Brain & Development xxx (2014) xxx–xxx
www.elsevier.com/locate/braindev

Case report

Overlapping MERS and mild AESD caused by HHV-6 infection
Mari Hatanaka a, Mitsuru Kashiwagi b,⇑, Takuya Tanabe c, Hiroshi Nakahara d,
Kazumi Ohta a, Hiroshi Tamai e
a

Department of Pediatrics, Rakuwakai Otowa Hospital, Japan
b
Department of Pediatrics, Hirakata City Hospital, Japan
c
Department of Child Neurology, Tanabe Children’s Clinic, Japan
d
Department of Pediatrics, Nakahara Hiroshi Kids Clinic, Japan
e
Department of Pediatrics, Osaka Medical College, Japan
Received 23 January 2014; received in revised form 11 April 2014; accepted 30 April 2014

Abstract
We report the case of an overlapping encephalopathy syndrome consisting of clinically mild encephalitis/encephalopathy with a
reversible splenial lesion (MERS) and a mild form of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD)
caused by human herpesvirus-6.
A previously healthy 17-month-old girl was admitted to our hospital as a precaution because of seizures that had developed more
than 25 hours (h) after fever. Brain diffusion-weighted images (DWI) showed high signal intensity in the central splenial region on
Day 2. She regained consciousness 16 h after the second seizure. On Day 6, she had a secondary cluster of partial seizures. DWI
showed resolution of the splenial lesion and revealed reduced diffusion in the fronto-subcortical white matter. She regained consciousness 36 h after the secondary cluster of seizures without any sequelae. A third DWI performed on Day 15 showed that the
fronto-subcortical white matter lesions had completely disappeared. Based on the clinicoradiological findings, we diagnosed the
patient with overlapping MERS and mild AESD.
Our case, together with previous reports, suggests that patients can develop combined encephalopathy syndromes as a phenotype. Many encephalopathy syndromes have been established and classified; however, some may not present as independent
syndromes.
Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Keywords: Overlap; Human herpesvirus 6; Clinically mild encephalitis/encephalopathy with a reversible splenial lesion; Acute encephalopathy with
biphasic seizures and late reduced diffusion

1. Introduction
Human herpesvirus-6 (HHV-6) is the second most
common pathogen causing acute encephalopathy in

⇑ Corresponding author. Address: Department of Pediatrics,
Hirakata City Hospital, 2-14-1 Kinnya honnmachi Hirakata City,
Osaka 573-1013, Japan. Tel.: +81 72 847 2821; fax: +81 72 847 28215.
E-mail address: dbs003@art.osaka-med.ac.jp (M. Kashiwagi).

Japan [1]. Among encephalopathy syndromes associated
with HHV-6, acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is the most frequent, followed by acute necrotizing encephalopathy
(ANE). Clinically mild encephalitis/encephalopathy
with a reversible splenial lesion (MERS), hemorrhagic
shock and encephalopathy (HSES) syndrome, and limbic encephalitis are rare [1].
Patients develop various types of encephalopathy
syndromes with phenotypic differences; however, the

http://dx.doi.org/10.1016/j.braindev.2014.04.011
0387-7604/Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Please cite this article in press as: Hatanaka M et al. Overlapping MERS and mild AESD caused by HHV-6 infection.. Brain Dev (2014), http://
dx.doi.org/10.1016/j.braindev.2014.04.011

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M. Hatanaka et al. / Brain & Development xxx (2014) xxx–xxx

mechanisms underlying the development of different
encephalopathy syndromes from the same virus are
unknown. Although each encephalopathy syndrome is
established to some extent, it is unclear whether encephalopathy syndromes are completely independent from
one another.
This report presents a rare case with overlapping
MERS and mild AESD caused by HHV-6 infection
and specifically focuses on the clinicoradiological
findings.
2. Case report
A 17-month-old girl, the first child of healthy Japanese parents, was born at term by vaginal delivery and
had no previous developmental problems. There was
no family history of neurologic disease. The patient
had a 3-minute (min) long generalized tonic–clonic seizure, which stopped naturally. Because we estimated
that the seizure, which developed 25 hours (h) after fever
onset, did not have the typical clinical course of febrile
seizure, we judged that she required admission to the
hospital for a follow-up as a precaution. On admission,
she was alert without any neurological abnormalities.
Routine hematological studies, blood gas analysis, and
almost all biochemical studies were normal. Her serum
sodium level was 134 mmol/L (standard range of institute: 135–147 mmol/L) on Day 1 of admission. Four
hours after the first seizure, she had a generalized
tonic–clonic seizure lasting 4 min. Although the second
seizure also stopped without treatment, midazolam
was administered by intravenous injection for persisting

rigidity of the lower limbs. In addition, diazepam suppositories were given twice for recurrent seizures
(Fig. 1). The results of a routine cerebrospinal fluid
(CSF) examination were normal. Brain diffusionweighted images (DWI) acquired using magnetic resonance imaging (MRI) showed high signal intensity in
the central splenial region on Day 2 (Fig. 2). She
regained consciousness 16 h after the second seizure.
We diagnosed the patient with MERS based on the clinicoradiological findings [2,3]. Her fever was reduced on
Day 5, and she had a rash on Day 6.
On Day 6, she had a cluster of three tonic–clonic
seizures that occurred over 3 h, each lasting 5–6 min.
Although all seizures stopped naturally, a diazepam
suppository was given for irritability after the first seizure, and after the third seizure, midazolam was
administered by intravenous injection, and phenobarbital suppositories and oral valproate sodium were
administered regularly for preventing recurrent seizures. The second blood and CSF examinations were
normal. DWI on Day 6 showed resolution of the
high-intensity signal in the central splenial region identified on Day 2, and revealed reduced diffusion in the
fronto-subcortical white matter (Fig. 3a–c). Under a
diagnosis of AESD, methylprednisolone pulse therapy
(30 mg/kg per day) and gamma-globulin treatment
were administered. She regained consciousness 36 h
after the secondary cluster of seizures. After the treatment was administered, the patient’s consciousness
improved rapidly without seizures, and she had fully
recovered by Day 8. EEG findings appeared normal
on Day 9. A third brain MRI (DWI) performed on

Fig. 1. Clinical course. EEG, electroencephalogram; BLOOD, blood examination; CSF, cerebrospinal fluid examination; MRI, magnetic resonance
imaging; DZP, diazepam; suppo, suppository; MDZ, midazolam; PB, phenobarbital; VPA, valproate sodium; p.o., per os; iv, intravenous injection;
ACV, acyclovir; mPSL, steroid pulse therapy.

Please cite this article in press as: Hatanaka M et al. Overlapping MERS and mild AESD caused by HHV-6 infection.. Brain Dev (2014), http://
dx.doi.org/10.1016/j.braindev.2014.04.011

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Fig. 2. Magnetic resonance imaging on Day 2. (a) Diffusion-weighted image. A high-intensity lesion in the splenium of the corpus callosum
(arrowhead). (b) Apparent diffusion coefficient image. A low-intensity lesion in the splenium of the corpus callosum (arrowhead). (c) Fluidattenuated inversion recovery image. No lesion (arrowhead).

Day 15 showed that the fronto-subcortical white matter lesion had completely disappeared (Fig. 3d–f). EEG
findings also appeared normal on Day 22. HHV-6
DNA sequences were detected in the serum (504 copies/mL) and CSF (106 copies/mL) samples obtained
on Day 6. The patient was discharged on Day 15,
and no sequelae have been noted during the 5 years
of follow-up. Follow-up MRIs were normal and
showed no cerebral atrophy. Her full-scale intelligence
quotient on the Wechsler Intelligence Scale for Children Fourth Edition (WISC-IV) administered at
7 years of age was 84.
3. Discussion
Based on the clinicoradiological findings, we identified a patient presenting with the overlapping encephalopathy syndromes of MERS and mild AESD. Among
the 168 HHV-6 encephalopathy cases reported over
3 years in a nationwide survey of Japan, only 3 MERS
(1.8%) cases were reported [1]. Although there is a
report of a reversible splenial lesion induced by HHV6 infection [4], there were no detailed case reports on
MERS with HHV-6 encephalopathy. In fact, the clinicoradiological findings associated with MERS due to
HHV-6 infection are poorly understood.
Furthermore, overlapping encephalopathy syndromes, as in our case, are rare. One report has
described the overlap of the encephalopathy syndromes
ANE and AESD with HHV-6 encephalopathy [5]. To
the best of our knowledge, ours is the first report on
the overlap of the encephalopathy syndromes MERS
and mild AESD.
The patient reported herein was diagnosed with
MERS based on a reversible splenial lesion, hyponatremia, and a good outcome [3]. Our patient was also

diagnosed with mild AESD based on the clinicoradiological findings of two brief febrile seizures (the initial
neurological symptom), a secondary cluster of partial
seizures, and subcortical white matter lesions [3]. The
onset age of 17 months was also near the usual mean
age for AESD [1]. The patient’s WISC-IV scores indicated no mental retardation. Almost all cases with
MERS or clinically mild AESD recover completely [3].
Genetic and environmental factors may play a role in
the development of various types of phenotypic differences in patients’ seizures and inflammatory reactions
[6]; however, the mechanisms underlying the development of different encephalopathy syndromes from the
same virus infection are still unclear.
The exact pathogenesis of AESD is unknown; excitotoxic injury with delayed neuronal death is hypothesized as a possible mechanism [3]. Activations of the
adenosine A2A receptor may be a predisposing factor
of AESD [7]. We recommended gene analyses, but the
parents did not permit these analyses. The reason for
MERS is unknown, although a transient development
of intramyelinic edema due to separation of the myelin
layers has been suggested [3]. The involvement of autoimmune reactions has been reported in MERS [8].
Analyses of serum cytokines, chemokines, matrix
metalloproteinases, and tissue inhibitors of matrix
metalloproteinases implied that the pathogenesis of
AESD, ANE, and HSES with HHV-6 encephalitis
were different [9]. The pathophysiology of HHV-6
encephalopathy including central nervous system
(CNS) complications may be related to the complicated mechanism of direct viral invasion into the
CNS, or immune-mediated CNS damage and primary
or secondary cerebral vasculitis [10]. This complicated
mechanism may be associated with the overlapping
encephalopathy syndromes.

Please cite this article in press as: Hatanaka M et al. Overlapping MERS and mild AESD caused by HHV-6 infection.. Brain Dev (2014), http://
dx.doi.org/10.1016/j.braindev.2014.04.011

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M. Hatanaka et al. / Brain & Development xxx (2014) xxx–xxx

Fig. 3. Magnetic resonance imaging on Day 6 (a–e) and Day 15 (f–h). (a) Diffusion-weighted image (DWI) image. A high-intensity lesion in the
fronto-subcortical white matter (arrow). (b) DWI image. High-intensity lesions in the fronto-subcortical white matter (arrow). The high-intensity
lesion in the splenium of the corpus callosum disappeared (arrowhead). (c) Fluid-attenuated inversion recovery (FLAIR) image. No lesion. (d)
Apparent diffusion coefficient (ADC) image. A low-intensity lesion in the fronto-subcortical white matter (arrow). (e) ADC image. Low-intensity
lesions in the fronto-subcortical white matter (arrow). The low-intensity lesion in the splenium of the corpus callosum disappeared (arrowhead). (f)
DWI image. No lesion. (g) DWI image. No lesion. (f) FLAIR image. No lesion.

The important message of this case should be that febrile seizures associated with the splenial lesion suggesting
MERS do not rule out the possibility of AESD with late
seizures. The case presented here, together with previous

reports, suggests that patients will develop the combined
encephalopathy syndromes by HHV-6. Further cases are
necessary to elucidate the precise mechanisms of these
combined syndromes and to aid in their diagnosis.

Please cite this article in press as: Hatanaka M et al. Overlapping MERS and mild AESD caused by HHV-6 infection.. Brain Dev (2014), http://
dx.doi.org/10.1016/j.braindev.2014.04.011

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Please cite this article in press as: Hatanaka M et al. Overlapping MERS and mild AESD caused by HHV-6 infection.. Brain Dev (2014), http://
dx.doi.org/10.1016/j.braindev.2014.04.011