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Abnormal Diffusion-Weighted Magnetic Resonance Imaging in Creutzfeldt-Jakob Disease Following Corneal Transplantations
Alejandro A. Rabinstein, MD;
Michelle L. Whiteman, MD;
Robert T. Shebert, MD
Arch Neurol. 2002;59:637-639.
ABSTRACT
Background The value of magnetic resonance imaging of the brain in the diagnosis
of iatrogenic cases of Creutzfeldt-Jakob disease has been questioned.
Objective To illustrate the value of magnetic resonance imaging of the brain in
the diagnosis of iatrogenic Creutzfeldt-Jakob disease.
Methods Case report.
Results A patient with a history of 3 corneal transplantations exhibited the
alien hand sign on initial examination. Diffusion-weighted magnetic resonance
imaging of the brain revealed prominent cortical diffusion abnormalities.
During the following months, the patient developed rapidly progressive dementia.
The diagnosis of Creutzfeldt-Jakob disease was proven by brain biopsy.
Conclusion Brain magnetic resonance imaging, particularly diffusion-weighted magnetic
resonance imaging, can be very helpful in the diagnosis of Creutzfeldt-Jakob
disease, even in suspected iatrogenic cases.
INTRODUCTION
CREUTZFELDT-JAKOB disease (CJD) is a rare spongiform encephalopathy
clinically characterized by rapidly progressive dementia, myoclonus, ataxia,
visual disturbances, pyramidal and extrapyramidal features, and an inexorable
fatal outcome. Although most frequently sporadic, iatrogenic transmission
of the disease has occurred in recipients of contaminated corneal grafts,
cadaveric human growth hormone, and dura mater grafts.1
Abnormalities on diffusion-weighted magnetic resonance imaging (DWI) have
been previously observed in patients with CJD, and DWI has been suggested
to be useful for the early diagnosis of the disease.2-3
However, these changes have not been observed in iatrogenic cases, raising
questions about potential differences between sporadic and iatrogenic CJD.
We report a case of iatrogenic CJD with alien-hand syndrome at initial examination
and striking signal changes on DWI after corneal transplantations.
REPORT OF A CASE
A 56-year-old right-handed man noticed progressive loss of dexterity
of his right hand. Subtle initially, this symptom worsened rapidly, rendering
the hand useless for complex movements. At 2 months, his right hand started
to exhibit involuntary movements that were unrecognized by the patient. On
one occasion, his right hand punched his left eye to the patient's amazement,
and on several occasions he was unable to find objects he was holding with
his right hand. One month later, his left hand also became apraxic, and jerky
movements appeared in the right arm. Around that time, the family began to
observe changes in the patient's behavior and cognition. He became less talkative
and withdrawn. Six months after the onset of his symptoms, the patient was
admitted to another hospital. On admission, he was described to show akinetic
mutism and myoclonic movements in the upper extremities. These movements were
successfully controlled with valproic acid. Restricted diffusion in bilateral
parieto-occipital cortices was disclosed on DWI. Cerebral vasculitis was suspected
and the patient was treated with steroids and cyclophosphamide. However, continuous
clinical deterioration occurred during his 5-week hospital stay, with development
of sphincter incontinence and swallowing difficulties. The patient was transferred
to our institution 7 months after the initial symptoms.
The patient's medical history included 3 cadaveric corneal transplantations
(6, 4, and 2 years previously) in the left eye and an unclear rheumatologic
condition characterized by Raynaud phenomenon and recurrent hand swelling.
He also had a history of alcohol abuse but had remained abstinent for more
than 25 years.
At our initial examination, he was stuporous most of the time; when
he was awake he was mute and profoundly abulic. He had bilateral rigidity
and hyperreflexia. His motor inactivity was occasionally interrupted by involuntary,
although seemingly purposeful, movements of the right hand. Extensive blood
work results were unremarkable except for positive antinuclear (titer 1:160),
anti–SS-A (anti-Ro), and antiribonucleoprotein antibodies. Cerebrospinal
fluid (CSF) was acellular, with a normal glucose concentration and a protein
level of 120 mg/dL. Cultures were negative and there were no oligoclonal bands
on electrophoresis. No paraneoplastic markers (anti-Hu, anti-Yo, anti-Ri)
were present in either serum or CSF. Testing for 14-3-3 protein was not performed.
Results of an electroencephalogram (EEG) performed 3 days postadmission showed
continuous generalized slowing of the background rhythms.
A new brain magnetic resonance image (MRI) revealed fairly symmetric
bilateral cortical hyperintensity primarily involving the parieto-occipital
regions. An abnormal signal was also seen in the putamina bilaterally and
in the right caudate head. These findings were best visualized on a fluid-attenuated
inversion recovery (FLAIR) sequence (Figure
1A). There was no mass effect or abnormal enhancement. The DWI showed
extensive areas of restricted diffusion involving most prominently the parieto-occipital
regions but also both frontotemporal lobes (Figure 1B), which correlated with dark signals on the apparent diffusion
coefficient map (Figure 1C). Perfusion
MRI did not reveal any focal defect and the widespread diffusion abnormalities
did not correspond to any vascular distribution. Proton MR spectroscopy showed
a decreased peak of N-acetyl aspartate in both frontal
lobes.
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Figure 1. Comparison of fluid-attenuated
inversion recovery (FLAIR), diffusion-weighted magnetic resonance imaging,
and apparent diffusion coefficient (ADC) map. A, Axial FLAIR image at the
level of the lateral ventricles reveals cortical hyperintensity in the parieto-occipital
regions bilaterally (arrows). There is some frontal involvement, but it is
far less apparent. Fluid-attenuated inversion recovery parameters used were
repeat time/echo time/inversion time 6000/128/2000 milliseconds. B, Diffusion-weighted
images at the same level showing posterior abnormalities, which are much more
striking in appearance (arrows). Bifrontal involvement is better appreciated
as well. C, Corresponding ADC map demonstrates cortical hypointensity in regions
of diffusion abnormality (arrows), indicating restricted diffusion rather
than "T2 shine-through."
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A brain biopsy was performed on the fourth day of the admission. A pathologic
examination of the tissue sample obtained from the right frontal lobe revealed
spongiform degeneration of the cortex typical of CJD.
Repeated EEG obtained nearly 2 weeks later showed bilateral independent
spikes and sharp waves superimposed on a slow and disorganized background;
the epileptiform activity was more prominent in the right hemisphere and was
seen in association with episodic twitching of the left upper and lower extremities.
No typical periodic sharp-wave complexes were seen. The patient died a few
days later in a hospice, 7 months after the onset of the first symptom.
COMMENT
The clinical diagnosis of CJD is often difficult, especially early in
the course of the disease. Symptoms and signs may vary and corroborative findings,
such as the presence of periodic sharp-wave complexes on EEG or detection
of the 14-3-3 protein in the CSF, but neither are fully sensitive nor always
specific,4-5 as is well illustrated
by our case.
Isolated myoclonic alien hand has been reported before as the sole initial
clinical feature on initial examination in 2 patients with CJD.6
The alien hand sign is described as a feeling of estrangement between the
patient and one of his or her hands. It results in involuntary, seemingly
purposeful movements of the hand with the patient's denial of its ownership.
Commonly associated with callosal lesions, this sign has also been documented
with dominant mesial cortical injury.7 In fact,
2 different types of alien hand have been described, one "frontal" in the
dominant hand and the other "callosal" in the nondominant hand.6
However, this anatomic classification and the localizing value of the sign
have been questioned because alien hand has occurred in cases of corticobasal
ganglionic degeneration and Alzheimer disease. Nevertheless, the damage of
the mesial frontal cortex clearly seen on DWI (Figure 2) could explain the presence of the sign in our patient.
Previously described cases of alien hand in CJD involved the nondominant hand.6 To our knowledge, ours is the first case of CJD with
the alien hand sign on the dominant side.
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Figure 2. Diffusion-weighted magnetic resonance
imaging at the level of the centrum semiovale showing prominent signal abnormalities
involving the mesial frontal cortex in our patient (arrow).
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Bilateral symmetric high signal intensities affecting the caudate nuclei
and the putamina on long repetition-time MRIs have yielded a 67% sensitivity
and 93% specificity for the diagnosis of CJD.8
However, routine MRI may be less sensitive to some cortical abnormalities
visible on DWI2-3 as demonstrated
by our case. The sensitivity of DWI in the diagnosis of CJD remains to be
established but promises to be markedly superior to that of T2-weighted images,
especially in early stages of the illness. In addition, DWI seems to be useful
to monitor the progression of the disease3
and has been shown to correlate well with clinical findings, as it did in
our case.9 Good correlation was also found
with disturbed metabolism by nuclear medicine scans and EEGs.9
The pathogenesis of restricted diffusion in brains with CJD is not yet elucidated,
but it could be related to the initial accumulation of abnormal cytoplasmatic
vacuoles preceding the development of spongiform degeneration and gliosis.2 These latter changes are thought to be responsible
for the high intensity signals seen on T2-weighted and proton density–weighted
MRI.8 Our patient had a normal result on perfusion
scan despite his prominent diffusion abnormalities. This uncommon combination
of findings should direct attention away from ischemia and toward other conditions,
including CJD. Magnetic resonance proton spectroscopy showed a decreased peak
of the neuronal marker N-acetyl aspartate in our
case as it has in advanced cases of CJD in the past.10
Confirmation of horizontal transmission of CJD is not possible in this
case since we were unable to identify the corneal donors. However, the history
of 3 different corneal transplantations clearly increases the likelihood of
iatrogenic transmission. This is particularly important because, to our knowledge,
this is the first report of MR signal changes in iatrogenic CJD. Previously
reported iatrogenic CJD cases had no abnormal signal on MRI.11-14
Thus, potential underlying differences between sporadic and iatrogenic CJD
were suspected. The imaging abnormalities in our case are indistinguishable
from those seen in sporadic CJD. Our findings are in concert with the similarities
in pathologic examination observed between sporadic and iatrogenic CJD.13-14 We believe that technical issues
(low-field systems, protocols not including FLAIR and DWI) may have accounted
for the lack of sensitivity of MR in previous iatrogenic cases.
In summary, this case illustrates the usefulness of MR techniques, particularly
FLAIR and DWI, in the diagnosis of cases of CJD with atypical clinical manifestations,
even when iatrogenic transmission is suspected.
AUTHOR INFORMATION
Accepted for publication November 30, 2001.
Author contributions: Study concept and design (Drs Rabinstein and Whiteman); acquisition of data (Drs Rabinstein, Whiteman, and Shebert); analysis and interpretation
of data (Drs Rabinstein and Whiteman); drafting of
the manuscript (Dr Rabinstein); critical revision
of the manuscript for important intellectual content (Drs
Whiteman and Shebert); administrative, technical, and material support (Drs Whiteman and Shebert); study supervision (Drs Whiteman and Shebert).
Corresponding author and reprints: Alejandro A. Rabinstein, MD, University
of Miami School of Medicine D4-5, PO Box 016960, Miami, FL 33101 (e-mail: alerabas{at}yahoo.com).
From the Departments of Neurology (Drs Rabinstein and Shebert) and
Neuroradiology (Dr Whiteman), University of Miami School of Medicine, Miami,
Fla.
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