PATHOPHYSIOLOGY OF INTRACRANIAL CYTOKINES IN INFLUENZA-ASSOCIATED ENCEPHALOPATHY

20世纪90年代中期以来，S在日本《国家监测记录》中出现了流行性感冒与脑病流行同步的现象。从事急诊室工作的儿科医生已经认识到，在冬季，当流感四处传播时，有一种趋势是看到患有脑病的儿童。1998年，Morishima和他的同事们开始调查，以揭示流感相关性脑病的这种同步性和病理生理学。以下数字登记了患流感相关性脑病的患者：1998/99年度202例，1999/2000年度96例，2000/2001年度56例。第一次和第二次监测显示，每个季节都有33%的患者死亡，11%到13%的患者有严重的后遗症，尽管在重症监护病房接受治疗。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危状态。C…脑病的主要表现是更多的惊厥和随后的意识丧失，这些中枢神经系统症状在高热突然发作后几个小时或最多24小时内突然出现。在惊厥发作前几小时，大多数处于能够用语言表达情感的年龄的儿童都表现出视觉和情感的变化，这应该是边缘系统刺激的结果。实验室检查结果明显恶化，血小板和血红蛋白减少，AST/LDH升高。血糖水平正常或高水平，血氨水平没有升高或在正常范围内。脑脊液检查顺利，所有细胞计数、血糖和蛋白质均处于正常水平。而脑脊液中IL-6、肿瘤坏死因子-α等促炎细胞因子水平明显升高。提示在中枢神经系统，流感相关因子(S)强烈刺激神经胶质细胞、小胶质细胞和星形胶质细胞，从而在中枢神经系统内积聚促炎细胞因子，影响神经元和血脑屏障。流行性感冒相关性脑病的化验结果似乎与感染性休克或噬血细胞综合征相似，登记的流行性感冒相关性脑病患者如下：1998/99年度202例，1999/2000年度96例，2000/2001年度56例。第一次和第二次监测显示，每个季节都有33%的患者死亡，11%到13%的患者有严重的后遗症，尽管在重症监护病房接受治疗。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危状态。脑病的主要表现是惊厥和随后的意识丧失，这些中枢神经系统症状在高热突然发作后几个小时或最多24小时内突然出现。在惊厥发作前几小时，大多数处于能够用语言表达情感的年龄的儿童都表现出视觉和情感的变化，这应该是边缘系统刺激的结果。实验室检查结果明显恶化，血小板和血红蛋白减少，AST/LDH升高。血糖水平正常或高水平，血氨水平没有升高或在正常范围内。脑脊液检查顺利，所有细胞计数、血糖和蛋白质均处于正常水平。而脑脊液中IL-6、肿瘤坏死因子-α等促炎细胞因子水平明显升高。提示在中枢神经系统，流感相关因子(S)强烈刺激神经胶质细胞、小胶质细胞和星形胶质细胞，从而在中枢神经系统内积聚促炎细胞因子，影响神经元和血脑屏障。流感相关性脑病的实验室结果似乎与感染性休克或噬血细胞综合征相似。接受监测研究的婴儿和儿童没有接种流感疫苗，只有极少数例外。政府建议接种流感疫苗，并建议不要使用非甾体抗炎药(双氯芬酸和甲芬那酸)退烧，因为非甾体抗炎药的使用可能与预后不良有关。在公布了包括低温治疗、血浆置换和甲基强的松龙脉冲治疗在内的《流行性感冒相关性脑病治疗指南》后，第三次监测研究于2000/2001年度进行。病死率降至11%，有严重后遗症的患者也降至8%。较少

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