癲癇會導致患者有患病和死亡的機會，而突然不明原因死亡的癲癇（SUDEP）的機制可能由於自律神經功能的障礙。自律神經系統（ANS）功能的紊亂和腦血流自動調節的失調有可能影響癲癇的預後。癲癇患者的自律神經功能和腦自動調節的更深入的了解，將有助於降低死亡率和發病率，並幫助釐清和處理癲癇。在這論文中，先評估未發作區間的癲癇患者與年齡、性別相符的健康志願者並測試一系列自律神經系統（ANS）功能，腦血流自動調節的參數，自律神經問卷和神經營養因子(腦源性神經營養因子（BDNF）和胰島素樣生長因子-1（IGF -1）)檢測以測試以下假說：（1）自律神經功能的紊亂，可以發生於癲癇患者並且不同亞型的癲癇患者可能會導致自律神經功能紊亂的嚴重程度不同（2）未發作區間的癲癇患者的腦血流自動調節有可能改變（3）神經營養因子在自律神經功能障礙的癲癇患者中是有扮演角色的。 107位的癲癇患者和76位的對照組參與自律神經系統功能測試：深呼吸，Valsalva動作（VM），傾斜床測試（HUT）和Q-汗液試驗，腦血流自動調節的測試是利用在作屏氣、Valsalva動作和傾斜床測試時經顱內都普勒超音波（TCD）測腦血流。自律神經功能嚴重程度評分（腎上腺素，cardiovagal，sudomtor和改進的複合式自律神經評分量表（mCASS））和腦血流自動調節參數（屏氣指數（BHI），在Valsalva動作第二階段自動調節指數計算：ASI和第四階段: AIIV 和在做傾斜床測試時測得並計算的腦血管阻力（CVR），相對性的腦血管阻力（AC ratio），自律神經問卷和神經營養因子進行了評估。結論是，相對於年齡和性別匹配的控制組參與者，未發作區間的癲癇患者有腎上腺素，cardiovagal，排汗功能類的自律神經障礙，並有腦血流自動調節上受損的情形。顳葉型的癲癇患者有更嚴重的自律神經功能障礙，並且是經由降低平均血壓來做腦血流自動調節。在癲癇患者，在傾斜床測試抬起的第二分鐘的腦血管阻力顯著減少，這種現象有可能導致腦血流速度在傾斜床測試的抬起後續時間的持續下降，而損害腦血流自動調節。自律神經功能紊亂的嚴重程度和腦血流自動調節的嚴重程度有相關性。癲癇患者的自律神經功能是被改變的，並且腦血流自動調節是失調的，而兩者是有交互作用的。而腦源性神經營養因子（BDNF）和胰島素樣生長因子-1（IGF -1）兩者藉由不同的機制來扮演在自律神經系統紊亂的癲癇患者上的角色。
關鍵詞: 癲癇，突然不明原因死亡的癲癇，自律神經系統，腦血流自動調節，腦源性神經營養因子（BDNF），胰島素樣生長因子-1（IGF -1），自律神經問卷

Epilepsy leads patients to morbidity and mortality. The mechanisms of sudden unexplained death in epilepsy (SUDEP) are likely involved autonomic disturbance. The disturbance of autonomic nervous system (ANS) functions and the disorganization of cerebral autoregulation may contribute to the diseases’ prognosis of epilepsy. Better understanding of the ANS function and cerebral autoregulation in patients with epilepsy would help reduce the mortality and morbidity and to localize, manage the epilepsy. In this work, we evaluate serial ANS functions, cerebral autoregulation parameters, questionnaire, neurotrophic factors (brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1)) measurement in patients with inter-ictal epilepsy and the age- and sex-matched health volunteers to test these three hypothesis: (1) Disturbance in ANS functions, can occur in patients with epilepsy and different subtypes of epilepsy may contribute to different severity of ANS dysfunction (2) Changes in cerebral autoregulation can be involved in the inter-ictal epileptic patients (3) Neurotrophic factors play roles on ANS dysfunction in patients with epilepsy. 107 patients and 76 control subjects were investigated with a battery of ANS function tests: deep breathing, Valsalva maneuver (VM), Head-up Tilting (HUT), Q-sweat test and underwent the breath-holding test and tests for the cerebral autoregulation during VM and HUT using transcranial doppler (TCD). The autonomic severity score (adrenergic, cardiovagal, sudomtor and Modified Composite Autonomic Scoring Scale (mCASS)) and the cerebral autoregulation parameters (breath-hold index (BHI), autoregulation index calculated in phase II and IV during VM, cerebrovascular resistance (CVR), relatively cerebrovascular resistance (AC ratio) during HUT), questionnaire, BDNF and IGF-1 levels were assessed. In conclusion, patients with epilepsy inter-ictally have adrenergic, cardiovagal, sudomotor dysfunctions and impaired cerebral autoregulation compared to the controls. The temporal lobe epilepsy has more severe ANS profiles involvement and impairs cerebral autoregulation by reducing mean blood pressure. Reduced the cerebrovascular resistance at the 2nd minute of tilt-up was significant in patients with epilepsy, it may lead the cerebral blood flow velocity to drop in the following time of tilt-up and impair the cerebral autoregulation. The severity of ANS dysfunction correlated to the severity of cerebral vasomotor reactivity and cerebral autoregulation. The altered ANS functions interacted with disorganized cerebral autoregulation in patients with epilepsy. Both BDNF and IGF-1 play roles on ANS dysfunction prediction with different mechanisms in epilepsy.
Keywords : epilepsy, SUDEP, autonomic nervous system, cerebral autoregulation, brain-derived neurotrophic factor (BDNF) , insulin-like growth factor-1 (IGF-1), autonomic questionnaire

論文審定書………………………………………………………………………………i
誌謝…………………………………………….………………………...………………ii
中文摘要……………………………………………..…….…………………….……...iii
英文摘要…………………………………………………………..………….…………iv
目錄……………………………………………………………………………………...v
圖次…………………………………………………………..……………….…………ix
表次…………………………………………………………..………………….……….x
第一章 內容簡介Introduction…………….…………………………………………....1
第二章 核心推論 Central Hypothesis………………………………………………...4
第三章 研究對象和實驗方法 Patients and Methodology………….……………... .5
3.1 Participants………………………………………………………………...…..... .5
3.2 ANS measurement……………………………………………………………......5
3.2.1 Heart Rate response to deep breathing (HRDB) …………………..……6
3.2.2 The Valsalva ratio (VR) …………………………………………………... 7
3.3.3 Beat-to-beat BP measurements to the Valsalva maneuver………..…. 7
3.3.4 Orthostatic BP and HR response to head-up tilt (HUT) ………………...7
3.3.5 Q-sweat: sweat output at one upper and three lower limb sites…….... 8
3.3 Cerebral autoregulation measurement……………………………………...…....8
3.3.1 Breath Holding Index (BHI) ……………………………………….…….....9
3.3.2 Cerebral autoregulation evaluation by the Valsalva maneuver………....9
3.3.3 HUT Testing With TCD…………………………………………...….….....10
3.4 Serum BDNF and IGF-1 Measurement…………………………………..……....11
3.5 Autonomic Questionnaire………………………………..…………………….......11
3.6 Statistics……………………………………………………………………….........12
第四章 探討癲癇病人的自律神經系統功能的異常 The autonomic dysfunction in patients with epilepsy……………………………………………………………….......................…13
4.1 The Autonomic Nervous System and Epilepsy…………………………..... …..13
4.2 Material and Methods………………………………..…………......……….….....14
4.3 Results…………………………………………………………………….........…...14
4.4 Discussion………………………………………….…………………….........……17
4.4.1 The autonomic function and Epilepsy…………….………………......……17
4.4.2 Different types of epilepsy affect the autonomic functions…….......……18
4.5 Conclusion………………………………..………………………………............…19
第五章 探討癲癇病人腦血流自動調節的異常 The impaired cerebral autoregulation in patients with epielpsy………………………………………………..……………......……..………….20
5.1 The cerebral autoregulation and epilepsy......................................................20
5.2 Material and Methods………………………………..……………...………...........21
5.3 Results……………………………………………………………..…………............21
5.4 Discussion………………………………..………………………………….............32
5.4.1 The cerebral autoregulation and Epilepsy…………………………........…..32
5.4.2 Different types of epilepsy affect the cerebral autoregulation…….....…....34
5.4.3 The relationship between the autonomic function and cerebral autoregulation…………………..………………………………….......................................................................…..35
5.5 Conclusion………………………………..……………...………………............…..36
第六章 神經營養因子在自律神經功能障礙的癲癇患者中的角色The role of neurotrophic factors on autonomic dysfunction in patients with epilepsy…..………...................................…..............................37
6.1 The relationship among neurotrophic factors, autonomic function and epilepsy………………………………………………………………………...................37
6.2 Material and Methods………………………………..……………...………............38
6.3 Results………………………………..……………...……………………............….38
6.3.1 Clinical data.......................................................................................38
6.3.2 Autonomic Functions and Cerbral Autoregulation…………………….........39
6.3.3 BDNF and IGF-1 levels……………………………………………...........…..41
6.4 Discussion………………………………………………………………................….44
6.4.1 Decreased serum BDNF levels in patients with epilepsy…………......……44
6.4.2 Decreased serum BDNF levels at autonomic dysfunction in patients with epilepsy………………………………………………………..…...................................45
6.4.3 Decreased serum IGF-1 in patients with epilepsy…………………..…........46
6.4.4 Decreased serum IGF-1 levels at autonomic dysfunction in patients with
epilepsy……………………………………………………………..............................….47
6.4.5 Decreased serum IGF-1 levels at impaired cerebral autoregulation in
patients with epilepsy…………………………………………............................……….47
6.5 Conclusion……………………………………………………………................………48
第七章 探討癲癇病患者的泌汗功能The sudomotor function in patients with epilepsy..…………………………………………………………………….................................….49
7.1 The sudomotor function and epilepsy…………..……………...........…………….…49
7.2 Material and Methods……………………………………………….……..………........50
7.3 Results..........................................................................................................50
7.4 Discussion………………………………………………………………….................…57
7.5 Conclusion………………………………………………………………….................…57
第八章 利用癲癇模式檢驗自律神經中文問卷 Correlation the Chinese Autonomic Symptom Questionnaire using Epilepsy………………………………………………....................................................58
8.1 The Autonomic symptom Questionnaire and epilepsy……............…………………58
8.2 Material and Methods….......…………………………………………...............………58
8.3 results.............................................................................................................59
8.4 Discussion.......................................................................................................63
8.5 Conclusion.......................................................................................................64
第九章 討論 Discussion ………………………………..…………...................................65
9.1 The Autonomic Function and epilepsy..………………………………...............……..65
9.2 The cerebral autoregulation and epilepsy……………………………..............……….65
9.3 The BDNF, ICGF-1 and epilepsy………………………………………................…….67
9.4 The sudomotor function and epilepsy…………………………………….................…68
9.5 The autonomic questionnaire and epilepsy..........................................................68
第十章 結論 Conclusion ………………………………..…………...................................69
第十一章 研究限制和未來研究方向Limitation and Future Research.……......……………70
11.1 Limitations………………………………………………………………….....................70
11.2 Future Research………………………………………………………….................…..71
參考文獻………………………………...........................………………………........……..72
附 錄………………………………...........................……………………….…..................78
附錄 1 英文縮寫全文……………………...…………………………..................................78
附錄 2 Modefied Composite Autonomic Scoring Scale (mCASS) …....................……79
附錄 3 自律神經問卷……………………………………………………………...................80
附錄 4 Paper 1: BMC Neuroscience 2012 Jun 8;13:62..........................….................84
附錄 5 Paper 2: BMC Neurology 2011 May 31;11:63…….........................................92

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