Ingrid E Scheffer, Rima Nabbout, Lieven Lagae, Orrin Devinsky, Stéphane Auvin, Elizabeth A Thiele, Elaine C Wirrell, Tilman Polster, Nicola Specchio, Milka Pringsheim, Katsumi Imai, Michael D Lock, Mélanie Langlois, Rebecca Zhang Roper, Amélie Lothe, Joseph Sullivan
Objective: We analyzed the long-term safety and effectiveness of fenfluramine (FFA) in patients with Dravet syndrome (DS) in an open-label extension (OLE) study after participating in randomized controlled trials (RCTs) or commencing FFA de novo as adults.
Methods: Patients with DS who participated in one of three RCTs or were 19 to 35 years of age and started FFA de novo were included. Key endpoints were: incidence of treatment-emergent adverse events (TEAEs) in the safety population, and median percentage change in monthly convulsive seizure frequency (MCSF) from the RCT baseline to end of study (EOS) in the modified intent-to-treat (mITT) population. Post hoc analyses compared effectiveness in patients on concomitant stiripentol (STP) vs those not taking STP, and assessed safety (TEAEs) and effectiveness (Clinical Global Impression-Improvement [CGI-I] scale ratings) in patients enrolled as adults.
Results: A total of 374 patients, including 45 adults, received ≥1 FFA dose. Median FFA exposure was 824 days (range, 7-1280). TEAEs occurring in ≥10% of patients were pyrexia, nasopharyngitis, decreased appetite, seizure, decreased blood glucose, diarrhea, abnormal echocardiography (only physiologic regurgitation), upper respiratory tract infection, influenza, vomiting, and ear infection; no valvular heart disease or pulmonary arterial hypertension was observed over the OLE. In the mITT population (n = 324), median percentage change in MCSF from baseline to EOS was -66.8% (p < .001). The post hoc analyses of MCSF change from baseline to EOS in patients on concomitant STP (n = 75) was -36.2% vs -71.6% in those not on concomitant STP (n = 234) (p < .0001). In adult patients, 29 of 41 (70.7%) and 29 of 42 patients (69.1%) demonstrated clinically meaningful improvement on CGI-I at last visit as rated by caregivers and investigators, respectively.
Significance: Our OLE study of FFA in patients with DS confirmed previous positive findings and extended the exposure up to 3.5 years. No new or unexpected safety signals were observed and FFA demonstrated sustained and clinically meaningful reduction in MCSF.
{"title":"Long-term safety and effectiveness of fenfluramine in children and adults with Dravet syndrome.","authors":"Ingrid E Scheffer, Rima Nabbout, Lieven Lagae, Orrin Devinsky, Stéphane Auvin, Elizabeth A Thiele, Elaine C Wirrell, Tilman Polster, Nicola Specchio, Milka Pringsheim, Katsumi Imai, Michael D Lock, Mélanie Langlois, Rebecca Zhang Roper, Amélie Lothe, Joseph Sullivan","doi":"10.1111/epi.18342","DOIUrl":"https://doi.org/10.1111/epi.18342","url":null,"abstract":"<p><strong>Objective: </strong>We analyzed the long-term safety and effectiveness of fenfluramine (FFA) in patients with Dravet syndrome (DS) in an open-label extension (OLE) study after participating in randomized controlled trials (RCTs) or commencing FFA de novo as adults.</p><p><strong>Methods: </strong>Patients with DS who participated in one of three RCTs or were 19 to 35 years of age and started FFA de novo were included. Key endpoints were: incidence of treatment-emergent adverse events (TEAEs) in the safety population, and median percentage change in monthly convulsive seizure frequency (MCSF) from the RCT baseline to end of study (EOS) in the modified intent-to-treat (mITT) population. Post hoc analyses compared effectiveness in patients on concomitant stiripentol (STP) vs those not taking STP, and assessed safety (TEAEs) and effectiveness (Clinical Global Impression-Improvement [CGI-I] scale ratings) in patients enrolled as adults.</p><p><strong>Results: </strong>A total of 374 patients, including 45 adults, received ≥1 FFA dose. Median FFA exposure was 824 days (range, 7-1280). TEAEs occurring in ≥10% of patients were pyrexia, nasopharyngitis, decreased appetite, seizure, decreased blood glucose, diarrhea, abnormal echocardiography (only physiologic regurgitation), upper respiratory tract infection, influenza, vomiting, and ear infection; no valvular heart disease or pulmonary arterial hypertension was observed over the OLE. In the mITT population (n = 324), median percentage change in MCSF from baseline to EOS was -66.8% (p < .001). The post hoc analyses of MCSF change from baseline to EOS in patients on concomitant STP (n = 75) was -36.2% vs -71.6% in those not on concomitant STP (n = 234) (p < .0001). In adult patients, 29 of 41 (70.7%) and 29 of 42 patients (69.1%) demonstrated clinically meaningful improvement on CGI-I at last visit as rated by caregivers and investigators, respectively.</p><p><strong>Significance: </strong>Our OLE study of FFA in patients with DS confirmed previous positive findings and extended the exposure up to 3.5 years. No new or unexpected safety signals were observed and FFA demonstrated sustained and clinically meaningful reduction in MCSF.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604443","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}
Stella Jung-Hyun Kim, Clara Marquina, Emma Foster, J Simon Bell, Jenni Ilomäki
Objective: The aim of this study was to compare the risk of seizure, recurrent stroke, fall or fracture, and mortality in individuals prescribed different antiseizure medications (ASMs) following an ischemic stroke.
Methods: We identified all patients admitted to a Victorian public or private hospital with a principal diagnosis of an incident ischemic stroke between 2013 and 2017 and dispensed an ASM within 12 months of discharge. Cox proportional hazards regression was used to estimate the risk of cause-specific rehospitalization or emergency department visits (seizure, fall or fracture, recurrent stroke) and all-cause mortality over a 2-year period. Inverse probability of treatment weighting was applied to each model to adjust for baseline covariates.
Results: Of 19 601 individuals hospitalized for incident ischemic stroke, 897 initiated ASM treatment within 12 months. More than three quarters were initiated on a non-enzyme-inducing ASM (78.0%). Levetiracetam (41.9%), valproate (28.4%), and carbamazepine (11.4%) were commonly dispensed initial ASMs. Non-enzyme-inducing ASMs demonstrated similar risk of seizure (hazard ratio [HR] = .93, 95% confidence interval [CI] = .63-1.37), fall or fracture (HR = 1.47, 95% CI = .92-2.34), stroke (HR = .83; 95% CI = .52-1.33), and mortality (HR = .96; 95% CI = .69-1.32) compared to enzyme-inducing ASMs. However, when valproate was grouped as a separate class, non-enzyme-inducing ASMs (HR = 1.67, 95% CI = 1.04-2.71) showed higher risk of fall or fracture compared to enzyme-inducing ASMs.
Significance: At a population level, ASMs of different types showed no significant differences in the risk of hospitalization or emergency department presentation for seizure, fall or fracture, stroke, and mortality within 2 years of an incident stroke presentation, suggesting similar short-term health outcomes in a real-world setting. Future research should investigate decision-making around ASM choice for stroke survivors and examine the impact of long-term ASM exposure on health outcomes.
{"title":"Comparative risk of major health events among individuals prescribed different antiseizure medications following ischemic stroke.","authors":"Stella Jung-Hyun Kim, Clara Marquina, Emma Foster, J Simon Bell, Jenni Ilomäki","doi":"10.1111/epi.18336","DOIUrl":"https://doi.org/10.1111/epi.18336","url":null,"abstract":"<p><strong>Objective: </strong>The aim of this study was to compare the risk of seizure, recurrent stroke, fall or fracture, and mortality in individuals prescribed different antiseizure medications (ASMs) following an ischemic stroke.</p><p><strong>Methods: </strong>We identified all patients admitted to a Victorian public or private hospital with a principal diagnosis of an incident ischemic stroke between 2013 and 2017 and dispensed an ASM within 12 months of discharge. Cox proportional hazards regression was used to estimate the risk of cause-specific rehospitalization or emergency department visits (seizure, fall or fracture, recurrent stroke) and all-cause mortality over a 2-year period. Inverse probability of treatment weighting was applied to each model to adjust for baseline covariates.</p><p><strong>Results: </strong>Of 19 601 individuals hospitalized for incident ischemic stroke, 897 initiated ASM treatment within 12 months. More than three quarters were initiated on a non-enzyme-inducing ASM (78.0%). Levetiracetam (41.9%), valproate (28.4%), and carbamazepine (11.4%) were commonly dispensed initial ASMs. Non-enzyme-inducing ASMs demonstrated similar risk of seizure (hazard ratio [HR] = .93, 95% confidence interval [CI] = .63-1.37), fall or fracture (HR = 1.47, 95% CI = .92-2.34), stroke (HR = .83; 95% CI = .52-1.33), and mortality (HR = .96; 95% CI = .69-1.32) compared to enzyme-inducing ASMs. However, when valproate was grouped as a separate class, non-enzyme-inducing ASMs (HR = 1.67, 95% CI = 1.04-2.71) showed higher risk of fall or fracture compared to enzyme-inducing ASMs.</p><p><strong>Significance: </strong>At a population level, ASMs of different types showed no significant differences in the risk of hospitalization or emergency department presentation for seizure, fall or fracture, stroke, and mortality within 2 years of an incident stroke presentation, suggesting similar short-term health outcomes in a real-world setting. Future research should investigate decision-making around ASM choice for stroke survivors and examine the impact of long-term ASM exposure on health outcomes.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604435","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}
Melissa Eilbes, Alexander Gallo, Wasif A Osmani, Paloma Bittencourt-Silva, Anna D Manis, Matthew R Hodges
Objective: Patients with uncontrolled epilepsy are at high risk for sudden unexpected death in epilepsy (SUDEP), which likely results from a pathological, seizure-induced disruption of vital physiological systems. The objective of this study was to characterize seizure-induced physiological dysfunction leading to death in SSKcnj16-/- rats and determine the importance of time of day of seizures regarding mortality rates.
Methods: Male and female SSKcnj16-/- rats were surgically implanted with an arterial pressure telemeter and chronically housed in a custom plethysmograph. This setup allowed for continuous measurement of breathing, blood pressure, heart rate, body temperature, and behavior before and during a 10-day seizure protocol. Audiogenic seizure inductions were time-restricted to the early (8-10 a.m.) or late (4-6 p.m.) inactive periods. We assessed acute and chronic physiological functions before, during, and after repeated seizures in both survival and death events.
Results: Time-restricted audiogenic seizures in SSKcnj16-/- rats induced transient disruptions in breathing, blood pressure, heart rate, and temperature, which eventually normalized in both survival and death events. However, after returning to physiological normalization, death was preceded by subsequent spontaneous physiological decompensation, characterized by altered breathing patterns, hypotension, and hypothermia. Finally, seizure-induced mortality was highest during the early and late inactive periods compared to historical data without time restriction and was greater in females than in males but did not correlate with prior seizure severity or number.
Significance: Understanding the causes of SUDEP in patients with epilepsy is limited due to unpredictable and heterogeneous circumstances and incomplete physiological data. This study provides insights into seizure-induced and delayed physiological decompensation leading to SUDEP-like events, demonstrating a need for additional prospective, integrated physiological measures for a more complete picture of SUDEP.
{"title":"Unique features of seizure-induced cardiorespiratory failure in SS<sup>Kcnj16-/-</sup> rats: Implications for sudden unexpected death in epilepsy.","authors":"Melissa Eilbes, Alexander Gallo, Wasif A Osmani, Paloma Bittencourt-Silva, Anna D Manis, Matthew R Hodges","doi":"10.1111/epi.18360","DOIUrl":"https://doi.org/10.1111/epi.18360","url":null,"abstract":"<p><strong>Objective: </strong>Patients with uncontrolled epilepsy are at high risk for sudden unexpected death in epilepsy (SUDEP), which likely results from a pathological, seizure-induced disruption of vital physiological systems. The objective of this study was to characterize seizure-induced physiological dysfunction leading to death in SS<sup>Kcnj16-/-</sup> rats and determine the importance of time of day of seizures regarding mortality rates.</p><p><strong>Methods: </strong>Male and female SS<sup>Kcnj16-/-</sup> rats were surgically implanted with an arterial pressure telemeter and chronically housed in a custom plethysmograph. This setup allowed for continuous measurement of breathing, blood pressure, heart rate, body temperature, and behavior before and during a 10-day seizure protocol. Audiogenic seizure inductions were time-restricted to the early (8-10 a.m.) or late (4-6 p.m.) inactive periods. We assessed acute and chronic physiological functions before, during, and after repeated seizures in both survival and death events.</p><p><strong>Results: </strong>Time-restricted audiogenic seizures in SS<sup>Kcnj16-/-</sup> rats induced transient disruptions in breathing, blood pressure, heart rate, and temperature, which eventually normalized in both survival and death events. However, after returning to physiological normalization, death was preceded by subsequent spontaneous physiological decompensation, characterized by altered breathing patterns, hypotension, and hypothermia. Finally, seizure-induced mortality was highest during the early and late inactive periods compared to historical data without time restriction and was greater in females than in males but did not correlate with prior seizure severity or number.</p><p><strong>Significance: </strong>Understanding the causes of SUDEP in patients with epilepsy is limited due to unpredictable and heterogeneous circumstances and incomplete physiological data. This study provides insights into seizure-induced and delayed physiological decompensation leading to SUDEP-like events, demonstrating a need for additional prospective, integrated physiological measures for a more complete picture of SUDEP.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604465","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}
Flavia Privitera, Camilla Meossi, Filippo Maria Santorelli, Emanuele Bartolini
{"title":"Epileptic spasms and RNA analysis in a new case of Kabuki syndrome type 2.","authors":"Flavia Privitera, Camilla Meossi, Filippo Maria Santorelli, Emanuele Bartolini","doi":"10.1111/epi.18362","DOIUrl":"https://doi.org/10.1111/epi.18362","url":null,"abstract":"","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604437","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}
Objective: Clinical investigators have hypothesized that interictal epileptiform discharges (IEDs) generated by hypothalamic hamartoma (HH) lead to cognitive dysfunction in patients with drug-resistant gelastic seizures. Herein we provide causal evidence supporting this hypothesis by demonstrating that excitatory neural bursts, when propagating from the HH to the mediodorsal thalamus during the encoding period, impair working memory.
Methods: By employing channelrhodopsin-2 photostimulation, we induced excessive neural excitation in Long-Evans rats, resembling IEDs, at the axon terminals of the lateral hypothalamus projecting toward the mediodorsal thalamus and prelimbic cortex. We recorded local field potentials (LFPs) at these sites and assessed the performance of working memory tasks with and without photostimulation. Utilizing support vector machine analysis on LFP trials under sham photostimulation, we identified the neural correlates of successful task performance. Through mixed model analyses, we evaluated the impacts of photostimulation timing and the alteration in LFP amplitude induced by photostimulation on task performance.
Results: Ten rats completed operant conditioning using a spout lever system after receiving an average of 70.7 days of training, at a rate of 135.2 trials per day. During sham photostimulation, successful trials were associated with a shorter duration of the working memory maintenance period, as well as an augmentation in the 10- to 14-Hz LFP amplitude at the mediodorsal thalamus and prelimbic cortex during the memory encoding phase. Photostimulation at the mediodorsal thalamus during encoding reduced the odds of a trial being successful by 0.19. Conversely, excessive mediodorsal thalamus LFP augmentation induced by photostimulation during encoding increased the odds of a trial being unsuccessful by 1.04.
Significance: Excessive neural excitation, specifically propagating from the lateral hypothalamus to the mediodorsal thalamus during encoding, alters physiological neural activity and transiently impairs working memory. This study clarifies the pathophysiological mechanism underlying cognitive disabilities associated with working memory impairment in HH-related epileptic encephalopathy.
{"title":"Optogenetically-induced sustained hypothalamic hyperexcitability impairs memory via thalamic spread.","authors":"Masaki Sonoda, Hisao Aimi, Keisuke Kawasaki, Haruo Toda, Shinobu Hirai, Masao Horie, Reiko Meguro, Eishi Asano, Haruo Okado, Shigeki Kameyama, Tetsuya Yamamoto, Isao Hasegawa","doi":"10.1111/epi.18321","DOIUrl":"https://doi.org/10.1111/epi.18321","url":null,"abstract":"<p><strong>Objective: </strong>Clinical investigators have hypothesized that interictal epileptiform discharges (IEDs) generated by hypothalamic hamartoma (HH) lead to cognitive dysfunction in patients with drug-resistant gelastic seizures. Herein we provide causal evidence supporting this hypothesis by demonstrating that excitatory neural bursts, when propagating from the HH to the mediodorsal thalamus during the encoding period, impair working memory.</p><p><strong>Methods: </strong>By employing channelrhodopsin-2 photostimulation, we induced excessive neural excitation in Long-Evans rats, resembling IEDs, at the axon terminals of the lateral hypothalamus projecting toward the mediodorsal thalamus and prelimbic cortex. We recorded local field potentials (LFPs) at these sites and assessed the performance of working memory tasks with and without photostimulation. Utilizing support vector machine analysis on LFP trials under sham photostimulation, we identified the neural correlates of successful task performance. Through mixed model analyses, we evaluated the impacts of photostimulation timing and the alteration in LFP amplitude induced by photostimulation on task performance.</p><p><strong>Results: </strong>Ten rats completed operant conditioning using a spout lever system after receiving an average of 70.7 days of training, at a rate of 135.2 trials per day. During sham photostimulation, successful trials were associated with a shorter duration of the working memory maintenance period, as well as an augmentation in the 10- to 14-Hz LFP amplitude at the mediodorsal thalamus and prelimbic cortex during the memory encoding phase. Photostimulation at the mediodorsal thalamus during encoding reduced the odds of a trial being successful by 0.19. Conversely, excessive mediodorsal thalamus LFP augmentation induced by photostimulation during encoding increased the odds of a trial being unsuccessful by 1.04.</p><p><strong>Significance: </strong>Excessive neural excitation, specifically propagating from the lateral hypothalamus to the mediodorsal thalamus during encoding, alters physiological neural activity and transiently impairs working memory. This study clarifies the pathophysiological mechanism underlying cognitive disabilities associated with working memory impairment in HH-related epileptic encephalopathy.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604447","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}
Objective: Temporal lobe epilepsy (TLE) has been recognized as a network disorder with widespread gray matter atrophy. However, the role of connectome architecture in shaping morphological alterations and identifying atrophy epicenters remains unclear. Furthermore, individualized modeling of atrophy epicenters and their potential clinical applications have not been well established. This study aims to explore how gray matter atrophy correlates with normal connectome architecture, identify potential atrophy epicenters, and employ individualized modeling approach to evaluate the impact of different epicenter patterns on surgical outcomes in patients with TLE.
Methods: This study utilized anatomic MRI data from 126 refractory TLE patients who underwent anterior temporal lobectomy and 60 healthy controls (HCs), along with normative functional and structural connectome data, to investigate the relationship between gray matter volume (GMV) changes and functional or structural connectivity. Two models were employed to identify atrophy epicenters: a data-driven approach evaluating nodal and neighbor atrophy rankings, and a network diffusion model (NDM) simulating the spread of pathology from different seed regions. K-means clustering was applied in patient-tailored modeling to uncover distinct epicenter subtypes.
Results: Our findings indicate that the pattern of gray matter atrophy in TLE is constrained primarily by structural connectivity rather than by functional connectivity. Using the structural connectome, we pinpointed the hippocampus and adjacent temporo-limbic regions as key atrophy epicenters. The patient-tailored modeling revealed significant variability in epicenter distribution, allowing us to categorize them into two distinct subtypes. Notably, patients in subtype 2, with epicenters localized to the ipsilateral temporal pole and medial temporal lobe, exhibited significantly higher seizure-free rates compared to patients in subtype 1, whose epicenters situated in frontocentral regions.
Significance: These findings highlight the central role of structural connectivity in shaping TLE-related morphological changes. Individualized epicenter modeling may enhance surgical decisions and improve prognostic stratification in TLE management.
{"title":"Connectome architecture for gray matter atrophy and surgical outcomes in temporal lobe epilepsy.","authors":"Qiuxing Lin, Danyang Cao, Wei Li, Yingying Zhang, Yuming Li, Peiwen Liu, Xiang Huang, Kailing Huang, Qiyong Gong, Dong Zhou, Dongmei An","doi":"10.1111/epi.18343","DOIUrl":"https://doi.org/10.1111/epi.18343","url":null,"abstract":"<p><strong>Objective: </strong>Temporal lobe epilepsy (TLE) has been recognized as a network disorder with widespread gray matter atrophy. However, the role of connectome architecture in shaping morphological alterations and identifying atrophy epicenters remains unclear. Furthermore, individualized modeling of atrophy epicenters and their potential clinical applications have not been well established. This study aims to explore how gray matter atrophy correlates with normal connectome architecture, identify potential atrophy epicenters, and employ individualized modeling approach to evaluate the impact of different epicenter patterns on surgical outcomes in patients with TLE.</p><p><strong>Methods: </strong>This study utilized anatomic MRI data from 126 refractory TLE patients who underwent anterior temporal lobectomy and 60 healthy controls (HCs), along with normative functional and structural connectome data, to investigate the relationship between gray matter volume (GMV) changes and functional or structural connectivity. Two models were employed to identify atrophy epicenters: a data-driven approach evaluating nodal and neighbor atrophy rankings, and a network diffusion model (NDM) simulating the spread of pathology from different seed regions. K-means clustering was applied in patient-tailored modeling to uncover distinct epicenter subtypes.</p><p><strong>Results: </strong>Our findings indicate that the pattern of gray matter atrophy in TLE is constrained primarily by structural connectivity rather than by functional connectivity. Using the structural connectome, we pinpointed the hippocampus and adjacent temporo-limbic regions as key atrophy epicenters. The patient-tailored modeling revealed significant variability in epicenter distribution, allowing us to categorize them into two distinct subtypes. Notably, patients in subtype 2, with epicenters localized to the ipsilateral temporal pole and medial temporal lobe, exhibited significantly higher seizure-free rates compared to patients in subtype 1, whose epicenters situated in frontocentral regions.</p><p><strong>Significance: </strong>These findings highlight the central role of structural connectivity in shaping TLE-related morphological changes. Individualized epicenter modeling may enhance surgical decisions and improve prognostic stratification in TLE management.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585144","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}
Objective: The identification of epileptic lesions is crucial for improving surgical outcomes. Nevertheless, substantial focal cortical dysplasia (FCD) may be invisible on magnetic resonance imaging (MRI). We aimed to characterize the expression pattern of 18-kDa translocator protein (TSPO) in FCD and to evaluate the effectiveness of this inflammation-reflective molecular imaging technique for detecting FCD.
Methods: Patients clinically diagnosed with FCD, based on clinical features, interictal electroencephalographic (EEG) findings, and MRI characteristics, underwent positron emission tomography (PET) imaging using 18F-DPA714 and 18F-fluorodeoxyglucose (FDG) tracers. TSPO-PET activation patterns were qualitatively evaluated. Semiquantitative analysis using the Highlight Index (HI) was further performed to investigate its correlation with clinical characteristics. For patients who underwent stereo-EEG (SEEG) monitoring, the site of high-level TSPO-PET activation was compared with the seizure onset zone identified by SEEG. For patients who underwent resection surgery, the relationship between TSPO-PET uptake and histopathological findings was studied.
Results: Twenty-four patients were enrolled. Three groups were identified: MRI-positive with visible high-level TSPO-PET activation (six patients), MRI-negative with visible high-level TSPO-PET activation (thirteen patients), and MRI-positive with invisible low-level TSPO-PET activation (five patients). Regions of high-level TSPO-PET activation showed concordance with ictal discharges in five patients who underwent SEEG. Compared with FDG-PET, TSPO-PET exhibited a more prominent signal against the background (p = .0158). HI was correlated with seizure frequency (p = .0362) and the occurrence of focal to bilateral tonic-clonic seizures (p = .0294), and shorter interval between the TSPO-PET scan and the last seizure was associated with higher TSPO-PET HI (R = -.4323, p = .0349). Postoperative histopathological examination confirmed high-level TSPO-PET activation rates of 3/3 for FCD type IIb and 1/3 for FCD type IIa.
Significance: TSPO-PET activation patterns offer clinical significance for improving surgical outcomes by enhancing FCD detection during presurgical evaluation. Also, our observations offer new insights into the histopathological basis for increased TSPO uptake in humans.
{"title":"Emerging translocator protein-positron emission tomographic imaging improves detection of focal cortical dysplasia.","authors":"Zichen Qiao, Yingxue Yang, Yuanhong Chen, Linai Guo, Qing Xue, Lehong Gao, Jia Chen, Bixiao Cui, Jinghui Liu, Haoxun Yang, Xueyuan Wang, Yihe Wang, Huaqiang Zhang, Cuiping Xu, Yicong Lin, Tao Yu, Yuping Wang, Yueshan Piao, Jie Lu, Liankun Ren","doi":"10.1111/epi.18351","DOIUrl":"https://doi.org/10.1111/epi.18351","url":null,"abstract":"<p><strong>Objective: </strong>The identification of epileptic lesions is crucial for improving surgical outcomes. Nevertheless, substantial focal cortical dysplasia (FCD) may be invisible on magnetic resonance imaging (MRI). We aimed to characterize the expression pattern of 18-kDa translocator protein (TSPO) in FCD and to evaluate the effectiveness of this inflammation-reflective molecular imaging technique for detecting FCD.</p><p><strong>Methods: </strong>Patients clinically diagnosed with FCD, based on clinical features, interictal electroencephalographic (EEG) findings, and MRI characteristics, underwent positron emission tomography (PET) imaging using <sup>18</sup>F-DPA714 and <sup>18</sup>F-fluorodeoxyglucose (FDG) tracers. TSPO-PET activation patterns were qualitatively evaluated. Semiquantitative analysis using the Highlight Index (HI) was further performed to investigate its correlation with clinical characteristics. For patients who underwent stereo-EEG (SEEG) monitoring, the site of high-level TSPO-PET activation was compared with the seizure onset zone identified by SEEG. For patients who underwent resection surgery, the relationship between TSPO-PET uptake and histopathological findings was studied.</p><p><strong>Results: </strong>Twenty-four patients were enrolled. Three groups were identified: MRI-positive with visible high-level TSPO-PET activation (six patients), MRI-negative with visible high-level TSPO-PET activation (thirteen patients), and MRI-positive with invisible low-level TSPO-PET activation (five patients). Regions of high-level TSPO-PET activation showed concordance with ictal discharges in five patients who underwent SEEG. Compared with FDG-PET, TSPO-PET exhibited a more prominent signal against the background (p = .0158). HI was correlated with seizure frequency (p = .0362) and the occurrence of focal to bilateral tonic-clonic seizures (p = .0294), and shorter interval between the TSPO-PET scan and the last seizure was associated with higher TSPO-PET HI (R = -.4323, p = .0349). Postoperative histopathological examination confirmed high-level TSPO-PET activation rates of 3/3 for FCD type IIb and 1/3 for FCD type IIa.</p><p><strong>Significance: </strong>TSPO-PET activation patterns offer clinical significance for improving surgical outcomes by enhancing FCD detection during presurgical evaluation. Also, our observations offer new insights into the histopathological basis for increased TSPO uptake in humans.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585145","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}
Salvatore Citro, Sam S Javidi, Ankeeta Ankeeta, Xiaosong He, Qirui Zhang, Yolanda Kry, Michael R Sperling, Joseph I Tracy
Objective: Subjects with left temporal lobe epilepsy may either show altered hemispheric language lateralization or retain typical, left lateralization. Examining the integrity of white matter pathways involved in the adaptation or maintenance of language lateralization in these patients could have important clinical implications for preserving or potentiating compensatory language mechanisms.
Methods: We combined task functional magnetic resonance imaging and structural diffusion metrics to determine the dependency of lobe-based language laterality on white matter integrity in healthy participants and left temporal lobe epilepsy (TLE) patients. We tested for differences between individuals who expressed typical, left hemisphere laterality compared to those with atypical laterality patterns (bilateral or right hemisphere biased).
Results: A total of 41 left TLE patients and 51 sex- and age-matched healthy participants (HPs) were enrolled. In left temporal lobe epilepsy, typical patterns of frontal and temporal lateralities were less conditioned by the language-related white matter connections of the left temporal lobe. In typically organized epilepsy subjects, temporal lobe language laterality was dependent upon the structural connectivities of the left parietal lobe. Among atypically organized individuals, compared to HPs, TLE patients displayed frontal and parietal language lateralities mediated by the structural connectivities of the left parietal lobe.
Significance: Language-related left parietal lobe connections were critical both for maintaining typical left hemisphere-biased language processing in the temporal lobe and for the formation of noncanonical, potentially adaptive language processing asymmetries in the frontal and parietal lobes. Assessments of the laterality and integrity of language skills in left temporal lobe epilepsy will require modeling white matter structural influences.
{"title":"Left parietal structural connectivity mediates typical and atypical language laterality in temporal lobe epilepsy.","authors":"Salvatore Citro, Sam S Javidi, Ankeeta Ankeeta, Xiaosong He, Qirui Zhang, Yolanda Kry, Michael R Sperling, Joseph I Tracy","doi":"10.1111/epi.18298","DOIUrl":"https://doi.org/10.1111/epi.18298","url":null,"abstract":"<p><strong>Objective: </strong>Subjects with left temporal lobe epilepsy may either show altered hemispheric language lateralization or retain typical, left lateralization. Examining the integrity of white matter pathways involved in the adaptation or maintenance of language lateralization in these patients could have important clinical implications for preserving or potentiating compensatory language mechanisms.</p><p><strong>Methods: </strong>We combined task functional magnetic resonance imaging and structural diffusion metrics to determine the dependency of lobe-based language laterality on white matter integrity in healthy participants and left temporal lobe epilepsy (TLE) patients. We tested for differences between individuals who expressed typical, left hemisphere laterality compared to those with atypical laterality patterns (bilateral or right hemisphere biased).</p><p><strong>Results: </strong>A total of 41 left TLE patients and 51 sex- and age-matched healthy participants (HPs) were enrolled. In left temporal lobe epilepsy, typical patterns of frontal and temporal lateralities were less conditioned by the language-related white matter connections of the left temporal lobe. In typically organized epilepsy subjects, temporal lobe language laterality was dependent upon the structural connectivities of the left parietal lobe. Among atypically organized individuals, compared to HPs, TLE patients displayed frontal and parietal language lateralities mediated by the structural connectivities of the left parietal lobe.</p><p><strong>Significance: </strong>Language-related left parietal lobe connections were critical both for maintaining typical left hemisphere-biased language processing in the temporal lobe and for the formation of noncanonical, potentially adaptive language processing asymmetries in the frontal and parietal lobes. Assessments of the laterality and integrity of language skills in left temporal lobe epilepsy will require modeling white matter structural influences.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585147","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}
Atsuro Daida, Saarang Panchavati, Shingo Oana, Sotaro Kanai, Yipeng Zhang, Yuanyi Ding, Rajaraman R Rajsekar, Noriko Salamon, Raman Sankar, Aria Fallah, Shaun A Hussain, Vwani Roychowdhury, William Speier, Hiroki Nariai
Objective: Although the role of subcortical structures in the generation of epileptic spasms has been proposed, supporting evidence remains limited. This study aimed to provide neurophysiological evidence of thalamocortical network involvement during epileptic spasms.
Methods: We analyzed four patients (ages 2.7-16.9 years) with epileptic spasms who underwent intracranial electroencephalography (EEG) monitoring with thalamic sampling in preparation for potential neurostimulation. Epileptic spasms were initially assessed using visual inspection and time-frequency analysis. We then evaluated undirected connectivity through coherence analysis and directed connectivity using spectral Granger causality analysis between the thalamus and the seizure-onset zone, focusing on ictal connectivity changes in both slow (0.5-10 Hz) and fast (10-80 Hz) frequency bands. In addition, phase-amplitude coupling was assessed with a modulation index to examine the interaction between ictal slow and fast band activities.
Results: A total of 84 epileptic spasms were analyzed. Ictal EEG changes of slow wave complex were visually confirmed in the thalamic channels. There was an increase in signal power in both the slow and fast bands at the thalamus. Undirected (coherence) and directed (spectral Granger causality) connectivity analyses showed a significant increase in connectivity between the thalamus and seizure-onset zone in both the slow and fast bands compared to baseline. Directed connectivity in the slow bands increased equally from the thalamus to the seizure-onset zone (outflow) and vice versa (inflow). However, fast band inflow was more pronounced than outflow. The modulation index increased significantly during epileptic spasms at the thalamus. Furthermore, a higher modulation index in the cortex correlated with more pronounced clinical manifestations of epileptic spasms.
Significance: Ictal slow-wave complexes on EEG during epileptic spasms may reflect long-range thalamocortical network activation, highlighting the critical role of subcortical structures in ictogenesis and the potential treatment implications for thalamic neuromodulation.
{"title":"Evidence of thalamocortical network activation during epileptic spasms: A thalamic stereotactic EEG study.","authors":"Atsuro Daida, Saarang Panchavati, Shingo Oana, Sotaro Kanai, Yipeng Zhang, Yuanyi Ding, Rajaraman R Rajsekar, Noriko Salamon, Raman Sankar, Aria Fallah, Shaun A Hussain, Vwani Roychowdhury, William Speier, Hiroki Nariai","doi":"10.1111/epi.18349","DOIUrl":"https://doi.org/10.1111/epi.18349","url":null,"abstract":"<p><strong>Objective: </strong>Although the role of subcortical structures in the generation of epileptic spasms has been proposed, supporting evidence remains limited. This study aimed to provide neurophysiological evidence of thalamocortical network involvement during epileptic spasms.</p><p><strong>Methods: </strong>We analyzed four patients (ages 2.7-16.9 years) with epileptic spasms who underwent intracranial electroencephalography (EEG) monitoring with thalamic sampling in preparation for potential neurostimulation. Epileptic spasms were initially assessed using visual inspection and time-frequency analysis. We then evaluated undirected connectivity through coherence analysis and directed connectivity using spectral Granger causality analysis between the thalamus and the seizure-onset zone, focusing on ictal connectivity changes in both slow (0.5-10 Hz) and fast (10-80 Hz) frequency bands. In addition, phase-amplitude coupling was assessed with a modulation index to examine the interaction between ictal slow and fast band activities.</p><p><strong>Results: </strong>A total of 84 epileptic spasms were analyzed. Ictal EEG changes of slow wave complex were visually confirmed in the thalamic channels. There was an increase in signal power in both the slow and fast bands at the thalamus. Undirected (coherence) and directed (spectral Granger causality) connectivity analyses showed a significant increase in connectivity between the thalamus and seizure-onset zone in both the slow and fast bands compared to baseline. Directed connectivity in the slow bands increased equally from the thalamus to the seizure-onset zone (outflow) and vice versa (inflow). However, fast band inflow was more pronounced than outflow. The modulation index increased significantly during epileptic spasms at the thalamus. Furthermore, a higher modulation index in the cortex correlated with more pronounced clinical manifestations of epileptic spasms.</p><p><strong>Significance: </strong>Ictal slow-wave complexes on EEG during epileptic spasms may reflect long-range thalamocortical network activation, highlighting the critical role of subcortical structures in ictogenesis and the potential treatment implications for thalamic neuromodulation.</p>","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572502","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}