研究目的: 癲癇病患在臨床上會有日間嗜睡、睡眠障礙或智能行為的改變，這些現象被觀察到與癲癇特徵 (如發病年齡，藥物治療種類與劑量，發作頻率)，癲癇共病症，基因或是大腦結構網絡改變相關。過去研究指出血液中生化指標，可以反映癲癇發作的強度，然而，這些指標是否可以預測慢性癲癇病患在神經行為的表現，則仍待確定。此研究目的有二: (一) 了解門診癲癇病患之睡眠抱怨與日間嗜睡的關係; (二) 了解顳葉癲癇病患血液中生化指標與神經行為量表的分數或大腦結構改變之相關性。

研究方法: 此研究對象為門診追蹤之癲癇病患，使用制式睡眠問卷量表(匹茲堡睡眠品質量表、愛普渥斯嗜睡度量表、歐洲生活品質測量)探討睡眠障礙的特性、嚴重度與生活滿意度，並探討與癲癇特徵的相關性。在診斷顳葉癲癇之病患，收集神經行為量表的分數與測量血液中生化指標(包含熱休克蛋白70、S100β蛋白、神經原特異烯醇脢、腦衍生神經滋養因子、血漿與粒線體DNA)，大腦核磁共振影像資料，在分析上，與同齡受試者比較，或彼此之間做相關性分析。

結果: 共117位病患完成睡眠問卷量表，分析顯示有20%病患有日間嗜睡的情形，其夜間睡眠障礙主要為入睡困難與睡眠效度差，在癲癇特徵分析上與部分發作癲癇，頑固型癲癇或使用多項抗癲癇藥物相關。共34位病患完成神經行為量表評估、血液生化指標與大腦核磁共振影像掃描。病患有較高的熱休克蛋白70、S100β蛋白，而在每月癲癇超過2次的病患，在熱休克蛋白70、S100β蛋白、神經原特異烯醇脢則有明顯上升。與對照組相比，病患大腦萎縮部分包含海馬迴與周圍顳葉組織，豆狀核，視丘與運動輔助區。在相關性分析上，病患之熱休克蛋白70濃度會跟海馬迴的萎縮程度相關。

結論: 此研究顯示癲癇特徵、血液中生化指標以及大腦萎縮部分與癲癇病患日間嗜睡，夜間睡眠障礙與智能行為的改變相關。

Purpose: Excessive day time sleepiness, sleep disorders and neurobehavior changes are common clinical observations in the patients with epilepsy. From literature review, they were highly related with epilepsy risk characteristics (age of onset, types or numbers of drugs, seizure frequency), co-morbidities or neuronal network changes. The serological biomarkers have been reported to reflect the phenomenon of seizure, while their correlations with neurobehavior changes were still not concluded. There were two purposes of this thesis. (1) To understand the relationship between sleep disturbance with day time performances (2) To understand the relationships between serological biomarkers, neurobehavior performances and neuronal networks in patients with temporal lobe epilepsy.

Material and Methods: The study enrolled patients from epilepsy outpatient clinic. By using self-appreciated questionnaire (The Pittsburgh Sleep Quality Index, The Epworth Sleepiness Scale, Euroqol Quality of Life Scale-5D), we collected the characteristics of sleep related behavior and life quality changes and explored the relationship with epilepsy risk characteristics. In patients with temporal lobe epilepsy, we assessed the neurobehavior performances, measured the serological biomarkers (heat shock protein 70, S100βprotein, neuron specific enolase, brain derived neurotrophic factor, plasma and mitochondrial DNA) and brain magnetic resonance imaging. In statistical analysis, we compared the differences with age matched controls or performed correlation analysis among the parameters

Result: One hundred and seventeen patients with epilepsy completed the sleep quality questionnaires. The results showed that 20 percent of patients had day time sleepiness, while the sleep disorder was prolong sleep latency and impaired sleep efficiency. In epilepsy characteristics, patients with complex partial seizure, intractable seizure or with multi-pharmacy were related with poor sleep quality. A total of 34 patients completed the serological, neurobehavior and brain magnetic resonance analysis. The results showed that patients with temporal lobe epilepsy had higher heat shock protein 70 and S100βprotein levels, while those with attacks more than twice per month had significant higher heat shock protein 70, S100βprotein and neuron specific enolase levels. Compared with the matched controls, the regions showing atrophy included hippocampus and parahippocampus, putamen, thalamus and supplementary motor areas. In correlation study, only heat shock protein 70 showed an inverse correlation with hippocampal volume (R square = 0.22, p = 0.007) after controlling for the effect of age.

Conclusion: The study suggested that epilepsy risk characteristics, serological biomarkers, brain atrophic regions were important factors for day time sleepiness, sleep disturbances and neurobehavior changes in patients with epilepsy.

論文審定書…………………………………………………………… i
Dedication…………………………………………………………ii
誌謝………………………………………………………………...… iii
中文摘要……………………………………………………………vi
英文摘要…………………………………………………………. vii

第一章Introduction and study design………………………............. 1
1.1 Temporal lobe epilepsy………………………………….…......... 1
1.2 Sleep disorder in epilepsy…………….…………….………........ 1
1.3 Select proper serological biomarker can extend the diagnostic repertoire……….…………….………………………………..…. 2
1.4 Gray matter atrophy in temporal lobe epilepsy………………..… 3
1.5 White matter damage in temporal lobe epilepsy…………….……3
1.6 Study design.…….…….….………………………..................4
第 二 章 Literature review in relation to the study rationale …...….…..7
2.1 Prognostic factors of epilepsy….….……….….…...…….….……7
2.2 Heat shock protein with neuronal damages ….….…….…………8
2.3 Neuron-Specific Enolase with epilepsy ….….………...…………9
2.4 S-100 ß Protein with blood brain barrier damages…....…………10
2.5 Plasma nuclear and mitochondrial DNA…............…….….…… 12
2.6 Cognitive performance in patients with temporal lobe epilepsy... 12
2.7 Rationales for using brain magnetic resonance imaging including diffusion tensor imaging, three-dimensional T1 images and cognitive tests as outcome measures ........................................ 13
第三章 Material and methods….….……….….……….……...……..…15
3.1 Participants….….……….….……….….……….….………....... 15
3.1.1 Study design.……….….……….….………………..……. 15
3.1.2 Patient Enrolment…….….……….….……….….……...... 15
3.1.2.1 Patients with epilepsy….….……….….……….…........15
3.1.2.2 Patients with temporal lobe epilepsy….……….............16
3.2 Clinical assessments….….….….….….….….….…..………….. 18
3.2.1 Clinical demographic registration…..…...………..…….… 18
3.2.2 Sleep quality questionnaire….….…....….….….………..… 18
3.2.3 Neuropsychological evaluation….….….….………..…...... 19
3.3 Methods for serological biomarkers….….….….….….…..…… 20
3.4 Plasma nuclear and mitochondrial DNA analysis............…….... 22
3.5 Brain magnetic resonance imaging ….….….….….………........ 22
3.5.1 Imaging acquisition….….….….….….…………………. 22
3.5.2 Data pre-processing….….….….….….….…….…….....… 26
3.5.3 Diffusion-tensor imaging analysis using tract based spatial statistic…………………………………....................…………… 26
3.5.4 Gray matter atrophy using voxel-based morphometry…... 30
3.6 Statistical Analysis….......….….….…….……….……….. 31
3.6.1 Biomarkers and cognitive tests statistics….….….….……. 31
3.6.2 Sleep quality data statistics….….….….……………….… 32
3.6.3 Voxel-based morphometry statistics….…...……………… 33
3.6.4 White matter damage statistics….….….……………....…. 33
3.6.5 Correlation with Neuropsychological Tests ….……..….... 35
第 四 章Results-Excessive daytime sleepiness and poor sleep quality in patient with epilepsy….….….….….….…………………............… 36
4.1 Characteristics and demographic data of the subjects....... 36
4.2 Study questionnaire comparisons..................................36
4.3 Risk factors for poor sleep quality in patients with epilepsy........37
第 五 章 Results - serological biomarkers, brain networks and neuropsychological performances in patients with temporal lobe epilepsy….….….….….……………………………....………48
5.1 Demographic data and clinical characteristics of the patients and control ........................................................................................45
5. 2 Biomarkers and cognitive tests................................................... 45
5.3 Correlation study between biomarkers with cognitive tests.......................................................................................... 46
5.4 Gray matter atrophy and regional variability.................. 47
5.5 Clinical characteristics, biomarkers and neuropsychological tests results between Group 1 and 2.......................................... 48
5.6 Changes in fractional anisotropy, mean, axial and radial diffusivity.......................................................................................... 48
第六章Discussion and Conclusion ......................................................... 59
6.1 Discussion.....................................................................................59
6.2 Conclusion.....................................................................................66
第七章 Technical considerations and possible limitation........................68
第八章Future direction….….….….….….….………....…………….… 77
8.1 Functional connectivity of brain….….….…..…….….……….. 77
8.2 Acquisition protocols and data analysis.….….….….….…….…78
8.3 Improvement of structural analysis technique.…..….….……… 78
8.3.1 tractography method using the diffusion tensor imaging… 78
8.3.2 Using Tractography methods to construct whole brain tracking…………….………………….………………..… 78
參考文獻…………………………………………………..….….….…80
附錄………………………………………………………….….…...…. 94
匹茲堡睡眠品質量表
愛普渥斯嗜睡度量
歐洲生活品質測量
Abstract for sleep quality assessment in patients with epilepsy
Abstract for serological biomarkers in patients with temporal lobe epilepsy
Sleep Quality and Daytime Sleepiness in Patients with Epilepsy
Clinical significance of serological biomarkers and neuropsychological performances in patients with temporal lobe epilepsy

[1]. Engel J, Jr.: A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on Classification and Terminology. Epilepsia. 2001; 42: 796-803.
[2]. Engel J, Jr.: Report of the ILAE classification core group. Epilepsia. 2006; 47: 1558-1568.
[3]. Andersson-Roswall L, Engman E, Samuelsson H, Malmgren K: Cognitive outcome 10 years after temporal lobe epilepsy surgery: a prospective controlled study. Neurology. 74: 1977-1985.
[4]. Baxendale S, Heaney D, Thompson PJ, Duncan JS: Cognitive consequences of childhood-onset temporal lobe epilepsy across the adult lifespan. Neurology. 75: 705-711.
[5]. The international classification of sleep disorders, revised: Diagnostic and coding manual. In: Byusse D.J., ed. Chicago: American Academy of Sleep Medicine, 2001.
[6]. Maganti R, Hausman N, Koehn M, Sandok E, Glurich I, Mukesh BN: Excessive daytime sleepiness and sleep complaints among children with epilepsy. Epilepsy Behav. 2006; 8: 272-277.
[7]. Piperidou C, Karlovasitou A, Triantafyllou N, et al.: Influence of sleep disturbance on quality of life of patients with epilepsy. Seizure. 2008; 17: 588-594.
[8]. de Weerd A, de Haas S, Otte A, et al.: Subjective sleep disturbance in patients with partial epilepsy: a questionnaire-based study on prevalence and impact on quality of life. Epilepsia. 2004; 45: 1397-1404.
[9]. Foldvary-Schaefer N: Sleep complaints and epilepsy: the role of seizures, antiepileptic drugs and sleep disorders. J Clin Neurophysiol. 2002; 19: 514-521.
[10]. Foldvary N: Sleep and Epilepsy. Curr Treat Options Neurol. 2002; 4: 129-135.
[11]. Crespel A, Baldy-Moulinier M, Coubes P: The relationship between sleep and epilepsy in frontal and temporal lobe epilepsies: practical and physiopathologic considerations. Epilepsia. 1998; 39: 150-157.
[12]. Drake ME, Jr., Pakalnis A, Bogner JE, Andrews JM: Outpatient sleep recording during antiepileptic drug monotherapy. Clin Electroencephalogr. 1990; 21: 170-173.
[13]. Ryvlin P, Rheims S, Risse G: Nocturnal frontal lobe epilepsy. Epilepsia. 2006; 47 Suppl 2: 83-86.
[14]. Placidi F, Scalise A, Marciani MG, Romigi A, Diomedi M, Gigli GL: Effect of antiepileptic drugs on sleep. Clin Neurophysiol. 2000; 111 Suppl 2: S115-119.
[15]. Lu C, Li J, Sun W, et al.: Elevated plasma S100B concentration is associated with mesial temporal lobe epilepsy in Han Chinese: a case-control study. Neurosci Lett. 2010; 484: 139-142.
[16]. Griffin WS, Yeralan O, Sheng JG, et al.: Overexpression of the neurotrophic cytokine S100 beta in human temporal lobe epilepsy. J Neurochem. 1995; 65: 228-233.
[17]. Palmio J, Keranen T, Alapirtti T, et al.: Elevated serum neuron-specific enolase in patients with temporal lobe epilepsy: a video-EEG study. Epilepsy Res. 2008; 81: 155-160.
[18]. Ryufuku M, Toyoshima Y, Kitaura H, et al.: Hypertrophy of hippocampal end folium neurons in patients with mesial temporal lobe epilepsy. Neuropathology.
[19]. Hashimoto K, Watanabe K, Nishimura T, Iyo M, Shirayama Y, Minabe Y: Behavioral changes and expression of heat shock protein hsp-70 mRNA, brain-derived neurotrophic factor mRNA, and cyclooxygenase-2 mRNA in rat brain following seizures induced by systemic administration of kainic acid. Brain Res. 1998; 804: 212-223.
[20]. Yang T, Hsu C, Liao W, Chuang JS: Heat shock protein 70 expression in epilepsy suggests stress rather than protection. Acta Neuropathol. 2008; 115: 219-230.
[21]. Chang CC, Chang WN, Lui CC, et al.: Longitudinal study of carbon monoxide intoxication by diffusion tensor imaging with neuropsychiatric correlation. J Psychiatry Neurosci. 2010; 35: 115-125.
[22]. Tsai NW, Lin TK, Chen SD, et al.: The value of serial plasma nuclear and mitochondrial DNA levels in patients with acute ischemic stroke. Clin Chim Acta. 2011; 412: 476-479.
[23]. Cavanagh JB, Meyer A: Aetiological aspects of Ammon's horn sclerosis associated with temporal lobe epilepsy. Br Med J. 1956; 2: 1403-1407.
[24]. Fujikawa DG, Itabashi HH, Wu A, Shinmei SS: Status epilepticus-induced neuronal loss in humans without systemic complications or epilepsy. Epilepsia. 2000; 41: 981-991.
[25]. Keller SS, Roberts N: Voxel-based morphometry of temporal lobe epilepsy: an introduction and review of the literature. Epilepsia. 2008; 49: 741-757.
[26]. Le Bihan D: Looking into the functional architecture of the brain with diffusion MRI. Nat Rev Neurosci. 2003; 4: 469-480.
[27]. Smith SM, Jenkinson M, Johansen-Berg H, et al.: Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage. 2006; 31: 1487-1505.
[28]. Pierpaoli C, Basser PJ: Toward a quantitative assessment of diffusion anisotropy. Magn Reson Med. 1996; 36: 893-906.
[29]. ILAE Commission Report. The epidemiology of the epilepsies: future directions. International League Against Epilepsy. Epilepsia. 1997; 38: 614-618.
[30]. Forsgren L, Beghi E, Oun A, Sillanpaa M: The epidemiology of epilepsy in Europe - a systematic review. Eur J Neurol. 2005; 12: 245-253.
[31]. Chen CC, Chen TF, Hwang YC, et al.: Population-based survey on prevalence of adult patients with epilepsy in Taiwan (Keelung community-based integrated screening no. 12). Epilepsy Res. 2006; 72: 67-74.
[32]. Gastaut H: Classification of status epilepticus. Adv Neurol. 1983; 34: 15-35.
[33]. DeLorenzo RJ, Hauser WA, Towne AR, et al.: A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia. Neurology. 1996; 46: 1029-1035.
[34]. Logroscino G, Hesdorffer DC, Cascino G, Annegers JF, Hauser WA: Short-term mortality after a first episode of status epilepticus. Epilepsia. 1997; 38: 1344-1349.
[35]. Coeytaux A, Jallon P, Galobardes B, Morabia A: Incidence of status epilepticus in French-speaking Switzerland: (EPISTAR). Neurology. 2000; 55: 693-697.
[36]. Knake S, Rosenow F, Vescovi M, et al.: Incidence of status epilepticus in adults in Germany: a prospective, population-based study. Epilepsia. 2001; 42: 714-718.
[37]. Rossetti AO, Hurwitz S, Logroscino G, Bromfield EB: Prognosis of status epilepticus: role of aetiology, age, and consciousness impairment at presentation. J Neurol Neurosurg Psychiatry. 2006; 77: 611-615.
[38]. Franklin TB, Krueger-Naug AM, Clarke DB, Arrigo AP, Currie RW: The role of heat shock proteins Hsp70 and Hsp27 in cellular protection of the central nervous system. Int J Hyperthermia. 2005; 21: 379-392.
[39]. Henshall DC, Murphy BM: Modulators of neuronal cell death in epilepsy. Curr Opin Pharmacol. 2008; 8: 75-81.
[40]. Lindquist S: The heat-shock response. Annu Rev Biochem. 1986; 55: 1151-1191.
[41]. Yost HJ, Petersen RB, Lindquist S: RNA metabolism: strategies for regulation in the heat shock response. Trends Genet. 1990; 6: 223-227.
[42]. Lively S, Brown IR: Extracellular matrix protein SC1/hevin in the hippocampus following pilocarpine-induced status epilepticus. J Neurochem. 2008; 107: 1335-1346.
[43]. Sharp FR, Kinouchi H, Koistinaho J, Chan PH, Sagar SM: HSP70 heat shock gene regulation during ischemia. Stroke. 1993; 24: I72-75.
[44]. Vass K, Berger ML, Nowak TS, Jr., Welch WJ, Lassmann H: Induction of stress protein HSP70 in nerve cells after status epilepticus in the rat. Neurosci Lett. 1989; 100: 259-264.
[45]. Thom M, Seetah S, Sisodiya S, Koepp M, Scaravilli F: Sudden and unexpected death in epilepsy (SUDEP): evidence of acute neuronal injury using HSP-70 and c-Jun immunohistochemistry. Neuropathol Appl Neurobiol. 2003; 29: 132-143.
[46]. Schreiber SS, Sun N, Tocco G, Baudry M, DeGiorgio CM: Expression of neuron-specific enolase in adult rat brain following status epilepticus. Exp Neurol. 1999; 159: 329-331.
[47]. Sankar R, Shin DH, Wasterlain CG: Serum neuron-specific enolase is a marker for neuronal damage following status epilepticus in the rat. Epilepsy Res. 1997; 28: 129-136.
[48]. DeGiorgio CM, Correale JD, Gott PS, et al.: Serum neuron-specific enolase in human status epilepticus. Neurology. 1995; 45: 1134-1137.
[49]. DeGiorgio CM, Heck CN, Rabinowicz AL, Gott PS, Smith T, Correale J: Serum neuron-specific enolase in the major subtypes of status epilepticus. Neurology. 1999; 52: 746-749.
[50]. Hasegawa D, Orima H, Fujita M, Hashizume K, Tanaka T: Complex partial status epilepticus induced by a microinjection of kainic acid into unilateral amygdala in dogs and its brain damage. Brain Res. 2002; 955: 174-182.
[51]. Rabinowicz AL, Correale JD, Bracht KA, Smith TD, DeGiorgio CM: Neuron-specific enolase is increased after nonconvulsive status epilepticus. Epilepsia. 1995; 36: 475-479.
[52]. Marshak DR: S100 beta as a neurotrophic factor. Prog Brain Res. 1990; 86: 169-181.
[53]. Kapural M, Krizanac-Bengez L, Barnett G, et al.: Serum S-100beta as a possible marker of blood-brain barrier disruption. Brain Res. 2002; 940: 102-104.
[54]. Steinhoff BJ, Tumani H, Otto M, et al.: Cisternal S100 protein and neuron-specific enolase are elevated and site-specific markers in intractable temporal lobe epilepsy. Epilepsy Res. 1999; 36: 75-82.
[55]. Otto M, Wiltfang J, Mogge S: Changing levels of S100 protein in serum after epileptic seizures.
. Epilepsia. 1998; 39: 73.
[56]. Leutmezer F, Wagner O, Baumgartner C: Serum s-100 protein is not a suitable seizure marker in temporal lobe epilepsy. Epilepsia. 2002; 43: 1172-1174.
[57]. Buttner T, Lack B, Jager M, et al.: Serum levels of neuron-specific enolase and s-100 protein after single tonic-clonic seizures. J Neurol. 1999; 246: 459-461.
[58]. Palmio J, Peltola J, Vuorinen P, Laine S, Suhonen J, Keranen T: Normal CSF neuron-specific enolase and S-100 protein levels in patients with recent non-complicated tonic-clonic seizures. J Neurol Sci. 2001; 183: 27-31.
[59]. Fournie GJ, Martres F, Pourrat JP, Alary C, Rumeau M: Plasma DNA as cell death marker in elderly patients. Gerontology. 1993; 39: 215-221.
[60]. Lu CH, Chang WN, Tsai NW, Chuang YC, Huang CR, Wang HC: The value of serial plasma nuclear and mitochondrial DNA levels in adult community-acquired bacterial meningitis. QJM. 2010; 103: 169-175.
[61]. Hermann BP, Seidenberg M, Schoenfeld J, Davies K: Neuropsychological characteristics of the syndrome of mesial temporal lobe epilepsy. Arch Neurol. 1997; 54: 369-376.
[62]. Oyegbile TO, Dow C, Jones J, et al.: The nature and course of neuropsychological morbidity in chronic temporal lobe epilepsy. Neurology. 2004; 62: 1736-1742.
[63]. Natsume J, Bernasconi N, Andermann F, Bernasconi A: MRI volumetry of the thalamus in temporal, extratemporal, and idiopathic generalized epilepsy. Neurology. 2003; 60: 1296-1300.
[64]. Chang CC, Lui CC, Lee CC, et al.: Clinical significance of serological biomarkers and neuropsychological performances in patients with temporal lobe epilepsy. BMC Neurol. 2012; 12: 15.
[65]. Rausch R, Henry TR, Ary CM, Engel J, Jr., Mazziotta J: Asymmetric interictal glucose hypometabolism and cognitive performance in epileptic patients. Arch Neurol. 1994; 51: 139-144.
[66]. Igarashi K, Oguni H, Osawa M, et al.: Wisconsin card sorting test in children with temporal lobe epilepsy. Brain Dev. 2002; 24: 174-178.
[67]. Keller SS, Mackay CE, Barrick TR, Wieshmann UC, Howard MA, Roberts N: Voxel-based morphometric comparison of hippocampal and extrahippocampal abnormalities in patients with left and right hippocampal atrophy. Neuroimage. 2002; 16: 23-31.
[68]. Keller SS, Baker G, Downes JJ, Roberts N: Quantitative MRI of the prefrontal cortex and executive function in patients with temporal lobe epilepsy. Epilepsy Behav. 2009; 15: 186-195.
[69]. Riley JD, Moore S, Cramer SC, Lin JJ: Caudate atrophy and impaired frontostriatal connections are linked to executive dysfunction in temporal lobe epilepsy. Epilepsy Behav. 2011; 21: 80-87.
[70]. Ringman JM, O'Neill J, Geschwind D, et al.: Diffusion tensor imaging in preclinical and presymptomatic carriers of familial Alzheimer's disease mutations. Brain. 2007; 130: 1767-1776.
[71]. Basser PJ, Pierpaoli C: Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI. Journal of Magnetic Resonance-Series B. 1996; 111: 209-219.
[72]. Sykova E: Diffusion properties of the brain in health and disease. Neurochem Int. 2004; 45: 453-466.
[73]. Rorschach HE, Lin C, Hazlewood CF: Diffusion of water in biological tissues. Scanning Microsc Suppl. 1991; 5: S1-10.
[74]. Kraus MF, Susmaras T, Caughlin BP, Walker CJ, Sweeney JA, Little DM: White matter integrity and cognition in chronic traumatic brain injury: a diffusion tensor imaging study. Brain. 2007; 130: 2508-2519.
[75]. Tan TY, Lu CH, Chuang HY, et al.: Long-term antiepileptic drug therapy contributes to the acceleration of atherosclerosis. Epilepsia. 2009; 50: 1579-1586.
[76]. Kwan P, Arzimanoglou A, Berg AT, et al.: Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010; 51: 1069-1077.
[77]. Rabin R, de Charro F: EQ-5D: a measure of health status from the EuroQol Group. Ann Med. 2001; 33: 337-343.
[78]. Johns MW: A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991; 14: 540-545.
[79]. Buysse DJ, Hall ML, Strollo PJ, et al.: Relationships between the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and clinical/polysomnographic measures in a community sample. J Clin Sleep Med. 2008; 4: 563-571.
[80]. Knutson KL, Rathouz PJ, Yan LL, Liu K, Lauderdale DS: Stability of the Pittsburgh Sleep Quality Index and the Epworth Sleepiness Questionnaires over 1 year in early middle-aged adults: the CARDIA study. Sleep. 2006; 29: 1503-1506.
[81]. Chang CC, Chang YY, Chang WN, et al.: Cognitive deficits in multiple system atrophy correlate with frontal atrophy and disease duration. Eur J Neurol. 2009; 16: 1144-1150.
[82]. Chang CC, Lee YC, Chang WN, et al.: Damage of white matter tract correlated with neuropsychological deficits in carbon monoxide intoxication after hyperbaric oxygen therapy. J Neurotrauma. 2009; 26: 1263-1270.
[83]. Chang CC, Kramer JH, Lin KN, et al.: Validating the Chinese version of the Verbal Learning Test for screening Alzheimer's disease. J Int Neuropsychol Soc. 2010; 16: 244-251.
[84]. Lo YM, Tein MS, Lau TK, et al.: Quantitative analysis of fetal DNA in maternal plasma and serum: implications for noninvasive prenatal diagnosis. Am J Hum Genet. 1998; 62: 768-775.
[85]. Chiu RW, Chan LY, Lam NY, et al.: Quantitative analysis of circulating mitochondrial DNA in plasma. Clin Chem. 2003; 49: 719-726.
[86]. Good CD, Johnsrude IS, Ashburner J, Henson RN, Friston KJ, Frackowiak RS: A voxel-based morphometric study of ageing in 465 normal adult human brains. Neuroimage. 2001; 14: 21-36.
[87]. Ashburner J, Friston KJ: Voxel-based morphometry--the methods. Neuroimage. 2000; 11: 805-821.
[88]. Rueckert D, Sonoda LI, Hayes C, Hill DL, Leach MO, Hawkes DJ: Nonrigid registration using free-form deformations: application to breast MR images. IEEE Trans Med Imaging. 1999; 18: 712-721.
[89]. Nichols TE, Holmes AP: Nonparametric permutation tests for functional neuroimaging: a primer with examples. Hum Brain Mapp. 2002; 15: 1-25.
[90]. Wakana S, Jiang H, Nagae-Poetscher LM, van Zijl PC, Mori S: Fiber tract-based atlas of human white matter anatomy. Radiology. 2004; 230: 77-87.
[91]. Vignatelli L, Bisulli F, Naldi I, et al.: Excessive daytime sleepiness and subjective sleep quality in patients with nocturnal frontal lobe epilepsy: a case-control study. Epilepsia. 2006; 47 Suppl 5: 73-77.
[92]. Malow BA, Bowes RJ, Lin X: Predictors of sleepiness in epilepsy patients. Sleep. 1997; 20: 1105-1110.
[93]. Weatherwax KJ, Lin X, Marzec ML, Malow BA: Obstructive sleep apnea in epilepsy patients: the Sleep Apnea scale of the Sleep Disorders Questionnaire (SA-SDQ) is a useful screening instrument for obstructive sleep apnea in a disease-specific population. Sleep Med. 2003; 4: 517-521.
[94]. Manni R, Terzaghi M, Arbasino C, Sartori I, Galimberti CA, Tartara A: Obstructive sleep apnea in a clinical series of adult epilepsy patients: frequency and features of the comorbidity. Epilepsia. 2003; 44: 836-840.
[95]. Khatami R, Zutter D, Siegel A, Mathis J, Donati F, Bassetti CL: Sleep-wake habits and disorders in a series of 100 adult epilepsy patients--a prospective study. Seizure. 2006; 15: 299-306.
[96]. Macey PM, Woo MA, Kumar R, Cross RL, Harper RM: Relationship between obstructive sleep apnea severity and sleep, depression and anxiety symptoms in newly-diagnosed patients. PLoS One. 2010; 5: e10211.
[97]. Comella CL: Sleep disturbances and excessive daytime sleepiness in Parkinson disease: an overview. J Neural Transm Suppl. 2006: 349-355.
[98]. Kotagal P, Yardi N: The relationship between sleep and epilepsy. Semin Pediatr Neurol. 2008; 15: 42-49.
[99]. Boddy F, Rowan EN, Lett D, O'Brien JT, McKeith IG, Burn DJ: Subjectively reported sleep quality and excessive daytime somnolence in Parkinson's disease with and without dementia, dementia with Lewy bodies and Alzheimer's disease. Int J Geriatr Psychiatry. 2007; 22: 529-535.
[100]. Seidel S, Hartl T, Weber M, et al.: Quality of sleep, fatigue and daytime sleepiness in migraine - a controlled study. Cephalalgia. 2009; 29: 662-669.
[101]. Zucconi M, Oldani A, Smirne S, Ferini-Strambi L: The macrostructure and microstructure of sleep in patients with autosomal dominant nocturnal frontal lobe epilepsy. J Clin Neurophysiol. 2000; 17: 77-86.
[102]. Sammaritano M, Gigli GL, Gotman J: Interictal spiking during wakefulness and sleep and the localization of foci in temporal lobe epilepsy. Neurology. 1991; 41: 290-297.
[103]. Bell C, Vanderlinden H, Hiersemenzel R, Otoul C, Nutt D, Wilson S: The effects of levetiracetam on objective and subjective sleep parameters in healthy volunteers and patients with partial epilepsy. J Sleep Res. 2002; 11: 255-263.
[104]. Ramsay RE, Wilder BJ, Berger JR, Bruni J: A double-blind study comparing carbamazepine with phenytoin as initial seizure therapy in adults. Neurology. 1983; 33: 904-910.
[105]. Theodore WH, Porter RJ: Removal of sedative-hypnotic antiepileptic drugs from the regimens of patients with intractable epilepsy. Ann Neurol. 1983; 13: 320-324.
[106]. Declerck AC, Wauquier A: Influence of antiepileptic drugs on sleep patterns. Epilepsy Res Suppl. 1991; 2: 153-163.
[107]. Legros B, Bazil CW: Effects of antiepileptic drugs on sleep architecture: a pilot study. Sleep Med. 2003; 4: 51-55.
[108]. Lanneau D, Wettstein G, Bonniaud P, Garrido C: Heat shock proteins: cell protection through protein triage. ScientificWorldJournal. 2010; 10: 1543-1552.
[109]. Chen DK, So YT, Fisher RS: Use of serum prolactin in diagnosing epileptic seizures: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2005; 65: 668-675.
[110]. Ayala GX, Tapia R: HSP70 expression protects against hippocampal neurodegeneration induced by endogenous glutamate in vivo. Neuropharmacology. 2008; 55: 1383-1390.
[111]. Ryufuku M, Toyoshima Y, Kitaura H, et al.: Hypertrophy of hippocampal end folium neurons in patients with mesial temporal lobe epilepsy. Neuropathology. 2011.
[112]. Pham N, Fazio V, Cucullo L, et al.: Extracranial sources of S100B do not affect serum levels. PLoS One. 2010; 5.
[113]. Kleindienst A, Meissner S, Eyupoglu IY, Parsch H, Schmidt C, Buchfelder M: Dynamics of S100B release into serum and cerebrospinal fluid following acute brain injury. Acta Neurochir Suppl. 2010; 106: 247-250.
[114]. Chuang YC, Chen SD, Liou CW, et al.: Contribution of nitric oxide, superoxide anion, and peroxynitrite to activation of mitochondrial apoptotic signaling in hippocampal CA3 subfield following experimental temporal lobe status epilepticus. Epilepsia. 2009; 50: 731-746.
[115]. Chuang YC, Chuang HY, Lin TK, et al.: Effects of long-term antiepileptic drug monotherapy on vascular risk factors and atherosclerosis. Epilepsia. 2012; 53: 120-128.
[116]. Cui J, Wang Y, Dong Q, et al.: Morphine protects against intracellular amyloid toxicity by inducing estradiol release and upregulation of Hsp70. J Neurosci. 2011; 31: 16227-16240.
[117]. Jambaque I, Hertz-Pannier L, Mikaeloff Y, et al.: Severe memory impairment in a child with bihippocampal injury after status epilepticus. Dev Med Child Neurol. 2006; 48: 223-226.
[118]. Greicius MD, Krasnow B, Reiss AL, Menon V: Functional connectivity in the resting brain: a network analysis of the default mode hypothesis. Proc Natl Acad Sci U S A. 2003; 100: 253-258.
[119]. Greicius M: Resting-state functional connectivity in neuropsychiatric disorders. Curr Opin Neurol. 2008; 21: 424-430.
[120]. Rombouts S, Scheltens P: Functional connectivity in elderly controls and AD patients using resting state fMRI: a pilot study. Curr Alzheimer Res. 2005; 2: 115-116.
[121]. Zhang Z, Lu G, Zhong Y, et al.: Impaired perceptual networks in temporal lobe epilepsy revealed by resting fMRI. J Neurol. 2009.
[122]. Zhang ZQ, Lu GM, Zhong Y, et al.: [Application of amplitude of low-frequency fluctuation to the temporal lobe epilepsy with bilateral hippocampal sclerosis: an fMRI study]. Zhonghua Yi Xue Za Zhi. 2008; 88: 1594-1598.
[123]. Zhang Z, Lu G, Zhong Y, et al.: Impaired attention network in temporal lobe epilepsy: a resting FMRI study. Neurosci Lett. 2009; 458: 97-101.
[124]. Waites AB, Briellmann RS, Saling MM, Abbott DF, Jackson GD: Functional connectivity networks are disrupted in left temporal lobe epilepsy. Ann Neurol. 2006; 59: 335-343.
[125]. Lui S, Ouyang L, Chen Q, et al.: Differential interictal activity of the precuneus/posterior cingulate cortex revealed by resting state functional MRI at 3T in generalized vs. partial seizure. J Magn Reson Imaging. 2008; 27: 1214-1220.
[126]. Bettus G, Guedj E, Joyeux F, et al.: Decreased basal fMRI functional connectivity in epileptogenic networks and contralateral compensatory mechanisms. Hum Brain Mapp. 2009; 30: 1580-1591.
[127]. Tournier JD, Calamante F, Connelly A: Robust determination of the fibre orientation distribution in diffusion MRI: non-negativity constrained super-resolved spherical deconvolution. Neuroimage. 2007; 35: 1459-1472.