【作者】 彭炳蔚；

【导师】 吴立文；

【作者基本信息】 中国协和医科大学 ， 临床医学， 2008， 博士

【摘要】 研究背景及目的内侧颞叶癫痫(MTLE)患者存在选择性记忆损害,即外显记忆受损而内隐记忆保留,被认为是研究记忆的模型。同时影响MTLE者记忆受损的因素很多,而记忆与人类学习工作密切相关。我们通过对不同组MTLE患者的记忆损害及影响因素的研究,并应用MRI定量技术,从临床上进一步证实MTLE者记忆功能损害、重塑的机制以及内侧颞叶结构在人类记忆保持中的作用,为MTLE病人认知障碍的预防及治疗提供理论基础。资料与方法收集2006年6月至2007年12月我院癫痫中心门诊和住院病人,经过临床资料、EEG和MRI海马像综合评价后诊断为MTLE且智力正常的病例,详细记录患者的年龄、发病年龄、病程、教育水平、职业、生活环境、既往史以及发作和药物治疗情况。根据患者首次脑损害的年龄划分为小于5岁,5～14岁,成年三组;根据治疗效果分为药物难治组和药物反应良好组;根据MRI海马像结果分为左侧海马结构异常、右侧海马结构异常及无海马结构异常、双侧海马结构异常。应用临床记忆量表(CMS)对患者进行记忆功能评定,并计算记忆商(MQ)值,同时记录5个分量表:指向记忆、联想学习、自由图像回忆、无意义图形再认和人像回忆的年龄量表分及联想学习中的无联系记忆的粗分。根据不同病例资料进行四组研究。第一部分纳入年龄在14～30岁之间,从事脑力劳动,教育水平匹配的MTLE者54例和特发性全面性癫痫(IGE)者33例进行病例对照研究。第二部分纳入190例MTLE患者,将所有可能影响因素进行GLM方差分析和协方差分析,对结构异常组间进行单因素方差分析。第三部分对进行89例进行~1H-MRS检查者和64例进行双侧海马、双侧杏仁核、双侧内嗅皮层的体积测量者进行定量值与记忆评分的相关性研究。定量值为原始值的Z分数和体积不对称指数。第四部分为前瞻性研究,纳入者均为难治性MTLE者,自愿选择手术治疗或添加新药治疗,经过1年随访,确定完全无发作或发作较治疗前减少大于90%(即EngleⅠ-Ⅱ级)的患者纳入研究。病例组10例为手术治疗组,对照组10例为药物治疗组,保证各影响因素匹配。在手术治疗前或药物治疗前用CMS甲套进行第一次记忆测试,在治疗后4个月～1年用CMS乙套进行第二次记忆测试,前后2次测量值采用重复测量数据的方差分析。结果1、MTLE组MQ、无联系记忆、无意义图形再认及人像回忆的分量表值显著低于IGE组,其中药物反应良好组仅无联系记忆初分比IGE组更差。2、MTLE中脑损害年龄小于5岁组,其MQ、联想学习、无联系记忆、无意义图形再认和人像回忆均显著低于IGE组;脑损害在5岁～14岁组,仅MQ、人像回忆比IGE组显著低。小于5岁组左侧海马体积显著小于5～14岁组和成人组;成人组右侧杏仁核体积显著大于5～14岁组和小于5岁组。3、在内侧颞叶癫痫患者,职业对指向记忆和人像回忆有影响,治疗反应影响无联系记忆,是否单药治疗影响MQ、指向记忆、联想学习,海马病变的区别影响MQ、无联系记忆和人像回忆,测试的年龄主要影响联想学习和人像回忆,病程主要影响指向记忆。4、左侧结构异常组对结构正常组在指向记忆、联想学习、无联系记忆均明显差,而左侧结构异常组比右侧结构异常组在指向记忆更差,人像回忆则在海马结构异常组(不论什么性质、什么位置)比海马结构正常组更差。非语言记忆测试,包括自由图像回忆和无意义图形再认在右侧结构异常组并未显示差别。5、内嗅皮层的不对称指数与指向记忆、无联系记忆、自由图像回忆正相关,而杏仁核的不对称指数与联想学习、无意义图形再认和人像回忆负相关,左侧海马体积与无联系记忆负相关,右侧海马体积与人像回忆正相关。6、不论经药物治疗还是手术治疗,治疗后人像回忆值均有显著提高,手术治疗组更加明显。对于药物治疗组,治疗后比治疗前无意义图形再认有显著降低。7、在术前,右侧MTLE在人像回忆的分值显著好于左侧MTLE组。对于左侧MTLE者,术后语言记忆比术前有损害,而右侧MTLE组,术后语言记忆较术前有改善,尤其在指向记忆方面。而对于非语言记忆(自由图像回忆和无意义图形再认),本组数据无统计学差异。结论1.MTLE患者的记忆损害是广泛的,相对特异的,是与IGE患者区别的重要的神经心理的特征。2.CMS对于评价MTLE的记忆功能是有价值的,人像回忆是CMS中最敏感的分量表,对于评价双侧颞叶功能和轻微变化均有价值,对左侧MTLE的定位价值更大。3.不论哪一侧MTLE,其记忆损害是双侧性的。而记忆中的人像回忆的功能是更容易受损或恢复的。4.早年脑损害的MTLE患者,其记忆功能的损害更加普遍和明显。5.病程和是否单药治疗是影响MTLE记忆功能的重要因素,并对语言记忆的影响更加明显。6.不论药物还是手术,控制发作后MTLE患者的记忆功能可部分改善。7.左侧MTLE者,术后语言记忆比术前差,而右侧MTLE组,术后语言记忆较术前有改善。8.杏仁核和内嗅皮层是记忆巩固的重要结构,对语言记忆和非语言记忆起综合调节作用。更多还原

【Abstract】 Background and ObjectivesThe memory impairments in the patients with mesial temporal lobe epilepsy are characterized by the deficits in explicit memory and the retention in implicit memory, so MTLE was considered as a model to understand human memory. Memory is important for study and work and is affected by many factors in the patients with MTLE. The studies in the different groups of patients with MTLE are to prove the mechanism of memory impairment and plasticity in MTLE, and quantitative MRI was applied to explain the contribution of mesial temporal lobe structure to memory consolidation. The study is valuable for the therapy and prevention of the congnitive disorders in MTLE.Materials and MethodsAll patients with normal intelligence who were diagnosed as MTLE by the clinical information, EEG and MRI between Jun. 2006 and Dec. 2007 were investigated including age, age onset, duration, education level, occupation, farmer or not, the past history, seizure and medication. All cases were classified as the left MRI-positive (MRI (+)) group, the right MRI (+) group, the MRI (—) group, the bilateral MRI (+) group by high-quality MRI protocol, as the less than 5 year-old group, the 5 to 14 year-old group, the adult group by the first cerebral damage age, also as the drug-resistant group and the drug-responsive group. The Clinical Memory Scale was administered as memory assessment of MTLE. MQ, the scale scores by age of the direct memory, the associated study, the free picture recall, the non-sense graphics recognition, the recognition memory test for faces and the primary scores of the unrelated memory were analyzed. Four studies for the different groups of cases were performed. The first part was a case-control study between 54 patients with MTLE and 33 patients with IGE who were 14 to 30 year-old and had the similar occupation and education. In the second part, the general linear model multivariate analysis of variance and covariance were used to analyze the data of 190 patients with MTLE. ANOVA was used to analyze the data among the groups with the different MRI results. The third part was the correlative study between the MRI quantitative data: the Z scores or asymmetry index and the memory scale scores about 89 patients with ~1H-MRS and 64 patients with MRI volumetric measurement of the hippocampus, the amygdala, and the entorhinal area. A 1 year follow-up study in the refractory MTLE was carried out in the forth part. 10 seizure-free patients with the surgery and 10 seizure-free patients with the new anti-epilepsy drugs (AEDs) addition therapy were tested by CMS I before the therapy and repeated by CMS II during 4 months to 1 year after the therapy. The repeated measures analyse of variance was used to analyzed the data.Results1. MQ, the scores of the unrelated memory, the non-sense graphics recognition and the recognition memory test for faces in the MTLE group were significantly lower than those in the IGE group, only the score of the unrelated momory in the drug-responsive group was lower than the IGE group.2. MQ, the scores of the associated study, the unrelated memory, the non-sense graphics recognition and the recognition memory test for faces in the less than 5 year-old group were significantly lower than those in the IGE group, only MQ and the score of recognition memory test for faces in the 5～14 year-old group were lower than the IGE group. The left hippocampal volumes in the less than 5 year-old group were significantly smaller than those in the 5～14 year-old group and the adult group, amygdalic volumes in the adult group were significantly larger than the other two groups.3. For the patients with MTLE, occupation affected the direct memory and the recognition memory test for faces, drug-response affected the unrelated memory, medication affected MQ, the direct memory, the associated study, the difference in the MRI results affected MQ, the unrelated memory and the recognition memory test for faces, age affected the associated study and the recognition memory test for faces, duration affected the direct memory.4. The scores of the direct memory, the associated study, the unrelated memory in the left MRI(+) group were significantly lower than those in the MRI(-) group, the scores of the direct memory in the left MRI(+) group were lower than those in the right MRI(+) group, the scores of the recognition memory test for faces in all MRI(+) groups were lower than those in the MRI(-) group. However, the scores of the non-verbal tests, such as the free picture recall and the non-sense graphics recognition, showed no significant difference among groups.5. The asymmetry index of entorhinal area was positive correlated with the scores of the direct memory, the unrelated memory and the free picture recall, the asymmetry index of amygdala was negtive correlated with the scores of the associated study, the non-sense graphics recognition and the recognition memory test for faces, the left hippocampal volumes were negtive correlated with the scores of the unrelated memory, and the right hippocampal volumes were positive correlated with the scores of the recognition memory test for faces.6. The scores of the recognition memory test for faces in either the new anti-epilepsy drugs (AEDs) addition therapy group or the surgery group were improved after the therapy, the more significant in the surgery group. In the new anti-epilepsy drugs (AEDs) addition therapy group, the scores of the non-sense graphics recognition were worse after the therapy.7. The scores of the recognition memory test for faces in the right MTLE group were better than those in the left MTLE group before the surgery. The verbal memory, especially in the direct memory was worse in the left MTLE group and improved in the right MTLE group after the surgery. For the non-verbal memory, the data showed no significant difference.Conclusion1. The patients with MTLE have the general and special memory impairment.2. CMS is valuable for the memory assessment of MTLE, the recognition memory test for faces is the most sensitive sub-scale that is valuble to estimate the memory function of bilateral temporal lobe especially left temporal lobe or the minut change of memory.3. The memory impairment is bilateral in the patients with either the left or the right MTLE, the faces recognition or naming function of memory is easier for the damage or the recovery.4. The memory impairment is more general and significant in the patients with the early cerabral damage.5. Memory can be improved by seizure-free through the medication or the surgery.6. Duration and medication affect the verbal memory in the patients with MTLE.7. The verbal memory was worse in the left MTLE group and improved in the right MTLE group after the surgery.8. The amygdala and the entorhinal area that affect verbal memory or non-verbal memory are the important structure of memory consolidation.更多还原