Physiologic And Pharmacologic Studies In Epilepsy

患者接受视频脑电监测，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)被用来研究大脑的代谢、血流、神经递质受体的结合和结构。获得抗癫痫药物的血药浓度。研究是与NIMH和NIH临床中心PET部门合作进行的。我们使用几种配体进行PET，包括用于5-羟色胺转运体活性评估的11CDASB，用于5HT1A受体可视化的FCWAY PET，以及用于TSPO结合的11CPBR28，氟脱氧葡萄糖，致痫区域的临床标记物，以及用于PET数据的部分体积校正和致痫损伤检测的结构MRI。在最近的研究中，我们比较了13名患者和16名健康志愿者的PET数据，其中11CDASB用于5HTT，18FFCWAY用于5-HT1A受体结合、MRI和精神病学评估。我们使用参考组织模型来估计11CDASB结合。根据血浆游离分数对18FFCWAY分布体积进行校正。图像被归一化到公共空间。主要结果是区域不对称指数。阳性不对称性提示癫痫灶同侧结合相对减少(反映转运蛋白活性)。结果显示，患者和对照组之间11CDASB的平均区域结合和不对称性没有差异。患者组在海马区、杏仁核和梭形回的FFCWAY不对称性显著大于对照组。在以区域为重复指标的方差分析中，抑郁症的诊断对11CDASB的不对称性有显著影响，其中岛叶皮质11CDASB的不对称性显著高于11CDASB(倾向于梭形回)。在岛叶皮质，18FFCWAY不对称与11CDASB不对称显著相关。与单纯TLE患者相比，TLE和抑郁症患者的脑岛和梭状回11CDASB不对称性增加，转运蛋白活性相对降低，意味着重摄取减少，从而增加突触5-羟色胺的可获得性。这一发现可能代表了5-HT1A受体丢失的一种代偿机制，并为5-羟色胺能机制在TLE和伴随的抑郁症中发挥重要作用提供了额外的证据。为了比较5HT1a受体PET和脑葡萄糖代谢(CMRglc)PET在颞叶切除术计划中的应用价值，我们对41例接受前颞叶切除术的患者进行了术前18FFCWAY PET和18FFDG脑葡萄糖代谢(CMRglc)测定。手术是根据个体化的术前评估和术中皮层脑电描记进行的。比较16例健康志愿者癫痫发作和非癫痫发作患者的平均区域不对称值，以及不对称超过2个标准差的区域数目。18FFCWAY而不是18F-FDG18FFDG和MRI数据被掩盖，用于手术决定和结果评估。在41例术后无癫痫发作的患者中，26例(63%)在18FFCWAY(F1，39=5.87，p=0.02)和18FFDG PET(F1，38=5.79，p=0.021)两组中有15例无癫痫发作的患者有显著不同的内侧颞叶不对称。18FFDG和18FFCWAYPET均可解释癫痫发作消失的概率，但MRI不能解释，在18FFCWAY效应后，18FFCWAY效应显著(卡方=9.8796，p=0.0072)。尽管MRI本身并不能预测癫痫发作，但两种偏侧化成像研究的任何组合都能很好地预测癫痫发作的缓解。 我们的研究表明，5HT1a受体PET和CMRglc PET都可以为颞叶切除术的计划做出贡献。其他研究应根据发作间期脑电和微创成像研究来探索颞叶切除术的可能性。PET数据还表明，使用实验性的5HT1A激动剂治疗可能会减少癫痫发作。我们已经启动了一项针对癫痫患者的实验性5HT1A激动剂的双盲安慰剂对照交叉试验，以测试这种受体的激活增加可能改善癫痫发作和情绪障碍的假设。&#8232；&#8232； 为了研究炎症在癫痫中的作用，与美国国立卫生研究院罗伯特·因尼斯博士合作，对16例单侧颞叶癫痫患者和30例健康人进行了11CPBR28PET和MRI检查。注射11CPBR28后，测量双侧MRI图像上感兴趣区的放射性摄取。用配对样本t检验比较同侧和对侧大脑半球的脑摄取。我们发现，癫痫灶同侧的大脑摄取在海马区、海马旁回、杏仁核、梭形回和脉络丛较高，而在其他脑区则不明显。这种不对称性在患有海马区硬化症的患者中比在非硬化症患者中更加明显。这些结果与TSPO的表达增加相一致。我们正在对其他致痫病变的患者进行额外的研究，并与NINDS的Steven Jacobson博士合作研究组织中是否存在HHV6。

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, binding of neurotransmitter receptors, and structure. Antiepileptic drug blood levels are obtained. Studies are performed in collaboration with NIMH and the NIH Clinical Center PET Department.
 We perform PET with several ligands, including 11CDASB, for serotonin transporter activity estimation, PET with FCWAY for 5HT1A receptor visualization, and 11CPBR28 for TSPO binding, fluorodeoxyglucose, a clinical marker of epileptogenic regions, as well as structural MRI both for partial volume correction of PET data and detection of epileptogenic lesions. In recent studies we compared data from 13 patients and 16 healthy volunteers who had PET with 11CDASB for 5HTT, and 18FFCWAY for 5-HT1A receptor binding, MRI, and psychiatric assessment. We used a reference tissue model to estimate 11CDASB binding. 18FFCWAY volume of distribution was corrected for plasma free fraction. Images were normalized to common space. The main outcome was the regional asymmetry index. Positive asymmetry indicates relatively reduced binding (reflecting transporter activity) ipsilateral to epileptic foci. The results showed that mean regional 11CDASB binding and asymmetry did not differ between patients and controls. 18FFCWAY asymmetry was significantly greater for patients than controls in hippocampus, amygdala, and fusiform gyrus. On ANOVA with region as a repeated measure, depression diagnosis had a significant effect on 11CDASB asymmetry, with significantly higher 11CDASB asymmetry in insular cortex (trend for fusiform gyrus). In insular cortex, patients had a significant correlation between 18FFCWAY asymmetry and 11CDASB asymmetry. Increased 11CDASB asymmetry in insula and fusiform gyrus, and relatively reduced transporter activity, in subjects with both TLE and depression, as compared to subjects with TLE alone, implies reduced reuptake and thus increased synaptic 5-HT availability. This finding may represent a compensatory mechanism for 5-HT1A receptor loss, and provides additional evidence of an important role for serotonergic mechanisms in TLE and concomitant depression. In order to compare 5HT1A receptor PET and cerebral glucose metabolism (CMRglc) PET for temporal lobectomy planning, we performed preoperative 5HT1A receptor binding estimation with 18FFCWAY PET and CMRglc measurement with 18FFDG in regions drawn on coregistered qMRI after partial volume correction, in 41 patients who had anterior temporal lobectomy, with at least one-year follow-up. Surgery was tailored to individual preresection evaluations as well as intraoperative electrocorticography. Mean regional asymmetry values, and the number of regions with asymmetry exceeding 2 standard deviations in 16 healthy volunteers were compared between seizure-free and not seizure-free patients. 18FFCWAY but not 18F-FDG18FFDG and MRI data were masked for surgical decisions and outcome assessment. Twenty-six of 41 (63 %) patients seizure-free since surgery had significantly different mesial temporal asymmetries compared to 15 not seizure=free patients for both 18FFCWAY (F1,39 = 5.87, p = 0.02) and 18FFDG PET (F1,38 = 5.79, p =0.021). The probability of being seizure-free was explained by both 18FFDG and 18FFCWAY PET, but not MRI, with a significant additional 18FFCWAY effect (chi-square =9.8796, p=0.0072) after the probability of being seizure free was explained by FDG. Although MRI alone was not predictive, any combination of two lateralizing imaging studies was highly predictive of seizure-freedom. Our study suggests that both 5HT1A receptor PET and CMRglc PET can make a contribution to temporal lobectomy planning. Additional studies should explore the potential for temporal lobectomy based on interictal EEG and minimally invasive imaging studies. The PET data suggest as well that treatment with an experimental 5HT1A agonist might reduce seizures.

 We have started a double-blind placebo-controlled cross-over trial of an experimental 5HT1A agonist in patients with epilepsy, to test the hypothesis that increased activation of this receptor may ameliorate both seizures and mood disorders. 

 In order to study the role of inflammation in epilepsy, in collaboration with Dr Robert Innis of NIMH, 11CPBR28 PET and MRI in 16 patients with unilateral temporal lobe epilepsy and 30 healthy subjects. Uptake of radioactivity after injection of 11CPBR28 was measured from regions of interest drawn bilaterally on MRI images. Brain uptake from ipsilateral and contralateral hemispheres was compared using a paired samples t-test. We found that brain uptake was higher ipsilateral to the seizure focus in the hippocampus, parahippocampal gyrus, amygdala, fusiform gyrus, and choroid plexus, but not in other brain regions. This asymmetry was more pronounced in patients with hippocampal sclerosis than in those without. These results are consistent with increased expression of TSPO. We are performing additional studies in patients with other epileptogenic lesions, as well as studying tissue for the presence of HHV6 in collaboration with Dr Steven Jacobson of NINDS.