PATHOPHYSIOLOGY OF INTRACRANIAL CYTOKINES IN INFLUENZA-ASSOCIATED ENCEPHALOPATHY

从20世纪90年代中期开始，日本的国家监测记录显示流感和脑病的流行同时发生。从事急诊室的儿科医生已经认识到，在冬季，当流感四处蔓延时，有一种趋势是看到儿童受到脑病的影响。1998年，Morishima和他的同事们开始研究流感相关脑病的同步性和病理生理学，以下数量的患者被招募为流感相关脑病：1998/99季节202例患者，1999/2000季节96例患者，2000/2001季节56例患者。第一次和第二次监测显示，每个季节的患者死亡率为33%，11%至13%的患者在高度重症监护病房治疗后仍有严重后遗症。大多数患者是5岁以下的儿童（占总数的75%），特别是0至2岁的婴儿被发现处于高风险中。C ...更多信息 惊厥和随后的意识丧失是脑病的主要表现，这些CNS症状在高热突然发作后数小时或长达24小时内突然发生。在惊厥发作前2小时，大多数处于能用语言表达情感年龄的儿童出现视觉和情绪变化，估计是边缘系统刺激的结果。观察到实验室检查结果明显恶化;血小板和血红蛋白数量减少，AST/LDH升高。葡萄糖水平正常或偏高，血清铵水平未升高或在正常范围内。CSF检查正常，所有细胞计数、葡萄糖和蛋白质均处于正常水平。CSF中IL 6、TNFα等促炎细胞因子水平明显升高。这表明在CNS中，流感相关因子强烈刺激胶质细胞、小胶质细胞和星形胶质细胞，从而在CNS中积累促炎细胞因子并影响神经元和血脑屏障。流感相关脑病的实验室检查结果似乎与感染性休克或噬血细胞综合征相似。入组的流感相关脑病患者数量如下：1998/99年流感季202例，1999/2000年流感季96例，2000/2001年流感季56例。第一次和第二次监测显示，每个季节的患者死亡率为33%，11%至13%的患者在高度重症监护病房治疗后仍有严重后遗症。大多数患者是5岁以下的儿童（占总数的75%），特别是0至2岁的婴儿被发现处于高风险中。惊厥和随后的意识丧失是脑病的主要表现，这些CNS症状在高热突然发作后数小时或长达24小时内突然发生。在惊厥发作前2小时，大多数处于能用语言表达情感年龄的儿童出现视觉和情绪变化，估计是边缘系统刺激的结果。观察到实验室检查结果明显恶化;血小板和血红蛋白数量减少，AST/LDH升高。葡萄糖水平正常或偏高，血清铵水平未升高或在正常范围内。CSF检查正常，所有细胞计数、葡萄糖和蛋白质均处于正常水平。CSF中IL 6、TNFα等促炎细胞因子水平明显升高。这表明在CNS中，流感相关因子强烈刺激胶质细胞、小胶质细胞和星形胶质细胞，从而在CNS中积累促炎细胞因子并影响神经元和血脑屏障。流感相关脑病的实验室检查结果似乎与感染性休克或噬血细胞综合征相似。除极少数例外，接受监测研究的婴儿和儿童未接种流感疫苗。政府建议接种流感疫苗，不要使用NSAIDs（双氯酚酸和甲芬那酸）作为退热剂，因为NSAIDs的使用可能与不良预后有关。在《流感相关脑病治疗指南》（包括低温治疗、血浆置换和甲基强的松龙冲击治疗）出版后，在2000/2001年季节进行了第三次监测研究。死亡率下降到11%，严重后遗症患者的数量也下降到8%的总患者。少

From the middle of 1990's, it showed a synchronizing phenomenon of epidemics between influenza and encephalopathy in National Surveillance Records in Japan. Pediatricians engaged in emergency room have recognized that in winter season, when influenza is spreading around, there has been a tendency o see children affected with encephalopathy. In 1998, Morishima and his colleagues started investigation to reveal this synchronization and pathophysiology of influenza-associated encephalopathy.The following numbers of patients were enrolled with influenza-associated encephalopathy; 202 patients in 1998/99 season 96 patients in 1999/2000 season, and 56 patients in 2000/2001 season. The first and second surveillance demonstrated that 33% of patients in each season were dead, and 11 to 13% had severe sequelae though treated in highly intensive care units. Most patients were children under 5 year-old (75% of total), and especially infants between 0 and 2 year-old were found to be at high risk. C … More onvulsion and subsequent unconsciousness were the primary manifestation of encephalopathy, and these CNS symptoms occurred suddenly in a few hours or up to 24 hours after the abrupt onset of high fever. A couple of hours before onset of convulsion, most children who were in age of being able to express their feelings in language, manifested visual and emotional changes, which should be estimated to be the results of limbic system stimulation. Marked deterioration of laboratory findings was noticed; decreased number of platelets and hemoglobin and increased AST/LDH. Glucose levels were normal or high and serum ammonium levels were not increased or within normal range. Examination of CSF was uneventful, all cell counts, glucose, and protein were at normal levels. However, CSF levels of proinflammatory cytokines including IL6 and TNFα were markedly increased. It suggested that in CNS influenza-related factor(s) vigorously stimulates glial cells microglia and astrocytes, thereby accumulating proinflammatory cytokines in CNS and affecting neurons and blood-brain barrier. Laboratory findings in influenza-associated encephalopathy seem to be similar to those seen in septic shock or hemophagocytic syndrome.The following numbers of patients were enrolled with influenza-associated encephalopathy; 202 patients in 1998/99 season 96 patients in 1999/2000 season, and 56 patients in 2000/2001 season. The first and second surveillance demonstrated that 33% of patients in each season were dead, and 11 to 13% had severe sequelae though treated in highly intensive care units. Most patients were children under 5 year-old (75% of total), and especially infants between 0 and 2 year-old were found to be at high risk. Convulsion and subsequent unconsciousness were the primary manifestation of encephalopathy, and these CNS symptoms occurred suddenly in a few hours or up to 24 hours after the abrupt onset of high fever. A couple of hours before onset of convulsion, most children who were in age of being able to express their feelings in language, manifested visual and emotional changes, which should be estimated to be the results of limbic system stimulation. Marked deterioration of laboratory findings was noticed; decreased number of platelets and hemoglobin and increased AST/LDH. Glucose levels were normal or high and serum ammonium levels were not increased or within normal range. Examination of CSF was uneventful, all cell counts, glucose, and protein were at normal levels. However, CSF levels of proinflammatory cytokines including IL6 and TNFα were markedly increased. It suggested that in CNS influenza-related factor(s) vigorously stimulates glial cells microglia and astrocytes, thereby accumulating proinflammatory cytokines in CNS and affecting neurons and blood-brain barrier. Laboratory findings in influenza-associated encephalopathy seem to be similar to those seen in septic shock or hemophagocytic syndrome.Infants and children subjected to the surveillance study were not given influenza vaccine with very few exceptions. The Government recommended influenza vaccination, and not to use NSAIDs(diclophenac and mefenamic acid) as anti-febrile because of possible relationship between poor prognosis and usage of NSAIDs.After publication of "Guideline for Therapy of Influenza-associated Encephalopathy" including hypothermia therapy, plasma exchange, and methylprednisolone-pulses, the third surveillance study was performed in 2000/2001 season. The mortality rate was reduced to 11% and the number of patients with severe sequelae was also decreased to 8% of total patients. Less