京都大学 / 新制・論文博士 / 博士(医学) / 乙第13397号 / 論医博第2221号 / 新制||医||1051(附属図書館) / (主査)教授 伊佐 正, 教授 中本 裕士, 教授 渡邉 大 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Indiana University-Purdue University Indianapolis (IUPUI) / Stroke is the second leading cause of mortality worldwide, accounting for 5.5 million deaths annually. In addition to its high mortality rate, stroke is the most common cause of acquired epilepsy. Three to thirty percent of stroke survivors develop post-stroke epilepsy. Although currently available therapies such as thrombolytics and mechanical thrombectomy prevent immediate mortality by restoring blood flow after stroke, these treatments do not target the cellular and molecular mechanisms that lead to post-stroke epileptogenesis. With the increasing number of stroke survivors, there is an urgent need for therapies that prevent epilepsy development in this population. Here, we showed that homeostatic plasticity is involved in the development of hyperexcitability after stroke and can be targeted to prevent the development of post-stroke epilepsy. Using two-photon calcium imaging, we found that homeostatic regulation leads to cortical hyperexcitability after stroke. We also found that activity enhancement by optogenetic and pharmacological approaches can target homeostatic plasticity to prevent post-stroke epilepsy. This study demonstrates the high translational potential of activity enhancement as a novel strategy to prevent post-stroke epilepsy through regulating cortical homeostatic plasticity. Sudden premature death is a leading cause of death in patients with medically refractory epilepsy. This unanticipated death of a relatively healthy person with epilepsy in which no structural or toxicological cause of death can be identified after postmortem analysis is referred to as sudden unexpected death in epilepsy patients (SUDEP). Respiratory failure during seizures is an important underlying mechanism of SUDEP. Here, we showed that LPS-induced peripheral inflammation is protective against SUDEP. This protection is mediated at least in part via enhancing serotonergic function in the brain stem. To the best of our knowledge, this is the first study demonstrating the relationship between peripheral inflammation and SUDEP prevention. / 2024-11-01

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13554号 / 論医博第2283号 / 新制||医||1067(附属図書館) / (主査)教授 村井 俊哉, 教授 永井 洋士, 教授 井上 治久 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Base teórica: O Acidente Vascular Cerebral (AVC) é a causa mais comum de novos diagnósticos de epilepsia no idoso. Embora a epilepsia pós-AVC seja um fenômeno clínico reconhecido há muito tempo, seguem muitas questões não resolvidas. Além disso, nas últimas duas décadas, o tratamento do AVC isquêmico sofreu mudanças radicais com a introdução da trombólise e da hemicraniectomia descompressiva (HD) para o tratamento do infarto maligno de artéria cerebral média (ACM). As consequências destas duas novas abordagens terapêuticas nas características da epilepsia pós-AVC ainda são pouco exploradas. Objetivo: Estudar as características e estimar fatores de risco para as crises epilépticas ou a epilepsia pós-AVC em pacientes submetidos ao tratamento agudo (Estudo 1) ou HD para infarto maligno de ACM (Estudo 2). Métodos: O estudo 1 é uma coorte de 153 pacientes submetidos a trombólise. Variáveis estudadas incluiram fatores de risco para o AVC e variáveis associadas ao AVC isquêmico agudo e trombólise. Utilizamos a análise de regressão de Cox para o estudo das variáveis que se associaram de forma independente com crises epilépticas, epilepsia pós-AVC e o desfecho do AVC. O estudo 2 é também uma coorte que retrospectivamente avaliou 36 pacientes com infarto maligno de ACM tratados com HD. Tempo, incidência e fatores de risco para crises epilépticas e desenvolvimento de epilepsia foram analisados. Resultados: Estudo 1: 74 pacientes (48,4%) eram mulheres; média de idade foi 67,2 anos (DP=13,1). Média do NIHSS na chegada foi 10,95 (DP=6,25) e 2,09 (DP=3,55) após 3 meses. Transformação hemorrágica ocorreu em 22 (14,4%) dos pacientes. Foi considerado desfecho bom classificação na escala modificada de Rankin (mRS) 0-1, sendo encontrado em 87 (56,9%) dos pacientes. Vinte e um pacientes (13,7%) tiveram crises epilépticas e 15 (9,8%) desenvolveram epilepsia após a trombólise. Crises epilépticas foram associadas de forma independente com transformação hemorrágica e desfecho não favorável (mRS ≥ 2) em três meses após o AVC. Transformação hemorrágica e mRS ≥ 2 avaliados em 3 meses, associaram-se de forma independente com epilepsia pós-AVC. Crises epilépticas surgiram como um fator de risco independente para desfecho pobre. Estudo 2. A média de seguimento dos pacientes foi de 1.086 (DP= 1.172) dias. Nove pacientes morreram antes de receberem alta hospitalar e no período de um ano, 11 pacientes haviam morrido. Quase 60% alcançaram mRS ≤ 4. Treze pacientes desenvolveram crises dentro da primeira semana após o AVC. No total, crises epilépticas ocorreram em 22 (61%) dos 36 pacientes. Dezenove pacientes (56%) dos 34, sobreviveram ao período agudo e desenvolveram epilepsia após infarto da ACM e HD. Questionamos aos pacientes ou responsáveis se eles se arrependeram de terem autorizado a HD no momento do AVC. Também foi perguntado se eles autorizariam a HD novamente. Trinta e dois (89%) não se arrependeram de ter autorizado a HD no momento do infarto agudo da ACM, e autorizaria novamente em retrospecto. Conclusão: Confirmamos que as frequências de crises ou epilepsia pós-AVC e trombolítico são comparáveis com as frequências das décadas da era pré-trombólise e confirmamos a alta incidência de crises epilépticas e epilepsia após infartos malignos de ACM submetidos a HD. Em nosso estudo, as crises epilépticas associaram-se de forma independente com pior prognóstico após terapia trombolítica. / Background: The most common cause of newly diagnosed epilepsies in the elderly is stroke. Although post-stroke epilepsy is a well-studied stroke complication, many questions remain unsolved. In addition, during the past two decades, the treatment of stroke has changed dramatically with the introduction of thrombolysis for treatment of acute ischemic stroke (AIS) and decompressive hemicraniectomy (DHC) for malignant middle cerebral artery infarction (MCA). The consequences of these two new therapeutic approaches for characteristics of post-stroke epilepsy remains poorly explored. Objective: To study characteristics and estimate risk factors for acute seizures or post-stroke epilepsy in patients submitted to thrombolysis for treatment of acute stroke (Study 1) or DHC for malignant MCA infarction. Methods: Study 1 is a cohort study of 153 patients submitted to thrombolysis. Variables studied included risk factors for stroke, and variables related to acute stroke and thrombolysis. Variables independently associated with seizures, pos-stroke epilepsy or stroke outcome were defined using Cox regression analysis. Study 2 is also a cohort study that retrospectively assessed 36 patients with malignant stroke of the MCA submitted to DHC. Timing, incidence and plausible risk factors for seizure and epilepsy development were analyzed in these patients. Results: Study 1. Seventy-four patients (48.4%) were female; mean age of patients was 67.2 years-old (SD=13.1). Initial NIHSS mean score was 10.95 (SD=6.25) and 2.09 (SD=3.55) after three months. Hemorrhagic transformation occurred in 22 (14.4%) patients. A good outcome, as defined by a modified Rankin Scale (mRS) of 0-1, was observed in 87 (56.9%) patients. Twenty one (13.7%) patients had seizures and 15 (9.8%) patients developed epilepsy after thrombolysis. Seizures were independently associated with hemorrhagic transformation and with mRS ≥ 2 three months after stroke. Hemorrhagic transformation and unfavorable outcome, as measured by mRS ≥ 2 after three months, were variables independently associated with post-stroke epilepsy. Seizures emerged as an independent factor for poor outcome in stroke thrombolysis. Study 2. Mean patient follow-up time was of 1.086 (SD=1.172) days. Nine patients died before being discharged and after one year eleven patients died. Almost 60% had the modified Rankin score ≤ 4. Thirteen patients developed seizures within the first week after stroke. In total, seizures occurred in 22 (61%) of 36 patients. Nineteen patients (56%) out of 34 patients who survived the acute period developed epilepsy after MCA infarcts and DHC. Also, we asked patients or the person responsible for them whether they regretted, in retrospect, having authorized DHC at the time of the stroke. It was also asked whether they would authorize DHC again. Thirty- two (89%) did not regret having authorized DHC at the time of acute MCA infarct, and would authorize DHC again in retrospect. Conclusion: We confirm that seizures or post-stroke epilepsy rates after thrombolysis are comparable with rates from pre-thrombolysis decades and a high incidence of seizures and epilepsy after malignant MCA infarcts submitted to DHC. In our study, seizures were an independent risk factor associated with worst outcome after thrombolysis therapy.

Base teórica: O Acidente Vascular Cerebral (AVC) é a causa mais comum de novos diagnósticos de epilepsia no idoso. Embora a epilepsia pós-AVC seja um fenômeno clínico reconhecido há muito tempo, seguem muitas questões não resolvidas. Além disso, nas últimas duas décadas, o tratamento do AVC isquêmico sofreu mudanças radicais com a introdução da trombólise e da hemicraniectomia descompressiva (HD) para o tratamento do infarto maligno de artéria cerebral média (ACM). As consequências destas duas novas abordagens terapêuticas nas características da epilepsia pós-AVC ainda são pouco exploradas. Objetivo: Estudar as características e estimar fatores de risco para as crises epilépticas ou a epilepsia pós-AVC em pacientes submetidos ao tratamento agudo (Estudo 1) ou HD para infarto maligno de ACM (Estudo 2). Métodos: O estudo 1 é uma coorte de 153 pacientes submetidos a trombólise. Variáveis estudadas incluiram fatores de risco para o AVC e variáveis associadas ao AVC isquêmico agudo e trombólise. Utilizamos a análise de regressão de Cox para o estudo das variáveis que se associaram de forma independente com crises epilépticas, epilepsia pós-AVC e o desfecho do AVC. O estudo 2 é também uma coorte que retrospectivamente avaliou 36 pacientes com infarto maligno de ACM tratados com HD. Tempo, incidência e fatores de risco para crises epilépticas e desenvolvimento de epilepsia foram analisados. Resultados: Estudo 1: 74 pacientes (48,4%) eram mulheres; média de idade foi 67,2 anos (DP=13,1). Média do NIHSS na chegada foi 10,95 (DP=6,25) e 2,09 (DP=3,55) após 3 meses. Transformação hemorrágica ocorreu em 22 (14,4%) dos pacientes. Foi considerado desfecho bom classificação na escala modificada de Rankin (mRS) 0-1, sendo encontrado em 87 (56,9%) dos pacientes. Vinte e um pacientes (13,7%) tiveram crises epilépticas e 15 (9,8%) desenvolveram epilepsia após a trombólise. Crises epilépticas foram associadas de forma independente com transformação hemorrágica e desfecho não favorável (mRS ≥ 2) em três meses após o AVC. Transformação hemorrágica e mRS ≥ 2 avaliados em 3 meses, associaram-se de forma independente com epilepsia pós-AVC. Crises epilépticas surgiram como um fator de risco independente para desfecho pobre. Estudo 2. A média de seguimento dos pacientes foi de 1.086 (DP= 1.172) dias. Nove pacientes morreram antes de receberem alta hospitalar e no período de um ano, 11 pacientes haviam morrido. Quase 60% alcançaram mRS ≤ 4. Treze pacientes desenvolveram crises dentro da primeira semana após o AVC. No total, crises epilépticas ocorreram em 22 (61%) dos 36 pacientes. Dezenove pacientes (56%) dos 34, sobreviveram ao período agudo e desenvolveram epilepsia após infarto da ACM e HD. Questionamos aos pacientes ou responsáveis se eles se arrependeram de terem autorizado a HD no momento do AVC. Também foi perguntado se eles autorizariam a HD novamente. Trinta e dois (89%) não se arrependeram de ter autorizado a HD no momento do infarto agudo da ACM, e autorizaria novamente em retrospecto. Conclusão: Confirmamos que as frequências de crises ou epilepsia pós-AVC e trombolítico são comparáveis com as frequências das décadas da era pré-trombólise e confirmamos a alta incidência de crises epilépticas e epilepsia após infartos malignos de ACM submetidos a HD. Em nosso estudo, as crises epilépticas associaram-se de forma independente com pior prognóstico após terapia trombolítica. / Background: The most common cause of newly diagnosed epilepsies in the elderly is stroke. Although post-stroke epilepsy is a well-studied stroke complication, many questions remain unsolved. In addition, during the past two decades, the treatment of stroke has changed dramatically with the introduction of thrombolysis for treatment of acute ischemic stroke (AIS) and decompressive hemicraniectomy (DHC) for malignant middle cerebral artery infarction (MCA). The consequences of these two new therapeutic approaches for characteristics of post-stroke epilepsy remains poorly explored. Objective: To study characteristics and estimate risk factors for acute seizures or post-stroke epilepsy in patients submitted to thrombolysis for treatment of acute stroke (Study 1) or DHC for malignant MCA infarction. Methods: Study 1 is a cohort study of 153 patients submitted to thrombolysis. Variables studied included risk factors for stroke, and variables related to acute stroke and thrombolysis. Variables independently associated with seizures, pos-stroke epilepsy or stroke outcome were defined using Cox regression analysis. Study 2 is also a cohort study that retrospectively assessed 36 patients with malignant stroke of the MCA submitted to DHC. Timing, incidence and plausible risk factors for seizure and epilepsy development were analyzed in these patients. Results: Study 1. Seventy-four patients (48.4%) were female; mean age of patients was 67.2 years-old (SD=13.1). Initial NIHSS mean score was 10.95 (SD=6.25) and 2.09 (SD=3.55) after three months. Hemorrhagic transformation occurred in 22 (14.4%) patients. A good outcome, as defined by a modified Rankin Scale (mRS) of 0-1, was observed in 87 (56.9%) patients. Twenty one (13.7%) patients had seizures and 15 (9.8%) patients developed epilepsy after thrombolysis. Seizures were independently associated with hemorrhagic transformation and with mRS ≥ 2 three months after stroke. Hemorrhagic transformation and unfavorable outcome, as measured by mRS ≥ 2 after three months, were variables independently associated with post-stroke epilepsy. Seizures emerged as an independent factor for poor outcome in stroke thrombolysis. Study 2. Mean patient follow-up time was of 1.086 (SD=1.172) days. Nine patients died before being discharged and after one year eleven patients died. Almost 60% had the modified Rankin score ≤ 4. Thirteen patients developed seizures within the first week after stroke. In total, seizures occurred in 22 (61%) of 36 patients. Nineteen patients (56%) out of 34 patients who survived the acute period developed epilepsy after MCA infarcts and DHC. Also, we asked patients or the person responsible for them whether they regretted, in retrospect, having authorized DHC at the time of the stroke. It was also asked whether they would authorize DHC again. Thirty- two (89%) did not regret having authorized DHC at the time of acute MCA infarct, and would authorize DHC again in retrospect. Conclusion: We confirm that seizures or post-stroke epilepsy rates after thrombolysis are comparable with rates from pre-thrombolysis decades and a high incidence of seizures and epilepsy after malignant MCA infarcts submitted to DHC. In our study, seizures were an independent risk factor associated with worst outcome after thrombolysis therapy.

Base teórica: O Acidente Vascular Cerebral (AVC) é a causa mais comum de novos diagnósticos de epilepsia no idoso. Embora a epilepsia pós-AVC seja um fenômeno clínico reconhecido há muito tempo, seguem muitas questões não resolvidas. Além disso, nas últimas duas décadas, o tratamento do AVC isquêmico sofreu mudanças radicais com a introdução da trombólise e da hemicraniectomia descompressiva (HD) para o tratamento do infarto maligno de artéria cerebral média (ACM). As consequências destas duas novas abordagens terapêuticas nas características da epilepsia pós-AVC ainda são pouco exploradas. Objetivo: Estudar as características e estimar fatores de risco para as crises epilépticas ou a epilepsia pós-AVC em pacientes submetidos ao tratamento agudo (Estudo 1) ou HD para infarto maligno de ACM (Estudo 2). Métodos: O estudo 1 é uma coorte de 153 pacientes submetidos a trombólise. Variáveis estudadas incluiram fatores de risco para o AVC e variáveis associadas ao AVC isquêmico agudo e trombólise. Utilizamos a análise de regressão de Cox para o estudo das variáveis que se associaram de forma independente com crises epilépticas, epilepsia pós-AVC e o desfecho do AVC. O estudo 2 é também uma coorte que retrospectivamente avaliou 36 pacientes com infarto maligno de ACM tratados com HD. Tempo, incidência e fatores de risco para crises epilépticas e desenvolvimento de epilepsia foram analisados. Resultados: Estudo 1: 74 pacientes (48,4%) eram mulheres; média de idade foi 67,2 anos (DP=13,1). Média do NIHSS na chegada foi 10,95 (DP=6,25) e 2,09 (DP=3,55) após 3 meses. Transformação hemorrágica ocorreu em 22 (14,4%) dos pacientes. Foi considerado desfecho bom classificação na escala modificada de Rankin (mRS) 0-1, sendo encontrado em 87 (56,9%) dos pacientes. Vinte e um pacientes (13,7%) tiveram crises epilépticas e 15 (9,8%) desenvolveram epilepsia após a trombólise. Crises epilépticas foram associadas de forma independente com transformação hemorrágica e desfecho não favorável (mRS ≥ 2) em três meses após o AVC. Transformação hemorrágica e mRS ≥ 2 avaliados em 3 meses, associaram-se de forma independente com epilepsia pós-AVC. Crises epilépticas surgiram como um fator de risco independente para desfecho pobre. Estudo 2. A média de seguimento dos pacientes foi de 1.086 (DP= 1.172) dias. Nove pacientes morreram antes de receberem alta hospitalar e no período de um ano, 11 pacientes haviam morrido. Quase 60% alcançaram mRS ≤ 4. Treze pacientes desenvolveram crises dentro da primeira semana após o AVC. No total, crises epilépticas ocorreram em 22 (61%) dos 36 pacientes. Dezenove pacientes (56%) dos 34, sobreviveram ao período agudo e desenvolveram epilepsia após infarto da ACM e HD. Questionamos aos pacientes ou responsáveis se eles se arrependeram de terem autorizado a HD no momento do AVC. Também foi perguntado se eles autorizariam a HD novamente. Trinta e dois (89%) não se arrependeram de ter autorizado a HD no momento do infarto agudo da ACM, e autorizaria novamente em retrospecto. Conclusão: Confirmamos que as frequências de crises ou epilepsia pós-AVC e trombolítico são comparáveis com as frequências das décadas da era pré-trombólise e confirmamos a alta incidência de crises epilépticas e epilepsia após infartos malignos de ACM submetidos a HD. Em nosso estudo, as crises epilépticas associaram-se de forma independente com pior prognóstico após terapia trombolítica. / Background: The most common cause of newly diagnosed epilepsies in the elderly is stroke. Although post-stroke epilepsy is a well-studied stroke complication, many questions remain unsolved. In addition, during the past two decades, the treatment of stroke has changed dramatically with the introduction of thrombolysis for treatment of acute ischemic stroke (AIS) and decompressive hemicraniectomy (DHC) for malignant middle cerebral artery infarction (MCA). The consequences of these two new therapeutic approaches for characteristics of post-stroke epilepsy remains poorly explored. Objective: To study characteristics and estimate risk factors for acute seizures or post-stroke epilepsy in patients submitted to thrombolysis for treatment of acute stroke (Study 1) or DHC for malignant MCA infarction. Methods: Study 1 is a cohort study of 153 patients submitted to thrombolysis. Variables studied included risk factors for stroke, and variables related to acute stroke and thrombolysis. Variables independently associated with seizures, pos-stroke epilepsy or stroke outcome were defined using Cox regression analysis. Study 2 is also a cohort study that retrospectively assessed 36 patients with malignant stroke of the MCA submitted to DHC. Timing, incidence and plausible risk factors for seizure and epilepsy development were analyzed in these patients. Results: Study 1. Seventy-four patients (48.4%) were female; mean age of patients was 67.2 years-old (SD=13.1). Initial NIHSS mean score was 10.95 (SD=6.25) and 2.09 (SD=3.55) after three months. Hemorrhagic transformation occurred in 22 (14.4%) patients. A good outcome, as defined by a modified Rankin Scale (mRS) of 0-1, was observed in 87 (56.9%) patients. Twenty one (13.7%) patients had seizures and 15 (9.8%) patients developed epilepsy after thrombolysis. Seizures were independently associated with hemorrhagic transformation and with mRS ≥ 2 three months after stroke. Hemorrhagic transformation and unfavorable outcome, as measured by mRS ≥ 2 after three months, were variables independently associated with post-stroke epilepsy. Seizures emerged as an independent factor for poor outcome in stroke thrombolysis. Study 2. Mean patient follow-up time was of 1.086 (SD=1.172) days. Nine patients died before being discharged and after one year eleven patients died. Almost 60% had the modified Rankin score ≤ 4. Thirteen patients developed seizures within the first week after stroke. In total, seizures occurred in 22 (61%) of 36 patients. Nineteen patients (56%) out of 34 patients who survived the acute period developed epilepsy after MCA infarcts and DHC. Also, we asked patients or the person responsible for them whether they regretted, in retrospect, having authorized DHC at the time of the stroke. It was also asked whether they would authorize DHC again. Thirty- two (89%) did not regret having authorized DHC at the time of acute MCA infarct, and would authorize DHC again in retrospect. Conclusion: We confirm that seizures or post-stroke epilepsy rates after thrombolysis are comparable with rates from pre-thrombolysis decades and a high incidence of seizures and epilepsy after malignant MCA infarcts submitted to DHC. In our study, seizures were an independent risk factor associated with worst outcome after thrombolysis therapy.