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1.
Artigo em Inglês | MEDLINE | ID: mdl-32457227

RESUMO

OBJECTIVE: To describe a novel case of coronavirus disease 2019 (COVID-19)-associated acute necrotizing encephalopathy (ANE) in a patient with aplastic anemia where there was early brain stem-predominant involvement. METHODS: Evaluation of cause, clinical symptoms, and treatment response. RESULTS: A 59-year-old woman with a background of transfusion-dependent aplastic anemia presented with seizures and reduced level of consciousness 10 days after the onset of subjective fever, cough, and headache. Nasopharyngeal swab testing for severe acute respiratory syndrome coronavirus (SARS-CoV-2) was positive, and CT during admission demonstrated diffuse swelling of the brain stem. She required intubation and mechanical ventilation for airway protection, given her reduced level of consciousness. The patient's condition deteriorated, and MRI on day 6 demonstrated worsening brain stem swelling with symmetrical hemorrhagic lesions in the brain stem, amygdalae, putamina, and thalamic nuclei. Appearances were consistent with hemorrhagic ANE with early brain stem involvement. The patient showed no response to steroid therapy and died on the eighth day of admission. CONCLUSIONS: COVID-19 may be associated with an acute severe encephalopathy and, in this case, was considered most likely to represent an immune-mediated phenomenon. As the pandemic continues, we anticipate that the spectrum of neurologic presentation will broaden. It will be important to delineate the full clinical range of emergent COVID-19-related neurologic disease.


Assuntos
Anemia Aplástica/complicações , Infecções por Coronavirus/complicações , Leucoencefalite Hemorrágica Aguda/etiologia , Pneumonia Viral/complicações , Tonsila do Cerebelo/diagnóstico por imagem , Anemia Aplástica/terapia , Edema Encefálico/diagnóstico por imagem , Edema Encefálico/etiologia , Edema Encefálico/fisiopatologia , Edema Encefálico/terapia , Tronco Encefálico/diagnóstico por imagem , Infecções por Coronavirus/terapia , Dexametasona/uso terapêutico , Imagem de Difusão por Ressonância Magnética , Evolução Fatal , Feminino , Glucocorticoides/uso terapêutico , Humanos , Hemorragias Intracranianas/diagnóstico por imagem , Hemorragias Intracranianas/etiologia , Hemorragias Intracranianas/fisiopatologia , Leucoencefalite Hemorrágica Aguda/diagnóstico por imagem , Leucoencefalite Hemorrágica Aguda/fisiopatologia , Leucoencefalite Hemorrágica Aguda/terapia , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Pandemias , Transfusão de Plaquetas , Pneumonia Viral/terapia , Hemorragia Putaminal/diagnóstico por imagem , Hemorragia Putaminal/etiologia , Hemorragia Putaminal/fisiopatologia , Respiração Artificial , Convulsões/etiologia , Núcleos Talâmicos/diagnóstico por imagem , Tomografia Computadorizada por Raios X
2.
PLoS One ; 14(12): e0224610, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31869339

RESUMO

Malaria is an infectious disease of major worldwide clinical importance that causes a variety of severe, or complicated, syndromes including cerebral malaria, which is often fatal. Leukocyte integrins are essential for host defense but also mediate physiologic responses of the innate and adaptive immune systems. We previously showed that targeted deletion of the αD subunit (αD-/-) of the αDß2 integrin, which is expressed on key leukocyte subsets in mice and humans, leads to absent expression of the integrin heterodimer on murine macrophages and reduces mortality in mice infected with Plasmodium berghei ANKA (P. berghei ANKA). To further identify mechanisms involved in the protective effect of αD deletion in this model of severe malaria we examined wild type C57BL/6 (WT) and αD-/- mice after P. berghei ANKA infection and found that vessel plugging and leukocyte infiltration were significantly decreased in the brains of αD-/- animals. Intravital microscopy demonstrated decreased rolling and adhesion of leukocytes in cerebral vessels of αD-/- mice. Flow cytometry analysis showed decreased T-lymphocyte accumulation in the brains of infected αD-/- animals. Evans blue dye exclusion assays demonstrated significantly less dye extravasation in the brains of αD-/- mice, indicating preserved blood-brain barrier integrity. WT mice that were salvaged from P. berghei ANKA infection by treatment with chloroquine had impaired aversive memory, which was not observed in αD-/- mice. We conclude that deletion of integrin αDß2 alters the natural course of experimental severe malaria, demonstrating previously unrecognized activities of a key leukocyte integrin in immune-inflammatory responses that mediate cerebral involvement.


Assuntos
Antígenos CD11/metabolismo , Cadeias alfa de Integrinas/metabolismo , Malária/fisiopatologia , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Edema Encefálico/metabolismo , Edema Encefálico/fisiopatologia , Antígenos CD11/fisiologia , Cloroquina/metabolismo , Modelos Animais de Doenças , Inflamação/metabolismo , Cadeias alfa de Integrinas/fisiologia , Integrinas/imunologia , Integrinas/metabolismo , Contagem de Leucócitos , Leucócitos/metabolismo , Leucócitos/fisiologia , Macrófagos/metabolismo , Malária/genética , Malária Cerebral/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasmodium berghei/metabolismo
3.
BMC Neurosci ; 20(1): 62, 2019 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-31864286

RESUMO

BACKGROUND: Sodium ion transportation plays a crucial role in the pathogenesis of hypoxic-ischemic brain injury. Amiodarone, a Vaughan-Williams class III antiarrhythmic drug, has been widely used to treat life-threatening arrhythmia and cardiac arrest worldwide. In addition to its inhibitory effects on the potassium channel, amiodarone also blocks various sodium ion transporters, including the voltage-gated sodium channel, sodium pump, and Na+/Ca+ exchanger. Considering these pharmacological profile, amiodarone may affect the influx-efflux balance of sodium ion in the hypoxic-ischemic brain. Previous studies suggest that the blockade of the voltage-gated sodium channel during hypoxic-ischemic brain injury exerts neuroprotection. On the contrary, the blockade of sodium pump or Na+/Ca+ exchanger during hypoxia-ischemia may cause further intracellular sodium accumulation and consequent osmotic cell death. From these perspectives, the effects of amiodarone on sodium ion balance on the hypoxic-ischemic brain can be both protective and detrimental depending on the clinical and pathophysiological conditions. In this study, we therefore investigated the effect of amiodarone on hypoxic-ischemic brain injury using a murine experimental model. RESULTS: Compared with the control group mice, mice that received amiodarone after induction of 40-min hypoxic-ischemic brain injury exhibited lower survival rates over 7 days and worse neurological function. After 25-min hypoxic-ischemic brain injury, amiodarone treated mice exhibited larger infarct volumes (16.0 ± 6.9 vs. 24.2 ± 6.8 mm3, P < 0.05) and worse neurological function. In addition, the brains harvested from the amiodarone-treated mice contained larger amounts of sodium (194.7 ± 45.1 vs. 253.5 ± 50.9 mEq/kg dry weight, P < 0.01) and water (259.3 ± 8.9 vs. 277.2 ± 12.5 mg, P < 0.01). There were no significant differences in hemodynamic parameters between groups. CONCLUSIONS: Amiodarone exacerbated brain injuries and neurological outcomes after hypoxic-ischemic insults. Severe brain sodium accumulation and brain edema were associated with the detrimental effects of amiodarone. Amiodarone at the clinical dose can exacerbate brain injury after hypoxic-ischemic insult by affecting sodium ion transportation and facilitate intracellular sodium accumulation in the brain.


Assuntos
Amiodarona/efeitos adversos , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Hipóxia-Isquemia Encefálica/fisiopatologia , Bloqueadores dos Canais de Sódio/efeitos adversos , Animais , Antiarrítmicos/efeitos adversos , Encéfalo/patologia , Edema Encefálico/patologia , Edema Encefálico/fisiopatologia , Modelos Animais de Doenças , Hipóxia-Isquemia Encefálica/patologia , Masculino , Camundongos Endogâmicos C57BL , Neuroproteção/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/efeitos adversos , Sódio/metabolismo
4.
Stroke ; 50(12): 3424-3430, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31665994

RESUMO

Background and Purpose- Poor collateral flow is associated with poor clinical outcome in acute ischemic stroke and may indicate futile recanalization after successful thrombectomy. Pronounced early formation of cerebral ischemic edema may be the link between poor collateral status and declined functional outcome, but this relationship has not been investigated yet. We hypothesized that collateral status is associated with early lesion water uptake as quantitative marker for edema progression. Methods- One hundred seventy-six patients with middle cerebral artery stroke who underwent mechanical thrombectomy were analyzed. Status of cerebral collateral circulation (collaterals status [CS]) was derived using an established 5-point scoring system in admission computed tomography angiography, and good collaterals were defined as CS 3 to 4. Ischemic brain edema dynamics were quantified using early edema progression rate (EPR). EPR was derived from quantitative lesion water uptake in admission computed tomography divided by time from symptom onset to imaging. Good clinical outcome was defined as modified Rankin Scale score 0 to 2 after 90 days. Results- The median EPR was 1.4% per hour (interquartile range, 0.5-3.5%) in patients with good collaterals, which was lower than the median EPR in patients with poor collaterals of 5.8% per hour (interquartile range, 2.1-5.9%; P<0.0001). In multivariable regression analysis, lower CS was significantly and independently associated with higher EPR (1.6% EPR per 1-point CS; P=0.002). A higher EPR was associated with reduced likelihood of good clinical outcome: odds ratio 0.87; (95% CI, 0.76-0.99; P=0.03). Conclusions- Patients with poor CS had significantly higher EPR, which was associated with worse clinical outcome. These patients might benefit from adjuvant antiedematous treatment.


Assuntos
Edema Encefálico/etiologia , Encéfalo/irrigação sanguínea , Circulação Colateral/fisiologia , Acidente Vascular Cerebral/patologia , Idoso , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Edema Encefálico/patologia , Edema Encefálico/fisiopatologia , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Angiografia Cerebral/métodos , Angiografia por Tomografia Computadorizada , Feminino , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/fisiopatologia
5.
Stroke ; 50(11): 3246-3254, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31558140

RESUMO

Background and Purpose- Perihemorrhagic edema (PHE) is associated with poor outcome after intracerebral hemorrhage (ICH). Infiltration of immune cells is considered a major contributor of PHE. Recent studies suggest that immunomodulation via S1PR (sphingosine-1-phosphate receptor) modulators improve outcome in ICH. Siponimod, a selective modulator of sphingosine 1-phosphate receptors type 1 and type 5, demonstrated an excellent safety profile in a large study of patients with multiple sclerosis. Here, we investigated the impact of siponimod treatment on perihemorrhagic edema, neurological deficits, and survival in a mouse model of ICH. Methods- ICH was induced by intracranial injection of 0.075 U of bacterial collagenase in 123 mice. Mice were randomly assigned to different treatment groups: vehicle, siponimod given as a single dosage 30 minutes after the operation or given 3× for 3 consecutive days starting 30 minutes after operation. The primary outcome of our study was evolution of PHE measured by magnetic resonance-imaging on T2-maps 72 hours after ICH, secondary outcomes included evolution of PHE 24 hours after ICH, survival and neurological deficits, as well as effects on circulating blood cells and body weight. Results- Siponimod significantly reduced PHE measured by magnetic resonance imaging (P=0.021) as well as wet-dry method (P=0.04) 72 hours after ICH. Evaluation of PHE 24 hours after ICH showed a tendency toward attenuated brain edema in the low-dosage group (P=0.08). Multiple treatments with siponimod significantly improved neurological deficits measured by Garcia Score (P=0.03). Survival at day 10 was improved in mice treated with multiple dosages of siponimod (P=0.037). Mice treated with siponimod showed a reduced weight loss after ICH (P=0.036). Conclusions- Siponimod (BAF-312) attenuated PHE after ICH, increased survival, and reduced ICH-induced sensorimotor deficits in our experimental ICH-model. Findings encourage further investigation of inflammatory modulators as well as the translation of BAF-312 to a human study of ICH patients.


Assuntos
Azetidinas/farmacologia , Compostos de Benzil/farmacologia , Edema Encefálico , Hemorragia Cerebral , Transdução de Sinais/efeitos dos fármacos , Animais , Edema Encefálico/tratamento farmacológico , Edema Encefálico/etiologia , Edema Encefálico/metabolismo , Edema Encefálico/fisiopatologia , Hemorragia Cerebral/complicações , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/fisiopatologia , Modelos Animais de Doenças , Masculino , Camundongos , Receptores de Esfingosina-1-Fosfato/metabolismo
6.
Neurology ; 93(15): e1463-e1473, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31492719

RESUMO

OBJECTIVES: To explore the relationship between insufficient ipsilateral cerebral venous drainage and the development of perihematomal edema (PHE) and functional outcome in patients with acute intracerebral hemorrhage (ICH). METHODS: We retrospectively reviewed our prospectively collected database for patients with acute spontaneous supratentorial ICH and analyzed patients who underwent baseline CT perfusion (CTP) within 6 hours of onset and noncontrast CT at 24 hours. Absence of filling of 1 or more of the ipsilateral superficial middle cerebral vein, vein of Trolard, vein of Labbé, basal vein of Rosenthal, and internal cerebral vein, evaluated on venous maps generated from baseline CTP, was identified as absent ipsilateral venous filling (AIVF). Relative PHE (rPHE) was calculated as the ratio of PHE volume to hematoma volume on follow-up CT. RESULTS: A total of 138 patients were included. Median absolute PHE volume on follow-up CT was 3.5 (1.0-9.3) mL and rPHE was 24.3% (9.0%-49.4%). One absent ipsilateral vein was observed in 38 (27.5%) patients, and 2 absent veins were observed in 5 (3.6%) patients. Multivariate analysis showed that AIVF was independently associated with large rPHE at 24 hours (odds ratio [OR] 4.032, 95% confidence interval [CI] 1.739-9.347, p < 0.001). Large PHE volume was independently associated with poor outcome (OR 1.109, 95% CI 1.009-1.218, p = 0.031). CONCLUSION: AIVF was observed in about one-third of patients with acute ICH, which might be attributed to hypoperfusion after ICH and was strongly related to the development of PHE. Identification of cerebral venous filling status might be a promising imaging marker for PHE and a potential therapeutic target in ICH.


Assuntos
Edema Encefálico/complicações , Hemorragia Cerebral/complicações , Veias Cerebrais/fisiopatologia , Hematoma/complicações , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Edema Encefálico/fisiopatologia , Hemorragia Cerebral/fisiopatologia , Drenagem/métodos , Edema/complicações , Edema/fisiopatologia , Feminino , Hematoma/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada
7.
Neurocrit Care ; 31(3): 534-545, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31486026

RESUMO

Within the last couple of decades, advances in critical care medicine have led to increased survival of critically ill patients, as well as the discovery of notable, long-term health challenges in survivors and their loved ones. The terms post-intensive care syndrome (PICS) and PICS-family (PICS-F) have been used in non-neurocritical care populations to characterize the cognitive, psychiatric, and physical sequelae associated with critical care hospitalization in survivors and their informal caregivers (e.g., family and friends who provide unpaid care). In this review, we first summarize the literature on the cognitive, psychiatric, and physical correlates of PICS and PICS-F in non-neurocritical patient populations and draw attention to their long-term negative health consequences. Next, keeping in mind the distinction between disease-related neurocognitive changes and those that are associated directly with the experience of a critical illness, we review the neuropsychological sequelae among patients with common neurocritical illnesses. We acknowledge the clinical factors contributing to the difficulty in studying PICS in the neurocritical care patient population, provide recommendations for future lines of research, and encourage collaboration among critical care physicians in all specialties to facilitate continuity of care and to help elucidate mechanism(s) of PICS and PICS-F in all critical illness survivors. Finally, we discuss the importance of early detection of PICS and PICS-F as an opportunity for multidisciplinary interventions to prevent and treat new neuropsychological deficits in the neurocritical care population.


Assuntos
Encefalopatias/psicologia , Cuidadores/psicologia , Doença Crônica/psicologia , Disfunção Cognitiva/psicologia , Estado Terminal/psicologia , Atividades Cotidianas , Ansiedade/psicologia , Encefalopatias/fisiopatologia , Edema Encefálico/fisiopatologia , Edema Encefálico/psicologia , Lesões Encefálicas Traumáticas/fisiopatologia , Lesões Encefálicas Traumáticas/psicologia , Hemorragia Cerebral/fisiopatologia , Hemorragia Cerebral/psicologia , Disfunção Cognitiva/fisiopatologia , Cuidados Críticos , Depressão/psicologia , Humanos , Debilidade Muscular/fisiopatologia , Doenças Musculares/fisiopatologia , Neurologia , Polineuropatias/fisiopatologia , Qualidade de Vida , Estado Epiléptico/fisiopatologia , Estado Epiléptico/psicologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/psicologia , Hemorragia Subaracnóidea/fisiopatologia , Hemorragia Subaracnóidea/psicologia
8.
Int Rev Neurobiol ; 146: 45-81, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31349932

RESUMO

Several lines of evidences show that anesthetics influence neurotoxicity and neuroprotection. The possibility that different anesthetic agents potentially influence the pathophysiological and functional outcome following neurotrauma was examined in a rat model of concussive head injury (CHI). The CHI was produced by an impact of 0.224N on the right parietal bone by dropping a weight of 114.6g from a 20cm height under different anesthetic agents, e.g., inhaled ether anesthesia or intraperitoneally administered ketamine, pentobarbital, equithesin or urethane anesthesia. Five hour CHI resulted in profound volume swelling and brain edema formation in both hemispheres showing disruption of the blood-brain barrier (BBB) to Evans blue and radioiodine. A marked decrease in the cortical CBF and a profound increase in plasma or brain serotonin levels were seen at this time. Neuronal damages were present in several parts of the brain. These pathological changes were most marked in CHI under ether anesthesia followed by ketamine (35mg/kg, i.p.), pentobarbital (50mg/kg, i.p.), equithesin (3mL/kg, i.p.) and urethane (1g/kg, i.p.). The functional outcome on Rota Rod performances or grid walking tests was also most adversely affected after CHI under ether anesthesia followed by pentobarbital, equithesin and ketamine. Interestingly, the plasma and brain serotonin levels strongly correlated with the development of brain edema in head injured animals in relation to different anesthetic agents used. These observations suggest that anesthetic agents are detrimental to functional and pathological outcomes in CHI probably through influencing the circulating plasma and brain serotonin levels, not reported earlier. Whether anesthetics could also affect the efficacy of different neuroprotective agents in CNS injuries is a new subject that is currently being examined in our laboratory.


Assuntos
Anestésicos/efeitos adversos , Barreira Hematoencefálica/metabolismo , Edema Encefálico/fisiopatologia , Encéfalo/metabolismo , Encéfalo/patologia , Traumatismos Craniocerebrais/fisiopatologia , Serotonina/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Circulação Cerebrovascular , Traumatismos Craniocerebrais/metabolismo , Azul Evans/metabolismo , Radioisótopos do Iodo/metabolismo , Masculino , Destreza Motora/efeitos dos fármacos , Ratos , Teste de Desempenho do Rota-Rod , Serotonina/sangue
9.
Int Rev Neurobiol ; 146: 83-102, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31349933

RESUMO

There is a growing trend of hypertension among military and civilian populations due to lifetime stressful situations. If hypertension is uncontrolled it leads to development of diabetes and serious neurological complications. Most of the World populations live in temperate zone across the World. Thus, a possibility exists that these hypertensive and diabetic people may have external heat as potential risk factors for brain damage. We have seen brain edema and brain damage following exposure to heat stress at 38°C for 4h. A possibility exists that heat exposure in diabetic-hypertensive (DBHY) cases exacerbates exacerbation of brain pathology and edema formation. This hypothesis is examined in a rat model. The role of nitric oxide (NO) in exacerbation of HS-induced brain pathology was also evaluated using nitric oxide synthase (NOS) immunoreactivity. Hypertensive rats (produced by two-kidney one clip (2K1C) method) were made diabetic with streptozotocine (50mg/kg, i.p./day for 3days) treatment. After 6weeks, DBHY rats show 20-30mM/L Blood Glucose and hypertension (180-200mmHg). Subjection of these rats to 4h HS resulted in six- to eightfold higher BBB breakdown, brain edema formation and brain pathology. At this time, neuronal or inducible NOS expression was four- to sixfold higher in DBHY rats compared to controls. Interestingly, iNOS expression was higher than nNOS in DBHY rats. Cerebrolysin in high doses (10-mL/kg, i.v. instead of 5-mL/kg) induced significant neuroprotection and downregulation of nNOS and iNOS in DBHY animals whereas normal animals need only 5-mL/kg doses for this purpose. Our observations demonstrate that co-morbidly factors exacerbate brain damage in HS through NOS expression and require double dose of cerebrolysin for neuroprotection as compared to normal rats, not reported earlier.


Assuntos
Aminoácidos/farmacologia , Barreira Hematoencefálica/metabolismo , Edema Encefálico/fisiopatologia , Encéfalo/patologia , Diabetes Mellitus Experimental/prevenção & controle , Golpe de Calor/patologia , Golpe de Calor/fisiopatologia , Hipertensão/prevenção & controle , Óxido Nítrico Sintase/biossíntese , Animais , Encéfalo/metabolismo , Diabetes Mellitus Experimental/complicações , Hipertensão/complicações , Masculino , Neuroproteção/efeitos dos fármacos , Ratos , Estreptozocina , Regulação para Cima
10.
Neuroscience ; 413: 99-107, 2019 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-31247236

RESUMO

Ischemic stroke occurs following arterial occlusion and subsequent blood flow cease, and restoration of blood supply by thrombolytic therapy may cause cerebral ischemic reperfusion (IR) injury resulting in breakdowns of blood-brain barrier (BBB). Dl-3-n-butylphthalide (NBP) is an extraction from Chinese celery Apium graveolens Linn seeds and has neuroprotective effects in ischemic stroke. This study explored effects of NBP on BBB disruption caused by cerebral IR and transformation of tight junctions (TJs)-associated proteins and caveolae. Our results demonstrated that NBP alleviated cerebral IR-induced deterioration of vascular permeability by up-regulating TJ-associated proteins but down-regulating caveolin-1. NBP significantly improved neurological function and cerebral blood flow but reduced cerebral edema and infarct volume after IR. In conclusion, NBP exerts neuroprotective effects through attenuating cerebral infarct volume and neurological deficit score, reducing cerebral edema and BBB permeability. The neuroprotective effect of NBP is possibly related to its ability to improve blood flow in cerebral ischemic areas. NBP may turn into a novel treatment drug to prevent BBB dysfunction in ischemic stroke.


Assuntos
Benzofuranos/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Permeabilidade Capilar/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Barreira Hematoencefálica/fisiopatologia , Edema Encefálico/tratamento farmacológico , Edema Encefálico/fisiopatologia , Isquemia Encefálica/fisiopatologia , Permeabilidade Capilar/fisiologia , Caveolina 1/metabolismo , Circulação Cerebrovascular/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Camundongos , Distribuição Aleatória , Traumatismo por Reperfusão/fisiopatologia , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo
11.
PLoS One ; 14(6): e0218415, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31220136

RESUMO

Aquaporin-4 (AQP4) plays an important role in regulating water exchange across the blood-brain barrier (BBB) and brain-cerebrospinal fluid interface. Studies on AQP-4 knockout mice (AQP4-KO) have reported considerable protection from brain edema induced by acute water intoxication and ischemic stroke, identifying AQP4 as a potential target for therapeutic interventions. However, the long-term effects of chronic AQP4 suppression are yet to be elucidated. In the current study, we evaluated the physiological and structural changes in adult AQP4-KO mice using magnetic resonance imaging (MRI) and immunohistochemical analysis. Water exchange across BBB was assessed by tracking an intravenous bolus injection of oxygen-17 (17O) water (H217O) using 17O-MRI. Cerebral blood flow (CBF) was quantified using arterial spin-labeling (ASL) MRI. Capillary density was determined by immunohistochemical staining for glucose transporter-1 (GLUT1). Compared to wildtype control mice, AQP4-KO mice showed a significant reduction in peak and steady-state H217O uptake despite unaltered CBF. Interestingly, a 22% increase in cortical capillary density was observed in AQP4-KO mice. These results suggest that increased cerebral vascularization may be an adaptive response to chronic reduction in water exchange across BBB in AQP4-KO mice.


Assuntos
Aquaporina 4/genética , Edema Encefálico/genética , Encéfalo/irrigação sanguínea , Neovascularização Patológica/genética , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Transporte Biológico/genética , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Edema Encefálico/metabolismo , Edema Encefálico/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Knockout , Neovascularização Patológica/patologia , Água/metabolismo
12.
Neurología (Barc., Ed. impr.) ; 34(5): 326-335, jun. 2019. graf, ilus
Artigo em Espanhol | IBECS | ID: ibc-180849

RESUMO

Introducción: El ictus es una de las principales causas de mortalidad en el mundo y debido al incremento en la expectativa de vida su incidencia va en aumento; sin embargo, el desarrollo de nuevos medicamentos con utilidad clínica ha sido prácticamente nulo, por lo que hasta la fecha el tratamiento de estos pacientes es muy limitado. Desarrollo: La evidencia básica y clínica en el área señala que tras un infarto cerebral se producen una serie de cambios neuroquímicos, entre los que se encuentran: la depleción energética, la producción de radicales libres, la acumulación de calcio, la desregulación de neurotransmisores, la excitotoxicidad, y de manera tardía, la activación del sistema inmune caracterizada como inflamación. Esta respuesta del sistema inmunológico ha mostrado ser un evento central en la progresión de la patología, en el que destaca la participación de las citocinas proinflamatorias como TNF, que aumentan el daño por excitotoxicidad y por acumulación de calcio, favorecen la formación de radicales libres y en general promueven la muerte celular. Por otro lado, algunas citocinas antiinflamatorias como IL-10 e IL-4 han mostrado tener efectos neuroprotectores e incluso favorecen la recuperación de sinapsis y la neurogénesis, haciendo de la modulación de la respuesta inmunológica un área con mucho potencial terapéutico. Conclusiones: El entendimiento de las relaciones entre el sistema inmunológico y el sistema nervioso no solo nos permite entender con mayor profundidad el fenómeno del ictus, sino que también nos ofrece un nuevo arsenal de estrategias diagnósticas, pronósticas y terapéuticas que podrían mejorar la calidad de vida de las personas aquejadas por esta terrible enfermedad


Introduction: Stroke is one of the leading causes of death in the world; its incidence is increasing due to increased life expectancy. However, treatment options for these patients are limited since no clinically effective drugs have been developed to date. Development: According to clinical evidence, a number of neurochemical changes take place after stroke, including energy depletion, increased free radical synthesis, calcium accumulation, neurotransmitter imbalance, excitotoxicity, and, at a later stage, immune system activation leading to inflammation. Immune response has been shown to be a major factor in disease progression. The release of proinflammatory cytokines such as TNF increase brain damage secondary to excitotoxicity and calcium accumulation, and promote free radical synthesis and cell death through various mechanisms. On the other hand, certain anti-inflammatory cytokines, such as IL-10 and IL-4, have been shown to have a neuroprotective effect and even promote neurogenesis and synapse remodeling, which makes immune modulation a promising treatment approach. Conclusions: Understanding the relationship between the immune system and the nervous system not only deepens our knowledge of stroke but also provides new diagnostic, prognostic, and therapeutic strategies that may increase the quality of life of stroke patients


Assuntos
Humanos , Neuroimunomodulação/fisiologia , Acidente Vascular Cerebral/fisiopatologia , Neurogênese/fisiologia , Neuroproteção/fisiologia , Trifosfato de Adenosina/deficiência , Edema Encefálico/fisiopatologia , Microglia/fisiologia , Macrófagos/fisiologia
14.
Pediatr Neurol ; 92: 60-66, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30611519

RESUMO

BACKGROUND: Unilateral brain edema is a rare peri-ictal imaging abnormality related to focal status epilepticus. We present the largest series of these patients, describe their clinical features and magnetic resonance imaging (MRI) findings, and analyze the possible underlying pathophysiology. METHODS: We reviewed the medical records in Southwest China's largest tertiary's children's medical center from 2011 to 2017. Patients with focal status epilepticus were included if acute-phase cerebral MRI showed unilateral edematous swelling of the epileptic hemisphere. RESULTS: Eleven children were included. The age at which the patients presented with status epilepticus ranged from seven months to 10.8 years. All patients showed prolonged clonic seizures with marked unilateral predominance followed by hemiplegia of the ipsilateral limbs. The seizure duration ranged from one to 72 hours. All patients showed hyperintensities on T2-weighted images and diffusion-weighted images involving the whole pathologic hemisphere. Three patients showed involvement of the contralateral cerebellar hemisphere and one showed hippocampal herniation. Magnetic resonance angiography of the brain was performed in seven patients, among which three showed dilation of the affected hemispheric arteries. Three patients underwent follow-up MRI, and all the examinations revealed ipsilateral cerebral hemisphere atrophy. CONCLUSIONS: Focal status epilepticus may cause unilateral brain edema, and cytotoxic edema probably plays an important role in the pathophysiology of brain injury.


Assuntos
Edema Encefálico , Epilepsias Parciais , Hemiplegia , Imagem por Ressonância Magnética , Estado Epiléptico , Edema Encefálico/diagnóstico por imagem , Edema Encefálico/patologia , Edema Encefálico/fisiopatologia , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Criança , Pré-Escolar , China , Imagem de Difusão por Ressonância Magnética , Eletroencefalografia , Epilepsias Parciais/diagnóstico por imagem , Epilepsias Parciais/patologia , Epilepsias Parciais/fisiopatologia , Hemiplegia/diagnóstico por imagem , Hemiplegia/patologia , Hemiplegia/fisiopatologia , Hipocampo/diagnóstico por imagem , Hipocampo/patologia , Humanos , Lactente , Angiografia por Ressonância Magnética , Estudos Retrospectivos , Estado Epiléptico/diagnóstico por imagem , Estado Epiléptico/patologia , Estado Epiléptico/fisiopatologia
15.
Neurol Sci ; 40(4): 745-752, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30659418

RESUMO

OBJECTIVES: To produce a scoring system for predicting the development of edema in ischemic stroke patients without edema on admission. METHODS: This retrospective study included 572 ischemic stroke patients (73.3 ± 13.0 years, 300 male) without signs of cerebral edema on the first CT scan, which was performed on admission. Another scan was normally performed 3 days later, and subsequently whenever needed. Edema was defined as cerebral hypodensity with compression of lateral ventricles. The main clinical, laboratory, and instrumental variables obtained during the first 24 h were related to the appearance of edema on the CT scans performed after the first one. RESULTS: Cerebral edema occurred in 158 patients (27.6%) after a median time of 4 days. The variables independently associated with edema development were (odds ratio, 95% CI) the following: (1) total anterior circulation syndrome (4.20, 2.55-6.93; P < 0.0001), (2) hyperdense appearance of middle cerebral artery (4.12, 2.03-8.36; P = 0.0001), (3) closed eyes (2.53, 1.39-4.60; P = 0.002), (4) vomiting (3.53, 1.45-8.60; P = 0.006), (5) lacunar cerebral syndrome (0.36, 0.17-0.77; P = 0.008); and (6) white matter lesions (0.53, 0.33-0.86; P = 0.01). Counting one positive point for the first four variables and one negative point for the last two variables, a scoring system (E-score) was built. Cerebral edema could be predicted when the score was ≥ 1 (positive predictive value 61.6%, specificity 85.3%, sensitivity 62.0%). The area under the receiver operating characteristic curve was 0.78. CONCLUSIONS: In ischemic stroke patients, six variables obtained during the first 24 h of hospitalization were predictive of subsequent cerebral edema development.


Assuntos
Edema Encefálico/diagnóstico , Isquemia Encefálica/diagnóstico , Índice de Gravidade de Doença , Acidente Vascular Cerebral/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Edema Encefálico/diagnóstico por imagem , Edema Encefálico/etiologia , Edema Encefálico/fisiopatologia , Isquemia Encefálica/complicações , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/fisiopatologia , Tomografia Computadorizada por Raios X
16.
Neurocrit Care ; 30(2): 340-347, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30251075

RESUMO

BACKGROUND: An external ventricular drain (EVD) is the gold standard for measurement of intracranial pressure (ICP) and allows for drainage of cerebrospinal fluid (CSF). Different causes of elevated ICP, such as CSF outflow obstruction or cerebral swelling, respond differently to CSF drainage. This is a widely recognized but seldom quantified distinction. We sought to define an index to characterize the response to CSF drainage in neurocritical care patients. METHODS: We studied consecutive patients admitted to the neurointensive care unit who had an EVD. The EVD was closed for 30 min prior to assessment. We documented pre-drainage ICP, opened EVD to drainage allowing CSF to drain until it ceased, and recorded post-drainage ICP at EVD closure. We calculated the pressure equalization (PE) ratio as the difference between pre-drainage ICP and post-drainage ICP divided by the difference between pre-drainage ICP and EVD height. RESULTS: We studied 60 patients (36 traumatic brain injury [TBI], 24 non-TBI). As expected, TBI patients had more signs of cerebral swelling on CT and smaller ventricles. Although TBI patients had significantly higher pre-drainage ICP (26 ± 10 mm Hg) than non-TBI patients (19 ± 5 mm Hg, p < 0.001) they drained less CSF (7 cc vs. 4 cc, p < 0.01). PE ratio was substantially higher in non-TBI than in TBI patients (0.86 ± 0.36 vs. 0.43 ± 0.31, p < 0.0001), indicating that non-TBI patients were better able to equalize pressure with EVD height than TBI patients. CONCLUSIONS: PE ratio reflects the ability to equalize pressure with the preset height of the EVD and differs substantially between TBI and non-TBI patients. A high PE ratio likely indicates CSF outflow obstruction effectively treated by CSF diversion, while a lower PE ratio occurs when cerebral swelling predominates. Further studies could assess whether the PE ratio would be useful as a surrogate marker for cerebral edema or the state of intracranial compliance.


Assuntos
Edema Encefálico/fisiopatologia , Lesões Encefálicas Traumáticas/fisiopatologia , Derivações do Líquido Cefalorraquidiano , Cuidados Críticos , Pressão Intracraniana/fisiologia , Monitorização Neurofisiológica , Adulto , Idoso , Edema Encefálico/etiologia , Edema Encefálico/cirurgia , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
17.
J Clin Neurosci ; 61: 298-301, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30385166

RESUMO

We report a child with hypotonia, optic atrophy, progressive encephalopathy and intractable infantile spasms who was diagnosed with PEHO syndrome. Extensive investigation was performed to diagnose an underlying etiology. Electron transport chain activities in muscle biopsies showed an isolated complex IV deficiency. Genetic examination focused on complex IV genes such as mtDNA and relevant nuclear DNA analysis was unremarkable. Whole exome sequencing with trio revealed a heterozygous de novo mutation at c.757G>A (p.E253K) in the KIF1A gene. The protein encoded by this gene functions as an anterograde motor protein that transports membranous organelles along axonal microtubules. The relation between this genetic mutation and decreased activity of the mitochondrial respiratory chain complex is discussed in details. Our study further confirmed that the molecular basis of PEHO syndrome at least in a subset of patients is a dominant KIF1A variant affecting the motor domain of the protein. This is the first description of the decreased activity of mitochondrial respiratory chain complex in association with either PEHO syndrome or KIF1A mutation. This study emphasizes that the results of the mitochondrial enzymes should be interpreted with caution and clinicians should be actively looking for other underlying diagnoses with further comprehensive studies.


Assuntos
Edema Encefálico/genética , Edema Encefálico/fisiopatologia , Deficiência de Citocromo-c Oxidase/genética , Complexo IV da Cadeia de Transporte de Elétrons , Cinesina/genética , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/fisiopatologia , Atrofia Óptica/genética , Atrofia Óptica/fisiopatologia , Espasmos Infantis/genética , Espasmos Infantis/fisiopatologia , Complexo IV da Cadeia de Transporte de Elétrons/genética , Feminino , Humanos , Lactente , Mutação
18.
Neurocrit Care ; 30(2): 307-315, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30298336

RESUMO

BACKGROUND: Osmotic therapy is a critical component of medical management for cerebral edema. While up to 90% of neurointensivists report using these treatments, few quantitative clinical measurements guide optimal timing, dose, or administration frequency. Its use is frequently triggered by a qualitative assessment of neurologic deterioration and/or pupil size, and anecdotally appears to improve pupil asymmetry suggestive of uncal herniation. However, subjective pupil assessment has poor reliability, making it difficult to detect or track subtle changes. We hypothesized that osmotic therapy reproducibly improves quantitative pupil metrics. METHODS: We included patients at two centers who had recorded quantitative pupil measurements within 2 h before and after either 20% mannitol or 23.4% hypertonic saline in the neurosciences intensive care unit. The primary outcome was the Neurologic Pupil Index (NPi), a composite metric ranging from 0 to 5 in which > 3 is considered normal. Secondary outcomes included pupil size, percent change, constriction and dilation velocity, and latency. Results were analyzed with Wilcoxon signed-rank tests, Chi-square and multi-level linear regression to control for other edema-reducing interventions. RESULTS: Out of 72 admissions (403 paired pupil observations), NPi significantly differed within 2 h of osmotic therapy when controlling for other commonly used interventions in our whole cohort (ß = 0.08, p = 0.0168). The effect was most pronounced (ß = 0.57) in patients with abnormal NPi prior to intervention (p = 0.0235). CONCLUSIONS: Pupil reactivity significantly improves after osmotic therapy in a heterogenous critically ill population when controlling for various other interventions. Future work is necessary to determine dose-dependent effects and clinical utility.


Assuntos
Encefalopatias/tratamento farmacológico , Encefalopatias/fisiopatologia , Edema Encefálico/tratamento farmacológico , Edema Encefálico/fisiopatologia , Cuidados Críticos/métodos , Diuréticos Osmóticos/farmacologia , Manitol/farmacologia , Pupila , Solução Salina Hipertônica/farmacologia , Adulto , Idoso , Diuréticos Osmóticos/administração & dosagem , Feminino , Humanos , Masculino , Manitol/administração & dosagem , Pessoa de Meia-Idade , Estudos Prospectivos , Solução Salina Hipertônica/administração & dosagem
19.
Neuropharmacology ; 145(Pt B): 230-246, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30086289

RESUMO

Cerebral edema (CE) and resultant intracranial hypertension are associated with unfavorable prognosis in traumatic brain injury (TBI). CE is a leading cause of in-hospital mortality, occurring in >60% of patients with mass lesions, and ∼15% of those with normal initial computed tomography scans. After treatment of mass lesions in severe TBI, an important focus of acute neurocritical care is evaluating and managing the secondary injury process of CE and resultant intracranial hypertension. This review focuses on a contemporary understanding of various pathophysiologic pathways contributing to CE, with a subsequent description of potential targeted therapies. There is a discussion of identified cellular/cytotoxic contributors to CE, as well as mechanisms that influence blood-brain-barrier (BBB) disruption/vasogenic edema, with the caveat that this distinction may be somewhat artificial since molecular processes contributing to these pathways are interrelated. While an exhaustive discussion of all pathways with putative contributions to CE is beyond the scope of this review, the roles of some key contributors are highlighted, and references are provided for further details. Potential future molecular targets for treating CE are presented based on pathophysiologic mechanisms. We thus aim to provide a translational synopsis of present and future strategies targeting CE after TBI in the context of a paradigm shift towards precision medicine. This article is part of the Special Issue entitled "Novel Treatments for Traumatic Brain Injury".


Assuntos
Edema Encefálico/fisiopatologia , Edema Encefálico/terapia , Lesões Encefálicas Traumáticas/fisiopatologia , Lesões Encefálicas Traumáticas/terapia , Animais , Edema Encefálico/etiologia , Lesões Encefálicas Traumáticas/complicações , Humanos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico
20.
Behav Brain Res ; 356: 8-17, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30092249

RESUMO

Ischemia/reperfusion (I/R) injuries commonly lead to breakdown of the blood-brain barrier (BBB). Restoration of the BBB can relieve neurologic damage caused by I/R injuries. The Hippo/YAP signaling pathway mediates cell proliferation, regulated cell death, and differentiation in various organisms and has been shown to participate in the restoration of the heart after I/R. In this study, we investigated whether the Hippo/YAP pathway plays a role in I/R injury in brain, especially in regard to I/R-induced BBB breakdown. The results of our study indicate that I/R injury led to an overall decrease in activity of the core proteins, YAP and TAZ, over a 24-h period. The most dramatic change was observed 1.5 h after reperfusion. In rats that underwent 1.5 h of reperfusion, intraperitoneal injection of YAP agonist dexamethasone activated YAP and TAZ and led to improved neurologic function, smaller brain infarct sizes, increased levels of tight junction proteins, decreased BBB permeability, decreased cerebral edema, and less apoptosis. Our results suggest that YAP exerts neuroprotective effects on the damaged brain that are likely related to restoration of the BBB.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Fatores de Transcrição/metabolismo , Animais , Proteínas Reguladoras de Apoptose/fisiologia , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Edema Encefálico/fisiopatologia , Isquemia Encefálica/fisiopatologia , Dexametasona/farmacologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Fármacos Neuroprotetores/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/prevenção & controle , Transdução de Sinais/fisiologia
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