Mathern G W, Babb T L, Leite J P, Pretorius K, Yeoman K M, Kuhlman P A
Division of Neurosurgery, University of California, Los Angeles School of Medicine, USA.
Epilepsy Res. 1996 Dec;26(1):151-61. doi: 10.1016/s0920-1211(96)00052-6.
To design useful experimental models of epilepsy, it is necessary to clearly understand the known clinical-pathologic features of the disease process. Studies of mesial temporal lobe epilepsy (MTLE) patients have identified several distinctive clinical and pathophysiologic characteristics and many of these can be analyzed in experimental models. For example, patients with typical MTLE have medical histories that often contain an initial precipitating injury (IPI), are likely to have hippocampal sclerosis in the surgical specimen, and have better seizure outcomes than patients with typical idiopathic temporal seizures (i.e. cryptogenic). Hippocampal from children as young as age 1 year with IPI histories also demonstrate neuron damage similar to adults with hippocampal sclerosis. Compared to IPI patients without seizures (i.e. trauma, hypoxia, etc.), IPI cases with severe seizures showed younger ages at the IPI, shorter latent periods, and longer durations of habitual MTLE. Hippocampal damage is often bilateral, however, the epileptogenic side shows hippocampal sclerosis and the opposite side usually shows only mild neuron losses. Moreover, MTLE patients show declines in hippocampal neuron densities with very long histories of habitual seizures (15 to 20 years), however, the additional neuron loss adds to the template of hippocampal sclerosis and occurs in limited subfields (granule cells, CA1 and prosubiculum). Hippocampal axon and synaptic reorganization is another pathologic feature of MTLE, and involves granule cell mossy fibers and axons immunoreactive for neuropeptide upsilon, somatostatin, and glutamate decarboxylase (which synthesizes GABA). Finally, MTLE patients with hippocampal sclerosis show increased granule cell mRNA levels for brain derived neurotropic factor, nerve growth factor, and neurotrophin-3 that correlate with mossy fiber sprouting or with declines in Ammon's horn neuron densities. Taken together, our data support the following concepts: (1) The pathogenesis of MTLE is associated with IPI histories that probably injure the hippocampus at some time prior to habitual seizure onsets, (2) most of the damage seems to occur with the IPI, (3) there can be additional neuron loss associated with long histories, (4) another pathologic feature of MTLE is axon reorganization of surviving fascia dentata and hippocampal neurons, and (5) reorganized axon circuits probably contribute to seizure or propagation.
为了设计出有用的癫痫实验模型，有必要清楚地了解该疾病过程已知的临床病理特征。对内侧颞叶癫痫（MTLE）患者的研究已经确定了几个独特的临床和病理生理特征，其中许多特征可以在实验模型中进行分析。例如，典型MTLE患者的病史通常包含初始促发损伤（IPI），手术标本中可能存在海马硬化，并且与典型特发性颞叶癫痫（即隐源性癫痫）患者相比，癫痫发作结局更好。有IPI病史的1岁儿童的海马也表现出与患有海马硬化的成年人相似的神经元损伤。与无癫痫发作的IPI患者（即创伤、缺氧等）相比，有严重癫痫发作的IPI患者在IPI时年龄更小，潜伏期更短，习惯性MTLE持续时间更长。海马损伤通常是双侧的，然而，致痫侧表现出海马硬化，而对侧通常仅表现出轻度神经元丢失。此外，MTLE患者在有很长的习惯性癫痫发作病史（15至20年）时，海马神经元密度会下降，然而，额外的神经元丢失会增加海马硬化的模板，并发生在有限的亚区（颗粒细胞、CA1和前下托）。海马轴突和突触重组是MTLE的另一个病理特征，涉及颗粒细胞苔藓纤维以及对神经肽υ、生长抑素和谷氨酸脱羧酶（合成GABA）免疫反应的轴突。最后，患有海马硬化的MTLE患者的颗粒细胞中脑源性神经营养因子、神经生长因子和神经营养素-3的mRNA水平升高，这与苔藓纤维发芽或海马角神经元密度下降相关。综上所述，我们的数据支持以下概念：（1）MTLE的发病机制与IPI病史有关，IPI可能在习惯性癫痫发作开始前的某个时间损伤海马；（2）大多数损伤似乎发生在IPI时；（3）长期病史可能会导致额外的神经元丢失；（4）MTLE的另一个病理特征是存活的齿状回和海马神经元的轴突重组；（5）重组的轴突回路可能有助于癫痫发作或传播。
