Open Journal of Pediatrics, 2011, 1, 72-74 OJPed
doi:10.4236/ojped.2011.14017 Published Online December 2011 (http://www.SciRP.org/journal/ojped/)
Published Online December 2011 in SciRes. http://www.scirp.org/journal/OJPed
Acute encephalopathy with biphasic seizures and late reduced
diffusion associated with Epstein-Barr virus
Nobuyuki Nosaka1, Yoshinori Ito2*, Shinya Hara1
1Department of Pediatrics, Toyota Memorial Hospital, Toyata, Japan;
2Department of Pediatrics, Graduate School of Medicine, Nagoya University, Nagoya, Japan.
Received 8 October 2011; revised 12 November 2011; accepted 23 November 2011.
ABSTRACT
We report the case of a 12 month-old female diag-
nosed with acute encephalopathy with biphasic sei-
zures and late reduced diffusion. Epstein-Barr virus
DNA was detected in both cerebrospinal fluid (511
copies/mL) and in serum (828 copies/mL) during the
early stage of disease, suggesting a role for this virus
in pathogenesis.
Keywords: Acute Encephalopathy with Biphasic Sei-
zures and Late Reduced Diffusion; Acute Encephalopa-
thy; Epstein-Barr Virus; MRI
1. INTRODUCTION
Studies on acute encephalopathy have progressed rapidly
in recent years. The classification of acute encephalo-
pathies has advanced with the discovery of further sub-
types based on clinical, radiologic, and laboratory find-
ings [1-4]. Recently, acute encephalopathy with biphasic
seizures and late reduced diffusion (AESD) has been
described in a cohort of Japanese children [1]. AESD is
characterized by a febrile seizure followed within sev-
eral days by a cluster of secondary seizures and late re-
duced diffusion on magnetic resonance imaging (MRI).
Although the prognosis of patients with AESD was ini-
tially reported to be poor, milder forms of AESD without
neurologic sequelae have since been recognized [5,6].
Several pathogens—for example, influenza virus and
human herpesvirus 6 (HHV-6)—have been reported as
causative agents of AESD; however, infectious agents
have not been detected in all individuals with AESD [1].
Infection with other microorganisms may be associated
with AESD but go unrecognized as such, due to difficul-
ties in detection of such pathogens.
We report a case of a 12 month-old female with a mild
type of AESD concurrent with detection of Epstein-Barr
virus (EBV) DNA in serum and cerebrospinal fluid
(CSF). This virus has, until now, not been reported to be
associated with AESD.
2. CASE REPORT
A 12-month-old, previously healthy, third-generation
Japanese-Peruvian female presented to a local emer-
gency department with a self-limited generalized tonic-
clonic seizure lasting a few minutes. She was on no
medication prior to the first seizure and was discharged
with a diazepam suppository. The patient remained feb-
rile and slightly drowsy after the first seizure. On day
four she was admitted to the hospital with a cluster of
seizures. Upon arrival she was alert with a body tem-
perature of 38.8˚C. The seizures were tonic, refractory to
typical doses of intravenous diazepam and subsequently
required a bolus of intravenous midazolam to be con-
trolled. On examination she displayed mild motor dete-
rioration of the extremities with associated hypotonia,
verbal deterioration and inability to visually fixate on
objects. Standard laboratory tests showed abnormalities
in white blood cell count (13,200/μL; normal, 3900 to
9100/μL) without atypical lymphocytes, aspartate
transaminase (106 IU/L; normal, 13 to 33 IU/L), alanine
transaminase (175 IU/L; normal, 6 to 30 IU/L) and crea-
tinine kinase (1223 IU/L; normal, 62 to 287 IU/L) levels.
The blood cell count and levels of protein and sugar in
CSF were normal. MRI on admission revealed reduced
diffusion in the frontal and parietal lobes bilaterally and
in the right temporal lobe (Figure 1(a)). No signal ab-
normalities were present on the T2-weighted image
(Figure 1(b)). An initial electroencephalogram displayed
frequent right-dominant frontal spikes. Treatment with
phenobarbital and steroid pulse therapy (methylpredni-
solone, 30 mg/kg/day for the next three days) was initi-
ated. Psychomotor status gradually improved over the
succeeding days. The patient showed improvement in
visual pursuit by day eight, was able to hold her head
steady by day 10, and was able to sit without support by
day 18. On day 10 the patient developed a generalized,

N. Nosaka et al. / Open Journal of Pediatrics 1 (2011) 72-74 73
(a) (b)
(c) (d)
Figure 1. MRI images from a patient with acute encephalopa-
thy with biphasic seizures and late reduced diffusion. (a) Re-
duced diffusion was observed in the frontal and parietal lobes,
bilaterally, on the diffusion-weighted image (DWI) at day 4; (b)
T2-weighted image on day 4 showing no signal abnormality; (c)
MRI obtained on day 9; the regions that showed abnormalities
on the initial MRI displayed higher signals on the DWI; (d)
Follow-up DWI image on day 22 showed disappearance of the
signal abnormalities without apparent cerebral atrophy.
red, morbilliform eruption without lymphadenopathy. A
phenobarbital lymphocyte stimulation test produced a
positive result, resulting in a diagnosis of phenobarbital
allergy. A repeat MRI was obtained on days 9 and 22.
Regions in which abnormalities were present on the ini-
tial MRI displayed higher signals on both diffusion and
T2 weighted MRI images on day nine (Figure 1(c)).
These abnormalities were no longer present upon MRI
on day 22; no cerebral atrophy was observed (Figure
1(d)). The patient’s development was normal at 18
months.
Testing for several infectious agents in the patient’s
serum and CSF was performed by molecular and sero-
logic methods. Levels of EBV DNA in both serum and
CSF from the patient were quantified by real-time poly-
merase chain reaction. EBV DNA was detected at 828
copies/mL in serum and 511 copies/mL in CSF during
the early stage of disease. Serologic tests for anti-EBV
antibodies on day five produced the following results:
positive for viral capsid antigen (VCA) IgG (×320, im-
munofluorescence antibody assay; negative, <10); nega-
tive for VCA IgM (negative, <10) and EBV nuclear an-
tigen (EBNA; negative, <10) (VCA IgM, negative; VCA
IgG, ×320; EBNA, ×10, in the convalescent period)
(Figure 2). HHV-6, HHV-7, VZV, HSV-1 and cytome-
Figure 2. Clinical course of the patient. mPSL, methylpredni-
solone; PSL, prednisolone; ACV, acyclovir; PB, phenobarbital;
EBV, Epstein-Barr virus; VCA, viral capsid antigen; EBNA,
Epstein-Barr virus nuclear antigen; S, serum; C, cerebrospinal
fluid.
galovirus DNA were not detected in either CSF or serum.
A viral antigen test for influenza virus from a naso-
pharyngeal swab was negative at the onset of the disease.
Serologic tests for viruses other than EBV were positive
for HHV-6 IgG (×160, immunofluorescence antibody
assay; negative, <10) and negative for HHV-6 IgM, in-
fluenza A (H1N1, H3N2) and influenza B.
3. DISCUSSION
Infectious agents have been previously identified in 10
of 17 reported patients with AESD. The pathogens de-
tected were influenza A and B (four patients), HHV-6
(three patients), HHV-7 (one patient), varicella-zoster
virus (one patient), and adenovirus (one patient) [1]. In
the case reported here these agents were negative by
either serologic tests for viral specific IgM or real-time
PCR assay. In contrast, EBV DNA was detected both in
CSF (511 copies/mL) and serum (828 copies/mL) during
the early stage of disease. Serologic assays detected
VCA IgG at ×320, but were negative for VCA IgM and
EBV nuclear antigen, but were positive for EBNA in the
convalescent phase. Although these data are not suffi-
cient to confirm acute EBV infection, the PCR results
provide some evidence that EBV infection was associ-
ated with AESD in this patient. However, it is also pos-
sible that detection of EBV DNA in both CSF and serum
resulted from a reactivation of latent EBV infection in
C
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N. Nosaka et al. / Open Journal of Pediatrics 1 (2011) 72-74 74
the context of severe illness.
To our knowledge, this report is the first to describe a
patient with AESD associated with EBV infection. EBV
is one of the most common identifiable causes of acute
childhood encephalitis; EBV has been detected in the
central nervous system of 10% of children with acute
encephalitis [7,8]. Neurologic complications of EBV
infection are diverse and include encephalitis, cerebelli-
tis, aseptic meningitis, transverse myelitis, Guillain-
Barre syndrome, cranial neuritis and others [8,9]. EBV
encephalitis does not occur in the majority of patients
presenting with infectious mononucleosis [9]. MRI has a
low specificity for EBV encephalitis [10]. The prognosis
associated with EBV encephalitis is controversial and
ranges in severity from mild to fatal [8,9]. These features
were consistent with the present case with the exception
of the biphasic clinical course. Because the classic labo-
ratory hallmarks of infectious mononucleosis—for ex-
ample, typical lymphocytosis—are absent and early di-
agnosis of EBV infection is sometimes difficult, EBV
may be not recognized as a pathogen in cases of AESD.
A combination serologic and PCR assay will allow de-
tection of any association of EBV with AESD.
REFERENCES
[1] Takanashi, J., Oba, H., Barkovich, A.J., et al. (2006)
Diffusion MRI abnormalities after prolonged febrile sei-
zures with encephalopathy. Neurology, 66, 1304-1309.
doi:10.1212/01.wnl.0000210487.36667.a5
[2] Maegaki, Y., Kondo, A., Okamoto, R., et al. (2006)
Clinical characteristics of acute encephalopathy of ob-
scure origin: A biphasic clinical course is a common fea-
ture. Neuropediatrics, 37, 269-277.
doi:10.1055/s-2006-955928
[3] Okamoto, R., Fujii, S., Inoue, T., et al. (2006) Biphasic
clinical course and early white matter abnormalities may
be indicators of neurological sequelae after status epilep-
ticus in children. Neuropediatrics, 37, 32-41.
doi:10.1055/s-2006-923949
[4] Yamanouchi, H., Kawaguchi, N., Mori, M., et al. (2006)
Acute infantile encephalopathy predominantly affecting
the frontal lobes. Pediatric Neurology, 34, 93-100.
doi:10.1016/j.pediatrneurol.2005.08.002
[5] Takanashi, J., Tsuji, M., Amemiya, K., Tada, H. and
Barkovich, A.J. (2007) Mild influenza encephalopathy
with biphasic seizures and late reduced diffusion. Journal
of the Neurological Sciences, 256, 86-89.
doi:10.1016/j.jns.2007.02.006
[6] Okumura, A., Kidokoro, H., Tsuji, T., et al. (2009) Dif-
ferences of clinical manifestations according to the pat-
terns of brain lesions in acute encephalopathy with re-
duced diffusion in the bilateral hemispheres. American
Journal of Neuroradiology, 30, 825-830.
doi:10.3174/ajnr.A1431
[7] Bale, J.F. (1999) Human herpesviruses and neurological
disorders of childhood. Seminars in Pediatric Neurology,
6, 278-287. doi:10.1016/S1071-9091(99)80026-6
[8] Doja, A., Bitnun, A., Ford Jones, E.L., et al. (2006) Pedi-
atric Epstein-Barr virus-associated encephalitis: 10-Year
review. Journal of Child Neurology, 21, 384-391.
[9] Domachowske, J.B., Cunningham, C.K. and Cummings,
D.L. (1996) Acute manifestations and neurologic seque-
lae of Epstein-Barr virus encephalitis in children. Pediat-
ric Infectious Disease Journal, 15, 871-875.
doi:10.1097/00006454-199610000-00008
[10] Shian, W.J. and Chi, C.S. (1996) Epstein-Barr virus en-
cephalitis and encephalomyelitis: MR findings. Pediatric
Radiology, 26, 690-693. doi:10.1007/BF01356839