Dissertation (Ph.D.)--University of South Florida, 2009. / Title from PDF of title page. Document formatted into pages; contains 164 pages. Includes vita. Includes bibliographical references.

Objetivo: Avaliar a relação das alterações de fluxo na artéria cerebral média (ACM) com a ocorrência de acidemia no nascimento, em gestações com insuficiência placentária. Métodos: estudo transversal prospectivo com 91 gestações com diagnóstico de insuficiência placentária pelo Doppler de artéria umbilical (AU) alterado (índice de pulsatilidade [IP] > p95). Os critérios de inclusão foram: gestações únicas com idade gestacional (IG) superior a 26 semanas completas, membranas ovulares íntegras, ausência de anomalias cromossômicas ou congênitas. Os parâmetros da dopplervelocimetria analisados foram: IP da AU, IP da ACM, pico de velocidade sistólica (PVS) da ACM, relação cerebroplacentária (RCP) e índice de pulsatilidade para veias (IPV) do ducto venoso (DV). Foi analisada a última avaliação fetal realizada imediatamente antes do parto ou anterior à corticoterapia. Todos os parâmetros foram analisados por meio do escore zeta ou múltiplos da mediana (MoM), baseados nas médias, desvio-padrão e valores de referência para cada IG. Imediatamente após o parto, uma amostra de sangue da artéria umbilical foi obtida para a medida do pH, e os casos classificados de acordo com a presença (pH < 7,20) ou ausência de acidemia no nascimento. Resultados: Quarenta e sete (51,6%) recémnascidos apresentaram acidemia no nascimento. Os fetos que evoluíram com acidemia apresentaram valor de escore zeta do IP da AU significativamente maior (mediana 2,1 vs 1,7; p=0,014), assim como maior proporção de casos com diástole zero ou reversa (51,0% vs 31,8%; p=0,006). Quanto à ACM, o escore zeta mostrou-se significativamente menor nos casos com pH < 7,20 (mediana -2,7 vs -2,1; p=0,042), porém, em relação ao PVS não foi possível estabelecer diferença significativa entre os grupos (p=0,051). A acidemia no nascimento se associou a menores valores de RCP (mediana 0,5 vs 0,7; p=0,006), porém não ao seu escore zeta (p=0,055). Em relação ao território venoso, maiores valores do escore zeta do IPV do DV associaram-se à acidemia (mediana 2,4 vs 0,6; p=0,015). Na análise de correlação entre os valores de pH no nascimento e os resultados da avaliação da dopplervelocimetria fetal, foi constatada correlação significativa entre o valor do pH no nascimento e o escore zeta do IP da AU (rho=-0,31; p=0,003), IP da ACM (rho=0,26; p=0,012), da RCP (rho 0,25; p=0,015) e IPV do DV (rho=-0,32; p=0,002), e PVS da ACM MoM (rho=-0,21; p=0,042). A regressão logística identificou o escore zeta do IP da AU e escore zeta IP da ACM como variáveis independentes para a predição de acidemia no nascimento, classificando corretamente 67,03% dos casos. Conclusão: em casos de insuficiência placentária, o IP da AU e da ACM são preditores independentes associados com a acidemia no nascimento. Este estudo reforça que o grau de insuficiência placentária e a capacidade de adaptação fetal estão diretamente relacionados com a acidemia no nascimento / Objectives: To evaluate the relationship between middle cerebral artery (MCA) parameters and acidemia at birth, in pregnancies complicated by placental insufficiency. Methods: The study was performed as a prospective cross-sectional analysis of Doppler measurements in 91 patients with the diagnosis of placental dysfunction by abnormal umbilical artery (UA) Doppler (pulsatility index [PI] > p95). Inclusion criteria were: singleton pregnancy, intact membranes, abscence of fetal congenital or chromosomal abnormalities. The Doppler parameters analyzed were: UA PI, MCA PI, MCA peak systolic velocity (PSV), cerebroplacental ratio (CPR) and pulsatilility index for veins (PIV) of ductus venosus (DV). It was analyzed the last assessment obtained right before birth or the antenatal steroids. Umbical artey blood samples were collected at birth, and acidemia was defined as pH below 7.20. Results: Forty seven (51.6%) newborns had acidemia at birth. Those who developed acidemia showed a UA PI z-score significantly higher (median 2.1 vs 1.7, p = 0.014), as well as a higher proportion of cases with absent or reverse end diastolic flow (51.0% vs 31.8%, p = 0.006). Regarding the MAC, the PI z-score was significantly lower in cases with pH < 7.20 (median -2.7 vs. -2.1, p = 0.042), but concerning PSV z-score, no significant relation between the groups could be established (p = 0.051).The acidemia at birth was associated with lower values of CPR (median 0.5 vs 0.7, p = 0.006), but not with its z-score (p = 0.055). In relation to the venous territory, greater values of DV PIV z-score were associated with acidemia (median 2.4 vs 0.6, p = 0.015).The correlation analysis between the pH values at birth and the Doppler measurements, a significant correlation was observed between the pH at birth and UA PI z-score (rho = -0.31, p = 0.003 ), MCA PI z-score (rho = 0.26, p = 0.012), CPR z-score (rho 0.25, p = 0.015), PIV DV zscore (rho = -0.32, p = 0.002), and PSV MCA MoM (rho = -0.21, p = 0.042). Logistic regression identified the UA PI z-score and the MCA PI z-score as independent predictors for acidemia at birth, correctly classifying 67.03% of cases. Conclusion: In pregnancies with placental insufficiency, the UA PI and the MCA PI are independent predictors associated with acidemia at birth. This study reinforces that the degree of placental insufficiency and the fetal adaptation capacity are directly related to acidemia at birth

Objetivo: Avaliar a relação das alterações de fluxo na artéria cerebral média (ACM) com a ocorrência de acidemia no nascimento, em gestações com insuficiência placentária. Métodos: estudo transversal prospectivo com 91 gestações com diagnóstico de insuficiência placentária pelo Doppler de artéria umbilical (AU) alterado (índice de pulsatilidade [IP] > p95). Os critérios de inclusão foram: gestações únicas com idade gestacional (IG) superior a 26 semanas completas, membranas ovulares íntegras, ausência de anomalias cromossômicas ou congênitas. Os parâmetros da dopplervelocimetria analisados foram: IP da AU, IP da ACM, pico de velocidade sistólica (PVS) da ACM, relação cerebroplacentária (RCP) e índice de pulsatilidade para veias (IPV) do ducto venoso (DV). Foi analisada a última avaliação fetal realizada imediatamente antes do parto ou anterior à corticoterapia. Todos os parâmetros foram analisados por meio do escore zeta ou múltiplos da mediana (MoM), baseados nas médias, desvio-padrão e valores de referência para cada IG. Imediatamente após o parto, uma amostra de sangue da artéria umbilical foi obtida para a medida do pH, e os casos classificados de acordo com a presença (pH < 7,20) ou ausência de acidemia no nascimento. Resultados: Quarenta e sete (51,6%) recémnascidos apresentaram acidemia no nascimento. Os fetos que evoluíram com acidemia apresentaram valor de escore zeta do IP da AU significativamente maior (mediana 2,1 vs 1,7; p=0,014), assim como maior proporção de casos com diástole zero ou reversa (51,0% vs 31,8%; p=0,006). Quanto à ACM, o escore zeta mostrou-se significativamente menor nos casos com pH < 7,20 (mediana -2,7 vs -2,1; p=0,042), porém, em relação ao PVS não foi possível estabelecer diferença significativa entre os grupos (p=0,051). A acidemia no nascimento se associou a menores valores de RCP (mediana 0,5 vs 0,7; p=0,006), porém não ao seu escore zeta (p=0,055). Em relação ao território venoso, maiores valores do escore zeta do IPV do DV associaram-se à acidemia (mediana 2,4 vs 0,6; p=0,015). Na análise de correlação entre os valores de pH no nascimento e os resultados da avaliação da dopplervelocimetria fetal, foi constatada correlação significativa entre o valor do pH no nascimento e o escore zeta do IP da AU (rho=-0,31; p=0,003), IP da ACM (rho=0,26; p=0,012), da RCP (rho 0,25; p=0,015) e IPV do DV (rho=-0,32; p=0,002), e PVS da ACM MoM (rho=-0,21; p=0,042). A regressão logística identificou o escore zeta do IP da AU e escore zeta IP da ACM como variáveis independentes para a predição de acidemia no nascimento, classificando corretamente 67,03% dos casos. Conclusão: em casos de insuficiência placentária, o IP da AU e da ACM são preditores independentes associados com a acidemia no nascimento. Este estudo reforça que o grau de insuficiência placentária e a capacidade de adaptação fetal estão diretamente relacionados com a acidemia no nascimento / Objectives: To evaluate the relationship between middle cerebral artery (MCA) parameters and acidemia at birth, in pregnancies complicated by placental insufficiency. Methods: The study was performed as a prospective cross-sectional analysis of Doppler measurements in 91 patients with the diagnosis of placental dysfunction by abnormal umbilical artery (UA) Doppler (pulsatility index [PI] > p95). Inclusion criteria were: singleton pregnancy, intact membranes, abscence of fetal congenital or chromosomal abnormalities. The Doppler parameters analyzed were: UA PI, MCA PI, MCA peak systolic velocity (PSV), cerebroplacental ratio (CPR) and pulsatilility index for veins (PIV) of ductus venosus (DV). It was analyzed the last assessment obtained right before birth or the antenatal steroids. Umbical artey blood samples were collected at birth, and acidemia was defined as pH below 7.20. Results: Forty seven (51.6%) newborns had acidemia at birth. Those who developed acidemia showed a UA PI z-score significantly higher (median 2.1 vs 1.7, p = 0.014), as well as a higher proportion of cases with absent or reverse end diastolic flow (51.0% vs 31.8%, p = 0.006). Regarding the MAC, the PI z-score was significantly lower in cases with pH < 7.20 (median -2.7 vs. -2.1, p = 0.042), but concerning PSV z-score, no significant relation between the groups could be established (p = 0.051).The acidemia at birth was associated with lower values of CPR (median 0.5 vs 0.7, p = 0.006), but not with its z-score (p = 0.055). In relation to the venous territory, greater values of DV PIV z-score were associated with acidemia (median 2.4 vs 0.6, p = 0.015).The correlation analysis between the pH values at birth and the Doppler measurements, a significant correlation was observed between the pH at birth and UA PI z-score (rho = -0.31, p = 0.003 ), MCA PI z-score (rho = 0.26, p = 0.012), CPR z-score (rho 0.25, p = 0.015), PIV DV zscore (rho = -0.32, p = 0.002), and PSV MCA MoM (rho = -0.21, p = 0.042). Logistic regression identified the UA PI z-score and the MCA PI z-score as independent predictors for acidemia at birth, correctly classifying 67.03% of cases. Conclusion: In pregnancies with placental insufficiency, the UA PI and the MCA PI are independent predictors associated with acidemia at birth. This study reinforces that the degree of placental insufficiency and the fetal adaptation capacity are directly related to acidemia at birth

<p>Diabetes is a major risk factor for ischemic stroke and is associated with increased mortality. Additionally, hyperglycemia, a common complication in acute stroke, is associated with poor outcome.</p><p>In order to identify the correlation between blood glucose and early mortality, multiple logistic regression analyses were used and odds ratios calculated in a retrospective study of 447 stroke patients. Eighty-one patients (18%) had diabetes. The odds ratios for 30-day case-fatality and blood glucose were 1.9 and 1.6 in diabetic and non-diabetic patients respectively. Optimal blood glucose concentrations in respective group were 10.3 and 6.3 mmol/L, as determined by receiver operator characteristic (ROC) curves.</p><p>Cerebral ischemia triggers different signaling pathways including mitogen-activated protein kinases (MAPK) which regulate fundamental cell functions. In an experimental rat model of combined hyperglycemia and transient middle cerebral artery occlusion (MCAO), the activation pattern of one such MAPK, extracellular signal-regulated kinase (ERK) was studied along with infarct volumes and neurological function. Hyperglycemia resulted in markedly increased ERK activation and approximately three-fold increase of infarcts compared with controls. </p><p>Based on the increased ERK activation, further experiments were conducted to limit the hyperglycemic-ischemic damage by interfering with ERK and supposedly related mechanisms. Consequently, rats were given U0126 (inhibiting ERK activation), PBN (anti-oxidative), PP2 (inhibiting src-family kinases), or vehicle. PBN reduced infarcts and improved neurological function compared with controls while no statistically significant effects were observed for U0126 or PP2. However, when the dose was doubled, U0126 significantly reduced infarcts and improved neurological function after 1 day in hyperglycemic rats. Post-ischemic ERK activation was completely inhibited by U0126 as demonstrated with Western immunoblotting. The findings suggest that ERK is an important mediator of hyperglycemic-ischemic brain injury and possible target for future interventions.</p>

Diabetes is a major risk factor for ischemic stroke and is associated with increased mortality. Additionally, hyperglycemia, a common complication in acute stroke, is associated with poor outcome. In order to identify the correlation between blood glucose and early mortality, multiple logistic regression analyses were used and odds ratios calculated in a retrospective study of 447 stroke patients. Eighty-one patients (18%) had diabetes. The odds ratios for 30-day case-fatality and blood glucose were 1.9 and 1.6 in diabetic and non-diabetic patients respectively. Optimal blood glucose concentrations in respective group were 10.3 and 6.3 mmol/L, as determined by receiver operator characteristic (ROC) curves. Cerebral ischemia triggers different signaling pathways including mitogen-activated protein kinases (MAPK) which regulate fundamental cell functions. In an experimental rat model of combined hyperglycemia and transient middle cerebral artery occlusion (MCAO), the activation pattern of one such MAPK, extracellular signal-regulated kinase (ERK) was studied along with infarct volumes and neurological function. Hyperglycemia resulted in markedly increased ERK activation and approximately three-fold increase of infarcts compared with controls. Based on the increased ERK activation, further experiments were conducted to limit the hyperglycemic-ischemic damage by interfering with ERK and supposedly related mechanisms. Consequently, rats were given U0126 (inhibiting ERK activation), PBN (anti-oxidative), PP2 (inhibiting src-family kinases), or vehicle. PBN reduced infarcts and improved neurological function compared with controls while no statistically significant effects were observed for U0126 or PP2. However, when the dose was doubled, U0126 significantly reduced infarcts and improved neurological function after 1 day in hyperglycemic rats. Post-ischemic ERK activation was completely inhibited by U0126 as demonstrated with Western immunoblotting. The findings suggest that ERK is an important mediator of hyperglycemic-ischemic brain injury and possible target for future interventions.

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.

Bakgrund: Hjärnskakning är en vanlig diagnos och vissa patienter upplever att fysisk ansträngning utlöser symtom lång tid efter hjärnskakningen. En förändring i reglering av cerebralt blodflöde (CBF) har visats vara en potentiell orsak bakom detta. Konditionsträning under tröskeln för symtomexacerbation kan förkorta återhämtningstiden för patienterna. På Neurorehab vid Norrlands universitetsjukhus i Umeå identifieras tröskeln med ett stegrat arbetsprov på ergometercykel. Det finns inte någon studie där transkraniell doppler (TCD) använts för att mäta förändringar i cerebralt blodflöde (CBF) under detta arbetsprov. Syfte: Att undersöka genomförbarhet och klinisk relevans av att använda TCD för mätning av blodflödeshastighet i arteria cerebri media (ACMh), hos friska män, under stegrat arbetsprov. Metod: Sex friska och regelbundet aktiva män genomförde ett stegrat arbetsprov på ergometercykel under samtidig mätning av hjärtfrekvens, blodtryck, partialtryck end-tidal CO2 (PetCO2) och blodflödeshastighet i arteria cerebri media (ACMh, mätt med TCD). Smärta från TCD-utrustning och upplevd ansträngning skattades. Tidsåtgången för TCD-tillägget samt eventuell signalförlust noterades. Resultat: Fem studiedeltagare rapporterade ökad smärta (huvudvärk), skattad med Borg CR10 skala, från TCD-utrustningen. Total tidsåtgång för TCD-tillägget var 7 minuter och 40 sekunder i median (IQR, 5 minuter och 32 sekunder). Signalförlust uppstod för en studiedeltagare på vänster sida. PetCO2 och ACMh följdes åt under arbetsprovet bortsett från avvikelser vid två tillfällen. Slutsatser: Studien visar att mätning av ACMh med TCD är genomförbart och ger relevant information om hur CBF ter sig under genomförandet av stegrat arbetsprov. TCD-utrustningen orsakade smärta vilket kan vara problematiskt vid genomförande för personer med postkontusionellt syndrom.

Univerzita Karlova v Praze 1. lékařská fakulta Autoreferát disertační práce Optimalizace indikací chirurgického a endovaskulárního ošetření intrakraniálních aneurysmat Anna Štekláčová 2018 2 Doktorské studijní programy v biomedicíně Univerzita Karlova v Praze a Akademie věd České republiky Obor: Neurovědy Předseda oborové rady: Prof. MUDr. Karel Šonka, DrSc. Školicí pracoviště: Neurochirurgická a neuroonkologická klinika 1. LF UK a ÚVN, Praha Školitel: Prof. MUDr. Vladimír Beneš, DrSc. Disertační práce bude nejméně pět pracovních dnů před konáním obhajoby zveřejněna k nahlížení veřejnosti v tištěné podobě na Oddělení pro vědeckou činnost a zahraniční styky Děkanátu 1. lékařské fakulty. 3 Obsah Abstrakt - Česky ..................................................................................... 4 Abstract - English ................................................................................... 5 Úvod........................................................................................................ 6 Hypotézy a cíle studie............................................................................. 6 Materiál a metody ................................................................................... 7 Výsledky...