Viral Encephalopathy

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<p>Acta Neurol Scand 2007: 115 (Suppl. 186): 4556</p> <p>Copyright 2007 The Authors Journal compilation 2007 Blackwell MunksgaardACTA NEUROLOGICA SCANDINAVICA</p> <p>Acute encephalopathy associated with inuenza and other viral infectionsMizuguchi M, Yamanouchi H, Ichiyama T, Shiomi M. Acute encephalopathy associated with inuenza and other viral infections. Acta Neurol Scand 2007: 115 (Suppl. 186): 4556. 2007 The Authors Journal compilation 2007 Blackwell Munksgaard. Acute encephalopathy is the most serious complication of pediatric viral infections, such as inuenza and exanthem subitum. It occurs worldwide, but is most prevalent in East Asia, and every year several hundreds of Japanese children are aected by inuenza-associated encephalopathy. Mortality has recently declined, but is still high. Many survivors are left with motor and intellectual disabilities, and some with epilepsy. This article reviews various syndromes of acute encephalopathy by classifying them into three major categories. The rst group caused by metabolic derangement consists of various inherited metabolic disorders and the classical Reye syndrome. Salicylate is a risk factor of the latter condition. The second group, characterized by a systemic cytokine storm and vasogenic brain edema, includes Reye-like syndrome, hemorrhagic shock and encephalopathy syndrome, and acute necrotizing encephalopathy. Non-steroidal antiinammatory drugs, such as diclofenac sodium and mephenamic acid, may aggravate these syndromes. Severe cases are complicated by multiple organ failure and disseminated intravascular coagulation. Mortality is high, although methylprednisolone pulse therapy may be benecial in some cases. The third group, characterized by localized edema of the cerebral cortex, has recently been termed acute encephalopathy with febrile convulsive status epilepticus, and includes hemiconvulsion-hemiplegia syndrome and acute infantile encephalopathy predominantly aecting the frontal lobes. Theophylline is a risk factor of these syndromes. The pathogenesis is yet to be claried, but an increasing body of evidence points to excitotoxicity and delayed neuronal death.</p> <p>M. Mizuguchi1, H. Yamanouchi2, T. Ichiyama3, M. Shiomi41 Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; 2 Department of Pediatrics, Dokkyo University School of Medicine, Mibu, Japan; 3Department of Pediatrics, Yamaguchi University School of Medicine, Ube, Japan; 4 Department of Pediatric Emergency Medicine, Osaka City General Hospital, Osaka, Japan</p> <p>All authors declare no conflict of interests</p> <p>Key words: acute encephalopathy; Reye-like syndrome; hemorrhagic shock and encephalopathy syndrome; acute necrotizing encephalopathy; acute encephalopathy with febrile convulsive status epilepticus; hemiconvulsion-hemiplegia syndrome; acute infantile encephalopathy predominantly affecting the frontal lobes Masashi Mizuguchi, Department of Pediatrics, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan Tel.: +81 3 5800 8902 Fax: +81 3 5800 8902 e-mail: Accepted for publication 11 December, 2006</p> <p>Introduction</p> <p>Acute encephalopathy is a generic term for acute brain dysfunction usually preceded by infection. Its main symptoms are impaired consciousness and signs of increased intracranial pressure, often accompanied by convulsions or seizures. Its incidence is highest in infancy and early childhood. The antecedent infection is viral in the majority of cases, although bacteria such as enterohemorrhagic Escherichia coli (hemorrhagic colitis), Salmonella enteritidis, Bordetella pertussis, and Bartonella henselae (cat scratch disease) may also cause acute encephalopathy. The pathologic substrate of acute encephalopathy is diuse or widespread, non-inammatory</p> <p>brain edema, which is either cellular (cytotoxic) or vascular (vasogenic). Cellular edema is ascribed to the dysfunction of channels on the cell membrane of neurons and glial cells, which often results from the disruption of mitochondria (1). Vascular edema is caused by disruption of the bloodbrain barrier. This article summarizes recent advances in the study of acute encephalopathy associated with viral infections, focusing on the classication, pathology, pathogenesis, risk factors, and treatment.Classification based on the pathogenic virus</p> <p>Virus infection-associated acute encephalopathy is classied by two means; the pathogenic virus of the antecedent infection (Table 1) and the 45</p> <p>Mizuguchi et al.Table 1 Classification according to the pathogenic virus of antecedent infection Influenza encephalopathy Exanthem subitum (human herpes virus 6) encephalopathy Rotavirus encephalopathy Chickenpox (varicella-zoster virus) encephalopathy Measles encephalopathy Respiratory syncytial virus encephalopathy Other virus-associated encephalopathy</p> <p>associated with acute infantile encephalopathy predominantly aecting the frontal lobes (AIEF) (5), and with hemiconvulsion-hemiplegia (HH) syndrome (6). HHV-6 is also an important cause of ANE, accounting for about 10% of cases (3, 6).Classification based on the suspected pathomechanism</p> <p>Table 2 Classification according to the clinicopathologic features Classical Reye syndrome Reye-like syndrome Hemorrhagic shock and encephalopathy syndrome Acute necrotizing encephalopathy Hemiconvulsion-hemiplegia syndrome Acute infantile encephalopathy predominantly affecting the frontal lobes Others</p> <p>clinicopathologic features of encephalopathy (Table 2). Neither classication is fully comprehensive as a virus cannot be identied in some cases, and the clinicopathologic ndings are atypical or nonspecic in others. There is no specic correlation between the virus and encephalopathic syndromes. Namely, any virus may cause any type of encephalopathy. In each syndrome, the clinical, laboratory, and radiologic features are essentially the same between dierent viruses.Influenza encephalopathy</p> <p>Since the 1990s, the high morbidity and mortality of inuenza encephalopathy has prompted Japanese investigators to explore the pathogenesis of acute encephalopathy, and to distinguish new encephalopathic syndromes, such as ANE (7) and AIEF (5). Based on the results of these studies, this article attempts to classify the syndromes into three major categories: metabolic error, cytokine storm, and excitotoxicity (Table 3). The denition, clinicopathologic ndings, pathogenesis, and treatment of the syndromes will be described in the following sections.Acute encephalopathy due to metabolic error</p> <p>This category consists of inherited metabolic disorders and classical Reye syndrome.Inherited metabolic disorders The brain is aected by many inherited metabolic disorders, which typically are slowly progressive. However, some metabolic disorders of fatty acids, organic acids, carbohydrates and the urea cycle (Table 4) may aggravate rapidly. Triggered by infection and fasting, their acute exacerbation often mimics acute encephalopathy such as Reye syndrome. Although excluded from acute encephalopathy in its strict sense, metabolic disorders should be included in acute encephalopathy from practical viewpoints because their diagnosis is often difcultTable 3 Classification according to the pathomechanism Pathomechanism Diseases and syndromes Metabolic error Inherited metabolic disorders Classical Reye syndrome Diffuse Mild to severe Rare Middle Salicylate Cytokine storm Reye-like syndrome HSE syndrome ANE Diffuse Mild to severe Common High NSAIDs Excitotoxicity AIEF HH syndrome Localized None to mild Rare Low Theophylline</p> <p>With regard to incidence, inuenza virus is the most important pathogen of acute encephalopathy. In Japan, 100500 cases of inuenza encephalopathy occur every year. Inuenza A/H3 virus shows a higher incidence of encephalopathy compared with A/H1 and B virus (2). Inuenza encephalopathy includes all encephalopathic syndromes (Table 2). In particular, inuenza encephalopathy accounts for 4050% of patients with Reye-like syndrome and acute necrotizing encephalopathy (ANE) (3). The overall mortality rate of inuenza encephalopathy was about 30% before the year 2000, but declined to about 15% after 2000 (4). Thus, inuenza encephalopathy is an important cause of mortality and morbidity in children.Exantem subitum (human herpes virus 6) encephalopathy</p> <p>Primary infection with human herpes virus 6 (HHV-6) is the second most common cause of acute encephalopathy. As is the case with inuenza, all known encephalopathic syndromes may be induced by HHV-6. Notably, HHV-6 is strongly 46</p> <p>Distribution of brain edema Liver dysfunction DIC/multiple organ failure Mortality Risk factors</p> <p>DIC, disseminated intravascular coagulation; HSE, hemorrhagic shock and encephalopathy; AIEF, acute infantile encephalopathy predominantly affecting the frontal lobes; ANE, acute necrotizing encephalopathy; HH, hemiconvulsion-hemiplegia; NSAIDs, non-steroidal anti-inflammatory drugs.</p> <p>Viral infection-associated encephalopathiesTable 4 Inherited metabolic disorders that may mimic acute encephalopathy Disorders of fatty acid transport and beta-oxidation Systemic carnitine deficiency Carnitine palmitoyltransferase II deficiency Medium chain acyl-CoA dehydrogenase deficiency Glutaric acidemia type II Others Disorders of organic acid metabolism Propionic acidemia Methylmalonic acidemia Isovaleric acidemia Glutaric acidemia type I Others Disorders of glycolysis Pyruvate dehydrogenase deficiency Fructose-1,6-bisphosphatase deficiency Others Disorders of urea cycle Ornithine transcarbamoylase deficiency Carbamoylphosphate synthetase deficiency Argininosuccinate synthetase deficiency Others Table 5 Diagnostic criteria of Reye syndrome (Centers for Disease Control of the USA) (10) Acute non-inflammatory encephalopathy documented clinically by an alteration in consciousness and, if available, a record of cerebrospinal fluid containing </p>