Department of Neurology, Neuroscience Center at Dartmouth, Dartmouth Medical School, One Medical Center Drive, Lebanon, New Hampshire, USA.
Brain. 2011 Jun;134(Pt 6):1684-93. doi: 10.1093/brain/awr087. Epub 2011 May 20.
One of the most common and serious co-morbidities in patients with epilepsy is cognitive impairment. While early-life seizures are considered a major cause for cognitive impairment, it is not known whether it is the seizures, the underlying neurological substrate or a combination that has the largest impact on eventual learning and memory. Teasing out the effects of seizures from pre-existing neurological disorder is critical in developing therapeutic strategies. We therefore investigated the additional cognitive effects of seizures on rodents with malformations of cortical development induced with methylazoxymethanol acetate. Pregnant rats were injected with saline or methylazoxymethanol acetate at embryonic Day 15 or 17 to induce differing malformation severity. From the day of birth to 9 days of age, half the pups received 50 flurothyl-induced seizures. All rats underwent testing in the Morris water maze to test spatial memory at 25 days of age (immediate post-weaning) or during adolescence at 45 days of age. Post-weaning rats had severe spatial cognitive deficits in the water maze and seizures worsened performance. In contrast, in animals tested during adolescence, there was no longer an additional adverse effect of seizures. We also investigated whether the severity of the structural abnormality and seizures impacted brain weight, cortical thickness, hippocampal area and cell dispersion area. The mean brain weight in control animals was greater than in rats exposed to methylazoxymethanol acetate at embryonic Day 17, which was greater than rats exposed to methylazoxymethanol acetate at embryonic Day 15. Rats exposed to methylazoxymethanol acetate at embryonic Day 15 had a thinner cortical mantle compared with rats exposed at embryonic Day 17 and control animals. The hippocampal area was similar in rats exposed at embryonic Days 15 and 17 but was smaller compared with controls. Methylazoxymethanol at embryonic Day 17 caused dispersion of the CA1-4 cell layers in the hippocampus, whereas methylazoxymethanol at embryonic Day 15 caused focal nodules in or above the CA1 layer, but the CA1-4 layers were intact and similar to control. Early-life seizures did not have a significant impact on any of these parameters. These observations indicate that the major factor responsible for the cognitive impairment in the rats with cortical dysplasia was the underlying brain substrate, not seizures. These findings have significant implications for the understanding of cognitive impairments in childhood epilepsy and suggest that early aggressive therapy of seizures alone may not be an adequate strategy for minimizing cognitive effects.
癫痫患者最常见和最严重的合并症之一是认知障碍。虽然早期癫痫发作被认为是认知障碍的主要原因，但尚不清楚是癫痫发作、潜在的神经基质还是两者的结合对最终的学习和记忆产生最大影响。在制定治疗策略时，必须将癫痫发作的影响与预先存在的神经障碍区分开来。因此，我们研究了皮质发育畸形诱导的鼠类的癫痫发作对认知的额外影响，这些畸形是通过醋酸甲氧基甲基甲醇诱导的。在胚胎第 15 天或第 17 天，给怀孕的大鼠注射生理盐水或醋酸甲氧基甲基甲醇，以诱导不同的畸形严重程度。从出生到 9 天大，一半的幼崽接受氟烷诱导的癫痫发作。所有大鼠均在 25 天大（即断奶后立即）或 45 天大（青春期）进行 Morris 水迷宫测试，以测试空间记忆。断奶后大鼠在水迷宫中的空间认知能力严重受损，癫痫发作使表现更差。相比之下，在青春期接受测试的动物中，癫痫发作不再有额外的不利影响。我们还研究了结构异常的严重程度和癫痫发作是否会影响脑重、皮质厚度、海马区和细胞分散区。对照组动物的平均脑重大于胚胎第 17 天接受醋酸甲氧基甲基甲醇暴露的大鼠，而胚胎第 17 天接受醋酸甲氧基甲基甲醇暴露的大鼠又大于胚胎第 15 天接受醋酸甲氧基甲基甲醇暴露的大鼠。胚胎第 15 天接受醋酸甲氧基甲基甲醇暴露的大鼠皮质帽比胚胎第 17 天接受暴露的大鼠和对照组动物更薄。在胚胎第 15 天和第 17 天接受暴露的大鼠中，海马区相似，但与对照组相比，海马区较小。胚胎第 17 天的甲氧基甲基甲醇导致海马 CA1-4 细胞层分散，而胚胎第 15 天的甲氧基甲基甲醇导致 CA1 层上方或上方出现局灶性结节，但 CA1-4 层完整且与对照组相似。早期癫痫发作对这些参数均无显著影响。这些观察结果表明，皮质发育不良大鼠认知障碍的主要原因是潜在的大脑基质，而不是癫痫发作。这些发现对理解儿童癫痫中的认知障碍具有重要意义，并表明单独早期积极治疗癫痫发作可能不是最大限度减少认知影响的充分策略。
