Division of Clinical Neurophysiology, Inflammation and Stem Cell Therapy Group, Lund University, Lund, Sweden.
Department of Clinical Sciences, Epilepsy Center, Lund University, Lund, Sweden.
Epilepsia. 2018 May;59(5):945-958. doi: 10.1111/epi.14070. Epub 2018 Apr 10.
Status epilepticus (SE) is an abnormally prolonged epileptic seizure that if associated with convulsive motor symptoms is potentially life threatening for a patient. However, 20%-40% of patients with SE lack convulsive events and instead present with more subtle semiology such as altered consciousness and less motor activity. Today, there is no general consensus regarding to what extent nonconvulsive SE (NCSE) is harmful to the brain, which adds uncertainty to stringent treatment regimes.
Here, we evaluated brain pathology in an experimental rat and mouse model of complex partial NCSE originating in the temporal lobes with Western blot analysis, immunohistochemistry, and ex vivo diffusion tensor imaging (DTI). The NCSE was induced by electrical stimulation with intrahippocampal electrodes and terminated with pentobarbital anesthesia. Video-electroencephalographic recordings were performed throughout the experiment.
DTI of mice 7 weeks post-NCSE showed no robust long-lasting changes in fractional anisotropy within the hippocampal epileptic focus. Instead, we found pathophysiological changes developing over time when measuring protein levels and cell counts in extracted brain tissue. At 6 and 24 hours post-NCSE in rats, few changes were observed within the hippocampus and cortical or subcortical structures in Western blot analyses of key components of the cellular immune response and synaptic protein expression, while neurodegeneration had started. However, 1 week post-NCSE, both excitatory and inhibitory synaptic protein levels were decreased in hippocampus, concomitant with an excessive microglial and astrocytic activation. At 4 weeks, a continuous immune response in the hippocampus was accompanied with neuronal loss. Levels of the excitatory synaptic adhesion molecule N-cadherin were decreased specifically in rats that developed unprovoked spontaneous seizures (epileptogenesis) within 1 month following NCSE, compared to rats only exhibiting acute symptomatic seizures within 1 week post-NCSE.
These findings provide evidence for a significant brain pathology following NCSE in an experimental rodent model.
癫痫持续状态（SE）是一种异常延长的癫痫发作，如果伴有惊厥性运动症状，可能对患者的生命构成威胁。然而，20%-40%的 SE 患者没有惊厥发作，而是表现出更微妙的症状，如意识改变和较少的运动活动。目前，对于 NCSE 对大脑的危害程度尚无普遍共识，这给严格的治疗方案增加了不确定性。
在这里，我们通过 Western blot 分析、免疫组织化学和离体弥散张量成像（DTI）评估了起源于颞叶的复杂部分 NCSE 的实验大鼠和小鼠模型中的脑病理学。NCSE 通过海马内电极的电刺激诱导，并通过戊巴比妥麻醉终止。在整个实验过程中进行视频-脑电图记录。
NCSE 后 7 周的小鼠 DTI 显示，在海马癫痫灶内的各向异性分数没有明显的持久变化。相反，当测量提取脑组织中的蛋白水平和细胞计数时，我们发现随着时间的推移会出现病理生理变化。在 NCSE 后 6 和 24 小时的大鼠中，在海马和皮质或皮质下结构的 Western blot 分析中观察到细胞免疫反应和突触蛋白表达的关键成分的变化很少，而神经退行性变已经开始。然而，在 NCSE 后 1 周，海马中兴奋性和抑制性突触蛋白水平均降低，同时伴有过度的小胶质细胞和星形胶质细胞激活。在 4 周时，海马中的持续免疫反应伴随着神经元丢失。与仅在 NCSE 后 1 周内出现急性症状性发作的大鼠相比，在 1 个月内自发发作（癫痫发生）的大鼠中，兴奋性突触粘附分子 N-钙粘蛋白的水平降低。
这些发现为实验性啮齿动物模型中的 NCSE 后显著的脑病理学提供了证据。
