Early Seizure Prophylaxis in Mild and Moderate Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

Importance: Guidelines recommend seizure prophylaxis for early posttraumatic seizures (PTS) after severe traumatic brain injury (TBI). Use of antiseizure medications for early seizure prophylaxis after mild or moderate TBI remains controversial. Objective: To determine the association between seizure prophylaxis and risk reduction for early PTS in mild and moderate TBI. Data Sources: PubMed, Google Scholar, and Web of Science (January 1, 1991, to April 18, 2023) were systematically searched. Study Selection: Observational studies of adult patients presenting to trauma centers in high-income countries with mild (Glasgow Coma Scale [GCS], 13-15) and moderate (GCS, 9-12) TBI comparing rates of early PTS among patients with seizure prophylaxis with those without seizure prophylaxis. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) reporting guidelines were used. Two authors independently reviewed all titles and abstracts, and 3 authors reviewed final studies for inclusion. A meta-analysis was performed using a random-effects model with absolute risk reduction. Main Outcome Measures: The main outcome was absolute risk reduction of early PTS, defined as seizures within 7 days of initial injury, in patients with mild or moderate TBI receiving seizure prophylaxis in the first week after injury. A secondary analysis was performed in patients with only mild TBI. Results: A total of 64 full articles were reviewed after screening; 8 studies (including 5637 patients) were included for the mild and moderate TBI analysis, and 5 studies (including 3803 patients) were included for the mild TBI analysis. The absolute risk reduction of seizure prophylaxis for early PTS in mild to moderate TBI (GCS, 9-15) was 0.6% (95% CI, 0.1%-1.2%; P = .02). The absolute risk reduction for mild TBI alone was similar 0.6% (95% CI, 0.01%-1.2%; P = .04). The number needed to treat to prevent 1 seizure was 167 patients. Conclusion and Relevance: Seizure prophylaxis after mild and moderate TBI was associated with a small but statistically significant reduced risk of early posttraumatic seizures after mild and moderate TBI. The small absolute risk reduction and low prevalence of early seizures should be weighed against potential acute risks of antiseizure medications as well as the risk of inappropriate continuation beyond 7 days.

Effectiveness of Levetiracetam versus phenytoin in preventing seizure in traumatic brain injury patients: A systematic review and meta-analysis.

OBJECTIVE: Traumatic brain injury (TBI) and the subsequent Post-traumatic seizure (PTS) is a growing public health concern. Generally, anti-seizure drugs (ASDs) are recommended for PTS prophylaxis and treatment. This meta-analysis aimed to review the current state of knowledge and the evidence for the efficacy and safety of Levetiracetam (LEV) on the incidence of seizure in TBI patients compared to Phenytoin (PHT). METHODS: A search was carried out based on PubMed, MEDLINE, Europe PMC database, and Cochrane Library up to November 2023. A total of 16 studies (3 randomized clinical trials, 10 retrospective cohort studies, and 3 prospective cohort studies) including 5821 TBI patients included in our meta-analysis. We included studies comparing LEV and PHT after brain injury in both adults and children. Risk of bias assessment was done for randomized controlled trials (RCTs) with a risk-of-bias tool (RoB-2) and the Newcastle-Ottawa Scale (NOS) was used to assess the quality of cohort studies. Two RCTs in our meta-analysis had a high risk of bias, therefore we applied sensitivity analysis to evaluate the robustness of our results. RESULTS: The most commonly reported dosage for LEV was 500 mg twice daily and for PHT it was 5 mg/kg. There was no significant difference between LEV and PHT groups in reducing the early seizure incidence (OR = 0.85; 95% CI = [0.60, 1.21]; p = 0.375, fixed-effect, I2 = 21.75%). The result of sensitivity analysis for late seizure showed no significant difference between LEV and PHT in reducing the late seizure occurrence after TBI (OR = 0.87; 95% CI = [0.21, 3.67]; p = 0.853, fixed-effect, I2 = 0%). The mortality in TBI patients treated with LEV was not statistically significant compared to the PHT group (OR = 1.11; 95% CI = [0.92, 1.34], p = 0.266). The length of stay in the hospital was not significantly different between the LEV and PHT groups (MD = -1.33; 95% CI = [-4.55, 1.90]; p = 0.421). However, in comparison to PHT, LEV shortened the length of ICU stay (MD = -2.25; 95% CI = [-3.58, -0.91]; p =0.001). In terms of adverse effects, more patients in the PHT group have experienced adverse events compared to LEV but the difference was not significant (OR = 0.69; 95% CI = [0.44, 1.08]; p = 0. 11). CONCLUSION: The results of our meta-analysis showed LEV and PHT have similar effects on the occurrence of early and late seizures in TBI patients. Therefore, none of the drugs is superior to the other in reducing PTS. However, treating TBI patients with LEV did not shorten the length of hospital stay in comparison to PHT but reduced the length of ICU stay significantly. The analysis showed that patients in the LEV experienced fewer side effects than in the PHT group, while it was not sufficiently clear whether all reported side effects were related to the drug alone or other factors. The mortality was similar between the LEV and PHT groups. Finally, we recommend more high-quality randomized controlled trials to confirm the current findings before making any recommendations in practice.

Berberine and hesperidin prevent the memory consolidation impairment induced by pentylenetetrazole in zebrafish.

This study verified the effects of the natural compounds berberine and hesperidin on seizure development and cognitive impairment triggered by pentylenetetrazole (PTZ) in zebrafish. Adult animals were submitted to a training session in the inhibitory avoidance test and, after 10 minutes, they received an intraperitoneal injection of 25, 50, or 100 mg/kg berberine or 100 or 200 mg/kg hesperidin. After 30 minutes, the animals were exposed to 7.5 mM PTZ for 10 minutes. Animals were submitted to the test session 24 h after the training session to verify their cognitive performance. Zebrafish larvae were exposed to 100 µM or 500 µM berberine or 10 µM or 50 µM hesperidin for 30 minutes. After, larvae were exposed to PTZ and had the seizure development evaluated by latency to reach the seizure stages I, II, and III. Adult zebrafish pretreated with 50 mg/kg berberine showed a longer latency to reach stage III. Zebrafish larvae pretreated with 500 µM berberine showed a longer latency to reach stages II and III. Hesperidin did not show any effect on seizure development both in larvae and adult zebrafish. Berberine and hesperidin pretreatments prevented the memory consolidation impairment provoked by PTZ-induced seizures. There were no changes in the distance traveled in adult zebrafish pretreated with berberine or hesperidin. In larval stage, berberine caused no changes in the distance traveled; however, hesperidin increased the locomotion. Our results reinforce the need for investigating new therapeutic alternatives for epilepsy and its comorbidities.

Synthesis, in silico screening, and biological evaluation of novel pyridine congeners as anti-epileptic agents targeting AMPA (α-amino-3-hydroxy-5-methylisoxazole) receptors.

The research involves the synthesis of a series of new pyridine analogs 5(i-x) and their evaluation for anti-epileptic potential using in silico and in vivo models. Synthesis of the compounds was accomplished by using the Vilsmeier-Haack reaction principle. AutoDock 4.2 was used for their in silico screening against AMPA (-amino-3-hydroxy-5-methylisoxazole) receptor (PDB ID:3m3f). For in vivo testing, the maximal electroshock seizure (MES) model was used. The physicochemical, pharmacokinetic, drug-like, and drug-score features of all synthesized compounds were assessed using the online Swiss ADME and Protein Plus software. The in silico results showed that all the synthesized compounds 5(i-x) had 1-3 interactions and affinities ranging from -6.5 to -8.0 kJ/mol with the targeted receptor compared to the binding affinities of the standard drug phenytoin and the original ligand of the target (P99), which were -7.6 and -6.8 kJ/mol, respectively. In vivo study results showed that the compound 5-Carbamoyl-2-formyl-1-[2-(4-nitrophenyl)-2-oxo-ethyl]-pyridinium gave 60% protection against epileptic seizures compared to 59% protection afforded by regular phenytoin. All of them met Lipinski's rule of five and had drug-likeness and drug score values of 0.55 and 0.8, respectively, making them chemically and functionally like phenytoin. According to the findings of the studies, the synthesized derivatives have the potential to be employed as a stepping stone in the development of novel anti-epileptic drugs.

Evaluation of the anticonvulsant and neuroprotective effect of intracerebral administration of growth hormone in rats / Evaluación del efecto anticonvulsivante y neuroprotector de la administración intracerebral de la hormona de crecimiento en ratas

Introduction The growth hormone (GH) has been reported as a crucial neuronal survival factor in the hippocampus against insults of diverse nature. Status epilepticus (SE) is a prolonged seizure that produces extensive neuronal cell death. The goal of this study was to evaluate the effect of intracerebroventricular administration of GH on seizure severity and SE-induced hippocampal neurodegeneration. Methodology Adult male rats were implanted with a guide cannula in the left ventricle and different amounts of GH (70, 120 or 220 ng/3 μl) were microinjected for 5 days; artificial cerebrospinal fluid was used as the vehicle. Seizures were induced by the lithium–pilocarpine model (3 mEq/kg LiCl and 30 mg/kg pilocarpine hydrochloride) one day after the last GH administration. Neuronal injury was assessed by Fluoro-Jade B (F-JB) staining. Results Rats injected with 120 ng of GH did not had SE after 30 mg/kg pilocarpine, they required a higher number of pilocarpine injections to develop SE than the rats pretreated with the vehicle, 70 ng or 220 ng GH. Prefrontal and parietal cortex EEG recordings confirmed that latency to generalized seizures and SE was also significantly higher in the 120 ng group when compared with all the experimental groups. FJ-B positive cells were detected in the hippocampus after SE in all rats, and no significant differences in the number of F-JB cells in the CA1 area and the hilus was observed between experimental groups. Conclusion Our results indicate that, although GH has an anticonvulsive effect in the lithium–pilocarpine model of SE, it does not exert hippocampal neuroprotection after SE. (AU)

Introducción La hormona de crecimiento (HC) es un factor que favorece la supervivencia neuronal en el hipocampo ante agresiones de diversa naturaleza. El status epilepticus (SE) es un tipo de crisis epiléptica de larga duración que produce muerte neuronal. El objetivo de este estudio fue evaluar el efecto de la administración intracerebroventricular de HC en la severidad de las convulsiones y la neurodegeneración hipocampal debida al SE. Metodología A ratas macho adultas se les implantó una cánula guía en el ventrículo lateral izquierdo y se les microinyectaron diferentes cantidades de HC (70, 120 o 220 ng/3 μl) durante 5 días; como vehículo se inyectó líquido cefalorraquídeo artificial. Las convulsiones se generaron con el modelo de litio-pilocarpina (3 mEq/kg LiCl y 30 mg/kg clorhidrato pilocarpina) un día después de la última inyección de HC. La neurodegeneración se identificó con la tinción de Fluoro-Jade B (F-JB). Resultados Las ratas a las que se les inyectaron 120 ng de HC requirieron 2 o 3 inyecciones de pilocarpina para desarrollar SE, en comparación con el resto de los grupos experimentales que requirieron solo una aplicación del convulsivante. Los registros EEG de la corteza prefrontal y parietal confirmaron que la latencia a las crisis generalizadas y al SE fue mayor en dicho grupo experimental. Todas las ratas con SE presentaron células positivas al FJ-B en el área CA1 e hilus del hipocampo, y no se identificaron diferencias entre los tratamientos. Conclusión Nuestros resultados muestran que, aunque la HC tiene un efecto anticonvulsivante, una vez que se ha desarrollado el SE no promueve neuroprotección en el hipocampo. (AU)

Modelo de riesgo de crisis en acúmulos o estado epiléptico e intervención en servicios de urgencias / Risk model of seizure cluster or status epilepticus and intervention in the emergency department

Objetivos Identificar posibles factores predictores de crisis epilépticas en acúmulos o estado epiléptico (EE) y evaluar si estos pacientes reciben una mayor intervención en urgencias. Metodología Análisis secundario del Registro ACESUR el cual es un registro observacional de cohortes multipropósito, prospectivo y multicéntrico de pacientes adultos con crisis epilépticas en 18 servicios de urgencias. Se recogen variables clínico-asistenciales. Se identifican factores y modelo de riesgo de presentar crisis en acúmulos o EE y se evalúa el efecto de intervención en servicios de urgencias extrahospitalarios y hospitalarios. Resultados Del registro ACESUR se analizan 186 (28%) con crisis en acúmulos (126; 19%) o EE (60; 9%) frente a 478 (72%) pacientes con crisis aislada. El modelo de riesgo de crisis en acúmulo o EE en urgencias incluyó la presencia de alta comorbilidad según índice de Charlson > 3 (OR: 1,60; IC95%: 1,05-2,46; p = 0,030), > 2 fármacos antiepilépticos habituales (OR: 2,29; IC95%: 1,49-3,51; p < 0,001) y crisis focal (OR: 1,56; IC95%: 1,05-2,32; p = 0,027). El ABC del modelo fue de 0,735 (IC95%: 0,693-0,777; p = 0,021). La intervención en pacientes con crisis en acúmulos y EE fue mayor en los servicios de urgencias extrahospitalarios (OR: 2,89; IC95%: 1,91-4,36; p < 0,001) y en los servicios de urgencias hospitalarios (OR: 4,41; IC95%: 2,69-7,22; p < 0,001). Conclusiones El modelo presentado podría ser una herramienta con valor predictivo de utilidad para identificar al paciente adulto con riesgo de presentar crisis en acúmulos o EE en urgencias. Estos pacientes recibieron una mayor intervención frente a pacientes con crisis epiléptica aislada por parte de los servicios de urgencias extrahospitalarios y más aún por los servicios de urgencias hospitalarios en nuestra muestra. (AU)

Objectives To identify possible predictors of seizure cluster or status epilepticus (SE) and to evaluate whether these patients receive greater interventions in emergency departments. Methodology We conducted a secondary analysis of the ACESUR Registry, a multipurpose, observational, prospective, multicentre registry of adult patients with seizures from 18 emergency departments. Clinical and care-related variables were collected. We identified risk factors and risk models for seizure cluster or SE and assessed the effect of interventions by prehospital emergency services and the hospital emergency department. Results We identified a total of 186 (28%) patients from the ACESUR registry with seizure cluster (126 [19%]) or SE (60 [9%]); the remaining 478 patients (72%) had isolated seizures. The risk model for seizure cluster or SE in the emergency department included Charlson Comorbidity Index scores ≥ 3 (OR: 1.60; 95% CI, 1.05-2.46; P = .030), ≥ 2 habitual antiepileptic drugs (OR: 2.29; 95% CI, 1.49-3.51; P < .001), and focal seizures (OR: 1.56; 95% CI, 1.05-2.32; P = .027). The area under the curve of the model was 0.735 (95% CI, 0.693-0.777; P = .021). Patients with seizure cluster and SE received more aggressive interventions both by prehospital emergency services (OR: 2.89; 95% CI, 1.91-4.36; P < .001) and at the emergency department (OR: 4.41; 95% CI, 2.69-7.22; P < .001). Conclusions This risk model may be of prognostic value in identifying adult patients at risk of presenting seizure cluster or SE in the emergency department. In our sample, these patients received more aggressive treatment than adult patients with isolated seizures before arriving at hospital, and even more so in the emergency department. (AU)

Evaluation of the anticonvulsant and neuroprotective effect of intracerebral administration of growth hormone in rats / Evaluación del efecto anticonvulsivante y neuroprotector de la administración intracerebral de la hormona de crecimiento en ratas

Introduction The growth hormone (GH) has been reported as a crucial neuronal survival factor in the hippocampus against insults of diverse nature. Status epilepticus (SE) is a prolonged seizure that produces extensive neuronal cell death. The goal of this study was to evaluate the effect of intracerebroventricular administration of GH on seizure severity and SE-induced hippocampal neurodegeneration. Methodology Adult male rats were implanted with a guide cannula in the left ventricle and different amounts of GH (70, 120 or 220 ng/3 μl) were microinjected for 5 days; artificial cerebrospinal fluid was used as the vehicle. Seizures were induced by the lithium–pilocarpine model (3 mEq/kg LiCl and 30 mg/kg pilocarpine hydrochloride) one day after the last GH administration. Neuronal injury was assessed by Fluoro-Jade B (F-JB) staining. Results Rats injected with 120 ng of GH did not had SE after 30 mg/kg pilocarpine, they required a higher number of pilocarpine injections to develop SE than the rats pretreated with the vehicle, 70 ng or 220 ng GH. Prefrontal and parietal cortex EEG recordings confirmed that latency to generalized seizures and SE was also significantly higher in the 120 ng group when compared with all the experimental groups. FJ-B positive cells were detected in the hippocampus after SE in all rats, and no significant differences in the number of F-JB cells in the CA1 area and the hilus was observed between experimental groups. Conclusion Our results indicate that, although GH has an anticonvulsive effect in the lithium–pilocarpine model of SE, it does not exert hippocampal neuroprotection after SE. (AU)

Introducción La hormona de crecimiento (HC) es un factor que favorece la supervivencia neuronal en el hipocampo ante agresiones de diversa naturaleza. El status epilepticus (SE) es un tipo de crisis epiléptica de larga duración que produce muerte neuronal. El objetivo de este estudio fue evaluar el efecto de la administración intracerebroventricular de HC en la severidad de las convulsiones y la neurodegeneración hipocampal debida al SE. Metodología A ratas macho adultas se les implantó una cánula guía en el ventrículo lateral izquierdo y se les microinyectaron diferentes cantidades de HC (70, 120 o 220 ng/3 μl) durante 5 días; como vehículo se inyectó líquido cefalorraquídeo artificial. Las convulsiones se generaron con el modelo de litio-pilocarpina (3 mEq/kg LiCl y 30 mg/kg clorhidrato pilocarpina) un día después de la última inyección de HC. La neurodegeneración se identificó con la tinción de Fluoro-Jade B (F-JB). Resultados Las ratas a las que se les inyectaron 120 ng de HC requirieron 2 o 3 inyecciones de pilocarpina para desarrollar SE, en comparación con el resto de los grupos experimentales que requirieron solo una aplicación del convulsivante. Los registros EEG de la corteza prefrontal y parietal confirmaron que la latencia a las crisis generalizadas y al SE fue mayor en dicho grupo experimental. Todas las ratas con SE presentaron células positivas al FJ-B en el área CA1 e hilus del hipocampo, y no se identificaron diferencias entre los tratamientos. Conclusión Nuestros resultados muestran que, aunque la HC tiene un efecto anticonvulsivante, una vez que se ha desarrollado el SE no promueve neuroprotección en el hipocampo. (AU)

Modelo de riesgo de crisis en acúmulos o estado epiléptico e intervención en servicios de urgencias / Risk model of seizure cluster or status epilepticus and intervention in the emergency department

Objetivos Identificar posibles factores predictores de crisis epilépticas en acúmulos o estado epiléptico (EE) y evaluar si estos pacientes reciben una mayor intervención en urgencias. Metodología Análisis secundario del Registro ACESUR el cual es un registro observacional de cohortes multipropósito, prospectivo y multicéntrico de pacientes adultos con crisis epilépticas en 18 servicios de urgencias. Se recogen variables clínico-asistenciales. Se identifican factores y modelo de riesgo de presentar crisis en acúmulos o EE y se evalúa el efecto de intervención en servicios de urgencias extrahospitalarios y hospitalarios. Resultados Del registro ACESUR se analizan 186 (28%) con crisis en acúmulos (126; 19%) o EE (60; 9%) frente a 478 (72%) pacientes con crisis aislada. El modelo de riesgo de crisis en acúmulo o EE en urgencias incluyó la presencia de alta comorbilidad según índice de Charlson > 3 (OR: 1,60; IC95%: 1,05-2,46; p = 0,030), > 2 fármacos antiepilépticos habituales (OR: 2,29; IC95%: 1,49-3,51; p < 0,001) y crisis focal (OR: 1,56; IC95%: 1,05-2,32; p = 0,027). El ABC del modelo fue de 0,735 (IC95%: 0,693-0,777; p = 0,021). La intervención en pacientes con crisis en acúmulos y EE fue mayor en los servicios de urgencias extrahospitalarios (OR: 2,89; IC95%: 1,91-4,36; p < 0,001) y en los servicios de urgencias hospitalarios (OR: 4,41; IC95%: 2,69-7,22; p < 0,001). Conclusiones El modelo presentado podría ser una herramienta con valor predictivo de utilidad para identificar al paciente adulto con riesgo de presentar crisis en acúmulos o EE en urgencias. Estos pacientes recibieron una mayor intervención frente a pacientes con crisis epiléptica aislada por parte de los servicios de urgencias extrahospitalarios y más aún por los servicios de urgencias hospitalarios en nuestra muestra. (AU)

Objectives To identify possible predictors of seizure cluster or status epilepticus (SE) and to evaluate whether these patients receive greater interventions in emergency departments. Methodology We conducted a secondary analysis of the ACESUR Registry, a multipurpose, observational, prospective, multicentre registry of adult patients with seizures from 18 emergency departments. Clinical and care-related variables were collected. We identified risk factors and risk models for seizure cluster or SE and assessed the effect of interventions by prehospital emergency services and the hospital emergency department. Results We identified a total of 186 (28%) patients from the ACESUR registry with seizure cluster (126 [19%]) or SE (60 [9%]); the remaining 478 patients (72%) had isolated seizures. The risk model for seizure cluster or SE in the emergency department included Charlson Comorbidity Index scores ≥ 3 (OR: 1.60; 95% CI, 1.05-2.46; P = .030), ≥ 2 habitual antiepileptic drugs (OR: 2.29; 95% CI, 1.49-3.51; P < .001), and focal seizures (OR: 1.56; 95% CI, 1.05-2.32; P = .027). The area under the curve of the model was 0.735 (95% CI, 0.693-0.777; P = .021). Patients with seizure cluster and SE received more aggressive interventions both by prehospital emergency services (OR: 2.89; 95% CI, 1.91-4.36; P < .001) and at the emergency department (OR: 4.41; 95% CI, 2.69-7.22; P < .001). Conclusions This risk model may be of prognostic value in identifying adult patients at risk of presenting seizure cluster or SE in the emergency department. In our sample, these patients received more aggressive treatment than adult patients with isolated seizures before arriving at hospital, and even more so in the emergency department. (AU)

Electroencephalographic profile of Salvia amarissima Ortega and amarisolide A in the absence and presence of PTZ-induced seizures in mice.

Salvia amarissima Ortega is a plant used in traditional medicine to treat CNS's affections. Despite its depressant properties in anxiety and fibromyalgia, there is no scientific evidence about its capability to control seizure activity. This study aimed to investigate the effects of the S. amarissima aqueous extract (SAAE) and its metabolite amarisolide A (AMA) on the electrocorticographic (ECoG) activity. The ECoG profiles were previously and concurrently analyzed to the pentylenetetrazole (85 mg/kg, i.p.)-induced seizure behavior after thirty min of the administration of several doses of the SAAE (1, 10, 30, and 100 mg/kg, i.p.) and two doses of AMA (0.5 and 1 mg/kg, i.p.). A dosage of AMA (1 mg/kg,i.p.) was selected to explore a possible mechanism of action by using antagonists of inhibitory receptors such as GABAA (picrotoxin, 1 mg/kg, i.p.) or 5-HT1A of serotonin (WAY100635, 1 mg/kg, i.p.). Significant changes in the frequency bands and the spectral power were observed after the treatment alone. Additionally, SAAE and AMA produced significant and dose-dependent anticonvulsant effects by reducing the incidence and severity of seizures and increasing latency or survival. Both antagonists prevented the effects of AMA in the severity score of seizures and survival during the tonic-clonic seizures. In conclusion, our preclinical data support that S. amarissima possesses anticonvulsant properties, in part due to the presence of amarisolide A, mediated by different inhibitory mechanisms of action. Our scientific evidence suggests that this Salvia species and amarisolide A are potential neuroprotective alternatives to control seizures in epilepsy therapy.

Polysaccharide-rich extract of Genipa americana leaves protects seizures and oxidative stress in the mice model of pentylenetetrazole-induced epilepsy.

Plant polysaccharides have biological activities in the brain and those obtained from Genipa americana leaves present antioxidant and anticonvulsant effects in the mice model of pentylenetetrazole (PTZ)-induced acute seizures. This study aimed to evaluate the polysaccharide-rich extract of Genipa americana leaves (PRE-Ga) in the models of acute seizures and chronic epilepsy (kindling) induced by PTZ. In the acute seizure model, male Swiss mice (25-35 g) received PRE-Ga (1 or 9 mg/kg; intraperitoneal- IP), alone or associated with diazepam (0.01 mg/kg), 30 min before induction of seizures with PTZ (70 mg/kg; IP). In the chronic epilepsy model, seizures were induced by PTZ (40 mg/kg) 30 min after treatment and in alternated days up to 30 days and evaluated by video. Brain areas (prefrontal cortex, hippocampus, striatum) were assessed for inflammatory and oxidative stress markers. Diazepam associated to PRE-Ga (9 mg/kg; i.p.) increased the latency of seizures in acute (222.4 ± 47.57 vs. saline: 62.00 ± 4.709 s) and chronic models (6.267 ± 0.502 vs. saline: 4.067 ± 0.407 s). In hippocampus, PRE-Ga (9 mg/kg) inhibited TNF-α (105.9 ± 5.38 vs. PTZ: 133.5 ± 7.62 pmol/g) and malondialdehyde (MDA) (473.6 ± 60.51) in the chronic model. PTZ increased glial fibrillar acid proteins (GFAP) and Iba-1 in hippocampus, which was reversed by PRE-Ga (GFAP: 1.9 ± 0.23 vs PTZ: 3.1 ± 1.3 and Iba-1: 2.2 ± 0.8 vs PTZ: 3.2 ± 1.4). PRE-Ga presents neuroprotector effect in the mice model of epilepsy induced by pentylenetetrazole reducing seizures, gliosis, inflammatory cytokines and oxidative stress.

Transient targeting of hypothalamic orexin neurons alleviates seizures in a mouse model of epilepsy.

Lateral hypothalamic (LH) hypocretin/orexin neurons (HONs) control brain-wide electrical excitation. Abnormally high excitation produces epileptic seizures, which affect millions of people and need better treatments. HON population activity spikes from minute to minute, but the role of this in seizures is unknown. Here, we describe correlative and causal links between HON activity spikes and seizures. Applying temporally-targeted HON recordings and optogenetic silencing to a male mouse model of acute epilepsy, we found that pre-seizure HON activity predicts and controls the electrophysiology and behavioral pathology of subsequent seizures. No such links were detected for HON activity during seizures. Having thus defined the time window where HONs influence seizures, we targeted it with LH deep brain stimulation (DBS), which inhibited HON population activity, and produced seizure protection. Collectively, these results uncover a feature of brain activity linked to seizures, and demonstrate a proof-of-concept treatment that controls this feature and alleviates epilepsy.

The Prevalence of Seizures in Brain Metastasis Patients on Anticonvulsant Prophylaxis: A Systematic Review and Meta-Analysis.

BACKGROUND: Brain metastasis (BM) prognosis is incredibly poor and is often associated with considerable morbidity. Seizures are commonly present in these patients, and their biopsychosocial impact can be dangerous. The use of antiepileptic drugs (AEDs) as primary prophylaxis remains controversial. This systematic review and meta-analysis aim to evaluate the efficacy of AED prophylaxis in patients with BM. METHODS: MEDLINE via PubMed, Web of Science, EMBASE, and Cochrane were searched for articles pertinent to AED prophylaxis use in patients with BM. Patients with BM previously treated for cancer who were seizure naive at the time of inclusion were included. Data regarding patient characteristics, type of AED, prior treatments, and groups at a high risk of seizure were extracted. Seizure prevalence was obtained. RESULTS: Eight studies were included in this systematic review and meta-analysis; 1902 total patients with BM were included, with 381 receiving antiepileptic prophylaxis, and 1521 receiving no prophylaxis. Although the odds of a seizure in the treatment group was found to be 1.158 times the odds of a seizure in the control group, the odds ratio was not statistically significant (t-statistic = 0.62, P value = 0.5543). CONCLUSIONS: There was no significant difference in the odds of seizure development in control groups compared to patients receiving prophylactic antiepileptic therapy. As patients with BM present with heterogeneity in tumor characteristics and receive various treatment modalities, future research is needed to identify groups that may benefit more significantly from AED prophylaxis.

H2S inhibits LiCl/pilocarpine-induced seizures and promotes neuroprotection by regulating TRPV2 expression via the AC3/cAMP/PKA pathway.

It is widely acknowledged that epilepsy is a neurological disorder characterized by recurrent and atypical neuronal discharges, resulting in transient dysfunction within the brain. The protective role of hydrogen sulfide (H2S) in epilepsy has been elucidated by recent studies, but the underlying mechanisms remain poorly understood. To investigate this, the concentration of H2S was measured by spectrophotometry and a fluorescent probe in LiCl/Pilocarpine (LiCl/Pilo)-induced seizures in rats. The localization of proteins was examined using immunofluorescence. Electroencephalogram and behavioral tests were employed to evaluate the occurrence of seizures. Neuropathological changes in the hippocampus were examined by hematoxylin-eosin staining, Nissl staining, and transmission electron microscopy. Through proteomics and bioinformatics analysis, we identified the differential proteins in the hippocampus of rats following H2S intervention. Protein changes were detected through western blotting. The results showed that H2S treatment significantly alleviated seizures and minimized post-seizures neurological damage in rats. Proteomics analysis revealed adenylate cyclase 3 (AC3) as a protein potentially targeted by H2S. Moreover, the AC3 activator forskolin reversed the downregulation effect of H2S on the AC3/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/transient receptor potential vanilloid 2 (TRPV2) signaling pathway. In conclusion, H2S targets and downregulates the expression of AC3, thereby modulating the AC3/cAMP/PKA signaling pathway to regulate the expression of TRPV2 in LiCl/Pilo-induced seizures, ultimately leading to seizure inhibition and neuroprotection.

The Effect of Body Mass Index on Post-Bolus Magnesium Levels in the Obstetric Patient.

OBJECTIVE: In the setting of a growing obese obstetric population, we sought to determine whether differences in body mass index (BMI) and obesity class influenced both serum magnesium levels and the likelihood of achieving therapeutic levels for eclampsia prophylaxis after standard boluses of magnesium sulfate. STUDY DESIGN: This is a retrospective cohort study of patients treated with magnesium sulfate in the setting of either preeclampsia with severe features or preterm labor between 2010 and 2016. Subjects were categorized by BMI: Normal (BMI < 30 kg/m2), Class 1 (BMI 30-34.9 kg/m2), Class 2 (BMI 35-39.9 kg/m2), and Class 3 (BMI ≥ 40 kg/m2). Study participants' demographics, intrapartum characteristics, and adverse reactions were compared among the groups. Logistic regression models were used to calculate unadjusted and adjusted odds ratios comparing the likelihood of each BMI class reaching therapeutic eclamptic prophylactic levels. Linear regression models were also evaluated to determine the relationship between BMI and post-bolus serum magnesium levels. RESULTS: Of the 760 people who met the inclusion criteria, 313 (41.1%) had normal BMI, 190 (25.0%) had Class 1 obesity, 135 (17.8%) had Class 2 obesity, and 122 (16.1%) had Class 3 obesity. When adjusted for confounders, those with Class 1 obesity were 54% less likely to achieve serum levels deemed therapeutic for seizure prophylaxis compared with normal BMI counterparts. Meanwhile, those with Class 2 or 3 obesity were 90% less likely. Linear regression models also demonstrated an inverse association between BMI and post-bolus serum magnesium levels. CONCLUSION: Increasing BMI has a significant effect on post-bolus serum magnesium levels regardless of standard loading dose used. Immediately after bolus administration, obese gravidas are significantly less likely to reach levels effective for eclamptic seizure prophylaxis. When considering which bolus to administer in an obese gravida, it may be more beneficial to choose a 6 g load. KEY POINTS: · BMI has an inverse relationship with post-bolus serum magnesium levels.. · Obese gravidas were less likely to reach eclampsia prophylaxis levels regardless of bolus type.. · Obesity class, not just the presence or absence of obesity, plays a role in serum magnesium levels..

Anti-PD-1 treatment protects against seizure by suppressing sodium channel function.

AIMS: Although programmed cell death protein 1 (PD-1) typically serves as a target for immunotherapies, a few recent studies have found that PD-1 is expressed in the nervous system and that neuronal PD-1 might play a crucial role in regulating neuronal excitability. However, whether brain-localized PD-1 is involved in seizures and epileptogenesis is still unknown and worthy of in-depth exploration. METHODS: The existence of PD-1 in human neurons was confirmed by immunohistochemistry, and PD-1 expression levels were measured by real-time quantitative PCR (RT-qPCR) and western blotting. Chemoconvulsants, pentylenetetrazol (PTZ) and cyclothiazide (CTZ), were applied for the establishment of in vivo (rodents) and in vitro (primary hippocampal neurons) models of seizure, respectively. SHR-1210 (a PD-1 monoclonal antibody) and sodium stibogluconate (SSG, a validated inhibitor of SH2-containing protein tyrosine phosphatase-1 [SHP-1]) were administrated to investigate the impact of PD-1 pathway blockade on epileptic behaviors of rodents and epileptiform discharges of neurons. A miRNA strategy was applied to determine the impact of PD-1 knockdown on neuronal excitability. The electrical activities and sodium channel function of neurons were determined by whole-cell patch-clamp recordings. The interaction between PD-1 and α-6 subunit of human voltage-gated sodium channel (Nav1.6) was validated by performing co-immunostaining and co-immunoprecipitation (co-IP) experiments. RESULTS: Our results reveal that PD-1 protein and mRNA levels were upregulated in lesion cores compared with perifocal tissues of surgically resected specimens from patients with intractable epilepsy. Furthermore, we show that anti-PD-1 treatment has anti-seizure effects both in vivo and in vitro. Then, we reveal that PD-1 blockade can alter the electrophysiological properties of sodium channels. Moreover, we reveal that PD-1 acts together with downstream SHP-1 to regulate sodium channel function and hence neuronal excitability. Further investigation suggests that there is a direct interaction between neuronal PD-1 and Nav1.6. CONCLUSION: Our study reveals that neuronal PD-1 plays an important role in epilepsy and that anti-PD-1 treatment protects against seizures by suppressing sodium channel function, identifying anti-PD-1 treatment as a novel therapeutic strategy for epilepsy.

Early Initiation of Antiretroviral Therapy is Protective Against Seizures in Children With HIV in Zambia: A Prospective Case-Control Study.

BACKGROUND: Seizures are relatively common among children with HIV in low- and middle-income countries and are associated with significant morbidity and mortality. Early treatment with antiretroviral therapy (ART) may reduce this risk by decreasing rates of central nervous system infections and HIV encephalopathy. METHODS: We conducted a prospective, unmatched case-control study. We enrolled children with new-onset seizure from University Teaching Hospital in Lusaka, Zambia and 2 regional hospitals in rural Zambia. Controls were children with HIV and no history of seizures. Recruitment took place from 2016 to 2019. Early treatment was defined as initiation of ART before 12 months of age, at a CD4 percentage >15% in children aged 12-60 months or a CD4 count >350 cells/mm 3 for children aged 60 months or older. Logistic regression models were used to evaluate the association between potential risk factors and seizures. RESULTS: We identified 73 children with new-onset seizure and compared them with 254 control children with HIV but no seizures. Early treatment with ART was associated with a significant reduction in the odds of seizures [odds ratio (OR) 0.04, 95% confidence interval: 0.02 to 0.09; P < 0.001]. Having an undetectable viral load at the time of enrollment was strongly protective against seizures (OR 0.03, P < 0.001), whereas history of World Health Organization Stage 4 disease (OR 2.2, P = 0.05) or CD4 count <200 cells/mm 3 (OR 3.6, P < 0.001) increased risk of seizures. CONCLUSIONS: Early initiation of ART and successful viral suppression would likely reduce much of the excess seizure burden in children with HIV.

Protective Activity of Novel Hydrophilic Synthetic Neurosteroids on Organophosphate Status Epilepticus-induced Chronic Epileptic Seizures, Non-Convulsive Discharges, High-Frequency Oscillations, and Electrographic Ictal Biomarkers.

Nerve agents and organophosphates (OP) are neurotoxic chemicals that induce acute seizures, status epilepticus (SE), and mortality. Long-term neurologic and neurodegenerative effects manifest months to years after OP exposure. Current benzodiazepine anticonvulsants are ineffective in preventing such long-term neurobehavioral and neuropathological changes. New and effective anticonvulsants are needed for OP intoxication, especially for mitigating the long-term sequelae after acute exposure. We developed neurosteroids as novel anticonvulsants and neuroprotectants in OP exposure models. In this study, we evaluated the long-term efficacy of novel synthetic neurosteroids in preventing the development of chronic epilepsy and hyperexcitable ictal events in a rat OP model of SE. Rats were exposed to the OP nerve agent surrogate diisopropylfluorophosphate (DFP), and the experimental groups were treated with the synthetic neurosteroid valaxanolone (VX) or lysaxanolone (LX) 40 minutes post-exposure in conjunction with midazolam. Video-electroencephalography was monitored for two months to assess spontaneous recurrent seizures (SRS), epileptiform discharges, interictal spikes, and high-frequency oscillations (HFOs). Within 60 days of DFP exposure, rats developed chronic epilepsy characterized by frequent SRS, epileptiform discharges, and HFOs. LX treatment was associated with a dose-dependent reduction of epilepsy occurrence and overall seizure burden with a significant decrease in SRS and epileptiform discharges. It also significantly reduced the occurrence of epileptic biomarkers of HFOs and interictal spikes, indicating potential disease-modifying activity. Similarly, the neurosteroid analog VX also significantly attenuated SRS, discharges, HFOs, and ictal events. These results demonstrate the long-term protective effects of synthetic neurosteroids in the OP-exposed post-SE model, indicating their disease-modifying potential to prevent epilepsy and ictal abnormalities. SIGNIFICANCE STATEMENT: The effects of nerve agents and organophosphate (OP) exposure are persistent, and survivors suffer from a number of devastating, chronic neurological dysfunctions. Currently, there is no specific therapy for preventing this disastrous impact of OP exposure. We propose synthetic neurosteroids that activate tonic inhibition provide viable options for preventing the long-term neurological effects of OP intoxication. The results from this study reveal the disease-modifying potential of two novel synthetic neurosteroids in preventing epileptogenesis and chronic epileptic seizures after OP-induced SE.

Risk Factors for Seizures After Titanium Cranioplasty: Five-Year Experience from a Single Institution.

OBJECTIVE: Seizures are one of the complications that can occur after cranioplasty (CP). In some regions, titanium mesh remains the material of choice for CP. However, risk factors for seizures after titanium CP have been less studied. The purpose of this study was to identify potential risk factors for early seizures (≤7 days) and late seizures (>8 days) after titanium CP in a single institution. METHODS: A retrospective review was conducted of 241 consecutive patients who received titanium CP at the First Affiliated Hospital of Harbin Medical University from January 2016 to December 2020. Univariate and multivariable logistic regression analyses were performed to determine the independent risk factors for new-onset seizures after titanium CP. RESULTS: Fifteen patients (6.22%) experienced early post-CP seizures, and late post-CP seizures were observed in 81 patients (33.61%). A flaccid concave cranial defect (P = 0.042) was associated with early post-CP seizures, whereas hypertension (P < 0.001) was the only significant predictor for late seizures after titanium CP. CONCLUSIONS: Seizure is a common complication after titanium CP, especially in patients who do not receive prophylactic antiepileptic drugs before the procedure. Risk factors for new-onset seizures at different periods after titanium CP were found to be different. In addition, radiologic factors before titanium CP may play a role in early new-onset seizures after titanium CP and should not be ignored.

Exploring the neuroprotective potential of antimicrobial peptides from Dinoponera quadriceps venom against pentylenetetrazole-induced seizures in vivo.

Epilepsy affects around 50 million people worldwide and 30% of patients have difficulty controlling the disease. The search for substances that can fill the existing gaps in the treatment of epilepsy is of great importance. Arthropod venoms are promising sources for this purpose due to the presence of small peptides that modulate the activity of ion channels and neuron receptors. The aim of this study was to investigate dinoponeratoxins from the Dinoponera quadriceps ant venom (M-PONTX-Dq3a, M-PONTX-Dq3b and M-PONTX-Dq3c) as potential anticonvulsants. We evaluated them in a seizure model induced by pentylenetetrazole (PTZ) in male swiss mice. Interestingly, intraperitoneal treatment with each peptide increased the time until the first seizure and the percentage of survival, with M-PONTX-Dq3b showing the best results. M-PONTX-Dq3a was discarded due to the appearance of some signs of toxicity with the increase in malondialdehyde (MDA) levels in the striatum. Both, M-PONTX-Dq3b and M-PONTX-Dq3c decreased iNOS and TNF-α in the hippocampus. Notably, M-PONTX-Dq3c treatment decreased the levels of MDA and nitrite in the cortex and hippocampus. Our results indicate that, M-PONTX-Dq3b and M-PONTX-Dq3c have anticonvulsant activity and exhibit anti-inflammatory effects in epilepsy, offering new perspectives for biopharmaceutical development.

Post-stroke epilepsy: From clinical predictors to possible mechanisms.

BACKGROUND: Stroke is the most common cause of newly diagnosed epilepsy in the elderly, ahead of degenerative disorders, brain tumors, and head trauma. Stroke accounts for 30-50% of unprovoked seizures in patients aged ≥ 60 years. This review discusses the current understanding of epidemiology, risk factors, mechanisms, prevention, and treatment opportunities for post-stroke epilepsy (PSE). METHODS: We performed a literature search in the PubMed and Cochrane Library databases. The keywords "stroke, epilepsy", "stroke, seizure", "post-stroke seizure", "post-stroke epilepsy" were used to identify the clinical and experimental articles on PSE. All resulting titles and abstracts were evaluated, and any relevant article was considered. The reference lists of all selected papers and reference lists of selected review papers were manually analyzed to find other potentially eligible articles. RESULTS: PSE occurs in about 6% of stroke patients within several years after the event. The main risk factors are cortical lesion, initial stroke severity, young age and seizures in acute stroke period (early seizures, ES). Other risk factors, such as a cardioembolic mechanism or circulation territory involvement, remain debated. The role of ES as a risk factor of PSE could be underestimated especially in young age. Mechanism of epileptogenesis may involve gliosis scarring, alteration in synaptic plasticity, etc.; and ES may enhance these processes. Statins especially in the acute period of stroke are possible agents for PSE prevention presumably due to their anticonvulsant and neuroprotection effects. Antiepileptic drugs (AED) monotherapy is enough for seizure prevention in most cases of PSE; but no evidence was found for its efficiency against epileptic foci formation. The growing interest in PSE has led to a notable increase in the number of published articles each year. To aid in navigating this expanding body of literature, several tables are included in the manuscript. CONCLUSION: Further studies are needed for better understanding of the pathophysiology of PSE and searching the prevention strategies.