Pub Date : 2025-02-01Epub Date: 2024-11-19DOI: 10.1111/epi.18187
Pablo M Casillas-Espinosa, Jennifer C Wong, Wanda Grabon, Ana Gonzalez-Ramos, Massimo Mantegazza, Nihan Carcak Yilmaz, Manisha Patel, Kevin Staley, Raman Sankar, Terence J O'Brien, Özlem Akman, Ganna Balagura, Adam L Numis, Jeffrey L Noebels, Stéphanie Baulac, Stéphane Auvin, David C Henshall, Aristea S Galanopoulou
The early onset epilepsies encompass a heterogeneous group of disorders, some of which result in drug-resistant seizures, developmental delay, psychiatric comorbidities, and sudden death. Advancement in the widespread use of targeted gene panels as well as genome and exome sequencing has facilitated the identification of different causative genes in a subset of these patients. The ability to recognize the genetic basis of early onset epilepsies continues to improve, with de novo coding variants accounting for most of the genetic etiologies identified. Although current disease-specific and disease-modifying therapies remain limited, novel precision medicine approaches, such as small molecules, cell therapy, and other forms of genetic therapies for early onset epilepsies, have created excitement among researchers, clinicians, and caregivers. Here, we summarize the main findings of presentations and discussions on novel therapeutic strategies for targeted treatment of early onset epilepsies that occurred during the Workshop on Neurobiology of Epilepsy (WONOEP XVI, Talloires, France, July 2022). The presentations discussed the use of chloride transporter inhibitors for neonatal seizures, targeting orexinergic signaling for childhood absence epilepsy, targeting energy metabolism in Dravet syndrome, and the role of cannabinoid receptor type 2, reversible acetylcholinesterase inhibitors, cell therapies, and RNA-based therapies in early life epilepsies.
{"title":"WONOEP appraisal: Targeted therapy development for early onset epilepsies.","authors":"Pablo M Casillas-Espinosa, Jennifer C Wong, Wanda Grabon, Ana Gonzalez-Ramos, Massimo Mantegazza, Nihan Carcak Yilmaz, Manisha Patel, Kevin Staley, Raman Sankar, Terence J O'Brien, Özlem Akman, Ganna Balagura, Adam L Numis, Jeffrey L Noebels, Stéphanie Baulac, Stéphane Auvin, David C Henshall, Aristea S Galanopoulou","doi":"10.1111/epi.18187","DOIUrl":"10.1111/epi.18187","url":null,"abstract":"<p><p>The early onset epilepsies encompass a heterogeneous group of disorders, some of which result in drug-resistant seizures, developmental delay, psychiatric comorbidities, and sudden death. Advancement in the widespread use of targeted gene panels as well as genome and exome sequencing has facilitated the identification of different causative genes in a subset of these patients. The ability to recognize the genetic basis of early onset epilepsies continues to improve, with de novo coding variants accounting for most of the genetic etiologies identified. Although current disease-specific and disease-modifying therapies remain limited, novel precision medicine approaches, such as small molecules, cell therapy, and other forms of genetic therapies for early onset epilepsies, have created excitement among researchers, clinicians, and caregivers. Here, we summarize the main findings of presentations and discussions on novel therapeutic strategies for targeted treatment of early onset epilepsies that occurred during the Workshop on Neurobiology of Epilepsy (WONOEP XVI, Talloires, France, July 2022). The presentations discussed the use of chloride transporter inhibitors for neonatal seizures, targeting orexinergic signaling for childhood absence epilepsy, targeting energy metabolism in Dravet syndrome, and the role of cannabinoid receptor type 2, reversible acetylcholinesterase inhibitors, cell therapies, and RNA-based therapies in early life epilepsies.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":"328-340"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01Epub Date: 2024-12-10DOI: 10.1111/epi.18210
Nabil Awan, Raj G Kumar, Shannon B Juengst, Dominic DiSanto, Cynthia Harrison-Felix, Kristen Dams-O'Connor, Mary Jo Pugh, Ross D Zafonte, William C Walker, Jerzy P Szaflarski, Robert T Krafty, Amy K Wagner
Objective: Although traumatic brain injury (TBI) and post-traumatic epilepsy (PTE) are common, there are no prospective models quantifying individual epilepsy risk after moderate-to-severe TBI (msTBI). We generated parsimonious prediction models to quantify individual epilepsy risk between acute inpatient rehabilitation for individuals 2 years after msTBI.
Methods: We used data from 6089 prospectively enrolled participants (≥16 years) in the TBI Model Systems National Database. Of these, 4126 individuals had complete seizure data collected over a 2-year period post-injury. We performed a case-complete analysis to generate multiple prediction models using least absolute shrinkage and selection operator logistic regression. Baseline predictors were used to assess 2-year seizure risk (Model 1). Then a 2-year seizure risk was assessed excluding the acute care variables (Model 2). In addition, we generated prognostic models predicting new/recurrent seizures during Year 2 post-msTBI (Model 3) and predicting new seizures only during Year 2 (Model 4). We assessed model sensitivity when keeping specificity ≥.60, area under the receiver-operating characteristic curve (AUROC), and AUROC model performance through 5-fold cross-validation (CV).
Results: Model 1 (73.8% men, 44.1 ± 19.7 years, 76.1% moderate TBI) had a model sensitivity = 76.00% and average AUROC = .73 ± .02 in 5-fold CV. Model 2 had a model sensitivity = 72.16% and average AUROC = .70 ± .02 in 5-fold CV. Model 3 had a sensitivity = 86.63% and average AUROC = .84 ± .03 in 5-fold CV. Model 4 had a sensitivity = 73.68% and average AUROC = .67 ± .03 in 5-fold CV. Cranial surgeries, acute care seizures, intracranial fragments, and traumatic hemorrhages were consistent predictors across all models. Demographic and mental health variables contributed to some models. Simulated, clinical examples model individual PTE predictions.
Significance: Using information available, acute-care, and year-1 post-injury data, parsimonious quantitative epilepsy prediction models following msTBI may facilitate timely evidence-based PTE prognostication within a 2-year period. We developed interactive web-based tools for testing prediction model external validity among independent cohorts. Individualized PTE risk may inform clinical trial development/design and clinical decision support tools for this population.
{"title":"Development of individualized risk assessment models for predicting post-traumatic epilepsy 1 and 2 years after moderate-to-severe traumatic brain injury: A traumatic brain injury model system study.","authors":"Nabil Awan, Raj G Kumar, Shannon B Juengst, Dominic DiSanto, Cynthia Harrison-Felix, Kristen Dams-O'Connor, Mary Jo Pugh, Ross D Zafonte, William C Walker, Jerzy P Szaflarski, Robert T Krafty, Amy K Wagner","doi":"10.1111/epi.18210","DOIUrl":"10.1111/epi.18210","url":null,"abstract":"<p><strong>Objective: </strong>Although traumatic brain injury (TBI) and post-traumatic epilepsy (PTE) are common, there are no prospective models quantifying individual epilepsy risk after moderate-to-severe TBI (msTBI). We generated parsimonious prediction models to quantify individual epilepsy risk between acute inpatient rehabilitation for individuals 2 years after msTBI.</p><p><strong>Methods: </strong>We used data from 6089 prospectively enrolled participants (≥16 years) in the TBI Model Systems National Database. Of these, 4126 individuals had complete seizure data collected over a 2-year period post-injury. We performed a case-complete analysis to generate multiple prediction models using least absolute shrinkage and selection operator logistic regression. Baseline predictors were used to assess 2-year seizure risk (Model 1). Then a 2-year seizure risk was assessed excluding the acute care variables (Model 2). In addition, we generated prognostic models predicting new/recurrent seizures during Year 2 post-msTBI (Model 3) and predicting new seizures only during Year 2 (Model 4). We assessed model sensitivity when keeping specificity ≥.60, area under the receiver-operating characteristic curve (AUROC), and AUROC model performance through 5-fold cross-validation (CV).</p><p><strong>Results: </strong>Model 1 (73.8% men, 44.1 ± 19.7 years, 76.1% moderate TBI) had a model sensitivity = 76.00% and average AUROC = .73 ± .02 in 5-fold CV. Model 2 had a model sensitivity = 72.16% and average AUROC = .70 ± .02 in 5-fold CV. Model 3 had a sensitivity = 86.63% and average AUROC = .84 ± .03 in 5-fold CV. Model 4 had a sensitivity = 73.68% and average AUROC = .67 ± .03 in 5-fold CV. Cranial surgeries, acute care seizures, intracranial fragments, and traumatic hemorrhages were consistent predictors across all models. Demographic and mental health variables contributed to some models. Simulated, clinical examples model individual PTE predictions.</p><p><strong>Significance: </strong>Using information available, acute-care, and year-1 post-injury data, parsimonious quantitative epilepsy prediction models following msTBI may facilitate timely evidence-based PTE prognostication within a 2-year period. We developed interactive web-based tools for testing prediction model external validity among independent cohorts. Individualized PTE risk may inform clinical trial development/design and clinical decision support tools for this population.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":"482-498"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01Epub Date: 2024-11-22DOI: 10.1111/epi.18193
David G Vossler, Brenda E Porter, Ryutaro Kira, Jeehun Lee, Alec Aeby, Anna Patten, Jocelyn Y Cheng, Leock Y Ngo
Objectives: The Phase 3 Study 338 (NCT02834793) assessed long-term clinical outcomes of adjunctive perampanel in patients ≥2 years of age with uncontrolled seizures associated with Lennox-Gastaut syndrome (LGS).
Methods: Eligible patients were diagnosed with LGS and receiving one to four concomitant antiseizure medications with an average of two or more drop seizures/week during baseline. The study comprised an 18-week double-blind, randomized, placebo-controlled Core Study and ≥52-week open-label Extension. The primary endpoint was median percent change in drop seizure frequency per 28 days during the Core Study. Key secondary endpoints included responder rates, seizure-freedom rates, and safety outcomes. Post hoc analyses were performed encompassing a broader range of drop seizures or all countable motor seizures.
Results: Seventy patients were randomized into the Core Study (perampanel, n = 34; placebo, n = 36), and 58 entered the Extension. In the Core Study, numerically greater median percent reductions in drop seizure frequency were observed with perampanel (23.1%) vs placebo (4.5%) using prespecified assessments (p = .107), whereas significantly greater reductions were detected using the broader definition (48.6% vs -.7%, respectively, p = .001) or all countable motor seizures (44.0% vs -.6%, respectively, p = .017). The 50% responder rate for drop seizures was higher with perampanel vs placebo using modern definitions. Reductions in seizure frequency with perampanel were maintained over 52 weeks. Treatment-emergent adverse events occurred in 85.3% of perampanel-treated patients (somnolence [23.5%] was the most frequent) and 72.2% of placebo-treated patients.
Significance: This study had a reduced sample size and was underpowered. Although the difference in reductions in drop seizure frequency between treatments was not statistically significant by prespecified assessments, adjunctive perampanel demonstrated sustained efficacy in reducing drop seizures associated with LGS for ≤71 weeks using modern definitions. No new safety signals emerged. These observations suggest the long-term efficacy and safety of perampanel in the LGS population.
{"title":"Efficacy and safety of perampanel in patients with seizures associated with Lennox-Gastaut syndrome: A randomized trial.","authors":"David G Vossler, Brenda E Porter, Ryutaro Kira, Jeehun Lee, Alec Aeby, Anna Patten, Jocelyn Y Cheng, Leock Y Ngo","doi":"10.1111/epi.18193","DOIUrl":"10.1111/epi.18193","url":null,"abstract":"<p><strong>Objectives: </strong>The Phase 3 Study 338 (NCT02834793) assessed long-term clinical outcomes of adjunctive perampanel in patients ≥2 years of age with uncontrolled seizures associated with Lennox-Gastaut syndrome (LGS).</p><p><strong>Methods: </strong>Eligible patients were diagnosed with LGS and receiving one to four concomitant antiseizure medications with an average of two or more drop seizures/week during baseline. The study comprised an 18-week double-blind, randomized, placebo-controlled Core Study and ≥52-week open-label Extension. The primary endpoint was median percent change in drop seizure frequency per 28 days during the Core Study. Key secondary endpoints included responder rates, seizure-freedom rates, and safety outcomes. Post hoc analyses were performed encompassing a broader range of drop seizures or all countable motor seizures.</p><p><strong>Results: </strong>Seventy patients were randomized into the Core Study (perampanel, n = 34; placebo, n = 36), and 58 entered the Extension. In the Core Study, numerically greater median percent reductions in drop seizure frequency were observed with perampanel (23.1%) vs placebo (4.5%) using prespecified assessments (p = .107), whereas significantly greater reductions were detected using the broader definition (48.6% vs -.7%, respectively, p = .001) or all countable motor seizures (44.0% vs -.6%, respectively, p = .017). The 50% responder rate for drop seizures was higher with perampanel vs placebo using modern definitions. Reductions in seizure frequency with perampanel were maintained over 52 weeks. Treatment-emergent adverse events occurred in 85.3% of perampanel-treated patients (somnolence [23.5%] was the most frequent) and 72.2% of placebo-treated patients.</p><p><strong>Significance: </strong>This study had a reduced sample size and was underpowered. Although the difference in reductions in drop seizure frequency between treatments was not statistically significant by prespecified assessments, adjunctive perampanel demonstrated sustained efficacy in reducing drop seizures associated with LGS for ≤71 weeks using modern definitions. No new safety signals emerged. These observations suggest the long-term efficacy and safety of perampanel in the LGS population.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":"379-393"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01Epub Date: 2024-12-20DOI: 10.1111/epi.18188
Ashley L B Raghu, Jonathan Lau, Matthew A Stern, Razan R Faraj, Faical Isbaine, Dayton Grogan, Katie Bullinger, Rebecca W Roth, Adam S Dickey, Jon T Willie, Daniel L Drane, Robert E Gross
Objective: Stereotactic laser amygdalohippocampotomy (SLAH) is a minimally invasive procedure for mesial temporal lobe epilepsy that preserves more tissue than open procedures. As a result, although patients have better functional outcomes, more patients do not achieve seizure freedom. The rate at which this occurs is evolving with improved surgical practices. However, the risks and benefits of further surgical management for these patients remains a question with limited data to guide decision-making.
Methods: We retrospectively reviewed a continuous series (2011-2019) of SLAH operations at our institution to determine trends in surgical management, identifying cases where further surgery was performed. Pre-operative and follow-up seizure, cognitive, and functional data, and surgical complications were collated.
Results: Of 108 patients undergoing primary SLAH, 21 (19%) underwent further surgery (23 procedures). Stereo-electroencephalography (SEEG) informed seven procedures (30%). There was a trend for quicker SLAH failure in the earlier patients. Similarly, surgical chronology was associated with progression to repeat surgery (p = .007). At 1-year follow-up, 6 of 13 patients (46%) achieved seizure freedom after repeat SLAH and 5 of 8 patients (63%) achieved seizure freedom after anterior temporal lobectomy (ATL), one of whom had failed two SLAHs. Two of three patients undergoing an ablation outside the mesial temporal lobe achieved seizure freedom at 1 year. Neuropsychological sequelae were more prevalent with ATL than SLAH, including decline in visual naming (p = .01) and functional status (p = .007).
Significance: Repeat SLAH and ATL post-SLAH are both practicable and can be effective. Surgical experience, risk to cognition, and marginal benefit relative to existing improvement are principal considerations for further surgery.
{"title":"A single-center learning curve for stereotactic laser amygdalohippocampotomy and a surgical framework to manage failures.","authors":"Ashley L B Raghu, Jonathan Lau, Matthew A Stern, Razan R Faraj, Faical Isbaine, Dayton Grogan, Katie Bullinger, Rebecca W Roth, Adam S Dickey, Jon T Willie, Daniel L Drane, Robert E Gross","doi":"10.1111/epi.18188","DOIUrl":"10.1111/epi.18188","url":null,"abstract":"<p><strong>Objective: </strong>Stereotactic laser amygdalohippocampotomy (SLAH) is a minimally invasive procedure for mesial temporal lobe epilepsy that preserves more tissue than open procedures. As a result, although patients have better functional outcomes, more patients do not achieve seizure freedom. The rate at which this occurs is evolving with improved surgical practices. However, the risks and benefits of further surgical management for these patients remains a question with limited data to guide decision-making.</p><p><strong>Methods: </strong>We retrospectively reviewed a continuous series (2011-2019) of SLAH operations at our institution to determine trends in surgical management, identifying cases where further surgery was performed. Pre-operative and follow-up seizure, cognitive, and functional data, and surgical complications were collated.</p><p><strong>Results: </strong>Of 108 patients undergoing primary SLAH, 21 (19%) underwent further surgery (23 procedures). Stereo-electroencephalography (SEEG) informed seven procedures (30%). There was a trend for quicker SLAH failure in the earlier patients. Similarly, surgical chronology was associated with progression to repeat surgery (p = .007). At 1-year follow-up, 6 of 13 patients (46%) achieved seizure freedom after repeat SLAH and 5 of 8 patients (63%) achieved seizure freedom after anterior temporal lobectomy (ATL), one of whom had failed two SLAHs. Two of three patients undergoing an ablation outside the mesial temporal lobe achieved seizure freedom at 1 year. Neuropsychological sequelae were more prevalent with ATL than SLAH, including decline in visual naming (p = .01) and functional status (p = .007).</p><p><strong>Significance: </strong>Repeat SLAH and ATL post-SLAH are both practicable and can be effective. Surgical experience, risk to cognition, and marginal benefit relative to existing improvement are principal considerations for further surgery.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":"458-470"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01Epub Date: 2024-12-12DOI: 10.1111/epi.18211
Derek K Hu, Marco A Pinto-Orellana, Mandeep Rana, Linda Do, David J Adams, Shaun A Hussain, Daniel W Shrey, Beth A Lopour
Objective: The discovery and validation of electroencephalography (EEG) biomarkers often rely on visual identification of waveforms. However, bias toward visually striking events restricts the search space for new biomarkers, and low interrater reliability can limit rigorous validation. We present a data-driven approach to biomarker discovery called scalp EEG Pattern Identification and Categorization (s-EPIC), which enables automated, unsupervised identification of EEG waveforms. S-EPIC is validated on Lennox-Gastaut syndrome (LGS), an epilepsy that is difficult to diagnose and assess due to its variable presentation and insidious evolution of symptoms.
Methods: We retrospectively collected 10-min scalp EEG clips during non-rapid eye movement (NREM) sleep from 20 subjects with LGS and 20 approximately age-matched healthy controls. For s-EPIC, EEG events of interest (EOIs) were detected in all subjects using time-frequency analysis. The 11 705 EOIs were characterized based on 11 features and were collectively grouped using both k-means clustering and feature categorization. To provide clinical context, 1350 EOIs were visually reviewed and classified by three epileptologists.
Results: s-EPIC identified four clusters as candidate biomarkers of LGS, each having significantly more LGS EOIs than control EOIs. Two clusters contained EOIs resembling known LGS biomarkers such as interictal epileptiform discharges and generalized paroxysmal fast activity. The other two LGS-associated EEG clusters contained short bursts of power in beta and gamma frequency bands that were primarily unrecognized by epileptologists. This approach also uncovered significant differences in sleep spindles between LGS and control cohorts.
Significance: s-EPIC provides a quantitative approach to waveform identification that could be broadly applied to EEG from both healthy subjects and those with suspected pathology. s-EPIC can objectively identify and characterize relevant EEG waveforms without visual review or assumptions about the waveform's morphology and could therefore be a powerful tool for the discovery and refinement of EEG biomarkers.
{"title":"Discovering EEG biomarkers of Lennox-Gastaut syndrome through unsupervised time-frequency analysis.","authors":"Derek K Hu, Marco A Pinto-Orellana, Mandeep Rana, Linda Do, David J Adams, Shaun A Hussain, Daniel W Shrey, Beth A Lopour","doi":"10.1111/epi.18211","DOIUrl":"10.1111/epi.18211","url":null,"abstract":"<p><strong>Objective: </strong>The discovery and validation of electroencephalography (EEG) biomarkers often rely on visual identification of waveforms. However, bias toward visually striking events restricts the search space for new biomarkers, and low interrater reliability can limit rigorous validation. We present a data-driven approach to biomarker discovery called scalp EEG Pattern Identification and Categorization (s-EPIC), which enables automated, unsupervised identification of EEG waveforms. S-EPIC is validated on Lennox-Gastaut syndrome (LGS), an epilepsy that is difficult to diagnose and assess due to its variable presentation and insidious evolution of symptoms.</p><p><strong>Methods: </strong>We retrospectively collected 10-min scalp EEG clips during non-rapid eye movement (NREM) sleep from 20 subjects with LGS and 20 approximately age-matched healthy controls. For s-EPIC, EEG events of interest (EOIs) were detected in all subjects using time-frequency analysis. The 11 705 EOIs were characterized based on 11 features and were collectively grouped using both k-means clustering and feature categorization. To provide clinical context, 1350 EOIs were visually reviewed and classified by three epileptologists.</p><p><strong>Results: </strong>s-EPIC identified four clusters as candidate biomarkers of LGS, each having significantly more LGS EOIs than control EOIs. Two clusters contained EOIs resembling known LGS biomarkers such as interictal epileptiform discharges and generalized paroxysmal fast activity. The other two LGS-associated EEG clusters contained short bursts of power in beta and gamma frequency bands that were primarily unrecognized by epileptologists. This approach also uncovered significant differences in sleep spindles between LGS and control cohorts.</p><p><strong>Significance: </strong>s-EPIC provides a quantitative approach to waveform identification that could be broadly applied to EEG from both healthy subjects and those with suspected pathology. s-EPIC can objectively identify and characterize relevant EEG waveforms without visual review or assumptions about the waveform's morphology and could therefore be a powerful tool for the discovery and refinement of EEG biomarkers.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":"541-553"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01Epub Date: 2024-11-23DOI: 10.1111/epi.18194
Veronica Pegoraro, Renaud Viellevoye, Geneviève Malfilatre, Robertino Dilena, Jacopo Proietti, Isabella Mauro, Cecilia Zardini, Mark Dzietko, Laure Lacan, Beatrice Desnous, Duccio Maria Cordelli, Francesca Campi, Monica Reis Da Silva, Monica Fumagalli, Sylvie Nguyen The Tich, Ursula Felderhoff-Müser, Giulia Ventura, Stefano Sartori, Manon Benders, Carla Pittini, Maria Elena Cavicchiolo, Mathieu Milh, Gaetano Cantalupo, Aline van Maanen, Maria Luisa Tataranno, Maria Roberta Cilio
Objective: Few studies have evaluated the efficacy of antiseizure medications (ASMs) according to the etiology of neonatal acute provoked seizures. We aimed to investigate the response to ASMs in term/near term neonates with acute arterial ischemic stroke (AIS), as well as the type of seizure at presentation and the monitoring approach.
Methods: We retrospectively evaluated neonates from 15 European level IV neonatal intensive care units who presented with seizures due to AIS and were monitored by continuous electroencephalography (cEEG) and/or amplitude-integrated EEG (aEEG) in whom actual recordings, timing, doses, and response to ASMs were available for review.
Results: One hundred seven neonates were referred, and 88 were included. Of those, 56 met the criteria for evaluating the treatment response. The mean time to treatment was 7.9 h (SD = 16.4), and the most frequently administered first-line ASM was phenobarbital (PB; 74/88, 84.1%). Seizures were controlled within 24 h from onset of symptoms in 64.3% (36/56) of neonates. Phenytoin (PHT) was effective in almost all neonates in whom it was trialed (24/25, 96.0%), whereas PB was effective in only 22.0% of patients (11/50). Infants treated with PB or PHT as first-line treatment (53/56, 94.6%) showed a higher response rate with PHT (6/6, 100.0%) than with PB (11/47, 23.4%). Monitoring approach and seizure types were evaluated in 88 infants. Forty-six of 88 (52.3%) were monitored with cEEG and 47.7% (42/88) with aEEG, with or without intermittent cEEG. The mean monitoring duration was 65.8 h (SD = 39.21). In 83 of 88 (94.3%) infants, the type of seizure suspected clinically prior to monitoring was confirmed afterward. Unilateral focal clonic seizures were seen in 71 of 88 infants (80.7%), whereas 11 of 88 (12.5%) presented with ictal apneas.
Significance: Our findings provide evidence in a large, homogenous cohort that PHT is more effective than PB in treating neonatal acute symptomatic seizures due to AIS.
{"title":"Effectiveness of sodium channel blockers in treating neonatal seizures due to arterial ischemic stroke.","authors":"Veronica Pegoraro, Renaud Viellevoye, Geneviève Malfilatre, Robertino Dilena, Jacopo Proietti, Isabella Mauro, Cecilia Zardini, Mark Dzietko, Laure Lacan, Beatrice Desnous, Duccio Maria Cordelli, Francesca Campi, Monica Reis Da Silva, Monica Fumagalli, Sylvie Nguyen The Tich, Ursula Felderhoff-Müser, Giulia Ventura, Stefano Sartori, Manon Benders, Carla Pittini, Maria Elena Cavicchiolo, Mathieu Milh, Gaetano Cantalupo, Aline van Maanen, Maria Luisa Tataranno, Maria Roberta Cilio","doi":"10.1111/epi.18194","DOIUrl":"10.1111/epi.18194","url":null,"abstract":"<p><strong>Objective: </strong>Few studies have evaluated the efficacy of antiseizure medications (ASMs) according to the etiology of neonatal acute provoked seizures. We aimed to investigate the response to ASMs in term/near term neonates with acute arterial ischemic stroke (AIS), as well as the type of seizure at presentation and the monitoring approach.</p><p><strong>Methods: </strong>We retrospectively evaluated neonates from 15 European level IV neonatal intensive care units who presented with seizures due to AIS and were monitored by continuous electroencephalography (cEEG) and/or amplitude-integrated EEG (aEEG) in whom actual recordings, timing, doses, and response to ASMs were available for review.</p><p><strong>Results: </strong>One hundred seven neonates were referred, and 88 were included. Of those, 56 met the criteria for evaluating the treatment response. The mean time to treatment was 7.9 h (SD = 16.4), and the most frequently administered first-line ASM was phenobarbital (PB; 74/88, 84.1%). Seizures were controlled within 24 h from onset of symptoms in 64.3% (36/56) of neonates. Phenytoin (PHT) was effective in almost all neonates in whom it was trialed (24/25, 96.0%), whereas PB was effective in only 22.0% of patients (11/50). Infants treated with PB or PHT as first-line treatment (53/56, 94.6%) showed a higher response rate with PHT (6/6, 100.0%) than with PB (11/47, 23.4%). Monitoring approach and seizure types were evaluated in 88 infants. Forty-six of 88 (52.3%) were monitored with cEEG and 47.7% (42/88) with aEEG, with or without intermittent cEEG. The mean monitoring duration was 65.8 h (SD = 39.21). In 83 of 88 (94.3%) infants, the type of seizure suspected clinically prior to monitoring was confirmed afterward. Unilateral focal clonic seizures were seen in 71 of 88 infants (80.7%), whereas 11 of 88 (12.5%) presented with ictal apneas.</p><p><strong>Significance: </strong>Our findings provide evidence in a large, homogenous cohort that PHT is more effective than PB in treating neonatal acute symptomatic seizures due to AIS.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":"394-406"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01Epub Date: 2024-12-05DOI: 10.1111/epi.18199
Johannes M Nico Enslin, Carrie R Muh, Xiongfei Wang, Tatiana von Hertwig Fernandes de Olivera, Guy M McKhann, Eyiyemisi Damisah, Faisal Al-Otaibi, Bertil Rydenhag, Rushna P Ali, Christian Dorfer, Dario J Englot, Arthur Cukiert
Up to 80% of the world's population with epilepsy lives in low and middle-income countries. Around one-third of these patients will have drug-resistant epilepsy, for which epilepsy surgery is an option. Unfortunately, many of these regions, as well as some more developed nations, lack sufficient epilepsy surgery units and trained neurosurgeons. With this in mind, the International League Against Epilepsy (ILAE) formed the Epilepsy Surgery Education Taskforce to address the shortage of further educational opportunities for surgeons and neurologists and to promote the creation of more epilepsy surgery units around the world. In this article, we publish our findings from a web-based international survey, in which we investigated the global distribution and experience of neurosurgeons who perform epilepsy surgery, their educational paths, and opinions on the further need for epilepsy surgery education, as well as the resources available to them. We report a detailed analysis of the 202 survey replies received from 35 different countries across six continents. The lack of adequate numbers of epilepsy surgery units in the Southern Hemisphere is notable, and the aim of this task force with other ILAE committees, is to improve access to epilepsy surgery for patients and to enhance training for their health care providers.
{"title":"Epilepsy surgery education and practice around the globe: An ILAE taskforce report.","authors":"Johannes M Nico Enslin, Carrie R Muh, Xiongfei Wang, Tatiana von Hertwig Fernandes de Olivera, Guy M McKhann, Eyiyemisi Damisah, Faisal Al-Otaibi, Bertil Rydenhag, Rushna P Ali, Christian Dorfer, Dario J Englot, Arthur Cukiert","doi":"10.1111/epi.18199","DOIUrl":"10.1111/epi.18199","url":null,"abstract":"<p><p>Up to 80% of the world's population with epilepsy lives in low and middle-income countries. Around one-third of these patients will have drug-resistant epilepsy, for which epilepsy surgery is an option. Unfortunately, many of these regions, as well as some more developed nations, lack sufficient epilepsy surgery units and trained neurosurgeons. With this in mind, the International League Against Epilepsy (ILAE) formed the Epilepsy Surgery Education Taskforce to address the shortage of further educational opportunities for surgeons and neurologists and to promote the creation of more epilepsy surgery units around the world. In this article, we publish our findings from a web-based international survey, in which we investigated the global distribution and experience of neurosurgeons who perform epilepsy surgery, their educational paths, and opinions on the further need for epilepsy surgery education, as well as the resources available to them. We report a detailed analysis of the 202 survey replies received from 35 different countries across six continents. The lack of adequate numbers of epilepsy surgery units in the Southern Hemisphere is notable, and the aim of this task force with other ILAE committees, is to improve access to epilepsy surgery for patients and to enhance training for their health care providers.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":"319-327"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01Epub Date: 2024-12-06DOI: 10.1111/epi.18190
Carmen Stevering, Maarten Lequin, Kinga Szczepaniak, Krzysztof Sadowski, Saba Ishrat, Alberto De Luca, Alexander Leemans, Willem Otte, David J Kwiatkowski, Paolo Curatolo, Bernhard Weschke, Kate Riney, Martha Feucht, Pavel Krsek, Rima Nabbout, Anna Jansen, Konrad Wojdan, Kamil Sijko, Jagoda Glowacka-Walas, Julita Borkowska, Dorota Domanska-Pakiela, Romina Moavero, Christoph Hertzberg, Hanna Hulshof, Theresa Scholl, Bořivoj Petrák, Miroslav Maminak, Eleonora Aronica, Jessie De Ridder, Lieven Lagae, Sergiusz Jozwiak, Katarzyna Kotulska, Kees Braun, Floor Jansen
Objective: Previous retrospective studies have reported vigabatrin-associated brain abnormalities on magnetic resonance imaging (VABAM), although clinical impact is unknown. We evaluated the association between vigabatrin and predefined brain magnetic resonance imaging (MRI) changes in a large homogenous tuberous sclerosis complex (TSC) cohort and assessed to what extent VABAM-related symptoms were reported in TSC infants.
Methods: The Dutch TSC Registry and the EPISTOP cohort provided retrospective and prospective data from 80 TSC patients treated with vigabatrin (VGB) before the age of 2 years and 23 TSC patients without VGB. Twenty-nine age-matched non-TSC epilepsy patients not receiving VGB were included as controls. VABAM, specified as T2/fluid-attenuated inversion recovery hyperintensity or diffusion restriction in predefined brain areas, were examined on brain MRI before, during, and after VGB, and once in the controls (at approximately age 2 years). Additionally, the presence of VABAM accompanying symptoms was evaluated.
Results: Prevalence of VABAM in VGB-treated TSC patients was 35.5%. VABAM-like abnormalities were observed in 13.5% of all patients without VGB. VGB was significantly associated with VABAM (risk ratio [RR] = 3.57, 95% confidence interval [CI] = 1.43-6.39), whereas TSC and refractory epilepsy were not. In all 13 VGB-treated patients with VABAM for whom posttreatment MRIs were available, VABAM entirely resolved after VGB discontinuation. The prevalence of symptoms was 11.7% in patients with VABAM or VABAM-like MRI abnormalities and 4.3% in those without, implicating no significant association (RR = 2.76, 95% CI = .68-8.77).
Significance: VABAM are common in VGB-treated TSC infants; however, VABAM-like abnormalities also occurred in children without either VGB or TSC. The cause of these MRI changes is unknown. Possible contributing factors are abnormal myelination, underlying etiology, recurrent seizures, and other antiseizure medication. Furthermore, the presence of VABAM (or VABAM-like abnormalities) did not appear to be associated with clinical symptoms. This study confirms that the well-known antiseizure effects of VGB outweigh the risk of VABAM and related symptoms.
{"title":"Vigabatrin-associated brain magnetic resonance imaging abnormalities and clinical symptoms in infants with tuberous sclerosis complex.","authors":"Carmen Stevering, Maarten Lequin, Kinga Szczepaniak, Krzysztof Sadowski, Saba Ishrat, Alberto De Luca, Alexander Leemans, Willem Otte, David J Kwiatkowski, Paolo Curatolo, Bernhard Weschke, Kate Riney, Martha Feucht, Pavel Krsek, Rima Nabbout, Anna Jansen, Konrad Wojdan, Kamil Sijko, Jagoda Glowacka-Walas, Julita Borkowska, Dorota Domanska-Pakiela, Romina Moavero, Christoph Hertzberg, Hanna Hulshof, Theresa Scholl, Bořivoj Petrák, Miroslav Maminak, Eleonora Aronica, Jessie De Ridder, Lieven Lagae, Sergiusz Jozwiak, Katarzyna Kotulska, Kees Braun, Floor Jansen","doi":"10.1111/epi.18190","DOIUrl":"10.1111/epi.18190","url":null,"abstract":"<p><strong>Objective: </strong>Previous retrospective studies have reported vigabatrin-associated brain abnormalities on magnetic resonance imaging (VABAM), although clinical impact is unknown. We evaluated the association between vigabatrin and predefined brain magnetic resonance imaging (MRI) changes in a large homogenous tuberous sclerosis complex (TSC) cohort and assessed to what extent VABAM-related symptoms were reported in TSC infants.</p><p><strong>Methods: </strong>The Dutch TSC Registry and the EPISTOP cohort provided retrospective and prospective data from 80 TSC patients treated with vigabatrin (VGB) before the age of 2 years and 23 TSC patients without VGB. Twenty-nine age-matched non-TSC epilepsy patients not receiving VGB were included as controls. VABAM, specified as T2/fluid-attenuated inversion recovery hyperintensity or diffusion restriction in predefined brain areas, were examined on brain MRI before, during, and after VGB, and once in the controls (at approximately age 2 years). Additionally, the presence of VABAM accompanying symptoms was evaluated.</p><p><strong>Results: </strong>Prevalence of VABAM in VGB-treated TSC patients was 35.5%. VABAM-like abnormalities were observed in 13.5% of all patients without VGB. VGB was significantly associated with VABAM (risk ratio [RR] = 3.57, 95% confidence interval [CI] = 1.43-6.39), whereas TSC and refractory epilepsy were not. In all 13 VGB-treated patients with VABAM for whom posttreatment MRIs were available, VABAM entirely resolved after VGB discontinuation. The prevalence of symptoms was 11.7% in patients with VABAM or VABAM-like MRI abnormalities and 4.3% in those without, implicating no significant association (RR = 2.76, 95% CI = .68-8.77).</p><p><strong>Significance: </strong>VABAM are common in VGB-treated TSC infants; however, VABAM-like abnormalities also occurred in children without either VGB or TSC. The cause of these MRI changes is unknown. Possible contributing factors are abnormal myelination, underlying etiology, recurrent seizures, and other antiseizure medication. Furthermore, the presence of VABAM (or VABAM-like abnormalities) did not appear to be associated with clinical symptoms. This study confirms that the well-known antiseizure effects of VGB outweigh the risk of VABAM and related symptoms.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":"356-368"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01Epub Date: 2024-12-16DOI: 10.1111/epi.18182
Jennifer Kilmer, Sebatian Rodrigo, Ana-Maria Petrescu, Nozar Aghakhani, Anne Herbrecht, Claire Leroy, Nicolas Tournier, Michel Bottlaender, Delphine Taussig, Viviane Bouilleret
Objectives: Resective surgery in drug-resistant focal epilepsy (DRFE) requires extensive evaluation to localize the epileptogenic zone (EZ). When non-invasive phase 1 assessments (electroencephalography, EEG; magnetic resonance imaging, MRI; and 18F-Fluorodeoxyglucose-positron emission tomography, [18F]FDG-PET) are inconclusive for EZ localization, invasive investigations such as stereo-EEG (SEEG) are necessary. Epileptogenicity maps (Ems) visualize the EZ using SEEG-identified ictal high-frequency oscillations (iHFOs). PET imaging with radioligands targeting the18-kDa translocator protein (TSPO), a marker of glial activation, may aid EZ localization. This study investigates the correlation between TSPO-PET imaging and SEEG iHFOs in DRFE to determine the utility of TSPO-PET in pre-surgical assessments, especially in complex or non-lesional cases.
Methods: Patients with DRFE and inconclusive phase 1 assessments were recruited from Bicêtre Hospital (AP-HP) for a prospective study (Eudract 2017-003381-27). They underwent SEEG and [18F]DPA-714 (N,N-diethyl-2-(2-(4-(2-(fluoro-18F)ethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide) (TSPO radioligand) PET imaging. Statistical parametric mapping (SPM) techniques analyzed significant [18F]DPA-714-PET uptake (TSPO-map) and generated epileptogenicity maps (EM-map). Correlation analyses at regional and voxel-of-interest (VOI) levels assessed the relationship between TSPO-map and EM-map.
Results: We were able to obtain and analyze both maps in 12 of 17 patients recruited. A significant positive correlation between EM-map and TSPO-map in focal epilepsies was found regionally (r = .81, p < .00004) and at the VOI level (r = .79, p < .00003). Temporal, insular, parietal, and occipital regions showed particularly strong correspondence. In frontal epilepsies, TSPO-map was more focal than EM-map, suggesting increased specificity for SEEG planning. This study also demonstrated the benefit of the TSPO-map in identifying multiple foci in multifocal epilepsies, with or without lesions.
Significance: These findings suggest that neuroinflammation may be a molecular substrate of the EZ in non-lesional focal epilepsy. Identifying the EZ inpatients with complex DRFE and inconclusive MRI/[18F]FDG-PET imaging is essential to improve resective surgery outcomes. Combining TSPO-PET imaging with SEEG recordings may help bridge this gap.
{"title":"TSPO-PET in pre-surgical evaluations: Correlation of neuroinflammation and SEEG epileptogenicity mapping in drug-resistant focal epilepsy.","authors":"Jennifer Kilmer, Sebatian Rodrigo, Ana-Maria Petrescu, Nozar Aghakhani, Anne Herbrecht, Claire Leroy, Nicolas Tournier, Michel Bottlaender, Delphine Taussig, Viviane Bouilleret","doi":"10.1111/epi.18182","DOIUrl":"10.1111/epi.18182","url":null,"abstract":"<p><strong>Objectives: </strong>Resective surgery in drug-resistant focal epilepsy (DRFE) requires extensive evaluation to localize the epileptogenic zone (EZ). When non-invasive phase 1 assessments (electroencephalography, EEG; magnetic resonance imaging, MRI; and <sup>18</sup>F-Fluorodeoxyglucose-positron emission tomography, [<sup>18</sup>F]FDG-PET) are inconclusive for EZ localization, invasive investigations such as stereo-EEG (SEEG) are necessary. Epileptogenicity maps (Ems) visualize the EZ using SEEG-identified ictal high-frequency oscillations (iHFOs). PET imaging with radioligands targeting the18-kDa translocator protein (TSPO), a marker of glial activation, may aid EZ localization. This study investigates the correlation between TSPO-PET imaging and SEEG iHFOs in DRFE to determine the utility of TSPO-PET in pre-surgical assessments, especially in complex or non-lesional cases.</p><p><strong>Methods: </strong>Patients with DRFE and inconclusive phase 1 assessments were recruited from Bicêtre Hospital (AP-HP) for a prospective study (Eudract 2017-003381-27). They underwent SEEG and [<sup>18</sup>F]DPA-714 (N,N-diethyl-2-(2-(4-(2-(fluoro-<sup>18</sup>F)ethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide) (TSPO radioligand) PET imaging. Statistical parametric mapping (SPM) techniques analyzed significant [<sup>18</sup>F]DPA-714-PET uptake (TSPO-map) and generated epileptogenicity maps (EM-map). Correlation analyses at regional and voxel-of-interest (VOI) levels assessed the relationship between TSPO-map and EM-map.</p><p><strong>Results: </strong>We were able to obtain and analyze both maps in 12 of 17 patients recruited. A significant positive correlation between EM-map and TSPO-map in focal epilepsies was found regionally (r = .81, p < .00004) and at the VOI level (r = .79, p < .00003). Temporal, insular, parietal, and occipital regions showed particularly strong correspondence. In frontal epilepsies, TSPO-map was more focal than EM-map, suggesting increased specificity for SEEG planning. This study also demonstrated the benefit of the TSPO-map in identifying multiple foci in multifocal epilepsies, with or without lesions.</p><p><strong>Significance: </strong>These findings suggest that neuroinflammation may be a molecular substrate of the EZ in non-lesional focal epilepsy. Identifying the EZ inpatients with complex DRFE and inconclusive MRI/[<sup>18</sup>F]FDG-PET imaging is essential to improve resective surgery outcomes. Combining TSPO-PET imaging with SEEG recordings may help bridge this gap.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":"430-443"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01Epub Date: 2024-12-05DOI: 10.1111/epi.18201
Karen Gale, David Dybdal, Evan Wicker, Carolina Campos-Rodriguez, Rafael S Maior, Catherine Elorette, Ludise Malkova, Patrick A Forcelli
Objective: Area tempestas, a functionally defined region in the anterior piriform cortex, was identified as a crucial ictogenic trigger zone in the rat brain in the 1980s. However, whether the primate piriform cortex can trigger seizures remains unknown. Here, in a nonhuman primate model, we aimed to localize a similar trigger zone in the piriform cortex and, subsequently, evaluated the ability of focal inhibition of the substantia nigra pars reticulata (SNpr) to suppress the evoked seizures.
Methods: Focal microinjection of the γ-aminobutyric acid type A (GABAA) antagonist bicuculline methiodide into the piriform cortex was performed, in macaque monkeys, on a within-subject basis to map the ictogenic regions within this area. Glutamate antagonists were used to characterize the local circuit pharmacology. Focal inhibition of the substantia nigra by infusion of the GABAA agonist muscimol suppressed seizures evoked from piriform cortex.
Results: We documented a well-defined region highly susceptible to bicuculline-induced seizures in the piriform cortex, just posterior to the junction of the frontal and temporal lobes, indicating that a functional homolog to the rodent area tempestas is present in the primate brain. Focal infusion of glutamate receptor antagonists into the area tempestas revealed that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated, but not N-methyl-D-aspartate-mediated, neurotransmission was necessary for the expression of seizures. Pharmacological inhibition of the SNpr robustly suppressed area tempestas-evoked seizures.
Significance: Together, these data point to the area tempestas as a potent ictogenic zone in the primate brain and underscore the antiseizure effects of inhibition of the SNpr. Building on decades of studies in rodents, our present findings emphasize the relevance of these targets to the primate brain and provide further rationale for exploring these targets for clinical use.
目的:风暴区是20世纪80年代大鼠脑内梨状皮质前部的一个功能明确的区域,被认为是一个重要的致孕触发区。然而,灵长类动物的梨状皮质是否会引发癫痫仍然未知。在非人类灵长类动物模型中,我们旨在定位梨状皮质中类似的触发区,并随后评估黑质网状部(SNpr)的局灶抑制抑制诱发癫痫发作的能力。方法:将γ-氨基丁酸A型(GABAA)拮抗剂甲氧二库林在猕猴梨状皮质内局部显微注射,在受试者基础上绘制该区域内的致孕区。谷氨酸拮抗剂被用来表征局部回路药理学。输注GABAA激动剂muscimol对黑质的局灶性抑制抑制梨状皮质诱发的癫痫发作。结果:我们在额叶和颞叶交界处后方的梨状皮质中记录了一个明确定义的区域,该区域对双核碱诱发的癫痫非常敏感,这表明灵长类动物的大脑中存在与啮齿动物区域风暴的功能同源。谷氨酸受体拮抗剂局部输注到痉挛区显示α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体介导的神经传递是癫痫发作表达所必需的,而不是n -甲基- d -天冬氨酸介导的神经传递。SNpr的药理抑制有力地抑制了风暴诱发的区域癫痫发作。意义:综上所述,这些数据表明,在灵长类动物大脑中,风暴区是一个强有力的致痫区,并强调了抑制SNpr的抗癫痫作用。基于数十年来对啮齿动物的研究,我们目前的发现强调了这些靶点与灵长类动物大脑的相关性,并为探索这些靶点的临床应用提供了进一步的理论依据。
{"title":"Piriform cortex is an ictogenic trigger zone in the primate brain.","authors":"Karen Gale, David Dybdal, Evan Wicker, Carolina Campos-Rodriguez, Rafael S Maior, Catherine Elorette, Ludise Malkova, Patrick A Forcelli","doi":"10.1111/epi.18201","DOIUrl":"10.1111/epi.18201","url":null,"abstract":"<p><strong>Objective: </strong>Area tempestas, a functionally defined region in the anterior piriform cortex, was identified as a crucial ictogenic trigger zone in the rat brain in the 1980s. However, whether the primate piriform cortex can trigger seizures remains unknown. Here, in a nonhuman primate model, we aimed to localize a similar trigger zone in the piriform cortex and, subsequently, evaluated the ability of focal inhibition of the substantia nigra pars reticulata (SNpr) to suppress the evoked seizures.</p><p><strong>Methods: </strong>Focal microinjection of the γ-aminobutyric acid type A (GABA<sub>A</sub>) antagonist bicuculline methiodide into the piriform cortex was performed, in macaque monkeys, on a within-subject basis to map the ictogenic regions within this area. Glutamate antagonists were used to characterize the local circuit pharmacology. Focal inhibition of the substantia nigra by infusion of the GABA<sub>A</sub> agonist muscimol suppressed seizures evoked from piriform cortex.</p><p><strong>Results: </strong>We documented a well-defined region highly susceptible to bicuculline-induced seizures in the piriform cortex, just posterior to the junction of the frontal and temporal lobes, indicating that a functional homolog to the rodent area tempestas is present in the primate brain. Focal infusion of glutamate receptor antagonists into the area tempestas revealed that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated, but not N-methyl-D-aspartate-mediated, neurotransmission was necessary for the expression of seizures. Pharmacological inhibition of the SNpr robustly suppressed area tempestas-evoked seizures.</p><p><strong>Significance: </strong>Together, these data point to the area tempestas as a potent ictogenic zone in the primate brain and underscore the antiseizure effects of inhibition of the SNpr. Building on decades of studies in rodents, our present findings emphasize the relevance of these targets to the primate brain and provide further rationale for exploring these targets for clinical use.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":"569-582"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}