Acute encephalopathy and encephalitis caused by influenza

virus infection
Gefei F. Wang, Weizhong Li and Kangsheng Li
Department of Microbiology and Immunology, Key
Immunopathology Laboratory of Guangdong Province,
Shantou University Medical College, Shantou,
Guangdong, P.R. China
Correspondence to Kangsheng Li, Shantou University
Medical College, 22 Xinling Road, Shantou 515041,
Guangdong, P.R. China
Tel: +86 754 8890 0456; e-mail: ksli@stu.edu.cn
Current Opinion in Neurology 2010, 23:305–311
Purpose of review
Influenza-associated acute encephalopathy/encephalitis (IAE) is an uncommon but
serious complication with high mortality and neurological sequelae. This review
discusses recent progress in IAE research for a better understanding of the disease
features, populations, outcomes, diagnosis, and pathogenesis.
Recent findings
In recent years, many IAE cases were reported from many countries, including Japan,
Canada, Australia, Austria, the Netherlands, United States, Sweden, and other
countries and regions. During the novel influenza A/H1N1 pandemic, many IAE cases
with A/H1N1 infection in children were reported, particularly in those hospitalized with
influenza infection. Pathogenesis of IAE is not fully understood but may involve viral
invasion of the CNS, proinflammatory cytokines, metabolic disorders, or genetic
susceptibility. An autosomal dominant viral acute necrotizing encephalopathy (ANE)
was recently found to have missense mutations in the gene Ran-binding 2 (RANBP2).
Another recurrent ANE case following influenza A infection was also reported in a
genetically predisposed family with an RANBP2 mutation.
Summary
Although IAE is uncommon, compared with the high incidence of influenza infection, it is
severe. However, this complication is not duly recognized by health practitioners.
Recent advances highlight the threat of this complication, which will help us to have a
better understanding of IAE.

Keywords
acute encephalopathy and encephalitis, acute necrotizing encephalopathy, influenza,
influenza-associated acute encephalopathy/encephalitis

Curr Opin Neurol 23:305–311

ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
1350-7540

throat, myalgia, and sometimes diarrhea or vomiting. In

Introduction
Influenza-associated acute encephalopathy/encephalitis
(IAE) is a central nervous system (CNS) complication
with high mortality and neurological sequelae, which is a
particular threat to children hospitalized with influenza
infection. This complication is often not recognized by
health practitioners. This review discusses recent pro-
gress in IAE research for a better understanding of the
disease features, populations, outcomes, diagnosis, and
pathogenesis.
Influenza and central nervous system
complications
Influenza virus can cause common respiratory tract infec-
tions and rarely multiorgan system disorders, resulting in
mild infection, severe respiratory disease, or systemic
disease and complications. Symptoms of mild influenza
infection usually include fever, headache, cough, sore
1350-7540 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
general, it is usually self-limited and not serious. How-
ever, certain patients, especially children, elderly people,
pregnant women, and people with certain diseases, have a
higher risk of incurring pneumococcal pneumonia and
CNS complications.
CNS dysfunction, an important complication of influenza
infection [1,2], includes IAE [3,4], febrile seizure [5],
Reye’s syndrome [6,7], postinfluenza encephalitic Par-
kinson’s disease [1,2], and encephalitis lethargica [8,9].
Febrile seizure is common among the CNS complications
with influenza infection in children and has been
reported to occur in more than 20% of the children
hospitalized with influenza [10]. Acute encephalopa-
thy/encephalitis and Reye’s syndrome have similar
clinical symptoms of CNS dysfunction, such as lowered
consciousness [7], but unlike IAE, Reye’s syndrome
involves fatty acid degeneration in the liver caused by
mitochondrial failure and is characterized by low blood
DOI:10.1097/WCO.0b013e328338f6c9

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 306 Inflammatory diseases and infection
glucose and high blood ammonia. The interval from the
onset of fever to the onset of neurological symptoms for
IAE is usually 1–2 days, which is shorter than that for
Reye’s syndrome [11].
Influenza-associated acute encephalopathy/
encephalitis
IAE is a rapid progressive encephalopathy that usually
presents in the early phase of influenza infection [1].
Because of lack of inflammation in the CNS, IAE is
always named influenza-associated acute encephalopa-
thy, which includes acute necrotizing encephalopathy
(ANE) [12].
IAE is an uncommon but serious complication with high
mortality and neurological sequelae. Cases of IAE during
influenza epidemics have been reported mostly from
Japan since 1995 [13], with a few cases from other areas,
including Taiwan [14–17], North America [18–21,22,
23,24], and Europe [25–30]. Most cases involve children
younger than 5 years. Both influenza A (including novel
H1N1 and H5N1) and B and even C can cause this
complication [15,23,28,31].
The clinical symptoms of IAE are diverse. In general, the
clinical characteristics include symptoms of both flu and
CNS dysfunction. Typical flu symptoms involved are
fever, cough, nasal discharge, sore throat, and headache,
and CNS neurological manifestations including seizure,
altered or loss of consciousness, decreased cognitive
processing including speech, motor paralysis or sensory
loss, abnormal or delirious behavior, and change in
mental status. Neurological complications may develop
within several days of the first symptoms of flu
[11,14,27,32,33,34,35].
Populations and outcomes of influenza-
associated acute encephalopathy
The data from the Japan National Epidemiological Sur-
veillance of Infectious Diseases in 1998–1999 influenza
season [36] indicated that neurologic complications such
as acute encephalitis/encephalopathy are associated with
influenza virus infection, especially among young chil-
dren. The Japanese Ministry of Health and Welfare
performed a cross-sectional survey of influenza in all
medical facilities during the 1998–1999 influenza season.
Of the 217 identified IAE cases, in which diagnosis of
encephalopathy was based on clinical symptoms, 179
(82.6%) were children younger than 5 years, 58 (26.7%)
died, and 56 (25.8%) had neurological sequelae. There
was no sex difference in prognosis and incidence [32].
Subsequent analysis of the same data by Morishima et al.
[33] confirmed 148 cases of IAE, which were diagnosed
on the basis of virologic analysis. One hundred twenty-
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
one children (81.8%) involved were less than 5 years old.
The mortality rate (31.8%) and frequency of neurological
sequelae (27.7%) were also high. Togashi et al. [11] also
investigated the incidence of IAE in Hokkaido, Japan,
during eight influenza seasons from 1994 to 2002. In each
season, the peak incidence of cases coincided with the
peak of the influenza epidemic; among a total of 89 cases
reported, 70 (78.7%) were children (<5 years), 33 (37.1%)
died, and 17 (19.1%) had neurological sequelae. Yoshi-
kawa et al. [37] studied 20 patients with IAE during the
1997–2001 influenza seasons. Among them, five (25%)
patients died and eight (40%) had neurological sequelae.
They also noted that patients with coagulopathy, hepatic
dysfunction, and computed tomographic abnormalities
had a poor prognosis. Based on the severity of disability,
the neurologic sequelae include mild sequelae and severe
sequelae that require personal help for daily life activities
[33]. Diverse neurologic sequelae occurred in these
patients, such as impaired cognitive function, mutism,
behavioral disturbances, ataxia, paralysis, dystonia, hand
tremor, spasticity, and so on [29,38–40].
In recent years, IAE complication has received inter-
national recognition and concern. Similar populations and
outcomes of IAE were reported from Canada [20,21],
Australia [41,42,43], Austria [28], the Netherlands
[29,30], United States [19,22,24,44,45], Sweden
[27,46], and other countries and regions [15,17,25,26].
Review of data from 1994 to 2004 by Amin et al. [20]
showed that influenza virus infection was associated with
about 5% (14 of 311) of acute childhood encephalopathy/
encephalitis cases in the Hospital for Sick Children,
Toronto, Canada, and 11 (78.6%) children were under
5 years old. More than 50% of patients had neurological
sequelae. In addition, the prevalence of neuroimaging
abnormalities was higher in children under 2 years of age.
Those reports suggest that children, especially those
under 5 years of age, are inclined to suffer from neuro-
logic complications with influenza infection. Most of the
patients with IAE recovered within 2–6 weeks. The
serious outcomes including death and neurological
sequelae could be as high as 50%.
Diagnosis of influenza-associated acute
encephalopathy
The diagnosis of IAE takes account of definition of both
influenza infection and encephalitis/encephalopathy.
Influenza infection definition is different in some reports.
The cases of influenza infection included cases that met
the clinical case definition (sudden onset of a fever over
398C, respiratory symptoms, myalgia, and headache)
and/or laboratory-confirmed definition [32]. The latter
defined influenza infection on the basis of either positive
viral culture, viral antigen test, or viral RNA PCR or by

significant increases in the titer of hemagglutination
inhibition test [33]. In the report by Smidt et al. [29], a
more rigorous influenza infection definition was used,
including repeated isolation of influenza A virus from
nasopharyngeal aspirates and seroconversion between
acute and convalescent sera. In addition, serological tests
of Epstein–Barr virus, cytomegalovirus, herpes simplex
virus, varicella-zoster virus, mumps, measles, and Myco-
plasma pneumoniae have been used to exclude other
encephalopathy/encephalitis pathogens.
The diagnosis of encephalitis/encephalopathy has been
based on clinical symptoms and signs. Patients with
meningitis, myelitis, and febrile seizure should be
excluded. Neuroimaging, such as MRI and computed
tomography (CT), and electroencephalographic (EEG)
analyses were performed in some reports. Diffuse invol-
vement of the cerebral cortex and diffuse brain edema
were detected by neuroimaging in severe cases, and the
degree of radiological change was associated with
the prognosis [18,47,48]. Some (about 20–30%) of the
patients, who developed severe illness and/or acute
necrotizing encephalopathy, exhibited multifocal, sym-
metrically distributed brain lesions of the thalamus,
cerebral white matter, brainstem, cerebellum, and par-
enchyma by CT and MRI [12,33,49,50]. Different from
other encephalitides, such as Reye’s syndrome, the bilat-
eral thalamic necrosis on neuroimaging was considered to
be one of the features of IAE [12,50]. EEG abnormalities
such as focal slowing or sharp waves in the frontal or
temporal area, diffuse slowing, abnormal background,
electrographic seizure, and generalized slow-wave
activity were found in many cases [20,22,25,27]. There-
fore, neuroimaging and EEG can be used to make
laboratory diagnosis and predict prognosis of encephali-
tis/encephalopathy.
In conclusion, the influenza infection should be defined by
both clinical features and laboratory results. Other ence-
phalopathy/encephalitis pathogens should be excluded.
Neurological symptoms should develop usually within
2 days after the onset of flu symptoms.
Novel H1N1 and influenza-associated acute
encephalopathy
Neurological symptoms were reportedly associated with
some cases of the novel influenza A/H1N1 infection.
Neurologic complications, including encephalopathy
and seizure, in children in Dallas, Texas, were reported
in MMWR by the United States Centers for Disease
Control and Prevention [22]. Gonzalez and Brust [24]
reported a mother and her daughter in Florida presenting
with an acute febrile encephalopathy. Lyon et al. [18]
reported a 12-year-old girl from Texas infected with
influenza A H1N1 who suffered from acute necrotizing
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Influenza-associated acute encephalopathy Wang et al. 307
encephalopathy with rapid progressive neurologic
deterioration. Larcombe et al. [41] reported the clinical
spectrum of 43 children with A/H1N1 pandemic virus
from a single Australian hospital during the peak winter
influenza season of 2009 and 7% (3/43) had an encepha-
lopathy. Therefore, IAE should still be considered a
threat to children, especially the hospitalized children,
in this H1N1 pandemic.
Pathogenesis of influenza-associated acute
encephalopathy/encephalitis: viral invasion
of central nervous system
Whether the influenza virus invades the CNS or not
is still controversial. Fujimoto et al. [4] reported that
influenza virus RNA was detected frequently (71.4%,
five positives in seven patients) in the cerebrospinal
fluid (CSF) of patients who developed IAE. However,
in other reports, only a small number of patients were
positive for viral RNA in CSF and brain, and there was
lack of inflammation in brain tissue of fatal cases
[11,22,33,51]. Okumura et al. [34] reported that the
clinical symptoms, laboratory data, and outcomes were
not different between influenza and noninfluenza
patients with ANE, suggesting that the pathogenetic
mechanism of ANE is not dependent on infectious
agents.
Some data from animal model and in-vitro experiments
however indicated that influenza virus can enter the CNS
from peripheral nerves and induce encephalopathy and
neuroinflammation. Vascular endothelial cells, astrocytes,
and neurons can be infected and undergo induced apop-
tosis by influenza virus [52–54]. With regard to the
pathogenesis of IAE, viral invasion of the CNS is short
of direct evidence. Viral invasion of the CNS is more
likely a result not a cause of disease or may contribute to
the pathogenetic process in some patients.
Pathogenesis of influenza-associated acute
encephalopathy/encephalitis: cytokine storm
The concentrations of proinflammatory cytokines such as
interleukin (IL)-6, IL-1b, tumor necrosis factor (TNF)-a,
and soluble TNF receptor were reportedly elevated in
the CSF and plasma of patients with IAE [55–58]. The
concentrations of other cytokines/chemokines, including
CXCL8/IL-8, CCL2/MCP-1, and CXCL10/IP-10, were
also highly elevated both in CSF and plasma [59]. The
serum IL-6 level was correlated with worse prognosis and
the time course of serum IL-6 levels also reflected the
clinical condition [60,61]. Serum IL-6, IL-10, TNF-a,
and CSF IL-6 are part of the regulatory system of
cytokines in some acute encephalopathy cases [62].
The severity of IAE is positively correlated with the
concentration of proinflammatory cytokines.
 308 Inflammatory diseases and infection
In encephalopathy due to infection with other viruses,
such as human herpesvirus-6 and respiratory syncytial
virus, elevated levels of proinflammatory cytokines
(especially IL-6) in serum and CSF are also important
for predicting neurological sequelae and have been con-
sidered to mediate the pathogenesis of acute encephalo-
pathy [63,64].
Proinflammatory cytokines, such as IL-6 and TNF-a, can
induce apoptosis and injury of vascular endothelium, glial
cells, and neurons, cause vascular lesions and breakdown
of the blood–brain barrier (BBB), and thereby induce
brain edema and damage, CNS disorders, and/or systemic
symptoms [13,37,58,65–67].
Some proteins, such as cytochrome c and e-selectin,
which are associated with apoptosis and vascular endo-
thelial injury, were increased in some cases [57,67–69].
Serum cytochrome c was related to the development of
severe encephalopathy in the initial phase [69]. Cyto-
chrome c, an apoptosis marker of several organs including
the cerebrum and liver, was increased under the influ-
ence of hypercytokinemia [67]. Therefore, cytokine
storm is a more likely pathogenesis of IAE.
Pathogenesis of influenza-associated acute
encephalopathy/encephalitis: other factors
Some patients had hepatic and/or renal dysfunction, such
as increased serum creatinine and aspartate transaminase,
and hematuria or proteinuria, suggesting IAE is frequently
associated with metabolic disorders [28,35,70,71]. Hypo-
prothrombinemia, disseminated intravascular coagulation
(DIC), and decreased serum CD40 ligand were also
reported in some cases [28,66,72,73]. Therefore, metabolic
Figure 1 The pathogenesis of influenza-associated acute encephalopathy/encephalitis
BBB, blood–brain barrier; CNS, central nervous system; DIC, disseminated intravascular coagulation.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
disorders and coagulopathy might also be involved in the
pathogenesis of IAE in some cases [74].
The case of a mother and her daughter presenting with an
acute encephalopathy after novel influenza A (H1N1)
infection suggests a genetic susceptibility to IAE [24].
Recurrent or relapsing IAE cases have been occasionally
reported [25,75]. It is not clear whether patients with
certain genetic backgrounds are more susceptible to IAE.
Mutations in the gene Ran-binding 2 (RANBP2) have
been shown to be associated with familial or recurrent
viral ANE [76]. For example, an autosomal-dominant
ANE was reported to have missense mutations in
RANBP2 [76]. Another recurrent ANE case following
influenza A infection was also reported in a genetically
predisposed family with an RANBP2 mutation [75].
Pathogenesis of influenza-associated acute
encephalopathy/encephalitis: in summary
In summary, as indicated in Fig. 1, some patients with
certain genetic backgrounds infected by certain influenza
strains have disorders in proinflammatory cytokine
release and hypercytokinemia. Proinflammatory cyto-
kines could induce vascular endothelial injury and
increased BBB permeability. Proinflammatory cytokines
could penetrate into the CNS through a damaged BBB,
induce the immunopathogenesis and apoptosis of
neurons and glia, and activate glia to release more cyto-
kines, therefore influencing the function of the CNS. In
some patients, viruses could infect the CNS through the
peripheral nerve or damaged BBB, thereby inducing a
CNS cytokine storm, direct damage, and promotion of
apoptosis of neurons and glial cells. Cytokine storm may
also contribute to apoptosis of liver cells, hepatic/renal

dysfunction, metabolic disorders, and coagulopathy and
DIC, which may induce or aggravate severity of disease.
Treatment of influenza-associated acute
encephalopathy/encephalitis
Because IAE is induced by influenza infection, antiviral
therapy using amantadine or oseltamivir phosphate is
necessary. Antiviral medicine was administered in some
reports and clinical conditions of some patients were
gradually improved [11,12,39,77].
Mild hypothermia therapy and anticytokine agents may
be effective for severe IAE treatment. In a report by
Yokota et al. [66], four children with IAE were enrolled for
hypothermia treatment for the purpose of stabilizing the
cytokine storm in the CNS. The children were soon
cooled down to approximately 348C for 3 days, and
rewarmed to normal temperature at a rate of no greater
than 1.08C per day during the next 3 days. The mild
hypothermia was effective for suppressing brain edema
and protecting the brain from subsequent irreversible
neural cell damage and systemic expansion [66]. Sub-
sequently, treatment with a combination of mild
hypothermia, anticytokine agents (high-dose methyl-
prednisolone and ulinastatin), and amantadine was effec-
tive for two children with severe IAE [78].
Conclusion
Although IAE is uncommon compared with the high
incidence of influenza infection, it is severe. It is one
of the recognized complications of influenza infection in
children, with high mortality and neurological sequelae.
Awareness and diagnosis of encephalopathy/encephalitis
in the setting of influenza is important in order to provide
appropriate monitoring and treatment for this life-
threatening condition.
Acknowledgements
This study was supported by the National Natural Science Foundation of
China (30771988, 30972766), Guangdong Natural Science Foundation
(8151503102000022, 9451503102003499), Specialized Research
Fund for the Doctoral Program of Higher Education (20094402110004),
211 Project of Guangdong Province (Mechanism and Prevention of
Emerging Infectious Diseases), and Shantou University Medical College
Research Foundation. We thank Li Rui for critical discussion and Dr
William Ba-Thein and Zhang Chi for manuscript editing.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
 of special interest
 of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (p. 338).
1 Toovey S. Influenza-associated central nervous system dysfunction: a litera-
ture review. Travel Med Infect Dis 2008; 6:114–124.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Influenza-associated acute encephalopathy Wang et al. 309
2 Kuiken T, Taubenberger JK. Pathology of human influenza revisited. Vaccine
2008; 26 (Suppl 4):D59–D66.
3 Delorme L, Middleton PJ. Influenza A virus associated with acute encephalo-
pathy. Am J Dis Child 1979; 133:822–824.
4 Fujimoto S, Kobayashi M, Uemura O, et al. PCR on cerebrospinal fluid to show
influenza-associated acute encephalopathy or encephalitis. Lancet 1998;
352:873–875.
5 Chiu SS, Tse CY, Lau YL, Peiris M. Influenza A infection is an important cause
of febrile seizures. Pediatrics 2001; 108:E63.
6 Ruben FL, Michaels RH. Reye syndrome with associated influenza A and B
infection. JAMA 1975; 234:410–412.
7 Studahl M. Influenza virus and CNS manifestations. J Clin Virol 2003;
28:225–232.
8 Vilensky JA, Foley P, Gilman S. Children and encephalitis lethargica: a
historical review. Pediatr Neurol 2007; 37:79–84.
9 McCall S, Vilensky JA, Gilman S, Taubenberger JK. The relationship between
encephalitis lethargica and influenza: a critical analysis. J Neurovirol 2008;
14:177–185.
10 Nicholson KG, Webster RG, Hay AJ. Textbook of Influenza. Oxford: Blackwell
Science; 1998:; pp. 222–223.
11 Togashi T, Matsuzono Y, Narita M, Morishima T. Influenza-associated acute
encephalopathy in Japanese children in 1994–2002. Virus Res 2004;
103:75–78.
12 Sugaya N. Influenza-associated encephalopathy in Japan: pathogenesis and
treatment. Pediatr Int 2000; 42:215–218.
13 Takahashi M, Yamada T, Nakashita Y, et al. Influenza virus-induced encepha-
lopathy: clinicopathologic study of an autopsied case. Pediatr Int 2000;
42:204–214.
14 Wang YH, Huang YC, Chang LY, et al. Clinical characteristics of children with
influenza A virus infection requiring hospitalization. J Microbiol Immunol Infect
2003; 36:111–116.
15 Huang SM, Chen CC, Chiu PC, et al. Acute necrotizing encephalopathy of
childhood associated with influenza type B virus infection in a 3-year-old girl.
J Child Neurol 2004; 19:64–67.
16 Lin CH, Huang YC, Chiu CH, et al. Neurologic manifestations in children with
influenza B virus infection. Pediatr Infect Dis J 2006; 25:1081–1083.
17 Li WC, Shih SR, Huang YC, et al. Clinical and genetic characterization of
severe influenza B-associated diseases during an outbreak in Taiwan. J Clin
Virol 2008; 42:45–51.
18 Lyon JB, Remigio C, Milligan T, Deline C. Acute necrotizing encephalopathy
in a child with H1N1 influenza infection. Pediatr Radiol 2010; 40:200–
205.
19 Newland JG, Laurich VM, Rosenquist AW, et al. Neurologic complications
in children hospitalized with influenza: characteristics, incidence, and risk
factors. J Pediatr 2007; 150:306–310.
20 Amin R, Ford-Jones E, Richardson SE, et al. Acute childhood encephalitis and
encephalopathy associated with influenza: a prospective 11-year review.
Pediatr Infect Dis J 2008; 27:390–395.
21 Kirton A, Busche K, Ross C, Wirrell E. Acute necrotizing encephalopathy in
caucasian children: two cases and review of the literature. J Child Neurol
2005; 20:527–532.
22 Neurologic complications associated with novel influenza A (H1N1) virus
 infection in children–Dallas, Texas, May 2009. MMWR Morb Mortal Wkly Rep
2009; 58:773–778.
As with seasonal influenza, neurologic complications can occur after respiratory
tract infection with novel A/H1N1. CNS complications should be considered a
threat to children in this H1N1 pandemic.
23 Sazgar M, Robinson JL, Chan AK, Sinclair DB. Influenza B acute necrotizing
encephalopathy: a case report and literature review. Pediatr Neurol 2003;
28:396–399.
24 Gonzalez BE, Brust DG. Novel influenza A (H1N1) presenting as an acute
 febrile encephalopathy in a mother and daughter. Clin Infect Dis 2009;
49:1966–1967.
The cases were from one family. The genetic feature of the patients associated with
susceptibility to acute encephalopathy is worth further research.
25 Fasano A, Natoli GF, Cianfoni A, et al. Acute necrotizing encephalopathy: a
relapsing case in a European adult. J Neurol Neurosurg Psychiatry 2008;
79:227–228.
26 Voudris KA, Skaardoutsou A, Haronitis I, et al. Brain MRI findings in influenza
A-associated acute necrotizing encephalopathy of childhood. Eur J Paediatr
Neurol 2001; 5:199–202.
 310 Inflammatory diseases and infection

27 Fowler A, Stodberg T, Eriksson M, Wickstrom R. Childhood encephalitis in 50 Mizuguchi M. Acute necrotizing encephalopathy of childhood: a novel form of
Sweden: etiology, clinical presentation and outcome. Eur J Paediatr Neurol acute encephalopathy prevalent in Japan and Taiwan. Brain Dev 1997;
2008; 12:484–490. 19:81–92.
28 Steininger C, Popow-Kraupp T, Laferl H, et al. Acute encephalopathy asso- 51 Ito Y, Ichiyama T, Kimura H, et al. Detection of influenza virus RNA by reverse
ciated with influenza A virus infection. Clin Infect Dis 2003; 36:567–574. transcription-PCR and proinflammatory cytokines in influenza-virus-asso-
ciated encephalopathy. J Med Virol 1999; 58:420–425.
29 Smidt MH, Stroink H, Bruinenberg JF, Peeters M. Encephalopathy associated
with influenza A. Eur J Paediatr Neurol 2004; 8:257–260. 52 Wang G, Zhang J, Li W, et al. Apoptosis and proinflammatory cytokine
responses of primary mouse microglia and astrocytes induced by human
30 Gooskens J, Kuiken T, Claas EC, et al. Severe influenza resembling hemor-
H1N1 and avian H5N1 influenza viruses. Cell Mol Immunol 2008; 5:113–
rhagic shock and encephalopathy syndrome. J Clin Virol 2007; 39:136–140.
120.
31 Takayanagi M, Umehara N, Watanabe H, et al. Acute encephalopathy
53 Sumikoshi M, Hashimoto K, Kawasaki Y, et al. Human influenza virus infection
 associated with influenza C virus infection. Pediatr Infect Dis J 2009;
and apoptosis induction in human vascular endothelial cells. J Med Virol 2008;
28:554.
80:1072–1078.
The first influenza C virus infected acute encephalopathy case suggests that
detection of influenza C virus might be considered in the virologic testing of 54 Jang H, Boltz D, Sturm-Ramirez K, et al. Highly pathogenic H5N1 influenza
childhood encephalopathy. virus can enter the central nervous system and induce neuroinflammation
and neurodegeneration. Proc Natl Acad Sci U S A 2009; 106:14063–
32 Kasai T, Togashi T, Morishima T. Encephalopathy associated with influenza
14068.
epidemics. Lancet 2000; 355:1558–1559.
55 Ichiyama T, Morishima T, Isumi H, et al. Analysis of cytokine levels and
33 Morishima T, Togashi T, Yokota S, et al. Encephalitis and encephalopathy
NF-kappaB activation in peripheral blood mononuclear cells in influenza
associated with an influenza epidemic in Japan. Clin Infect Dis 2002;
virus-associated encephalopathy. Cytokine 2004; 27:31–37.
35:512–517.
56 Ichiyama T, Endo S, Kaneko M, et al. Serum cytokine concentrations of
34 Okumura A, Abe S, Kidokoro H, Mizuguchi M. Acute necrotizing encephalo-
influenza-associated acute necrotizing encephalopathy. Pediatr Int 2003;
 pathy: a comparison between influenza and non-influenza cases. Microbiol
45:734–736.
Immunol 2009; 53:277–280.
The pathogenesis of acute necrotizing encephalopathy was not dependent on 57 Ichiyama T, Isumi H, Ozawa H, et al. Cerebrospinal fluid and serum levels of
infectious agents. cytokines and soluble tumor necrosis factor receptor in influenza virus-
associated encephalopathy. Scand J Infect Dis 2003; 35:59–61.
35 Wada T, Morishima T, Okumura A, et al. Differences in clinical manifestations
 of influenza-associated encephalopathy by age. Microbiol Immunol 2009; 58 Kawada J, Kimura H, Ito Y, et al. Systemic cytokine responses in patients with
53:83–88. influenza-associated encephalopathy. J Infect Dis 2003; 188:690–698.
The clinical course, laboratory data, and brain imaging findings of IAE exhibit
59 Lee N, Wong CK, Chan PK, et al. Acute encephalopathy associated with
variable patterns with age.
influenza A infection in adults. Emerg Infect Dis 16:139–142.
36 Okabe N, Yamashita K, Taniguchi K, Inouye S. Influenza surveillance system of
60 Aiba H, Mochizuki M, Kimura M, Hojo H. Predictive value of serum interleukin-
Japan and acute encephalitis and encephalopathy in the influenza season.
6 level in influenza virus-associated encephalopathy. Neurology 2001;
Pediatr Int 2000; 42:187–191.
57:295–299.
37 Yoshikawa H, Yamazaki S, Watanabe T, Abe T. Study of influenza-associated
61 Fukumoto Y, Okumura A, Hayakawa F, et al. Serum levels of cytokines and
encephalitis/encephalopathy in children during the 1997 to 2001 influenza
EEG findings in children with influenza associated with mild neurological
seasons. J Child Neurol 2001; 16:885–890.
complications. Brain Dev 2007; 29:425–430.
38 Wang IJ, Lee PI, Huang LM, et al. The correlation between neurological
62 Ichiyama T, Suenaga N, Kajimoto M, et al. Serum and CSF levels of cytokines
evaluations and neurological outcome in acute encephalitis: a hospital-based
in acute encephalopathy following prolonged febrile seizures. Brain Dev
study. Eur J Paediatr Neurol 2007; 11:63–69.
2008; 30:47–52.
39 Takanashi J, Barkovich AJ, Yamaguchi K, Kohno Y. Influenza-associated
63 Otake Y, Yamagata T, Morimoto Y, et al. Elevated CSF IL-6 in a patient
encephalitis/encephalopathy with a reversible lesion in the splenium of the
with respiratory syncytial virus encephalopathy. Brain Dev 2007; 29:117–
corpus callosum: a case report and literature review. AJNR Am J Neuroradiol
120.
2004; 25:798–802.
64 Ichiyama T, Ito Y, Kubota M, et al. Serum and cerebrospinal fluid levels of
40 Wong AM, Simon EM, Zimmerman RA, et al. Acute necrotizing encephalo-
 cytokines in acute encephalopathy associated with human herpesvirus-6
pathy of childhood: correlation of MR findings and clinical outcome. AJNR Am
infection. Brain Dev 2009; 31:731–738.
J Neuroradiol 2006; 27:1919–1923.
Increased cytokines in acute encephalopathy associated with influenza and other
41 Larcombe PJ, Moloney SE, Schmidt PA. Pandemic (H1N1) 2009: a clinical viruses provide a clue that cytokine storm is more likely a pathogenesis of acute
 spectrum in the general paediatric population. Arch Dis Child 2009 [Epub encephalopathy.
ahead of print].
65 Nakai Y, Itoh M, Mizuguchi M, et al. Apoptosis and microglial activation in
Encephalopathy occurred in some hospitalized children in Australia, and should be
influenza encephalopathy. Acta Neuropathol 2003; 105:233–239.
considered in this H1N1 pandemic.
66 Yokota S, Imagawa T, Miyamae T, et al. Hypothetical pathophysiology of acute
42 Troedson C, Gill D, Dale RC. Emergence of acute necrotising encephalopathy
encephalopathy and encephalitis related to influenza virus infection and
in Australia. J Paediatr Child Health 2008; 44:599–601.
hypothermia therapy. Pediatr Int 2000; 42:197–203.
43 Milne BG, Williams S, May ML, et al. Influenza A associated morbidity and
67 Nunoi H, Mercado MR, Mizukami T, et al. Apoptosis under hypercytokinemia is
mortality in a Paediatric Intensive Care Unit. Commun Dis Intell 2004;
a possible pathogenesis in influenza-associated encephalopathy. Pediatr Int
28:504–509.
2005; 47:175–179.
44 Weitkamp JH, Spring MD, Brogan T, et al. Influenza A virus-associated acute
68 Hosoya M, Nunoi H, Aoyama M, et al. Cytochrome c and tumor necrosis
necrotizing encephalopathy in the United States. Pediatr Infect Dis J 2004;
factor-alpha values in serum and cerebrospinal fluid of patients with influenza-
23:259–263.
associated encephalopathy. Pediatr Infect Dis J 2005; 24:467–470.
45 Severe morbidity and mortality associated with influenza in children and
69 Hosoya M, Kawasaki Y, Katayose M, et al. Prognostic predictive values of
young adults–Michigan, 2003. MMWR Morb Mortal Wkly Rep 2003;
serum cytochrome c, cytokines, and other laboratory measurements in acute
52:837–840.
encephalopathy with multiple organ failure. Arch Dis Child 2006; 91:469–
46 Hjalmarsson A, Blomqvist P, Brytting M, et al. Encephalitis after influenza in 472.
Sweden 1987–1998: a rare complication of a common infection. Eur Neurol
70 Purevsuren J, Hasegawa Y, Kobayashi H, et al. Urinary organic metabolite
2009; 61:289–294.
screening of children with influenza-associated encephalopathy for inborn
47 Kimura S, Ohtuki N, Nezu A, et al. Clinical and radiological variability of errors of metabolism using GC/MS. Brain Dev 2008; 30:520–526.
influenza-related encephalopathy or encephalitis. Acta Paediatr Jpn 1998; 71 Nagao T, Morishima T, Kimura H, et al. Prognostic factors in influenza-
40:264–270.  associated encephalopathy. Pediatr Infect Dis J 2008; 27:384–389.
48 Iijima H, Wakasugi K, Ayabe M, et al. A case of adult influenza A virus- The elevation of aspartate aminotransferase, hyperglycemia, the presence of
associated encephalitis: magnetic resonance imaging findings. J Neuro- hematuria or proteinuria, and use of diclofenac sodium were associated with a
imaging 2002; 12:273–275. poor prognosis.
49 Mizuguchi M, Abe J, Mikkaichi K, et al. Acute necrotising encephalopathy of 72 Mizuguchi M, Yamanouchi H, Ichiyama T, Shiomi M. Acute encephalopathy
childhood: a new syndrome presenting with multifocal, symmetric brain associated with influenza and other viral infections. Acta Neurol Scand Suppl
lesions. J Neurol Neurosurg Psychiatry 1995; 58:555–561. 2007; 186:45–56.

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

73 Ichiyama T, Morishima T, Suenaga N, et al. Analysis of serum soluble CD40
ligand in patients with influenza virus-associated encephalopathy. J Neurol Sci
2005; 239:53–57.
74 Yao D, Kuwajima M, Chen Y, et al. Impaired long-chain fatty acid metabolism
in mitochondria causes brain vascular invasion by a non-neurotropic epidemic
influenza A virus in the newborn/suckling period: implications for influenza-
associated encephalopathy. Mol Cell Biochem 2007; 299:85–92.
75 Gika AD, Rich P, Gupta S, et al. Recurrent acute necrotizing encephalopathy
 following influenza A in a genetically predisposed family. Dev Med Child
Neurol 2009; 52:99–102.
A recurrent acute necrotizing encephalopathy case following influenza A infection
was confirmed in a genetically predisposed family with an RANBP2 mutation.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Influenza-associated acute encephalopathy Wang et al. 311
76 Neilson DE, Adams MD, Orr CM, et al. Infection-triggered familial or recur-
 rent cases of acute necrotizing encephalopathy caused by mutations in a
component of the nuclear pore, RANBP2. Am J Hum Genet 2009; 84:44–
51.
RANBP2 missense mutations are involved in the susceptibility for acute necrotiz-
ing encephalopathy.
77 Sugaya N, Miura M. Amantadine therapy for influenza type A-associated
encephalopathy. Pediatr Infect Dis J 1999; 18:734.
78 Munakata M, Kato R, Yokoyama H, et al. Combined therapy with hypothermia
and anticytokine agents in influenza A encephalopathy. Brain Dev 2000;
22:373–377.