Pathologic image of sCJD. Figure 4 is a pathologic image from right frontal lobe of a biopsy case. It shows the classic pathological features of CJD: spongiform degeneration, astrocytes gliosis and nerve cell loss. The black arrows show the diffuse spongiform changes. doi:10.1371/journal.pone.0058442.g004 

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... were sourced from medical records and attending medical care providers. Follow-up information on patient condition and time of death after discharge was collected through interviews, telephone calls or comprehensive questionnaires. 14-3- 3 protein was determined in western blot by standard methods in the same institution [3]. The procedure of pathological morphol- ogy observation was as follows: brain tissue with formaldehyde 24 hours, embedded in paraffin, making pathological section and HE staining. We retrospectively reviewed the data of the fifty-seven patients, including demographic data, clinical symptoms and signs, laboratory examinations, electroencephalogram (EEG), diffusion- weighted imaging (DWI), 18F-FDG PET/CT, biopsy and autopsy, focusing on the differences between patients in China and patients in other countries. Eleven of the fifty-seven enrolled patients were pathologically confirmed to have sCJD (one case by autopsy and ten cases by biopsy). Thirty-nine cases were probable diagnoses of sCJD and seven cases were possible diagnoses. Thirty-three of the patients were male, and twenty-four were female (M:F = 1:0.727). The age of onset ranged from 36 to 75 years (mean: 55.5 years, median: 57 years). As shown in Figure 1, 5 (8.8%) patients were in the 30- to 39-year-old age of onset group, 8 patients (14.0%) were in the 40–49 age of onset group, 20 patients (35.1%) were in the 50–59 age group, 21 (36.8%) were in the 60–69 age group, and the remaining 3 (5.3%) patients were in the over 70 years group. 52.6% of the patients (30/57) came to our hospital within 3 months of illness onset, and 71.9% of the patients (41/57) came to our hospital within 6 months of illness onset. The time from onset to death ranged from 5 to 22 months (mean: 11.6 months, median: 11 months). Fifty-four patients died, and one case was lost to follow up. Two patients are still alive and have lived for more than 7 months since their disease onset. The two living patients and the one lost to follow up were all diagnosed as probable sCJD according to the diagnostic criteria [2]. Among the cases in which the patients died, 51.9% of the patients (28/54) died 7 to 12 months after disease onset, and 31.5% of the patients (17/ 54) lived longer than 1 year after disease onset. Only 16.7% of the patients (9/54) died within 6 months of illness onset. Twelve cases were acute onset, forty-one cases were sub-acute onset, and four cases were chronic. The predominant onset symptom was progressive dementia (50.9%, 29/57), followed by cerebellar ataxia (22.8%, 13/57), visual disturbance (17.5%, 10/ 57), mental disorders (5.3%, 3/57), and Parkinson syndrome (3.5%, 2/57). It is worth noting that one probable sCJD patient had an onset of right hemiparesis without any other evidence supporting a diagnosis of stroke. Patient symptoms and signs over the course of the disease are summarized in Figure 2. In nine patients (four pathologically confirmed cases and five probable cases), 14-3-3 protein analysis of the cerebrospinal fluid(CSF) showed that only three probable patients had a positive test result, with a sensitivity of 33.3%, which is much lower than other reports. The sensitivity of periodic sharp wave complexes (PSWCs) in EEG was 79.6% (43/54). Of the fifty patients who underwent DWI examination, abnormal hyper-intensity was observed in forty-seven patients (sensitivity: 94%), with 45/50 patients having abnormalities in the cortex, 25/50 in the basal ganglia and 8/50 in the thalamus. Lesions in both the basal ganglia and the cerebral cortex were found in 23/50 (46.0%) patients. Two cases only showed hyper-intensity in the basal ganglia during the course of the disease. Three possible patients had normal DWI scans. The abnormal regions may have been unilateral at disease onset but later became bilateral. The signal intensity sometimes decreased as the disease advanced. Seventeen patients underwent PET examination, and sixteen of them showed hypo-metabolism (sensitivity: 94.1%): 16/17 showed hypo-metabolism in the cortex, 11/17 in the basal ganglia, and 7/17 in the thalamus. One probable patient did not show any abnormalities on PET. In the seven patients who did not show typical hyper- intensities in the first DWI examination, abnormalities of hypo- metabolism in the cerebral cortex were clearly detected by PET at the same time of the first DWI scan. Two patients with extrapyramidal tract signs had no abnormalities in the basal ganglia using DWI, but hypo-metabolism in the basal ganglia was detected by PET. Additionally, in thirteen out of the seventeen patients who underwent PET, extra abnormal regions in addition to the hyper-intense areas on DWI were detected. The PET images of sCJD patients were shown in Figure 3. One case examined by autopsy and ten cases examined by biopsy presented the classic pathological features of CJD: spongiform degeneration, astrocytes gliosis and nerve cell loss. The diffuse spongiform changes are shown in Figure 4 (inset, black arrows). CJD is widely recognized in the Western countries. However, the research on CJD started late in China, and the diagnostic rate of CJD is lower than in other countries. According to the search results in medical article database, the total number of CJD cases reported in China from January 1, 1981 to January 1, 2000 is less than 35. In 2007, one domestic study with seven years data reported only 23 cases [4]. And in 2008, another study in China with fifteen years data reported only 30 cases [5]. China CJD surveillance started in 2006 but the project has not been well completed. The patients’ data in surveillance program were limited, lacking detailed data of disease course and MRI result, and the surveillance members did not do follow-up observations. Among the national studies on sCJD with detailed disease history, clinical manifestations, 14-3-3 protein analysis, EEG, MRI, pathology and follow-up results, our study has the largest case number and covers the longest time span of data collection in China. In this study, we retrospectively analyzed the data of fifty- seven Chinese sCJD patients observed from January 1, 1992, to December 31, 2011, and found significant differences and similarities between Chinese patients and patients from other countries. We compared the onset age of Chinese sCJD patients with patients from other countries. In this study, the mean age of onset in Chinese patients was 55.5 years, and the median age of onset was 57 years, ranged from 36 to 75 years. Other studies of Chinese sCJD patients showed similar results as follows. One domestic study showed that the mean onset age of 23 sCJD cases was 59.4 years [4], and another study of 30 Chinese sCJD cases reported the mean onset age was 53.3 years [5]. The report based on 2008 surveillance data in China showed that the mean age of onset in probable and possible Chinese sCJD patients were 56.7 and 57.4 years old, respectively [6]. The results of studies above were all similar to ours. In contrast, other populations had a much older onset age, including 66 years in Japan (mean) [7,8], 64.8 years in Australia (mean) [9], 65.2 years in Germany (median) [10], and 64 years in twelve countries (median) [2]. One study also showed that the median age at death of American patients was 68 years [11]. Because most sCJD patients die within two years of disease onset, the median age of onset in America was similar to European countries but higher than China. Additionally, 57.9% of patients in our study were younger than sixty at the time of onset compared to 23.3% of patients in a study conducted by EUROCJD (the prospective CJD surveillance program conducted by the European Union and allied countries) [12]. The onset age of sCJD in China was approximately 8–9 years younger than in other countries. A younger age of disease onset is a specific feature of Chinese sCJD patients and is probably related to racial differences. Detailed information regarding onset age and disease duration is summarized in Table 1. Another unique feature of Chinese sCJD patients was a longer duration from disease onset to death. The mean disease duration in our study was 11.6 months, and the median duration was 11 months, ranged from 5 to 22 months. In contrast, other studies reported 6.6 months (mean, Australia [9]), 7.0 months (median, Germany [10]) and 6.4 months (median, data from twelve countries [2]) (Table 1). In this study, only 16.7% of patients had a disease duration less than 6 months, and 31.5% of patients survived for longer than 1 year. In the EUROCJD study, 58.8% of patients died within 6 months of illness onset, and only 14.2% of patients lived longer than 1 year [12]. The disease duration of sCJD patients was longer in China, and a similar situation was also observed in Japan (mean duration, 15.7 months) [7], where the disease duration was much longer than in Western countries. These results indicated that the longer disease duration was not only a specific feature of Chinese patients but was most likely due to a difference between patients in Asian and Western countries. Prior studies suggested a possible reason for why patients with sCJD lived longer in some countries. In Western countries, because of ethical and financial concerns, intensive life-sustaining treatments are not commonly provided to patients with progressive, fatal neurological conditions [7,13]. In Japan, however, the social and ethical environment allows patients with end-stage disease to receive intensive life-sustaining treatments, even after deterioration to akinetic mutism [13–15]. In addition, a well- organized health care system reduces the financial burden on patients and their families. Thus, some researchers have suggested that these elements prolong the patients’ lives [7]. However, we disagree with this opinion. First, before coming to our department, eleven of the fifty-seven patients had endured the disease for approximately seven months ...