Background: Temporal lobe epilepsy is often accompanied by comorbid symptoms such as anxiety, depression, and cognitive dysfunction. Research indicates a close relationship between blood-brain barrier (BBB) impairment and these symptoms. DL-3n-butylphthalide (NBP) has been reported to protect the BBB, but the molecular mechanisms by which NBP protects the BBB in epilepsy models remain unclear. This study investigated the protective effects of NBP on the BBB in epileptic mice to alleviate the comorbid symptoms associated with epilepsy.
Methods: We utilized Mendelian randomization to explore the association between VEGFA and epilepsy. In the animal experiments, adult male C57BL/6 mice were used to establish a KA-induced epilepsy model, receiving daily intraperitoneal injections of NBP for 30 days. After this period, behavioral experiments and Western blot analyses were conducted to assess whether the comorbid symptoms of epilepsy and BBB disruption were alleviated. Subsequently, RNA sequencing was performed to analyze potential signaling pathways involved in the pharmacological effects of NBP.
Results: Elevated circulating levels of VEGFA may be a risk factor for the onset of epilepsy. Animal experiments demonstrated that NBP treatment improved BBB disruption in KA-induced epileptic mice and alleviated depressive and anxious behaviors, as well as cognitive impairments. RNA sequencing results suggest that the pharmacological effects of NBP may be mediated through the inhibition of complement and coagulation cascades.
Conclusion: NBP can protect the integrity of the BBB in KA-induced epileptic mice, inhibiting depression, anxiety behaviors, and cognitive dysfunction. This pharmacological effect may be associated with pathways involving complement and coagulation cascades.
Objective: To investigate the impact of epilepsy surgery on the developmental outcome in infancy with pharmacoresistant epilepsy and its associated factors.
Method: This systematic review and meta-analysis was conducted in adherence with PRISMA 2020. Literature searching was done using PubMed, CENTRAL, and Scopus database. The risk of bias within included studies was evaluated using ROBINS-I. The developmental outcome was explored by comparing the developmental quotient (DQ) between before and after the epilepsy surgery. The subgroup analysis was planned for sex, etiology, affected side, affected lobe, surgical method and intention, and seizure-free state after the surgery. Age at onset of epilepsy, age at surgery, duration of disease, and follow-up time were explored as well in meta-regression.
Result: Ten articles were included in this review yielded 361 participants. The overall meta-analysis did not show a significant change of DQ after the surgery (MD -2.38; 95%CI -5.53 - 0.78). The comparison of delta DQ between seizure-free and not seizure-free population was not significantly different (seizure-free group; MD -4.33; 95%CI -20.37 - 11.70 vs. non-seizure-free group; MD -4.34; 95%CI -16.22 - 7.54). No independent significant moderator was identified.
Conclusion: Epilepsy surgery may offer some benefits in infants with PRE despite most participants having stable developmental progress. Seizure-free state following epilepsy surgery is crucial for infants' development; however, not all epileptogenic lesions are located in the favourable and resectable area. Hence, seizure control with palliative surgery shall be offered.
Epilepsies are complex neurological entities usually co-existing with neuropsychiatric comorbidities. We already demonstrated that microinjection of oxytocin (OT) into the central nucleus of amygdala (CeA) induces hypergrooming in Wistar rats, a model of compulsion. Furthermore, the Wistar Audiogenic Rat (WAR) strain is a genetic model of generalized tonic-clonic seizures. Here we quantified grooming behavior in WAR, with grooming scores, flowcharts and directed graphs of syntactic and non-syntactic grooming chains, after bilateral administration of OT or saline (SAL) into the CeA. Our current pioneer behavioral description considers that hypergrooming (compulsion) in WARs is a comorbidity because: (1) WARs have the highest grooming scores, when exposed only to novelty (2), WARs have better grooming scores than Wistars after CeA-SAL, (3) Epileptic WARs perform much better than Wistars in OT-CeA-dependent stereotyped behavioral sequences (flowcharts of syntactic/non-syntactic grooming chains). One additional observation is that the behavioral sequences here demonstrated can be modeled as reliable Markov chains. In conclusion we can drive hypergrooming in WARs, defined previously as a model of ritualistic motor behavior in Wistar rats, with OT from CeA, one of the principal amygdala complex outputs. As perspectives, ongoing cellular studies are on their way, to demonstrate the neural network, certainly incorporating cortico-striatal-thalamic-basal ganglia-cortical circuits, driven from CeA OT-dependent grooming pattern, a stereotyped, sequential and complex array of behaviors, and its association with seizure susceptibility.
Purpose: Late-onset epilepsy (LOE) usually refers to the development of epilepsy at the age of 50 years or older. Approximately 20 % of LOE cases are diagnosed as late-onset epilepsy of unknown etiology (LOUE) due to a lack of an identifiable cause. The aim of this study was to investigate the clinical features, seizure and cognitive outcomes of patients with LOUE in West China.
Methods: Patients diagnosed with LOUE at West China Hospital between January 2015 and December 2022 were retrospectively recruited. The seizure and cognitive outcome were followed up for at least 1 year after discharge. Logistic regression models were applied to investigate the risk factors of recurrent seizure and cognitive impairment in patients with LOUE.
Results: We included 286 LOUE patients with a median seizure onset age of 59 years. The most common seizure types were focal to bilateral tonic-clonic seizure (61.9 %) and focal non-motor seizure (37.0 %). Two-hundred and seventy-seven (96.9 %) patients underwent video electroencephalography (VEEG), with seizures recorded in 11.9 % of patients and interictal epileptiform discharges in 58.2 % cases. Majority of the patients (73.4 %) received monotherapy, with levetiracetam, oxcarbazepine and valproate being the most commonly prescribed anti-seizure medications. During the follow-up, 69.1 % of patients achieved seizure-free. Multivariate analysis identified ictal event recorded during VEEG monitoring (OR:0.205, 95 % CI: 0.045-0.932, p = 0.040) and memory impairment (OR:2. 470, 95 % CI: 1.181-5.167, p = 0.016) as significant factors associated with recurrent seizure. Twenty-two patients were classified as cognitive impairment. The onset age (OR:1.095, 95 % CI:1.032-1.162, p = 0.003) and total Fazekas score (OR = 6.770, 95 % CI:1.972-23.241, p = 0.002) were significant risk factors associated with cognitive dysfunction.
Conclusion: LOUE is generally a benign form of epilepsy with a high percentage of patients achieving seizure-free status. However, these patients are at a higher risk of memory decline and cognitive dysfunction.
Purpose: Recent studies have shown that late-onset epilepsy (LOE) is accompanied with cognitive decline and increased risk of dementia, particularly Alzheimer's disease (AD). However, the pathophysiological mechanism underlying the cognitive decline in LOE remains unclear. The aim of current study was to evaluate the relationship between glymphatic system (GS) function and cognitive decline in LOE patients using the diffusion tensor imaging (DTI) analysis along the perivascular space (DTI-ALPS).
Methods: Medical records and neuro-imaging data were obtained from 21 LOE patients with cognitive decline, 14 LOE patients without cognitive decline, and 20 age- and sex-matched healthy controls (HCs). Plasma biomarkers including Aβ42 and Aβ40 were examined using single-molecule array (Simoa) assays. The DTI-ALPS parameter was calculated and correlated with the clinical characteristics of LOE, including age, seizure frequency, duration of epilepsy, Mini-Mental State Examination (MMSE), and Aβ42/40. Regression models were used to evaluate the influencing factors of DTI-ALPS index.
Results: LOE patients exhibited a decreased ALPS index and Aβ42/40 compared with the HCs. Post-hoc analysis indicated that the DTI-ALPS index and Aβ42/40 in LOE patients with cognitive decline was significantly lower in relative to LOE patients without cognitive decline and HCs. Spearman correlations showed a negative correlation between DTI-ALPS index and age, seizure frequency and disease duration while a positive correlations between the DTI-ALPS index and Aβ42/40 and MMSE scores in LOE patients. Linear regression analysis suggested that the DTI-ALPS index was independently related to age, Aβ42/40 and MMSE score after correcting for gender, education, and vascular risk factors.
Conclusion: Our findings using DTI-ALPS method found a positive correlation between cognitive decline and GS dysfunction in LOE patients, and may indicate a potential internal link between age-related LOEU and dementia formation. Therefore, the DTI-ALPS index may serve as a potential imaging marker for diagnosing and monitoring the GS function in LOE patients.
Epilepsy imposes substantial challenges on informal caregivers, who play a vital role in supporting individuals with this condition. This review aims to explore the burden experienced by informal caregivers of adults with epilepsy and identify critical factors that influence their overall experience. A literature review was conducted following PRISMA guidelines. PubMed and ScienceDirect were searched for identifying original research articles published in English from January 2005 till the end of February 2024. Studies were critically appraised using the AXIS Critical Appraisal Tool for Cross-Sectional Studies. Data were extracted and a narrative synthesis was performed. Twelve studies involving 1.265 participants were included. Eight studies were rated as high quality, while four were rated as fair quality. Six primary determinants of caregiver burden were identified: care-recipient characteristics, caregiver characteristics, psychological and physical factors, availability of support system, ethnicity and culture, and stigma. The majority of studies reported mild-to-moderate levels of caregiver burden, reflecting the diverse challenges faced by caregivers providing assistance to adults with epilepsy. While this review identifies several factors influencing caregiver burden, prospective longitudinal and qualitative studies are essential to unravel the multidimensional nature of caregiver burden and its variations across diverse cultural settings.
The objective of this study was to evaluate the effect of seletracetam (SEL), a potent modulator of synaptic vesicle glycoprotein 2A (SV2A), in patients with photoparoxysmal EEG response (PPR) to intermittent photic stimulation (IPS) as proof-of-principle of efficacy in patients with epilepsy. In this multicenter, single-blind Phase II study, adults with photosensitive epilepsy, with/without concomitant antiseizure medication therapy, underwent IPS under 3 eye conditions (at eye closure, eyes closed and eyes open) after a single oral dose of placebo (day - 1) or SEL (day 1; 0.5, 1, 2, 4, 10, or 20 mg). Complete suppression was a standardized photosensitivity range reduction to 0 over ≥ 1 time points for all eye conditions. Partial suppression was a ≥ 3-point reduction over ≥ 3 testing times vs the same time points on day - 1 in ≥ 1 eye condition. In addition, pharmacokinetics and safety were assessed. Of 27 evaluable patients, 9 reentered to receive a 2nd dosing 1-6 months later, providing a total of 36 individual exposures. At all doses administered - even the lowest -, several subjects reached a complete abolishment of PPR, with a rapid onset of effect. Overall, complete abolishment of PPR was obtained in 40-71 % of the patients; the effect increasing with the dose. In terms of effective doses to suppress PPR, SEL was at least 1,500 times more potent than levetiracetam and 10-20 times more potent than brivaracetam. Adverse events of SEL, including dizziness and somnolence, were mild to moderate. Pharmacokinetics of SEL demonstrated rapid absorption and a linear dose:plasma level relationship. This proof-of-principle study demonstrates that - based on our own experience - SEL is the most potent compound ever tested in the photosensitivity model.
This narrative review aims to identify and summarize existing research to better understand the pathophysiological and neuroanatomical bases of social cognition deficits in people with epilepsy. The neuroanatomical basis of social cognition was primarily examined in healthy subjects. In healthy individuals, social cognition is supported by a complex network of interconnected brain regions. Facial emotion recognition relies on a distributed set of structures, including the occipitotemporal neocortex, the temporoparietal and prefrontal areas, and the putamen with a pivotal role of the amygdala. Theory of mind primarily involves the dorsal medial prefrontal cortex and temporoparietal junction, while empathy engages the anterior insular and cingulate cortices. In people with epilepsy, most functional neuroimaging studies have focused on facial emotion recognition, primarily in patients with temporal lobe epilepsy. Nevertheless, across various domains of social cognition, abnormal activations and disrupted connectivity within social cognition networks are consistently observed, regardless of the focus location. Aberrant connectivity has also been noted in the few studies involving patients with generalized epilepsy. In focal epilepsy, the amygdala remains a central region for facial emotion recognition, irrespective of whether the epilepsy is localized to the temporal or frontal lobes. For theory of mind studies, regions typically identified in healthy individuals, such as the medial prefrontal cortex, exhibit either hyperactivation or reduced activation in people with focal epilepsy, complicating interpretation. In the domain of empathy, a study involving patients with idiopathic generalized epilepsy reported decreased activation in core regions commonly identified in healthy individuals, particularly the anterior cingulate cortex and anterior insula. The limited data available in the literature suggest that key regions shared between social cognition and epilepsy networks consistently contribute to these disruptions and may serve as potential targets for future neuromodulation interventions.
Traumatic brain injury is a significant risk factor for the development of post-traumatic epilepsy (PTE), posing a major clinical challenge. This review discusses the critical role of GABAergic interneurons and reactive astrogliosis in the pathophysiology of post-traumatic epilepsy, integrating findings from our research group within the traumatic brain injury context with recent literature to highlight the impact of excitation-inhibition imbalance. We analyzed alterations in interneuron populations, specifically subtypes expressing the calcium-binding proteins parvalbumin, calretinin, and calbindin, and their association with an increased risk of epileptogenesis after TBI. Furthermore, we detail the role of reactive astrogliosis, elucidating how dysregulated astrocytic functions, including impaired glutamate homeostasis and aberrant calcium signaling, contribute to an environment conducive to seizure activity. Increased expression of glial fibrillary acidic protein and crystallin alpha-B in reactive astrocytes identified in contused human tissue suggests their involvement in exacerbating epileptogenic circuits. Our findings emphasize the intricate interactions between GABAergic interneurons and astrocytes, underscoring the need for a comprehensive understanding of the mechanisms underlying post-traumatic epilepsy. By bridging our group's data with existing evidence, this review establishes a foundation for future studies aimed at validating systemic biomarkers and developing targeted therapies to prevent or mitigate epilepsy progression following TBI. These insights are essential for addressing the complexities of drug-resistant epilepsy in affected patients.
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