PATHOPHYSIOLOGY OF INTRACRANIAL CYTOKINES IN INFLUENZA-ASSOCIATED ENCEPHALOPATHY

从20世纪90年代中期开始，在日本的国家监测记录中，流感和脑病的流行呈现出同步现象。在急诊室工作的儿科医生已经认识到，在流感四处传播的冬季，儿童有患脑病的趋势。1998年，Morishima和他的同事开始研究流感相关脑病的同步性和病理生理学。以下数量的流感相关脑病患者入组：1998/99季202例，1999/2000季96例，2000/2001季56例。第一次和第二次监测表明，每个季节33%的患者死亡，尽管在高度重症监护病房接受治疗，但仍有11%至13%的患者有严重的后遗症。大多数患者为5岁以下儿童（占总数的75%），特别是0 - 2岁的婴儿是高危人群。更多的惊厥和随后的意识不清是脑病的主要表现，这些中枢神经系统症状在突然发高烧后几小时或24小时内突然发生。在抽搐发作前的几个小时，大多数处于能够用语言表达感情的年龄的儿童，表现出视觉和情绪上的变化，这应该估计是边缘系统受到刺激的结果。注意到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。血糖水平正常或偏高，血清铵水平未升高或在正常范围内。脑脊液检查无异常，所有细胞计数、葡萄糖和蛋白质均在正常水平。然而，脑脊液的促炎细胞因子包括il - 6和tnf - α水平明显升高。提示在中枢神经系统中，流感相关因子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中积累促炎细胞因子，影响神经元和血脑屏障。流感相关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。以下数量的流感相关脑病患者入组：1998/99季202例，1999/2000季96例，2000/2001季56例。第一次和第二次监测表明，每个季节33%的患者死亡，尽管在高度重症监护病房接受治疗，但仍有11%至13%的患者有严重的后遗症。大多数患者为5岁以下儿童（占总数的75%），特别是0 - 2岁的婴儿是高危人群。惊厥和随后的无意识是脑病的主要表现，这些中枢神经系统症状在突然发高烧后几小时或24小时内突然发生。在抽搐发作前的几个小时，大多数处于能够用语言表达感情的年龄的儿童，表现出视觉和情绪上的变化，这应该估计是边缘系统受到刺激的结果。注意到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。血糖水平正常或偏高，血清铵水平未升高或在正常范围内。脑脊液检查无异常，所有细胞计数、葡萄糖和蛋白质均在正常水平。然而，脑脊液的促炎细胞因子包括il - 6和tnf - α水平明显升高。提示在中枢神经系统中，流感相关因子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中积累促炎细胞因子，影响神经元和血脑屏障。流感相关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，并且不使用非甾体抗炎药（双氯芬酸和甲氧胺酸）作为退热药，因为不良预后可能与非甾体抗炎药的使用有关。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脉冲治疗）出版后，在2000/2001年度进行了第三次监测研究。死亡率降至11%，严重后遗症患者数量也降至8%。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