Anticonvulsant effects of Paeonia daurica subsp. macrophylla root extracts in pentylenetetrazol-induced seizure models in mice / Efectos anticonvulsivos de Paeonia daurica subsp. macrophylla extractos de raíz en modelos de convulsiones inducidas por pentilentetrazol en ratones

Introduction: In the present study, anticonvulsant effects of aqueous extract (AE), hydro-alcoholic crude extract (HE), and its fractions (F-CHCl3, F-EtOAc, F-MeOH) of Paeonia daurica subsp. macrophylla (P. daurica ssp. macrophylla) root examined by using a pentylenetetrazol-induced model (PTZ) on mice. Methods: HE and its fractions as well as AE, in concentrations of (100, 200 and 400 mg/kg), valproate (Val) (100 and 200 mg/kg), and saline (negative control) (10 mg/kg) were injected intraperitoneally (i.p.) 30 min before PTZ (80 mg/kg, i.p.). The time taken before the onset of myoclonic convulsions (MC), MC duration, time taken before the onset of generalized tonic-clonic seizures (GTCS), the duration of GTCS, and the percentage of GTCS and mortality protection recorded. The plant's anticonvulsant mechanisms were assessed using flumazenil (5 mg/kg, i.p.) before AE (100, 200, and 400 mg/kg, i.p.) injection. GraphPad Prism software was used to compare the differences between various treatment groups with one-way analysis of variance (ANOVA) followed by Tukey–Krammer multiple comparison tests. Results: All the plant samples except F-EtOAc significantly delayed the onset and decreased the duration of PTZ-induced MCS and GTCS, and significantly reduced the GTCS and mortality rate. Pretreatment with flumazenil diminished the significant anticonvulsant effects of AE against PTZ-induced seizures. Conclusions: It can report that extract of P. daurica ssp. macrophylla might be a helpful guide for future studies in the treatment of epilepsy.(AU)

Introducción: Epilepsia es el término usado para un grupo de trastornos caracterizado por las convulsiones espontáneas recurrentes. Un estudio enfocado en los productos naturales de los recursos tradicionales ofrece ventajas significativas que se están utilizando de manera más amplia en modelos animales de epilepsia y candidatos a mayor desarrollo clínico y sus fracciones (F-CHCl3, F-EtOAc, F-MeOH) de Paeonia daurica subsp. macrophylla (P. daurica ssp. macrophylla) raíz examinada utilizando un modelo inducido por pentilentetrazol (PTZ) en ratones. Métodos: La maceración dinámica utilizada para extraer HE de la planta y técnica de cromatografía en columna de sílice utilizada para obtener F-CHCl3, F-EtOAc, así como fracciones de F-MeOH. La extracción de raíces secas se utilizó con agua destilada y se provocó AE. Las muestras de plantas (100, 200 y 400 mg/kg), valproato (Val) (100 y 200 mg/kg) y suero (control negativo) se inyectaron por vía intraperitoneal (ip) 30 min antes de PTZ (80 mg/kg, ip). El tiempo transcurrido antes del comienzo de convulsiones mioclónicas (MC), duración de las MC, tiempo transcurrido antes del comienzo de convulsiones tónico-clónicas generalizadas (GTCS), la duración de GTCS, así como el porcentaje de GTCS y protección contra la mortalidad registrada. Los mecanismos anticonvulsivos de planta fueron evaluados mediante el uso de flumazenil (5 mg/kg, ip) antes de AE (100, 200 y 400 mg/kg, ip) inyección. Se utilizaba el software GraphPad Prism® comparando las diferencias entre varios grupos de tratamiento con un análisis unilateral de variación (ANOVA) seguido por las pruebas de comparación múltiple de Tukey's Krammer. Resultados: Todas las muestras de plantas, excepto F-EtOAc, retrasaron de manera considerable el inicio, y disminuyeron la duración de PTZ inducidos por MCS y GTCS, y redujo significativamente el GTCS, así como la tasa de mortalidad...(AU)

Predictors of Seizure Recurrence in Women With Idiopathic Generalized Epilepsy Who Switch From Valproate to Another Medication.

BACKGROUND AND OBJECTIVES: To investigate the predictors of seizure recurrence in women of childbearing age with idiopathic generalized epilepsy (IGE) who switched from valproate (VPA) to alternative antiseizure medications (ASMs) and compare the effectiveness of levetiracetam (LEV) and lamotrigine (LTG) as VPA alternatives after switch. METHODS: This multicenter retrospective study included women of childbearing age diagnosed with IGE from 16 epilepsy centers. Study outcomes included worsening or recurrence of generalized tonic-clonic seizure (GTCS) at 12 months and 24 months after the switch from VPA to an alternative ASM. The comparative effectiveness of LEV and LTG as alternative ASM following VPA discontinuation was assessed through inverse probability treatment-weighted (IPTW) Cox regression analysis. RESULTS: We included 426 women with IGE, with a median (interquartile range) age at VPA switch of 24 (19-30) years and a median VPA dosage of 750 (500-1,000) mg/d. The most common reason for VPA switch was teratogenicity concern in 249 women (58.6%), and the most common ASM used in place of VPA was LEV in 197 (46.2%) cases, followed by LTG in 140 (32.9%). GTCS worsening/recurrence occurred in 105 (24.6%) and 139 (32.6%) women at 12 and 24 months, respectively. Catamenial worsening of seizures, higher VPA dosage during switch, multiple seizure types, and shorter duration of GTCS freedom before switch were independent predictors of GTCS recurrence or worsening at 12 months according to mixed multivariable logistic regression analysis. After internal-external validation through 16 independent cohorts, the model showed an area under the curve of 0.71 (95% CI 0.64-0.77). In the subgroup of 337 women who switched to LEV or LTG, IPTW Cox regression analysis showed that LEV was associated with a reduced risk of GTCS worsening or recurrence compared with LTG (adjusted hazard ratio 0.59, 95% CI 0.40-0.87, p = 0.008) during the 24-month follow-up. DISCUSSION: Our findings can have practical implications for optimizing counselling and treatment choices in women of childbearing age with IGE and may help clinicians in making informed treatment decisions in this special population of patients. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for women with IGE switching from VPA, LEV was associated with a reduced risk of GTCS worsening or recurrence compared with LTG.

Structural basis for antiepileptic drugs and botulinum neurotoxin recognition of SV2A.

More than one percent of people have epilepsy worldwide. Levetiracetam (LEV) is a successful new-generation antiepileptic drug (AED), and its derivative, brivaracetam (BRV), shows improved efficacy. Synaptic vesicle glycoprotein 2a (SV2A), a putative membrane transporter in the synaptic vesicles (SVs), has been identified as a target of LEV and BRV. SV2A also serves as a receptor for botulinum neurotoxin (BoNT), which is the most toxic protein and has paradoxically emerged as a potent reagent for therapeutic and cosmetic applications. Nevertheless, no structural analysis on AEDs and BoNT recognition by full-length SV2A has been available. Here we describe the cryo-electron microscopy structures of the full-length SV2A in complex with the BoNT receptor-binding domain, BoNT/A2 HC, and either LEV or BRV. The large fourth luminal domain of SV2A binds to BoNT/A2 HC through protein-protein and protein-glycan interactions. LEV and BRV occupy the putative substrate-binding site in an outward-open conformation. A propyl group in BRV creates additional contacts with SV2A, explaining its higher binding affinity than that of LEV, which was further supported by label-free spectral shift assay. Numerous LEV derivatives have been developed as AEDs and positron emission tomography (PET) tracers for neuroimaging. Our work provides a structural framework for AEDs and BoNT recognition of SV2A and a blueprint for the rational design of additional AEDs and PET tracers.

Brain activation and connection across resting and motor-task states in patients with generalized tonic-clonic seizures.

AIMS: Motor abnormalities have been identified as one common symptom in patients with generalized tonic-clonic seizures (GTCS) inspiring us to explore the disease in a motor execution condition, which might provide novel insight into the pathomechanism. METHODS: Resting-state and motor-task fMRI data were collected from 50 patients with GTCS, including 18 patients newly diagnosed without antiepileptic drugs (ND_GTCS) and 32 patients receiving antiepileptic drugs (AEDs_GTCS). Motor activation and its association with head motion and cerebral gradients were assessed. Whole-brain network connectivity across resting and motor states was further calculated and compared between groups. RESULTS: All patients showed over-activation in the postcentral gyrus and the ND_GTCS showed decreased activation in putamen. Specifically, activation maps of ND_GTCS showed an abnormal correlation with head motion and cerebral gradient. Moreover, we detected altered functional network connectivity in patients within states and across resting and motor states by using repeated-measures analysis of variance. Patients did not show abnormal connectivity in the resting state, while distributed abnormal connectivity in the motor-task state. Decreased across-state network connectivity was also found in all patients. CONCLUSION: Convergent findings suggested the over-response of activation and connection of the brain to motor execution in GTCS, providing new clues to uncover motor susceptibility underlying the disease.

Genetic exploration of Dravet syndrome: two case report.

BACKGROUND: Dravet syndrome is an infantile-onset developmental and epileptic encephalopathy (DEE) characterized by drug resistance, intractable seizures, and developmental comorbidities. This article focuses on manifestations in two Indonesian children with Javanese ethnicity who experienced Dravet syndrome with an SCN1A gene mutation, presenting genetic analysis findings using next-generation sequencing. CASE PRESENTATION: We present a case series involving two Indonesian children with Javanese ethnicity whom had their first febrile seizure at the age of 3 months, triggered after immunization. Both patients had global developmental delay and intractable seizures. We observed distinct genetic findings in both our cases. The first patient revealed heterozygous deletion mutation in three genes (TTC21B, SCN1A, and SCN9A). In our second patient, previously unreported mutation was discovered at canonical splice site upstream of exon 24 of the SCN1A gene. Our patient's outcomes improved after therapeutic evaluation based on mutation findings When comparing clinical manifestations in our first and second patients, we found that the more severe the genetic mutation discovered, the more severe the patient's clinical manifestations. CONCLUSION: These findings emphasize the importance of comprehensive genetic testing beyond SCN1A, providing valuable insights for personalized management and tailored therapeutic interventions in patients with Dravet syndrome. Our study underscores the potential of next-generation sequencing in advancing genotype-phenotype correlations and enhancing diagnostic precision for effective disease management.

Obstetric and neonatal outcomes, antiseizure medication profile, and seizure types in pregnant women in a vulnerability state from Brazil.

This retrospective cohort study described the obstetric and neonatal outcomes, antiseizure medication (ASM) use, and types of seizures in pregnant women with epilepsy (PWWE). Data collected from the medical records of 224 PWWE aged < 40 years with controlled or refractory seizures and 492 pregnant women without epilepsy (PWNE) control group from high-risk maternity hospitals in Alagoas between 2008 and 2021 were included in this study. The obstetric and neonatal outcomes observed in PWWE were pregnancy-related hypertension (PrH) (18.4%), oligohydramnios (10.3%), stillbirth (6.4%), vaginal bleeding (6%), preeclampsia (4.7%), and polyhydramnios (3%). There was a greater likelihood of PrH in PWWE with generalized tonic-clonic seizures (GTCS) and that of maternal intensive care unit (ICU) admissions in those with GTCS and status epilepticus, and phenytoin and lamotrigine use. PWWE with GTCS had a higher risk of stillbirth and premature delivery. PWWE with status epilepticus were treated with lamotrigine. Phenobarbital (PB) with diazepam were commonly used in GTCS and status epilepticus. Total 14% patients did not use ASM, while 50.2% used monotherapy and 35.8% used polytherapy. Total 60.9% of patients used PB and 25.2% used carbamazepine. This study described the association between the adverse obstetric and neonatal outcomes and severe seizure types in PWWE.

Sudden Cardiac Death or Ventricular Arrythmia in Patients Taking Levetiracetam or Oxcarbazepine.

BACKGROUND AND OBJECTIVES: Levetiracetam is a widely used antiseizure medication. Recent concerns have been raised regarding the potential prolongation of the QT interval by levetiracetam and increased risk of sudden cardiac death. This could have profound implications for patient safety and for prescribing practice. This study assessed the potential association of levetiracetam with cardiac outcomes related to QT interval prolongation. We compared outcomes of patients taking levetiracetam with those taking oxcarbazepine as a comparator medication that has not been associated with prolongation of the QT interval. METHODS: The sample included patients who were newly prescribed levetiracetam or oxcarbazepine from January 31, 2010, to December 31, 2019, using administrative claims data from the OptumLabs Data Warehouse (OLDW). The analysis focused on a combined endpoint of sudden cardiac death or ventricular arrythmia, which are both linked to QT interval prolongation. We used a new user design and selected oxcarbazepine as an active comparator with levetiracetam to minimize bias. We used propensity score weighting to balance the levetiracetam and oxcarbazepine cohorts and then performed weighted Cox regressions to evaluate the association of levetiracetam with the combined endpoint. RESULTS: We identified 104,655 enrollees taking levetiracetam and 39,596 enrollees taking oxcarbazepine. At baseline, enrollees taking levetiracetam were older, more likely to have diagnosed epilepsy, and more likely to have diagnosed comorbidities including hypertension, cerebrovascular disease, and coronary artery disease. In the main analysis, we found no significant difference between levetiracetam and oxcarbazepine in the rate of the combined endpoint for the Cox proportional hazards model (hazard ratio [HR] 0.79, 95% CI 0.42-1.47) or Cox regression with time-varying characteristics (HR 0.78, 95% CI 0.41-1.50). DISCUSSION: When compared with oxcarbazepine, levetiracetam does not correlate with increased risk of ventricular arrythmia and sudden cardiac death. Our finding does not support the concern for cardiac risk to indicate restriction of levetiracetam use nor the requirement of cardiac monitoring when using it. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that sudden cardiac death and ventricular arrythmia are not more frequent in patients older than 17 years newly prescribed levetiracetam, compared with those prescribed oxcarbazepine.

Chronic Low Back Pain in Adults: Evaluation and Management.

Chronic low back pain, defined as lumbar pain persisting for 12 weeks or more, occurs in about 13% of U.S. adults. Patients with chronic low back pain should have a history and physical examination to identify red flags that may indicate serious conditions that warrant immediate intervention or yellow flags (i.e., psychological, environmental, and social factors) that indicate risk of disability. The examination should include an evaluation for radicular symptoms. Routine imaging is not recommended but is indicated when red flags are present, there is a neuromuscular deficit, or if pain does not resolve with conservative therapy. Patients should avoid bed rest. Nonpharmacologic treatment is first-line management and may include therapies with varying evidence of support, such as counseling, exercise therapy, spinal manipulation, massage, heat, dry needling, acupuncture, transcutaneous electrical nerve stimulation, and physical therapy. Pharmacologic interventions are second-line treatment. Nonsteroidal anti-inflammatory drugs are the initial medication of choice; duloxetine may also be beneficial. Evidence is inconclusive to recommend the use of benzodiazepines, muscle relaxants, antidepressants, corticosteroids, insomnia agents, anticonvulsants, cannabis, acetaminophen, or long-term opioids. Epidural corticosteroid injections are not recommended except for short-term symptom relief in patients with radicular pain. Most patients with chronic low back pain will not require surgery; evaluation for surgery may be considered in those with persistent functional disabilities and pain from progressive spinal stenosis, worsening spondylolisthesis, or herniated disk. Physicians should consider prevention of chronic low back pain when patients present with acute back pain. Screening tools are available to predict the progression from acute to chronic low back pain, and targeted treatment strategies are beneficial for preventing progression.

Virus-Induced Epilepsy vs. Epilepsy Patients Acquiring Viral Infection: Unravelling the Complex Relationship for Precision Treatment.

The intricate relationship between viruses and epilepsy involves a bidirectional interaction. Certain viruses can induce epilepsy by infecting the brain, leading to inflammation, damage, or abnormal electrical activity. Conversely, epilepsy patients may be more susceptible to viral infections due to factors, such as compromised immune systems, anticonvulsant drugs, or surgical interventions. Neuroinflammation, a common factor in both scenarios, exhibits onset, duration, intensity, and consequence variations. It can modulate epileptogenesis, increase seizure susceptibility, and impact anticonvulsant drug pharmacokinetics, immune system function, and brain physiology. Viral infections significantly impact the clinical management of epilepsy patients, necessitating a multidisciplinary approach encompassing diagnosis, prevention, and treatment of both conditions. We delved into the dual dynamics of viruses inducing epilepsy and epilepsy patients acquiring viruses, examining the unique features of each case. For virus-induced epilepsy, we specify virus types, elucidate mechanisms of epilepsy induction, emphasize neuroinflammation's impact, and analyze its effects on anticonvulsant drug pharmacokinetics. Conversely, in epilepsy patients acquiring viruses, we detail the acquired virus, its interaction with existing epilepsy, neuroinflammation effects, and changes in anticonvulsant drug pharmacokinetics. Understanding this interplay advances precision therapies for epilepsy during viral infections, providing mechanistic insights, identifying biomarkers and therapeutic targets, and supporting optimized dosing regimens. However, further studies are crucial to validate tools, discover new biomarkers and therapeutic targets, and evaluate targeted therapy safety and efficacy in diverse epilepsy and viral infection scenarios.

Hemodynamics and arrhythmia disorder caused by lithium poisoning: A case report. / 锂中毒导致心律失常、血流动力学障碍1例.

Bipolar affective disorder refers to a category of mood disorders characterized clinically by the presence of both manic or hypomanic episodes and depressive episodes. Lithium stands out as the primary pharmacological intervention for managing bipolar affective disorder. However, its therapeutic dosage closely approaches toxic levels. Toxic symptoms appear when the blood lithium concentration surpasses 1.4 mmol/L, typically giving rise to gastrointestinal and central nervous system reactions. Cardiac toxicity is rare but serious in cases of lithium poisoning. The study reports a case of a patient with bipolar affective disorder who reached a blood lithium concentration of 6.08 mmol/L after the patient took lithium carbonate sustained-release tablets beyond the prescribed dosage daily and concurrently using other mood stabilizers. This resulted in symptoms such as arrhythmia, shock, impaired consciousness, and coarse tremors. Following symptomatic supportive treatment, including blood dialysis, the patient's physical symptoms gradually improved. It is necessary for clinicians to strengthen the prevention and recognition of lithium poisoning.

Effect of levetiracetam on DNA oxidation and glutathione content in a temporal lobe epilepsy model.

Levetiracetam (LEV) is a drug commonly used as an anticonvulsant. However, recent evidence points to a possible role as an antioxidant. We previously demonstrated the antioxidant properties of LEV by significantly increasing catalase and superoxide dismutase activities and decreasing the hydrogen peroxide (H2O2) levels in the hippocampus of rats with temporal lobe epilepsy (TLE) showing scavenging properties against the hydroxyl radical. The aim of the present work was to evaluate, the effect of LEV on DNA oxidation, by determining 8­hydroxy­2­deoxyguanosine (8­OHdG) levels, and glutathione content, through reduced (GSH) and oxidized (GSSG) glutathione levels, in the hippocampus of rats with TLE. Male Wistar rats were assigned to the control (CTRL), CTRL+LEV, epileptic (EPI) and EPI+LEV groups. TLE was induced using the lithium­pilocarpine model. Thirteen weeks after TLE induction, LEV was administered for one week through osmotic pumps implanted subcutaneously. The determination of 8­OHdG, GSH and GSSG levels were measured using spectrophotometric methods. We showed that LEV alone significantly increased 8­OHdG and GSSG levels in the hippocampus of control rats compared to those in epileptic condition. No significant differences in GSH levels were observed. LEV could induce changes in the hippocampus increasing DNA oxidation and GSSG levels under nonepileptic condition but not protecting against the mitochondrial dysfunction observed in TLE probably by mechanisms related to changes in chromatin structure, neuroinflammation and alterations in redox components.

Novel diarylated tacrine derivatives: Synthesis, characterization, anticancer, antiepileptic, antibacterial, and antifungal activities.

In this study, our goal was to synthesize novel aryl tacrine derivatives and assess their potential as anticancer, antibacterial agents, and enzyme inhibitors. We adopted a two-step approach, initiating with the synthesis of dibromotacrine derivatives 3 and 4 through the Friedlander reaction. These intermediates underwent further transformation into diarylated tacrine derivatives 3a-e and 4a-e using a Suzuki-Miyaura cross-coupling reaction. Thorough characterization of these novel diarylated tacrines was achieved using various spectroscopic techniques. Our findings highlighted the potent anticancer effects of these innovative compounds across a range of cancer cell lines, including lung, gynecologic, bone, colon, and breast cancers, while demonstrating low cytotoxicity against normal cells. Notably, these compounds surpassed the control drug, 5-Fluorouracil, in terms of antiproliferative activity in numerous cancer cell lines. Moreover, our investigation included an analysis of the inhibitory properties of these novel compounds against various microorganisms and cytosolic carbonic anhydrase enzymes. The results suggest their potential for further exploration as cancer-specific, enzyme inhibitory, and antibacterial therapeutic agents. Notably, four compounds, namely, 5,7-bis(4-(methylthio)phenyl)tacrine (3d), 5,7-bis(4-(trifluoromethoxy)phenyl)tacrine (3e), 2,4-bis(4-(trifluoromethoxy)phenyl)-7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-11-amine (4e), and 6,8-dibromotacrine (3), emerged as the most promising candidates for preclinical studies.

Anticonvulsant effects of Paeonia daurica subsp. macrophylla root extracts in pentylenetetrazol-induced seizure models in mice.

INTRODUCTION: In the present study, anticonvulsant effects of aqueous extract (AE), hydro-alcoholic crude extract (HE), and its fractions (F-CHCl3, F-EtOAc, F-MeOH) of Paeonia daurica subsp. macrophylla (P. daurica ssp. macrophylla) root examined by using a pentylenetetrazol-induced model (PTZ) on mice. METHODS: HE and its fractions as well as AE, in concentrations of (100, 200 and 400mg/kg), valproate (Val) (100 and 200mg/kg), and saline (negative control) (10mg/kg) were injected intraperitoneally (i.p.) 30min before PTZ (80mg/kg, i.p.). The time taken before the onset of myoclonic convulsions (MC), MC duration, time taken before the onset of generalized tonic-clonic seizures (GTCS), the duration of GTCS, and the percentage of GTCS and mortality protection recorded. The plant's anticonvulsant mechanisms were assessed using flumazenil (5mg/kg, i.p.) before AE (100, 200, and 400mg/kg, i.p.) injection. GraphPad Prism software was used to compare the differences between various treatment groups with one-way analysis of variance (ANOVA) followed by Tukey-Krammer multiple comparison tests. RESULTS: All the plant samples except F-EtOAc significantly delayed the onset and decreased the duration of PTZ-induced MCS and GTCS, and significantly reduced the GTCS and mortality rate. Pretreatment with flumazenil diminished the significant anticonvulsant effects of AE against PTZ-induced seizures. CONCLUSIONS: It can report that extract of P. daurica ssp. macrophylla might be a helpful guide for future studies in the treatment of epilepsy.

A systematic review and meta-analysis of factors related to first line drugs refractoriness in patients with juvenile myoclonic epilepsy (JME).

INTRODUCTION: Juvenile Myoclonic Epilepsy (JME) is a prevalent form of epileptic disorder, specifically categorized within the realm of Genetic Generalized Epilepsy (GGE). Its hallmark features encompass unprovoked bilateral myoclonus and tonic-clonic seizures that manifest during adolescence. While most JME patients respond favorably to anti-seizure medication (ASM), a subset experiences refractory JME, a condition where seizures persist despite rigorous ASM treatment, often termed "Drug-Resistant Epilepsy" (DRE). This systematic review and meta-analysis aims to determine the prevalence of refractory JME, and further to identify socio-demographic, electrophysiological and clinical risk factors associated with its occurrence. Pinpointing these factors is crucial as it offers the potential to predict ASM responsiveness, enabling early interventions and tailored care strategies for patients. MATERIAL AND METHODS: The systematic review and meta-analysis followed the Cochrane Handbook and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The study evaluated outcomes post ASM treatment in JME cohorts by searching papers published up to September 2023 in PubMed/MEDLINE, Scopus, and Google Scholar databases. Predefined inclusion criteria were met by 25 eligible studies, forming the basis for analysis. RESULTS: A total of 22 potential risk factors for refractory JME were documented. Notably, robust risk factors for treatment resistance included Psychiatric Disorder (Odds Ratio (OR), 3.42 [2.54, 4.61] (95% Confidence Inverval (Cl)), Febrile Seizures (OR, 1.83 [1.14, 2.96] (95% Cl)), Alcohol Consumption (OR, 16.86 [1.94, 146.88] (95%Cl)), Aura (OR, 2.15 [1.04, 4.47] (95%Cl)), childhood absence epilepsy (CAE) evolving into JME (OR, 4.54 [1.61, 12.78] (95%CI)), occurrence of three seizure types (OR, 2.96 [1.96, 4.46] (95%CI)), and Focal EEG abnormalities (OR, 1.85 [1.13, 3.01] (95%Cl)). In addition, there were some non-significant risk factors for DRE because of noticeable heterogeneity. CONCLUSION: In aggregate, over 36% of JME patients demonstrated drug resistance, with seven significant risk factors closely linked to this refractoriness. The interplay between these factors and whether they denote treatment non-response or heightened disease burden remains an open question and more studies would be required to fully examine their influence.

Efficacy and Safety of Levetiracetam for Childhood Epilepsies.

Background: Levetiracetam (LEV) is a broad spectrum second-generation antiepileptic drug (AED). Objective: The objective of the study was to investigate the efficacy and safety of levetiracetam for childhood epilepsies. Methods: This is single, tertiary centre observational, prospective study, that included paediatric patients who were treated with levetiracetam at Paediatric hospital University Clinical Centre Sarajevo, during the period of 15 years (2008-2022). Inclusion criteria were: paediatric patients age > 1 month, diagnosed with epilepsy according to International League Against Epilepsy. After the introduction of levetiracetam, each patient has been followed up at least 12 months. According to the outcome the patients were divided into 5 groups: seizure reduction >50%, seizure reduction <50%, complete seizure freedom, the same number of seizures and increased number of seizures. From these groups two intergroups have been formed: responders (seizure reduction >50% and complete seizure freedom) and non-responders (seizure reduction <50%, the same number of seizures and increased number of seizures). Results: The study enrolled 259 patients (141 female and 118 male), with mean age 7 years (3,0-12.0). Comorbidities were present at 129/259 (49.8%) patients. After 12 months of treatment, 25/259 (9.7%) patients had seizure reduction >50%, 30/259 (11.6%) patients had seizure reduction <50%, 154/259 (56.5%) patients had achieved seizure freedom, 31/259 (12%) patients had same number of seizures, while 19/259 (7.3%) patients had increased number of seizures. Seizure frequency between responders and non-responders, before treatment and after 12 months of treatment was statistically significant (p<0.001). Discussion: Non responders had the best outcome with ditherapy (30/79; 38%), while responders had the best outcome with monotherapy (161/180;89.4%). Conclusion: Levetiracetam is efficient antiepileptic drug for different types of epilepsies in childhood, used as mono, di or polytherapy.

Effect of the closed-loop hippocampal low-frequency stimulation on seizure severity, learning, and memory in pilocarpine epilepsy rat model.

AIMS: In this study, the anticonvulsant action of closed-loop, low-frequency deep brain stimulation (DBS) was investigated. In addition, the changes in brain rhythms and functional connectivity of the hippocampus and prefrontal cortex were evaluated. METHODS: Epilepsy was induced by pilocarpine in male Wistar rats. After the chronic phase, a tripolar electrode was implanted in the right ventral hippocampus and a monopolar electrode in medial prefrontal cortex (mPFC). Subjects' spontaneous seizure behaviors were observed in continuous video recording, while the local field potentials (LFPs) were recorded simultaneously. In addition, spatial memory was evaluated by the Barnes maze test. RESULTS: Applying hippocampal DBS, immediately after seizure detection in epileptic animals, reduced their seizure severity and duration, and improved their performance in Barnes maze test. DBS reduced the increment in power of delta, theta, and gamma waves in pre-ictal, ictal, and post-ictal periods. Meanwhile, DBS increased the post-ictal-to-pre-ictal ratio of theta band. DBS decreased delta and increased theta coherences, and also increased the post-ictal-to-pre-ictal ratio of coherence. In addition, DBS increased the hippocampal-mPFC coupling in pre-ictal period and decreased the coupling in the ictal and post-ictal periods. CONCLUSION: Applying closed-loop, low-frequency DBS at seizure onset reduced seizure severity and improved memory. In addition, the changes in power, coherence, and coupling of the LFP oscillations in the hippocampus and mPFC demonstrate low-frequency DBS efficacy as an antiepileptic treatment, returning LFPs to a seemingly non-seizure state in subjects that received DBS.

Diagnosing epileptic seizures in patients with Alzheimer's disease and deciding on the appropriate treatment plan.

INTRODUCTION: Alzheimer's disease (AD) is the predominant cause of dementia and a significant contributor to morbidity among the elderly. Patients diagnosed with AD face an increased risk of epileptic seizures. AREAS COVERED: Herein, the authors review the challenges in the diagnosis of seizures in patients with AD, the risks of seizures related to medications used in AD and the pharmacological treatment of seizures in AD. The authors also provide the reader with their expert opinion on the subject matter and future perspectives. EXPERT OPINION: Healthcare professionals should maintain a vigilant approach to suspecting seizures in AD patients. Acute symptomatic seizures triggered by metabolic disturbances, infections, toxins, or drug-related factors often have a low risk of recurrence. In such cases, addressing the underlying cause may suffice without initiating antiseizure medications (ASMs). However, unprovoked seizures in certain AD patients carry a higher risk of recurrence over time, warranting the use of ASMs. Although data is limited, both lamotrigine and levetiracetam appear to be reasonable choices for controlling seizures in elderly AD patients. Decisions should be informed by the best available evidence, the treating physician's clinical experience, and the patient's preferences.

The latest advances in the pharmacological management of focal epilepsies in children: a narrative review.

INTRODUCTION: Focal epilepsy constitutes the most common epilepsy in children, and medical treatment represents the first-line therapy in this condition. The main goal of medical treatment for children and adolescents with epilepsy is the achievement of seizure freedom or, in drug-resistant epilepsies, a significant seizure reduction, both minimizing antiseizure medications (ASM)-related adverse events, thus improving the patient's quality of life. However, up to 20-40% of pediatric epilepsies are refractory to drug treatments. New ASMs came to light in the pediatric landscape, improving the drug profile compared to that of the preexisting ones. Clinicians should consider several factors during the drug choice process, including patient and medication-specific characteristics. AREAS COVERED: This narrative review aims to summarize the latest evidence on the effectiveness and tolerability of the newest ASMs administered as monotherapy or adjunctive therapy in pediatric epilepsies with focal onset seizures, providing a practical appraisal based on the existing evidence. EXPERT OPINION: The latest ASMs have the potential to be effective in the pharmacological management of focal onset seizures in children, and treatment choice should consider several drug- and epilepsy-related factors. Future treatments should be increasingly personalized and targeted on patient-specific pathways. Future research should focus on discovering new chemical compounds and repurposing medications used for other indications.