Physical examination revealed severe dementia and mutism in 2 patients, Wernicke's aphasia in 1, choreoathetosis in 3, decreased gag reflex, reduced muscle tone, the bilateral absence of abdominal reflexes and cremesteric reflexes in 2, bilateral Babinski's sign negative in 4 and positive in 1, increased muscle tone and symmetric deep tendon reflexes in 2, and spastic gait and lead pipe rigidity in 1 (Table). All the 5 patients had characteristic periodic complex on electroencephalogram (EEG) suggestive of CJD.
One patient died of respiratory failure 22 days after hospitalization and another was hospitalized again for serious dementia, limb atrophy and decreased muscle tone 6 months after the first hospitalization.
RESULTS
Clinical results
Three patients were confirmed pathologically and 2 patients were confirmed clinically. EEG showed periodic sharp waves or spikes in 4 patients. Negative EEG in 1 patient was recorded for three times, but 24-hour EEG revealed abnormality for two times. The routine and biochemical results of cerebrospinal fluid (CSF) were normal. The 4 patients underwent CSF immunofluorescence examination related to 14-3-3 protein and the result showed elevated level (<1 g/L) in 2 patients, negative in 1 and suspicious positive on the first time and negative on the second time in 1.
MR manifestations
Brain volume
One patient had no definite brain atrophy and abnormal signal intensity at the early stage, but follow-up examination after 2 months showed the volume of the brain was smaller than before, and bilateral basal ganglia demonstrated high signal intensity on T2WI. The other 3 patients showed mild brain atrophy at the first examination. Another patient had no obvious brain atrophy.
Signal intensity
Multiple patchy slightly long T1 and long T2 signal intensity at the centrum semiovale and bilateral paraventricular white matter were seen in 3 patients. One of them had symmetric slightly high intensity at the bilateral globus pallidus and putamen without mass effect on T2WI. Abnormal signal intensity was not obvious on T1WI and there was no midline shift.
DWI images showed symmetric high signal intensity at the bilateral globus pallidus and the head of caudate nucleus with widely increased signal intensity in the cerebral cortex, and T2WI images showed symmetric slightly high signal at the bilateral globus pallidus and putamen in 1 patient. Follow-up images after 6 months presented bilateral subdural hemorrhage (Fig. 1). One patient had high signal intensity at the basal ganglia and cerebral cortex only with abnormal T2 signal intensity at bilateral paraventricular white matter on routine MRI. Two patients presented widely gyri-like high signal intensity at the frontal, parietal, occipital and temporal lobes cortex on DWI without symmetric characteristics, and the basal ganglia had no abnormal signal intensity (Fig. 2). Routine examination showed bilateral paraventricular long T2 signal intensity in 1 patient and no abnormal findings in 1. One of these patients had no abnormality on both routine MRI and DWI.
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Fig. 1. MR images of a 33- year-old male CJD patient. T1-weighted images (A and D), T2-weighted images (B and E) show cerebral atrophy and slightly long T2 signal intensity of the paraventricular white matter with symmetric high signal intensity at the bilateral globus pallidus and the head of the caudate nucleus on T2WI. DW images (C and F) show abnormal high signal intensity at the bilateral globus pallidus, the head of the caudate nucleus, and the cerebral cortex. After 6 months, episodic cerebral hypertension appears. T1WI (G), T2WI (H) and DWI (I) show bilateral subdural crescent abnormal signal intensity suggestive of subdural hemorrhage. |
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Fig. 2. MR images of a 56-year-old male CJD patient. T1WI (A), T2WI (B) and contrast T1WI (C) show multiple slightly long T1 and long T2 signal intensity of the paraventricular white matter and no cortical abnormalities or enhancement. DWI (D, E and F) show widely high signal in the cortex but normal basal ganglia. |
The lesions in the 5 patients were only limited in the cerebral hemisphere and basal ganglia and had no enhancement. Abnormal signal intensity was not observed in the brainstem and cerebellum.
Pathological results
Autopsy revealed lesions in the right occipital lobe (1 patient), the left frontal lobe (1), and the frontal lobe and the right corpus striatum (1). Histological results showed focal ischemic lesions, proliferation of astrocytes in the cortex and gray matter, and spongiform degeneration in neural fibril nets. The axon was dyed normally. Two specimens from 1 patient demonstrated loss of neurons accompanied with widespread spongiform degeneration of the white matter and proliferation of astrocytes, and the lesions in the cortex were more marked than in the basal ganglia. PrP deposits were detected immunohistochemically in small areas of the cerebellar molecular layer in 3 patients.
DISCUSSION
CJD is an invariably fatal transmissible disorder of the central nervous system characterized by rapidly progressive dementia and variable focal involvement of the cerebral cortex, basal ganglia, cerebellum, brainstem, and spinal cord. The annual incidence of the disease is about 1 in one million population.2 The naturally acquired disease occurs in patients at 16－82 years of age, with a peak incidence between 60 and 64 years. 5%－10% of patients were family members and conjugal cases were rare.
Proteinaceous infectious particle (prion) is the etiological agent of the disease. Familial cases, although they are not common, have been associated with mutations in the prion protein (PrPc) that is expressed by normal neurons. In sporadic patients, an abnormal prion protein (PrPsc) different from PrPc in its secondary (folding) structure has been proposed as the infectious agent. To explain the ability of PrPsc prions to replicate in the brain (despite the fact that they contain no detectable nucleic acids), it has been suggested that infectious PrPsc prions induce a conformational change in normally expressed PrPsc prions that convert them to the PrPsc form.
Although transmission from humans to animals has been demonstrated experimentally, documented human-to-human transmission by corneal transplantation, cortical electrode implantation, or administration of human growth hormone is rare. The infectious agent is present in the brain, spinal cord, eyes, lungs, lymph nodes, kidneys, spleen, liver, and CSF, but not other body fluids. CJD is divided into 4 types including familial form, iatrogenic form, variant form and sporadic form. The sporadic form is the most common type and accounts for 85%. Laboratory tests (14-3-3 protein in CSF) and ECG (periodic sharp-wave complexes, PSWC) along with the clinical signs observed during disease progression make diagnosis of probable CJD possible. The disease can be diagnosed by neuropathologic or biochemical examination of the brain. According to these diagnostic criteria, 3 patients in our study can be diagnosed as having definite CJD and 2 patients as having probable CJD. The exact incidence of CJD in China is obscure. It may be related to the insufficient knowledge about the disease. Sporadic cases of CJD have been reported.3,4
The incubation period of CJD ranges from 3 to 22 years with subacute onset and progressive deterioration. In our 5 patients, 4 had acute or subacute onset. Typical clinical presentations of CJD included progressive dementia, myoclonus, ataxia, and visual disturbance. The 5 patients had the same symptoms, and in the early stage of the disease, 4 had cerebellar signs and visual disturbance. Periodic sharp wave complexes of EEG are important to diagnose CJD, with a reported diagnostic rate of 67% to 86%.4 Four patients in our study showed typical EEG changes, and 1 patient had abnormal changes after repeated EEG examinations. Repeated EEG is necessary because of false negative EEG changes in the early stage or even the later stage of CJD. Previous reports showed that the sensitivity of 14-3-3 brain protein in CSF was 96% and the specificity was 88%.5 In our study, CSF examination revealed positive results in 2 patients, negative in 1, and suspicious positive in the first time and negative in the second time in 1.
Patients with CJD are often associated with cerebral atrophy. In our study, 1 patient did not show cerebral atrophy at the early stage, but follow-up examination after 2 months showed the volume of the brain became smaller. On the first examination, 3 patients showed mild cerebral atrophy and 1 patient no atrophy. Cerebral atrophy may be due to the progression of the disease and could not be seen at the early stage of the disease. Follow-up images of 1 of our patients presented bilateral subdural hemorrhage after 6 months. Rarely reported previously, the sign may be related to the rupture of bridging cortical veins resulting from the enlarged subdural cavity caused by cerebral atrophy.
Conventional MR images sometimes demonstrated abnormal high signal on T2WI of the basal ganglia and paraventricular white matter.6 The high signal intensity of paraventricular white matter on T2WI is a common feature in the elderly, and the high signal intensity of the basal ganglia on T2WI can be seen in many diseases (e.g. ischemic diseases, poisoning, metabolic diseases, and degenerative diseases).
DWI showed abnormalities in patients with CJD.7 DWI may demonstrate a markedly increased signal in the basal ganglia and cortical regions and it is more sensitive than T2WI and FLAIR MRI. Therefore DWI may be useful in the early diagnosis of CJD. Conventional MRI can reveal discrete abnormalities only in the basal ganglia, whereas DWI may demonstrate multifocal regions of increased signal intensity in the cerebral cortex in addition to lesions of the basal ganglia. These findings appear to be specific for CJD. Although the physicochemical basis for diffusion abnormalities in CJD remains unclear, Kim et al8 suggested that the cause of the observed diffusion restriction might be related to the presence of vacuoles seen histologically in spongiform degeneration. Diffusion of water molecules might be reduced owing to compart-mentalization within the vacuoles. In addition, deposition of prion protein might somehow restrict the free diffusion of water.
Diffusion coefficient (ADC) values in patients with CJD vary. Researchers8,9 found that ADC values were significantly lower in lesions than in normal brain parenchyma, whereas those of lesions of 2 patients were normal or mildly elevated.10 However, the abnormalities shown by DWI in some cortical lesions might result from the synergistic effect of T2 shine-through and restriction of water diffusion. ADC values were nearly normal, and retrospective review of T2-weighted images showed subtle hyperintense signal in the same areas.
Variant CJD or "mad cow disease" is seen in young patients. The disease is associated with the intake of bio-productions polluted by bovine spongiform encephalopathy. The important MRI feature of variant CJD is bilateral thalamic high signal. In the pulvinar, the so-called "pulvinar sign" occurs. Thalamic changes in variant CJD are symmetrical, in contrast to those in the basal ganglia in sporadic CJD cases, which may be asymmetrical.11 Compared to DWI images, PET can reveal abnormalities at the early stage of CJD, i.e. lower metabolism of the temporal lobe, parietal lobe, occipital lobe and cerebellum or basal ganglia.
Other disorders must be distinguished from CJD. Alzheimer's disease is often considered in patients with a less fulminant course and a paucity of cerebellar and extrapyramidal signs. When subcortical involvement is prominent, Parkinson's disease, cerebellar degeneration or progressive supranuclear palsy may be suspected. Striking focal signs indicate a possible intracerebral mass. Acute metabolic disorders that produce altered mentation and myoclonus (e.g. withdrawal of sedative drug) can mimic CJD.12 To our knowledge, diffusion abnormalities in both basal ganglia and cortices have not been identified in other diseases. These findings appear to be specific for CJD.
In conclusion, DWI is more sensitive than conventional MRI in CJD. DWI appears to improve the in vivo diagnosis of CJD and may thus reduce the false negative results of MRI. In the absence of abnormalities on conventional MR images, DWI findings may be helpful for brain biopsy. The specificity of these findings in CJD awaits further investigation.
REFERENCES
1. Zerr I, Schulz-Schaeffer WJ, Giese A, Bodemer M, Schroter A, Henkel K, et al. Current clinical diagnosis in CJD: identification of uncommon variants. Ann Neurol 2000;48:323-329.
2. Castellani RJ, Colucci M, Xie Z, Zou W, Li C, Parchi P, et al. Sensitivity of 14-3-3 protein test varies in subtypes of sporadic Creutzfeldt-Jakob disease. Neurology 2004; 63:436-442.
3. Hamaguchi T, Kitamoto T, Sato T, Mizusawa H, Nakamura Y, Noguchi M, et al. Clinical diagnosis of MM2-type sporadic Creutzfeldt-Jakob disease. Neurology 2005; 64:643-648.
4. Duan XY, Lin SH. The diagnostic advancement in Creutzfeldt-Jakob disease. China J Neurol (Chin) 2003; 36:382-384.
5. Otto M, Wiltfang J, Cepek L, Neumann M, Mollenhauer B, Steinacker P, et al. Taupotein and 14-3-3 protein in the differential diagnosis of Creutzfeldt Jakob disease. Neurology 2002;58:192-197.
6. Nakamura Y, Yanagawa H, Hoshi K, Yoshino H, Urata J, Sato T. Incidence rate of Creutzfeldt Jakob disease in Japan. Int J Epidemiol 1999;28:130-134.
7. Shiga Y, Miyazawa K, Sato S, Fukushima R, Shibuya S, Sato Y, et al. Diffusion-weighted MRI abnormalities as an early diagnostic marker for Creutzfeldt-Jakob disease. Neurology 2004;63:443-449.
8. Kim HC, Chang KH, Song IC, Lee SH, Kwon BJ, Han MH, et al. Diffusion-weighted MR imaging in Biopsy-proven Creutzfeldt-Jakob disease. Korean J Radiol 2001;2: 192-196.
9. Bahn MM, Parchi P. Abnormal diffusion-weighted magnetic resonance images in Creutzfeldt-Jakob disease. Arch Neurol 1999;56:577-583.
10. Demaerel P, Heiner L, Robberecht W, Sciot R, Wilms G. Diffusion-weighted MRI in sporadic Creutzfeldt-Jakob disease. Neurology 1999;52:205-208.
11. Zeidler M, Sellar RJ, Collie DA, Knight R, Stewart G, Macleod MA, et al. The pulvinar sign on magnetic resonance imaging in variant Creutzfeldt-Jakob disease. Lancet 2000;355:1412-1418.
12. Meissner B, Kortner K, Bartl M, Jastrow U, Mollenhauer B, Schroter A, et al. Sporadic Creutzfeldt-Jakob disease: Magnetic resonance imaging and clinical findings. Neurology 2004;63:450-456.
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