Acute encephalopathy with biphasic seizures and late reduced diffusion associated with Epstein-Barr virus

doi:10.4236/ojped.2011.14017

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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.

Email: *[email protected]

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)

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

N. Nosaka et al. / Open Journal of Pediatrics 1 (2011) 72-74

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.

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