【作者】 李楠；

【导师】 林卫红；

【作者基本信息】 吉林大学 ， 神经病学， 2022， 博士

【摘要】 第1章规范管理下新诊断癫痫患者治疗及预后目的:分析规范管理下我院神经内科门诊成人新诊断癫痫患者治疗预后及认知情绪共患病。方法:连续纳入515例成人新诊断癫痫患者进行规范化管理,定期随访12个月以上,根据患者病情调整用药,收集基线临床数据并记录随访时病情及用药变化,通过蒙特利尔认知量表(Montreal cognitive assessment,MOCA)、广泛性焦虑障碍量表(Generalized Anxiety Disorder,GAD-7)和中文版癫痫相关神经系统疾病抑郁障碍量表(Chinese version Neurological Disorders Depression Inventory Epilepsy,c-NDDI-E)检查患者认知及情绪状态。结果:(1)52%(n=265)新诊断癫痫患者达到无发作,13%(n=68)患者诊断为难治性癫痫。末次随访时共有315例(61%)以初始抗发作药(ASM)作为单药治疗,其中187例(59%)达到无发作。奥卡西平保留率相对较高,卡马西平保留率最低,第二代ASM保留率高于第一代ASM。21例(24%)初次判定(随访过程中首次达到诊断标准)为难治性癫痫的患者经药物调整后在末次随访时达到无发作,52例(18%)初次判定为无发作的患者在维持治疗过程中出现癫痫再发作(其中75%在无发作后1年内再发作),1例在无发作后转变为难治性癫痫。(2)基线发作频率较高(OR=1.20,95%CI:1.04-1.39)和治疗后第一个发作周期出现发作(OR=5.00,95%CI:2.75-9.08)均为难治性癫痫危险因素;将基线MOCA、GAD-7和c-NDDI-E量表得分纳入回归模型后,治疗后第一个发作周期出现发作(OR=6.03,95%CI:2.88-12.60)、基线发作频率较高(OR=1.21,95%CI:1.02-1.44)和发病年龄早(OR=1.34,95%CI:1.07-1.68)为难治性癫痫危险因素。(3)49%新诊断癫痫患者存在认知损伤,9.7%存在抑郁,42%患者存在焦虑。经治疗后GAD-7评分下降(P<0.001),高入组年龄(B=-1.22,P<0.001)、低文化程度(B=-1.16,P<0.001)和病因明确(B=-1.56,P=0.001)是MOCA得分较低的危险因素;女性(B=1.93,P<0.001)、低文化程度(B=0.62,P=0.003)是GAD-7得分较高的危险因素;女性(B=1.00,P=0.006)、低文化程度(B=0.45,P=0.014)、较高基线发作频率(B=0.24,P=0.044)和低收入(B=1.22,P=0.038)是c-NDDI-E得分较高的危险因素。结论:新诊断癫痫药物治疗效果总体较好,通过分析难治性癫痫危险因素,有利于医师尽快准确地识别可能发展为难治性癫痫的患者。无发作和难治性癫痫可能只是暂时性的结局,达到无发作尚不足以安全停药,难治性癫痫患者经过适当的药物调整也可能达到无发作。第2章癫痫患者规范药物治疗相关经济负担目的:分析吉林省城镇和农村地区成年癫痫患者癫痫相关直接及间接经济负担。方法:连续纳入吉林省成人新诊断癫痫患者,分析城镇患者和农村患者的癫痫相关直接和间接经济负担,并分析高经济负担的危险因素。结果:共有371例(240例城镇患者)吉林省新诊断癫痫患者纳入研究,随访至少12个月。城镇患者平均年总费用和平均年直接费用分别为4393.85元和3676.73元,农村地区为5127.98元和3993.55元;城镇患者平均年总经济负担和平均年直接经济负担分别为12%和9.4%,农村患者为28%和20%。城镇地区患者首诊检查检验费用和该项负担为3737.00元和12%,农村地区患者为3925.00元和21%。高直接经济负担的危险因素为农村地区患者(B=0.10,P<0.001)、丧失劳动力(B=0.06,P=0.007)和难治性癫痫(B=0.15,P<0.001);高总经济负担的唯一危险因素为丧失劳动力(B=1.40,P<0.001)。结论:癫痫对吉林省患者造成大的经济负担,尤其是农村地区、丧失劳动力的难治性癫痫患者。第3章难治性癫痫静息态脑部内在连接网络研究目的:分析常规头部MRI无责任病灶的难治性癫痫患者的内在脑网络改变。方法:纳入常规头部MRI无责任病灶的成年难治性癫痫患者14例和无发作患者9例,进行静息态功能磁共振扫描,并在扫描前完善简易智力状态检查量表(Mini-mental State Examination,MMSE)、GAD-7、c-NDDI-E和爱丁堡利手问卷检查,分析两组患者基于体素的形态学分析(VBM)、局部一致性(Re Ho)、低频振幅(ALFF)和比例低频振幅(f ALFF),并对全脑信号进行独立成分分析,对比网络内及网络间内在连接网络(intrinsic connectivity network,ICN)差异。结果:与无发作患者相比,难治性癫痫患者右侧中央前回(Precentral＿R)(t=4.92,P FDRcorr=0.020)、扣带回和扣带旁回中部(Cingulum＿Mid＿L、Cingulum＿Mid＿R)(t=4.84,P FDR-corr=0.012)、左侧辅助运动区(Supp＿Motor＿Area＿L)(t=7.64,P FDR-corr=0.004)和右侧旁中央小叶(Paracentral＿Lobule＿R)(t=5.99,P FDR-corr=0.002)灰质体积减少;右侧角回(Angular＿R)的Re Ho值减弱(t=6.91,P FDR-corr=0.001),左侧距状沟周围皮质(Calcarine＿L)Re Ho值(t=4.44,P FDR-corr=0.021)和f ALFF值(t=4.76,P FDR-corr=0.049)增强;右侧枕上回(Occipital＿Sup＿R)Re Ho值增强(t=6.31,P FDR-corr=0.021),左侧枕中回(Occipital＿Mid＿L)f ALFF值增强(t=4.78,P FDR-corr=0.040);腹侧注意网络的网络内功能连接减弱(t=6.46,P FDR-corr=0.015),视觉网络的网络内功能连接增强(t=5.38,P FDR-corr=0.002);后默认网络-感觉运动网络(t=3.249,Puncorr=0.005)、执行控制网络-背侧注意网络(t=3.286,Puncorr=0.004)和执行控制网络-感觉运动网络(t=4.303,Puncorr<0.001)的网络间连接增强。结论:难治性癫痫患者与无发作患者相比,右侧角回活动减弱,网络间连接代偿性增强,这些差异反映难治性癫痫的潜在病理生理改变,与ASM治疗反应差可能存在因果联系。更多还原

【Abstract】 Part 1 Treatment Outcome and Risk Factors of Adult Newly Diagnosed EpilepsyObjective: The study was conducted to summarize the treatment outcomes of newly diagnosed epilepsy(NDE)and analyze the risk factors for refractory epilepsy(RE)in Northeast China.Methods: A total of 515 adult patients with NDE were consecutively enrolled in this program.Clinical data were collected at baseline and each follow-up.Several scales concerning recognition and mood were also completed at the first visit.Results: Seizure-free status was achieved by 52%(n = 265)of the patients;however,13%(n = 68)manifested RE.A total of 315(61%)patients continued with the first ASM as monotherapy,among which 187(59%)patients became seizure-free.Oxcarbazepine has the higher probability of retention and carbamazepine has the lowest one.Twenty-one(24%)patients with RE became seizure-free following ASM adjustment and 52 patients(18%)had breakthrough seizures after being classified as seizure-free.One patient developed RE after attaining seizure-free status.Breakthrough seizures during the first expected interictal interval(OR = 6.03,95% CI: 2.88-12.60),high seizure frequency at baseline(OR = 1.21,95% CI: 1.02-1.44)and younger age of onset(OR = 1.34,95% CI: 1.07-1.68)were risk factors for RE.The GAD-7 scores decrease after ASM treatment(p < 0.001).Older baseline age(B =-1.22,p <0.001),less education(B =-1.16,p <0.001)and definite etiology(B =-1.56,p = 0.001)are risk factors of lower scores of MOCA.Female gender(B = 1.93,p < 0.001)and less education(B = 0.62,p = 0.003)are risk factors of higher scores of GAD-7.Female gender(B = 1.00,p = 0.006),less education(B = 0.45,p = 0.014),high seizure frequency at baseline(B = 0.24,p = 0.044)and lower income(B = 1.22,p = 0.038)are risk factors of higher scores of c-NDDI-E.Significance: Treatment outcomes of the majority of NDE cases are good.To analyze the risk factors could help physicians more promptly and accurately identify patients who are likely to develop RE.Seizure-free state is not long enough to commence the withdrawal of ASMs.RE is not permanent and seizure-free may be achieved subsequently by appropriate drug adjustment.Part 2 Economic burden of adult newly diagnosed epilepsy in urban and rural areas in Jilin ProvinceObjective: To provide direct and indirect costs related to epilepsy in Jilin Province.Methods: Consecutive patients diagnosed with NDE in Jilin Province were included in the program and were divided into the urban group and the rural group.Direct and indirect costs were recorded prospectively and risk factors were analyzed.Result: A total of 371 patients(240 from the urban areas)were included and followed up for at least 12 months.The average annual total costs and direct costs were 4393.85 yuan and 3676.73 yuan in urban areas,and 5127.98 yuan and 3993.55 yuan in rural areas.The total and direct burdens were 12% and 9.4% in urban areas,and 28% and 209% in rural areas.The costs of the first investigation procedure were 3737.00 yuan and 3925.00 yuan in urban and rural areas,accounting for 12% and 21% of average annual family income.Rural residents(B = 0.10,p < 0.001),unemployment(B = 0.06,p = 0.007)and RE(B = 0.15,p < 0.001)were risk factors of higher direct burden.Unemployment(B=1.40,p <0.001)was the only risk factor of the higher total burden.Significance: Epilepsy lays a heavy burden on the people in Jilin Province,especially on the unemployed rural RE patients.Part 3 Alternation of intrinsic connectivity network in refractory epilepsyObjective: To analyze the intrinsic connectivity network(ICN)of conventional MRInegative RE patients.Methods: Fourteen conventional MRI-negative RE patients and 9 conventional MRI-negative SF patients were enrolled in the study.T1 weighted image(T1WI)and Echo Planar Imaging(EPI)were obtained and Mini-mental state examination(MMSE),GAD-7,c-NDDI-E and Edinburgh handness questionnaire were finished before the examination.Voxel-based morphometry(VBM),regional homogeneity(Re Ho),amplitude of low-frequency fluctuations (ALFF),and fractional ALFF(f ALFF)were compared between RE and SF patients.Independent Component Analysis was applied to extract the independent components for intranetwork and internetwork comparison.Results: The volume of grey matter of RE patients decreased in right precentral gyrus(Precentral＿R)(t = 4.92,p FDR-corr = 0.020),median cingulate and paracingulate gyri(Cingulum＿Mid＿L、Cingulum＿Mid＿R)(t = 4.84,p FDR-corr = 0.012),left supplementary motor area(Supp＿Motor＿Area＿L)(t = 7.64,p FDR-corr = 0.004)and right paracentral lobule(Paracentral＿Lobule＿R)(t = 5.99,p FDR-corr = 0.002)compared to SF patients.The Re Ho of RE patients decreased in right angular gyrus(Angular＿R)(t = 6.91,p FDR-corr = 0.001)and increased in left calcarine fissure and surrounding cortex(Calcarine＿L)(t = 4.44,p FDR-corr = 0.021)and right superior occipital gyrus(Occipital＿Sup＿R)(t = 6.31,p FDR-corr = 0.021).The f ALFF of RE patients increased in left calcarine fissure and surrounding cortex(Calcarine＿L)(t = 4.76,p FDR-corr = 0.049)and left middle occipital gyrus(Occipital＿Mid＿L)(t = 4.78,p FDR-corr = 0.040).Intranetwork connectivity decreased in ventral attention network(VAN)(t = 6.46,p FDR-corr = 0.015)and increased in vision network(VN)(t = 5.38,p FDR-corr = 0.002)in RE patients.Internetwork connectivity increased between posterior default network(p DMN)and sensorymotor network(SMN)(t = 3.249,puncorr = 0.005),executive-control network(ECN)and dorsal attention network(DAN)(t = 3.286,puncorr = 0.004),ECN-SMN(t = 4.303,puncorr < 0.001)in RE patients.Conclusion: Compared to SF patients,the right angular gyrus was attenuated and internetwork connectivity was strengthened to compensate for the impairment in RE patients.The alternation indicated the potential pathophysiological changes in RE.更多还原