Evaluation and treatment of drug-resistant epilepsy

耐药性癫痫的评估和治疗

基本信息

批准号：
10252607
负责人：
William Theodore
金额：
$ 122.42万
依托单位：
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10252607
关键词：
6 year old Address Age Age of Onset Amobarbital Anatomy Anterior Temporal Lobectomy Antiepileptic Agents Area Attention Auditory Bilateral Binding Blood flow Brain Brain region Broca&apos s area Case Series Cerebrum Classification Cortical Dysplasia Data Deposition Development Diffusion Disease Drug Evaluation Economics Electrodes Electroencephalography Ensure Epilepsy Etiology Evaluation Excision Female Functional Imaging Functional Magnetic Resonance Imaging Functional disorder General Population Handedness Herpesviridae Hippocampus (Brain)Human Human Herpesvirus 6 Impairment Implant Incidence Institute of Medicine (U.S.)Intracarotid Intractable Epilepsy Investigation Ipsilateral Language Language Disorders Language Tests Left Lobectomy Magnetic Resonance Imaging Maps Masks Measures Medical Memory Memory Loss Metabolism Methods Middle frontal gyrus structure Monitor Morbidity - disease rate Names Neuropsychological Tests Neuropsychology Neurotransmitter Receptor Operative Surgical Procedures Outcome Partial Epilepsies Patients Performance Population Positron-Emission Tomography Postoperative Period Predictive Value Procedures Radial Refractory Reporting Resected Rest Risk Role Sclerosis Secure Seeds Seizures Sensitivity and Specificity Side Site Specificity Specimen Structure Surveys Temporal Lobe Epilepsy Testing Time Topectomies base blood-brain barrier permeabilization brain tissue comorbidity cortex mapping digital experience follow-up healthy volunteer imaging modality implantation indexing inflammatory marker language outcome mortality neurobehavioral neuroimaging novel novel strategies outcome prediction prospective social study population tool viral DNA

项目摘要

Patients undergo video-EEG monitoring to determine seizure type and focus localization. Positron emission tomography (PET) and magnetic resonance imaging (MRI) are used to study the functional anatomy of language and memory activation, cerebral metabolism, blood flow, binding to neurotransmitter receptors, deposition of inflammatory markers, alterations in blood-brain barrier permeability and structure. Presurgical language assessment can help minimize damage to eloquent cortex during resective epilepsy surgery. Two methods for language mapping are functional MRI and direct cortical stimulation (DCS) of implanted subdural electrodes. We compared fMRI results to DCS to optimize non-invasive language localization and assess its validity. We studied 19 patients referred for presurgical evaluation of drug-resistant epilepsy. Patients completed 4 language tasks during preoperative fMRI. After subdural electrode implantation, we used DCS to localize language areas. For each stimulation site, we determined whether electrode pairs intersected with significant fMRI activity clusters for each language task. Sensitivity and specificity depended on electrode ROI radii and statistical thresholding. For patients with at least one language positive stimulation site, an auditory description task provided the best tradeoff between sensitivity and specificity. For patients with no language positive stimulation sites, fMRI was a dependable method of ruling out language areas. 17 patients subsequently had temporal lobectomy. Four had postoperative language decline one year after surgery. Two of four had overlap of fMRI activated voxels, language positive electrodes in basal temporal regions (within 1cm), and resection. Two had overlap with fMRI activated voxels but not language positive electrodes. Patients who experienced language decline tended to have more fMRI activated voxels overlapping the resection than patients who did not. Age of seizure onset, resection side, resection type (standard anterior temporal lobectomy, amygdalohippocampectomy, or topectomy), resection volume, or seizure outcome at one year did not predict language decline. Language localization overlap of fMRI and direct cortical stimulation in resection influences postoperative language performance. Our preliminary study suggests fMRI may be more sensitive and less specific than direct cortical stimulation in predicting postoperative language outcome. fMRI and direct cortical stimulation together may predict postoperative language outcome after epilepsy surgery better than either test alone. Language fMRI is an effective tool for determining language lateralization prior to electrode implantation, and is especially useful for excluding unexpected critical language areas. In an additional study Using fMRI, we found a significant negative relationship between resected volume of the voxels within the top 10% of fMRI activation and BNT score change, with or without controlling for other potential factors, including resection volume, language LI, resection side dominance, and brain shrinkage after surgery. The amount of resected top 10% activation accounted for 20-25% of the variance in language naming ability decline. In a prospective case series, 17 patients with drug-resistant epilepsy had intracranial monitoring and resection from 2012 to 2016 with 1-year follow-up. All patients completed preoperative language fMRI, mapping with DCS of subdural electrodes, pre- and postoperative neuropsychological testing for language function, and resection. Changes in language function before and after surgery were assessed. fMRI activation and DCS electrodes in the resection were evaluated as potential predictors of language decline. Four of 17 patients (12 female; median range age, 43 23-59 years) experienced postoperative language decline 1 year after surgery. Two of 4 patients had overlap of fMRI activation, language-positive electrodes in basal temporal regions (within 1 cm), and resection. Two had overlap between resection volume and fMRI activation, but not DCS. fMRI demonstrated 100% sensitivity and 46% specificity for outcome compared to DCS (50% and 85%, respectively). When fMRI and DCS language findings were concordant, the combined tests showed 100% sensitivity and 75% specificity for language outcome. Seizure-onset age, resection side, type, volume, or 1 year seizure outcome did not predict language decline. Language localization overlap of fMRI and direct cortical stimulation in the resection influences postoperative language performance. Our preliminary study suggests that fMRI may be more sensitive and less specific than direct cortical stimulation. Together they may predict outcome better than either test alone. In order to investigate alternative methods for preoperative language localization, we compared resting state (RS) functional connectivity and task-based fMRI to lateralize language dominance in 30 epilepsy patients (mean age = 33; SD = 11; 12 female), a measure used for presurgical planning. Language laterality index (LI) was calculated from task fMRI in frontal, temporal, and frontal + temporal regional masks using LI bootstrap method from SPM12. RS language LI was assessed using two novel methods of calculating RS language LI from bilateral Broca's area seed based connectivity maps across regional masks and multiple thresholds (p < .05, p < .01, p < .001, top 10% connections). We compared LI from task and RS fMRI continuous values and dominance classifications. We found significant positive correlations between task LI and RS LI when functional connectivity thresholds were set to the top 10% of connections. Concordance of dominance classifications ranged from 20% to 30% for the intrahemispheric resting state LI method and 50% to 63% for the resting state LI intra- minus interhemispheric difference method. Approximately 40% of patients left dominant on task showed RS bilateral dominance. There was no difference in LI concordance between patients with right-sided and left-sided resections. Early seizure onset (<6 years old) was not associated with atypical language dominance during task-based or RS fMRI. While a relationship between task LI and RS LI exists in patients with epilepsy, language dominance is less lateralized on RS than task fMRI. Concordance of language dominance classifications between task and resting state fMRI depends on brain regions surveyed and RS LI calculation method. Human herpes virus 6 (HHV-6) is a potential cause of temporal lobe epilepsy with mesial temporal sclerosis (TLE-MTS). In 87 patients who had resections for focal epilepsy, we used real time quantitative PCR and digital droplet PCR to detect HHV6 in surgical specimens. Viral DNA was isolated from fresh brain tissue. Patients with MTS were significantly more likely to have actively replicating HHV6 than those with other etiologies such as focal cortical dysplasia. We studied effects of HHV-6 using FreeSurfer to segment cortical structures and obtain whole hippocampal and subfield volumes in 41 patients with TLE-MTS. Twenty-two patients were positive and 19 negatives for HHV-6. HHV-6 negative patients had significantly greater AI and lower total hippocampal volume ipsilateral to seizure foci than HHV-6 positive patients. Epilepsy duration and age of onset did not affect results. Our data suggest multiple potential etiologies for MTS. HHV-6 may have a less severe effect on the hippocampus than other TLE-MTS etiologies.

患者接受视频脑电图监测以确定癫痫发作类型和病灶定位。正电子发射断层扫描（PET）和磁共振成像（MRI）用于研究语言和记忆激活、脑代谢、血流、与神经递质受体的结合、炎症标记物的沉积、血脑屏障通透性的改变和结构。术前语言评估有助于最大程度地减少癫痫切除手术期间对口才皮层的损害。语言映射的两种方法是功能性 MRI 和植入硬膜下电极的直接皮质刺激 (DCS)。我们将 fMRI 结果与 DCS 进行比较，以优化非侵入性语言本地化并评估其有效性。我们研究了 19 名转诊进行耐药性癫痫术前评估的患者。患者在术前功能磁共振成像期间完成了 4 项语言任务。硬膜下电极植入后，我们使用 DCS 来定位语言区域。对于每个刺激部位，我们确定电极对是否与每个语言任务的显着 fMRI 活动簇相交。灵敏度和特异性取决于电极 ROI 半径和统计阈值。对于至少有一个语言积极刺激部位的患者，听觉描述任务提供了敏感性和特异性之间的最佳权衡。对于没有语言阳性刺激部位的患者，功能磁共振成像是排除语言区域的可靠方法。 17 名患者随后接受了颞叶切除术。术后一年，四人出现术后语言能力下降。四分之二的 fMRI 激活体素、基底颞区语言正电极（1 厘米内）和切除有重叠。其中两个与功能磁共振成像激活的体素重叠，但与语言正电极不重叠。与没有经历过语言衰退的患者相比，经历过语言衰退的患者往往有更多的功能磁共振成像激活体素与切除重叠。癫痫发作年龄、切除部位、切除类型（标准前颞叶切除术、杏仁核海马切除术或顶部切除术）、切除体积或一年时癫痫发作结果并不能预测语言能力下降。切除过程中功能磁共振成像和直接皮质刺激的语言定位重叠会影响术后语言表现。我们的初步研究表明，在预测术后语言结果方面，功能磁共振成像可能比直接皮层刺激更敏感，但特异性较差。功能磁共振成像和直接皮质刺激一起可以比单独的任何一种测试更好地预测癫痫手术后的术后语言结果。语言功能磁共振成像是在电极植入之前确定语言偏侧化的有效工具，对于排除意外的关键语言区域特别有用。在另一项使用 fMRI 的研究中，我们发现 fMRI 激活前 10% 内体素的切除体积与 BNT 评分变化之间存在显着的负相关关系，无论是否控制其他潜在因素，包括切除体积、语言 LI、切除侧优势和手术后大脑萎缩。被切除的前 10% 激活量占语言命名能力下降方差的 20-25%。在一项前瞻性病例系列中，2012年至2016年对17名耐药性癫痫患者进行了颅内监测和切除，并随访1年。所有患者均完成术前语言功能磁共振成像、硬膜下电极 DCS 标测、术前和术后语言功能神经心理学测试以及切除。评估手术前后语言功能的变化。功能磁共振成像激活和切除中的 DCS 电极被评估为语言衰退的潜在预测因素。 17 名患者中的 4 名（12 名女性；中位年龄 43 岁，23-59 岁）在术后 1 年出现术后语言能力下降。 4 名患者中的 2 名存在 fMRI 激活、基底颞区语言阳性电极（1 厘米以内）和切除重叠的情况。其中两个在切除体积和功能磁共振成像激活之间有重叠，但 DCS 没有重叠。与 DCS 相比，fMRI 表现出 100% 的敏感性和 46% 的特异性（分别为 50% 和 85%）。当 fMRI 和 DCS 语言结果一致时，组合测试显示语言结果的敏感性为 100%，特异性为 75%。癫痫发作年龄、切除侧、类型、体积或 1 年癫痫发作结果并不能预测语言能力下降。切除过程中功能磁共振成像和直接皮质刺激的语言定位重叠会影响术后语言表现。我们的初步研究表明，功能磁共振成像可能比直接皮质刺激更敏感，但特异性较低。它们一起可以比单独的任何一个测试更好地预测结果。为了研究术前语言定位的替代方法，我们比较了 30 名癫痫患者（平均年龄 = 33；SD = 11；12 名女性）的静息态 (RS) 功能连接和基于任务的 fMRI，以偏向语言优势，使用的测量方法用于术前计划。语言偏侧性指数 (LI) 是使用 SPM12 的 LI bootstrap 方法根据额叶、颞叶和额叶 + 颞叶区域掩模中的任务 fMRI 计算得出的。使用两种新颖的方法来评估 RS 语言 LI，该方法根据跨区域掩模和多个阈值的双边布罗卡面积种子连接图计算 RS 语言 LI（p < .05、p < .01、p < .001、前 10% 连接）。我们比较了任务 LI 和 RS fMRI 连续值和优势分类。当功能连接阈值设置为前 10% 的连接时，我们发现任务 LI 和 RS LI 之间存在显着的正相关性。对于半球内静息态 LI 方法，优势分类的一致性范围为 20% 至 30%；对于静息态 LI 半球内负半球间差异法，优势分类的一致性为 50% 至 63%。大约 40% 的患者在任务中表现出 RS 双侧优势。右侧和左侧切除患者的 LI 一致性没有差异。在基于任务或 RS fMRI 期间，早期癫痫发作（<6 岁）与非典型语言优势无关。虽然癫痫患者的任务 LI 和 RS LI 之间存在相关性，但与任务 fMRI 相比，RS 上的语言优势较少偏侧化。任务和静息状态之间语言优势分类的一致性 fMRI 取决于所调查的大脑区域和 RS LI 计算方法。人类疱疹病毒 6 (HHV-6) 是颞叶癫痫伴内侧颞叶硬化 (TLE-MTS) 的潜在原因。在 87 例接受局灶性癫痫切除的患者中，我们使用实时定量 PCR 和数字微滴 PCR 检测手术标本中的 HHV6。从新鲜脑组织中分离出病毒DNA。与患有局灶性皮质发育不良等其他病因的患者相比，患有 MTS 的患者更有可能活跃复制 HHV6。我们使用 FreeSurfer 来研究 HHV-6 的效果，以分割 41 名 TLE-MTS 患者的皮质结构并获得整个海马体和亚区体积。 22 名患者 HHV-6 呈阳性，19 名患者呈阴性。与 HHV-6 阳性患者相比，HHV-6 阴性患者的癫痫病灶同侧 AI 显着更高，海马总体积更低。癫痫持续时间和发病年龄不影响结果。我们的数据表明 MTS 的多种潜在病因。与其他 TLE-MTS 病因相比，HHV-6 对海马体的影响可能不太严重。

项目成果

期刊论文数量（47）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Epilepsy diagnosis: positron emission tomography.

癫痫诊断：正电子发射断层扫描。

DOI：
10.1016/b978-0-444-52898-8.00026-4
发表时间：
2012
期刊：
Handbook of clinical neurology
影响因子：
0
作者：
Kumar,Ajay;Semah,Franck;Chugani,HarryT;Theodore,WilliamH
通讯作者：
Theodore,WilliamH

Initial subspecialty certification in epilepsy application deadline april 15.

癫痫初步亚专业认证申请截止日期为 4 月 15 日。

DOI：
10.5698/1535-7597-13.2.60
发表时间：
2013
期刊：
Epilepsy currents
影响因子：
3.6
作者：
Bergey,GregoryK;Kanner,AndresM;Theodore,WilliamH
通讯作者：
Theodore,WilliamH

Alcohol and Aldehyde Dehydrogenases Contribute to Sex-Related Differences in Clearance of Zolpidem in Rats.

酒精和醛脱氢酶导致大鼠中唑吡坦清除率存在性别相关差异。

DOI：
10.3389/fphar.2016.00260
发表时间：
2016
期刊：
Frontiers in pharmacology
影响因子：
5.6
作者：
Peer,CodyJ;Strope,JonathanD;Beedie,Shaunna;Ley,ArielM;Holly,Alesia;Calis,Karim;Farkas,Ronald;Parepally,Jagan;Men,Angela;Fadiran,EmmanuelO;Scott,Pamela;Jenkins,Marjorie;Theodore,WilliamH;Sissung,TristanM
通讯作者：
Sissung,TristanM

Is seizure frequency variance a predictable quantity?