Case Report

Kurume Medical Journal, 54, 95-99, 2007

Serial Magnetic Resonance Imaging and Single Photon Emission Computed
Tomography Study of Acute Disseminated Encephalomyelitis
Patient after Japanese Encephalitis Vaccination
TAKASHI OHYA, SHINICHIRO NAGAMITSU, YUSHIRO YAMASHITA
AND TOYOJIRO MATSUISHI
Department of Pediatrics and Child Health, Kurume University School of Medicine,
Kurume 830-0011, Japan
Received 9 October 2007, accepted 16 January 2008

Summary: We report a 5-year-old mentally retarded Japanese boy who developed acute disseminated encephalomyelitis (ADEM) two weeks after Japanese encephalitis vaccination (Beijing strain). He presented sudden status epilepticus, fever, and disturbance of consciousness. Initial neuroradiological findings revealed multifocal
cortical swellings without any white matter lesions, suggesting the existence of partial encephalitis or focal status epilepticus. On the follow-up neuroradiological examinations, small white matter lesions were identified as
having gradually extended in spite of clinical improvement by methylprednisolone pulse therapy. The cortical
involvement became temporarily worse along with the extension and delayed appearance of white matter lesions.
Single photon emission computed tomography (SPECT) showed marked hypoperfusion of cerebral blood flow
(CBF) in the cortical lesions at both the acute and the recovery period. The serial neuroradiological findings
indicated involvement of white matter and gray matter regions at different stages of the illness and a delay
between the onset of symptoms and the appearance of ADEM-associated MR imaging of white-matter lesions.
Key words ADEM, JE vaccination, ADEM-associated MR imaging

INTRODUCTION

Japanese encephalitis (JE) is one of the most common

causes of epidemic viral encephalitis in the world, especially in South-East Asia. The annual incidence and
mortality estimates for JE in South-East Asia are
30,000-50,000 and 10,000, respectively. However,
this figure might be an underestimate, one study estimated the annual incidence at 175,000 per year [1].
The number of patients with JE in Japan was several
thousand per year in the 1950’s. Beginning in 1967,
vaccination was actively recommended, the incidence
was about a dozen per year in the 1980’s and several
per year after 1992 [2].
Acute disseminated encephalomyelitis (ADEM) is
an acute demyelinating disorder of the central nervous

system. It usually follows an infection or vaccination.
It is clinically characterized by the acute or subacute
onset of a multifocal neurological disturbance that
typically follows a monophasic course. MRI findings
typically reveal multifocal increased signal intensities
on T2-weighted image in the white matter, subcortical
white matter, basal ganglia, brainstem, or spinal cord
[3]. Fourteen cases of ADEM after JE vaccination
have been reported since 1991 in Japan [4]. Because
some cases were severe, the Japanese Ministry of
Health, Labor and Welfare recommended a suspension of JE vaccination in May, 2005.
Here we report a patient having ADEM associated
with JE vaccination who showed atypical neuroradiological findings in the various stages of the illness.

Corresponding author: Toyojiro Matsuishi M.D., Ph.D, Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahimachi, Kurume 830-0011, Japan. Tel: 81-942-31-7565 Fax: 81-942-38-1792 E-mail: tmatsu@med.kurume-u.ac.jp
Abbreviations: ADEM, acute disseminated encephalomyelitis; CBF, cerebral blood flow; CSF, cerebrospinal fluid; JE, Japanese encephalitis; SPECT,
single photon emission computed tomography.

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CASE REPORT
A 5-year-old mentally retarded boy suddenly developed generalized tonic-clonic seizure that lasted
about 60 min, 2 weeks after his third JE vaccination
was administered. He had been diagnosed as having
delayed motor milestones, mental retardation (developmental quotient: 27), congenital anomalies of the
trachea (tracheobronchial malacia, stenosis of the left
main trachea), and asthma. Screening for inborn errors
of metabolism was negative. Chromosome study revealed normal male karyotype. He was allergic to soybeans, wheat and corn before the onset of this episode.
There was no family history of epileptic, neuromuscular, metabolic, collagen-related, vascular or demyelinating disorders. He had previously received vaccinations for measles, BCG, rubella, polio, chickenpox
and mumps without any complications.
When he was admitted to Kurume University Hospital with status epilepticus, he had fever, dyspnea

with wheeze, and disturbance of consciousness. No
meningeal signs were observed. The peripheral white
blood cell count was increased (32400 /mm3) and Creactive protein was positive (6.76 mg/dl). Serum levels of electrolites, glucose, transaminase and ammonium were normal. Cerebrospinal fluid (CSF)
contained leukocytes at 3 /mm3, all leukocytes were
mononuclear cells. Total protein and myelin basic protein (MBP) in the CSF were 20 mg/dl and 377 pg/ml
(normal<102 pg/ml), respectively. No IgG oligoclonal band was detected. We examined JE virus hemaggulutination inhibited titers and IgM (enzyme-immunoassay) of varicella-zoster virus, herpes simplex
virus, cytomegalovirus and Mycoplasma pneumoniae
(Particle agglutination) in CSF. They were all negative. Brain CT on admission revealed no hemorrhage
or cortical edema. Electroencephalogram at 3 days of
illness revealed diffuse high-amplitude delta waves
without any focal epileptic discharge. At 6 days of illness, neuroradiological examinations including brain

Fig. 1. Magnetic resonance imaging of the brain. Upper row: T1-weighted MR imaging. Lower row: T2-weighted
MR imaging. A. 6 days of illness. Cortical swellings with increased signal intensities in T2-weighted axial imaging
appear in the bilateral frontal and right occipital regions (arrows). B. 18 days of illness. The cortical swelling is diminished in the bilateral frontal and right occipital regions. Increased signal intensities in the bilateral frontal white matter
appear in the T2-weighted imaging (arrowheads). C. 1 month of illness. The cortical swelling and white matter lesions
of bilateral frontal lobes and right occipital lobe have worsened again. (arrowheads). Marked cerebral atrophy is also
seen. D. 3 months of illness. The cortical lesions have disappeared and the white matter lesions remained behind. R:
right, L: left.
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Fig. 2. 123I-IMP single photon emission computed tomography and T2-weighted MR imaging. Upper row: At 6 days
of illness; 123I-IMP SPECT showed decreased cerebral blood flow (CBF) in the bilateral frontal, right occipital, and
right parietal regions, where these regions had cortical swellings on MRI (arrows). In frontal regions, CBF was much
decreased in the right. Lower row: At 2 years of illness; MRI showed the cortical and white matter lesions in the bilateral frontal and right parietal regions where 123I-IMP SPECT showed decreased CBF (arrowheads).

CT, MRI, 123I-IMP single photon emission computed
tomography (SPECT) were performed. Brain CT revealed poor differentiation between the cortex and the
white matter, and MRI showed focal cortical swellings in the bilateral frontal and right occipital regions
(Fig. 1A). 123I-IMP SPECT showed decreased cerebral
blood flow (CBF) in the bilateral frontal, right occipital, and right parietal regions , where these regions had
cortical swellings on MRI (Fig. 2A). In frontal regions,
CBF was much decreased in the right. Although we
examined MRI of the spinal cord, it was normal at
acute phase.
Initially, we suspected partial encephalitis or focal
status epilepticus based on clinical symptoms and
neuroradiological findings, thus, we treated the patient
with intravenous administration of an antiepileptic
agent and mannitol to lower intracranial pressure.
However, we could not deny the existence of ADEM
on account of the recent vaccination, therefore, we
started methylprednisolone pulse therapy (dose; 30
mg/kg/day, 3 days a week, total 9 times) at 7 days of
illness. On the follow-up MRI at 18 days of illness,
increased signal intensities in the bilateral frontal

white matter were identified on the T2-weighted image (Fig. 1B), the size of these lesions showed gradual
increase at 1 and 3 months of illness (Fig. 1C, D). In
addition, the signal intensity in the right occipital region was increased at 1 month of illness (Fig. 1C). The
focal cortical swellings in the bilateral frontal and
right occipital regions were decreased at 18 days of
illness, however, these regions seemed to swell again
along with enlargement or delayed appearance of
white matter lesions at 1 month of illness before disappearing at 3 months of illness (Fig. 1A-D). At 3 months
of illness, the white matter lesions remained behind
(Fig. 1D). The patient’s consciousness was gradually
improved at 3 days after the beginning of the methylprednisolone pulse therapy. He could smile at 9 days,
maintain a sitting position at 14 days, and stand up at
24 days after the therapy. After methylprednisolone
pulse therapy, prednisolone (1 mg/kg/day) was orally
administered, the medication was tapered and discontinued within six months. He has shown no neurological sequel except intractable complex partial seizures
with multifocal spikes.
On the follow-up neuroradiological examination

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at 2 years of illness, MRI showed marked cortical atrophy predominantly in the bilateral frontal and temporal regions (Fig. 2B). MRI also showed the cortical
and white matter lesions in the bilateral frontal and
right parietal regions where 123I-IMP SPECT showed
decreased CBF (Fig. 2B).
DISCUSSION
The incidence of severe neurological complications associated with JE vaccination has been reported
to be 1-2.3 per million vaccinations [5]. We previously
reported seven cases of ADEM after JE vaccination
[4], in which various neurological symptoms such as
seizure, disturbance of consciousness, paralysis, gait
disturbance, and headache, were seen. Initially, we
suspected our patient of having partial encephalitis or
focal status epilepticus based on his clinical symptoms
and initial neuroradiological findings. However, the
serial neuroradiological findings–in particular, the late
appearance of abnormal signal intensities in the white
matter regions, the history of JE vaccination, good
clinical response to methylprednisolone therapy, and
good clinical prognosis–confirmed the existence of
ADEM in this patient. We also could determine that
the patient did not have cerebral infarction or a progressive white matter disease such as metachromatic
leukodystrophy, adrenoleukodystrophy, Krabbe disease and other metabolic demyelinating diseases.
According to the previous literature, MRI findings
of ADEM after JE vaccination typically reveal multifocal lesions predominantly in the deep white matter,
thalamus, cerebellum and optic nerve, generally identified at the early stage of neurological symptoms [4].
In our case, we could detect a few characteristic MRI
findings in the serial examinations. First, multifocal
cortical swellings without the white matter legions
were found at the onset of neurological symptoms.
Second was the late appearance of white matter lesions in spite of the improvement of clinical symptoms. Third, the cortical swellings became worse temporarily along with the enlargement or appearance of
white matter lesions.
It is known that MRI findings of patients with generalized tonic-clonic seizure or status epilepticus reveal transient changes including focally increased T2
signal intensity, swelling, and increased volume of the
involved cortical gyrus due to seizure-induced transient cytotoxic and vasogenic cerebral edema [6,7]. In
our case, the initial cortical swellings and their diminutions between 6 days and 18 days of illness may
reflect transient cortical edema due to prolonged sei-

zure activity. On the other hand, white matter lesions
on MRI obtained from some patients with ADEM
have been reported to appear shortly after symptom
onset [8,9]. Honkaniemi et al. [8] reported three cases
of ADEM in which white matter lesions did not appear
until several weeks after the onset of the disease and
increased during the recovery period. Kimura et al. [9]
also reported that initial MR imaging failed to show
ADEM-related lesions in children with postinfectious
encephalitis. Although ADEM is typically described
as affecting the white matter, gray matter involvement
is not unusual because it also contains myelin [3,10].
Taken together, the delayed appearance of white matter lesions during a phase in which clinical symptoms
was absent may indicate ADEM-related demyelination. The pathological mechanism of the delay between the neuroradiological findings and neurological
symptoms remains unknown. It is important to know
that both white matter and gray matter are involved at
different stages of the illness and that consecutive neuroradiological evaluation is necessary if the clinical
picture is suggestive for ADEM.
Because of the delay between the onset of symptoms and the appearance of ADEM-associated MR
imaging, SPECT has contributed to identification of
regions with functional deficits at different stages of
the disease [11-13]. Okamoto et al. [12] reported that
persistent hypoperfusion both at rest and in response
to acetazolamide administration remained even after
disappearance of hyperintensive lesions from MRI,
suggesting persistent impairment of cerebral circulation affecting cognitive abilities. A previous HMPAOSPECT study of a patient with ADEM revealed a combined pattern of hyper and hypoperfusion regions and
the presence of inflammatory cells and cortical deactivation secondary to disconnection from the subcortical structures, respectively [13]. Serial SPECT study
in our case showed persistent hypoperfusion in several
cortical regions indicating impairment of cortical activity, which resulted from the decreased volume of
the involved cortical gyrus. We cannot always detect
these abnormalities on MRI. We considered that it is
useful to follow serial SPECT.
In conclusion, serial MRI and SPECT may contribute to assessing the involvement of lesions and
functional impairment at different stages of the disease.
REFERENCES
1. Tsai TF. New initiatives for the control of Japanese encephalitis by vaccination: minutes of a WHO/CVI meeting,
Bangkok, Thailand, 13-15 October 1998. Vaccine 2000; 18

Kurume Medical Journal Vol. 54, No. 3, 4, 2007

ADEM AFTER JE VACCINATION

Suppl 2:1-25.
2. Arai S, Taya K, Okabe N, Takasaki T, and Kurane I.
Japanese encephalitis in Japan. Rinshou to Uirusu 2004;
32:13-22. (in Japanese)
3. Hynson JL, Kornberg AJ, Coleman LT, Shield L, Harvey
AS et al. Clinical and neuroradiologic features of acute disseminated encephalomyelitis in children. Neurology 2001;
56:1308-1312.
4. Ohtaki E, Matsuishi T, Hirano Y, and Maekawa K. Acute
disseminated encephalomyelitis after treatment with
Japanese B encephalitis vaccine (Nakayama-Yoken and
Beijing strains). J Neurol Neurosurg Psychiatry 1995;
59:316-317.
5. Inactivated Japanese encephalitis virus vaccine.
Recommendations of the Advisory Committee on
Immunization Practices (ACIP). MMWR Recomm Rep
1993; 42:1-15.
6. Kim JA, Chung JI, Yoon PH, Kim DI, Chung TS et al.
Transient MR signal changes in patients with generalized tonicoclonic seizure or status epilepticus: periictal
diffusion-weighted imaging. AJNR Am J Neuroradiol
2001; 22:1149-1160.

99

7. Kramer RE, Luders H, Lesser RP, Weinstein MR, Dinner
DS et al. Transient focal abnormalities of neuroimaging
studies during focal status epilepticus. Epilepsia 1987;
28:528-532.
8. Honkaniemi J, Dastidar P, Kahara V, and Haapasalo H.
Delayed MR imaging changes in acute disseminated
encephalomyelitis. AJNR Am J Neuroradiol 2001; 22:11171124.
9. Kimura S, Nezu A, Ohtsuki N, Kobayashi T, Osaka H et
al. Serial magnetic resonance imaging 1996; 18:461-465.
10. Murthy SN, Faden HS, Cohen ME, and Bakshi R. Acute
disseminated encephalomyelitis in children. Pediatrics
2002; 110:e21.
11. Hung KL, Liao HT, and Tsai ML. Postinfectious encephalomyelitis: etiologic and diagnostic trends. J Child Neurol
2000; 15:666-670.
12. Okamoto M, Ashida KI, and Imaizumi M. Hypoperfusion
following encephalitis: SPECT with acetazolamide. Eur J
Neurol 2001; 8:471-474.
13. Broich K, Horwich D, and Alavi A. HMPAO-SPECT and
MRI in acute disseminated encephalomyelitis. J Nucl Med
1991; 32:1897-1900.

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