Search Results (66)

Status epilepticus occurs when a seizure lasts more than five minutes or when multiple seizures occur with incomplete return to baseline. SE induces a myriad of pathological changes involving synaptic and extra-synaptic factors. The transition from a self-limiting seizure to a self-sustaining one is established by maladaptive receptor trafficking, whereby GABA_A receptors are progressively endocytosed while glutamatergic receptors (NMDA and AMPA) are transported to the synaptic membrane, causing excitotoxicity and alteration in glutamate-dependent downstream signaling. The subsequent influx of Ca²⁺ exposes neurons to increased levels of [Ca²⁺]i, which overwhelms mitochondrial buffering, resulting in irreversible mitochondrial membrane depolarization and mitochondrial injury. Oxidative stress resulting from mitochondrial leakage and increased production of reactive oxygen species activates the inflammasome and induces a damage-associated molecular pattern. Neuroinflammation perpetuates oxidative stress and exacerbates mitochondrial injury, thereby jeopardizing mitochondrial energy supply in a state of accelerated ATP consumption. Additionally, Ca²⁺ overload can directly damage neurons by activating enzymes involved in the breakdown of proteins, phospholipids, and nucleic acids. The cumulative effect of these effector pathways is neuronal injury and neuronal death. Surviving neurons undergo long-term alterations that serve as a substrate for epileptogenesis. This review highlights the multifaceted mechanisms underlying SE self-sustainability, pharmacoresistance, and subsequent epileptogenesis. Full article

Background: Pharmacoresistant epilepsy affects approximately one-third of all epilepsy patients, and resective surgery may offer favorable outcomes for carefully selected patients with focal epilepsy. The accurate identification of the epileptogenic zone (EZ) is essential for successful surgery, particularly in cases where non-invasive diagnostics are inconclusive. Invasive diagnostics with stereoelectroencephalography (SEEG) offer a reliable approach to localizing the EZ, especially in MRI-negative cases. Methods: This retrospective study analyzed the data of 22 patients with pharmacoresistant epilepsy who underwent frameless stereotactic SEEG electrode implantation with automated CT-based registration between September 2016 and November 2024. For measuring accuracy, Euclidean distance, radial deviation, angular deviation, and depth deviation were calculated for each electrode. Results: A total of 153 depth electrodes were implanted, targeting various cortical regions. The median Euclidean distance at the entry point was 1.54 mm (IQR 1.31), with a radial deviation of 1.33 mm (IQR 1.32). At the target level, the median Euclidean distance was 2.61 mm (IQR 1.53), with a radial deviation of 1.67 mm (IQR 1.54) and depth deviation of 0.95 mm (IQR 2.43). Accuracy was not significantly affected by electrode order, anatomical location, skull thickness, or intracranial length. Conclusions: These findings demonstrate that frameless stereotactic SEEG electrode implantation is safe and feasible for identifying the EZ. The integration of automatic intraoperative CT-based registration ensures precision. While maintaining workflow efficiency, it achieves accuracy comparable to frame-based methods. Further studies with larger cohorts are warranted to validate these results and assess their impact on surgical outcomes. Full article

Background: Temporal lobe epilepsy is the most common pharmaco-resistant type of epilepsy. The chance of obtaining seizure freedom after resective surgery in pharmaco-resistant mesial temporal lobe patients (mTLE) is significantly higher compared to pharmaceutical treatment (at least 50–60% compared to less than 15%). However, some factors (e.g., craniotomy) may prevent epilepsy patients undergoing surgery. A recent advancement in epilepsy surgery, i.e., magnetic resonance guided laser interstitial thermal therapy (MRgLITT), has become an attractive alternative for performance of selective amygdala-hippo-campectomy, especially because of its minimal invasiveness. Among other medial temporal lobe structures, the hippocampus is particularly important for successful processing of vestibular inputs. Nevertheless, it is still unclear whether mTLE patients who underwent MRgLITT perform worse on vestibular-dependent tests, including balancing, spatial orientation and rotational memory. Methods: Nine patients (Age 40.1 ± 14.5; 2 females) underwent vestibular-dependent assessments before and after MRgLITT using the following test battery: (I) clinical balancing test (CBT), (II) triangle completion test (TCT) and (III) rotational memory test (RM). Results: We found significant improvement from pre- to post-surgery in the vestibular-dependent spatial orientation test, namely in the wheelchair condition of the triangle completion test. Additionally, the obtained effect sizes were medium to large in favor of post-surgery assessment for the majority of conditions in the three tests applied in this study, indicating that the assessment of a larger number of patients could also, potentially, lead to significant results in these cases. Conclusions: This plausibility study is the first to assess vestibular-dependent balancing, spatial orientation and rotational memory functions before and after MRgLITT in mTLE patients. Even with a small sample of nine patients, significant changes and medium to high effect sizes in favor of surgery were observed. Nevertheless, prospective studies with larger sample sizes are necessary for appropriate estimation of MRgLITT effectiveness in these functional domains. Full article

Background: The Notch signaling pathway is an important regulator of stem cell activity in various tissues, including the central nervous system. It has been implicated in neurodevelopmental processes, including neuronal differentiation and synaptic plasticity. Research suggests that its expression may be associated with certain epileptogenic lesions, particularly those with neurodevelopmental origin. The aim of this study was to investigate the expression of Notch-1 in brain biopsies from various cases of pharmacoresistant epilepsy. Methods: Here, we used immunohistochemistry staining to retrospectively analyze 128 developmental lesions associated with pharmacoresistant epilepsy, including 13 cases with focal cortical dysplasia (FCD) type I, 39 with FCD type II, 37 with hippocampal sclerosis (HS), 23 with FCD IIIc, 9 with mild malformations of cortical development (MCD), 4 cases with mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy (MOGHE), and 3 with tuberous sclerosis (TS). The tissues were stained for Neurofilament protein, Vimentin, S-100 protein, NeuN, and GFAP, as well as the stem cell marker Notch-1. Tissue that stained positively for Notch-1 was further characterized. Results: A positive Notch-1 reaction was found in all cases of FCD type IIb and TS, where it appeared in balloon cells but not in dysmorphic neurons, and in a single case of meningioangiomatosis (FCD IIIc), where it stained spider-like cells. Notch-1-positive cells showed a stem-like, glio-neuronal precursor immunophenotype. No staining was observed in the remaining cases with FCD type I, type III, HS, mild MCD, and MOGHE. Conclusions: Notch-1 displays a distinct pattern of expression in some epileptogenic lesions, potentially highlighting a stem cell-like origin or neurodevelopmental abnormalities contributing to pharmacoresistant epilepsy; however, it is not a general marker of such lesions. Its differential expression may prove useful in distinguishing between different types of FCD or other cortical malformations, which could assist in both their diagnosis and potentially in the development of more targeted therapeutic approaches. Further studies with different stem cell markers are needed in this direction. Full article

Epilepsy of infancy with migrating focal seizures (EIMFS) is a rare, serious, and pharmacoresistant epileptic disorder often linked to gain-of-function mutations in the KCNT1 gene. KCNT1 encodes the sodium-activated potassium channel known as SLACK, making small molecule inhibitors of SLACK channels a compelling approach to the treatment of EIMFS and other epilepsies associated with KCNT1 mutations. In this manuscript, we describe a hit optimization effort executed within a series of 2-aryloxy-N-(pyrimidin-5-yl)acetamides that were identified via a high-throughput screen. We systematically prepared analogs in four distinct regions of the scaffold and evaluated their functional activity in a whole-cell, automated patch clamp (APC) assay to establish structure-activity relationships for wild-type (WT) SLACK inhibition. Two selected analogs were also profiled for selectivity versus other members of the Slo family of potassium channels, of which SLACK is a member, and versus a panel of structurally diverse ion channels. The same two analogs were evaluated for activity versus the WT mouse channel as well as two clinically relevant mutant human channels. Full article

Background: The pre-surgical evaluation for drug-resistant epilepsy achieves seizure freedom in only 50–60% of patients. Efforts to identify quantitative intracranial EEG (qEEG) biomarkers of epileptogenicity are needed. This review summarizes and evaluates the design of qEEG studies, discusses barriers to biomarker adoption, and proposes refinements of qEEG study protocols. Methods: We included exploratory and prediction prognostic studies from MEDLINE and Scopus published between 2017 and 2023 that investigated qEEG markers for identifying the epileptogenic network as the surgical target. Cohort parameters, ground truth references, and analytical approaches were extracted. Results: Out of 1789 search results, 128 studies were included. The study designs were highly heterogeneous. Half of the studies included a non-consecutive cohort, with sample sizes ranging from 2 to 166 patients (median of 16). The most common minimum follow-up was one year, and the seizure onset zone was the most common ground truth. Prediction studies were heterogeneous in their analytical approaches, and only 25 studies validated the marker through post-surgical outcome prediction. Outcome prediction performance decreased in larger cohorts. Conversely, longer follow-up periods correlated with higher prediction accuracy, and connectivity-based approaches yielded better predictions. The data and code were available in only 9% of studies. Conclusions: To enhance the validation qEEG markers, we propose standardizing study designs to resemble clinical trials. This includes using a consecutive cohort with long-term follow-up, validating against surgical resection as ground truth, and evaluating markers through post-surgical outcome prediction. These considerations would improve the reliability and clinical adoption of qEEG markers. Full article

Epilepsy is a brain disorder characterized by a persistent predisposition to epileptic seizures. With various etiologies of epilepsy, a significant proportion of patients develop pharmacoresistance to antiepileptic drugs, which necessitates the search for new therapeutic methods, in particular, using gene therapy. This review discusses the use of adeno-associated viral (AAV) vectors in gene therapy for epilepsy, emphasizing their advantages, such as high efficiency of neuronal tissue transduction and low immunogenicity/cytotoxicity. AAV vectors provide the possibility of personalized therapy due to the diversity of serotypes and genomic constructs, which allows for increasing the specificity and effectiveness of treatment. Promising orientations include the modulation of the expression of neuropeptides, ion channels, transcription, and neurotrophic factors, as well as the use of antisense oligonucleotides to regulate seizure activity, which can reduce the severity of epileptic disorders. This review summarizes the current advances in the use of AAV vectors for the treatment of epilepsy of various etiologies, demonstrating the significant potential of AAV vectors for the development of personalized and more effective approaches to reducing seizure activity and improving patient prognosis. Full article

Background: Epilepsy surgery for extratemporal lobe epilepsy (ETLE) is challenging, particularly when MRI findings are non-lesional and seizure patterns are complex. Invasive diagnostic techniques are crucial for accurately identifying the epileptogenic zone and its relationship with surrounding functional tissue. Microscope-based augmented reality (AR) support, combined with navigation, may enhance intraoperative orientation, particularly in cases involving subtle or indistinct lesions, thereby improving patient outcomes and safety (e.g., seizure freedom and preservation of neuronal integrity). Therefore, this study was conducted to prove the clinical advantages of microscope-based AR support in ETLE surgery. Methods: We retrospectively analyzed data from ten patients with pharmacoresistant ETLE who underwent invasive diagnostics with depth and/or subdural grid electrodes, followed by resective surgery. AR support was provided via the head-up displays of the operative microscope, with navigation based on automatic intraoperative computed tomography (iCT)-based registration. The surgical plan included the suspected epileptogenic lesion, electrode positions, and relevant surrounding functional structures, all of which were visualized intraoperatively. Results: Six patients reported complete seizure freedom following surgery (ILAE 1), one patient was seizure-free at the 2-year follow-up, and one patient experienced only auras (ILAE 2). Two patients developed transient neurological deficits that resolved shortly after surgery. Conclusions: Microscope-based AR support enhanced intraoperative orientation in all cases, contributing to improved patient outcomes and safety. It was highly valued by experienced surgeons and as a training tool for less experienced practitioners. Full article

Background: Evaluating the differential impact of vagus nerve stimulation (VNS) therapy across various seizure types, our study explores its efficacy specifically in patients with categorized minor and major seizures. Methods: We conducted a retrospective cohort study involving 76 patients with pharmacoresistant epilepsy treated at the University Emergency Hospital of Bucharest between 2021 and 2024. Seizures were classified as ‘minor’ (including focal-aware and non-motor/absence seizures) and ‘major’ (including focal to bilateral tonic-clonic and generalized motor seizures), based on modified International League Against Epilepsy (ILAE) criteria. This classification allowed us to assess the response to VNS therapy, defined by a 50% or greater reduction in seizure frequency at the 12-month follow-up. Results: Our findings reveal that major seizures respond more favorably to VNS therapy, significantly reducing both frequency and intensity. In contrast, minor seizures showed a less pronounced response in frequency reduction but noted improvements in neurocognitive functions, suggesting a nuanced benefit of VNS in these cases. Conclusion: The study underscores the importance of seizure type in determining the efficacy of VNS therapy, advocating for personalized treatment approaches based on seizure classification. This approach could potentially enhance clinical outcomes by tailoring VNS settings to specific seizure types, improving overall management strategies in pharmacoresistant epilepsy. Full article

Pharmacotherapy is the therapeutic mainstay in epilepsy; however, in about 30% of patients, epileptic seizures are drug-resistant. A ketogenic diet (KD) is an alternative therapeutic option. The mechanisms underlying the anti-seizure effect of a KD are not fully understood. Epileptic seizures lead to an increased energy demand of neurons. An improvement in energy provisions may have a protective effect. C8 and C10 fatty acids have been previously shown to activate mitochondrial function in vitro. This could involve sirtuins (SIRTs) as regulatory elements of energy metabolism. The aim of the present study was to investigate whether ß-hydroxybutyrate (ßHB), C8 fatty acids, C10 fatty acids, or a combination of C8 and C10 (250/250 µM) fatty acids, which all increase under a KD, could up-regulate SIRT1, -3, -4, and -5 in HT22 hippocampal murine neurons in vitro. Cells were incubated for 1 week in the presence of these metabolites. The sirtuins were measured at the enzyme (fluorometrically), protein (Western blot), and gene expression (PCR) levels. In hippocampal cells, the C8, C10, and C8 and C10 incubations led to increases in the sirtuin levels, which were not inferior to a ßHB incubation as the ‘gold standard’. This may indicate that both C8 and C10 fatty acids are important for the antiepileptic effect of a KD. A KD may be replaced by nutritional supplements of C8 and C10 fatty acids, which could facilitate the diet. Full article

Depression is emerging as the predominant psychiatric disorder globally. Despite the wide availability of antidepressants, up to 30% of patients exhibit poor response to treatment, falling into the category of treatment-resistant depression (TRD). This underscores the need for the exploration of novel therapeutic options. Our work aims to study the effect of chronic administration of the pyridoindole derivative SMe1EC2M3, a triple reuptake inhibitor, and the combination of zoletil and venlafaxine under conditions of stress induced by a 4-week chronic mild stress (CMS) procedure in Wistar-Kyoto male rats as an animal model of TRD. Therefore, we investigated the possible effect of the selected compounds in four experimental groups, i.e., stress + vehicle, stress + venlafaxine, stress + zoletil + venlafaxine and stress + SMe1EC2M3. The following variables were assessed: anhedonia in sucrose preference test (SPT), spontaneous locomotion and exploration in open field test (OF), anxiety-like behavior in elevated plus maze test (EPM), motivation and depressive-like behavior in forced swim test (FST) and nociception in tail flick test. We also evaluated cognition, particularly recognition memory, in the novel object recognition test (NOR). Sucrose preference was significantly increased in the SMe1EC2M3 group (p < 0.05) in comparison with the venlafaxine animals. In the OF, we observed a significantly higher number of entries into both the central and peripheral zones in the venlafaxine (p < 0.05 central zone; p ≤ 0.05 periphery zone) and SMe1EC2M3 (p < 0.05 central zone; p < 0.05 periphery zone) groups compared to the venlafaxine + zoletil group. SMe1EC2M3 was able to significantly increase the time of climbing in FST (p < 0.05) in comparison with the venlafaxine and control groups. The NOR test revealed a significantly higher discrimination ratio in the SMe1EC2M3 group (p < 0.05) compared to the control and venlafaxine groups. Analyses of the tail flick test showed a significant increase in reaction time to painful stimuli in the SMe1EC2M3 group (p < 0.05) in comparison to both the control and venlafaxine groups. Our findings suggest that SMe1EC2M3 has the potential to ameliorate some behavioral changes associated with TRD, and the venlafaxine + zoletil combination treatment was not a promising treatment alternative in the animal model of TRD. Full article

Phenobarbital (PB) remains the first-line medication for neonatal seizures. Yet, seizures in many newborns, particularly those associated with perinatal ischemia, are resistant to PB. Previous animal studies have shown that in postnatal day P7 mice pups with ischemic stroke induced by unilateral carotid ligation, the tyrosine receptor kinase B (TrkB) antagonist ANA12 (N-[2-[[(hexahydro-2-oxo-1H-azepin-3-yl)amino]carbonyl]phenyl]-benzo[b]thiophene-2-carboxamide, 5 mg/kg) improved the efficacy of PB in reducing seizure occurrence. To meet optimal standards of effectiveness, a wider range of ANA12 doses must be tested. Here, using the unilateral carotid ligation model, we tested the effectiveness of higher doses of ANA12 (10 and 20 mg/kg) on the ability of PB to reduce seizure burden, ameliorate cell death (assessed by Fluoro-Jade staining), and affect neurodevelopment (righting reflex, negative geotaxis test, open field test). We found that a single dose of ANA12 (10 or 20 mg/kg) given 1 h after unilateral carotid ligation in P7 pups reduced seizure burden and neocortical and striatal neuron death without impairing developmental reflexes. In conclusion, ANA12 at a range of doses (10–20 mg/kg) enhanced PB effectiveness for the treatment of perinatal ischemia-related seizures, suggesting that this agent might be a clinically safe and effective adjunctive agent for the treatment of pharmacoresistant neonatal seizures. Full article

Epilepsy is a chronic neurological disorder characterized by recurrent seizures resulting from abnormal neuronal hyperexcitability. In the case of pharmacoresistant epilepsy requiring resection surgery, the identification of the Epileptogenic Zone (EZ) is critical. Fast Ripples (FRs; 200–600 Hz) are one of the promising biomarkers that can aid in EZ delineation. However, recording FRs requires physically small electrodes. These microelectrodes suffer from high impedance, which significantly impacts FRs’ observability and detection. In this study, we investigated the potential of a conductive polymer coating to enhance FR observability. We employed biophysical modeling to compare two types of microelectrodes: Gold (Au) and Au coated with the conductive polymer poly(3,4-ethylenedioxythiophene)-poly(styrene sulfonate) (Au/PEDOT:PSS). These electrodes were then implanted into the CA1 hippocampal neural network of epileptic mice to record FRs during epileptogenesis. The results showed that the polymer-coated electrodes had a two-order lower impedance as well as a higher transfer function amplitude and cut-off frequency. Consequently, FRs recorded with the PEDOT:PSS-coated microelectrode yielded significantly higher signal energy compared to the uncoated one. The PEDOT:PSS coating improved the observability of the recorded FRs and thus their detection. This work paves the way for the development of signal-specific microelectrode designs that allow for better targeting of pathological biomarkers. Full article

Neuroplasticity is a crucial property of the central nervous system to change its activity in response to intrinsic or extrinsic stimuli. This is mainly achieved through the promotion of changes in the epigenome. One of the epi-drivers priming this process is suberoylanilide hydroxamic acid (SAHA or Vorinostat), a pan-histone deacetylase inhibitor that modulates and promotes neuroplasticity in healthy and disease conditions. Knowledge of the specific molecular changes induced by this epidrug is an important area of neuro-epigenetics for the identification of new compounds to treat cognition impairment and/or epilepsy. In this review, we summarize the findings obtained in cellular and animal models of various brain disorders, highlighting the multiple mechanisms activated by SAHA, such as improvement of memory, learning and behavior, and correction of faulty neuronal functioning. Supporting this evidence, in vitro and in vivo data underline how SAHA positively regulates the expression of neuronal genes and microtubule dynamics, induces neurite outgrowth and spine density, and enhances synaptic transmission and potentiation. In particular, we outline studies regarding neurodevelopmental disorders with pharmaco-resistant seizures and/or severe cognitive impairment that to date lack effective drug treatments in which SAHA could ameliorate defective neuroplasticity. Full article

Background: Epilepsy is one of the most common neurological disorders. Existing antiseizure medications (ASMs) are still unable to control seizures in one-third of these patients, making the discovery of antiseizure therapies with novel mechanisms of action a necessity. Aim of the Study: This study aimed to determine the safety and efficacy of perampanel (PER) as an adjuvant treatment for children with drug-resistant focal-onset seizures with or without focal to bilateral tonic-clonic seizures. Patients and methods: This is a single-center retrospective study of 38 epileptic pediatric patients, aged 2 to 14, at King Faisal Specialist Hospital and Research Center whose seizures were pharmaco-resistant to more than two antiseizure medications and followed for at least three months after PER adjuvant therapy initiation. Efficacy was assessed by the PER response rate at 3-, 6-, and 12-month follow-up evaluations, and side effects were also reported. Results: Multiple seizure types were reported. Myoclonic seizures were the predominant type of epilepsy in 17 children (44.7%). At 3 months, 6 months, and 12 months of follow-up, approximately 23.4%, 23.4%, and 18.4% of the patients were seizure-free at these time points, respectively. Adverse events were documented in 14 patients (35.7%) and led to the discontinuation of PER in 26.3%, 31.6%, and 36.8% of the studied group at the 3-, 6-, and 12-month follow-ups, respectively. The most common adverse events included dizziness or drowsiness, irritability, gait disturbance, and confusion; however, all were transient, and no serious adverse effects occurred. Conclusion: Our findings confirm the therapeutic efficacy of adjunctive PER in the treatment of drug-resistant epilepsy in children. As an adjunctive treatment for epilepsy, perampanel demonstrated sufficient effectiveness and tolerability. Full article