Acta Neurol Scand 2007: 115 (Suppl.

186): 4556

Copyright 2007 The Authors Journal compilation 2007 Blackwell Munksgaard

ACTA NEUROLOGICA SCANDINAVICA

Acute encephalopathy associated with inuenza and other viral infections

Mizuguchi 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.

M. Mizuguchi1, H. Yamanouchi2, T. Ichiyama3, M. Shiomi4

1 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

All authors declare no conflict of interests

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: [email protected] Accepted for publication 11 December, 2006

Introduction

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

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

Virus infection-associated acute encephalopathy is classied by two means; the pathogenic virus of the antecedent infection (Table 1) and the 45

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

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

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

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

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

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 difcult
Table 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

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

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

Distribution of brain edema Liver dysfunction DIC/multiple organ failure Mortality Risk factors

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.

Viral infection-associated encephalopathies

Table 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 <8 leukocytes/mm3, or by histologic specimen demonstrating cerebral edema without perivascular or meningeal inflammation Hepatopathy documented by results of either a liver biopsy or autopsy considered to be diagnostic of Reye syndrome, or a threefold or greater rise in the levels of either aspartate aminotransferase, alanine aminotransferase, or serum ammonia No more reasonable explanation for the cerebral or hepatic abnormalities

in the early stage of exacerbation. In Japan, metabolic errors such as fatty acid oxidation defects and carnitine palmitoyltransferase deciency account for about 5% of inuenza encephalopathy cases (8). A high index of suspicion is warranted in cases of recurrent encephalopathy, positive family history, and laboratory ndings of hypoglycemia, hyperammonemia, and lactic acidosis. Samples of blood, urine, and cerebrospinal uid (CSF) should be collected and kept frozen for specic biochemical studies. Proper diagnosis is imperative because specic treatment is available for some of these disorders. In many inherited metabolic disorders, cranial computed tomography (CT) and magnetic resonance imaging (MRI) demonstrate nonspecic abnormalities such as diuse brain atrophy. Several conditions, such as methylmalonic acidemia and glutaric acidemia type 1, show selective, bilateral symmetrical involvement of the deep gray matter including the basal ganglia. During acute encephalopathy-like episodes, these imaging ndings may rapidly worsen in some cases, and diuse brain edema may appear in others (9).
Classical Reye syndrome Reye syndrome is a transient disorder of various mitochondrial functions, triggered by viral infection. Among the commonly used diagnostic criteria (10) (Table 5), hyperammnonemia, microvesicular fatty metamorphosis of hepatocytes, and mitochondrial deformation are important for dening classical Reye syndrome. Hypoglycemia is also common (11). Cranial CT and MRI demonstrate diffuse brain edema.

Classical Reye syndrome is more prevalent in America, Europe, and Oceania than in Japan. Children older than 5 years of age are most often aected, and the onset is usually during convalescence after inuenza, chickenpox, and other viral infections. Drugs such as salicylates and valproic acid, as well as toxins such as hypoglycine and aatoxin, are known to be associated with this condition (12). At present, classical Reye syndrome is very rare in Japan as well as in many other countries, when mimicking metabolic disorders are adequately ruled out.
Pathogenesis Infection and fasting aggravate many inherited metabolic disorders, as decreased intake alters carbohydrate and fatty acid metabolism, and a lack of energy and excess inammatory cytokines accelerate protein catabolism. In classical Reye syndrome, inammatory cytokines and drugs (or toxins) impair hepatic mitochondria to produce toxic metabolites such as short-chain fatty acids and dicarbonic acids, which in turn aect brain function (12) (Fig. 1). Biochemical studies show evidence of hepatic cell damage (a marked rise in serum aminotransferases) and various aspects of mitochondrial dysfunction involving the urea cycle (hyperammonemia), gluconeogenesis (hypoglycemia), and fatty acid oxidation (free fatty acidemia). Treatment Many inherited metabolic disorders are treated with a combination of methods available for each condition (Table 6). The classical Reye syndrome is treated with intensive supportive methods to manage body uid, blood circulation, respiration, body temperature, and intracranial pressure. Correction of metabolic abnormalities (hypoglycemia, hyperammonemia, and metabolic acidosis) and coagulation disorder is important.
Acute encephalopathy caused by cytokine storm

Syndromes in this category are frequently seen in severe cases of inuenza encephalopathy in Japan. 47

Mizuguchi et al.
Gene mutation or polymorphism

Viral infection
Endotoxin Lipopolysaccharides

Drugs
Salicylates, valproate sodium, etc

Fasting

Hypercytokinemia Excessive catabolism

Protein, fat TNF- , IL-1, IL-6, etc

Hepatic mitochondrial damage

-oxidation, oxidative phosphorylation

Toxic substances in the liver

Short/ medium/ branched chain fatty acids, dicarbonic acid

Decreased ketone bodies

Toxic substances in the blood Liver damage

Hypoglycemia, hyperammonemia

Systemic organ damage Encephalopathy

Figure 1. Pathogenesis of classical Reye syndrome [modied from Visentin et al. (12)]. TNF-a, tumor necrosis factor-a; IL-1, interleukin-1; IL-6, interleukin-6.

Table 6 Treatments of inherited metabolic disorders affecting the brain Treatments of basic condition Adequate dietary intake of carbohydrates and lipids (as sources of energy) Dietary restriction of materials of toxic metabolites Drugs promoting the degradation or excretion of toxic metabolites Coenzymes augmenting residual enzymatic activity Liver transplantation Treatments of acute exacerbation Fluid therapy Supply of carbohydrates Correction of blood electrolytes and acidbase balance Prevention of toxic metabolite production (e.g., lactulose, kanamycin) Promotion of toxic metabolite excretion (e.g., sodium benzoate, sodium phenylacetate, L-carnitine) Blood purification (e.g., plasma exchange, hemodialysis)

Table 7 Comparison between Reye-like and classical Reye's syndrome (modified from Morishima (2)) Reye-like Geographic distribution Age preponderance Association with chickenpox Association with salicylates Association with NSAIDs Hyperammonemia Hypoglycemia Nature of brain edema Japan > US 15 years No No Yes No No Vascular Classical Reye US > Japan 510 years Yes Yes No Yes Yes Cellular

NSAIDs: non-steroidal anti-inflammatory drugs.

They aect not only the brain, but also visceral organs such as the liver, kidneys, heart and skeletal muscles, as well as blood cells and blood vessels. Thus, their clinical presentation includes encephalopathy, multiple organ failure, disseminated intravascular coagulation (DIC) and hemophagocytic syndrome (HPS). In general, the prognosis is poor with a high mortality rate of about 30%, and a large number of survivors are left with severe neurologic sequelae.
Reye-like syndrome In this ill-dened condition, acute encephalopathy is associated with severe liver damage. There is a marked increase in serum aminotransferases, which seemingly meets the Centers for Disease Control diagnostic criteria of Reye syndrome (Table 5). However, biochemical and histologic ndings characteristic of classical

Reye syndrome, such as hyperammonemia, microvesicular fatty metamorphosis of hepatocytes, and mitochondrial deformation, are lacking. From an epidemiologic viewpoint, several important differences have been noted between Reye-like and classical Reye syndrome (Table 7). On cranial CT and MRI, there is diffuse edema involving either the whole brain (Fig. 2A) or the entire cerebral cortex. Pathologic studies demonstrate that brain edema is vascular (13).
Hemorrhagic shock and encephalopathy (HSE) syndrome Some cases of acute encephalopathy show marked hemorrhagic diathesis (caused by DIC), hypovolemic shock, and dysfunction of multiple organs, which fulll the diagnostic criteria of HSE syndrome (14) (Table 8). Hemorrhagic shock and encephalopathy (HSE) syndrome was originally described in the United

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Viral infection-associated encephalopathies

(A) (B)

(C)

(D)

The diagnostic criteria of HSE syndrome (Table 8) consist of nonspecic ndings that are also seen in Reye-like and other syndromes. Although typical cases of HSE syndrome and Reye-like syndrome show clearly different features, their overlapping phenotypes often make it difcult to differentiate atypical cases. Cranial CT and MRI typically show edema of the entire cerebral cortex (17) (Fig. 2B), although edema may involve the whole brain. There are occasionally additional ndings of intracranial hemorrhage (Fig. 2C,D).
Acute necrotizing encephalopathy Although most prevalent in East Asia, ANE has been reported in other areas of the world. In addition to diuse brain edema, ANE shows multiple focal lesions of edematous necrosis which are symmetrically distributed in the bilateral thalami and other brain regions such as the putamina, cerebral and cerebellar deep white matter, and brainstem tegmentum (Fig. 3). Based on the pathognomonic CT/ MRI ndings, the intravitum diagnosis of ANE can be made clearly. Other clinical and laboratory ndings at the acute stage are nonspecic, although increased CSF protein, which occasionally shows xanthochromia, is characteristic of ANE (3) (Table 10). More than 30% of patients die, and many of the survivors have severe neurologic handicaps. In survivors with mild to moderate sequelae, motor decits are usually severer than mental decits, and a unique combination of focal neurologic signs is often recognized (18) (Table 11). Pathogenesis Reye-like, HSE syndrome, and ANE share many clinical features. Onset occurs during the early febrile period of a viral infection, and runs a fulminant course with the rapid development of coma. Of importance, severe cases often show signs of systemic inammatory response syndrome, such as shock, multiple organ failure and DIC. Acute necrotizing encephalopathy complicated by HPS has been reported in some cases (19), and concurrent ANE and macrophage activation syndrome have been described in a case of juvenile idiopathic arthritis (20). These clinical facts implicate macrophage activation and hypercytokinemia in the pathogenesis of these encephalopathies (21). During the acute stage of inuenza encephalopathy, the serum and CSF concentrations of inammatory cytokines, such as tumor necrosis factor-a and interleukin-6 (IL-6), are abnormally high in many cases of Reye-like syndrome, HSE syndrome, and ANE (2225). The levels are usually higher in serum than in CSF (Fig. 4). Taken

Figure 2. Cranial CT ndings of Reye-like syndrome and hemorrhagic shock and encephalopathy (HSE) syndrome. (A) Diffuse edema involving the whole brain in a case of Reye-like syndrome. (B) Diffuse edema involving the entire cerebral cortex in a case of HSE syndrome. (C, D) Edema of the entire cerebral cortex with multiple intracerebral hemorrhage in another case of HSE syndrome.
Table 8 Diagnostic criteria of hemorrhagic shock and encephalopathy (HSE) syndrome [modified from Chaves-Carballo et al. (14)] Age at onset during infancy (usually 210 months) Acute encephalopathy (respiratory arrest, seizures, or coma) Fever (rectal temperature, 39C) Shock (blood pressure, <50 mmHg) Disseminated intravascular coagulation [excessive bleeding from skin, mucous membranes, or gastrointestinal tract; coagulopathy demonstrated by thrombocytopenia (<100 109/l), prolonged prothrombin time, prolonged partial thromboplastin time, decreased fibrinogen level, and fibrin split products] Hepatic dysfunction (abnormal aminotransferase values greater than threefold upper limits of normal) Normal blood ammonia values Renal dysfunction (azotemia, hypernatremia, or metabolic acidosis) Exclusion of similar infantile conditions (e.g., septic shock, toxic shock syndrome, Reye syndrome, and hemolytic-uremic syndrome)

Table 9 Epidemiologic differences of hemorrhagic shock and encephalopathy (HSE) syndrome in Japan and UK Japanese HSE Age preponderance Association with overheating Association with influenza 6 months5 years No Yes British HSE (15, 16) 210 months Yes No

Kingdom (15), and there are several epidemiologic differences between British and Japanese cases (15, 16) (Table 9).

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(A) (B)

Figure 3. Cranial CT ndings in a case of acute necrotizing encephalopathy (ANE). (A) Multiple, low density lesions are symmetrically distributed in the bilateral thalami and periventricular white matter of the cerebrum. There also is diffuse brain edema. (B) In the posterior fossa, low density lesions are noted bilaterally in the pontine tegmentum and cerebellar hemispheres.

Table 10 Diagnostic criteria of acute necrotizing encephalopathy (3) Acute encephalopathy following a viral febrile disease. Rapid deterioration in the level of consciousness. Convulsions No CSF pleocytosis. Increase in CSF protein commonly observed CT or MRI evidence of symmetric, multifocal brain lesions. Involvement of the bilateral thalami. Lesions also common in the cerebral periventricular white matter, internal capsule, putamen, upper brainstem tegmentum, and cerebellar medulla. No involvement of other CNS lesions Elevation of serum aminotransferase to variable degrees. No increase in blood ammonia Exclusion of resembling diseases Differential diagnosis from clinical viewpoints Overwhelming bacterial and viral infections, and fulminant hepatitis; toxic shock, hemolytic uremic syndrome, and other toxin-induced diseases; Reye syndrome, HSE syndrome, and heat stroke Differential diagnosis from radiological (or pathological) viewpoints Leigh encephalopathy and related mitochondrial cytopathies; glutaric acidemia, methylmalonic acidemia, and infantile bilateral striatal necrosis; Wernicke encephalopathy, and carbon monoxide poisoning; acute disseminated encephalomyelitis, acute hemorrhagic leukoencephalitis, and other types of encephalitis and vasculitis; arterial or venous infarction, and the effects of severe hypoxia or head trauma

(pg/ml) 100,000 10,000 1,000 100 10 1

S C
ANE
n=3

S C
AEFCSE
n=5

S C
Others
n = 13

S C
Febrile seizure
n=7

Reye-like ReyeHSE
n= 4

Figure 4. Serum and cerebrospinal uid levels of interleukin-6 (IL-6) in various syndromes of acute encephalopathy, and in febrile seizure. Serum (S) and cerebrospinal uid (C) samples were simultaneously collected, and their IL-6 concentration was measured by enzyme immunoassay. AEFCSE, acute encephalopathy with febrile convulsive status epilepticus; others, acute encephalopathy not classied into any of the syndromes described here.

Table 11 Typical neurologic sequelae of acute necrotizing encephalopathy (18) Neurologic signs Athetosis, choreoathetosis Forced crying and laughing Ataxic gait, hypotonia, limb ataxia, intention tremor, scanning speech Hemiplegia Horizontal gaze palsy, abducens palsy, facial palsy Suspected responsible lesions Medial nucleus of the thalamus, lenticular nucleus Anterior nucleus of the thalamus Ventrolateral nucleus of the thalamus, cerebellum Internal capsule Tegmentum of the midbrain and pons

together, these encephalopathic syndromes are considered to be a systemic disorder in which the cytokine storm plays a major role (Fig. 5). Pathologic studies of the brain at necropsy have observed severe brain edema and perivasucular plasma exudation in Reye-like syndrome (13) (Fig. 6A), HSE syndrome, and ANE (3, 7). In addition, thalamic lesions of ANE show perivascular diapedesis of erythrocytes (petechial hemorrhage), indicating a severer injury of intracerebral blood vessels (26). Laboratory studies have demonstrated increased blood levels of E-selectin and

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Viral infection-associated encephalopathies

Viral infection
Influenza, etc

Gene mutation or polymorphism Age Race

Hypercytokinemia
IL-6, TNF- , etc

NSAIDs

Vascular endothelial injury

Apoptosis of parenchymal cells

Brain edema Encephalopathy

Systemic organ damage

DIC, multiple organ failure

Figure 5. Pathogenesis of acute encephalopathy caused by cytokine storm: Reye-like syndrome, HSE syndrome, and ANE [modied from Morishima (2)].

(A)

(B)

(C)

Figure 6. Neuropathologic ndings of Reye-like syndrome. (A) A histologic section of the cerebrum stained with hematoxylin and eosin shows extravasation of plasma (arrows) around the intracerebral arteries. The surrounding brain tissue is spongy, indicating edema. (B) In situ nick-end labeling (TUNEL) of fragmented DNA of the brainstem demonstrates numerous neurons and glial cells undergoing apoptosis (cells with a blue nucleus). (C) Immunostaining for Iba-1 (an immunohistochemical marker of microglial cells) of the cerebrum shows the presence of many microglial cells around the vessels and in the cerebral parenchyma.

thrombomodulin (2, 24, 27). These ndings indicate that vascular edema, namely damage to the bloodbrain barrier, is the pathologic substrate of encephalopathy in these syndromes. Vascular injury has been ascribed to endothelial damage by inammatory cytokines, although the precise mechanism remains unknown. The mechanism of cerebral parenchymal injury is dierent between ANE and other syndromes. In ANE brains, necrosis appears to play a major role. By contrast, many neurons and glial cells undergo apoptosis in brains with Reye-like syndrome and HSE syndrome, as evidenced by DNA fragmentation and caspase-3 activation (Fig. 6B), with activation of microglial cells (28) (Fig. 6C). High serum levels of cytochrome c also suggest apoptosis in the brain and other organs (29).

It has recently been demonstrated in Japan that the use of non-steroidal anti-inammatory drugs (NSAIDs), such as diclofenac sodium and mephenamic acid, is associated with signicant increase in the mortality rate of inuenza encephalopathy (2) (Table 12). Why NSAIDs aggravate inuenza
Table 12 Effect of antipyretics on the prognosis of influenza encephalopathy (2) Drugs Administration No. death 41 53 25 68 14 79 No. survival 139 134 29 243 15 257 Mortality rate, % 22.8 28.3 46.3 21.9 48.3 23.5 P-value/ odds ratio 0.22/0.75 0.0001/3.08 0.003/3.04

Aceto-aminophen Diclofenac sodium Mephenamic acid

Yes No Yes No Yes No

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Mizuguchi et al. encephalopathy remains unknown, but one possible mechanism is that their inhibitory activity in cyclooxygenase may either enhance thrombosis or disturb the repair of endothelial damage (Fig. 5).
Treatment In Reye-like syndrome, HSE syndrome and ANE, intensive supportive therapy alone is not as eective as in classical Reye syndrome. Since 2000 when specialists proposed a new treatment protocol of inuenza encephalopathy (30), Japanese pediatricians have treated their patients with more aggressive therapies, many of them designed either to combat a cytokine storm or to protect the brain (Table 13). Although it is difcult to evaluate the efcacy of each therapy, a questionnaire study has proved that the earlier methylprednisolone pulse therapy is started, the better the outcome (8). Furthermore, the overall mortality rate of inuenza encephalopathy has declined from about 30% (before 2000) to about 15% (after 2000) (2). At present, however, many severe cases are still fatal or left with severe brain damage. In particular, the majority of ANE cases are refractory to therapy, and the prognosis of ANE remains very poor (31).
Acute encephalopathy caused by excitotoxicity
Early seizure (status) Late seizure (cluster)

Aphasia Alteration of consciousness Fever

Day

Loss of spontaneity Stereotypic movements

Figure 7. Clinical course of acute encephalopathy with febrile convulsive status epilepticus (AEFCSE). Focal neurologic signs shown on the right are those of acute infantile encephalopathy predominantly affecting the frontal lobes (AIEF).

Although indistinguishable from complex febrile seizure (febrile status convulsivus) at initial presentation, acute encephalopathy in this category shows distinct neurologic and neuroradiologic features in the subsequent stages (Fig. 7) (32). Onset is usually on the rst day of a viral febrile disease, such as exanthem subitum and inuenza, with prolonged febrile convulsion (termed as early seizure) followed by post-ictal coma. On the second day, consciousness recovers in most cases, although many are listless and some are not fully alert. On the fourth or fth day, more than half of the cases have a cluster of brief convulsions (late seizure; either febrile or afebrile; partial seizures secondarily generalized in many cases), followed by the second post-ictal coma. After recovering consciousness, focal neurologic
Table 13 Novel therapies for influenza encephalopathy: proposal by Japanese specialists (30) Antiviral agents: Oseltamivir Intravenous immunoglobulin Methylprednisolone pulse therapy Antithrombin III Brain hypothermia Plasmapheresis Cyclosporin A Rehabilitation

signs of the cerebral cortex, such as reduced spontaneity, aphasia, apraxia and hemiparesis, become apparent (33). The mortality rate is low (<5%). Mild cases show recovery of higher cortical functions during the subsequent weeks or months; however, severe cases are left with mental decit and/or epilepsy. Cranial CT and MRI ndings are normal during the initial several days. After the late seizure, there is localized edema of the cerebral cortex, which typically shows lobar distribution (lobar edema), such as the bilateral frontal lobes (Fig. 8A) and entire cerebral hemisphere (Fig. 9A). Severe cases show widespread edema of the cerebral cortex, or even the whole brain (Fig. 10A,B). Diffusionweighted imaging (DWI), the most sensitive technique, visualizes edema of the subcortical white matter showing a characteristic pattern (bright tree appearance) (33, 34). It is noteworthy that pre- and post-central gyri are spared in most cases (Fig. 10C). Single photon-emission computed tomography (SPECT) shows hyperperfusion of the affected cortex (35, 36). At the subacute stage (1 week to 1 month after onset),

(A)

(B)

(C)

Figure 8. Neuroradiologic ndings of a case of AIEF. (A) MRI (T2-weighted image) on day 6 (acute stage) shows T2 prolongation of the bilateral frontal cortex, indicating edema. Both the gray and white matter are affected. (B) MRI (T2-weighted image) on day 12 (subacute stage) shows slight atrophy of the bilateral frontal cortex. Abnormal signals have mostly resolved. (C) 99mTc-ethyl cysteine dimer single photonemission computed tomography (99mTc ECD SPECT) on day 12 shows hypoperfusion of the bilateral frontal cortex.

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(A) (B) (C)

Figure 9. Serial CT ndings of a case of theophylline encephalopathy with hemiconvulsion-hemiplegia (HH) syndrome. (A) CT on day 1 shows no abnormal ndings. (B) CT on day 7 shows cortical edema of the entire left cerebral hemisphere. (C) CT on day 50 shows cortical atrophy of the left hemisphere.

(A)

(B)

epilepticus (AEFCSE) (32, 33). There are also eponyms or closely related entities, such as infection-related acute encephalopathy with imaging ndings that initially appear normal, but show cortex-dominant necrosis 45 days after the onset (37), acute encephalopathy with prolonged febrile seizures and late reduced diffusion (34) and encephalopathy with biphasic clinical course (38). AEFCSE is further classied into distinct subtypes, such as AIEF and HH syndrome.
Acute infantile encephalopathy predominantly aecting the frontal lobes In this recently described syndrome, onset is usually a prolonged generalized tonic convulsion (early seizure), although impaired consciousness is the rst presentation in a minority of patients. After a cluster of brief convulsions (late seizure), signs of frontal lobe dysfunction, such as loss of spontaneity and aphasia, become apparent (5, 39). At this stage (within a week after onset), DWI reveals high intensity of the bilateral frontal cortex, in particular the subcortical white matter. Severe cases may show high intensity of the same area even on T2-weighted and uid-attenuated inversion recovery (FLAIR) images (Fig. 8A). Laboratory ndings of the blood, urine, and CSF are nonspecic. Serum aminotransferases are normal or elevated only mildly. During the following several weeks, the frontal cortex shows progressive atrophy on MRI and hypoperfusion on SPECT (Fig. 8B,C). Many patients have stereotypic movements, and some have mood instability (5). Diagnostic criteria of AIEF have recently been proposed (35). Hemiconvulsion-hemiplegia syndrome Since the description by Gastaut in 1960 (40), this syndrome has been well known to pediatricians. The early seizure is a prolonged clonic convulsion,

(C)

(D)

Figure 10. Neuroradiologic ndings of AEFCSE cases with widespread or diffuse lesions. (A, B) CT of a case of theophylline encephalopathy (acute stage), showing diffuse edema of the whole brain. (C) MRI (diffusion-weighted image) of a case of inuenza encephalopathy with AEFCSE (acute stage), showing high intensity of the subcortical white matter (bright tree appearance) and sparing of the pre- and post-central gyri. (D) MRI (T1-weighted image) of a case of theophylline encephalopathy (convalescence), showing residual lesions of cerebral atrophy, cortical laminar necrosis, and a small infarct in the right globus pallidus.

CT and MRI show progressive atrophy of the cerebral cortical lesion, whereas SPECT shows progressive hypoperfusion of the same area (Fig. 8C). During convalescence (1 month to 1 year after onset), atrophy and hypoperfusion resolve gradually in mild cases, but persist in severe cases (5). The collective term for this category is acute encephalopathy with febrile convulsive status

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Mizuguchi et al. usually with marked unilateral predominance. Serum aminotransferases are often elevated mildly to moderately. Post-ictal neurologic decits include hemiparesis, intellectual deterioration, and epileptic seizures. A variant form of this syndrome with involvement of the dominant hemisphere presents with motor aphasia rather than hemiparesis (41). During the acute period, edema of the affected hemisphere is so severe as to be apparent on CT in many cases (Fig. 9B). SPECT shows hyperperfusion of the cortical lesion. At the subacute stage (1 week to 1 month after onset), there is progressive atrophy (Fig. 9C) and hypoperfusion (36).
Theophylline encephalopathy Xanthine derivatives are bronchodilators with anti-inammatory eects, administered either orally (theophylline) or intravenously (aminophylline). As a rst-line therapeutic drug for childhood asthma, theophylline has already been abandoned in many countries; however, in Japan, theophylline is still widely used to treat asthmatic children. When the serum level of theophylline reaches the toxic range, its neurologic adverse eects are termed theophylline toxicity; however, theophylline may cause neurotoxicity even when its serum level is within the therapeutic range. Convulsions are the most common sign, and are referred to as theophylline-associated seizures (42). Although the severity varies among cases, theophylline-associated seizures tend to be more prolonged, less likely to stop spontaneously, more resistant to benzodiazepine anticonvulsants, and more likely to require endotracheal intubation, when compared with non-theophyllineassociated cases (43, 44). As refractory status epilepticus is usually followed by prolonged postictal coma, the condition should be regarded as acute encephalopathy rather than a mere seizure (45). Most, if not all, cases of theophylline encephalopathy have AEFCSE. Cases of both AIEF and HH syndrome have been reported (6, 33) (Fig. 9). In the severest of cases, deep coma continues for weeks, and profound disabilities persist in both mental and motor functions. Cranial CT shows ndings of diffuse brain edema, mimicking those of Reye-like syndrome (Fig. 10A,B); however, the appearance of this nding is delayed for several days after onset, which is not the case with Reyelike syndrome. Residual lesions in these cases are cerebral atrophy, laminar necrosis of the cortex, and lacunar infarction of the basal ganglia or thalamus (46) (Fig. 10D). In theophylline encephalopathy, the incidence of DIC and multiple organ failure is low, as is the
Viral infection
Influenza, HHV-6, etc

Theophylline

Gene mutation or polymorphism Age

Cytokine in the blood/ CSF

Fever Status epilepticus convulsivus

Endothelial damage

Cerebrovascular dysfunction

Glial damage Hypoxia/ ischemia

Excessive glutamate release

Brain edema Delayed (apoptotic) neuronal death

Figure 11. Pathogenesis of acute encephalopathy caused by excitotoxicity: AEFCSE and theophylline encephalopathy (45).

mortality rate (34%). Many surviving patients have neurologic sequelae.

Pathogenesis Much remains to be claried with regard to the pathogenesis of AEFCSE. Pathologic ndings are scanty because of the low mortality; however, laboratory and neuroradiologic studies have accumulated evidence that excitotoxic, delayed (or apoptotic) neuronal death is the main pathologic event in this category (Fig. 11). The subacute nature of this pathologic process has been shown by the time course of SPECT ndings, showing hyperperfusion at the acute stage (within 1 week after onset), and progressive hypoperfusion at the subacute stage (1 week to 1 month after onset) (35, 36). Neuronal apoptosis is suggested by the serial change in CSF cytochrome c level, which rises in the subacute period (47). Evidence for the involvement of excitotoxin is still circumstantial; however, an increase in Glx (glutamine/glutamate) in the subcortical white matter has recently been shown in a case of AEFCSE, using magnetic resonance spectroscopy (34). In AEFCSE, brain damage is much more serious than in complex febrile seizure. This dierence may be explained by the involvement of inammatory cytokines. Although preliminary, the results of cytokine assay in the serum and CSF indicate that IL-6 shows a mild to moderate increase in AEFCSE, and tends to be higher than in febrile seizure (Fig. 4). Notably, the level was higher in the CSF than in the serum in many AEFCSE patients, suggesting the intracerebral production of IL-6. Inammatory cytokines in the brain may enhance seizure-induced excitotoxicity, resulting in apoptosis of neurons and/or glial cells (Fig. 10), although this hypothesis needs to be further tested.

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Viral infection-associated encephalopathies How theophylline aggravates this process is poorly understood (45): Theophylline may prolong seizures either by increasing the amount of cyclic nucleotides (48), by blocking neuronal adenosine receptors (49), by decreasing the amount of gamma-aminobutyric acid (GABA) (50), or by blocking GABA receptors (49). Theophylline may also block cerebrovascular adenosine receptors, thereby causing vasospasms and hypoperfusion (51) (Fig. 11).
Treatment At the initial stage of AEFSCE, aggressive anticonvulsive treatment is required. To stop the prolonged convulsion of theophylline-associated cases, a high-dose barbiturate should promptly be given intravenously (43), usually followed by continuous drip infusion under mechanical ventilation and management of intracranial pressure. The electroencephalogram should be continuously monitored because late seizure is occasionally not immediately obvious, and therefore electrical status epilepticus may easily be overlooked. Recently, Japanese doctors have tried methylprednisolone pulse therapy, intravenous immunoglobulin, and other therapies to suppress inammatory cytokines, as well as edaravone to scavenge free radical species. At present, however, there is no solid evidence for the ecacy of these treatments.
Conclusion
anion channels and provokes neuronal cell swelling. J Neurosci 1998;18:311723. Morishima T. Studies on the epidemiology and pathogenesis of encephalitis/encephalopathy occurring during the clinical course of inuenza. In: 20002002 General Report of the Research Committee for Research on Emerging and Re-emerging Diseases. Japan: Ministry of Health, Labor and Welfare, 2003;123 (in Japanese). Mizuguchi M. Acute necrotizing encephalopathy of childhood: a novel form of acute encephalopathy prevalent in Japan and Taiwan. Brain Dev 1997;19:8192. Morishima T. On the nationwide surveillance of inuenza encephalopathy in the year 2002/2003. In: 2003 Annual Report of the Research Committee for Research on Emerging and Re-emerging Diseases. Japan: Ministry of Health, Labor and Welfare, 2004;119. Yamanouchi H, Kawaguchi N, Mori M et al. Acute infantile encephalopathy predominantly aecting the frontal lobes. Pediatr Neurol 2006;34:93100. Shiomi M, Ishikawa J, Yoshimoto A, Sotokawa M. Acute encephalopathy associated with exanthem subitum or primary infection of HHV6 (in Japanese). Pediatr Jpn 2005;46:52431. Mizuguchi M, Abe J, Mikkaichi K et al. Acute necrotising encephalopathy of childhood: a new syndrome presenting with multifocal, symmetric brain lesions. J Neurol Neurosurg Psychiatry 1995;58:55561. The Research Committee on the Clarication of Etiology and on the Establishment of Therapeutic and Preventive Measures of Inuenza Encephalopathy. Guideline for inuenza encephalopathy. Japan: Ministry of Health, Labor and Welfare, 2005;121. Mizuguchi M, Usuda I, Yoneyama A, Kamoshita S. Infantile bilateral striatal necrosis: chronic and acute manifestations in a single case. Brain Dev 1994;16:614. CDC. Reye syndrome-United States, 1986. MMWR Morb Mortal Wkly Rep 1987;36:68991. Glasgow JFT. Clinical features and prognosis of Reyes syndrome. Arch Dis Child 1984;59:2305. Visentin M, Salmona M, Tacconi MT. Reyes and Reye-like syndromes, drug-related diseases? (causative agents, etiology, pathogenesis, and therapeutic approaches). Drug Metab Rev 1995;27:51739. Togashi T, Matsuzono Y, Takekoshi Y, Nagano N. Pathological ndings of two patients with inuenza-associated encephalopathy who died with a rapid fulminant course. J Jpn Pediatr Soc 2002;106:7680 (in Japanese). Chaves-Carballo E, Montes JE, Nelson WB, Chrenka BA. Hemorrhagic shock and encephalopathy: clinical denition of a catastrophic syndrome in infants. Am J Dis Child 1990;144:107982. Levin M, Hjelm M, Kay JD et al. Haemorrhagic shock and encephalopathy: a new syndrome with a high mortality in young children. Lancet 1983;2:647. Bacon CJ, Bell SA, Gaventa JM, Greenwood DC. Case control study of thermal environment preceding haemorrhagic shock encephalopathy syndrome. Arch Dis Child 1999;81:1558. Shiomi M. The tentative classication of inuenza encephalopathy and MRI, CT and electroencephalography ndings in each type. Rinsho Noha 2004;46:38091 (in Japanese). Mizuguchi M, Iai M, Takashima S. Acute necrotizing encephalopathy of childhood: recent advances and future prospects. No To Hattatsu 1998;30:18996 (in Japanese). Kanno K, Tsuchida M, Kinoshita S, Suzuki K, Maruyama S, Suda M. A case of acute necrotizing encephalopathy

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Inuenza and other virus-associated acute encephalopathies can be classied into three major categories, and into six or more syndromes. For each syndrome, the clinical, laboratory, radiologic, and pathologic features have been well delineated. Each syndrome has distinct risk factors, especially drugs such as salicylates, NSAIDs, and theophylline. Treatment has recently been improved, but is still unsatisfactory and, in the near feature, it should be customized for each syndrome based on better understanding of the pathogenesis.
Acknowledgements
This study was supported by a Grants-in-Aid for Scientic Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by a Grant for Research on Emerging and Re-emerging Diseases from the Ministry of Health, Labor and Welfare of Japan.

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