The clinical needs of patients with epilepsy are often unmet for the following reasons: (1) the clinical diagnosis of epilepsy in a hospital setting is challenging and there is a lack of longitudinal data from the time-point of initial triage to help clinicians go through the diagnostic process; (2) epilepsy patients who develop refractory illness may encounter problems of localization and lateralization of their seizure foci and (3) the technology required in the delineation of epileptogenic zones and functional cortices may not be accurate enough to support the clinicians in their diagnoses. / The current thesis begins with the exploration of the epidemiology of suspected seizure patients in a hospital setting where patients with first seizure, epilepsy and non-epileptic events may present at the same point-of-care entry. We designed a longitudinal, prospective study examining patients presenting with “seizure-specific“ and “non-specific“ labels. Among 531 patients with “seizure-specific“ labels, 27(5%) had non-epileptic events and among 1170 patients with “non-specific“ labels, 58(5%) had a first seizure or epilepsy. In particular, first seizure patients were prone to misdiagnosis as up to 22% of these patients had an initial “non-specific“ label. Components of evaluation contributing to revision of diagnosis included retrieval of witness accounts, epileptiform discharges on electroencephalogram(EEG), short-term monitoring of patients with acute symptomatic seizures and panel discussion of cases. These may represent the first step towards a multimodal investigation of patients with epilepsy. / In the second part of the current thesis, we examined the prognosis of first acute symptomatic seizures (ASS), an important component of the seizure diagnosis under the hospital setting. We challenged the traditional school of thought that “ASS are not necessarily considered epilepsy as their potential to generate unprovoked seizure is low“. By following 105 patients with ASS, we found that first ASS was associated with status epilepticus (29.5%), multiple-onset (>1 seizure within 24h on day of presentation, 35.2%) and multiple aetiologies (22.9%) with a mortality of 30% at 2 years by the Kaplan-Meier method. By using seizure recurrences in the setting of a persisting or re-emerging acute symptomatic cause, we were able to demonstrate a risk of recurrence following an ASS of 32% at 2 years with epileptiform EEG being an independent predictor2. This information sheds light onto the fact that even ASS can be “refractory insofar as the acute symptomatic cause takes a long time to treat, is prone to re-emergence, or is irreversible. This may be seen as the second step towards a multimodal investigation of patients with epilepsy. / In the next part of the current thesis, focus was placed on the refractory epilepsy patients. A formal treatise on a specific modality of investigation, namely video electroencephalogram (VEEG) was presented. The clinical appearance of patients at the time of seizure was known as semiology, and this was systematically explored in a cohort of patients undergoing VEEG. By carefully examining the localizing value (which cerebral lobe) and the lateralizing value (which side) of the semiology, we discovered a new set of semiology which might point towards an epileptic focus in the medial aspect of the frontal lobe. The gold standard for seizure localization was used in this study in the assembly of the cohort. Only patients with an Engel Class I outcome, seizure localization by analysis of resection margins and/or intracranial implantation were selected. The first part of study involved 152 patients who underwent frontal lobe surgery and the second part involved 253 patients with non-frontal lobe surgery. All habitual seizures were analyzed by VEEG using a semiology checklist of 47 items during the early (electrographic onset to 10s) and late phase (rest of episode). Localization semiology was analyzed by Chi-square test with Bonferroni correction and cluster analysis when occurrence exceeded 10% in at least 1 region. Ictal body turning along the horizontal body axis was a statistically significant localizing semiology for the mesial frontal region (57%) from the first part of study. In the second part, we found that ictal body turning along the horizontal axis and semiology with physiological movement together gave a positive predictive value of 85.7%. This modality of investigation may serve as clinicians’ hypothesis towards the localization of epileptic foci. / Electroencephalography (EEG) forms an essential part of the multi-modal investigation of epilepsy. Modern-day EEGs are performed with surface electrodes attached to the scalp to capture the electrographic information at the time of seizure but this can be hindered by muscle artifacts which decrease the localizing power of the EEG. We began with the exploration of the “hypersynchronous states of intracranial EEG in which no muscle artifact would be present. A total of 100 focal onset seizure episodes were analyzed from 60 patients undergoing intracranial implantation4. A multivariate method was used computing the eigenvalue spectrum of the zero-lag correlation matrix of a short sliding window. We showed that there were clearly observable and statistically significant changes of the correlation structure of focal onset seizures. These changes indicated that the zero-lag correlation of multi-channel EEG either remained approximately unchanged, or especially in the case of secondary generalization, decreased during the first half of seizures. The correlation then gradually increased again before the seizures terminated. This development was qualitatively independent of the anatomical location of the seizure onset zone and it appeared to be a generic property of focal onset seizures. We concluded that the de-correlation of EEG activity was due to the different propagation times of locally synchronous ictal discharges from the seizure onset zone to other brain areas and the increase of correlation during the second half of the seizures may be causally related to seizure termination. / In the next part of our multimodal investigations, focus was made on how to use applied mathematics in procuring an accurate EEG interpretation from surface EEG. A mathematical model known as discrete wavelet transform (DWT) is a powerful tool which may help denoise the ictal EEG. It can be coupled with an absolute slope method as described in the last part of the thesis which enhances the determination of ictal foci. Twelve patients achieving Engel Class I/IIa outcome following temporal lobe surgery at 1 year were selected for EEG analysis5. The EEG signals were denoised with DWT, followed by computing the normalized absolute slopes and spatial interpolation of scalp topography associated to detection of local maxima. For localization, the region with the highest normalized absolute slopes at the time when epileptiform activities were registered (>2.5 times standard deviation) was designated as the region of onset. For lateralization, the cerebral hemisphere with the first emergence of normalized absolute slopes >2.5 times the standard deviation was considered the side of onset. As comparison, all the EEG episodes were reviewed by two neurologists blinded to clinical information to determine the localization and lateralization of seizure onset by visual analysis. The wavelet and absolute slope method improved the diagnostic accuracy for localization from 64% (16/25) to 84% (21/25). Similarly, the wavelet and absolute slope method improved the diagnostic accuracy for lateralization from 48% (12/25) to 92% (23/25). The comparison between the wavelet/absolute slope method and the visual analysis showed statistical significance for lateralization (p=0.0026, McNemar test). It was conceivable that coupling DWT with the absolute slope method helps clinicians achieve a better EEG diagnostic accuracy. / To conclude, findings of the present thesis open up an area of neuroscience to researchers and biomedical engineers in relation to multi-modal investigations of epilepsy patients, which may play an essential role in fostering our understanding of the epileptic brain, through which more accurate and precise treatment may be delivered to patients with epilepsy. / Leung, Ho Wan Howan. / Thesis (M.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 172-185). / Chapter Chapter 1 --- Understanding first seizures and epilepsy / Introduction- epilepsy, past and present --- p.(Page 17) / The burden of epilepsy --- p.(Page 19) / From first seizures --- p.(Page 19) / Scrutiny of clinical first seizure studies --- p.(Page 21) / Symptomatology of first seizures --- p.(Page 22) / Prognosis of first seizures --- p.(Page 23) / The question of managing first seizures --- p.(Page 29) / From first seizure onto refractory seizures --- p.(Page 30) / From drugs to surgery --- p.(Page 32) / Chapter Chapter 2 --- A treatise on epilepsy from the local perspective of Hong Kong / Local epidemiological data --- p.(Page 34) / Use of antiepileptic agents in Hong Kong --- p.(Page 36) / Epilepsy surgery in Hong Kong --- p.(Page 37) / Chapter Chapter 3 --- What are multi-modal investigations? / Semiology as a modality of investigation --- p.(Page 41) / Electroencephalography as a modality of investigation --- p.(Page 44) / Neuroimaging as a modality of investigation --- p.(Page 53) / Additional modalities of neuroimaging --- p.(Page 56) / Methods of ascertaining the functional areas of the cerebral cortex --- p.(Page 63) / The scientific future of multi-modal investigations in Hong Kong --- p.(Page 66) / Chapter Chapter 4 --- The triage of patients before multi-modal investigations can be applied / Method --- p.(Page 70) / Setting and patients --- p.(Page 70) / Results --- p.(Page 73) / Exploring how diagnoses were revised --- p.(Page 75) / Completeness of patient inclusion --- p.(Page 77) / Thematic considerations of current study --- p.(Page 77) / Chapter Chapter 5 --- Consideration of a special category in the process of triage / Patient cohort --- p.(Page 81) / Definitions --- p.(Page 82) / Statistical analysis --- p.(Page 87) / Results --- p.(Page 88) / Demographics and clinical profile --- p.(Page 86) / Mortality --- p.(Page 92) / Seizure recurrence using acute symptomatic seizure as outcome --- p.(Page 93) / Seizure recurrence using unprovoked seizure as outcome --- p.(Page 96) / Risk factors for recurrence --- p.(Page 96) / Progressive symptomatic seizures as a separate category --- p.(Page 97) / Thematic considerations of current study --- p.(Page 97) / Chapter Chapter 6 --- Analyzing semiology with video monitoring as multi-modal investigation / Study part I --- p.(Page 103) / Study part II --- p.(Page 107) / Results --- p.(Page 108) / Semiology in the early phase of seizures --- p.(Page 108) / Semiology in the late phase of seizures --- p.(Page 109) / Cluster analysis of mesial frontal lobe epilepsy syndrome --- p.(Page 110) / Clinical utility of ictal body turning along the horizontal axis --- p.(Page 111) / Thematic considerations of current study --- p.(Page 111) / Chapter Chapter 7 --- Applying mathematical models in the analysis of electroencephalogram / Methods --- p.(Page 118) / Results --- p.(Page 126) / Discussion --- p.(Page 132) / An unanswered question in epileptology --- p.(Page 135) / Chapter Chapter 8 --- Wavelet theories in the analysis of electroencephalogram / Methods --- p.(Page 141) / Results --- p.(Page 150) / Localization --- p.(Page 151) / Lateralization --- p.(Page 154) / Discussion --- p.(Page 156) / Study by Battiston et al --- p.(Page 157) / Study by Ursino et al --- p.(Page 158) / Study by Senhadji et al --- p.(Page 158) / Thematic considerations including limitations --- p.(Page 162) / Chapter Chapter 9 --- Strengths and limitations of current thesis / General --- p.(Page 163) / Specific --- p.(Page 164) / Chapter Chapter 10 --- Conclusions and future research directions --- p.(Page 166)