119 participants (aged 8-18-year-old). Caregivers completed the Italian PedsQL-EM and the Italian version of the Child Behavior Checklist (CBCL) Social Problems subscale. Hierarchical multiple regression was performed to identify predictors of HRQoL, and a mediation model tested the indirect effects on the Social Problems subscale of the CBCL. RESULTS The Italian PedsQL-EM showed good internal consistency (ω = 0.72-.92). We found an high correlation between each domain of the PedsQL-EM, allowing to perform further analysis using a comprehensive total score. The total score strongly correlated with lower cognitive performances, neurological and psychiatric comorbidities, and was also significantly correlated with the subscale scores of the CBCL. HRQoL significantly mediated the relationship between clinical severity and social problems (indirect effect = 2.83; 95 % CI = 1.374-4.402). CONCLUSION In children with epilepsy, lower cognitive abilities and neurological/psychiatric comorbidities may affect social functioning through the mediation role of HRQoL. Utilizing PedsQL-EM as a screening tool can help identify these risks early, allowing for targeted interventions. Given the high psychiatric comorbidity in these patients, integrating behavioral health services into epilepsy care could improve comprehensive assessment and treatment, enhancing overall outcomes for affected children.

Objective: To explore the relationship between cognitive functioning and psychopathological features in Functional/Dissociative Seizures (FDS), and test whether this differs from that observed in epilepsy. Methods: We recruited a cross-sectional sample of adults (age > 18) with a diagnosis of non-lesional epilepsy or FDS between January 2021 and July 2022. Participants completed a series of psychiatric questionnaires and neuropsychological measures. Spearmans Correlation Coefficient was computed between each of the psychiatric and cognitive measures in each group. Fishers Z test of significance for independent correlation coefficients then tested the significance of the difference between correlation coefficients for the two groups. Results: There were no group differences in neuropsychological test scores. However, people with FDS reported higher seizure severity, depression levels, number of medically unexplained somatic symptoms, and exposure to traumatic events compared to epilepsy. Results of the Fishers Z-test revealed significant differences in correlation coefficients between groups in two instances. First, in the association between the number of traumatic experiences and cognitive switching (z = 2.77, p = 0.006); the number of traumatic experiences were positively associated with cognitive switching in epilepsy but showed a non-significant negative trend in FDS. Secondly, in the association between vocabulary abilities and the number of medically unexplained symptoms (z = -2.71; p = 0.007); higher vocabulary ability was associated with fewer somatic symptoms in epilepsy, while no such correlation was observed in FDS. Significance: This study provides preliminary evidence for the complex interplay between cognitive functioning and psychopathology in FDS and epilepsy. Neurocognitive functioning such as vocabulary abilities or attentional switching may play a role in the expression or maintenance of pathological features of FDS.

This exploratory cross-sectional multicenter study evaluated the presence of depression and anxiety traits in adolescents with idiopathic generalized epilepsy (IGE) and explored their association with epilepsy-related clinical variables. Sixty-eight patients aged 11-18 years with a confirmed IGE diagnosis participated. Emotional symptoms were assessed using the parent-reported Child Behavior Checklist (CBCL) and the self-reported Psychiatric Scales for Self-Administration for Youths and Adolescents (SAFA). While no clinically significant deficits emerged on the overall CBCL or SAFA scores, 33% of patients showed clinically relevant anxiety traits, 31% showed depressive symptoms, and 19% reported clinically significant somatic complaints. Correlation analyses showed that somatic symptoms were significantly associated with epilepsy-related variables. Higher somatic symptom scores were related to a shorter time since the last seizure and a later age at epilepsy onset, while an inverse association was observed with epilepsy duration. These findings suggest that affective symptoms in adolescents with IGE are linked to specific clinical characteristics of epilepsy. The results highlight the importance of comprehensive emotional assessment and targeted psychological support for this population.

DEPDC5-related epilepsy, caused by pathogenic germline variants(with or without additional somatic variants in the brain) of DEPDC5 (Dishevelled, Egl-10 and Pleckstrin domain-containing protein 5) gene, is a newly discovered predominantly focal epilepsy linked to enhanced mTORC1 pathway. DEPDC5-related epilepsy includes several familial epilepsy syndromes, including familial focal epilepsy with variable foci (FFEVF) and rare sporadic nonlesional focal epilepsy. DEPDC5 has been identified as one of the more common epilepsy genes linked to infantile spasms and sudden unexpected death (SUDEP). Although intelligence usually is unaffected in DEPDC5-related epilepsy, some people have been diagnosed with intellectual disabilities, autism spectrum disorder, and other psychiatric problems. DEPDC5 variants have also been found in 20% of individuals with various brain abnormalities, challenging the traditional distinction between lesional and nonlesional epilepsies. The most exciting development of DEPDC5 variants is the possibility of precision therapeutics using mTOR inhibitors, as evidenced with phenotypic rescue in many animal models. However, more research is needed to better understand the functional impact of diverse (particularly missense or splice-region) variants, the specific involvement of DEPDC5 in epileptogenesis, and the creation and utilization of precision therapies in humans. Precision treatments for DEPDC5-related epilepsy will benefit not only a small number of people with the condition, but they will also pave the way for new therapeutic approaches in epilepsy (including acquired epilepsies in which mTORC1 activation occurs, for example, post-traumatic epilepsy) and other neurological disorders involving a dysfunctional mTOR pathway.

Psychiatric disorders are frequently encountered in many neurological disorders, such as Alzheimer’s and Parkinson diseases along with epilepsy, migraine, essential tremors, and stroke. The most common comorbid diagnoses in neurological diseases are depression and anxiety disorders along with cognitive impairment. Whether the underlying reason is due to common neurochemical mechanisms or loss of previous functioning level, comorbidities are often overlooked. Various treatment options are available, such as pharmacological treatments, cognitive-behavioral therapy, somatic interventions, or electroconvulsive therapy. However oral antidepressant therapy may have some disadvantages, such as interaction with other medications, low tolerability due to side effects, and low efficiency. Natural compounds of plant origin are extensively researched to find a better and safer alternative treatment. Experimental studies have shown that phytochemicals such as alkaloids, terpenes, flavonoids, phenolic acids as well as lipids have significant potential in in vitro and in vivo models of psychiatric disorders. In this review, various efficacy of natural products in in vitro and in vivo studies on neuroprotective and their roles in psychiatric disorders are examined and their neuro-therapeutic potentials are shed light.

Drug‐resistant epilepsy remains to this day as a highly prevalent condition affecting around one‐third of patients with epilepsy, despite all the research and the development of several new antiseizure medications (ASMs) over the last decades. Epilepsies are multifactorial complex diseases, commonly associated with psychiatric, neurological, and somatic comorbidities. Thus, to solve the puzzling problem of pharmacoresistance, the diagnosis and modeling of epilepsy and comorbidities need to change toward a complex system approach. In this review, we have summarized the sequence of events for the definition of epilepsies and comorbidities, the search for mechanisms, and the major hypotheses of pharmacoresistance, drawing attention to some of the many converging aspects between the proposed mechanisms, their supporting evidence, and comorbidities‐related alterations. The use of systems biology applied to epileptology may lead to the discovery of new targets and the development of new ASMs, as may advance our understanding of the epilepsies and their comorbidities, providing much deeper insight on multidrug pharmacoresistance.

Surgical resection and neuromodulation are well-established treatments for those with medically refractory epilepsy. These treatments entail important ethical considerations beyond those which extend to the treatment of epilepsy generally. In this paper, the authors explore these unique considerations through a framework that relates foundational principles of bioethics to features of resective epilepsy surgery and neuromodulation. The authors conducted a literature review to identify ethical considerations for a variety of epilepsy surgery procedures and to examine how foundational principles in bioethics may inform treatment decisions. Healthcare providers should be cognizant of how an increased prevalence of somatic and psychiatric comorbidities, the dynamic nature of symptom burden over time, the individual and systemic barriers to treatment, and variable sociocultural contexts constitute important ethical considerations regarding the use of surgery or neuromodulation for the treatment of epilepsy. Moreover, careful attention should be paid to how resective epilepsy surgery and neuromodulation relate to notions of patient autonomy, safety and privacy, and the shared responsibility for device management and maintenance. A three-tiered approach-(1) gathering information and assessing the risks and benefits of different treatment options, (2) clear communication with patient or proxy with awareness of patient values and barriers to treatment, and (3) long-term decision maintenance through continued identification of gaps in understanding and provision of information-allows for optimal treatment of the individual person with epilepsy while minimizing disparities in epilepsy care.

OBJECTIVE Epilepsies are severe chronic neurological diseases that impair several domains in life and are often accompanied by various somatic and psychiatric comorbidities. Associations between epilepsy and its comorbidities remain poorly understood. As epidemiological research mainly relies on cross-sectional designs and descriptive results, homogeneities regarding comorbidities in individuals suffering from epilepsy remain uncovered. Therefore, we aimed to identify clusters of individuals based on selected seizure-related variables and somatic comorbidities, and their respective risk of experiencing affective disorders, using a Latent Class Analysis (LCA). METHODS Latent class analysis, is a model-driven statistical approach, which aims at latent, unobservable clusters on selected disease features. LCA has therefore the potential for uncovering previously unobservable groups or classes with similar comorbidity patterns. It allows for comparisons between those classes regarding risk or promotive factors - such as affective disorders. Our data derives from the Austrian cohort of the European Study on Burden and Care of Epilepsy (ESBACE; http://www.esbace.eu/). In ESBACE, multiple factors were collected to get a detailed picture on prevalence, epilepsy-related variables and comorbidities in a population-based cohort from the region of Salzburg, Austria. We used LCA to identify epilepsy-somatic-comorbidity-clusters and further, compared them to the observed the risk of suffering from affective disorders. RESULTS The prevalence of epilepsy in the study region was 9.14/1000 inhabitants. LCA unveiled a three-cluster solution, of which one cluster, mainly consisting of individuals with mixed seizure types, higher age, and discrete somatic comorbidities (stroke, cardiovascular - and respiratory/pulmonary diseases) had a higher risk of experiencing affective disorders. SIGNIFICANCE To our knowledge, this is the first large scale study that uses LCA to identify epilepsy-related comorbidity phenotypes, and therefore it might open a new way for epidemiological research.

Introduction Youth with psychogenic non-epileptic seizures (PNES) are an understudied group associated with significant medical and psychiatric morbidity. Several studies have examined characteristics associated with youth's development of this disorder, though the exploration of family factors including psychiatric illness, has been lacking. This study sought to establish the need for a more comprehensive future study. Methods A retrospective chart review was conducted on patients who had been admitted and diagnosed with PNES at the epilepsy monitoring unit at Children's Hospitals and Clinics of Minnesota. A total of 62 patients were included. All patients were evaluated by an epileptologist and psychologist during their diagnostic admission. “Spells” in question were captured via video EEG monitoring. PNES youth and family risk factors were assessed. Results Mean age of PNES symptom onset was 13.9 years. Patients (73%) were diagnosed within 6 months of onset of symptoms. Histories of other impairing somatic complaints were present in the youth (54%), with 67% having prior psychiatric diagnoses. Experiencing suicidal ideation or thoughts of self-harm occurred in 47% of this sample. Family members were unaware of the history of these symptoms with 12% of the parent's reporting awareness. Family history of psychiatric disorders (first-degree relatives of patient) was present in 54% of the sample, with anxiety, depression and conversion disorder being the most commonly endorsed diagnoses. Conclusions Youth with PNES present with comorbid psychiatric disorders, though prior assessment and treatment for these disorders was not common. Youth with PNES have history of suicidal ideation and thoughts of self-harm, though parental awareness of these co-occurring symptoms is limited. Family risk factors, such as history of psychiatric disorder in first degree relatives, was high. The impact of these family risk factors is understudied and should be further evaluated to better understand the impact on development and maintenance of this disorder in youth.

Objective Individuals with autism spectrum disorder often present somatic and/or psychiatric co-morbid disorders. The DSM-5 allows for consideration of additional diagnoses besides ASD and may have impacted the prevalence of co-morbidities as well as being limited in capturing the true differences in prevalence observed between males and females. We describe the prevalence of ASD and frequently observed co-morbidities in children and adolescents (<18 years) in the United States and five European countries. Methods Two systematic literature reviews were conducted in PubMed and Embase for the period 2014-2019 and focusing on the prevalence of ASD and nine co-morbidities of interest based on their frequency and/or severity: Attention Deficit Hyperactivity Disorder (ADHD), anxiety, depressive disorders, epilepsy, intellectual disability (ID), sleep disorders, sight/hearing impairment/loss, and gastro-intestinal syndromes (GI). Results Thirteen studies on prevalence of ASD and 33 on prevalence of co-morbidities were included. Prevalence of ASD was 1.70 and 1.85% in U.S children aged 4 and 8 years respectively, while prevalence in Europe ranged between 0.38 and 1.55%. Additionally, current evidence is supportive of a global increase in ASD prevalence over the past years. Substantial heterogeneity in prevalence of co-morbidities was observed: ADHD (0.00-86.00%), anxiety (0.00-82.20%), depressive disorders (0.00-74.80%), epilepsy (2.80-77.50%), ID (0.00-91.70%), sleep disorders (2.08-72.50%), sight/hearing impairment/loss (0.00-14.90%/0.00-4.90%), and GI syndromes (0.00-67.80%). Studies were heterogeneous in terms of design and method to estimate prevalence. Gender appears to represent a risk factor for co-morbid ADHD (higher in males) and epilepsy/seizure (higher in females) while age is also associated with ADHD and anxiety (increasing until adolescence). Conclusion Our results provide a descriptive review of the prevalence of ASD and its co-morbidities in children and adolescents. These insights can be valuable for clinicians and parents/guardians of autistic children. Prevalence of ASD has increased over time while co-morbidities bring additional heterogeneity to the clinical presentation, which further advocates for personalized approaches to treatment and support. Having a clear understanding of the prevalence of ASD and its co-morbidities is important to raise awareness among stakeholders.Appeared originally in Front Psychiatry 2021; 12:744709.

Elucidating complex, multifactorial phenomena like suicide and suicidal behaviors (SSB) require multidisciplinary fields such as Psychoneuroimmunology (PNI). Indeed, our appreciation of the bidirectional communication channels between the brain and the rest of the body with its immune arsenal as the key player has positioned PNI as a promising field of research. We now know that major psychiatric, behavioral, and somatic disorders related to SSB accompany neuroimmune dysregulation. These disorders range from depression, emotional dysregulation, atopy, and epilepsy to certain viral and parasitic infections. By utilizing epidemiological, genetic, microbial, and molecular approaches, the PNI research community has excogitated novel biomarker candidates and pathways in support of SSB risk stratification at individual level. This remarkable progress in just two previous decades shall, if successful, help implement personalized prevention and treatment strategies, using PNI-assisted tools. The aims of this narrative review and opinion piece are to summarize important discoveries concerning the role of neuroimmune activation in SSB and to highlight important future directions for the field. Major caveats of the findings concerning methodological approaches, clinical reality of frequent comorbid psychopathology, and novel molecular targets are presented. Finally, this review calls on the PNI research community for increased attention towards factors that promote resilience to suicide, while accepting “consciousness” under its wing. Thus, PNI represents the new frontier in suicide research. Future breakthroughs in this discipline shall bring us closer to understanding the biological substrates of qualia i.e., subjective, and experiential meanings of life and death.

Importance Several psychiatric disorders have been found to occur more frequently in persons with epilepsy (PWE) than in persons without epilepsy. Objective To summarize the prevalence of 20 psychiatric disorders in PWE compared with persons without epilepsy. Data Sources The search included records from inception to February 2024 in Ovid, MEDLINE, Embase, and PsycINFO. Study Selection Published epidemiological studies examining the prevalence of psychiatric disorders among PWE compared with persons without epilepsy were systematically reviewed. There were no restrictions on language or publication date. Data Extraction and Synthesis Abstracts were reviewed in duplicate, and data were extracted using a standardized electronic form. Descriptive statistics and meta-analyses are presented. Main Outcomes and Measures Data were recorded on the prevalence of 20 psychiatric disorders among PWE compared with persons without epilepsy. Meta-analyses were performed along with descriptive analyses. Results The systematic search identified 10 392 studies, 27 of which met eligibility criteria. The meta-analyses included 565 443 PWE and 13 434 208 persons without epilepsy. The odds of most psychiatric disorders studied were significantly increased in PWE compared with those without epilepsy, including anxiety (odds ratio [OR], 2.11; 95% CI, 1.73-2.58); depression (OR, 2.45; 95% CI, 1.94-3.09); bipolar disorder (OR, 3.12; 95% CI, 2.23-4.36); suicidal ideation (OR, 2.25; 95% CI, 1.75-2.88) but not suicide attempt (OR, 3.17; 95% CI, 0.49-20.46); psychotic disorder (OR, 3.98; 95% CI, 2.57-6.15); schizophrenia (OR, 3.72; 95% CI, 2.44-5.67); obsessive-compulsive disorder (OR, 2.71; 95% CI, 1.76-4.15); posttraumatic stress disorder (OR, 1.76; 95% CI, 1.14-2.73); eating disorders (OR, 1.87; 95% CI, 1.73-2.01); alcohol misuse (OR, 3.64; 95% CI, 2.27-5.83) and alcohol dependence (OR, 4.94; 95% CI, 3.50-6.96) but not alcohol abuse (OR, 2.10; 95% CI, 0.60-7.37); substance use disorder (OR, 2.75; 95% CI, 1.61-4.72); autism spectrum disorder (OR, 10.67; 95% CI, 6.35-17.91); and attention-deficit/hyperactivity disorder (OR, 3.93; 95% CI, 3.80-4.08). Conclusions and Relevance In this comprehensive study, most psychiatric comorbidities examined were significantly more prevalent in PWE than in those without epilepsy. These findings show the high burden of psychiatric comorbidities in PWE. This, in turn, underscores the need for appropriately identifying and treating psychiatric comorbidity in epilepsy to manage patients effectively and improve quality of life.

Amygdala enlargement has been the subject of controversial studies regarding its significance in terms of pathogenicity both in epilepsy and in psychiatric comorbidities such as anxiety, depression, and post‐traumatic stress disorder. However, no causal link has been established in either direction, and the role of distinct amygdala nuclei remains unknown. We investigated volumetric changes of the amygdala and its nine main nuclei and their associations with psychiatric comorbidities in patients with drug‐resistant focal epilepsy.

OBJECTIVE At least 30 % to 40 % of patients newly treated for epilepsy experience further seizures despite initiation of appropriate antiseizure medication (ASM) treatment. This study aimed to identify clinically useful predictors of seizure recurrence in newly treated adults with epilepsy which would have major clinical benefits. METHODS This work is a prospective cohort study conducted in Northeast China between June 2017 and May 2022. At enrolment, we collected information about demographics, clinical characteristics, and psychiatric comorbidities in newly treated adults with epilepsy. All patients were followed for 12 months for further seizures. Predictors of seizure recurrence were identified using logistic regression analyses. RESULTS A total of 836 newly treated adults with epilepsy were included in the final analysis. During follow-up, 362 (43.3 %) patients experienced at least one seizure recurrence, and 474 (56.7 %) entered seizure remission. Multivariable analysis showed that the odds of patients with depression having seizure recurrence were 1.74 times greater than those of patients without depression (Adjusted OR 1.74, 95 % CI 1.21-2.51). Similarly, the odds of patients with anxiety having seizure recurrence were 1.69 times greater than those of patients without anxiety (Adjusted OR 1.69, 95 % CI 1.21-2.37). Other Predictors of seizure recurrence included >5 seizures prior to treatment, brain MRI lesion, EEG epileptiform discharges. CONCLUSION We found that psychiatric comorbidities at baseline increase the risk of seizure recurrence in newly treated adults with epilepsy. Future studies are required to clarify the mechanisms underlying the links among psychiatric comorbidities and epilepsy. Furthermore, our findings might inform prospective studies investigating whether psychiatric treatment reduces the risk of seizure recurrence in these patients.

ABSTRACT Objective: While psychological trauma in people with epilepsy (PWE) is a major issue, there is limited research on the interactions between such trauma and epilepsy. Therefore, our primary aim is to describe types and timing of potentially psychologically traumatic experiences (PPTE) in relation to epilepsy onset. Our secondary objective is to evaluate the impact of the timing of the PPTE on patients’ psychiatric and neurological profiles. Methods: We conducted an observational study involving 182 PWE, excluding patients with comorbid functional/dissociative seizures. All participants underwent a comprehensive psychiatric evaluation, including biographical, neurological, psychiatric, and traumatic data collection through a semi-structured clinical interview and standardized scales. We compared the neurological and psychiatric characteristics of three groups of patients: those without PPTE, those with PPTE occurring before the onset of epilepsy, and those with PPTE occurring after the onset of their epilepsy. Results: Sixty-one patients (33.5%) reported having experienced PPTE before the onset of epilepsy, 65 patients (35.7%) reported having experienced PPTE after the onset of their epilepsy, and 56 patients (30.8%) had no history of PPTE neither before nor after the onset of epilepsy. The ‘before’ group had a significantly higher prevalence of epilepsy localized in the temporal lobe (p = .043). The ‘after’ group showed significantly more general psychiatric symptoms (p = .026), as well as more postictal mood and anxiety symptoms (p = .014). Additionally, the ‘before’ group reported a higher number of past traumatic experiences, with childhood traumatic experiences being more prevalent. According to our multinomial logistic regression model, higher temporal localization (p = .028) and fewer febrile seizures (p = .030) were significant predictors for the ‘before’ group. Significance: This study highlights the potential impact of the timing of PPTE on patients’ psychiatric and neurological profiles. It underscores the importance of systematically assessing psychiatric and posttraumatic comorbidities in PWE. The role of trauma in temporal epilepsy requires further investigation. HIGHLIGHTS The timing of potentially psychologically traumatic experiences (PPTE) may influence patients’ psychiatric and neurological profiles. Patients with a history of PPTE tend to have higher rates of psychiatric comorbidities. Early exposure to PPTE may impact the temporal localization of epilepsy.

OBJECTIVE Although quality of life (QOL) is impaired in patients with somatic symptom disorder (SSD), little is known about the relationship between SSD and QOL among patients with epilepsy (PWE) and the mechanisms underlying this association. This study aimed to identify the mediators of the association between SSD and QOL among PWE. METHODS A cross-sectional study was conducted at West China Hospital between July 2020 and May 2022. A total of 749 adults with epilepsy who attended the epilepsy center were consecutively enrolled via convenience sampling. All patients completed questionnaires that assessed demographic and clinical features, the Somatic Symptom Disorder-B Criteria Scale (SSD-12), the Patient Health Questionnaire-9 (PHQ-9), the Generalized Anxiety Disorder-7 (GAD-7), the Quality of Life in Epilepsy Inventory-31 (QOLIE-31), and the National Hospital Seizure Severity Scale (NHS3). The direct, indirect, and total effects of the predictors on QOL among PWE were tested based on the bootstrap method. RESULTS Up to 24.43 % of the adults with epilepsy were affected by SSD. Patients with SSD had significantly higher levels of depression and anxiety and lower levels of QOL. Correlation and mediation analyses revealed that the negative relationship between SSD and QOL was partially mediated by depression and anxiety (B = -10.412, 95 % CI [-12.730, -8.343]). The indirect effect accounted for 66.76 % of the total effect, among which depression accounted for a greater proportion (46.37 %). CONCLUSION This study offers new insight into the mechanism underlying the association between SSD and QOL among PWE. Interventions aimed at increasing QOL in patients with somatic symptoms should consider screening and treating depression and anxiety.

Background: Psychiatric disorders are common in epilepsy, occurring 2 to 3 times more frequently than in the general population. The authors performed comprehensive assessments in epilepsy patients with psychiatric comorbidities to delineate their psychiatric comorbidities, informing accurate diagnosis and effective management. Methods: A total of 70 cases were included in the study. Patients were categorized into 2 groups: epilepsy with psychiatric comorbidities and epilepsy without psychiatric comorbidities. In this study, we integrate cognitive function assessments, psychiatric scales measuring anxiety and depression, 24-hour long-term video-electroencephalogram (VEEG) monitoring, and epilepsy-specific magnetic resonance imaging (MRI) sequences. The MRI sequences cover 3D T1-weighted and 3D FLAIR T2 oblique coronal views. Results: Cognitive function scores showed no significant intergroup differences (P > 0.05). However, patients with psychiatric comorbidities demonstrated a significantly higher prevalence of structural brain abnormalities (P = 0.008) and increased occurrence of interictal epileptiform discharges (P = 0.012) compared with epilepsy without psychiatric comorbidities. Conclusions: Epilepsy patients with psychiatric comorbidities demonstrate significantly higher proportion of abnormal brain MRI and EEG findings compared with patients without psychiatric comorbidities. These findings emphasize the necessity for comprehensive evaluations in epilepsy patients particularly those with psychiatric comorbidities.

Importance Intermittent explosive disorder (IED) is an understudied psychiatric condition marked by impulsive aggression and poorly regulated emotional control, often resulting in interpersonal and societal consequences. Better understanding of comorbidities can improve screening, diagnosis, and treatment. Objective To investigate the prevalence of IED and its associations with psychiatric, neurological, and somatic disorders. Design, Setting, and Participants In this cohort study, matched groups of patients with and without IED were identified from the TriNetX Research Network (dated January 31, 2024). Electronic medical record data were analyzed. The mean (SD) time from the first to last known visits was 4.8 (5.4) years. Exposure Lifetime diagnosis of IED. Main Outcomes and Measures Main outcomes were International Statistical Classification of Diseases, Tenth Revision, Clinical Modification diagnostic categories and root codes. Cox proportional hazard models were used to estimate and compare probabilities of acquiring other diagnoses. Key measures include the numbers and proportions of patients with these diagnoses and adjusted hazard ratios (HRs) for IED. Results Overall, 30 357 individuals with IED and 30 357 demographically matched controls were included. In each group, 21 313 (70%) were male, with a mean (SD) age at the first visit 26 (17) years. Despite only 0.03% of the total patient population having an IED diagnosis, extensive comorbidities with psychiatric, neurological, and somatic conditions were found. A notable 95.7% of individuals with IED (29 054 individuals) had another psychiatric diagnosis. All psychiatric subcategories and 92% of the psychiatric diagnoses were significantly associated with IED, with HRs ranging from 2.1 (95% CI, 2.0-2.2) for substance use disorder to 76.6 (95% CI, 65.4-89.6) for disorders of adult personality and behavior (excluding IED). Among neurological conditions, neurodegenerative diseases (HR, 5.0; 95% CI, 4.1-6.1) and epilepsy (HR, 4.9; 95% CI, 4.3-5.6) had the highest HRs, followed by movement disorders (HR, 3.1; 95% CI, 2.8-3.5), cerebral palsy (HR, 2.6; 95% CI, 2.2-3.0), and sleep disorders (HR, 2.2; 95% CI, 2.1-2.3). Significant associations with IED were also observed for many somatic diseases, including obesity (HR, 1.6; 95% CI, 1.5-1.7), hyperlipidemia (HR, 1.5; 95% CI, 1.4-1.5), hypertension (HR, 1.6; 95% CI, 1.5-1.7), and gastroesophageal reflux disease (HR, 1.7; 95% CI, 1.7-1.9). Conclusion and Relevance These findings highlight the extensive comorbidities between IED and psychiatric, neurological, and somatic disorders, emphasizing the need for integrated diagnostic and treatment approaches addressing both psychological and physical health aspects of IED. Limitations related to reliance on medical records and low diagnostic rates of IED caution the generalizability of these findings, underscoring the need for further validation in prospective studies and more accurate, inclusive diagnosis of IED in patients with mental disorders.

Background: Long term anti epileptic drug (AED) therapy is required for epilepsy, a disorder of the nervous system, for which the sequelae might be associated with significant psychiatric problems. However, despite growing international awareness, there are few data from lower and lower-income countries such as Pakistan, where integrated neuropsychiatric screening is rarely practiced. The purpose of this study was to determine the prevalence and predictors of psychiatric morbidity in adult epilepsy patients on prolonged AED treatment. Methods: The study was conducted cross-sectionally at Ghurki Trust Teaching Hospital, Lahore, and Farooq Hospital, Lahore, Pakistan from November 2023 to October 2024 . Forty-five adult patients (≥ 18 years) with a proven diagnosis of epilepsy and on AED therapy for 12 months or more were enrolled. Hospital Anxiety and Depression Scale (HADS) and Mini International Neuropsychiatric Interview (MINI) were used to assess psychiatric symptoms. Demographic, clinical, pharmacologic, and biochemical data (serum B12, folate, and calcium) were recorded and analyzed in SPSS version 27.0 Results: 60% of patients had depression (HADS ≥8) and 48% anxiety. Major depressive disorder was diagnosed in 26%, generalized anxiety disorder in 18%, and psychotic symptoms in 6% by MINI-based diagnoses. A significantly greater psychiatric morbidity was found in patients on polytherapy than in those on monotherapy (p < 0.05). More commonly, polytherapy users had nutritional deficiencies. There was a significant correlation between longer AED duration and higher depression scores (p = 0.031, R² = 0.42). Conclusion: Adult epilepsy patients on long-term AEDs have a high prevalence of psychiatric morbidity, especially those on polytherapy and older agents. Improvement in neuropsychiatric outcomes in epilepsy care requires routine psychiatric screening and optimization of AED regimens.

BACKGROUND Observational studies have consistently indicated a significant correlation between abnormal cardiac conditions and epilepsy. However, the association and direction of this relationship remain a subject of debate. This study employs a two-sample bidirectional Mendelian randomization (MR) approach to investigate the association between abnormal cardiac conditions and epilepsy. METHODS Instrumental variables, represented by single nucleotide polymorphisms (SNPs) associated with epilepsy and various abnormal cardiac conditions, were derived from large-scale genome-wide association studies databases, including FinnGen and UK Biobank. Bidirectional MR analysis was conducted to estimate the association between epilepsy and abnormal cardiac conditions. Sensitivity analyses were performed using MR-Egger, weighted median, Inverse Variance Weighted, and MR pleiotropy residual sum and outlier methods. RESULTS The forward MR analysis suggested a potential positive effect of atrial fibrillation and flutter (AF) and valvular heart diseases (VHD) on the risk of epilepsy. Conversely, the reverse MR analysis indicated that epilepsy might increase the susceptibility to AF, VHD, and heart failure. CONCLUSION The findings support a bidirectional relationship between AF, VHD, and epilepsy, indicating that AF and VHD can elevate the risk of developing epilepsy, while epilepsy, in turn, can also increase the risk of developing AF and VHD. Furthermore, the study suggest that epilepsy may contribute to the development of heart failure. These results underscore the importance of screening for cardiac abnormalities in patients with epilepsy and vice versa, to better understand their clinical significance and potential as modifiable risk factors.

While a potential connection between epilepsy and frailty has been proposed in past research, the causal nature of this relationship requires additional study. This research was designed to evaluate the bidirectional causality between epilepsy and frailty index (FI) through two-sample Mendelian randomization (MR). In this study, we applied genome-wide association studies (GWAS) to perform forward and reverse MR within a two-sample context to explore the potential bidirectional causality between FI and epilepsy. The main analysis approach was the inverse variance weighted (IVW), used to assess the potential influence of causal relationships and to carry out sensitivity checks. MR analysis has revealed a positive correlation between FI and the heightened risk of epilepsy (ORIVW = 1.2126, 95% CI: 1.0143-1.4497, P = 0.0343). This correlation persists in MR analysis that excluded aberrant single nucleotide polymorphisms (SNPs)(ORIVW = 1.1862, 95% CI: 1.0236-1.3746, P = 0.0232). Reverse MR analysis corroborated a significant positive relationship between epilepsy and FI (ORIVW =1.0896, 95% CI: 1.0242-1.1592, P = 0.0066), which was confirmed in subsequent replication analysis (ORIVW =1.0975, 95% CI: 1.0532-1.1436, P = 9.69e-06). Sensitivity analysis further supported the hypothesis of a causal link between FI and epilepsy. There is an evident bidirectional causal relationship between FI and epilepsy.

Background/Objectives: Epilepsy and sleep disturbances frequently co-occur, yet the causal nature of this relationship remains uncertain, particularly in relation to epilepsy subtypes and status epilepticus. We investigated potential bidirectional causal associations between sleep-related traits and epilepsy, including subtypes and status epilepticus, using Mendelian randomization (MR). Methods: We conducted two-sample MR using genome-wide association study (GWAS) summary statistics from European ancestry cohorts. Epilepsy, its subtypes, and status epilepticus were analyzed using data from the International League Against Epilepsy Consortium on Complex Epilepsies (ILAE) and the FinnGen study. Nine self-reported sleep-related traits were derived from the UK Biobank-based GWAS. Causal estimates were primarily obtained using inverse variance weighted models with additional MR analysis methods. Pleiotropy and heterogeneity were assessed to enhance the robustness of the finding. Results: Several subtype-specific associations were identified, with direction and statistical significance varying across cohorts and subtypes. After correction for multiple testing and filtering for tests with ≥10 instrumental variables to ensure robust and reliable MR estimates, several consistent and potentially mutually reinforcing associations emerged. In the ILAE cohort, focal epilepsy with hippocampal sclerosis was associated with an increased risk of insomnia, and juvenile myoclonic epilepsy with reduced sleep duration. In the FinnGen cohort, overall epilepsy was associated with increased risk of both insomnia and daytime sleepiness. In reverse MR, daytime sleepiness and napping were associated with increased risk of epilepsy, while daytime napping and frequent insomnia symptoms were linked to elevated risk of status epilepticus. Conclusions: Our findings reveal subtype-specific and bidirectional causal links between epilepsy and sleep-related traits. These results highlight the biological interplay between epileptic networks and sleep regulation and underscore the need for further clinical and mechanistic studies.

BACKGROUND Epilepsy is frequently accompanied by psychiatric disorders in observational studies, but the causal direction and subtype-specific associations remain unclear. OBJECTIVE To examine causal relationships between 10 epilepsy subtypes and 17 psychiatric disorders using a bidirectional two-sample Mendelian randomization (MR) analysis. METHODS Genetic instruments were derived from large-scale genome-wide association studies (GWAS) of epilepsy and psychiatric traits. The inverse variance weighted (IVW) method was the primary approach, complemented by sensitivity analyses including maximum likelihood, MR-Egger regression, weighted median, weighted mode, and IVW under a fixed effect. RESULTS Epilepsy subtypes exerted heterogeneous effects on psychiatric risk. Focal epilepsy increased the risk of anorexia nervosa, major depressive disorder, and obsessive-compulsive disorder, whereas juvenile absence epilepsy reduced the risk of schizophrenia and other phobias. In contrast, focal epilepsy with hippocampal sclerosis increased risk of attention deficit hyperactivity disorder (ADHD) but reduced risk of suicide attempt. Conversely, psychiatric traits also influenced epilepsy risk. ADHD increased susceptibility to overall epilepsy, generalized epilepsy, and juvenile absence epilepsy, while obsessive-compulsive disorder reduced risk of childhood absence epilepsy but increased risk of juvenile myoclonic epilepsy. Most findings were consistent across sensitivity analyses without evidence of pleiotropy. CONCLUSIONS This comprehensive bidirectional MR analysis demonstrates that epilepsy and psychiatric disorders are linked by complex and subtype-specific causal pathways, highlighting shared neurobiological mechanisms and underscoring the need for integrated neuropsychiatric care. Identifying these causal relationships provides a foundation for precision medicine approaches in the prevention and management of comorbid epilepsy and psychiatric disorders.

Epidemiological data indicates that individuals with epilepsy exhibit an elevated susceptibility to autoimmune disorders, and conversely, those with systemic autoimmune diseases (SAD) demonstrate a heightened predisposition to epilepsy. Although an increasing number of publications support this association, the causal direction remains undetermined. This investigation offers evidence supporting a causal relationship between these conditions through a bidirectional two‐sample Mendelian randomization (MR) analysis.

Purpose Sleep traits are suggested as risk factors for epilepsy, yet the extent of their shared biological basis and the causal direction between these traits are not well understood. Our goal was to assess the associations and establish causal relationships between sleep traits and epilepsy through Mendelian randomization (MR) analyses. Materials and Methods Univariate and multivariate bidirectional MR analyses were used to assess the causal association between sleep traits and epilepsy. In this study, exposure factors of seven sleep traits and outcome variables related to epilepsy were obtained from the published Genome-Wide Association Study (GWAS). The major analysis utilized for MR was inverse-variance weighted. Results Univariable MR analysis indicated that both insomnia and chronotype were positively associated with the risk of generalized epilepsy (GE) [odds ratio (OR)=3.436, 95% confidence interval (CI): 1.081–10.919, p=0.036; OR=1.645, 95% CI: 1.054–2.566, p=0.028]. Additionally, a positive association was found between focal epilepsy (FE) and the risk of daytime napping (OR=1.003, 95% CI: 1.001–1.006, p=0.011). Multivariable MR analysis demonstrated that insomnia was causally and positively linked to GE (OR=5.214, 95% CI: 1.384–19.639, p=0.015). However, after adjusting for other sleep traits and potential confounders, chronotype was found to have no causal effect on GE. Similarly, no causal relationship was found from FE to daytime napping when adjusted for potential confounders. Conclusion Our results suggest a shared genetic foundation between sleep traits and epilepsy, indicating potential causal effect of insomnia on GE risk. Interventions targeting sleep disturbances could serve as therapeutic approaches in epilepsy management.

OBJECTIVE Numerous observational research reports have consistently demonstrated a significant association between migraines and epilepsy, but it remains uncertain whether a causal relationship exists between these two diseases. This study aims to explore the potential causal relationship between epilepsy and migraine through a two-sample bidirectional Mendelian randomization (MR) analysis. METHODS A two-sample bidirectional MR analysis was conducted using the data from the genome-wide association studies (GWAS) of epilepsy and migraine in the European population. The primary analytical approach was the inverse variance weighted (IVW) method, with additional MR methods, including MR-Egger and weighted median, employed for complementary analysis. Comprehensive sensitivity analyses were also performed to assess the robustness of the results. RESULTS The MR analysis showed no evidence of a causal relationship between epilepsy and migraine (P > 0.05) in either the forward or reverse analysis. Sensitivity analyses validated the reliability of the results. SIGNIFICANCE No evidence of a genetic causal relationship between migraine and epilepsy was identified. However, the mechanisms underlying the observed association between the two diseases in observational studies warrant further investigation.

Abstract Dysmenorrhea is associated with epilepsy. Existing evidence is mostly limited to observational studies, which are liable to confounding and bias. This study investigated the causal relevance of dysmenorrhea on epilepsy using Mendelian randomization (MR). We extracted instrumental variants for dysmenorrhea and epilepsy from published genomewide association study data, focusing on individuals of East Asian descent. A comprehensive suite of MR estimations and sensitivity analyses was performed to ensure the robustness of the findings. Each outcome database was analyzed separately in both directions. For dysmenorrhea and epilepsy, 7 and 3 genetic variants respectively were selectively extracted as instrumental variants. The results suggest that dysmenorrhea is causally associated with an elevated risk of epilepsy (inverse variance weighted [IVW]: OR = 1.26; 95% CI [1.07, 1.47]; p = 4.42 × 10−3); conversely, no strong evidence was found to corroborate that epilepsy exerts a causal effect on the incidence of dysmenorrhea (IVW: OR = 1.04; 95% CI [0.82, 1.33]; p = .72). These findings provide novel insights into the causal relationship between dysmenorrhea and epilepsy, which may have implications for clinical decision-making in patients with epilepsy and dysmenorrhea.

BACKGROUND Neuroinflammation plays an important pathophysiological role in epilepsy; however, the precise connection between immune cells and epilepsy remains unclear. This study used Mendelian randomization (MR) to analyze the causal relationship between 731 immune cell traits and epilepsy. METHODS Based on data from a genome-wide association study (GWAS), a bidirectional two-sample MR analysis was conducted to investigate the potential influence of immune cell phenotypes on epilepsy. Five MR methods were used to analyze the results, with the inverse variance weighted (IVW) method as the primary method, and the results were corrected using the false discovery rate (FDR) method. Sensitivity analyses were performed to test for heterogeneity and horizontal pleiotropy. RESULTS After correction for FDR, four immune traits remained significantly associated with epilepsy risk: CD25 expression on memory (OR = 1.04, 95 % CI = 1.02 ∼ 1.06,P = 2.55 × 10-4), IgD+CD38dim (OR = 1.05, 95 % CI = 1.02 ∼ 1.08, P = 4.73 × 10-4), CD24+CD27+ (OR = 1.04, 95 % CI = 1.02 ∼ 1.06, P = 4.82 × 10-4), and IgD-CD38dim (OR = 1.04, 95 % CI = 1.02 ∼ 1.06, P = 1.04 × 10-3) B cells. The risk of generalized epilepsy was significantly associated with two immune cell traits, whereas that of focal epilepsy was significantly associated with seven immune cell traits. Furthermore, immune cell phenotypes are not affected by genetically predicted epilepsy. CONCLUSION This MR study affirms the causal connection between circulating immune cells and epilepsy, offering guidance for further understanding of the immune mechanisms that underlie epilepsy and the discovery of novel targets for therapy.

Studies on the association between oxidative stress and epilepsy have yielded varied results. In this study, we aimed to investigate the causal relationship between oxidative stress markers and epilepsy. A bidirectional two-sample Mendelian randomization (MR) study was performed based on publicly available statistics from genome-wide association studies. To explore the causal effects, single nucleotide polymorphisms were selected as instrumental variables. Inverse-variance weighted method was performed for primary analysis, supplemented by weighted median, MR-Egger, simple mode, and weighted mode. Furthermore, sensitivity analyses were performed to detect heterogeneity and pleiotropy. Our results showed that part of the oxidative stress biomarkers are associated with epilepsy and its subtypes. Zinc is associated with increased risk of epilepsy and generalized epilepsy (odds ratio [OR] = 1.064 and 1.125, respectively). Glutathione transferase is associated with increased risk of generalized epilepsy (OR = 1.055), while albumin is associated with decreased risk of generalized epilepsy (OR = 0.723). Inverse MR analysis revealed that epilepsy is associated with increased levels of uric acid and total bilirubin (beta = 1.266 and 0.081, respectively), as well as decreased zinc level (beta =  − 0.278). Furthermore, generalized epilepsy is associated with decreased ascorbate and retinol levels (beta =  − 0.029 and − 0.038, respectively). Our study presented novel evidence of potential causal relationships between oxidative stress and epilepsy, suggesting potential therapeutic targets for epilepsy.

Background Although previous studies have reported a bidirectional relationship between ischemic stroke (IS) and epilepsy, the existence of a causal nexus and its directionality remains a topic of controversy. Methods The single nucleotide polymorphisms (SNPs) associated with IS were extracted from the Genome-Wide Association Study (GWAS) database. Pooled genetic data encompassing all epilepsy cases, as well as generalized and focal epilepsy subtypes, were acquired from the International League Against Epilepsy's GWAS study. In this study, the primary analysis approach utilized the inverse variance weighting (IVW) method as the main analytical technique. To enhance the robustness of the findings against potential pleiotropy, additional sensitivity analyses were conducted. Results In the forward analysis, the IVW method demonstrated that IS was associated with an increased risk of all epilepsy (odds ratio (OR) = 1.127, 95 % confidence interval (CI) = 1.038–1.224, P = 0.004) and generalized epilepsy (IVW: OR = 1.340, 95 % CI = 1.162–1.546, P = 5.70 × 10–5). There was no substantial causal relationship observed between IS and focal epilepsy (P > 0.05). Furthermore, generalized epilepsy, focal epilepsy, and all epilepsy did not show a causal relationship with IS. Conclusion This Mendelian randomization (MR) analysis demonstrates that IS increases the risk of developing epilepsy, especially generalized epilepsy. Conversely, no clear causal association was found between epilepsy and the onset of stroke. Therefore, the possible mechanisms of the effect of epilepsy on the pathogenesis of IS still need to be further investigated.

Background: The precise involvement of metabolites in the pathogenesis of Childhood absence epilepsy (CAE) and juvenile absence epilepsy (JAE) remains elusive. Consequently, this investigation introduces bidirectional Mendelian randomization (MR) as a tool to explore causality and underlying mechanisms. Methods: Bidirectional MR analysis was conducted employing a comprehensive set comprising 1091 human blood metabolites and 309 metabolite ratios, systematically probing potential causal associations with JAE and CAE. Genome-wide association study (GWAS) data pertaining to these epileptic conditions were meticulously obtained from the International League Against Epilepsy (ILAE) consortium. Sensitivity analyses were rigorously performed to evaluate for heterogeneity and pleiotropy. Reverse MR analysis was also conducted to verify the direction of causality, and no significant reverse causal relationships were identified. Results: Following rigorous genetic variant selection, significant associations were identified based on PIVW < .05, PWM < .05, and PMR–Egger < .05 criteria in MR analysis. Only 1 metabolite, (2 or 3)-decaonate levels, exhibited an association with JAE (P = .005, OR = 0.987, 95% CI = 0.978-0.996). Childhood absence epilepsy was associated with 5 metabolites: X-23648 (P = .012, OR = 0.982, 95% CI = 0.968-0.996), X-21845 levels (P = .045, OR = 1.018, 95% CI = 1.001-1.035), 2’-o-methylcytidine (P = .008, OR = 0.995, 95% CI = 0.991-1.001), 2’-o-methyluridine (P = .007, OR = 0.995, 95% CI = 0.99-0.999), and spermidine-to-pyruvate ratio (P = .014, OR = 0.973, 95% CI = 0.954-0.992). No evidence of reverse causality was found between JAE and CAE and the aforementioned metabolites. Conclusion: The study establishes causal relationships between the aforementioned 6 metabolites and CAE and JAE. This integration of genomics with metabolism offers novel insights into epilepsy mechanisms and has important implications for screening and prevention.

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Previous studies have found that patients with epilepsy are more likely to suffer impulsivity. However, the causal relationship between impulsivity and epilepsy is unknown. In this study, we conduct a bidirectional Mendelian randomization (MR) study to explore the causal relationship between impulsivity and epilepsy with recurrent seizure. Data of the genome-wide association studies (GWAS) on 14 impulsivity traits and epilepsy were obtained from the GWAS catalog and UK Biobank. Inverse-variance weighted (IVW) and weighted median (WM) methods were utilized for MR estimates. IVW, MR-Egger regression, and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods were used to assess heterogeneity and pleiotropy. Single-nucleotide polymorphisms (SNPs) related to the lack of perseverance were associated with a decreased risk of epilepsy with recurrent seizures according to the results of IVW (odd ratio [OR] = 0.93, 95% confident interval [CI] = 0.90–0.97, P = 0.001) and WM (OR = 0.93, 95%CI = 0.87–0.98, P = 0.007). Meanwhile, heterogeneity was not observed with a Cochran Q-derived P value of 0.819 for MR egger and a P value of 0.808 for IVW. Pleiotropy was not found according to the MR-PRESSO (P = 0.273). The other 13 impulsivity traits had no causal effect on epilepsy with recurrent seizures. Meanwhile, SNPs related with epilepsy with recurrent seizures had no causal effect on the 14 impulsivity traits. This MR study suggests that lack of perseverance may be a protective factor against epilepsy with recurrent seizures. However, epilepsy with recurrent seizures does not affect impulsivity.

STUDY OBJECTIVES Psychiatric comorbidities are relatively common among patients with epilepsy; however, the underlying mechanisms of this association remain largely unknown. The objective of this Mendelian randomization (MR) study was to analyze the genetic correlations and causality underlying these reciprocal associations. METHODS Single-nucleotide polymorphisms associated with epilepsy (29,677 controls and 15,212 cases) and seven psychiatric comorbidities (485,436 controls and 269,495 cases) were identified from genome-wide association studies. Causal significance was estimated using inverse variance weighting. Sensitivity analyses included the weighted median, MR-Egger, and MR-PRESSO. The psychiatric comorbidities analyzed in this study included attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder (OCD), and anorexia nervosa. RESULTS Both forward and reverse genetic associations were observed for the selected psychiatric disorders. Notably, ADHD was significantly associated with an increased risk of generalized epilepsy (odds ratio [OR], 1.09; 95 % confidence interval [CI], 1.01-1.18; p = 0.013). However, MR-PRESSO detected the existence of pleiotropy (p = 0.001). Additionally, focal epilepsy was significantly associated with a higher risk of OCD (OR, 1.44; 95 % CI, 1.08-1.92; p = 0.013), and all sensitivity tests yielded favorably nonsignificant results. There was no significant genetic association between epilepsy and other examined psychiatric disorders. However, due to the detection of pleiotropy by MR-Egger and considerations related to the threshold for genetic instruments, a cautious approach is warranted in interpreting some of the results. CONCLUSIONS This study revealed significant genetic causality between focal epilepsy and OCD, as well as between ADHD and generalized epilepsy. However, no casual significance was observed with other psychiatric comorbidities examined. Considering the inherent limitations of MR studies, further research is warranted to definitively clarify these genetic causal associations.

Epidemiological research has shown that a variety of circulating bioactive factors are associated with epilepsy, including macrophage colony-stimulating factor, interleukin-1β, and tumor necrosis factor-α. To further investigate the associations between epilepsy and 41 inflammatory cytokines, this Mendelian randomization was performed. This study presents genome-wide association study summary data on 41 inflammatory cytokines and epilepsy. Epilepsy incorporates generalized and focal epilepsy. A two-sample Mendelian randomization method was used. In order to analyze causal relationships between exposures and outcomes, the inverse variance-weighted method was mainly used. The findings suggested that increased levels of interleukin-1 receptor antagonists and interleukin-5 may be significantly associated with increased risks of focal epilepsy (beta: 0.080, P = .043; beta: 0.083, P = .015). In addition, regulated upon activation normal T cell expressed and secreted factor and Macrophage colony-stimulating factor may be significantly associated with generalized epilepsy (beta: 0.110, P = .042; beta: –0.114, P = .024). Furthermore, inflammatory cytokines such as interleukin-10, interleukin-1β, interleukin-1Ra, interleukin-7, tumor necrosis factor-α, and interferon-γ may be identified as the result of focal epilepsy (beta: 0.152, P = .031; beta: 0.214, P = .037; beta: 0.214, P = .047; beta: 0.222, P = .031; beta: 0.224, P = .025; beta: 0.161, P = .018). This study suggests that interleukin-5 and interleukin-1 receptor antagonists are potentially correlated factors with focal epilepsy etiology, macrophage colony-stimulating factor and regulated upon activation normal T cell expressed and secreted factor are potentially correlated factors with generalized epilepsy etiology, while several inflammatory cytokines possibly contribute to focal epilepsy development downstream.

BACKGROUND Inflammation plays a role in the development and advancement of epilepsy, but the relationship between inflammatory cytokines and epilepsy is still not well understood. Herein, we use two-sample Mendelian randomization (MR) to examine the causal association between systemic inflammatory cytokines and epilepsy. METHODS We conducted a bidirectional two-sample MR analysis based on genome-wide association study data of 41 serum cytokines from 8293 Finnish individuals with various epilepsy subtypes from the International League against Epilepsy Consortium. RESULTS Our study showed that three inflammatory cytokines were associated with epilepsy, five were associated with generalized epilepsy, four were associated with focal epilepsy, one was associated with focal epilepsy-documented lesion negative, three were associated with juvenile absence epilepsy, one was associated with childhood absence epilepsy, two were associated with focal epilepsy-documented lesion other than hippocampal sclerosis, and two were associated with juvenile myoclonic epilepsy. Furthermore, the expression of systemic inflammatory cytokines was unaffected by genetically predicted epilepsy. CONCLUSION This study suggested that several inflammatory cytokines are probably the factors correlated with epilepsy. Additional research is required to ascertain if these biomarkers have therapeutic potential to prevent or manage epilepsy.

Background Generalized convulsive epilepsy (GCE), an important subtype of epilepsy, is a syndrome of neuronal dysfunction characterized by diffuse abnormal discharge of neurons within the brain. Compounding evidence suggests a correlation between epilepsy and inflammatory factors, for instance, cyclooxygenase-2, interleukin-1β, and interleukin-6. Elevated levels of inflammatory factors have been observed in patients with epilepsy and several animal models. Therefore, inflammation may be closely associated with the pathogenesis and progression of GCE. However, the cause-and-effect relationship between the two is difficult to determine because of small sample sizes and confounding factors. Methods To test for causality of the 41 cytokines on GCE, we conducted a two-sample Mendelian randomization (MR) based on the largest and latest genome-wide association study (GWAS) involving 290 cases and 453,521 European controls and a GWAS meta-analysis consisting of 41 cytokines from 8,293 individuals. Results R confirmed a bidirectional causal link between cytokines and GCE. Genetically predicted increased levels of hepatocyte growth factor and decreased levels of eotaxin and interleukin-18 are associated with an increased risk of GCE (OR = 1.904, 95% CI = 1.019–3.561, p = 0.044; OR = 0.641, 95% CI = 0.417–0.984, p = 0.042; OR = 0.482, 95% CI = 0.251–0.927, p = 0.046). Furthermore, the presence of GCE is related to an increase in levels of multiple cytokines, such as macrophage inflammatory protein-1α, interleukin-12p70, interleukin-17, interleukin-1 receptor antagonist, and basic fibroblast growth factor (OR = 1.038, 95% CI = 1.005–1.073, p = 0.024; OR = 1.031, 95% CI = 1.009–1.054, p = 0.006; OR = 1.027, 95% CI = 1.002–1.053, p = 0.037; OR = 1.037, 95% CI = 1.003–1.072, p = 0.032; OR = 1.032, 95% CI = 1.000–1.066, p = 0.048; OR = 1.025, 95% CI = 1.003–1.048, p = 0026). Conclusion A bidirectional causal link existed between inflammation and GCE. Detecting significantly altered factor concentrations may be of great significance for screening GCE and predicting their occurrence. Moreover, available pharmacological treatments for GCE are focused primarily on suppressing seizures. In future, altering the concentration of these cytokines in the body through targeted anti-inflammatory therapy to modify the epileptogenic mechanism and prevent the recurrence and refractoriness of GCE may become the key to new treatments.

Background: There is a complex, bidirectional relationship between Alzheimer's disease (AD) and epilepsy. However, the causality of this association is unclear, as confounders play a role in this association.

Directionality of the Association Between Epilepsy and Depression: A Nationwide Register-Based Cohort Study Bølling-Ladegaard E, Dreier JW, Kessing LV, Budtz-Jørgensen E, Lolk K, Christensen J. Neurology. 2023;100(9):e932-e942. doi:10.1212/WNL.0000000000201542. Epub 2022 Nov 22. Background and objectives: Epilepsy and depression share a bidirectional relationship; however, its magnitude and long-term temporal association remain to be elucidated. This study investigates the magnitude and long-term association between epilepsy and depression, comparing with the risks of the 2 disorders after another chronic medical illness (asthma). Methods: In a nationwide register-based matched cohort study, we identified all individuals who received a first diagnosis of epilepsy, depression, and asthma from January 1, 1980, to December 31, 2016. We used a Cox regression model to estimate the risk of epilepsy after depression and vice versa and the risk of epilepsy or depression after asthma, compared with healthy references matched on age and sex, adjusting for medical comorbidity, substance abuse, and calendar time. Results were stratified by epilepsy subtype. We furthermore investigated the risk of admission with acute seizures for persons with epilepsy who became depressed. Results: In a population of 8,741,955 individuals, we identified 139,014 persons with epilepsy (54% males, median age at diagnosis 43 years [inter quartile range (IQR) 17-65 years]), 219,990 persons with depression (37% males, median age at diagnosis 43 years [IQR 29-60 years]), and 358,821 persons with asthma (49% males, median age at diagnosis 29 years [IQR 6-56 years]). The adjusted hazard ratio (aHR) of depression after epilepsy was 1.88 (95% CI 1.82-1.95), and the aHR of epilepsy after depression was 2.35 (95% CI 2.25-2.44). The aHR of depression after asthma was 1.63 (95% CI 1.59-1.67) and that of epilepsy after asthma, 1.48 (95% CI 1.44-1.53). The risk of depression was highest in the few years preceding and after an epilepsy diagnosis, and vice versa, but remained elevated during the entire follow-up period for both directions of the association. There was no evidence of a stronger association with depression for any epilepsy subtype. Receiving a diagnosis of depression subsequent to an epilepsy diagnosis was associated with a 1.20-fold (95% CI 1.07-1.36) increased HR of acute hospital admission with seizures. Discussion: We identified a long-term bidirectional relationship between depression and epilepsy in a large-scale cohort study. Risk estimates were higher than those of epilepsy or depression after asthma.

BACKGROUND The "epileptic heart" concept is emerging, but the causal relationship between epilepsy and atrial fibrillation (AF) remains unclarified. OBJECTIVE This study explores the genetic correlations and bidirectional causality between various epilepsy phenotypes and AF. METHODS Genome-wide association study (GWAS) statistics for 10 epilepsy subtypes (29,944 cases, 52,538 controls) and AF (60,620 cases, 970,216 controls) were sourced from the International League Against Epilepsy (ILAE) and HGRI-EBI Catalog-GWAS, respectively. Linkage disequilibrium score regression (LDSC) and genome-wide Mendelian Randomization (MR) evaluated genetic correlations and bidirectional causal relationships. Epilepsy-related DNA methylation data (N= ∼800) from EWAS catalog were analyzed to identify causal CpG sites influencing AF risk through epigenetic MR. RESULTS LDSC revealed significant genetic correlations between four epilepsy subtypes and AF (rg from 0.116 to 0.241). Forward MR suggested a significant causal effect of focal epilepsy with hippocampal sclerosis (FE with HS) on AF risk (IVW and MR-PRESSO: OR = 1.046, P ≤ 0.004), with results robust against heterogeneity, horizontal pleiotropy, and outliers. Epigenetic MR indicated that lower methylation at cg06222062 (OR = 0.994, P = 3.16E-04) mapped to PLA2G5 and cg08461451 mapped to SPPL2B gene (OR = 0.954, P = 1.19E-03), and higher cg10541930 in the C10orf143 promoter (OR = 1.043, P = 4.18E-22) increases AF risk. Sensitivity analyses affirmed no pleiotropic bias. CONCLUSION FE with HS significantly increases AF risk, highlighting the natural neural-cardiac connection and the need for cardiac monitoring in epilepsy patients. Specific methylated CpG sites may serve as biomarkers and preventive targets for AF susceptibility.

Affective disorders are frequent comorbidities of temporal lobe epilepsy (TLE). The endogenous opioid system has been implicated in both epilepsy and affective disorders, and may play a significant role in their bidirectional relationship. In this cross‐sectional study, we investigated the association between μ‐opioid receptor binding and affective disorders in patients with TLE.

Background Observational studies suggested a bidirectional relationship between severe autoimmune type 2 diabetes and focal epilepsy. However, it remains debated whether and in which direction a causal association exists. This genetics-based study aimed to explore the relationships of severe autoimmune type 2 diabetes (T2DM) and focal epilepsy outcomes with two sample Mendelian randomization (TSMR) method. Methods Genetic instruments were obtained from large-scale genome-wide meta-analysis of severe autoimmune T2DM (Ncase = 452, Ncontrol = 2,744), and focal epilepsy (Ncase = 929, Ncontrol = 212,532) of European ancestry. A series of analyses were performed to select eligible genetic instruments robustly associated with each of the traits using summary-level statistics. Inverse variance weighted was used for primary analysis, with alternative 11 MR methods. A scatter plot was utilized to illustrate the association between single nucleotide polymorphism (SNP) effects on the exposure and SNP effects on the outcome. The Wald ratio for individual SNPs and their cumulative effects was depicted using a forest plot. And diagnostics and sensitivity analyses were used to evaluate if the causal estimates are robust to violations of MR underlying assumptions, including pleiotropy, heterogeneity assessment, and leave-one-out analysis. Then the results were validated using CURATED database of DisGeNET platform. Results For forward analysis, genetic predisposition to severe autoimmune T2DM was associated with an increased risk of focal epilepsy (Inverse variance weighted (IVW) method: OR = 1.11, 95% CI = 1.03-1.18, p = 0.012). For reverse analysis, there was no enough instrument variables of focal epilepsy on severe autoimmune T2DM. Further, the interrelation between severe autoimmune T2DM and focal epilepsy was demonstrated via variant-disease association network analysis using the instrument SNPs. Discussion This MR study supports a causal link between severe autoimmune T2DM and focal epilepsy. More effort should be made to screen seizure in severe autoimmune T2DM, unravel its clinical implications, and explore its role as a putative modifiable risk factor.

BACKGROUND Observational studies suggest that hypertension and epilepsy have a high co-occurrence, and antihypertensive medications may have impacts on the prevention and treatment of epilepsy. However, the directionality of causation between them is elusive. METHOD By leveraging genome-wide association studies (GWAS) summary data of each trait, we firstly performed bidirectional univariate Mendelian randomization (UVMR) to assess the strength and direction of the associations between pairs of traits, then multivariate MR (MVMR) was conducted to adjust for potential confounders in causalities. Cochran's Q statistics, leave-one-out analysis, MR-Egger regression and MR-Pleiotropy Residual Sum and Outlier methods (MR-PRESSO) were employed to evaluate the robustness of the results. Drug target MR was proceeded to assess the association between five classes of first-line antihypertensive medications and epilepsy. Specifically, single nucleotide polymorphisms (SNPs) extracted from GWAS data on systolic blood pressure (SBP)/diastolic blood pressure (DBP), along with expression quantitative trait loci (eQTL) were utilized as proxies for antihypertensive medications, respectively. RESULTS Forward UVMR results provided evidence that genetically predicted blood pressure traits and hypertension have causal effects on epilepsy, while reverse UVMR indicated no causal impacts of epilepsy on blood pressure traits or hypertension. The sensitivity analysis results were robust. The causalities between DBP, hypertension and epilepsy remained remarkable after adjustment by MVMR. Inverse-variance-weighted MR (IVW-MR) yielded evidence of positive association only between Beta-Blockers target genes based on DBP GWAS screening and epilepsy. Summary-data-based MR (SMR) identified a positive correlation between Beta-Blockers target gene ADRA1D and epilepsy risk. CONCLUSIONS Hypertension has a causal effect on epilepsy and managing DBP in patients with hypertension through Beta-Blockers may help prevent epilepsy.

BACKGROUND Branched-chain amino acids (BCAAs) have been affected epilepsy, yet conclusions remain inconclusive, lacking causal evidence regarding whether BCAAs affect epilepsy. Systematic exploration of the causal relationship between BCAAs and epilepsy could hand out new ideas for the treatment of epilepsy. METHODS Utilizing bidirectional Mendelian randomization (MR) study, we investigated the causal relationship between BCAA levels and epilepsy. BCAA levels from genome-wide association studies (GWAS), including total BCAAs, leucine levels, isoleucine levels, and valine levels, were employed. Causal relationships were explored applying the method of inverse variance-weighted (IVW) and MR-Egger, followed by sensitivity analyses of the results to evaluate heterogeneity and pleiotropy. RESULTS Through strict genetic variant selection, we find some related SNPs, total BCAA levels (9), leucine levels (11), isoleucine levels (7), and valine levels (6) as instrumental variables for our MR analysis. Following IVW and sensitivity analysis, total BCAAs levels (OR = 1.14, 95 % CI = 1.019 ∼ 1.285, P = 0.022) and leucine levels (OR = 1.15, 95 % CI = 1.018 ∼ 1.304, P = 0.025) had significant correlation with epilepsy. CONCLUSIONS There exists a causal relationship between the levels of total BCAAs and leucine with epilepsy, offering the new ideas into epilepsy potential mechanisms, holding significant implications for its prevention and treatment.

The Bi-Directional Association Between Epilepsy and Dementia. The Framingham Heart Study Stefanidou M, Beiser AS, Himali JJ, et al. Neurology. 2020. doi:10.1212/WNL.0000000000011077. Objectives: To assess the risk of incident epilepsy among participants with prevalent dementia, and the risk of incident dementia among participants with prevalent epilepsy in the Framingham Heart Study (FHS). Methods: We analyzed prospectively collected data in the Original and Offspring FHS cohorts. To determine the risk of developing epilepsy among participants with dementia and the risk of developing dementia among participants with epilepsy we used separate, nested, case–control designs, and matched each case to 3 age-, sex-, and FHS cohort-matched controls. We used Cox proportional hazards regression analysis, adjusting for sex and age. In secondary analysis, we investigated the role of education level and apolipoprotein ε4 allele status in modifying the association between epilepsy and dementia. Results: A total of 4906 participants had information on epilepsy and dementia and dementia follow-up after age 65. Among 660 participants with dementia and 1980 dementia-free controls there were 58 incident epilepsy cases during follow-up. Analysis comparing epilepsy risk among dementia cases versus controls yielded (hazards ratio [HR] = 1.82 [95% CI:1.05-3.16], P = .034). Among 43 participants with epilepsy and 129 epilepsy-free controls, there were 51 incident dementia cases. Analysis comparing dementia risk among epilepsy cases versus controls yielded (HR = 1.99 [1.11-3.57], P = .021). In this group, among participants with any post-high school education, prevalent epilepsy was associated with a nearly 5-fold risk for developing dementia (HR = 4.67 [1.82-12.01], P = .001) compared to controls of the same educational attainment. Conclusions: There is a bidirectional association between epilepsy and dementia with either condition carrying a nearly 2-fold risk of developing the other when compared with controls. Dementia in Late Onset Epilepsy: The Atherosclerosis Risk in Communities Study Johnson EL, Krauss GL, Kucharska-Newton A, et al. Neurology. 2020. Objective: To determine the risk of dementia after the development of late-onset epilepsy (LOE). Methods: We used data from the Atherosclerosis Risk in Communities (ARIC) cohort study, which started in 1987 to 1989 with 15 792 mostly black and white men and women from 4 US communities. We identified LOE (seizures starting at age 67 or later) from linked Medicare claims data. We used a Cox proportional hazards regression model to evaluate associations between LOE and dementia through 2017 as ascertained from neuropsychological testing, interviews, and hospital discharge surveillance; and we used multinomial logistic regression to assess the risk of dementia and mild cognitive impairment in the subset with full neuropsychological assessments available. We adjusted for demographics, and vascular and Alzheimer disease risk factors. Results: Of 9033 ARIC participants with sufficient Medicare coverage data (4980 [55.1%] female, 1993 [22.1%] black), 671 met the definition of LOE. 279 (41.6%) participants with LOE and 1408 (16.8%) without LOE developed dementia (P < .001). After a diagnosis of LOE, the adjusted hazard ratio for developing subsequent dementia was 3.05 (95% CI: 2.65-3.51). The median time to dementia ascertainment after the onset of LOE was 3.66 years (Q1-Q3 1.28-8.28 years). Interpretation: The risk of incident dementia is substantially elevated in individuals with LOE. Further work is needed to explore causes for the increased risk of dementia in this growing population.

Background and Objectives Epilepsy and depression share a bidirectional relationship; however, its magnitude and long-term temporal association remain to be elucidated. This study investigates the magnitude and long-term association between epilepsy and depression, comparing with the risks of the 2 disorders after another chronic medical illness (asthma). Methods In a nationwide register-based matched cohort study, we identified all individuals who received a first diagnosis of epilepsy, depression, and asthma from January 1, 1980, to December 31, 2016. We used a Cox regression model to estimate the risk of epilepsy after depression and vice versa and the risk of epilepsy or depression after asthma, compared with healthy references matched on age and sex, adjusting for medical comorbidity, substance abuse, and calendar time. Results were stratified by epilepsy subtype. We furthermore investigated the risk of admission with acute seizures for persons with epilepsy who became depressed. Results In a population of 8,741,955 individuals, we identified 139,014 persons with epilepsy (54% males, median age at diagnosis 43 years [inter quartile range (IQR) 17–65 years]), 219,990 persons with depression (37% males, median age at diagnosis 43 years [IQR 29–60 years]), and 358,821 persons with asthma (49% males, median age at diagnosis 29 years [IQR 6–56 years]). The adjusted hazard ratio (aHR) of depression after epilepsy was 1.88 (95% CI 1.82–1.95), and the aHR of epilepsy after depression was 2.35 (95% CI 2.25–2.44). The aHR of depression after asthma was 1.63 (95% CI 1.59–1.67) and that of epilepsy after asthma, 1.48 (95% CI 1.44–1.53). The risk of depression was highest in the few years preceding and after an epilepsy diagnosis, and vice versa, but remained elevated during the entire follow-up period for both directions of the association. There was no evidence of a stronger association with depression for any epilepsy subtype. Receiving a diagnosis of depression subsequent to an epilepsy diagnosis was associated with a 1.20-fold (95% CI 1.07–1.36) increased HR of acute hospital admission with seizures. Discussion We identified a long-term bidirectional relationship between depression and epilepsy in a large-scale cohort study. Risk estimates were higher than those of epilepsy or depression after asthma.

Background: Alterations of brain connectivity within resting-state networks (RSNs) have been widely reported in observational studies on epilepsy. However, the causal relationship between epilepsy and structural connectivity (SC)/functional connectivity (FC) within RSNs remain unclear. We conducted a bidirectional two-sample Mendelian randomization (MR) to explore the causal relationship between epilepsy subtypes and brain connectivity properties within RSNs. Methods: Genetic instruments were obtained from the latest genome-wide association studies (GWAS) of 69,995 individuals (Ncases = 27,559, Ncontrols = 42,436) issued by the International League Against Epilepsy. The GWAS summary SC/FC data within RSNs (NSC = 23,985, NFC = 24,336) were sourced from the Center for Neurogenomics and Cognitive Research. We investigate the causal relationship between epilepsy subtypes and brain connectivity within RSNs through a bidirectional two-sample MR analysis. Results: We found that the increased risk of generalized genetic epilepsy is consistent with a causal effect on dorsal attention and somatomotor FC. In the reverse MR analysis, there was no suggestive causal effect of FC/SC connectivity on epilepsy subtypes. Conclusions: This study shed light on the associations of FC/SC levels within the RSNs and epilepsy along with its subtypes. This insight could yield crucial intervention strategies to different subtypes of epilepsy at the level of brain structure and functional networks.

Background Increased glial fibrillary acidic protein (GFAP) in blood, a biomarker of reactive astrogliosis and astrocytic injury, was observed in a variety of neurological disorders. However, the causal relationship between plasma GFAP and neurological disorders remains unclear. Objective We aim to investigate causal association between plasma GFAP levels and neurological disorders using bidirectional Mendelian randomization (MR). Methods The genome-wide association studies for neurological disorders, including neurodegenerative diseases, neuroimmune disorders, cerebrovascular diseases, and epilepsy, were collected. Genetic variables associated with plasma GFAP levels were obtained from the UK Biobank Pharma Proteomics Project. Inverse variance weighted or Wald ratio method was used as the main analysis to assess the causal association. Results Genetically predicted higher plasma GFAP levels were found to be associated with an increased risk of encephalitis (odds ratio [OR] = 2.52; 95% confidence interval [CI] = 1.67–3.47; p = 1.22 × 10–5). Furthermore, we found that Alzheimer's disease (β = 0.05; standard error [SE] = 0.01; p = 6.63 × 10–8), frontotemporal dementia (β = 0.12; SE = 0.01; p = 5.10 × 10–16), and dementia with Lewy bodies (β = 0.08; SE = 0.02; p = 5.45 × 10–5) were causally linked to an increase in plasma GFAP levels. Even after controlling for the influence of aging, these associations remained significant. Conclusions Our study found that higher plasma GFAP levels may increase the risk of encephalitis, while neurodegenerative dementia may enhance the plasma GFAP levels, supporting the clinical utility of blood GFAP as a reliable biomarker in neurological diseases.

Background: Alzheimer’s disease (AD) and epilepsy represent two complex neurological disorders with distinct clinical manifestations, yet recent research has highlighted their intricate interplay. This review examines the association between AD and epilepsy, with particular emphasis on late-onset epilepsy of unknown etiology, increasingly acknowledged as a prodrome of AD. It delves into epidemiology, pathogenic mechanisms, clinical features, diagnostic characteristics, treatment strategies, and emerging biomarkers to provide a comprehensive understanding of this relationship. Methods: A comprehensive literature search was conducted, identifying 128 relevant articles published between 2018 and 2024. Results: Findings underscore a bidirectional relationship between AD and epilepsy, indicating shared pathogenic pathways that extend beyond traditional amyloid-beta and Tau protein pathology. These pathways encompass neuroinflammation, synaptic dysfunction, structural and network alterations, as well as molecular mechanisms. Notably, epileptic activity in AD patients may exacerbate cognitive decline, necessitating prompt detection and treatment. Novel biomarkers, such as subclinical epileptiform activity detected via advanced electroencephalographic techniques, offer promise for early diagnosis and targeted interventions. Furthermore, emerging therapeutic approaches targeting shared pathogenic mechanisms hold potential for disease modification in both AD and epilepsy. Conclusions: This review highlights the importance of understanding the relationship between AD and epilepsy, providing insights into future research directions. Clinical data and diagnostic methods are also reviewed, enabling clinicians to implement more effective treatment strategies.

ABSTRACT One of the common nervous system diseases in older adults is Alzheimer's and epilepsy, and the possibility of occurrence increases with age. The chances of seizure are high for patients with mild cognitive impairment and Alzheimer's disease. So, there is a bidirectional association between Alzheimer's and epilepsy, as both affect the neurodegenerative processes. Electroencephalogram (EEG) is a possible non-invasive measurement technique widely used to measure the variations in brain signals. EEG signal is analyzed to discriminate the Alzheimer and epilepsy. Numerous research works evaluated the clinical relevance of Alzheimer's and epilepsy. Specifically, machine learning-based evaluation models developed recently bring the facts by extracting features from the EEG signals. However, machine learning-based models lag in performance due to high dimensional EEG features. For initial feature selection particle swarm optimization is included in the proposed model and to reduce the computation complexity of the classifier, kernel PCA is incorporated for dimensionality reduction. Experimentations using benchmark Bon and Dementia datasets confirms the proposed model better performances in terms of precision, recall, f1-score and accuracy. The attained accuracy of 94% is much better than existing Gaussian Mixture Model (GMM), Relevance Vector Machine (RVM), Support Vector Machine (SVM), and Artificial Neural Network (ANN) methods.

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The burden of comorbidity in people with epilepsy is high. Several diseases, including depression, anxiety, dementia, migraine, heart disease, peptic ulcers, and arthritis are up to eight times more common in people with epilepsy than in the general population. Several mechanisms explain how epilepsy and comorbidities are associated, including shared risk factors and bidirectional relations. There is a pressing need for new and validated screening instruments and guidelines to help with the early detection and treatment of comorbid conditions. Preliminary evidence suggests that some conditions, such as depression and migraine, negatively affect seizure outcome and quality of life. Further investigation is needed to explore these relations and the effects of targeted interventions. Future advances in the investigation of the comorbidities of epilepsy will strengthen our understanding of epilepsy and could play an important part in stratification for genetic studies.

Globally, as populations age there will be challenges and opportunities to deliver optimal health care to senior citizens. Epilepsy, a condition characterised by spontaneous recurrent seizures, is common in older adults (aged >65 years) and yet has received comparatively little attention in this age group. In this Review, we evaluate the underlying causes of epilepsy in older people, explore difficulties in establishing a diagnosis of epilepsy in this population, discuss appropriate antiseizure medications, and evaluate potential surgical treatment options. We consider cognitive, psychological, and psychosocial comorbidities and the effect that epilepsy might have on an older person's broader social or care network in high-income versus middle-income and low-income countries. We emphasise the need for clinical trials to be more inclusive of older people with epilepsy to help inform therapeutic decision making and discuss whether measures to improve vascular risk factors might be an important strategy to reduce the probability of developing epilepsy.

Epilepsy in children is occasionally associated with variable comorbidities although the frequency of such comorbidity is often difficult to determine. They can be divided into three categories: neurological, psychological, and physical comorbidities. The goal of the present review is to discuss the reported comorbidities of epilepsy in children. The possible mechanisms and associated risk factors-including the effect of seizure frequency and seizure control, types of epilepsy, age of seizure onset, duration of illness, and the possible detrimental effect of antiepileptic drugs-will be described.

Common somatic conditions are bound to occur by chance in individuals with neurological disorders as prevalent as epilepsy, but when biological links underlying the comorbidity can be uncovered, the relationship may provide clues into the origin and mechanisms of both. The expanding list of monogenic epilepsies and their associated clinical features offer a remarkable opportunity to mine the epilepsy genome for coordinate neurodevelopmental phenotypes and examine their pathogenic mechanisms. Defined single-gene-linked epilepsy syndromes identified to date include all of the most frequently cited comorbidities, such as cognitive disorders, autism, migraine, mood disorders, late-onset dementia, and even premature lethality. Gene-linked comorbidities may be aggravated by, or independent of, seizure history. Mutations in these genes establish clear biological links between abnormal neuronal synchronization and a variety of neurobehavioral disorders, and critically substantiate the definition of epilepsy as a complex spectrum disorder. Mapping the neural circuitry of epilepsy comorbidities and understanding their single-gene risk should substantially clarify this challenging aspect of clinical epilepsy management.

Epilepsy is one of the most common neurologic disorders seen in children, with the highest incidence in the first year of life. Diagnostic accuracy can be challenging because many seizure mimics must be considered. Electroencephalography and neuroimaging can be critical in determining etiology and syndrome. Genetic testing is a high-yield endeavor, particularly in early-life epilepsies. Up to one-fourth of children with epilepsy will develop drug-resistant seizures. Comorbidities are very common in children with epilepsy, including intellectual disability in 25% and learning disability and attention-deficit/hyperactivity disorder in a significant minority. These comorbidities must be recognized and addressed as part of the child's overall care.

Many studies on psychiatric comorbidity in epilepsy have been performed using many different patient groups and diagnostic instruments. This methodological heterogeneity complicates comparison of the findings. In this article, psychiatric disorders in epilepsy are reviewed from the perspective of the DSM classification system. The empirical findings of axis I clinical disorders and axis II personality disorders are described separately. Furthermore, the existence and specificity of conditions such as interictal dysphoric disorder, interictal behavior syndrome, and psychosis of epilepsy are discussed. From the many studies that have been performed on this topic it can be learned that there is a need for well-controlled studies using representative patient groups and valid and standardized diagnostic instruments. So far, the majority of the studies have concerned axis I disorders; relatively little research has been performed on axis II personality disorders. More research on personality disorders, as well as on the relative contributions of the different (brain- and non-brain-related) factors to the relationship between epilepsy and psychiatric disorders, is recommended.

The most common, and usually the only, endocrine disturbance in patients with hypothalamic hamartoma (HH) and epilepsy is central precocious puberty (CPP). The mechanism for CPP associated with HH may relate to ectopic generation and pulsatile release of gonadotropin-releasing hormone (GnRH) from the HH, but this remains an unproven hypothesis. Possible regulators of GnRH release that are intrinsic to HH tissue include the following: (1) glial factors (such as transforming growth factor α[TGFα) and (2) γ-aminobutyric acid (GABA)-mediated excitation. Both are known to be present in surgically-resected HH tissue, but are present in patients with and without a history of CPP, suggesting the possibility that symptoms related to HH are directly associated with the region of anatomic attachment of the HH to the hypothalamus, which determines functional network connections, rather than to differences in HH tissue expression or pathophysiology. CPP associated with HH presents with isosexual development prior to the age of 8 years in girls and 9 years in boys. It is not uncommon for CPP with HH to present in children at an earlier age in comparison to other causes of CPP, including in infancy. Surgical resection of the HH can be effective for treating CPP, but is reserved for patients with intractable epilepsy, since GnRH agonists are widely available and effective treatment. Other endocrine disturbances with HH are rare, but can include growth hormone deficiency, hypothyroidism, and adrenal insufficiency. Diabetes insipidus is commonly encountered postoperatively, but is not observed with HH prior to surgical intervention.

A range of medical and neurologic disorders occurs more frequently in people with epilepsy than in the general population and constitutes its somatic comorbidity. Common examples include cardiac, gastrointestinal, and respiratory disorders; stroke; dementia; and migraine. Alzheimer's disease and migraine are not only more common in epilepsy but are also risk factors for the development of seizures, suggesting a bidirectional association and shared disease mechanisms. Less well-appreciated associations with epilepsy include Parkinson's disease and obstructive sleep apnea. The association between epilepsy and other conditions can be due to a variety of interacting genetic, biologic, and environmental factors. We propose an etiologic classification of comorbidity into uncertain (coincidence or unknown), causal (cause), shared risk factors (common disease mechanisms or shared predisposing risk factors), and resultant (consequence). Co-occurrence of other conditions in a person with epilepsy can complicate diagnosis or have adverse prognostic implications. Management of these conditions may facilitate the treatment of epilepsy, as in the case of obstructive sleep apnea. The presence of somatic disorders in epilepsy is associated with increased health care needs, poorer health-related quality of life, and premature mortality. Prevention, identification, and adequate treatment of comorbid disorders in epilepsy should be an important part of epilepsy management at all levels of care.

Epilepsy and psychiatric comorbidities have a complex relation, which can be manifested by their relatively high comorbid occurrence and the existence of a bidirectional relation, whereby not only are people with epilepsy (PWE) at greater risk of developing psychiatric disorders, but patients with primary psychiatric disorders are at higher risk of developing epilepsy. The existence of common pathogenic mechanisms operant in primary psychiatric disorders and epilepsy has been postulated as one of the leading hypothesis to explain their close and very complex relation. The neurobiologic characteristics of mood disorders can be used as a model to test this hypothesis. In this manuscript, we highlight data that suggest how several neurobiologic aspects of mood disorders can facilitate the epileptogenic process in animal models and explain the increased risk of patients with primary mood disorders to develop epilepsy in general and treatment-resistant epilepsy in particular. It is our hope that the inclusion of these data in this Special Issue will motivate neurologists to screen common psychiatric comorbidities in PWE. This article is part of the Special Issue "Obstacles of Treatment of Psychiatric Comorbidities in Epilepsy".

Epilepsy is most common in older people and yet optimizing the management of seizures in this demographic has often been somewhat overlooked. With populations aging across the world and those with complex early-onset epilepsies thankfully living into later life, the prevalence of epilepsy in older people is escalating rapidly. Assessment and management in this age group can be challenging. Seizures may present in unusual ways and the complex comorbidities and polypharmacy that often characterize older age, might make establishing a diagnosis of epilepsy in older persons difficult. Drug choices and treatment options are often more limited and need to be specifically tailored to the older individual with careful consideration of relevant comorbidities. The complex inter-relationship between epilepsy, dementia, and vascular disease in older people would seem a research priority, as there might be interventions to help reduce adverse outcomes in a growing and potentially vulnerable group.

Migraine and epilepsy are comorbid conditions. While it is well known that epilepsy can have an impact on cognitive abilities, there is conflicting evidence in the literature on the relationship between migraine and cognitive function. The aim of this study was to assess whether migraine comorbidity in patients with newly diagnosed focal epilepsy is associated with cognitive dysfunction. This is a post hoc analysis of data prospectively collected for the Human Epilepsy Project (HEP). There were 349 participants screened for migraine with the 13 questions used in the American Migraine Prevalence and Prevention (AMPP) study. Participants were also screened for depression using the Neurological Disorder Depression Inventory for Epilepsy (NDDI-E) and the Center for Epidemiologic Studies Depression Scale (CES-D) and for anxiety using the Generalized Anxiety Disorder-7 (GAD-7) scale. Cognitive performance was assessed with the Cogstate Brief Battery and Aldenkamp-Baker Neuropsychological Assessment Schedule (ABNAS). About a fifth (21.2%) of patients with a new diagnosis of focal epilepsy screened positive for migraine. There were more women and less participants employed full time among the participants with comorbid migraine. They reported slightly more depressive and anxious symptoms than the participants without migraine. Migraine comorbidity was associated with ABNAS memory score (median: 2, range: 0-12, Mann Whitney U p-value: 0.015). However, migraine comorbidity was not associated with Cogstate scores nor ABNAS total scores or other ABNAS domain scores. In linear regressions, depression and anxiety scores were associated with the ABNAS memory score. In this study, there was no association between migraine comorbidity and objective cognitive scores in patients with newly diagnosed focal epilepsy. The relationship between migraine comorbidity and subjective memory deficits seemed to be mediated by the higher prevalence of depression and anxiety symptoms in patients with epilepsy with comorbid migraine.

Comorbidities are a common feature in epilepsy, but neither the entire spectrum nor the significance of such comorbidities has been fully explored. We review comorbidities associated with epilepsy and their associated burden, provide an overview of relationships, and discuss a new conceptualization of the comorbidities. The epidemiology of the comorbidities of epilepsy and effects on health outcomes, healthcare use, and healthcare expenditures have been partly delineated. Distinct mechanisms of the associations have been suggested but not entirely ascertained. Movement from conceptualizing epilepsy as a condition to a symptom-complex has occurred. Comorbidities are common among people with epilepsy and are associated with poorer clinical outcomes and quality of life, greater use of health resources, and increased expenditure. Becoming aware of the associated mechanisms and their uncertainty is central to understanding the relationships between epilepsy and comorbid health conditions, which have implications for diagnosis and screening, medical management, and surgical management. Conceptualizing comorbidities of epilepsy as precipitating factors and epilepsy as the symptom will improve the understanding of epilepsy and catalyze research and improvements in clinical practice.

An increasing amount of evidence suggests an association between epilepsy and multiple somatic and psychiatric conditions, which is more significant than in the general population. Furthermore, a bidirectional association has been established between epilepsy and several conditions, notably depression and suicide, cerebrovascular disease, stroke, dementia and migraine, which is best explained by the presence of common underlying mechanisms and risk factors. Gaining knowledge about these common mechanisms can provide insight into new therapeutic targets, screening and preventive measures. This review discusses several of the more significant somatic and psychiatric comorbidities of epilepsy, the mechanisms and direction of their association, as well as the implications of these comorbidities for treatment. Somatic and psychiatric comorbidity in epilepsy have been investigated in several population-based studies using medical records databases and different survey methods. All show a significantly higher prevalence for a number of medical conditions in people with epilepsy (PWE) compared to the general population. The coexistence of different medical conditions with epilepsy carries important implications for the assessment of the burden of the disease and the outcome and management of these patients, as they often require long-term antiepileptic drug intake.

Slater's work on the schizophrenia-like psychoses of epilepsy is re-examined in the light of subsequent developments in psychiatry and neurology. Simple causal links of the sort he postulated between epilepsies and psychoses appear increasingly tenuous, despite indications that some psychotic symptoms and some localised structural changes are linked. A resumption of the study of electrophysiological similarities between schizophrenia and limbic epilepsy may offer a useful alternative programme for research.

A variety of comorbid psychiatric conditions are frequently identified in children and adolescents with epilepsy, including depression, anxiety, psychosis, and attention-deficit hyperactivity disorder. Data regarding the epidemiology and precise prevalence of comorbid disorders in childhood epilepsy are incomplete and just now beginning to be compiled. Psychiatric and behavioral comorbidities are believed to affect approximately 40-50% of children and adolescents with epilepsy. Optimal diagnosis, clinical evaluation, and choice of treatment are predicated on the proper identification of coexisting psychiatric and behavioral disorders. Comorbid conditions in children and adolescents with epilepsy should be evaluated and treated as soon as they are recognized.

There is a notion that people with epilepsy have substantial and often unrecognized comorbidity of chronic conditions. However, most studies focus on selected patient groups; population-based studies are scarce. We compared the prevalence of chronic somatic conditions in people with epilepsy with that in the general population using Canadian, nationwide, population-based health data. We examined epilepsy-specific and general population health data obtained through two previously validated, independently performed, door-to-door Canadian health surveys, the National Population Health Survey (NPHS, N = 49,000) and the Community Health Survey (CHS, N = 130882), which represent 98% of the Canadian population. The prevalence of epilepsy and 19 other chronic conditions was ascertained through direct inquiry from respondents about physician-diagnosed illnesses. Weighted prevalence, prevalence ratios (PR), and 95% confidence intervals were obtained for the entire population and for males and females separately. Multivariate analyses assessed the strength of association of comorbid conditions with epilepsy as compared with the general population. People with epilepsy had a statistically significant higher prevalence of most chronic conditions than the general population. Conditions with particularly high prevalence in epilepsy (prevalence ratio > or = 2.0) include stomach/intestinal ulcers (PR, CHS 2.5, NPHS 2.7), stroke (PR, CHS 3.9, NPHS 4.7), urinary incontinence (PR, CHS 3.2, NPHS 4.4), bowel disorders (PR, CHS 2.0, NPHS 3.3), migraine (PR, CHS 2.0, NPHS 2.6), Alzheimer's disease (PR, NPHS 4.3), and chronic fatigue (PR, CHS 4.1). There were no gender-specific differences in prevalence of chronic conditions among people with epilepsy. People with epilepsy in the general population, not only those actively seeking medical care, have a high prevalence of chronic somatic comorbid conditions. The findings are consistent across two independent surveys, which show that people with epilepsy in the general population have a two- to five-fold risk of somatic comorbid conditions, as compared with people without epilepsy. This patient-centered comorbidity profile reflects health aspects that are important to people with epilepsy, and indicate the need for a more integrated approach to people with epilepsy. The impact of epilepsy relative to other comorbid conditions requires further analysis, as does the contribution of comorbidity to epilepsy intractability and to differential health care needs. Similarly, it remains to be determined whether the observed comorbidity patterns are specific to epilepsy or simply reflect a pattern that is common to chronic illnesses in general.

The basic pathophysiology of epilepsy is still not fully understood. Epidemiological evidence for epilepsy seems to suggest that it may not only be the propensity for seizures to occur. The high prevalence of comorbidity and the finding that premature mortality is still increased in those who are in long-term remission, suggest that there is a systemic component to the condition. This systemic component is an additional shared risk factor that can explain an important proportion of the comorbidities of epilepsy as well as how an individual with inactive epilepsy remains at an elevated risk of premature mortality. This systemic component can be viewed from the perspective of a number of fundamental pathophysiological processes: inflammation, oxidative stress, glycation, and methylation capacity. These processes are associated with all-cause mortality and there is also a growing understanding of their impact on seizure processes. We propose that epilepsy be considered as the sum of seizures and comorbidities caused by systemic dysfunction, and that the comprehensive management of epilepsy should also include the management of the systemic dysfunction.

The purpose of this study was to analyse the comorbidity between headache and epilepsy in a large series of children with headache (1,795). Fifty-six cases (3.1%) suffered from idiopathic headache and idiopathic or cryptogenic epilepsy or unprovoked seizures. There was a strong association between migraine and epilepsy: in migraineurs (46/56) the risk of epilepsy was 3.2 times higher when compared with tension-type headache, without significant difference between migraine with and without aura (P = 0.89); children with epilepsy had a 4.5-fold increased risk of developing migraine than tension-type headache. In cases with comorbidity, focal epilepsies prevailed (43/56, 76.8%). Migraineurs affected by focal epilepsies (36/56) had a three times higher risk of having a cryptogenic epilepsy (27/36, 75%) than an idiopathic epilepsy (9/36, 25%) (P = 0.003). In migraine with aura, epilepsy preceded migraine in 71% of cases. Photosensitivity (7/56, 12.5%) and positive family history for epilepsy (22/56, 39%) were frequent in cases with comorbidity.

This study aimed to assess the prevalence of Attention Deficit Hyperactivity Disorder (ADHD) and its characteristics and risk factors in children with epilepsy at a tertiary medical center in New Delhi. Children with active epilepsy, aged 6 to 12 years, were assessed for ADHD using DSM-IV-TR criteria. Epilepsy and psychiatric characteristics, sociodemographic indicators, and use of antiepileptic drugs were analyzed for differences between the ADHD and non-ADHD groups. Among the 73 children with epilepsy, 23% (n = 17) had comorbid ADHD, of whom 59% (n = 10) had predominantly inattentive type, 35% (n = 6) combined type, and 6% (n = 1) predominantly hyperactive-impulsive type. Lower IQ scores, epileptiform EEG activity, not attending school, and male sex were significantly associated with comorbid ADHD in children with epilepsy. Groups were similar in terms of age, socioeconomic indicators, family history of psychiatric disorders, seizure frequency in the last six months, seizure etiology, and seizure type. Epilepsy is a common pediatric neurological condition with frequent psychiatric comorbidities, including ADHD. Specialists should collaborate to optimize treatment for children with epilepsy and ADHD, especially for families in developing countries where the burden of disease can be great.

Epilepsy, a spectrum disorder characterized by recurring seizures, affects approximately 2.3 million U.S. adults. Epilepsy poses challenges because of uncontrolled seizures, treatment complexity, social disadvantages (e.g., unemployment), and stigma. Persons with epilepsy are at increased risk for early mortality and for comorbidities that can complicate epilepsy management, increase health-care costs, and shorten the lifespan. Numerous studies have described higher rates of psychiatric comorbidity (e.g., depression and anxiety) in persons with epilepsy. However, fewer studies have examined nonpsychiatric comorbidity in a nationally representative U.S. sample of adults with epilepsy. To assess the prevalence of nonpsychiatric comorbidities, CDC analyzed data from the 2010 National Health Interview Survey (NHIS). Adults with epilepsy had a higher prevalence of cardiovascular, respiratory, some inflammatory, and other disorders (e.g., headache, migraine, and various other types of pain) than adults without epilepsy. Public health agencies can work with health-care providers, the Epilepsy Foundation, and other partners to ensure that adults with epilepsy have access to health promotion resources and chronic disease self-management programs.

Epilepsy is more common in the elderly population, with a higher prevalence of epilepsy-related neurological diseases, such as stroke and traumatic brain injury. Although dementia is also known to be a potential cause of epilepsy in the elderly, estimating its accurate contribution is challenging because of its high prevalence in the general elderly population. To characterize the clinical features of patients with comorbid dementia, we compared the characteristics of these patients with those of elderly patients with post-stroke epilepsy and an unidentified etiology. Of the 494 patients who were first diagnosed with epilepsy after the age of 65 years, 194 were classified as having post-stroke epilepsy, 105 as having comorbid dementia, and 71 as having epilepsy of unidentified etiology. Patients with comorbid dementia were older at seizure onset (p < .001) and at the last treatment (p < .001) than those in the other groups. They were more likely to have depression (p = .04) and were more frequently treated with acetylcholine esterase inhibitors and memantine before the diagnosis of epilepsy (p < .001). In contrast, stroke-related risk factors, such as hypertension (p < .001) and dyslipidemia (p = .01), were more prevalent in patients with post-stroke epilepsy. Considering that stroke itself is a well-recognized risk factor for dementia and epilepsy in the elderly, our study suggests that dementia may be a major comorbidity and a risk factor for late-onset epilepsy.

Epilepsy is one of the most common comorbidities in individuals with autism spectrum disorders (ASDs). Risk factors include the presence of developmental delay/intellectual disability, female sex, age, and an underlying genetic condition. Due to higher prevalence of epilepsy in ASD, it is important to have a high index of suspicion for seizures and refer to a neurologist if there are concerns. Genetic testing is recommended for all children with ASD but it becomes more high yield in children with epilepsy and ASD.

Here, we aimed to investigate the associations of comorbidities in HIV patients given antiepileptic drugs. HIV patients given antiepileptic drugs for at least 6 months were considered. Comorbidities of the epileptic, HIV-positive patients were stratified according to patients' age and causes of epilepsy. Seventy-four of the 97 HIV patients identified had at least one comorbidity. Patients more than 50-years old had more comorbidities (1.9 ± 1.5 vs. 1.1 ± 1.2, p < 0.01) compared with younger subjects. The distribution of the psychiatric disorders was comparable between age-related categories. A marginally significant trend for higher frequency of psychiatric disorders was observed in patients with idiopathic epilepsy versus other causes of epilepsy (43% vs. 24%), Because the presence of comorbid disorders is a major driver for premature mortality both in HIV infection and epilepsy, strategies aimed at favoring prevention, early identification, and adequate treatment in these clinical settings should be pursued at all levels of care.

Children with epilepsy are at risk for behavioral and cognitive comorbidities. Potential etiologies can be assessed in part by neuroimaging. Functional magnetic resonance imaging (MRI) has a major role in presurgical evaluation and prediction of postoperative outcome by mapping of language and memory. Structural MRI and functional MRI have shown changes in children and adolescents with attention deficit hyperactivity disorder and disruptive behavior, common comorbidities in children with epilepsy. Neuroimaging has the potential for significantly increasing understanding of the basis of cognitive and behavioral problems in children with epilepsy.

Comorbid psychiatric conditions are highly prevalent in patients with epilepsy, yet the long-term implications across multiple mental health conditions are poorly understood. We examined the association between psychiatric diagnoses and self-reported health status in veterans with epilepsy. ANCOVA models were used to derive adjusted SF-36V scores for individuals with epilepsy alone (N=7379) or with additional psychiatric conditions (N=6320): depression, schizophrenia, bipolar disorder, anxiety disorder, substance abuse, and posttraumatic stress disorder (PTSD). Compared with patients with epilepsy alone, scores of veterans with comorbid psychiatric diagnoses averaged 21% lower across all domains. Role Limitation scales exhibited the greatest decrement across domains. A PTSD diagnosis consistently corresponded to lower scores, followed by depression. Schizophrenia contributed the least detriment to perceived health status. Comorbid psychiatric conditions impart significant emotional and physical burdens, requiring timely recognition and treatment of these disorders. Patients with epilepsy are uniquely at risk for high physical-psychiatric comorbidity profiles, with concomitant losses in perceived health status.

The purpose of this study was to analyze national survey data to provide estimates of prevalence of epilepsy and associated developmental disabilities and comorbid conditions. We analyzed data from Cycle 3 of Canada's National Longitudinal Survey of Children and Youth. The NLSCY captured, socio-demographic information, as well as age, sex, education, ethnicity, household income, chronic health related conditions from birth to 15 years old. The main survey question intended to identify "epilepsy", "cerebral palsy", "intellectual disability", "learning disability", and "emotional and nervous difficulties" in the population of children surveyed. Prevalence was based on the national cross-sectional sample and used 1000 bootstrap weights to account for survey design factors. Cycle 3 of the NLSCY had the largest number of patients with diagnosed epilepsy. Prevalence figures (n/1000) for epilepsy and cerebral palsy (EPI_CP), epilepsy and intellectual disability (EPI_ID), epilepsy and learning disability (EPI_LD), and epilepsy and emotional nervous difficulties (EPI_EMO_NERV) were 1.1, 1.17, 2.58 and 1.34 respectively. Amongst children with epilepsy, 43.17% reported the presence of one or more of the above comorbid conditions. These results provide an initial prevalence estimate of comorbid conditions with epilepsy in Canadian children. In a high proportion of children with epilepsy, the PMK had reported at least one comorbid disorder. These findings carry implications for health care utilization and long-term outcomes. We discuss methodological aspects related to the ascertainment of epilepsy in both surveys, and to the validity and implications of our findings.

Multimorbidity is an emerging priority in healthcare due to associations with the ageing population, frailty, polypharmacy, health and social care demands. It affects 60-70% of adults and 80% of children with epilepsy. Neurodevelopmental conditions are commonly seen in children with epilepsy, while cancer, cardiovascular and neurodegenerative conditions often afflict older people with epilepsy. Mental health problems are common across the lifespan. Genetic, environmental, social and lifestyle factors contribute to multimorbidity and its consequences. Multimorbid people with epilepsy (PWE) are at higher risk of depression and suicide, premature death, suffer lower health-related quality of life, and require more hospital admissions and health care costs. The best management of multimorbid PWE requires a paradigm shift from the traditional single disease-single comorbidity approach and a refocus on a person-centred approach. Improvements in health care must be informed by assessing the burden of multimorbidity associated with epilepsy, delineating disease clusters, and measuring the effects on health outcomes.

The prevalence of psychological distress, especially depressive and anxiety disorders, is higher in epilepsy than in other chronic health conditions. These comorbid conditions contribute even more than epileptic seizures themselves to impaired quality of life in patients with epilepsy (PWE). The link between these comorbidities and epilepsy appears to have a neurobiological basis, which is at least partly mediated by stress through psychological and pathophysiological pathways. The impact of stress in PWE is also particularly important because it is the most frequently reported seizure trigger. It is therefore crucial for clinicians to take stress-related conditions and psychiatric comorbidities into account when managing PWE and to propose clinical support to enhance self-control of stress. Screening tools have been specially designed and validated in PWE for depressive disorders and anxiety disorders (e.g. NDDI-E, GAD-7). Other instruments are useful for measuring stress-related variables (e.g. SRRS, PSS, SCS, MHLCS, DSR-15, ERP-R, QOLIE-31) in order to help characterize the individual "stress profile" and thus orientate patients towards the most appropriate treatment. Management includes both pharmacological treatment and nonpharmacological methods for enhancing self-management of stress (e.g. mindfulness-based therapies, yoga, cognitive-behavioral therapies, biofeedback), which may not only protect against psychiatric comorbidities but also reduce seizure frequency.

Patients with epilepsy frequently report dissatisfaction with their quality of life (QOL), and there is considerable interest in understanding the factors and mechanisms associated with this perception. To date, investigation has focused on the potential contribution of seizure variables (e.g., seizure control) and psychiatric conditions to QOL, but there has not been an examination of the potential role of comorbid medical conditions. Information was gathered concerning current medical and psychiatric conditions for 93 patients with temporal lobe epilepsy, and their relationship with QOL was examined. The numbers of medical and psychiatric conditions were distinct and significant predictors of QOL satisfaction, and both were stronger correlates than seizure-related factors and demographic variables. The implications of these findings for the treatment and management of patients with epilepsy are discussed.

Abnormalities in paracingulate gyrus (PCG) were found in both patients with temporal lobe epilepsy and patients with sleep disorders. These abnormalities include reduced functional connectivity between PCG and other brain regions, abnormal activity and reduced volume of PCG. PCG may be associated with comorbid sleep disorders in patients with temporal lobe epilepsy (TLE). This study aimed to explore the relationship between abnormal PCG function and comorbid sleep disorders in patients with TLE. We used Pittsburgh Sleep Quality Index -8/9 to divide fifty-eight patients into a group with sleep disorders and group without sleep disorders. Using the PCG as the seed, we examined the task-based seed-to-voxel functional connectivity identified by group-independent component analysis. Compared with the normal sleep group, we observed longer disease duration, higher frequency of seizures, higher Self-Rating Anxiety Scale scores in the comorbidity group (p < 0.05). During the verbal fluency character task, functional connectivity from the PCG to the right frontal and parietal regions was decreased in the comorbidity group (p < 0.05, FDR-corrected). Sensitivity analyses confirmed that our conclusions were not affected by factors such as laterality or hippocampal sclerosis. These abnormalities reveal brain lesions in patients with TLE comorbid sleep disorders, which may contribute to the pathogenesis of the comorbidity and be related to patients' preserved verbal functions.

Depression is one of the most common comorbid psychiatric condition associated with epilepsy. It has a negative impact on the patient's quality of life. However, the underlying molecular mechanisms leading to depression are currently unclear. The aim of this study was to determine the hub genes associated with epilepsy and depression. Gene expression profiles (GSE47752 and GSE20388) were downloaded from the gene expression omnibus (GEO) database. Differentially expressed genes (DEGs) for epilepsy and depression groups were separately searched. Subsequently, network analyses methods were employed to establish protein-protein interaction (PPI) networks, and to perform Gene Ontology (GO) terms and pathway enrichment analyses for co-expressed DEGs. A total of 772 genes were upregulated in patients with epilepsy whereas 91 genes were up-regulated in patients with depression. In addition, 1304 genes were down-regulated in epilepsy whereas 141 genes were down-regulated in patients with depression. Among co-expressed DEGs, 5 DEGs were up-regulated and 19 were down-regulated. Further analysis revealed that the co-expressed DEGs were involved in regulation of vasculature development, regulation of angiogenesis, glutamate receptor signaling pathway, cellular response to interleukin-1 and positive regulation of protein kinase B signaling. The Arc and Homer1 genes were identified as the common candidate genes involved in the pathogenesis of epilepsy and depression. Arc and Homer1 may contribute to the comorbidity of epilepsy and depression.

Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy. Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy. Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism. NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.

Psychiatric disorders are more common in patients with epilepsy than in the general population. The aims of the study were to assess the frequency and type of psychotropic drug usage in patients with epilepsy, to assess the risk factors for their use, and to assess their proconvulsive potential and the risk of interactions with antiepileptic drugs. This 20-month prospective study included patients treated at the university hospital outpatient clinic. Psychotropic drugs have been classified according to the Anatomical Therapeutic Chemical Classification System. Of the 621 patients (with a mean age of 35.4years), 60% were women, and 37.5% were in remission; 54.8% of the patients used antiepileptic drug monotherapy. The most commonly used antiepileptic drugs were valproate, levetiracetam, lamotrigine, and carbamazepine. Eighty-nine (14.3%) patients received psychiatric comedication. Sertraline, perazine, and hydroxyzine were the predominantly used psychotropic drugs. Independent variables associated with psychotropic drug usage in the logistic regression model included age, active epilepsy, combined focal and generalized epilepsy type, use of somatic comedication, and phenobarbital. Over one-third of the patients simultaneously received antiepileptic drugs and psychotropic drugs, between which clinically significant interactions may occur, 10% of patients used psychotropic drugs to lower the seizure threshold. The results of the study indicate the need for closer cooperation between doctors of various specialties when caring for patients with epilepsy.

INTRODUCTION A wide spectrum of somatic and psychiatric disorders occurs frequently in patients with epilepsy, which adds to the burden of this disease. OBJECTIVES The aim of the study was to estimate the prevalence and risk factors of somatic comorbidities and analyze somatic comedication in adult patients with epilepsy. PATIENTS AND METHODS This study involved patients with epilepsy treated in university epilepsy clinic. Data on epilepsy, antiepileptic drugs (AEDs), somatic comorbidities, and their treatment were collected from a structured interview and from medical records. RESULTS The sample population consisted of 636 patients (mean age, 35.3 years); 380 (59.7%) were female and 241 (37.9%) had well‑controlled epilepsy. At least 1 comorbid somatic condition was found in 216 patients (34%). The most prevalent somatic comorbidities were cardiovascular diseases, allergies, migraine, hyperlipidemia, thyroid disorders, and chronic lower respiratory diseases. Furthermore, 200 patients (31.4%) were prescribed at least 1 medication for somatic disorders. Logistic regression analysis revealed several independent risk factors for the occurrence of somatic comorbidities: older age, shorter duration of epilepsy, lower seizure frequency, and lower number of AEDs. CONCLUSIONS Somatic comorbidities and comedication with non‑AEDs were found in one‑third of the relatively young cohort of adult patients with epilepsy. Patients with pharmacoresistant epilepsy may be at risk of underdiagnosis and undertreatment of somatic comorbidities. The presence of comorbidities may have implications for the diagnosis and treatment of seizure disorder and coexisting condition.

Intermittent Explosive Disorder (IED) is an understudied psychiatric condition that presents with repeated episodes of impulsive aggression and poorly regulated emotional control, often resulting in interpersonal and societal consequences. Better understanding of comorbidities will allow for enhanced screening, diagnosis, and treatment of patients. To investigate prevalence and associations of IED with psychiatric, neurological, and somatic disorders using real-world data. Matched cohorts of patients with or without IED diagnosis were identified using data from the TriNetX Research Network (until January 31, 2024). Cox proportional hazard models were used to estimate and compare the probabilities of acquiring other diagnoses using patients' available medical records. Analysis of electronic medical records from two patient populations. 30,357 individuals with IED and equal number of demographically matched individuals without IED from the TriNetX Research. IED diagnosis identified through the associated ICD codes. The main outcomes were ICD-10-CM diagnostic categories and root codes for disorders and health conditions in both cohorts. Main measures are total numbers and proportions of patients who had the diagnostic codes, as well as adjusted hazard ratios for IED diagnosis. Although only 0.03% of the total patient population had an IED diagnosis, we found extensive and widespread comorbidities with psychiatric, neurological and somatic conditions. A significant 95.7% of the individuals with IED had another psychiatric diagnosis. All psychiatric sub-categories and 95% of the psychiatric diagnoses were significantly associated with IED, with HRs ranging from 2 to 77. Among neurological conditions, neurodegenerative diseases and epilepsy had the highest HRs, followed by extrapyramidal and movement disorders, cerebral palsy and other paralytic syndromes, and sleep disorders. Notable associations with IED also includes conditions such as obesity, hyperlipidemia, hypertension, and GERD. Our findings illuminate the extensive comorbid relationships between IED and psychiatric, neurological, and somatic disorders. This underscores the necessity for an integrated diagnostic and treatment approach that addresses both the psychological and physical health aspects of IED. Additionally, our work highlights the need for more accurate and inclusive diagnosis of IED in patients with mental disorders.

This study was undertaken to characterize somatic symptoms and related disorders (SSD) in epilepsy. Adults with epilepsy under active follow-up at a tertiary epilepsy center were consecutively enrolled. The diagnosis of SSD was performed by an experienced psychologist based on the structured clinical interview for Statistical Manual of Mental Disorders, 5th edition. Detailed social/demographic data, epilepsy features, psychiatric features, life quality, disability, and economic burden were collected and compared between people with SSD and those without. Bodily distress syndrome checklist, Somatic Symptom Disorder-B Criteria Scale, Patient Health Questionnaire-9, and Generalized Anxiety Disorder seven-item scale (GAD-7) were used to evaluate SSD individuals' somatic symptoms, symptom-related psychological distress, and depressive and anxious symptoms. Quality of life and disability were assessed by Quality of Life in Epilepsy Inventory 31 (QOLIE-31) and World Health Organization Disability Assessment Schedule V.2.0 (WHO DAS 2.0). A risk prediction nomogram was generated using least absolute shrinkage and selection operator (LASSO) analysis and validated. One hundred fifty of 631 participants (24%) were diagnosed with SSD. In people with SSD, the top three most common somatic symptoms were memory impairment, headache, and dizziness (85%, 80%, and 78%, respectively), and multiple systems were involved in most (82%) people with SSD. Compared with people without SSD, those with SSD had lower QOLIE-31 total scores, and higher WHO DAS 2.0 scores and disease economic burdens. LASSO analysis suggested that a history of severe traumatic brain injury, hippocampal sclerosis, low seizure worry and medication effects scores on QOLIE-31, multiple systems affected by somatic symptoms, and a high GAD-7 score were risk factors of SSD. The nomogram was validated for good accuracy in the training and testing cohorts. SSD are likely to be a common comorbidity in epilepsy and harm epilepsy prognosis. Our risk prediction nomogram was successfully developed but needs further validation in larger cohorts.

In one of the largest, most comprehensive studies on borderline personality disorder (BPD) to date, this article places into context associations between this diagnosis and (1) 16 different psychiatric disorders, (2) eight somatic illnesses, and (3) six trauma and adverse behaviors, e.g., violent crime victimization and self-harm. Second, it examines the sex differences in individuals with BPD and their siblings. A total of 1,969,839 Swedish individuals were identified from national registers. Cumulative incidence with 95% confidence intervals (CI) was evaluated after 5 years of follow-up from BPD diagnosis and compared with a matched cohort. Associations were estimated as hazard ratios (HR) with 95% CIs from Cox regression. 12,175 individuals were diagnosed with BPD (85.3% female). Individuals diagnosed with BPD had higher cumulative incidences and HRs for nearly all analyzed indicators, especially psychiatric disorders. Anxiety disorders were most common (cumulative incidence 95% CI 33.13% [31.48-34.73]). Other notable findings from Cox regressions include psychotic disorders (HR 95% CI 24.48 [23.14-25.90]), epilepsy (3.38 [3.08-3.70]), violent crime victimization (7.65 [7.25-8.06]), and self-harm (17.72 [17.27-18.19]). HRs in males and females with BPD had overlapping CIs for nearly all indicators. This indicates that a BPD diagnosis is a marker of vulnerability for negative events and poor physical and mental health similarly for both males and females. Having a sibling with BPD was associated with an increased risk for psychiatric disorders, trauma, and adverse behaviors but not somatic disorders. Clinical implications include the need for increased support for patients with BPD navigating the health care system.

Attention deficit/hyperactivity disorder (ADHD) is a developmental disorder caused by structural and functional brain abnormalities as well as genetic and environmental factors. ADHD symptoms are commonly observed in individuals with epilepsy. A few studies have reported a pattern of behavioral problems in children with combined epilepsy and ADHD. We aimed to evaluate comorbid behavioral problems and mental health concerns among children with epilepsy with ADHD and without ADHD including autism spectrum disorder, anxiety, depression, somatic problems, oppositional defiant disorder, and conduct disorder. A total of 100 children aged between 6 and 11 years were recruited and categorized into 1 of 5 groups (20 child/group): (1) epilepsy, (2) epilepsy with ADHD, (3) ADHD with electroencephalogram (EEG) changes, (4) ADHD without EEG changes, and (5) healthy control. The scales used in our study included the Childhood Autism Spectrum Test (CAST) to screen autism spectrum conditions and related social and communication conditions, Conners' Parent Rating Scale (CPRS) to assess ADHD and other comorbid behavioral and social-emotional difficulties, and Children Behavior Checklist (CBCL) to evaluate behavior problems. The CAST scale score showed no significant difference among the studied groups. Regarding the Conners-3 scale, the combined type of ADHD was predominant in the ADHD with EEG changes group and the ADHD with epilepsy group, while hyperactive ADHD was predominant in the ADHD without EEG changes group. The ADHD with EEG changes group and the ADHD with epilepsy group had equally high clinical rating scores for CBCL in internalizing and externalizing problems. There was a significant difference in the profile of all Diagnostic and Statistical Manual of Mental Disorders (DSM-5) scales of CBCL among the studied groups. This is the first study to use EEG in patients with ADHD in comparison with epilepsy. ADHD with epilepsy is closely related to ADHD with EEG changes regarding psychiatric comorbidity in terms of anxiety, depression, somatic problems, oppositional defiance problems, and conduct problems.

The mammalian target of rapamycin (mTOR) pathway has emerged as a key player for proper neural network development, and it is involved in epileptogenesis triggered by both genetic or acquired factors. Areas covered. The robust mTOR signaling deregulation observed in a large spectrum of epileptogenic developmental pathologies, such as focal cortical dysplasias and tuberous sclerosis complex (TSC), has been linked to germline and somatic mutations in mTOR pathway regulatory genes, increasing the spectrum of 'mTORopathies'. The significant advances in the field of TSC allowed for the validation of emerging hypotheses on the mechanisms of epileptogenesis and the identification of potential new targets of therapy. Recently, a double-blind phase III randomized clinical trial on patients with TSC related epilepsy, demonstrated that adjunctive treatment with mTOR inhibition is effective and safe in reducing focal drug resistant seizures. Expert commentary. mTOR signaling dysregulation represents a common pathogenic mechanism in a subset of malformations of cortical development, sharing histopathological and clinical features, including epilepsy, autism, and intellectual disability. EXIST-3 trial provided the first evaluation of the optimal dosage, conferring a higher chance of reducing seizure frequency and severity, with adverse events being similar to what observed with lower dosages.

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Observational studies suggested a bidirectional relationship between Alzheimer disease (AD) and epilepsies. However, it remains debated whether and in which direction a causal association exists. This study aims to explore the relationship between genetic predisposition to AD, CSF biomarkers of AD (β-amyloid [Aβ] 42 and phosphorylated tau [pTau]), and epilepsies with 2-sample, bidirectional Mendelian randomization (MR) method. Genetic instruments were obtained from large-scale genome-wide meta-analysis of AD (N For forward analysis, genetic predisposition to AD was associated with an increased risk of generalized epilepsy (odds ratio [OR] 1.053, 95% CI 1.002-1.105, This MR study supports a causal link between AD, amyloid pathology, and generalized epilepsy. This study also indicates a close association between AD and focal HS. More effort should be made to screen seizure in AD, unravel its clinical implications, and explore its role as a putative modifiable risk factor.

A study was undertaken to determine whether psychiatric disorders associated with suicide are more common in incident epilepsy than in matched controls without epilepsy, before and after epilepsy diagnosis. A matched, longitudinal cohort study was conducted in the UK General Practice Research Database. A total of 3,773 cases diagnosed with epilepsy between the ages of 10 and 60 years were compared to 14,025 controls matched by year of birth, sex, general practice, and years of medical records before the index date. We examined first diagnosis of psychosis, depression, anxiety, and suicidality in each of the 3 years before and after the index date and annual prevalence of suicide. Referent diagnoses were eczema and acute surgery. The incidence rate ratio (IRR) was calculated for each year in the study period; the prevalence ratio (PR) was calculated for suicidality. The IRR of psychosis, depression, and anxiety was significantly increased for all years before epilepsy diagnosis (IRR, 1.5-15.7) and after diagnosis (IRR, 2.2-10.9) and for suicidality before epilepsy diagnosis (IRR, 3.1-4.5) and 1 year after diagnosis (IRR, 5.3). The PR was increased for suicide attempt before epilepsy onset (PR, 2.6-5.2) and after onset (PR, 2.4-5.6). Eczema and acute surgery were both associated with epilepsy in the first and third year after diagnosis. Epilepsy is associated with an increased onset of psychiatric disorders and suicide before and after epilepsy diagnosis. These relations suggest common underlying pathophysiological mechanisms that both lower seizure threshold and increase risk for psychiatric disorders and suicide.

This study aimed to assess whether there is a bidirectional association between autism spectrum disorder (ASD) and epilepsy in child and adolescent patients. The National Health Insurance Research Database of Taiwan was used to conduct two cohort studies of patients who were under 18 years of age during the period 1997-2008. Cohort 1 comprised patients with newly diagnosed ASD but excluded those diagnosed with epilepsy prior to ASD. A non-ASD comparison group was matched to each case in terms of age and sex. Cohort 2 comprised patients with newly diagnosed epilepsy but excluded those diagnosed with ASD prior to epilepsy. A non-epilepsy comparison group was matched to each case in terms of age and sex. We calculated the incidence of epilepsy in patients with ASD and hazard ratio (HR) to estimate the risk of epilepsy in association with ASD in cohort 1, and the reverse in cohort 2. In cohort 1, the incidence of epilepsy was 13.7 in the ASD group and 1.3 in the non-ASD group (per 1000 person-years). The adjusted HR for epilepsy was 8.4 (95 % CI 5.5-12.7) in the ASD group when compared with the non-ASD group. In cohort 2, the incidence of ASD was 3.4 in the epilepsy group and 0.3 in the non-epilepsy group (per 1000 person-years). The adjusted HR for ASD was 8.4 (95 % CI 6.2-11.4) in the epilepsy group when compared with the non-epilepsy group. A bidirectional association was, therefore, found to exist between ASD and epilepsy. These findings implicate that ASD and epilepsy probably share common risk factors. However, further studies are required to reveal more detail on the mechanism of this bidirectional association.

Epilepsy with myoclonic-atonic seizures (EMAS) is a rare childhood onset epileptic encephalopathy. There is no clear consensus for recommended treatments, and pharmacoresistance is common. To better assess the clinical phenotype, most effective treatment, and determinants of cognitive and seizure outcomes, three major pediatric epilepsy centers combined data, creating the largest cohort of patients with EMAS ever studied to date. Authors performed a retrospective chart review of patients with EMAS who received care at the authors' institutions. A total of 166 children were identified. Global developmental delay (>1 domain) was present in 2% of children at onset and 49% during the course of the disease. Afebrile seizures occurred after the age of 2 years in 88%, generalized tonic-clonic seizures in 60%, and drop attack or myoclonic seizures in 30%. At onset, electroencephalography (EEG) found 28% normal, background slowing in 20%, and epileptiform discharges or seizures in 69%. Subsequent EEG found slowing in 62% and discharges or seizures in 90%. Response (>50% seizure reduction) to the first three antiseizure drugs (ASDs) was 26% (levetiracetam, 17%; valproic acid, 31%; other ASDs combined, 26%). Diet therapy was used as a second or third therapy in 19% and ultimately used in 57%; response was 79%, significantly greater than the first three ASDs (P = .005, χ This large cohort of children with EMAS clarifies areas of variability in practice. Diet therapy is by far the most effective treatment; failure to respond was associated with failure to attain seizure freedom. This therapy should be used early in the treatment in EMAS. This study also identified a bidirectional link between cognitive and seizure outcomes.

To investigate the bidirectional association between cognitive ability in young adulthood and epilepsy. This cohort study included 1 159 076 men enrolled in the mandatory conscription board examination from the Danish Conscription Database (DCD; 658 465 men examined 1957-84), the Danish Defence Personnel Organization Database (DPOD; 216 509 men examined 1987-2005) and the Danish Conscription Registry (DCR; 284 102 men examined 2006-15). A supplementary analysis included 14 814 female volunteers. Cognitive ability was measured at conscription, and epilepsy was ascertained by physician diagnoses in the Danish National Patient Registries 1977-2016 [using International Classification of Diseases (ICD) codes: ICD-8-345; ICD-10-G40-G41]. Differences in cognitive ability in relation to epilepsy status at the time of conscription (age 19) were calculated using linear regression. The risk of epilepsy associated with cognitive ability was estimated using Cox regression models, split at age at follow-up (40 and 60 years) and adjusted for year of birth, cerebrovascular disease, traumatic brain injury and education. In all, 5097 (1.0%) men from the DPOD and DCR were diagnosed with epilepsy before conscription, and they had about 0.25 standard deviation (SD) lower cognitive scores than men without epilepsy. The largest difference in cognition was seen for those with the largest number of hospital contacts. A total of 22 364 (1.9%) men developed epilepsy, and cognitive ability was inversely associated with the risk of epilepsy. With the end of follow-up at age 40 years, the adjusted hazard ratio (HR)per SD increase was 0.75 (95% confidence interval = 0.73-0.77). The association attenuated with increasing age at diagnosis. The findings were replicated in female conscripts. The cognitive impairment seen in adults with epilepsy seems to reflect combined effects of epileptic processes and lower premorbid cognitive ability.

Sleep and epilepsy have a complex and bidirectional relationship. We aimed to uncover genetic mechanisms underlying this connection. We leveraged genome-wide association studies that link sleep phenotypes and genetic loci and compared epilepsy genes with a random set of genes. Pathway analysis was applied to genes associated with both epilepsy and sleep phenotypes. To determine the specificity of our findings, we compared genes from other neurologic diseases and CNS cell types. A total of 8.1% of epilepsy genes (26/320) were associated with sleep phenotypes, 2.7-fold the rate of a random gene set (36/1,200 = 3%). Sleep-associated epilepsy genes were enriched in biological processes involving brain development and neuronal function. Other CNS disease genes also demonstrated strong genetic links to sleep phenotypes while peripheral nervous system diseases genes did not. Genes expressed in neurons, astrocytes, and oligodendrocytes were highly associated with sleep phenotypes while those in microglia and endothelial cells were not. While epilepsy and sleep phenotypes share genetic links, this finding extends to other CNS diseases and genes expressed in brain cells. The brain's effect on sleep likely has a genetic underpinning, as variation in genes expressed in cells responsible for brain function affects sleep phenotypes.

Epilepsy and amyotrophic lateral sclerosis (ALS) are common neurological disorders. The association between the two disorders has been raised in observational studies. However, it is uncertain to what extent they have mutual causal effects. In this study, we aimed to investigate their causal association using a two-sample Mendelian randomization (MR) method. We performed a two-sample bidirectional MR analysis to evaluate the causal association of epilepsy with the risk of ALS. Publicly published genome-wide association study statistics for epilepsy and ALS were used in the study. The primary analysis included genetic variants with a p value of less than 1 × 10 The primary MR analysis found no causal effect of epilepsy on risk of ALS (odds ration [OR]: 1.133, 95% confidence interval [CI]: 0.964-1.332, p = .130). Among subtypes of epilepsy, it also failed to observe any causal association between general epilepsy and ALS (OR: 1.036, 95% CI: 0.969-1.108, P = .300). However, focal epilepsy contributed to an increase in the risk of ALS (OR: 1.177, 95% CI: 1.027-1.348, p = .019). Moreover, the investigation of reverse causalities did not reveal significant results. The current study supports a causal influence of focal epilepsy on ALS risk. Future studies are needed to explore its potential role in ALS.