Personality disorders in people with epilepsy: a review.

Epileptologists and psychiatrists have long observed a correlation between epilepsy and personality disorders (PDs) in their clinical practice. We conducted a comprehensive PubMed search looking for evidence on PDs in people with epilepsy (PwE). Out of over 600 results obtained without applying any time restriction, we selected only relevant studies (both analytical and descriptive) limited to English, Italian, French and Spanish languages, with a specific focus on PDs, rather than traits or symptoms, thus narrowing our search down to 23 eligible studies. PDs have been investigated in focal epilepsy (predominantly temporal lobe epilepsy - TLE), juvenile myoclonic epilepsy (JME) and psychogenic non-epileptic seizures (PNES), with heterogeneous methodology. Prevalence rates of PDs in focal epilepsy ranged from 18 to 42% in surgical candidates or post-surgical individuals, with Cluster C personality disorders or related traits and symptoms being most common. In JME, prevalence rates ranged from 8 to 23%, with no strong correlation with any specific PDs subtype. In PNES, prevalence rates ranged from 30 to 60%, with a notable association with Cluster B personality disorders, particularly borderline personality disorder. The presence of a PD in PwE, irrespective of subtype, complicates treatment management. However, substantial gaps of knowledge exist concerning the neurobiological substrate, effects of antiseizure medications and epilepsy surgery on concomitant PDs, all of which are indeed potential paths for future research.

New-onset psychogenic nonepileptic seizures after intracranial neurosurgery: A meta-analysis.

BACKGROUND: The epidemiology of psychogenic non-epileptic seizures (PNES) is still unclear. Although approximately 14 million people need neurosurgical care annually, there is a dearth of thorough analysis on PNES occurrence following surgery. This study seeks to estimate the proportion of newly diagnosed PNES. METHODS: We conducted a literature search of the PubMed, Ovid, CINAHL, and Cochrane Library databases up to December 2023. We identified studies using an observational design on the occurrence of PNES in patients who underwent intracranial surgery, and confirmed diagnosis using video-EEG. Estimates are reported as proportions using random effects models. We reported both 95 % CIs and prediction intervals (PI). We assessed the risk of bias and identified the pooled odds ratio (OR) for mutually exclusive groups. The heterogeneity was investigated using the I² statistic and significance determined using Cochran's Q-test. Post-hoc Egger's regression test, and several sensitivity analyses were performed. This study was registered in PROSPERO (CRD42023488611). RESULTS: Of the 1766 unique studies identified, 86 were selected for full-text review. Eight studies (n = 3,699) were eligible for inclusion. Studies, spanning from 1995 to 2017, primarily focused on epilepsy surgeries. The pooled proportion was 3 % (95 % CI 2 %-5 %; 95 % PI 0 %-11 %). Temporal resections indicated twofold increase of PNES comparing to either resections (OR 2.05, 95 %CI 0.81-5.19). The risk of bias assessment indicated satisfactory quality for included studies, and heterogeneity in estimates was mainly explained by publication year of studies and their rounded sample size. CONCLUSIONS: Given the estimations, there is expected impact of intracranial procedures on functional seizures epidemiology. Further efforts need to understand the contribution of brain resections to PNES incidence.

Efficacy of verbal suggestion, verbal suggestion with a tuning fork, and verbal suggestion with a cotton swab for inducing the paroxysmal event during video-EEG recording in children with suspected psychogenic nonepileptic seizures.

INTRODUCTION: Video-electroencephalogram (EEG) with suggestion is widely considered the gold standard for diagnosing psychogenic nonepileptic seizures (PNES). However, ethical concerns and uncertainties persist regarding the most minimally invasive and least deceptive suggestion approach. MATERIALS AND METHODS: In an open-label randomized controlled trial, we evaluated the effectiveness of three suggestion methods (verbal suggestion, verbal suggestion with a tuning fork, and verbal suggestion with a cotton swab) during short-term video-EEG (STVEEG) recordings to induce PNES in children aged 5-18 years. If the paroxysmal event couldn't be elicited with the assigned method, alternative techniques were employed. RESULTS: Out of 97 initially screened children, 75 were enrolled, with 25 in each group. The efficacy of all three suggestion methods was comparable in reproducing paroxysmal events (success rate of 16/25, 17/25 and 17/25 in verbal suggestion only, verbal suggestion with tuning fork and sterile cotton swab group respectively, p = 0.83) and the time required for induction (median of 2, 3 and 3 min respectively, p = 0.21). After trying alternative methods, 20 %, 12 %, and 12 % more patients in these three groups, respectively, were able to reproduce the paroxysmal event, with the differences not reaching statistical significance (p = 0.74). The assigned induction method or the success/failure of event reproduction did not significantly impact clinical outcomes at 12 weeks, and none of the patients in whom PNES could not be reproduced during STVEEG were later found to have an organic cause. Only the presence of psychiatric comorbidity independently predicted successful event reproduction during STVEEG, with statistical significance even after adjusting for other variables (p = 0.03). CONCLUSION: The efficacy of verbal suggestion alone in inducing paroxysmal nonepileptic seizures is on par with using a tuning fork or cotton swab in conjunction with verbal suggestion during STVEEG.

Design and validation of a diagnostic suspicion checklist to differentiate epileptic from psychogenic nonepileptic seizures (PNES-DSC).

OBJECTIVE: Psychogenic non-epileptic seizures (PNES) are complex clinical manifestations and misdiagnosis as status epilepticus remains high, entailing deleterious consequences for patients. Video-electroencephalography (vEEG) remains the gold-standard method for diagnosing PNES. However, time and economic constraints limit access to vEEG, and clinicians lack fast and reliable screening tools to assist in the differential diagnosis with epileptic seizures (ES). This study aimed to design and validate the PNES-DSC, a clinically based PNES diagnostic suspicion checklist with adequate sensitivity (Se) and specificity (Sp) to discriminate PNES from ES. METHODS: A cross-sectional study with 125 patients (n = 104 drug-resistant epilepsy; n = 21 PNES) admitted for a vEEG protocolised study of seizures. A preliminary PNES-DSC (16-item) was designed and used by expert raters blinded to the definitive diagnosis to evaluate the seizure video recordings for each patient. Cohen's kappa coefficient, leave-one-out cross-validation (LOOCV) and balance accuracy (BAC) comprised the main validation analysis. RESULTS: The final PNES-DSC is a 6-item checklist that requires only two to be present to confirm the suspicion of PNES. The LOOCV showed 71.4% BAC (Se = 45.2%; Sp = 97.6%) when the expert rater watched one seizure video recording and 83.4% BAC (Se = 69.6%; Sp = 97.2%) when the expert rater watched two seizure video recordings. CONCLUSION: The PNES-DSC is a straightforward checklist with adequate psychometric properties. With an integrative approach and appropriate patient history, the PNES-DSC can assist clinicians in expediting the final diagnosis of PNES when vEEG is limited. The PNES-DSC can also be used in the absence of patients, allowing clinicians to assess seizure recordings from smartphones.

Death of a loved one: A potential risk factor for onset of functional seizures.

Functional seizures (FS) are a symptom of Functional Neurological Disorder (FND), the second most common neurological diagnosis made worldwide. Childhood trauma is associated with the development of FS, but more research is needed to truly understand the effects of trauma on FS onset. A sample of 256 responses by adults with FS to the Childhood Traumatic Events Scale were analyzed using a Cox proportional hazard model. When investigating each unique childhood traumatic exposure and its associated self-reported severity together, experiencing death of a loved one and experiencing violence were significantly associated with FS onset, suggesting reduced time from trauma exposure to first FS. Death of a loved one in childhood is often overlooked as an influential risk factor for future development of serious mental illnesses such as FS. In this study we show death of a loved one in childhood should be considered as an influential traumatic experience and recommend FND researchers examine its prevalence in patient histories and the potential effects on attachment-related processes and clinical treatment formulations. We recommend future studies incorporate loss of a loved one during childhood (before age 18) in both quantitative and qualitative assessments of persons with FND.

Medication use in patients with functional seizures from a public and a private hospital.

PURPOSE: Currently, we have limited knowledge of any potential differences among patients with functional seizures (FS), otherwise known as psychogenic non-epileptic seizures (PNES), from different socioeconomic backgrounds. Investigating medication use among these patients may provide insight into the quality and intensity of medical care they receive. Thus, we aimed to assess and compare the frequency and quantity of antiseizure medications (ASMs), and psychiatric and other medications used among patients with FS from a private and public epilepsy monitoring units (EMUs) in Cape Town, South Africa. METHODS: Only video-electroencephalographically (video-EEG) confirmed patients with FS with no comorbid epilepsy were eligible for the study. For this retrospective case-control study we collected data on patients' medication-taking histories using digital patient records, starting with the earliest available digital patient record for each hospital. RESULTS: A total of 305 patients from a private hospital and 67 patients from a public hospital were included in the study (N = 372). Patients with FS attending the public hospital had lower odds of taking any ASMs at presentation (aOR=0.39, 95% CI [0.20, 0.75]) and ever taking psychiatric medications (aOR=0.41, 95% CI [0.22, 0.78]) compared to FS patients from the private hospital. They did, however, have higher odds of being discharged with an ASM (aOR=6.60, 95% CI [3.27, 13.35]) and ever taking cardiovascular medication (aOR=2.69, 95% CI [1.22, 5.90]) when compared to the private hospital patients. With every additional presenting ASM (aOR=0.63, 95% CI [0.45, 0.89]) and psychiatric medication (aOR=0.58, 95% CI [0.40, 0.84]) the odds of being from the public hospital decreased. However, they increased with every additional discharge ASM (aOR=3.63, 95% CI [2.30, 5.72]) and cardiovascular medication (aOR=1.26, 95% CI [1.02, 1.55]). CONCLUSION: Standard approaches to pharmacological treatment for patients with FS differed between the public and private hospitals and may indicate a gap in quality of care.

EEG microstates show different features in focal epilepsy and psychogenic nonepileptic seizures.

OBJECTIVE: Electroencephalography (EEG) microstate analysis seeks to cluster the scalp's electric field into semistable topographical EEG activity maps at different time points. Our study aimed to investigate the features of EEG microstates in subjects with focal epilepsy and psychogenic nonepileptic seizures (PNES). METHODS: We included 62 adult subjects with focal epilepsy or PNES who received video-EEG monitoring at the epilepsy monitoring unit. The subjects (mean age = 42.8 ± 21.2 years) were distributed equally between epilepsy and PNES groups. We extracted microstates from a 4.4 ± 1.0-min, 21-channel resting-state EEG. We excluded subjects with interictal epileptiform discharges during resting-state EEGs. After preprocessing, we derived five main EEG microstates-MS1 to MS5-for the full frequency band (1-30 Hz) and frequency subbands (delta, 1-4 Hz; theta, 4-8 Hz; alpha, 8-12 Hz; beta, 12-30 Hz), using the MATLAB-based EEGLAB toolkit. Statistical features of microstates (duration, occurrence, contribution, global field power [GFP]) were compared between the groups, using logistic regression corrected for age and sex. RESULTS: We detected no differences in microstate parameters in the full frequency band. We found a longer duration (delta: B = -7.680, p = .046; theta: B = -16.200, p = .043) and a higher contribution (delta: B = -7.414, p = .035; theta: B = -7.509, p = .031) of MS4 in lower frequency bands in the epilepsy group. The PNES group showed a higher occurrence of MS5 in the delta subband (B = 3.283, p = .032). In the theta subband, a higher GFP of MS1 was associated with the PNES group (B = 5.674, p = .025), whereas a higher GFP of MS2 was associated with the epilepsy group (B = -6.579, p = .026). SIGNIFICANCE: Microstate features show differences between patients with focal epilepsy and PNES. EEG microstates could be a promising parameter, helping to understand changes in brain dynamics in subjects with epilepsy, and should be explored as a potential biomarker.

Using Verbally-Reported and Video-Observed Semiology to Identify Functional Seizures.

Diagnosis of functional seizures, also known as psychogenic nonepileptic seizures, starts with a clinical interview and description of the seizures. A targeted approach to this evaluation can provide valuable information to gauge the likelihood of functional seizures as compared with other similar conditions including but not limited to epileptic seizures. This review focuses on the use of patient and witness descriptions and seizure videos to identify patients with probable functional seizures. Particular emphasis is given to recognizing the limitations of the available data and the influence of health-care provider expertise on diagnostic accuracy.

Development and validation of a peripheral cell ratio and lactate score for differentiating status epilepticus from prolonged psychogenic nonepileptic seizures.

OBJECTIVE: Differentiating status epilepticus (SE) from prolonged psychogenic nonepileptic seizures (pPNES) can be difficult clinically. We aimed to define the utility of peripheral cell counts, cell ratios, and lactate levels in distinguishing SE from pPNES. METHODS: Retrospective two-center study investigating the sensitivity and specificity of acute (≤12 h of event offset) peripheral cell counts, cell ratios (neutrophil-lymphocyte ratio, neutrophil-monocyte ratio, monocyte-lymphocyte ratio, platelet-lymphocyte ratio, systemic immune-inflammatory index [SII], systemic inflammatory response index [SIRI]), and lactate levels in differentiating SE from pPNES. Patients were identified from two tertiary hospitals, with one forming the development cohort and the other the validation cohort. Using generalized additive models to generate biomarker vs time curves, optimal blood collection times were defined for set parameters. Three diagnostic scores combining neutrophil count, SII, or SIRI with lactate levels were developed and validated in separate cohorts. RESULTS: For the development cohort, 1262 seizure-like events were reviewed and 79 SE and 44 pPNES events were included. For the validation cohort, 241 events were reviewed and 20 SE and 11 pPNES events were included. Individually, the biomarkers generally had low sensitivity and reasonable specificity for differentiating SE from pPNES, with the neutrophil count, SIRI, and SII performing best with sensitivities of 0.65-0.84, specificities of 0.64-0.89, and ROC AUCs of 0.78-0.79. Lactate levels peaked at 60 min, while cell counts and ratios peaked after 240 min. Combining early peaking lactate levels and later peaking neutrophil count, SIRI or SII resulted in three scores that improved predictive potential with sensitivities of between 0.75 and 0.79, specificities between 0.93 and 1.00, and ROC AUCs of 0.89-0.91. SIGNIFICANCE: Lactate levels peak early post-SE, whereas cell counts and ratios do so later. The differing post-event time profiles of lactate levels vs neutrophil count, SIRI, and SII allow incorporation into three separate scores which can assist in differentiating SE from pPNES.

A Curious Case of a Child With Recurrent Twisting Movements of Limbs.

Paroxysmal kinesigenic dyskinesia (PKD) is characterized by recurrent attacks of abnormal involuntary movements that are triggered by sudden movement, intention to move, or acceleration. A 10-year-old boy presented with paroxysmal, involuntary twisting movements of the left upper and lower limbs, precipitated by sudden body movements, lasting for 10-15 seconds and subsiding spontaneously. On examination, choreiform movements were observed, which were precipitated by sudden movements during some activities. The patient responded to carbamazepine with complete subsidence of the movements. The diagnosis of PKD was further confirmed by genetic testing. A high suspicion index helps in the prompt and early diagnosis of this rare entity.

Psychiatric and psychological assessment of Spanish patients with drug-resistant epilepsy and psychogenic nonepileptic seizures (PNES) with no response to previous treatments.

OBJECTIVE: Psychogenic nonepileptic seizures (PNES) are common imitators of epileptic seizures. Refractoriness to antiseizure medication hinders the differential diagnosis between ES and PNES, carrying deleterious consequences in patients with PNES. Psychiatric and psychological characteristics may assist in the differential diagnosis between drug-resistant epilepsy (DRE) and PNES. Nevertheless, current comprehensive psychiatric and psychological descriptive studies on both patient groups are scarce and with several study limitations. This study provides a comprehensive psychiatric and psychological characterization of Spanish patients with DRE and PNES. METHOD: A cross-sectional and comparative study was completed with 104 patients with DRE and 21 with PNES. Psychiatric and psychological characteristics were assessed with the HADS, SCL-90-R, NEO-FFI-R, PDQ-4+, COPE, and QOLIE-31 tests. Parametric and non-parametric tests were used, and regression models were fit to further explore factors affecting patients' life quality. RESULTS: Patients with PNES had greater levels of somatization and extraversion and were associated with benzodiazepine intake. Patients with DRE showed greater narcissistic personality disorder symptoms than those with PNES. In patients with DRE, difficulty in performing basic needs-related tasks and greater psychological distress severity and seizure frequency were associated with poorer life quality. In contrast, being a woman, having a psychiatric disorder history, and greater psychiatric symptoms' intensity were associated with poorer life quality in patients with PNES. CONCLUSION: Patients with DRE and PNES share similar psychiatric and psychological characteristics, with only very few being significantly different.

Pediatric psychogenic non-epileptic seizures: A retrospective observational cohort study at a quaternary center.

BACKGROUND: Psychogenic non-epileptic seizures (PNES) represent a common functional disorder in the pediatric population. We aimed to characterize pediatric PNES by describing their clinical characteristics, PNES semiologies, and healthcare pathway towards and after diagnosis. MATERIAL AND METHODS: This was a retrospective, observational chart review of pediatric patients aged 6 to 18 years admitted between December 2020 and December 2021 for spell classification or suspected PNES. Psychogenic non-epileptic seizure diagnosis was made by the capture of a typical event on video electroencephalogram (vEEG). We used descriptive statistics to summarize demographic and clinical characteristics. RESULTS: We included 26 patients (18 females, 69.2%) with a mean age (SD) of 13.9 (2.5) years. Pre-morbid neurologic and psychiatric conditions included: epilepsy (23.1%), migraine (46.2%), mild traumatic brain injury (26.9%), anxiety (57.7%), ADHD (34.6%), and depression (30.8%). Six patients (23.1%) had a prior diagnosis of PNES. 14 patients (53.8%) presented with convulsive, and 6 (23.1%) each with non-convulsive and mixed PNES. Patients were seen by a range of providers prior to diagnosis including ED providers (50%), neurologists (53.8%), pediatricians (34.6%), and psychology/psychiatry (11.5%). Emergency department evaluation occurred for 13 patients (50%) on 15 occasions, and six (23.1%) were admitted to the hospital. The median (p25-p75) time from PNES onset to presentation and diagnosis at our institution was 3.5 (1.5-6.2) and 4.1 (3-7) months, respectively. A total of 33 events from the 26 patients were captured on vEEG. The most frequent semiologies in our cohort were rhythmic motor (27.3%) followed by equal frequency (18.2%) of complex motor and dialeptic. Eighteen patients (69.2%) were followed after the PNES diagnosis, for a median (p25-p75) of 17.3 months (6.3-21) with variable outcome. CONCLUSION: Pediatric PNES has female predominance and often presents with comorbid psychosocial stressors and psychiatric conditions. High clinical suspicion and early recognition are crucial to decrease healthcare utilization and establish timely diagnosis and treatment.

Principles for delivering improved care of people with functional seizures: Closing the treatment gap.

Patients diagnosed with functional (psychogenic nonepileptic) seizures have similar or greater levels of disability, morbidity and mortality than people with epilepsy, but there are far fewer treatment services. In contrast to epilepsy, the current understanding of pathophysiological mechanisms and the development of evidence-based treatments for functional seizures is rudimentary. This leads to high direct healthcare costs and high indirect costs to the patient, family and wider society. There are many patient, clinician and system-level barriers to improving outcomes for functional seizures. At a patient level, these include the heterogeneity of symptoms, diagnostic uncertainty, family factors and difficulty in perceiving psychological aspects of illness and potential benefits of treatment. Clinician-level barriers include sub-specialism, poor knowledge, skills and attitudes and stigma. System-level barriers include the siloed nature of healthcare, the high prevalence of functional seizures and funding models relying on individual medical practitioners. Through the examination of international examples and expert recommendations, several themes emerge that may address some of these barriers. These include (1) stepped care with low-level, brief generalised interventions, proceeding to higher level, extended and individualised treatments; (2) active triage of complexity, acuity and treatment readiness; (3) integrated interdisciplinary teams that individualise formulation, triage, and treatment planning and (4) shared care with primary, emergency and community providers and secondary consultation. Consideration of the application of these principles to the Australian and New Zealand context is proposed as a significant opportunity to meet an urgent need.

Subjective seizure symptom reporting in functional/dissociative seizures and epilepsy: Effects of sampling technique and patient characteristics.

BACKGROUND: Differences in subjectively reportable ictal experiences between epilepsy and functional/dissociative seizures (FDS) have received less attention than visible manifestations. Patients with FDS (pwFDS) tend to report seizure symptoms differently than patients with epilepsy (pwE). The effects of symptom elicitation method and mediation by psychopathological traits have not been examined and may aid in differentiating the disorders. METHOD: Analysis of responses of 24 pwE and 28 pwFDS in interviews exploring ictal experiences through open questioning followed by structured closed questioning using possible symptom prompts (74-item modified Psychosensory-Psychomotor Phenomena Interview, PPPI); self-report of psychological profile (HADS-A, HADS-D, PHQ-15, DES-T, THQ, PCL-C). RESULTS: Symptom prompting with PPPI elicited three times more seizure symptoms than open questions in pwE (median 34 vs. 11.5, p = 0.005) and over four times more in pwFDS (42.5 vs. 11, p = 0.001). Intra-ictal symptoms were reported freely more frequently by pwE (median 6.5 vs. 4, p = 0.005), while pwFDS reported more pre-ictal symptoms after prompts (median 6 vs 14.5, p = 0.004). The difference between freely reported and PPPI-elicited symptoms correlated with different psychopathological traits in pwE and pwFDS. Symptoms of anxiety (HADS-A) correlated more strongly with prompted symptoms among pwE than pwFDS (z = 2.731, p = 0.006). CONCLUSION: Prompting generates more detailed ictal symptom profiles than simply encouraging patients to narrate their subjective seizure experiences. While pwFDS freely reported fewer symptoms related to the intra-ictal period compared to pwE, pwFDS reported more pre-ictal symptoms than pwE when prompted. Differences in the psychopathological traits associated with the number of peri-ictal symptoms captured by symptom prompting in pwE and pwFDS possibly reflect etiological or psychological differences between these patient groups.

The clinical characteristics of childhood-onset and late-onset functional seizures: How do they differ?

BACKGROUND: We investigated childhood-onset functional seizures (FS) and late-onset FS and hypothesized that there are differences in their characteristics. METHODS: In this retrospective study, we investigated all patients with confirmed FS with an age at onset of 14 years or younger and those with an age at onset of 50 years or older, who were admitted to the epilepsy monitoring units at one center in Iran (Shiraz Comprehensive Epilepsy Center, from 2008 until 2022) and one center in the USA (Vanderbilt University Medical Center, from 2011 until 2022). RESULTS: One-hundred and forty patients were included. They included 80 patients with childhood-onset FS and 60 with late-onset FS. Those with late-onset FS were more likely to have medical comorbidities compared with the patients with childhood-onset FS (OR = 13.9). Those with late-onset FS more likely had a history of head injury compared with the patients with childhood-onset FS (OR = 5.97). Duration of illness was significantly longer in patients with childhood-onset FS compared with the patients with late-onset FS (6 years vs. 2 years). CONCLUSION: Our study identified several similarities and differences in the clinical characteristics and predisposing factors of patients with childhood-onset and late-onset FS. In addition, we found that childhood-onset FS is more likely to remain undiagnosed and thus untreated for many years. These findings provide additional evidence that FS is a heterogenous condition and we propose that a proportion of the differences between patients may be accounted for by age-associated factors.

Depersonalization/Derealization Disorder and Neural Correlates of Trauma-related Pathology: A Critical Review.

Depersonalization and derealization refer to an estranged state of mind that involves a profound feeling of detachment from one's sense of self and the surrounding environment, respectively. The phenomena co-occur on a continuum of severity, ranging from a transient experience as a normal reaction to a traumatic event to a highly debilitating condition with persistent symptoms, formally described as depersonalization/derealization disorder (DPDR). Lack of awareness of DPDR is partly due to a limited neurobiological framework, and there remains a significant risk of misdiagnosis in clinical practice. Earlier literature has focused on several brain regions involved in the experience of depersonalization and derealization, including adaptive responses to stress via defense cascades comprising autonomic functioning, the hypothalamic-pituitary-adrenal (HPA) axis, and various other neurocircuits. Recent evidence has also demonstrated the role of more complex mechanisms that are bolstered by dissociative features, such as emotional dysregulation and disintegration of the body schema. This review intends to abridge the prevailing knowledge regarding structural and functional brain alterations associated with DPDR with that of its heterogenic manifestations. DPDR is not merely the disruption of various sensory integrations, but also of several large-scale brain networks. Although a comprehensive antidote is not available for DPDR, a holistic route to the neurobiological context in DPDR may improve general understanding of the disorder and help afflicted individuals re-establish their sense of personal identity. Such information may also be useful in the development of novel pharmacological agents and targeted psychological interventions.

A systems biology approach for discovering the cellular and molecular aspects of psychogenic non-epileptic seizure.

Objectives: Psychogenic non-epileptic seizure (PNES) is the most common non-epileptic disorder in patients referring to epilepsy centers. Contrary to common beliefs about the disease's harmlessness, the death rate of PNES patients is similar to drug-resistant epilepsy. Meanwhile, the molecular pathomechanism of PNES is unknown with very limited related research. Thus, the aim of this in silico study was to find different proteins and hormones associated with PNES via a systems biology approach. Methods: Different bioinformatics databases and literature review were used to find proteins associated with PNES. The protein-hormone interaction network of PNES was constructed to discover its most influential compartments. The pathways associated with PNES pathomechanism were found by enrichment analysis of the identified proteins. Besides, the relationship between PNES-related molecules and psychiatric diseases was discovered, and the brain regions that could express altered levels of blood proteins were discovered. Results: Eight genes and three hormones were found associated with PNES through the review process. Proopiomelanocortin (POMC), neuropeptide Y (NPY), cortisol, norepinephrine, and brain-derived neurotrophic factor (BDNF) were identified to have a high impact on the disease pathogenesis network. Moreover, activation of Janus kinase-signaling transducer and activator of transcription (JAK-STAT) and JAK, as well as signaling of growth hormone receptor, phosphatidylinositol 3-kinase /protein kinase B (PI3K/AKT), and neurotrophin were found associated with PNES molecular mechanism. Several psychiatric diseases such as depression, schizophrenia, and alcohol-related disorders were shown to be associated with PNES predominantly through signaling molecules. Significance: This study was the first to gather the biochemicals associated with PNES. Multiple components and pathways and several psychiatric diseases associated with PNES, and some brain regions that could be altered during PNES were suggested, which should be confirmed in further studies. Altogether, these findings could be used in future molecular research on PNES patients.

FKBP5 blockade may provide a new horizon for the treatment of stress-associated disorders: An in-silico study.

OBJECTIVE: We searched for, from the FDA (Food and Drug Administration-USA)-approved drugs, inhibitors of FKBP5 with tolerable adverse effect profiles (eg, mild headache, sedation, etc.) and with the ability to cross the blood brain barrier (BBB), using bio-informatics tools (in-silico). This may pave the road for designing clinical trials of such drugs in patients with functional seizures (FS) and other stress-associated disorders. METHODS: Several databases were used to find all the approved drugs that potentially have interactions with FKBP51 protein [ie, CTD gene-chemical interaction section of FKBP51 protein of Harmonizome of Mayaanlab, DrugCenteral database, PDID (Protein Drug Interaction Database), DGIdb (the Drug Gene Interaction database)]. Other databases were also searched [eg, clinicaltrials.gov; DRUGBANK (the FASTA format of the FKBP51 protein was imported to the target sequencing section of the database to find the associated drugs), and the STITCH database (to find the related chemical interaction molecules)]. RESULTS: After a comprehensive search of the designated databases, 28 unique and approved drugs were identified. Fluticasone propionate and Mifepristone and Ponatinib, Mirtazapine, Clozapine, Enzalutamide, Sertraline, Prednisolone, Fluoxetine, Dexamethasone, Clomipramine, Duloxetine, Citalopram, Chlorpromazine, Nefazodone, and Escitalopram are inhibitors of FKBP5 and have BBB permeability. SIGNIFICANCE: While the current in-silico repurposing study could identify potential drugs (that are already approved and are widely available) for designing clinical trials in patients with stress-associated disorders (eg, FS), any future clinical trial should consider the pharmacological profile of the desired drug and also the characteristics and comorbidities of the patients in order to foster a success.

The value of ethical principles to reflect on emerging issues in epilepsy care and research.

In the age of patient participation, ethics are more important than ever to help guide clinicians in situations of uncertainty. Principles of Biomedical Ethics by James F. Childress and Thomas L. Beauchamp remains the most important reference in medical ethics. In their work, they conceptualize four principles designed to help guide clinicians in decision making, notably beneficence, non-maleficence, autonomy, and justice. While using ethical principles dates back to at least Hippocrates, the introduction by Beauchamp and Childress of the principles of autonomy and justice have helped to deal with new challenges. This contribution will discuss how the principles can help elucidate issues of patient participation in epilepsy care and research using two case studies. METHODS: In this paper, we will discuss the equilibrium to be found between two principles (beneficence and autonomy) in the context of emerging debates in epilepsy care and research. The methods section details the specificities of each principle and their relevance to epilepsy care and research. RESULTS AND DISCUSSION: Using two case studies, we will explore the potential and limits of patient participation and how the ethical principles may help to provide nuance and reflection in this emerging debate. First of all, we will explore a clinical case which involves a conflictual situation with the patient and family about psychogenic nonepileptic seizures. We will then discuss an emerging issue in epilepsy research, namely the integration of persons with severe refractory epilepsy as patient research partners.