Journal of the Neurological Sciences 250 (2006) 159 – 161
www.elsevier.com/locate/jns

Short communication

Acute encephalopathy with refractory status epilepticus: Bilateral mesial
temporal and claustral lesions, associated with a peripheral marker of
oxidative DNA damage
Takashi Shiihara a,⁎, Mitsuhiro Kato a , Takashi Ichiyama b , Yukitoshi Takahashi c ,
Naoyuki Tanuma d , Rie Miyata e , Kiyoshi Hayasaka a
a
Department of Pediatrics, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan
Department of Pediatrics, Yamaguchi University School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-8505, Japan
c
National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, 886 Urushiyama, Shizuoka 420-8688, Japan
d
Department of Pediatrics, Metropolitan Fuchu Medical Center for Severe Motor and Intellectual Disabilities, 2-9-2,
Musashidai, Fuchu, Tokyo 183-0042, Japan
e
Department of Pediatrics, Tokyo Kita Shakai Hoken Hospital, 4-17-56, Akabanedai, Kita-ku, Tokyo 115-0053, Japan
b

Received 28 March 2006; received in revised form 20 June 2006; accepted 12 July 2006
Available online 28 August 2006

Abstract
We describe a 12-year-old girl, who had been medicated with theophylline for bronchial asthma and developed acute encephalopathy with
refractory status epilepticus, showing bilateral mesial temporal and claustral lesions, which were evident on fluid-attenuated inversion
recovery images, obtained with 1.5 T magnetic resonance imaging. To date, oxidative stress has been implicated in aging or various
disorders, including inflammatory or degenerative neurological disorders. One of the oxidative stress markers, 8-hydroxydeoxyguanosine,
was increased in our patient's cerebro-spinal fluid, plasma and urine. We speculate that augmented oxidative stress was associated with
refractory status epilepticus in our patient, accompanying bilateral mesial temporal, claustral lesions and severe neuronal damage. Serial
measurements of oxidative stress markers in acute encephalitis, encephalopathy, or status epilepticus could clarify the relationships between
acute brain damage and free radicals.
© 2006 Elsevier B.V. All rights reserved.
Keywords: Acute encephalopathy; Status epilepticus; Theophylline; 8-hydroxydeoxyguanosine; Oxidative stress; Claustrum

1. Introduction
Acute encephalopathy or encephalitis presenting with
refractory status epilepticus is rare, but results in severe
mortality, and the known etiologies are diverse, including
infection, metabolic derangement, hypoxia–ischemia, and
intoxication. However, a certain part of the pathophysiology
remains an enigma [1–3]. To date, oxidative damage has
been implicated in aging or various disorders, including
⁎ Corresponding author. Department of Neurology, Gunma Children's
Medical Center, 779 Shimohakoda, Hokkitsu-machi, Shibukawa, Gunma
377-8577, Japan. Tel.: +81 279 52 3551; fax: +81 279 52 2045.
E-mail address: shiihara-ind@umin.net (T. Shiihara).
0022-510X/$ - see front matter © 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jns.2006.07.002

inflammatory or degenerative neurological disorders [4]. We
report a patient with acute encephalopathy presenting with
refractory status epilepticus, showing bilateral mesial
temporal and claustral lesions, which could be related to
DNA oxidative damage.
2. Case report
A 12-year-old girl developed frequent tonic convulsions
and was admitted to our hospital after mild drowsiness and
fever for 7 days. Since 9 years of age, she had been
medicated with theophylline (300 mg/day) with a blood level
of 6.7 μg/ml for bronchial asthma. There was no history of
neurological disorders nor any contributory family histories.

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T. Shiihara et al. / Journal of the Neurological Sciences 250 (2006) 159–161

She showed consciousness disturbance without focal
neurological signs. Routine hematology, blood chemistry,
cranial computed tomography and magnetic resonance
imaging (MRI) on day 7 of illness did not detect any
abnormalities. Cerebro-spinal fluid (CSF) examinations on
day 7 and 10 yielded normal findings, including cell count,
glucose, protein, bacterial and viral cultures, polymerase
chain reactions for herpes simplex and enteroviruses, and
autoantibodies against the glutamate receptors, except for
elevations of cytokines; interleukin-2, 4 and 6 were 5.0 pg/
ml (normal control b 4.6), 13.9 pg/ml (normal control b 11.6)
and 83.9 pg/ml (normal control b 9.7), respectively. Oxidative stress marker, 8-hydroxydeoxyguanosine (8-OHdG)
was measured with a commercial enzyme-linked immunosorbent assay kit (highly sensitive 8-OHdG check; Japan
Institute for the Control of Aging, Shizuoka, Japan. More
information is available at http://www.jaica.com/biotech/)
[5]. The levels of 8-OHdG concentration in CSF on day 10,
plasma on day 8 and 17 were 0.070, not detected and
0.245 ng/ml (not detected in normal control), respectively.
Urine 8-OHdG/creatinine ratio was 36.6 ng/mg creatinine
(normal control 12.1 ± 5.5, mean ± SD) on day 23 [6,7].
Because 8-OHdG was measured retrospectively with stored
samples, data from other days were not available. Although
the fever subsided, seizures progressed to an intractable
status; focal clonic convulsions involving the face or
extremities generalized after intervals of a few minutes.
Electroencephalography showed multifocal spikes or sharp
waves, tending to burst. Conventional anti-epileptic drugs,
including phenobarbital, phenytoin and valproate, and
anesthetic agents, including midazolam, thiamylal and
propofol, failed. Thiopental alleviated seizures, but withdrawal resulted in seizure recurrence. Cranial MRI on day 27
demonstrated bilateral mesial temporal and claustral lesions
(Fig. 1). Thiopental was stopped on day 82 due to side
effects, such as leukopenia, hypotension, atelectasis, thrombophlebitis, renal failure and liver failure. Thereafter,

Fig. 1. Axial fluid-attenuated inversion recovery (FLAIR) images (TR/TE/
TI 6000/120/2100 ms), using a 1.5 T imager, on day 27 showed high signal
lesions in both hippocampi (arrow), amygdalae (arrowhead) (A), and
claustrum (arrow) (B).

Fig. 2. Axial FLAIR images (TR/TE/TI 8002/104/2000 ms), using a 1.5 T
imager, on day 101 showed high signal lesions in both hippocampi (arrow),
amygdalae (arrowhead) (A) and ventricular rims (arrow) (B). Cerebellar and
cerebral atrophy were evident.

phenytoin and high-dose phenobarbital were administered
to reduce seizures. Cranial MRI on day 101 showed severe
brain atrophy, and bilateral mesial temporal lesions (Fig. 2).
Seven months after the onset, she could not speak or sit
alone.
3. Discussion
Deoxyguanosine is one of the constituents of DNA and
when it is oxidized, it is altered to 8-OHdG, which is
considered a key biomarker of oxidative DNA damage [4].
Furthermore, 8-OHdG is increased in aging or diverse
disorders, such as neoplasm, neurodegenerative disorders,
cardiovascular disease, diabetes mellitus and inflammatory
disorders [4,5,8]. Moreover, 8-OHdG is increased within the
brain, including the amygdala and hippocampus, in the
seizure-induced rat and it is associated with increased DNA
fragmentation, resulting in neuronal cell death [9]. The high
levels of 8-OHdG concentrations in our patient's CSF,
plasma and urine, indicate that oxidative stress plays a key
role in our patients, resulting in severe neuronal damage.
Claustrum, a thin sheet of gray matter between the insula
and putamen, is affected in several disorders. However, the
pathophysiology of these disorders remains obscure [10]. We
hypothesize that oxidative stress plays some role in claustral
lesions. Claustrum as well as the cortex, amygdala and
hippocampus, contains nitric oxide-producing neurons,
which were involved in our patient [11,12]. Neurotoxicity
in rats with kainic acid-induced status epileptics is associated
with increments in nitric oxide, possibly resulting in
augmented oxidative stress in these regions [12]. Other
studies also show that disorders involving the claustrum,
such as ischemia–hypoxia, Wilson's disease, mitochondrial
disorders, and encephalitis are associated with augmented
oxidative stress [10,13–16].
Theophylline affects the seizure threshold, and we
speculate that theophylline was associated with a protracted
course in our patient [17]. Although, the theophylline blood

T. Shiihara et al. / Journal of the Neurological Sciences 250 (2006) 159–161

level in our patient was within the accepted therapeutic
range, Delanty et al. reported that a surprisingly high rate of
status epilepticus patients (eleven out of 41; 27%) were
taking theophylline at the time status epilepticus developed
and all except one had shown standard therapeutic blood
levels [18]. Theophylline-induced seizures in mice may be
associated with free radicals, which also suggests a causative
role of augmented oxidative stress in our patient [19]. Drugs
other than theophylline, including anti-epileptic drugs and
anesthetic agents, could affect oxidative stress, however,
their effects were not one-way; some might augment
oxidative stress, others could reduce it [20–24].
There are some difficulties with chronological analysis
among symptoms, cranial MRI findings, and 8-OHdG
levels, because 8-OHdG serial examinations were lacking
and MRI examinations had long intervals. Convulsions
started on day 7, but cranial MRI on day 7 revealed no
abnormalities, plasma 8-OHdG was not detected on day 8,
CSF 8-OHdG was detected on day 10, urinary 8-OHdG was
high on day 23, and cranial MRI on day 27 demonstrated
bilateral mesial temporal and claustral lesions. In rat
experimental models, systemic kainic acid, which induces
seizures, increased cerebral 8-OHdG levels, up to seven-fold
within 72 h [9]. This is compatible with our patient's course.
Oxidative DNA damage could be evoked within a few days
after status epileptics and neuroimaging changes may
continue for some time beyond this.
In conclusion, it is possible that oxidative stress was
associated with refractory status epilepticus in our patients,
accompanying bilateral mesial temporal, claustral lesions
and severe neuronal damage, which is partly due to
theophylline. There may be a vicious cycle; refractory status
epilepticus could result in limbic lesions and limbic lesions
could worsen the refractoriness of status epilepticus itself.
Serial measurements of oxidative stress markers, including
8-OHdG in acute encephalitis, encephalopathy or status
epilepticus could clarify the relationships between acute
brain damage and free radicals.
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