Acute encephalopathy associated withinfluenza and other viral infections

Introduction

Acute encephalopathy is a generic term for acutebrain dysfunction usually preceded by infection. Itsmain symptoms are impaired consciousness andsigns of increased intracranial pressure, oftenaccompanied by convulsions or seizures. Its inci-dence is highest in infancy and early childhood.The antecedent infection is viral in the majority ofcases, although bacteria such as enterohemorrhagicEscherichia coli (hemorrhagic colitis), Salmonellaenteritidis, Bordetella pertussis, and Bartonellahenselae (cat scratch disease) may also causeacute encephalopathy.The pathologic substrate of acute encephalopa-

thy is diffuse or widespread, non-inflammatory

brain edema, which is either cellular (cytotoxic) orvascular (vasogenic). Cellular edema is ascribed tothe dysfunction of channels on the cell membraneof neurons and glial cells, which often results fromthe disruption of mitochondria (1). Vascular edemais caused by disruption of the blood–brain barrier.This article summarizes recent advances in the

study of acute encephalopathy associated with viralinfections, focusing on the classification, pathology,pathogenesis, risk factors, and treatment.

Classification based on the pathogenic virus

Virus infection-associated acute encephalopathyis classified by two means; the pathogenic virusof the antecedent infection (Table 1) and the

Acta Neurol Scand 2007: 115 (Suppl. 186): 45–56 Copyright � 2007 The AuthorsJournal compilation � 2007 Blackwell Munksgaard

ACTA NEUROLOGICASCANDINAVICA

Mizuguchi M, Yamanouchi H, Ichiyama T, Shiomi M. Acuteencephalopathy associated with influenza and other viral infections.Acta Neurol Scand 2007: 115 (Suppl. 186): 45–56.� 2007 The Authors Journal compilation � 2007 Blackwell Munksgaard.

Acute encephalopathy is the most serious complication of pediatricviral infections, such as influenza and exanthem subitum. It occursworldwide, but is most prevalent in East Asia, and every year severalhundreds of Japanese children are affected by influenza-associatedencephalopathy. Mortality has recently declined, but is still high. Manysurvivors are left with motor and intellectual disabilities, and somewith epilepsy. This article reviews various syndromes of acuteencephalopathy by classifying them into three major categories. Thefirst group caused by metabolic derangement consists of variousinherited 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 encephalopathysyndrome, and acute necrotizing encephalopathy. Non-steroidal anti-inflammatory drugs, such as diclofenac sodium and mephenamic acid,may aggravate these syndromes. Severe cases are complicated bymultiple organ failure and disseminated intravascular coagulation.Mortality is high, although methylprednisolone pulse therapy may bebeneficial in some cases. The third group, characterized by localizededema of the cerebral cortex, has recently been termed acuteencephalopathy with febrile convulsive status epilepticus, and includeshemiconvulsion-hemiplegia syndrome and acute infantileencephalopathy predominantly affecting the frontal lobes.Theophylline is a risk factor of these syndromes. The pathogenesis isyet to be clarified, but an increasing body of evidence points toexcitotoxicity and delayed neuronal death.

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

1Department of Pediatrics, Graduate School ofMedicine, University of Tokyo, Tokyo, Japan;2Department of Pediatrics, Dokkyo University School ofMedicine, Mibu, Japan; 3Department of Pediatrics,Yamaguchi University School of Medicine, Ube, Japan;4Department of Pediatric Emergency Medicine, OsakaCity 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; acuteencephalopathy with febrile convulsive statusepilepticus; hemiconvulsion-hemiplegia syndrome;acute infantile encephalopathy predominantlyaffecting the frontal lobes

Masashi Mizuguchi, Department of Pediatrics, GraduateSchool of Medicine, University of Tokyo, 7-3-1 Hongo,Bunkyo-ku, Tokyo 113-8655, JapanTel.: +81 3 5800 8902Fax: +81 3 5800 8902e-mail: mizuguchi-tky@umin.ac.jp

Accepted for publication 11 December, 2006

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clinicopathologic features of encephalopathy(Table 2). Neither classification is fully compre-hensive as a virus cannot be identified in somecases, and the clinicopathologic findings are atyp-ical or nonspecific in others.There is no specific correlation between the virus

and encephalopathic syndromes. Namely, anyvirus may cause any type of encephalopathy. Ineach syndrome, the clinical, laboratory, and radi-ologic features are essentially the same betweendifferent viruses.

Influenza encephalopathy

With regard to incidence, influenza virus is themost important pathogen of acute encephalopathy.In Japan, 100–500 cases of influenza encephalop-athy occur every year. Influenza A/H3 virus showsa higher incidence of encephalopathy comparedwith A/H1 and B virus (2). Influenza encephalop-athy includes all encephalopathic syndromes(Table 2). In particular, influenza encephalopathyaccounts for 40–50% of patients with Reye-likesyndrome and acute necrotizing encephalopathy(ANE) (3). The overall mortality rate of influenzaencephalopathy was about 30% before the year2000, but declined to about 15% after 2000 (4).Thus, influenza encephalopathy is an importantcause 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 ofacute encephalopathy. As is the case with influ-enza, all known encephalopathic syndromes maybe induced by HHV-6. Notably, HHV-6 is strongly

associated with acute infantile encephalopathypredominantly affecting the frontal lobes (AIEF)(5), and with hemiconvulsion-hemiplegia (HH)syndrome (6). HHV-6 is also an important causeof ANE, accounting for about 10% of cases (3, 6).

Classification based on the suspected pathomechanism

Since the 1990s, the high morbidity and mortalityof influenza encephalopathy has prompted Japan-ese investigators to explore the pathogenesis ofacute encephalopathy, and to distinguish newencephalopathic syndromes, such as ANE (7) andAIEF (5). Based on the results of these studies, thisarticle attempts to classify the syndromes into threemajor categories: metabolic error, cytokine storm,and excitotoxicity (Table 3).The definition, clinicopathologic findings, path-

ogenesis, and treatment of the syndromes will bedescribed in the following sections.

Acute encephalopathy due to metabolic error

This category consists of inherited metabolic dis-orders and classical Reye syndrome.

Inherited metabolic disorders – The brain is affectedby many inherited metabolic disorders, whichtypically are slowly progressive. However, somemetabolic disorders of fatty acids, organic acids,carbohydrates and the urea cycle (Table 4) mayaggravate rapidly. Triggered by infection andfasting, their acute exacerbation often mimicsacute encephalopathy such as Reye syndrome.Although excluded from acute encephalopathy inits strict sense, metabolic disorders should beincluded in acute encephalopathy from practicalviewpoints because their diagnosis is often difficult

Table 1 Classification according to the pathogenic virus of antecedent infection

Influenza encephalopathyExanthem subitum (human herpes virus 6) encephalopathyRotavirus encephalopathyChickenpox (varicella-zoster virus) encephalopathyMeasles encephalopathyRespiratory syncytial virus encephalopathyOther virus-associated encephalopathy

Table 3 Classification according to the pathomechanism

Pathomechanism Metabolic error Cytokine storm Excitotoxicity

Diseases andsyndromes

Inherited metabolicdisorders

Reye-like syndrome AIEFHSE syndrome

Classical Reyesyndrome

ANE HH syndrome

Distribution ofbrain edema

Diffuse Diffuse Localized

Liver dysfunction Mild to severe Mild to severe None to mildDIC/multipleorgan failure

Rare Common Rare

Mortality Middle High LowRisk factors Salicylate NSAIDs Theophylline

DIC, disseminated intravascular coagulation; HSE, hemorrhagic shock andencephalopathy; AIEF, acute infantile encephalopathy predominantly affecting thefrontal lobes; ANE, acute necrotizing encephalopathy; HH, hemiconvulsion-hemi-plegia; NSAIDs, non-steroidal anti-inflammatory drugs.

Table 2 Classification according to the clinicopathologic features

Classical Reye syndromeReye-like syndromeHemorrhagic shock and encephalopathy syndromeAcute necrotizing encephalopathyHemiconvulsion-hemiplegia syndromeAcute infantile encephalopathy predominantly affecting the frontal lobesOthers

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in the early stage of exacerbation. In Japan,metabolic errors such as fatty acid oxidationdefects and carnitine palmitoyltransferase defici-ency account for about 5% of influenza encephal-opathy cases (8). A high index of suspicion iswarranted in cases of recurrent encephalopathy,positive family history, and laboratory findings ofhypoglycemia, hyperammonemia, and lactic acid-osis. Samples of blood, urine, and cerebrospinalfluid (CSF) should be collected and kept frozen forspecific biochemical studies. Proper diagnosis isimperative because specific treatment is availablefor some of these disorders.In many inherited metabolic disorders, cranial

computed tomography (CT) and magnetic reson-ance imaging (MRI) demonstrate nonspecificabnormalities such as diffuse brain atrophy. Sev-eral conditions, such as methylmalonic acidemiaand glutaric acidemia type 1, show selective,bilateral symmetrical involvement of the deepgray matter including the basal ganglia. Duringacute encephalopathy-like episodes, these imagingfindings may rapidly worsen in some cases, anddiffuse brain edema may appear in others (9).

Classical Reye syndrome – Reye syndrome is atransient disorder of various mitochondrial func-tions, triggered by viral infection. Among thecommonly used diagnostic criteria (10) (Table 5),hyperammnonemia, microvesicular fatty metamor-phosis of hepatocytes, and mitochondrial defor-mation are important for defining classical Reyesyndrome. Hypoglycemia is also common (11).Cranial CT and MRI demonstrate diffuse brainedema.

Classical Reye syndrome is more prevalent inAmerica, Europe, and Oceania than in Japan.Children older than 5 years of age are most oftenaffected, and the onset is usually during convales-cence after influenza, chickenpox, and other viralinfections. Drugs such as salicylates and valproicacid, as well as toxins such as hypoglycine andaflatoxin, are known to be associated with thiscondition (12). At present, classical Reye syndromeis very rare in Japan as well as in many othercountries, when mimicking metabolic disorders areadequately ruled out.

Pathogenesis – Infection and fasting aggravatemany inherited metabolic disorders, as decreasedintake alters carbohydrate and fatty acid metabo-lism, and a lack of energy and excess inflammatorycytokines accelerate protein catabolism.In classical Reye syndrome, inflammatory

cytokines and drugs (or toxins) impair hepaticmitochondria to produce toxic metabolites such asshort-chain fatty acids and dicarbonic acids, whichin turn affect brain function (12) (Fig. 1). Bio-chemical studies show evidence of hepatic celldamage (a marked rise in serum aminotransferases)and various aspects of mitochondrial dysfunctioninvolving the urea cycle (hyperammonemia), glu-coneogenesis (hypoglycemia), and fatty acid oxi-dation (free fatty acidemia).

Treatment – Many inherited metabolic disordersare treated with a combination of methodsavailable for each condition (Table 6). The clas-sical Reye syndrome is treated with intensivesupportive methods to manage body fluid, bloodcirculation, respiration, body temperature, andintracranial pressure. Correction of metabolicabnormalities (hypoglycemia, hyperammonemia,and metabolic acidosis) and coagulation disorderis important.

Acute encephalopathy caused by cytokine storm

Syndromes in this category are frequently seen insevere cases of influenza encephalopathy in Japan.

Table 4 Inherited metabolic disorders that may mimic acute encephalopathy

Disorders of fatty acid transport and beta-oxidationSystemic carnitine deficiencyCarnitine palmitoyltransferase II deficiencyMedium chain acyl-CoA dehydrogenase deficiencyGlutaric acidemia type IIOthers

Disorders of organic acid metabolismPropionic acidemiaMethylmalonic acidemiaIsovaleric acidemiaGlutaric acidemia type IOthers

Disorders of glycolysisPyruvate dehydrogenase deficiencyFructose-1,6-bisphosphatase deficiencyOthers

Disorders of urea cycleOrnithine transcarbamoylase deficiencyCarbamoylphosphate synthetase deficiencyArgininosuccinate synthetase deficiencyOthers

Table 5 Diagnostic criteria of Reye syndrome (Centers for Disease Control of theUSA) (10)

Acute non-inflammatory encephalopathy documented clinically by an alteration inconsciousness and, if available, a record of cerebrospinal fluid containing <8leukocytes/mm3, or by histologic specimen demonstrating cerebral edema withoutperivascular or meningeal inflammationHepatopathy documented by results of either a liver biopsy or autopsy consideredto be diagnostic of Reye syndrome, or a threefold or greater rise in the levels ofeither aspartate aminotransferase, alanine aminotransferase, or serum ammoniaNo more reasonable explanation for the cerebral or hepatic abnormalities

Viral infection-associated encephalopathies

47

They affect not only the brain, but also visceralorgans such as the liver, kidneys, heart and skeletalmuscles, as well as blood cells and blood vessels.Thus, their clinical presentation includes encephal-opathy, multiple organ failure, disseminated intra-vascular coagulation (DIC) and hemophagocyticsyndrome (HPS). In general, the prognosis is poorwith a high mortality rate of about 30%, and alarge number of survivors are left with severeneurologic sequelae.

Reye-like syndrome – In this ill-defined condition,acute encephalopathy is associated with severe liverdamage. There is a marked increase in serumaminotransferases, which seemingly meets theCenters for Disease Control diagnostic criteria ofReye syndrome (Table 5). However, biochemicaland histologic findings characteristic of classical

Reye syndrome, such as hyperammonemia, micro-vesicular fatty metamorphosis of hepatocytes, andmitochondrial deformation, are lacking. From anepidemiologic viewpoint, several important differ-ences have been noted between Reye-like andclassical Reye syndrome (Table 7). On cranial CTand MRI, there is diffuse edema involving eitherthe whole brain (Fig. 2A) or the entire cerebralcortex. Pathologic studies demonstrate that brainedema is vascular (13).

Hemorrhagic shock and encephalopathy (HSE) syn-drome – Some cases of acute encephalopathyshow marked hemorrhagic diathesis (caused byDIC), hypovolemic shock, and dysfunction ofmultiple organs, which fulfill the diagnosticcriteria of HSE syndrome (14) (Table 8). Hemor-rhagic shock and encephalopathy (HSE) syn-drome was originally described in the United

Viral infectionEndotoxin

Lipopolysaccharides

Gene mutation or polymorphism

HypercytokinemiaTNF- α, IL-1, IL-6, etc

Toxic substances in the liverShort/ medium/ branched chain fatty acids, dicarbonic acid

Decreased ketone bodies

Systemic organ damage

Encephalopathy

Liver damageHypoglycemia, hyperammonemia

Excessive catabolismProtein, fat

Fasting

DrugsSalicylates, valproate sodium, etc

Hepatic mitochondrial damageβ-oxidation, oxidative phosphorylation

Toxic substances in the blood

Figure 1. Pathogenesis of classical Reye syndrome [modified 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 conditionAdequate dietary intake of carbohydrates and lipids (as sources of energy)Dietary restriction of materials of toxic metabolitesDrugs promoting the degradation or excretion of toxic metabolitesCoenzymes augmenting residual enzymatic activityLiver transplantation

Treatments of acute exacerbationFluid therapy

Supply of carbohydratesCorrection of blood electrolytes and acid–base balance

Prevention of toxic metabolite production (e.g., lactulose, kanamycin)Promotion of toxic metabolite excretion (e.g., sodium benzoate, sodiumphenylacetate, L-carnitine)

Blood purification (e.g., plasma exchange, hemodialysis)

Table 7 Comparison between Reye-like and classical Reye's syndrome (modifiedfrom Morishima (2))

Reye-like Classical Reye

Geographic distribution Japan > US US > JapanAge preponderance 1–5 years 5–10 yearsAssociation with chickenpox No YesAssociation with salicylates No YesAssociation with NSAIDs Yes NoHyperammonemia No YesHypoglycemia No YesNature of brain edema Vascular Cellular

NSAIDs: non-steroidal anti-inflammatory drugs.

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

The diagnostic criteria of HSE syndrome(Table 8) consist of nonspecific findings that arealso seen in Reye-like and other syndromes.Although typical cases of HSE syndrome andReye-like syndrome show clearly different features,their overlapping phenotypes often make it difficultto differentiate atypical cases. Cranial CT andMRI typically show edema of the entire cerebralcortex (17) (Fig. 2B), although edema may involvethe whole brain. There are occasionally additionalfindings of intracranial hemorrhage (Fig. 2C,D).

Acute necrotizing encephalopathy – Although mostprevalent in East Asia, ANE has been reported inother areas of the world. In addition to diffusebrain edema, ANE shows multiple focal lesions ofedematous necrosis which are symmetrically dis-tributed in the bilateral thalami and other brainregions such as the putamina, cerebral and cere-bellar deep white matter, and brainstem tegmen-tum (Fig. 3). Based on the pathognomonic CT/MRI findings, the intravitum diagnosis of ANEcan be made clearly. Other clinical and laboratoryfindings at the acute stage are nonspecific, althoughincreased CSF protein, which occasionally showsxanthochromia, is characteristic of ANE (3)(Table 10). More than 30% of patients die, andmany of the survivors have severe neurologichandicaps. In survivors with mild to moderatesequelae, motor deficits are usually severer thanmental deficits, and a unique combination of focalneurologic signs is often recognized (18)(Table 11).

Pathogenesis – Reye-like, HSE syndrome, andANE share many clinical features. Onset occursduring the early febrile period of a viral infection,and runs a fulminant course with the rapiddevelopment of coma. Of importance, severecases often show signs of systemic inflammatoryresponse syndrome, such as shock, multiple organfailure and DIC.Acute necrotizing encephalopathy complicated by

HPS has been reported in some cases (19), andconcurrent ANE and macrophage activationsyndrome have been described in a case of juvenileidiopathic arthritis (20).These clinical facts implicatemacrophage activation and hypercytokinemia in thepathogenesis of these encephalopathies (21).During the acute stage of influenza encephalop-

athy, the serum and CSF concentrations of inflam-matory cytokines, such as tumor necrosis factor-aand interleukin-6 (IL-6), are abnormally high inmany cases of Reye-like syndrome, HSE syn-drome, and ANE (22–25). The levels are usuallyhigher in serum than in CSF (Fig. 4). Taken

Table 9 Epidemiologic differences of hemorrhagic shock and encephalopathy(HSE) syndrome in Japan and UK

Japanese HSE British HSE (15, 16)

Age preponderance 6 months–5 years 2–10 monthsAssociation with overheating No YesAssociation with influenza Yes No

(A) (B)

(C) (D)

Figure 2. Cranial CT findings of Reye-like syndrome andhemorrhagic shock and encephalopathy (HSE) syndrome. (A)Diffuse edema involving the whole brain in a case of Reye-likesyndrome. (B) Diffuse edema involving the entire cerebralcortex in a case of HSE syndrome. (C, D) Edema of the entirecerebral cortex with multiple intracerebral hemorrhage inanother 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 2–10 months)Acute encephalopathy (respiratory arrest, seizures, or coma)Fever (rectal temperature, 39�C)Shock (blood pressure, <50 mmHg)Disseminated intravascular coagulation [excessive bleeding from skin, mucousmembranes, or gastrointestinal tract; coagulopathy demonstrated by thrombocy-topenia (<100 · 109/l), prolonged prothrombin time, prolonged partial thrombo-plastin time, decreased fibrinogen level, and fibrin split products]Hepatic dysfunction (abnormal aminotransferase values greater than threefoldupper limits of normal)Normal blood ammonia valuesRenal dysfunction (azotemia, hypernatremia, or metabolic acidosis)Exclusion of similar infantile conditions (e.g., septic shock, toxic shock syndrome,Reye syndrome, and hemolytic-uremic syndrome)

Viral infection-associated encephalopathies

49

together, these encephalopathic syndromes areconsidered to be a systemic disorder in which thecytokine storm plays a major role (Fig. 5).Pathologic studies of the brain at necropsy have

observed severe brain edema and perivasucularplasma exudation in Reye-like syndrome (13)(Fig. 6A), HSE syndrome, and ANE (3, 7). Inaddition, thalamic lesions of ANE show perivas-cular diapedesis of erythrocytes (petechial hemor-rhage), indicating a severer injury of intracerebralblood vessels (26). Laboratory studies have dem-onstrated increased blood levels of E-selectin and

Table 10 Diagnostic criteria of acute necrotizing encephalopathy (3)

Acute encephalopathy following a viral febrile disease. Rapid deterioration in thelevel of consciousness. ConvulsionsNo CSF pleocytosis. Increase in CSF protein commonly observedCT or MRI evidence of symmetric, multifocal brain lesions. Involvement of thebilateral thalami. Lesions also common in the cerebral periventricular white matter,internal capsule, putamen, upper brainstem tegmentum, and cerebellar medulla.No involvement of other CNS lesionsElevation of serum aminotransferase to variable degrees. No increase in bloodammoniaExclusion of resembling diseases

Differential diagnosis from clinical viewpointsOverwhelming bacterial and viral infections, and fulminant hepatitis; toxic

shock, hemolytic uremic syndrome, and other toxin-induced diseases; Reye syn-drome, HSE syndrome, and heat stroke

Differential diagnosis from radiological (or pathological) viewpointsLeigh encephalopathy and related mitochondrial cytopathies; glutaric acide-

mia, methylmalonic acidemia, and infantile bilateral striatal necrosis; Wernickeencephalopathy, and carbon monoxide poisoning; acute disseminated encephalo-myelitis, acute hemorrhagic leukoencephalitis, and other types of encephalitis andvasculitis; arterial or venous infarction, and the effects of severe hypoxia or headtrauma

Table 11 Typical neurologic sequelae of acute necrotizing encephalopathy (18)

Neurologic signs Suspected responsible lesions

Athetosis, choreoathetosis Medial nucleus of the thalamus,lenticular nucleus

Forced crying and laughing Anterior nucleus of the thalamusAtaxic gait, hypotonia,limb ataxia, intention tremor,scanning speech

Ventrolateral nucleus ofthe thalamus, cerebellum

Hemiplegia Internal capsuleHorizontal gaze palsy,abducens palsy, facial palsy

Tegmentum of the midbrain and pons

(A) (B)

Figure 3. Cranial CT findings in a case of acute necrotizing encephalopathy (ANE). (A) Multiple, low density lesions are sym-metrically 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.

SS CC11

1010

100100

1,0001,000

10,00010,000

100,000100,000

(pg/ml)(pg/ml)

ReyeReye--likelikeHSEHSE ANEANE AEFCSEAEFCSE OthersOthers FebrileFebrile

seizureseizure

n = 4n = 4 33 55 n = 13n = 13 77

SS SS SSCC CC CC SS CC

n = n = n = n = n = n =

Figure 4. Serum and cerebrospinal fluid levels of interleukin-6(IL-6) in various syndromes of acute encephalopathy, and infebrile seizure. Serum (S) and cerebrospinal fluid (C) sampleswere simultaneously collected, and their IL-6 concentrationwas measured by enzyme immunoassay. AEFCSE, acuteencephalopathy with febrile convulsive status epilepticus;others, acute encephalopathy not classified into any of thesyndromes described here.

Mizuguchi et al.

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thrombomodulin (2, 24, 27). These findings indi-cate that vascular edema, namely damage to theblood–brain barrier, is the pathologic substrate ofencephalopathy in these syndromes. Vascularinjury has been ascribed to endothelial damageby inflammatory cytokines, although the precisemechanism remains unknown.The mechanism of cerebral parenchymal injury

is different between ANE and other syndromes. InANE brains, necrosis appears to play a major role.By contrast, many neurons and glial cells undergoapoptosis in brains with Reye-like syndrome andHSE syndrome, as evidenced by DNA fragmenta-tion and caspase-3 activation (Fig. 6B), with acti-vation of microglial cells (28) (Fig. 6C). Highserum levels of cytochrome c also suggest apopto-sis in the brain and other organs (29).

It has recently been demonstrated in Japan thatthe use of non-steroidal anti-inflammatory drugs(NSAIDs), such as diclofenac sodium and mephe-namic acid, is associated with significant increase inthe mortality rate of influenza encephalopathy (2)(Table 12). Why NSAIDs aggravate influenza

Viral infectionInfluenza, etc

Gene mutation or polymorphism

AgeRace

HypercytokinemiaIL-6, TNF- , etc

Vascular endothelial injury Apoptosis of parenchymal cells

Systemic organ damageDIC, multiple organ failure

Brain edemaEncephalopathy

NSAIDs

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

(A) (B) (C)

Figure 6. Neuropathologic findings of Reye-like syndrome. (A) A histologic section of the cerebrum stained with hematoxylin andeosin shows extravasation of plasma (arrows) around the intracerebral arteries. The surrounding brain tissue is spongy, indicatingedema. (B) In situ nick-end labeling (TUNEL) of fragmented DNA of the brainstem demonstrates numerous neurons and glial cellsundergoing 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.

Table 12 Effect of antipyretics on the prognosis of influenza encephalopathy (2)

Drugs Administration No.death

No.survival

Mortalityrate, %

P-value/odds ratio

Aceto-aminophen Yes 41 139 22.8 0.22/0.75No 53 134 28.3

Diclofenac sodium Yes 25 29 46.3 0.0001/3.08No 68 243 21.9

Mephenamic acid Yes 14 15 48.3 0.003/3.04No 79 257 23.5

Viral infection-associated encephalopathies

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encephalopathy remains unknown, but one poss-ible mechanism is that their inhibitory activity incyclooxygenase may either enhance thrombosis ordisturb the repair of endothelial damage (Fig. 5).

Treatment – In Reye-like syndrome, HSE syn-drome and ANE, intensive supportive therapyalone is not as effective as in classical Reyesyndrome. Since 2000 when specialists proposed anew treatment protocol of influenza encephalopa-thy (30), Japanese pediatricians have treated theirpatients with more aggressive therapies, many ofthem designed either to combat a cytokine stormor to protect the brain (Table 13). Although it isdifficult to evaluate the efficacy of each therapy, aquestionnaire study has proved that the earliermethylprednisolone pulse therapy is started, thebetter the outcome (8). Furthermore, the overallmortality rate of influenza encephalopathy hasdeclined from about 30% (before 2000) to about15% (after 2000) (2). At present, however, manysevere cases are still fatal or left with severe braindamage. In particular, the majority of ANE casesare refractory to therapy, and the prognosis ofANE remains very poor (31).

Acute encephalopathy caused by excitotoxicity

Although indistinguishable from complex febrileseizure (febrile status convulsivus) at initial pres-entation, acute encephalopathy in this categoryshows distinct neurologic and neuroradiologicfeatures in the subsequent stages (Fig. 7) (32).Onset is usually on the first day of a viral febriledisease, such as exanthem subitum and influenza,with prolonged febrile convulsion (termed as earlyseizure) followed by post-ictal coma. On thesecond day, consciousness recovers in mostcases, although many are listless and some arenot fully alert. On the fourth or fifth day, morethan half of the cases have a cluster of briefconvulsions (late seizure; either febrile or afebrile;partial seizures secondarily generalized in manycases), followed by the second post-ictal coma.After recovering consciousness, focal neurologic

signs of the cerebral cortex, such as reducedspontaneity, aphasia, apraxia and hemiparesis,become apparent (33). The mortality rate is low(<5%). Mild cases show recovery of highercortical functions during the subsequent weeksor months; however, severe cases are left withmental deficit and/or epilepsy.Cranial CT and MRI findings are normal during

the initial several days. After the late seizure, thereis localized edema of the cerebral cortex, whichtypically shows lobar distribution (lobar edema),such as the bilateral frontal lobes (Fig. 8A) andentire cerebral hemisphere (Fig. 9A). Severe casesshow widespread edema of the cerebral cortex, oreven the whole brain (Fig. 10A,B). Diffusion-weighted imaging (DWI), the most sensitivetechnique, visualizes edema of the subcorticalwhite matter showing a characteristic pattern(bright tree appearance) (33, 34). It is noteworthythat pre- and post-central gyri are spared inmost cases (Fig. 10C). Single photon-emissioncomputed tomography (SPECT) shows hyperper-fusion of the affected cortex (35, 36). At thesubacute stage (1 week to 1 month after onset),

Fever

Aphasia

Loss of spontaneity

Stereotypic movements

Early seizure(status)

Late seizure(cluster)

Alteration ofconsciousness

Day

Figure 7. Clinical course of acute encephalopathy with febrileconvulsive status epilepticus (AEFCSE). Focal neurologicsigns shown on the right are those of acute infantileencephalopathy predominantly affecting the frontal lobes(AIEF).

Table 13 Novel therapies for influenza encephalopathy: proposal by Japanesespecialists (30)

Antiviral agents: OseltamivirIntravenous immunoglobulinMethylprednisolone pulse therapyAntithrombin IIIBrain hypothermiaPlasmapheresisCyclosporin ARehabilitation

(A) (B) (C)

Figure 8. Neuroradiologic findings of a case of AIEF. (A)MRI (T2-weighted image) on day 6 (acute stage) shows T2prolongation 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 slightatrophy of the bilateral frontal cortex. Abnormal signals havemostly resolved. (C) 99mTc-ethyl cysteine dimer single photon-emission computed tomography (99mTc ECD SPECT) on day12 shows hypoperfusion of the bilateral frontal cortex.

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CT and MRI show progressive atrophy of thecerebral cortical lesion, whereas SPECT showsprogressive hypoperfusion of the same area(Fig. 8C). During convalescence (1 month to1 year after onset), atrophy and hypoperfusionresolve gradually in mild cases, but persist insevere cases (5).The collective term for this category is acute

encephalopathy with febrile convulsive status

epilepticus (AEFCSE) (32, 33). There are alsoeponyms or closely related entities, such as �infec-tion-related acute encephalopathy with imagingfindings that initially appear normal, but showcortex-dominant necrosis 4–5 days after the onset�(37), �acute encephalopathy with prolonged febrileseizures and late reduced diffusion� (34) and�encephalopathy with biphasic clinical course�(38). AEFCSE is further classified into distinctsubtypes, such as AIEF and HH syndrome.

Acute infantile encephalopathy predominantly affectingthe frontal lobes – In this recently described syn-drome, onset is usually a prolonged generalizedtonic convulsion (early seizure), although impairedconsciousness is the first presentation in a minorityof patients. After a cluster of brief convulsions (lateseizure), signs of frontal lobe dysfunction, such asloss of spontaneity and aphasia, become apparent(5, 39). At this stage (within a week after onset),DWI reveals high intensity of the bilateral frontalcortex, in particular the subcortical white matter.Severe cases may show high intensity of the samearea even on T2-weighted and fluid-attenuatedinversion recovery (FLAIR) images (Fig. 8A).Laboratory findings of the blood, urine, and CSFare nonspecific. Serum aminotransferases arenormal or elevated only mildly. During the fol-lowing several weeks, the frontal cortex showsprogressive atrophy on MRI and hypoperfusion onSPECT (Fig. 8B,C). Many patients have stereo-typic movements, and some have mood instability(5). Diagnostic criteria of AIEF have recently beenproposed (35).

Hemiconvulsion-hemiplegia syndrome – Since thedescription by Gastaut in 1960 (40), this syn-drome has been well known to pediatricians. Theearly seizure is a prolonged clonic convulsion,

(A) (B) (C)

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

(A) (B)

(C) (D)

Figure 10. Neuroradiologic findings of AEFCSE cases withwidespread or diffuse lesions. (A, B) CT of a case of theoph-ylline encephalopathy (acute stage), showing diffuse edema ofthe whole brain. (C) MRI (diffusion-weighted image) of a caseof influenza encephalopathy with AEFCSE (acute stage),showing high intensity of the subcortical white matter (brighttree appearance) and sparing of the pre- and post-central gyri.(D) MRI (T1-weighted image) of a case of theophylline en-cephalopathy (convalescence), showing residual lesions ofcerebral atrophy, cortical laminar necrosis, and a small infarctin the right globus pallidus.

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usually with marked unilateral predominance.Serum aminotransferases are often elevatedmildly to moderately. Post-ictal neurologic deficitsinclude hemiparesis, intellectual deterioration, andepileptic seizures. A variant form of this syn-drome with involvement of the dominant hemi-sphere presents with motor aphasia rather thanhemiparesis (41). During the acute period, edemaof the affected hemisphere is so severe as to beapparent on CT in many cases (Fig. 9B). SPECTshows hyperperfusion of the cortical lesion. At thesubacute stage (1 week to 1 month after onset),there is progressive atrophy (Fig. 9C) and hypo-perfusion (36).

Theophylline encephalopathy – Xanthine derivativesare bronchodilators with anti-inflammatory effects,administered either orally (theophylline) or intra-venously (aminophylline). As a first-line therapeu-tic drug for childhood asthma, theophylline hasalready been abandoned in many countries; how-ever, in Japan, theophylline is still widely used totreat asthmatic children. When the serum level oftheophylline reaches the toxic range, its neurologicadverse effects are termed theophylline toxicity;however, theophylline may cause neurotoxicityeven when its serum level is within the therapeuticrange. Convulsions are the most common sign,and are referred to as theophylline-associatedseizures (42). Although the severity varies amongcases, theophylline-associated seizures tend to bemore prolonged, less likely to stop spontaneously,more resistant to benzodiazepine anticonvulsants,and more likely to require endotracheal intuba-tion, when compared with non-theophylline-associated cases (43, 44). As refractory statusepilepticus is usually followed by prolonged post-ictal coma, the condition should be regarded asacute encephalopathy rather than a mere seizure(45).Most, if not all, cases of theophylline encephal-

opathy have AEFCSE. Cases of both AIEF andHH syndrome have been reported (6, 33) (Fig. 9).In the severest of cases, deep coma continues forweeks, and profound disabilities persist in bothmental and motor functions. Cranial CT showsfindings of diffuse brain edema, mimicking those ofReye-like syndrome (Fig. 10A,B); however, theappearance of this finding is delayed for severaldays after onset, which is not the case with Reye-like syndrome. Residual lesions in these cases arecerebral atrophy, laminar necrosis of the cortex,and lacunar infarction of the basal ganglia orthalamus (46) (Fig. 10D).In theophylline encephalopathy, the incidence of

DIC and multiple organ failure is low, as is the

mortality rate (3–4%). Many surviving patientshave neurologic sequelae.

Pathogenesis – Much remains to be clarified withregard to the pathogenesis of AEFCSE. Pathologicfindings are scanty because of the low mortality;however, laboratory and neuroradiologic studieshave accumulated evidence that excitotoxic,delayed (or apoptotic) neuronal death is the mainpathologic event in this category (Fig. 11).The subacute nature of this pathologic process

has been shown by the time course of SPECTfindings, showing hyperperfusion at the acute stage(within 1 week after onset), and progressive hyp-operfusion at the subacute stage (1 week to1 month after onset) (35, 36). Neuronal apoptosisis suggested by the serial change in CSF cyto-chrome c level, which rises in the subacute period(47). Evidence for the involvement of excitotoxin isstill circumstantial; however, an increase in Glx(glutamine/glutamate) in the subcortical whitematter has recently been shown in a case ofAEFCSE, using magnetic resonance spectroscopy(34).In AEFCSE, brain damage is much more

serious than in complex febrile seizure. Thisdifference may be explained by the involvementof inflammatory cytokines. Although preliminary,the results of cytokine assay in the serum and CSFindicate that IL-6 shows a mild to moderateincrease in AEFCSE, and tends to be higherthan in febrile seizure (Fig. 4). Notably, the levelwas higher in the CSF than in the serum in manyAEFCSE patients, suggesting the intracerebralproduction of IL-6. Inflammatory cytokines inthe brain may enhance seizure-induced excitotox-icity, resulting in apoptosis of neurons and/or glialcells (Fig. 10), although this hypothesis needs to befurther tested.

Viral infectionInfluenza, HHV-6, etc Gene mutation or

polymorphismAge

Cytokine in the blood/ CSF

Excessive glutamate release

Status epilepticus convulsivus

Delayed (apoptotic) neuronal death

Theophylline

Glial damage

Hypoxia/ ischemia

Fever

Endothelial damage

Brain edema

Cerebrovascular dysfunction

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

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How theophylline aggravates this process ispoorly understood (45): Theophylline may prolongseizures either by increasing the amount of cyclicnucleotides (48), by blocking neuronal adenosinereceptors (49), by decreasing the amount ofgamma-aminobutyric acid (GABA) (50), or byblocking GABA receptors (49). Theophylline mayalso 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 theophyl-line-associated cases, a high-dose barbiturateshould promptly be given intravenously (43),usually followed by continuous drip infusionunder mechanical ventilation and management ofintracranial pressure. The electroencephalogramshould be continuously monitored because lateseizure is occasionally not immediately obvious,and therefore electrical status epilepticus mayeasily be overlooked.Recently, Japanese doctors have tried methyl-

prednisolone pulse therapy, intravenous immuno-globulin, and other therapies to suppressinflammatory cytokines, as well as edaravone toscavenge free radical species. At present, however,there is no solid evidence for the efficacy of thesetreatments.

Conclusion

Influenza and other virus-associated acute encep-halopathies can be classified into three majorcategories, and into six or more syndromes. Foreach syndrome, the clinical, laboratory, radiologic,and pathologic features have been well delineated.Each syndrome has distinct risk factors, especiallydrugs such as salicylates, NSAIDs, and theophyl-line. Treatment has recently been improved, but isstill unsatisfactory and, in the near feature, itshould be customized for each syndrome based onbetter understanding of the pathogenesis.

Acknowledgements

This study was supported by a Grants-in-Aid for ScientificResearch from the Ministry of Education, Culture, Sports,Science and Technology of Japan, and by a Grant for Researchon Emerging and Re-emerging Diseases from the Ministry ofHealth, Labor and Welfare of Japan.

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