Physiologic And Pharmacologic Studies In Epilepsy

癫痫是最常见的神经系统疾病之一，癫痫发作不受控制的患者会遭受许多不良影响。本研究的目的是研究癫痫对大脑结构和功能的影响，并在现有方法无法控制癫痫发作时测试创新的治疗方法。方法：对患者进行视频脑电图监测，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）用于研究脑代谢、血流和结构。测定抗癫痫药物血药浓度。最近的神经影像学研究发现：中枢5-羟色胺（5-HT）1A受体在脑干中叶、海马和颞叶新皮层中高密度激活，在各种实验性癫痫发作模型中发挥抗惊厥作用。先前，我们发现5-HT1A沉默拮抗剂[18F]FCWAY在颞叶癫痫灶同侧的颞外侧新皮质区和内侧颞区结合减少。我们现在报告基于磁共振（MR）的部分体积校正（PVC）结果。13例患者和10例对照组在大剂量注射[18F]FCWAY后获得2小时动态PET图像。将图像帧注册到分割的t1加权MR体积上，并使用灰质和白质掩膜应用PVC。校正了像素数据的血管内放射性、标记代谢物摄取和颅骨18f -氟化物活性的溢出。原始和PVC像素数据使用代谢物校正输入函数拟合到2组织室模型中，以产生分布体积(V)图像。将MR体积上绘制的roi应用于V图像。只采样了灰质体素。结合电位（BP） （mL/mL）计算为[V(ROI)-V（小脑）]/血浆游离分数。在PVC前后，患者的血压明显降低，同侧海马、海马副和梭状回的侧侧不对称性明显大于对照组（p< 0.05，经多次比较校正）。PVC前后对侧无差异。PVC前海马血压不对称为64？27%与11%相比？FDG占9%。PVC后，值为51？B25%和11？分别b12%。5-HT1A BP在颞叶内侧颞区显著降低，但在外侧新皮层无显著降低。这种减少不是部分体积平均的伪影。这些发现支持了我们在颞叶癫痫灶中减少5-HT1A受体结合的假设。5-HT1A活性降低可能导致局部高兴奋性。难治性部分性癫痫患者常表现为区域性代谢低下。目前尚不清楚代谢异常是在癫痫发作时出现还是随着时间的推移而发展。在之前的一项研究中，我们发现，与慢性部分性癫痫的成人相比，新发部分性癫痫的儿童中葡萄糖利用异常不常见，也不严重。磁共振成像研究表明，海马体积减小与发热性癫痫发作史、癫痫持续时间和全身性强直性阵挛发作次数有关。目前还不确定这些因素是否会对功能有同样的影响，因为它们对癫痫区完整性的结构测量有同样的影响。本文采用氟182脱氧葡萄糖正电子发射断层扫描对119例经视频脑电图定位的颞叶癫痫灶进行了研究。PET在清醒间歇静息状态下进行，耳塞眼补。我们在注射（5毫微克）和30分钟摄取期间记录体表脑电图。我们使用标准模板来分析PET扫描。有发热性惊厥史的患者，或有复杂或延长的发热性惊厥史的患者，在癫痫病灶同侧的低代谢并不比无低代谢的患者更严重。终生全身性强直-阵挛发作次数较多的患者在癫痫病灶的同侧有较大的相对低代谢的趋势，但不明显。我们发现癫痫持续时间与癫痫病灶同侧海马糖代谢呈显著负相关（F=6.81; p <0.02）。颞叶癫痫患者中颞叶完整性的功能测量受癫痫持续时间的影响，但不受热性癫痫发作史的影响。这表明癫痫引起的海马损伤可能是一个渐进的过程。在大鼠的平行研究中，我们正在与ERS和功能和分子成像实验室合作，我们正在使用MRI研究kainate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。我们正试图建立人体影像学显示的边缘损伤模型，并探讨其生理基础。在我们最初的研究中，我们发现特异性gluR5受体激动剂ATPA在立体定向注射到大鼠杏仁核时产生癫痫发作。这些癫痫发作在MRI测量的生理效应方面与注射特异性较低的谷氨酸激动剂kainic酸产生的生理效应相似。这表明gluR5受体激活本身就足以诱导癫痫发作。在研究的下一阶段，我们将尝试在抽搐后通过脑电图和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.