Brain & Development 31 (2009) 217–220

www.elsevier.com/locate/braindev

Original article

Encephalopathy with a reversible splenial lesion is associated

with hyponatremia
Jun-ichi Takanashi a,*, Hiroko Tada a,b, Masayuki Maeda c, Motomasa Suzuki d,
Hitoshi Terada e, A. James Barkovich f
a
Department of Pediatrics, Kameda Medical Center, 929 Higashi-cho, Kamogawa-shi, Chiba 296-8602, Japan
b
Segawa Neurological Clinic for Children, Tokyo, Japan
c
Department of Radiology, Mie University School of Medicine, Tsu, Japan
d
Department of Pediatrics, Okazaki City Hospital, Okazaki, Japan
e
Department of Radiology, Toho University Sakura Medical Center, Sakura, Japan
f
Department of Radiology, University of California at San Francisco, CA, USA

Received 15 January 2008; received in revised form 1 April 2008; accepted 8 April 2008

Abstract

We have encountered several patients with clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS)
associated hyponatremia. In order to better understand this phenomenon, Na levels were evaluated in a series of patients with
MERS. Na was 131.8 ± 4.1 mmol/l (mean ± SD, range 121–140) in 30 patients with MERS; 138.3 ± 2.7 mmol/l (range 134–144)
in age-matched 21 patients with upper respiratory infection; 136.6 ± 2.5 mmol/l (range 132–140) in nine patients with other type
of encephalopathy; and 136.2 ± 2.6 mmol/l (range 132–140) in 17 patients with febrile seizures. Twenty-five of the thirty patients
with MERS had Na < 136 mmol/l. There were significant differences between the Na levels of patients with MERS and those with
other groups. It is not possible, from the clinical perspective, to completely separate MERS from hyponatremic encephalopathy or
to rule out hyponatremia as a contributing factor of MERS.
Ó 2008 Elsevier B.V. All rights reserved.

Keywords: Encephalopathy; Encephalitis; Reversible; Splenium; Diffusion; Hyponatremia

1. Introduction
The MR imaging finding of a reversible isolated
lesion with transiently reduced diffusion in the central
portion of the splenium of the corpus callosum (SCC)
has been reported in patients with clinically mild
encephalitis/encephalopathy, leading to a new clinical–
radiological syndrome, clinically mild encephalitis/
encephalopathy with a reversible splenial lesion (MERS)
[1,2]. Reversible lesions with transiently reduced diffu-
sion have also been found with lateral extension from
* this phenomenon, sodium (Na) levels were evaluated in
Corresponding author. Tel.: +81 470 92 2211; fax: +81 470 99
1198.
E-mail address: jtaka@kameda.jp (J. Takanashi).
the splenium into the callosal radiations and into the
frontoparietal subcortical white matter [3], and with
anterior extension to involve the entire corpus callosum
involvement [4].
The reason for the transiently decreased diffusion
within the lesions is unknown; possibilities that have
been postulated include intramyelinic edema, interstitial
edema in tightly packed fibers, and a transient inflam-
matory infiltrate [1,5]. Recently, a patient with MERS
associated with hyponatremia has been reported [6],
and we have encountered several MERS patients with
associated hyponatremia. In order to better understand
a series of patients with MERS, and these values com-
pared with those of age-matched patients with mild

0387-7604/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.braindev.2008.04.002
218 J. Takanashi et al. / Brain & Development 31 (2009) 217–220

upper respiratory infection, those of patients with other
types of encephalopathy, and those of patients with feb-
rile seizures.
2. Patients and methods
The diagnosis of MERS was defined as presence of
clinically mild encephalitis/encephalopathy with com-
plete recovery associated with MR imaging finding of
a reversible lesion with transiently reduced diffusion
(1) isolated within the SCC, (2) within the SCC and
subcortical frontoparietal white matter, or (3) involving
the entire corpus callosum and subcortical frontoparie-
tal white matter (Fig. 1). We retrospectively reviewed
Na levels of 30 patients with newly diagnosed MERS;
these values were collected from the members of Japa-
nese Society of Pediatric Neurology in September,
2006 after Institutional Review Board approval from
Kameda Medical Center. The 30 patients (16 male and
14 female, age from 1 to 11) developed normally until
the onset of neurological symptoms, except for one 9-
year-old girl with mild speech delay. Two patients had

Fig. 1. Representative MRI of a three-year-old girl with MERS. T2: (A) and diffusion-weighted images (B) on day 5 showed a high intensity lesion in
the splenium of corpus callosum. The lesion had resolved on day 8 (C).
 J. Takanashi et al. / Brain & Development 31 (2009) 217–220
a history of febrile seizure, and three had a history of
bronchial asthma. No patient had oral antiepileptic
drugs (AEDs) before the onset of neurological symp-
toms. Neurological symptoms included disorders of
consciousness (14 patients), delirious behavior (14
patients), and seizures (nine patients). Four patients
received AEDs (phenobarbital for three patients and
phenytoin for another) at the time of MR studies. One
patient had hypoglycemia (44 mg/dl) on admission.
As age-matched controls, we evaluated the Na levels
of 21 patients with mild upper respiratory infection (12
male and 9 female, age from 1 to 9) with no AED or
intravenous transfusion before blood examination. We
also evaluated 10 patients with other types of encepha-
lopathy (three with acute necrotizing encephalopathy,
three with acute encephalopathy with biphasic seizures
and late reduced diffusion [7,8], and four with unclassi-
fied influenza encephalopathies (5 male and 4 female,
age from 9 months to 8 years, statistically younger than
those with MERS), and 17 patients with febrile seizures
(7 male and 10 female, age from 8 months to 6 years,
statistically younger than those with MERS). We used
the lowest Na level recorded during the period of neuro-
logical symptoms in patients with MERS, encephalopa-
thy, and febrile seizures. We also evaluated the
frequency of gastrointestinal symptoms, such as diar-
rhea or vomiting before neurological symptoms. For
the statistic analysis, Mann–Whitney’s U test or Fisher’s
exact probability test was used.
3. Results
Na was 131.8 ± 4.1 mmol/l (mean ± SD, range 121–
140) in patients with MERS; 138.3 ± 2.7 mmol/l (range
134–144) in those with upper respiratory infection;
136.6 ± 2.5 mmol/l (range 132–140) in those with other
type of encephalopathy; and 136.2 ± 2.6 mmol/l (range
132–140) in those with febrile seizures (Fig. 2). Twenty-
five of the thirty patients with MERS had Na < 136 m-
mol/l. Ten of the thirty patients with MERS had
Na < 130 mmol/l. Twenty-three of the twenty-five
MERS patients with Na < 136 mmol/l showed their low-
est Na on admission. MRI scan was performed within 2
days of lowest Na in 21 of the 25 MERS patients having
Na < 136 mmol/l. Gastrointestinal symptoms were
observed in 10/30 patients with MERS, 3/21 patients
with upper respiratory infection, 1/9 patient with other
type of encephalopathy, and 3/17 patients with febrile
seizures (no statistic significance between MERS and
three control groups, p > 0.1). In three MERS patients
with Na level of 121, 127, 129, urine and blood osmolal-
ity, and antidiuretic hormone were measured, the results
being consistent with the syndrome of inappropriated
antidiuretic hormone secretion (SIADH). The three
patients had no AED. There were significant differences
between the Na levels of patients with MERS and those
219
Fig. 2. Na in patients with MERS, upper respiratory infection (URI),
other type of encephalopathy (Ence), and febrile seizure (FS) showing
hyponatremia in those with MERS relative to those with other three
groups.
with upper respiratory infection (Fig. 2, p < 0.001),
between those of patients with MERS and other types
of encephalopathy (p = 0.0027), and between those of
patients with MERS and febrile seizures (p < 0.001).
4. Discussion
This study shows that Na levels are decreased in
patients with MERS. Hyponatremia, defined as a serum
Na less than 136 mmol/l, is a common electrolyte distur-
bance that occurs in patients with a wide range of disor-
ders and clinical manifestations, from asymptomatic to
critically ill [9]. Transfusion of hypotonic fluid is not
likely as a possible cause of hyponatremia in MERS,
because most of the patients had their lowest Na on
admission before transfusion if necessary. Another pos-
sible cause of hyponatremia is SIADH (three patients in
this study), which is also considered as a cause of hypo-
natremia in patients with La Crosse encephalitis in chil-
dren [10]. However, further studies of urine and blood
osmolality, and antidiuretic hormone in patients with
MERS are necessary to conclude.
Hypotonic hyponatremia results in entry of water
into the brain, resulting in cerebral edema. Because
the surrounding cranium limits expansion of the brain,
intracranial hypertension may develop, with a risk of
brain injury. Children under 16 years of age are at
increased risk for developing hyponatremic encepha-
lopathy due to their relatively large brain to intracra-
nial volume ratio, and are likely to become
symptomatic at higher serum Na levels than adults
[9]. The symptoms of hyponatremic encephalopathy
include headache, nausea, vomiting, confusion, and
seizures [9]. These symptoms are nonspecific, and are
frequently observed in patients with MERS [1–4].
220 J. Takanashi et al. / Brain & Development 31 (2009) 217–220
Therefore, it is not possible, from the clinical perspec-
tive, to completely separate MERS from hyponatremic
encephalopathy or to rule out hyponatremia as a con-
tributing factor of MERS.
Reversible SCC lesions with reduced diffusion may be
seen in patients taking AEDs, most often when reducing
AEDs rapidly [11]. Many AEDs target cation channels,
which can influence water balance [12]. There has been
speculation, for instance, that abrupt stopping of phenyt-
oin could lead to SIADH that might contribute to brain
edema [13]. It is, therefore, reasonable to consider that
reversible SCC lesions in patients with AEDs may reflect
transient cerebral edema mediated by the influence of the
AEDs. Though no difference in Na levels before reducing
AEDs has been reported between epileptic patients with
and without SCC lesions [11], Na levels might be
decreased after reducing AEDs. Most of the patients with
MERS in this study had no AED, therefore, it is unlikely
that a reversible splenial lesion observed in MERS results
from or is associated with AEDs.
Reversible SCC lesions are also described on MRI
studies of patients with high altitude cerebral edema
(HACE) [14,15]. Hemodynamic factors, such as sus-
tained vasodilatation, impaired cerebral autoregulation,
elevated cerebral capillary pressure, and hypoxia-
induced biochemical alteration of the blood–brain bar-
rier, most likely contribute to the formation of the
edema [16]. The initial symptoms of headache and nau-
sea can progress to ataxia, delirium, coma, and brain
herniation in HACE. The three conditions with a revers-
ible SCC lesion (MERS, AED administration or with-
drawal, HACE), therefore, seem to have cerebral
edema due to electrolyte/water imbalance as a common
underlying pathophysiology.
Acknowledgements
We appreciate helpful advice by Hideto Yoshikawa,
MD, Miyagi Children’s Hospital; George Imataka,
MD and Hideo Yamanouchi, MD, Dokkyo University
School of Medicine, Japan. We thank Go Kawano,
MD, St. Mary’s Hospital; Takashi Ichiyama, MD,
Yamaguchi University School of Medicine; Rie Miyata,
MD, Tokyo-kita Social Insurance Hospital; Chigusa
Ishii, MD, Showa General Hospital; Eiko Noda, MD,
Nagoya Daini Red Cross Hospital; Satoko Kumada,
MD, Tokyo Metropolitan Neurological Hospital; Nao
Suzuki, MD, Asahikawa Medical College; Katsuya
Yamamoto, MD, Sendai City Hospital; Noboru Fueki,
MD, Nagano Children’s Hospital, Katsunori Fujii,
MD, Chiba University Graduate School of Medicine;
Tomohide Goto, MD, Tokyo Metropolitan Kiyose
Children’s Hospital; Yoshiyuki Hoshi, MD, Tohoku
University School of Medicine; Takahiro Kato, MD,
Sapporo Medical University School of Medicine; Masa-
hiro Kikuchi, MD, Hitachi General Hospital; Tetsuo
Kubota, MD, Anjo Kosei Hospital; Masaya Kubota,
MD, Tokyo Metropolitan Hachioji Children’s Hospital;
Takashi Shiihara, MD, Gunma Children’s Medical Cen-
ter; Yuji Takizawa, MD, National Defense Medical
College; Shoko Yoshida, MD, Department of Radiol-
ogy, Kyoto City Hospital, Japan for their cooperation.
This study was supported in part by the Research
Grant (20A-14) for Nervous and Mental Disorders from
the Ministry of Health, Labor and Welfare of Japan;
and by the Japan Epilepsy Research Foundation.
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