Physiologic And Pharmacologic Studies In Epilepsy

癫痫是最常见的神经系统疾病之一，癫痫发作得不到控制的患者会遭受许多不良影响。本研究的目的是调查癫痫对大脑结构和功能的影响，并测试当癫痫发作无法通过现有方法控制时的创新治疗方法。方法：对患者进行视频脑电图监测，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）用于研究大脑代谢，血流和结构。获得抗癫痫药物的血液水平。最近的神经影像学研究发现：在脑干中缝、海马和颞叶新皮层中发现高密度的中枢5-羟色胺（5-HT）1A受体的激活，在各种实验性癫痫发作模型中发挥抗惊厥作用。以前，我们发现减少5-HT 1A沉默拮抗剂[18 F]FCWAY结合在颞叶癫痫病灶同侧的颞叶新皮质和内侧颞区。我们现在报告基于磁共振（MR）的部分容积校正（PVC）结果。在团注[18 F]FCWAY后，在13名患者和10名对照中采集了2小时动态PET图像。将图像帧配准到分割的T1加权MR体积，并使用灰色和白色物质掩模应用PVC。像素数据校正血管内放射性，标记的代谢物摄取，和溢出的头骨18F-氟化物活性。使用代谢物校正的输入函数将原始和PVC像素数据拟合至2-组织房室模型，以产生分布容积（V）图像。在MR体积上绘制的ROI应用于V图像。仅对灰质体素进行采样。结合电位（BP）（mL/mL）计算为[V（ROI）-V（CEREBELLUM）]/血浆游离分数。在PVC前后，患者的血压显著低于对照组，同侧海马、海马旁和梭状回的侧侧不对称性也高于对照组（p<0.05，经多重比较校正）。PVC前后对侧无差异。PVC前海马BP不对称为64？b 27%相比，11？b9%FDG。PVC后，值为51？b 25%和11？b分别为12%。5-HT 1A BP在TLE内侧颞叶区域显著降低，但在外侧新皮质不显著降低。这种减少不是部分体积平均伪影。这些发现支持我们的假设，减少5-HT 1A受体结合颞叶癫痫灶。5-HT 1A活性降低可能导致局部过度兴奋。难治性部分性癫痫患者常表现为局部代谢低下。尚不清楚代谢异常是否在癫痫发作时存在或随时间发展。在以前的研究中，我们发现葡萄糖利用异常在新发部分性癫痫儿童中比在慢性部分性癫痫成人中更不常见和深刻。使用磁共振成像的研究表明，海马体积减小与热性惊厥史、癫痫持续时间和全身强直阵挛性惊厥发作次数相关。目前还不确定这些因素是否会有相同的影响功能，因为他们做的结构措施的完整性癫痫区。本文应用正电子发射断层扫描（PET）技术对119例经发作期视频脑电图（EEG）定位的颞叶癫痫患者进行了研究。PET是在清醒的发作间期静息状态下进行的，耳朵塞住，眼睛贴着。我们记录了表面脑电图在注射（5毫居里）和30分钟的摄取期。我们使用标准模板来分析PET扫描。有任何热性惊厥史或复杂或长期热性惊厥史的患者，癫痫病灶同侧的低代谢性并不比无低代谢性的患者更严重。终生全身强直阵挛性癫痫发作较多的患者在癫痫病灶同侧的相对代谢低下程度更大，这一趋势不显著。结果发现癫痫病程与癫痫灶同侧海马葡萄糖代谢呈显著负相关（F=6.81; p <0.02）。颞叶癫痫患者颞叶内侧完整性的功能测量受癫痫持续时间的影响，但不受热性惊厥史的影响。这表明，海马损伤由于癫痫发作可能是一个渐进的过程。在大鼠的平行研究中，我们与ERS和功能和分子成像实验室合作，我们正在使用MRI研究红藻氨酸和AMPA受体激活在癫痫动物模型的功能和结构改变中的作用。我们正试图模拟人类影像学中显示的边缘系统损伤，并研究其生理基础。在我们最初的研究中，我们发现，特定的gluR 5受体激动剂ATPA立体定向注射到大鼠杏仁核时，产生癫痫发作。这些癫痫发作的MRI测量的生理效应相似，通过注射特异性较低的谷氨酸受体激动剂红藻氨酸。这表明gluR 5受体激活本身足以诱导癫痫发作。在下一阶段的研究中，我们将尝试通过癫痫给药后的EEG和MRI模拟慢性癫痫发生。

Epilepsy is one of the most common neurological disorders, and patients whose seizures are not controlled suffer from many adverse effects. The goal of this study is to investigate the effects of epilepsy on brain structure and function, and to test innovative approaches to treatment when seizures cannot be controlled by currently available approaches. Methods: 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 cerebral metabolism, blood flow, and structure. Antiepileptic drug blood levels are obtained. Recent neuroimaging study findings: Activation of central serotonin (5-HT)1A receptors, found in high density in brainstem raphe, hippocampus and temporal neocortex, exerts an anticonvulsant effect in various experimental seizure models. Previously, we found reduced 5-HT1A silent antagonist [18F]FCWAY binding in both lateral temporal neocortical and mesial temporal regions ipsilateral to temporal lobe epileptic foci. We now report magnetic resonance (MR)-based partial volume corrected (PVC) results. Two-hour dynamic PET images were acquired in 13 patients and 10 controls after bolus [18F]FCWAY injection. Image frames were registered to segmented T1-weighted MR volumes, and PVC applied using gray and white matter masks. Pixel data were corrected for intravascular radioactivity, labeled metabolite uptake, and spill-in of skull 18F-fluoride activity. Original and PVC pixel data were fitted to a 2-tissue compartment model using the metabolite-corrected input function to produce volume of distribution (V) images. ROIs drawn on MR volumes were applied to V images. Only gray matter voxels were sampled. Binding potential (BP) (mL/mL) was calculated as [V(ROI)-V(CEREBELLUM)]/ plasma free fraction. Both before and after PVC, patients had significantly lower BP, as well as greater side-side asymmetry than controls in ipsilateral hippocampus, parahippocampus and fusiform gyrus (p<.05, corrected for multiple comparisons). There were no contralateral differences before or after PVC. Hippocampal BP asymmetry before PVC was 64?b27% compared to 11?b9 % for FDG. After PVC, values were 51?b25% and 11?b12%, respectively. 5-HT1A BP is significantly reduced in TLE mesial temporal regions but not lateral neocortex. This reduction is not partial volume averaging artifact. These findings support our hypothesis of reduced 5-HT1A receptor binding in temporal lobe epileptic foci. Reduced 5-HT1A activity may contribute to regional hyperexcitability. Refractory partial epilepsy patients often exhibit regional hypometabolism. It is unknown whether the metabolic abnormalities are present at seizure onset or develop over time. In a previous study we found that abnormalities of glucose utilization are less common and profound in children with new onset partial seizures than in adults with chronic partial epilepsy. Studies using magnetic resonance imaging have shown that reduced hippocampal volume is associated with a history of febrile seizures, the duration of epilepsy, and the number of generalized tonic clonic seizures. It is uncertain whether these factors would have the same influence on functional as they do on structural measures of the integrity of the epileptogenic zone. We used positron emission tomography with fluorine 18 2 deoxy glucose to study 119 patients with temporal lobe seizure foci localized by ictal video-EEG. PET was performed in the awake interictal resting state with ears plugged and eyes patched. We recorded surface EEG during injection (5 millicuries) and the 30 minute uptake period. We used a standard template to analyze PET scans. Patients with a history of either any febrile seizures, or complex or prolonged febrile seizures, did not have greater hypometabolism ipsilateral to the epileptic focus than patients without hypometabolism. There was a non-significant trend for patients with more lifetime generalized tonic-clonic seizures to have greater relative hypometabolism ipsilateral to the epileptic focus. We found that there was a significant negative relation between the duration of epilepsy and hippocampal glucose metabolism ipsilateral to the epileptic focus (F=6.81; p <0.02). A functional measure of mesial temporal integrity in patients with temporal lobe epilepsy was affected by epilepsy duration, but not a history of febrile seizures. This suggests that hippocampal injury due to seizures may be a progressive process. In a parallel study in rats, we are in collaboration with ERS and the Laboratory of Functional and Molecular Imaging, we are using MRI to study the role of kainate and AMPA receptor activation in functional and structural alterations in animal models of epilepsy. We are attempting to model the limbic injury shown in human imaging, and investigate its physiologic basis. In our initial studies, we found that the specific gluR5 receptor agonist ATPA produces seizures when injected stereotactically into rat amygdala. These seizures were similar in terms of physiologic effects measured by MRI to those produced by injection of the less specific glutamate agonist kainic acid. This suggests that gluR5 receptor activation is sufficient by itself for seizure induction. In the next stage of the study, we will try to model chronic epileptogenesis via EEG and MRI after convulsant administration.