BACKGROUND: We report a female patient with familial Creutzfeldt-Jakob disease with V180I mutation (fCJD with V180I), who was serially followed up with magnetic resonance imaging (MRI) and electroencephalogram (EEG) for up to four years. CASE PRESENTATION: At 6 months after the onset, diffusion-weighted images (DWI) and fluid-attenuated inversion recovery (FLAIR) of brain MRI revealed an increased signal intensity in the bilateral frontal, temporal, and parietal cerebral cortex with left dominancy except for the occipital lobe. However, her follow-up MRI at four years showed the high-signal regions spreading to the occipital cerebral cortex in DWI and FLAIR images, and bilateral frontal cerebral white matter in FLAIR images. EEG showed a progressive and general slow high-voltage rhythm from 7–8 to 3–5 c/s over four years, without evidence of periodic synchronous discharge. These findings correspond to the symptom progression even after akinetic mutism at 18 months. CONCLUSION: We suggest that serial MRI and EEG examinations are useful for early diagnosis of fCJD with V180I and for monitoring disease progression

Kentaro Deguchi

Koji Abe

Motonori Takamiya

Nobutoshi Morimoto

Shoko Deguchi

Tomoko Kurata

Yoshio Ikeda

PubMed

Springer - Publisher Connector

Spreading brain lesions in a familial Creutzfeldt-Jakob disease with V180I mutation over 4 years

Deguchi et al. BMC Neurology 2012, 12:144
http://www.biomedcentral.com/1471-2377/12/144CASE REPORT Open AccessSpreading brain lesions in a familial
Creutzfeldt-Jakob disease with V180I mutation
over 4 years
Kentaro Deguchi, Motonori Takamiya, Shoko Deguchi, Nobutoshi Morimoto, Tomoko Kurata, Yoshio Ikeda
and Koji Abe*Abstract
Background: We report a female patient with familial Creutzfeldt-Jakob disease with V180I mutation (fCJD with
V180I), who was serially followed up with magnetic resonance imaging (MRI) and electroencephalogram (EEG) for
up to four years.
Case presentation: At 6 months after the onset, diffusion-weighted images (DWI) and fluid-attenuated inversion
recovery (FLAIR) of brain MRI revealed an increased signal intensity in the bilateral frontal, temporal, and parietal
cerebral cortex with left dominancy except for the occipital lobe. However, her follow-up MRI at four years showed
the high-signal regions spreading to the occipital cerebral cortex in DWI and FLAIR images, and bilateral frontal
cerebral white matter in FLAIR images. EEG showed a progressive and general slow high-voltage rhythm from 7–8
to 3–5 c/s over four years, without evidence of periodic synchronous discharge. These findings correspond to the
symptom progression even after akinetic mutism at 18 months.
Conclusion: We suggest that serial MRI and EEG examinations are useful for early diagnosis of fCJD with V180I and
for monitoring disease progression.
Keywords: Familial Creutzfeldt-Jakob disease, V180I, Magnetic resonance imaging, ElectroencephalogramBackground
Creutzfeldt-Jakob disease (CJD) is a transmissible neuro-
degenerative disease caused by abnormal prion protein
(PrP). Magnetic resonance imaging (MRI) in patients
with CJD have shown hyperintense signal abnormalities
in the striatum or thalamus on T2-weighted images [1].
In addition, diffusion-weighted imaging (DWI) has been
reported to be a useful technique for early diagnosis
of CJD [2-5]. Recently, Geshcwind et al. reported that
the pattern of fluid-attenuated inversion recovery
(FLAIR)/DWI hyperintensity and restricted diffusion
can differentiate sporadic CJD from other non-prion
causes of rapidly progressive dementia with a high
sensitivity and specificity [6]. Approximately 10–15%
of all CJD cases are familial CJD (fCJD), with variable* Correspondence: degu@cc.okayama-u.ac.jp
Department of Neurology, Graduate School of Medicine, Dentistry and
Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, kitaku,
Okayama 700-8558, Japan
© 2012 Deguchi et al.; licensee BioMed Centra
Commons Attribution License (http://creativec
reproduction in any medium, provided the orclinical features and MRI findings [7]. fCJD with a causa-
tive point mutation of valine to isoleucine at codon 180
(V180I) in the PrP gene shows a unique MRI finding of
marked high-intensity areas with ribboning in the cerebral
cortex at an early stage, except for the medial occipital
and cerebellar cortices [7]. However, serial changes on
MRI and electroencephalogram (EEG) during the long
follow-up period of CJD have not been fully reported.
Herein, we report serial changes of MRI and EEG findings
in relation to the clinical signs and symptoms in a case of
fCJD with a causative point mutation of V180I in the PrP
gene (fCJD with V180I) over a four year follow up.
Case presentation
A 79 year old Japanese woman first visited our Okayama
University Hospital in 2007 for the evaluation of cognitive
decline and walking unsteadiness that gradually pro-
gressed over six months. She had no past medical history
requiring blood transfusion or receiving other humanl Ltd. This is an Open Access article distributed under the terms of the Creative
ommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
iginal work is properly cited.
Deguchi et al. BMC Neurology 2012, 12:144 Page 2 of 4
http://www.biomedcentral.com/1471-2377/12/144dura mater. She had not traveled abroad. None of her
family suffered from similar symptoms or history.
Physical examination of the patient was normal. Psy-
chological examination revealed lack of initiative, severe
disorientation, acalculia, and short-term memory loss.
Mini-mental state examination (MMSE) was 12 out of 30,
mainly involving orientation, recent memory, and atten-
tion. Neurological examination of this patient showed no
abnormal findings in cranial nerves and the autonomic
system. However, bradykinesia was noted in her body,
face, and quadro extremities. Muscle tonus was increased
with rigidity in her four limbs and neck. Increased deep
tendon reflexes were observed in the bilateral upper limbs
without pathological reflexes. Assessment of the sensory
system was difficult owing to dementia. She was able to
stand with some support, but was unable to walk. Invo-
luntary movement such as myoclonus or startle reaction
was not observed.
Biochemical tests of blood showed no abnormal find-
ings. Cerebrospinal fluid (CSF) analysis revealed an ele-
vated neuron-specific enolase (NSE) to 74.1 ng/ml
(normal <35.0 ng/ml), although CSF cell count and pro-
tein and serum NSE (15.9 ng/ml, normal <16.3 ng/ml)
were normal. DWI (Figure 1A-D) and fluid-attenuated
inversion recovery (FLAIR) (Figure 2A-D) of brain MRI
revealed increased signal intensity in the bilateral frontal,
temporal, and parietal cerebral cortex with left domi-
nancy, but no change in the occipital lobe. EEG showed a
generalized slow basic rhythm at 7–8 c/s without periodic
synchronous discharge (PSD; Figure 3A). Prion protein
gene analysis of peripheral blood was then performed with
informed consent, which revealed a G to A transition at
codon 180 (GTC: Val→ATC: Ile; V180I). Her CSF onFigure 1 DWI images of brain MRI in the present case. Increased signa
with left dominancy, except for occipital lobe, was observed on admission
the occipital cerebral cortex at four years after the onset (E-H).admission was positive for 14-3-3 protein and total tau
protein (>1300 pg/ml).
Intellectual performance of the patient deteriorated
progressively, and she developed akinetic mutism with
stronger rigidity of four limbs at 18 months after onset.
Follow-up MRI at 54 months after onset showed spread
of the high-signal region to the occipital cerebral cortex
in DWI (Figure 1E-H) and FLAIR images (Figure 2E-H),
and evidence of bilateral frontal cerebral white matter
lesions in FLAIR images (Figure 2E-H). EEG at that
time showed a general slower high-voltage basic rhythm
than 4 years prior (to 3–5 c/s), but still without PSD
(Figure 3B). Although the patient remained in a vegetative
state in a chronic care unit at 60 months after the onset,
she still maintained oral intake with assistance.
Conclusions
We report a patient of familial Creutzfeldt-Jakob disease
(fCJD) with a causative point mutation of V180I in the
prion protein gene (fCJD with V180I). A high-signal
region on brain MRI was located at the cerebral cortex
in the early stage (Figure 1A-D; Figure 2A-D), which
progressively spread to the occipical lobe over the
parieto-occipical sulcus and finally to the bilateral frontal
white matter over four years follow-up (Figure 1E-H;
Figure 2E-H), but without PSD of EEG. This V180I
mutation is the most common cause of fCJD in Japan,
with only two cases reported from Europe [8,9]. Com-
pared with sporadic CJD (sCJD), fCJD with V180I showed
(1) older onset age, (2) slower disease progression,
(3) unique clinical symptoms such as frequent cognitive
dysfunction without visual or cerebellar symptoms, (4) a
lower positive rate of NSE and 14-3-3 protein in CSF,l intensity in the bilateral frontal, temporal, and parietal cerebral cortex
with axial imaging (A-D). Note that the high-signal region spread to
Figure 2 FLAIR images of brain MRI in the present case. Increased signal intensity was observed on admission (A-D). Note that the high-
signal region spread to the occipital cerebral cortex and the frontal white matter at four years after the onset with a marked ventricular dilatation
(E-H).
Deguchi et al. BMC Neurology 2012, 12:144 Page 3 of 4
http://www.biomedcentral.com/1471-2377/12/144and (5) a lack of PSD in EEG throughout the course
of the disease [7]. Our patient was compatible with
the clinical and laboratory characteristics of this fCJD
with V180I.
DWI is a useful technique for the early diagnosis of
CJD [2-5], and diffuse cortical high-intensity signals in
DWI and FLAIR image are characteristic feature of fCJD
with V180I. However, serial changes on DWI and FLAIR
image during the long-term period of fCJD with V180I
have not been fully reported. Kono et al. reported that
the abnormal lesions of a fCJD patient with V180I began
from the left cerebral cortex to the contralateral cerebral
cortex and the basal ganglia, with sparing the occipital,
parieto-occipital lobes, and the cerebellum until the
terminal stage at 25 months after the onset [10]. However,Figure 3 Electroencephalogram (EEG) in the present case. Note that E
admission (A) to a general slower high-voltage basic rhythm at 3–5 c/s aftethe present case involved involved the occipital cerebral
cortex and the frontal white matter over 4 years follow-up.
Serial EEG of fCJD with V180I usually shows a diffuse
slow basic pattern without PSD, although most patients
of sCJD demonstrate PSD in EEG, which is an accepted
diagnostic marker for sCJD [7]. The present case showed
a similar course of EEG to typical fCJD with V180I. The
general slower high-voltage basic rhythm of EEG
(Figure 3B) at four years after the onset may reflect a
severe deterioration in brain function such as akinetic
mutism, not but apallic syndrome.
Spongiform degeneration is a typical pathologic change
of CJD characterized by vacuoles in the neuropil, gliosis,
and nerve cell loss in the gray matter [11,12]. In fCJD cases
with V180I, increased DWI signals and a hypoperfusionEG changed from a generalized slow basic rhythm at 7–8 c/s on
r four years, but without PSD (B).
Deguchi et al. BMC Neurology 2012, 12:144 Page 4 of 4
http://www.biomedcentral.com/1471-2377/12/144region on single photon emission computed tomography
(SPECT) could reflect such spongiform changes [11]. In
addition, Iwasaki et al. reported a widespread fibrous
gliosis with hypertrophic astrocytosis and proliferation
of macrophages in the cerebral white matter in the brain
of fCJD with V180I [13]. Thus, in the present case of
fCJD with V180I, the prominent white matter lesions
of the frontal lobe might reflect secondary axonal degen-
eration due to widespread cerebral neocortical involve-
ment (Figure 2G,H).
In conclusion, during the long follow-up period of
fCJD with the present V180I case, MRI finding spread
from the frontal, temporal, and parietal cortical lobe to
occipital cortical lobe, with the possibly secondary
change of the frontal white matter. In addition, EEG
findings corresponded the symptom progression even
after akinetic mutism at 18 months. Thus, the present
case suggests that serial DWI, FLAIR, and EEG follow-up
is useful for early diagnosis of CJD and for monitoring
disease progress.
Consent
Written informed consent was obtained from the family
of the patient for publication of this case report and
accompanying images. A copy of the written consent
is available for review by the Editor-in-Chief of this
journal.
Abbreviations
CJD: Creutzfeldt-Jakob disease; fCJD with V180I: fCJD with a causative point
mutation of V180I in the prion protein gene; CSF: Cerebrospinal fluid;
DWI: Diffusion-weighted images; EEG: Electroencephalogram; fCJD: Familial
CJD; FLAIR: Fluid-attenuated inversion recovery; MMSE: Mini-mental state
examination; MRI: Magnetic resonance imaging; NSE: Neuron-specific
enolase; PrP: Prion protein; PSD: Periodic synchronous discharge;
sCJD: Sporadic CJD; V180I: G to A transition at codon 180.
Competing interests
All authors declare that they have no competing interests.
Authors’ contributions
KD examined and evaluated the patient, and drafted the manuscript. MT, SD,
NM, TK, YI, and KA made contributions to treat the patient. KA participated in
the design of the case report and helped to draft the manuscript. All authors
read and approved the final manuscript.
Acknowledgements
The authors thank Katsuya Sato, Department of Molecular Microbiology and
Immunology, Nagasaki University, for CSF analysis, and Tetsuyuki Kitamoto,
Center for Prion Research, United Centers for Advanced Research and
Translational Medicine, Tohoku University, for prion gene analysis of the
present patient.
This work was partly supported by Grant-in-Aid for Scientific Research (B)
21390267 and Young Scientists (B) 23790991 and the Ministry of Education,
Culture, Sports, Science, and Technology of Japan, and by Grants-in-Aid from
the Research Committee (Mizusawa H, Nakano I, Nishizawa M, Sasaki H, and
Aoki M) from the Ministry of Health, Labour and Welfare of Japan.
Received: 4 July 2012 Accepted: 19 November 2012
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Spreading brain lesions in a familial Creutzfeldt-Jakob disease with V180I mutation over 4 years

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