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1 Department of Radiology, Showa University Northern Yokohama Hospital, 35-1,
Chigasaki-chuo, Tsuzuki-ku, Yokohama 224-8503, Japan.
2 Department of Radiology, Showa University School of Medicine, 1-5-8,
Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan.
Received December 25, 2003;
accepted after revision July 14, 2004.
Address correspondence to R. Ukisu.
Abstract
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MATERIALS AND METHODS. We reviewed nine cases of CJD in which MRI was performed from the early to terminal phase of the disease. MRI findings were correlated before (early phase) and after (intermediate phase) the onset of the characteristic clinical findings of myoclonus and periodic synchronous discharges on electroencephalograms. The chronologic changes in imaging findings were followed from the akinetic mutism to the terminal phase of the disease (terminal phase). T2-weighted images had been obtained in all the patients, and diffusion-weighted images and FLAIR images had been obtained in six patients. We evaluated the images for the presence and location of abnormal signal intensities.
RESULTS. During the early phase, the T2-weighted images showed no abnormal findings. The diffusion-weighted images, however, revealed abnormal high signal intensities in the cortex in all patients and in the basal ganglia in five patients. In two cases, there were abnormal signals on FLAIR images that corresponded to diffusion-weighted imaging abnormalities. During the intermediate phase, the area of the high signal intensities on the diffusion-weighted images had expanded and progressive cerebral atrophy had become apparent. During the terminal phase, abnormal high signal intensities in the cerebral cortex and basal ganglia on the diffusion-weighted images in one patient disappeared.
CONCLUSION. Diffusion-weighted imaging is extremely useful in detecting CJD during the very early phase—even before the onset of characteristic clinical findings.
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Rapidly progressive brain atrophy and high signal intensities in the cerebral cortex and the basal ganglia are well known MRI findings of CJD. However, in the early phase of the disease, conventional MR images usually appear normal, and it is often impossible to diagnose CJD on the basis of a single examination [5, 6]. On the other hand, diffusion-weighted imaging by the echo-planar technique has gained attention as a means of early diagnosis of CJD [7–18], but to the best of our knowledge, no correlation between serial changes in imaging findings and clinical manifestations has ever been reported. In this study, we analyzed serial changes in MRI findings in relation to the clinical signs and symptoms of CJD from the early phase to the terminal phase of the disease.
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Imaging Data Acquisition
The MR apparatus used was a 1.5-T (Magnetom Vision, Siemens Medical
Solutions; Signa Horizon LX or HiSpeed, GE Healthcare) or 1.0-T (Magnetom
Impact, Siemens Medical Solutions) superconduction unit equipped with
conventional head coils. All images were obtained in the axial plane, with
optimum TRs and TEs selected for the individual machines. T2-weighted fast
spin-echo images were obtained in all patients. The T2-weighted imaging
parameters were TR range/TE range, 3,458–4,900/90–123; 20 axial
sections of 5-mm section thickness with a 1.5- to 3.0-mm intersection gap; 256
x 256 matrix; and 210- to 230-mm field of view. Diffusion-weighted
images acquired by single-shot spin-echo echo-planar imaging had been obtained
in six cases. The imaging parameters were 4,500–5,700/90–123;
number of excitations, 1; 12–15 axial sections of 5- or 6-mm section
thickness with a 1.5- to 3.0-mm intersection gap; 128 x 128 matrix;
220-mm field of view; and a diffusion-encoding strength (b factor) of zero and
1,000 sec/mm2. FLAIR images had been obtained in six cases. The
FLAIR imaging parameters were 5,700–9,000/100–120; inversion time,
1,700–2,200 msec; 5- or 6-mm section thickness; 1.5- to 3-mm
intersection gap; 192 x 192 or 256 x 256 matrix; and 210- to
230-mm field of view.
Evaluation of Lesions
We categorized the progression of the disease into three phases: early
phase, the period from the onset of psychotic or neurologic symptoms to
immediately before the appearance of myoclonus or periodic synchronous
discharge on the electroencephalograms; intermediate phase, the period during
which myoclonus or periodic synchronous discharges (or both) are observed; and
terminal phase, the period from onset of akinetic mutism to death.
Images were interpreted for abnormal signals in each sequence by three
radiologists on a consensus basis. When abnormal diffusion-weighted imaging
signals were seen in the early phase, apparent diffusion coefficients (ADC)
were measured in four locations and means ± SD were calculated using
the following equation [18]:
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Early Phase
No abnormal signals were seen in the cortex or basal ganglia on the
T2-weighted images (Fig. 1A).
Diffusion-weighted images were obtained in the six cases in which abnormal
signals unrelated to arterial circulation were observed. Abnormal cortical
intensities were seen in all six cases, in four bilaterally and in two in
either hemisphere. Abnormal signals were seen in the caudate nucleus in five
cases (four bilateral, one hemilateral), in the putamen in four cases (two
bilateral, two hemilateral), and in the thalamus in one case (hemilateral)
(Figs. 1B,
2A,
3B, and
4B). FLAIR image abnormalities
were observed in two patients in the same areas as on the diffusion-weighted
images (Fig. 4A). Low ADC
values were observed in the abnormal signal intensity areas on
diffusion-weighted imaging (Fig.
1C and Table
2).
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Intermediate Phase
After the onset of myoclonus or periodic synchronous discharges, abnormal
high signal intensities were observed in the basal ganglia on T2-weighted
images of four patients (Fig.
1D). The abnormal hemilateral cortical high signals seen on the
diffusion-weighted images in two patients progressed to the contralateral
cortex, and the abnormality became bilateral. The abnormality seen in the
hemilateral caudate nucleus also became bilateral. In the putamen, where only
the anterior portion was affected in the early stage, the abnormal high signal
intensities progressed to involve the posterior aspect of the putamen as well
(Figs. 1E and
2B). In one patient, an
abnormal cortical signal became less conspicuous
(Fig. 2B). The abnormal areas
of the cortex and putamen on the diffusion-weighted images all showed
abnormally high signals on the FLAIR images. By contrast, the putaminal high
intensities on the diffusion-weighted images were not detected in one case,
and no abnormal signals were observed in the thalamus. Progressive atrophy of
the brain was seen in eight of the nine cases.
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Terminal Phase
After progressing to akinetic mutism, brain atrophy became more prominent.
In one case, the diffusion-weighted imaging high signal in the cortex and the
basal ganglia disappeared, leaving only the signals in the insula. On the
T2-weighted images, both putamina showed low intensities similar to those on
the diffusion-weighted images (Figs.
3C and
3D). In another patient, no
abnormal high signal was seen in the basal ganglia at any time during the
clinical course, and bilateral putaminal low signal intensities were observed
in the latter stage instead (Fig.
4C).
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1 million population
worldwide after middle age, and it affects slightly more women than men.
Approximately 85% of prion-related diseases are sporadic and have an unknown
route or source of infection. Acquired by prion infection are iatrogenic CJD
and variant CJD from bovine spongiform encephalopathy
[1–3].
Iatrogenic causes include corneal transplantation
[19]; ingestion of
prion-contaminated human growth hormone
[14,
20]; and use of cadaveric dura
mater, which was common in Japan during the 1980s and caused iatrogenic CJD in
97 patients before 2003 and became a social issue there
[4].
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Hereditary prion disease accounts for 10–15% of CJD cases, most of which are classic Gerstmann-Sträussler-Scheinker disease [21]. The clinical manifestations of CJD differ according to the stage of the disease. Most patients exhibit rapidly progressive mental deterioration, with dementia developing within a few weeks to several months, but character disorganization and visual abnormalities are sometimes noted very early. As the disease progresses, pyramidal and extrapyramidal symptoms develop, and manifestation of myoclonus and periodic synchronous discharges on electroencephalograms, which is characteristic of CJD, becomes apparent. After a few months, the akinetic mutism phase begins, and patients typically die within a year. Periodic synchronous discharges or myoclonus is a late development of the disease, and sometimes never manifests during the course of the disease [20, 22].
The characteristic histopathologic features of CJD are spongiform degeneration of neurons and their processes, neuronal loss, intense reactive astrocytic gliosis, and amyloid plaque formation. The vacuoles that comprise spongiform degeneration tend to be round to oval and vary in diameter from 5 to 25 µm [23].
In the past, sensory-evoked potentials have been investigated, and some authors have reported of their abnormality in CJD [24]. The presence of 14-3-3 proteins in CSF strongly suggests CJD, but this protein may be seen in other central nervous system disorders and is not pathognomonic of CJD [25]. Brain biopsy is a highly accurate method of diagnosis, but its invasiveness and the possibility of secondary infection severely limit its use. Thus, CJD is an extremely difficult disease to diagnose, especially in its early stages.
The MRI findings reported in CJD are abnormal T2 signals in the cerebral cortex and basal ganglia and acutely progressive brain atrophy [4, 5]. However, early diagnosis of CJD using conventional MRI is difficult, and the use of MRI has been limited mostly to monitoring the progression of the disease and to making a prognosis. Diffusion-weighted imaging, on the other hand, provides image contrast that depends on the molecular motion of water within the tissue where the abnormalities are depicted according to changes in viscosity in and around cells or changes in membranous constituents. Diffusion-weighted imaging abnormalities are observed in many conditions, and diffusion-weighted imaging is used in a variety of settings including the early detection of brain infarction [18].
Diffusion-weighted imaging abnormalities reported in CJD have been seen in the cortical and basal ganglia (caudate nucleus and putamen), and abnormal high signal intensities that do not correspond to the arterial blood supply have been detected in the thalamus; cortical involvement is most common. Various cortical abnormalities have been reported, and they may be hemilateral or bilateral; or diffuse, focal, or symmetric. Basal ganglia and thalamic involvement may also be hemi- or bilateral. These diffusion-weighted imaging findings are reported to be characteristic of CJD by some and may be a clue to the diagnosis before the onset of brain atrophy or abnormal signals on T2-weighted imaging [7–17].
Early Phase
Abnormal cortical high diffusion-weighted imaging signals were observed
before the onset of myoclonus or periodic synchronous discharges in all the
patients in our series. Differentiation from venous hypertensive
encephalopathy and chronic herpes encephalitis may be necessary, because they
also present with progressive dementia and abnormal cortical
diffusion-weighted imaging signals
[26]. High intensities in the
caudate nucleus were seen in five of the six patients, and together with
cortical signal abnormalities, they were characteristic findings.
Diffusion-weighted imaging should be included in the MRI examinations of
patients with progressive dementia to detect CJD and thereby avoid
transmission to other patients and medical personnel. CJD should be suspected
whenever hyperintense diffusion-weighted imaging lesions are seen in the
cerebral cortex and deep gray matter, such as in the caudate nucleus, even if
characteristic clinical findings, such as myoclonus or periodic synchronous
discharge, are absent.
High signal intensities on diffusion-weighted images were accompanied by a decrease in ADC values, suggesting the presence of restricted diffusion within the tissue. Bahn and Parchi [9] correlated abnormal diffusion-weighted imaging findings with biopsied brain material in two cases of CJD and concluded that the high signals were strongly correlated with vacuole formation in the brain. Electron microscopy shows these vacuoles as focal swelling of a neuritic process and may cause a decrease in ADC values [15]. For many reasons, brain biopsy of CJD patients remains problematic, but pathologic–radiologic correlations in early CJD, especially with diffusion-weighted imaging findings, may provide many clues to understanding the nature of the disease.
FLAIR images tend to depict cortical lesions that T2-weighted images fail to detect [27, 28]. This tendency was confirmed in our series, although not at the diffusion-weighted imaging level. Abnormal signals on FLAIR images corresponding to diffusion-weighted imaging abnormalities were seen in two cases of early-stage abnormalities, but they were not clearly seen on T2-weighted images.
Intermediate Phase
With the onset of myoclonus and periodic synchronous discharges,
hemilateral abnormalities progressed to involve the contralateral side.
Lesions involving only the anterior portion of the putamen progressed to
involve the entire region. Murata et al.
[17] described the expansion
of an abnormality on diffusion-weighted imaging from the caudate nucleus to
involve the putamen, and they attributed the expansion to progression across
the nucleus accumbens septi and putaminocaudate gray matter bridges.
FLAIR images also showed abnormal hyperintensity in the same locations as the diffusion-weighted images in all cases, and they were more useful than the T2-weighted images. However, abnormalities are less conspicuous on FLAIR images than on diffusion-weighted images, and care should be exercised when interpreting them. The incidence of FLAIR abnormalities increases after the onset of myoclonus or periodic synchronous discharges, but the findings are still obscure compared with the diffusion-weighted imaging findings.
Terminal Phase
As the disease progressed further, disappearance of most of the cortical
and basal ganglia MRI abnormalities was observed in one case. There was also a
case in which no abnormal high intensities were seen in the caudate nucleus or
the putamen, but low signal intensities appeared in both putamina during the
terminal phase. These changes may have been attributable to changes in brain
tissue from spongiform degeneration to severe vacuolation, neuronal loss, and
severe astrocytosis, although it is impossible to exclude other explanations.
We therefore think that even though diffusion-weighted imaging is important in
the early diagnosis of CJD, its value may be somewhat limited in the diagnosis
of more advanced stages of the disease. Although it is unlikely that MRI would
be performed only in the advanced stages of the disease, focusing on
diffusion-weighted imaging findings alone may be misleading, and other imaging
sequences, clinical manifestations, and examinations should also be carefully
considered.
Although no cure for CJD exists and early detection does not alter the outcome, trials of treatment with quinacrine and chlorpromazine are in progress. Their effectiveness is still unknown, but early detection of the disease may become more important when effective therapeutic measures are available. Because CJD is an infectious disease, the handling of tissue specimens and body fluids requires special care. Human-to-human infection has also been reported [29, 30], and early diagnosis definitely plays a positive role in preventing its transmission.
In conclusion, diffusion-weighted imaging is useful in the detection of CJD in the early phase. The radiologist may play a role in the preclinical diagnosis of CJD in its early phase and thus prevent iatrogenic transmission of the disease. Abnormalities on diffusion-weighted images may become less conspicuous in more advanced disease. Clinical correlations and careful evaluation of other MRI sequences are essential.
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