China Sporadic Creutzfeldt-Jakob disease: A retrospective analysis of 104 cases
China Sporadic Creutzfeldt-Jakob disease: A retrospective analysis of 104 cases
Sporadic Creutzfeldt-Jakob disease: A retrospective analysis of 104 cases
Qi C, Zhang JT, Zhao W
European Neurology | May 15, 2020
The present study reported a retrospective review of 104 sporadic Creutzfeldt-Jakob disease (sCJD), a prion protein disease characterized by rapidly progressive dementia, visual disturbances, cerebellar ataxia, and akinetic mutism, cases [57 males and 47 females, with the age of onset ranging from 29 to 82 (mean: 58, median: 60) years] in China and examined variations between sCJD patients in China and those in other countries in order to further summarize the disease in terms of demographic data and auxiliary examinations. From 2003 to 2019, all sCJD patients participated in this research were admitted to the Department of Neurology of the First Medical Center of Chinese PLA General Hospital. A retrospective analysis of the medical records of 104 people presenting with sCJD was conducted based on demographic data, clinical manifestations, laboratory examinations, cerebrospinal fluid analysis, electroencephalograms, diffusion-weighted imaging scans, positron emission tomography (PET) scans, and prion protein gene mutations. Rapidly progressive dementia appeared as an initial symptom in most patients, followed by cerebellar ataxia, visual disturbances, and neurobehavioral disorders. The brain PET scans of 50 individuals with sCJD showed 96% sensitivity to the diagnosis of sCJD. Findings suggested that sCJD occurred in patients in China at an early age. The sensitivity of 14-3-3 protein detection was substantially poor however, in the diagnosis of sCJD, brain PET was extremely sensitive.
SNIP...
Discussion sCJD is a condition found worldwide, reported in both developed and developing countries. Due to the mostly subacute onset of the disease, clinical manifestations of patients in the early stage are mild but gradually worsen over time. As a result, sCJD may be easily misdiagnosed in the early stage. In this study, a systematic review was conducted on a large scale to retrospectively analyze sCJD from the perspectives of demographic data and auxiliary examinations.
In this study, the age of onset of sCJD in patients was 29–82 years, with a mean age of 58 years and a median age of 60 years, which was younger than the 65 years reported in countries in Europe, South America, and Asia [5] and the 65.5 ± 12.6 years reported in Japan [6]. It was believed that there might be some racial differences among sCJD patients in different countries. Moreover, although the sample size in this study was as large as 100 patients, there might still be bias in the research data. In recent years, an increasing number of young sCJD patients have been reported as clinicians continue to understand the disease [7, 8]. In this study, there were 4 patients aged from 20 to 39 years. None of these patients had a familial gene mutation in the PRNP gene. However, we still consider that these young patients are in urgent need of special attention from neuroscientists. Of the 104 sCJD patients, the time from disease onset to death ranged from 1 to 36 (mean: 8.43, median: 9) months, which was longer than that reported in other studies, for example, 6.6 months (Australia [9]), 7.0 months (Germany [10]), and 6.4 months (data from twelve countries [4]). It was believed that the age of disease onset in patients was younger, when their physical functions were better, and complications such as lung infection and malnutrition appeared later and progressed slowly, to a degree lower than that seen in the older patients. However, it had little to do with medical and nursing levels. Transmission of the condition between 2 patients who were nongenetic relatives had been reported in a foreign study [11, 12]. In the present study, however, individuals in close contact with the 104 patients and their nursing staff were not found to have the condition, and subsequent studies will continue to follow up these individuals.
The early misdiagnosis rate of sCJD was high. Approximately 56.7% (59/104) of the patients enrolled in this study had been misdiagnosed with viral encephalitis, anxiety and depression, cerebral infarction, or optic neuritis in other hospitals. These misdiagnoses were mostly caused by the lack of understanding of sCJD among some clinicians, especially those in primary healthcare services, due to the low incidence of the disease. In addition, the early symptoms of sCJD are not particularly typical. The most common clinical manifestation of sCJD in the early stage was rapid progressive dementia. In this study, in the early stage of the disease, most patients developed onset with rapid progressive dementia, cerebellar ataxia, visual disturbances, and psychiatric symptoms, which was similar to the onset of visual or auditory disturbances, isolated psychiatric manifestations, and isolated aphasia symptoms of sCJD reported in the literature [13].
Brain biopsy for sCJD is not as widely adopted as the diagnostic method for cerebrovascular or brain tumor diseases. Since sCJD has a high risk of disease transmission through surgical instruments, the preferred option to obtain pathological specimens is not by biopsy or autopsy in China. Therefore, it is urgent to find some examination methods with high sensitivity and specificity to improve the diagnosis of sCJD.
The relationships between sCJD and CSF proteins, such as 14-3-3, tau, and α-synuclein (α-syn), have been investigated for their potential value in premortem diagnosis [14]. In this study, we used only WB to test the level of 14-3-3 protein in the CSF, but the sensitivity was lower than the 82% reported in other countries [15]. Among the 218 sCJD patients reported by the Korean professor Jae-Sung Lin in 2015, only 106 patients were positive for CSF 14-3-3 protein, and the sensitivity was 48.6% [16]. In this regard, we consider that the lower sensitivity of 14-3-3 protein detection in this study may be related to ethnic differences. We also believe that the sensitivity and specificity of the 14-3-3 protein may be related to the progression of sCJD, during which the results of this test may be influenced [17]. In addition, in China, most patients can undergo the test for the 14-3-3 protein in the CSF only once throughout the course of the disease. It was hypothesized that if patients could undergo multiple CSF 14-3-3 protein tests during the course of the disease, the sensitivity might be increased. Recently, real-time quaking-induced conversion (RT-QuIC) assays of CSF and nasal-brushing specimens have been valuable in the diagnosis of sCJD. This technique exploits the ability of the misfolded pathological form of scrapie isoform of the prion protein (PrPSc) found in the CSF to induce the conversion of normal prion protein (PrP) to the misfolded form, which subsequently aggregates. The formation of these aggregates of misfolded PrP is monitored in real time using fluorescent dyes. RT-QuIC technology has achieved a higher detection sensitivity (95.8%) and specificity (100%) [18]. Due to its ultrahigh sensitivity and specificity, it has established itself as an important method in the diagnosis of sCJD. However, due to the special requirements for the use of equipment, this method has not been widely applied. In subsequent research, more attempts and attention should be given to the RT-QuIC detection technology. In this study, EEGs showed a sensitivity of 38.2% for PSWCs, which was significantly lower than the 53–60% [19, 20] reported in studies in other countries. In sCJD, EEGs exhibit characteristic changes depending on the stage of the disease, ranging from nonspecific findings such as diffuse slowing and frontal rhythmic delta activity in the early stages, to disease-typical PSWCs in the middle and late stages, to coma traces or even alpha coma in preterminal EEG recordings. PSWCs, either lateralized (in earlier stages) or generalized, occur in approximately two-thirds of patients with sCJD [20]. In this study, however, 1 patient underwent 6 EEG examinations during the course of the disease, with signals from normal at the beginning to moderate to severely abnormal before the typical PSWCs changed. As the disease progressed, in the later stages, the EEG of the patient became flat, and the PSWCs disappeared. It was hypothesized that repeat EEG examinations or 24-h dynamic EEG could significantly improve the sensitivity of the diagnosis and help clinicians improve their understanding of sCJD. The abnormal hyperintense signal on brain DWI corresponded to spongiform degeneration, mainly due to the small volume of vacuoles and thus reduced water diffusion. This also indicates that spongiform degeneration may be the imaging basis of nuclear magnetic changes. The DWI abnormal hyperintense signal of sCJD is mostly asymmetrical in the early stage, but as the disease progresses, it becomes more symmetrical. The abnormal hyperintense signal on DWI is most commonly found along the cortex, while the abnormal signals of the caudate nucleus and putamen and the abnormal hyperintense signal of posterior thalamic nodules are relatively rare. These signals are associated with the molecular subtype in sporadic cases, the stage and duration of the disease, and pathological findings [21]. Young et al. [22] reported that MRI had a sensitivity of 91% and a specificity of 95% in the diagnosis of sCJD, which were similar to the values in our data. PET uses radioisotopes to label tracers and to detect the level of glucose metabolism in brain cells. If neuronal damage occurs in sCJD patients, it will affect glucose metabolism in brain cells, leading to reduced fluorodeoxyglucose (FDG) uptake. However, because PET hypometabolism changes are more common in neurodegenerative diseases such as Lewy body dementia, Alzheimer’s disease, and progressive supranuclear palsy, PET hypometabolism changes have not been included in the diagnostic criteria for sCJD. In our research, a total of 50 patients received PET, and the sensitivity of PET-CT and PET-MRI examinations reached as high as 96%. In addition, in this study, 1 patient underwent PET-MRI examination. In the fusion of PET images and DWI images, PET-MRI of sCJD patients showed a wider range of lesions than DWI alone. Based on the extent and location of hypometabolism, we suppose that PET can help clinicians predict the progression of the disease earlier than DWI. From the aforementioned findings, we consider that changes in PET hypometabolism may provide guiding references for the disease’s early diagnosis and differential diagnosis, or even the judgment of disease progression of sCJD, if their analysis can be added to those of the patient’s clinical manifestations (rapidly progressive dementia) and other auxiliary examination results (such as high-density DWI, positive results for 14-3-3 protein in the CSF, or PSWCs in EEGs). In addition, as shown in Figure 5, we found that patients with different PRNP diseases had slightly different sites of FDG-PET hypometabolism. FDG-PET hypometabolism of sCJD occurs mainly in the cerebral cortex, basal ganglia, or thalamus, among which the cerebral cortex is the most common. Gerstmann-Sträussler-Scheinker syndrome hypometabolism occurs mainly in the cerebellum, and fatal familial insomnia hypometabolism occurs mainly in the thalamus [23-25]. These findings will help clinicians identify different PRNP diseases. PRNP gene detection plays an increasingly important role in the diagnosis of PRNP disease. In this study, 35.6% (37/104) of the patients received PRNP gene detection. All 129 codons were M/M and 219 codons were E/E homozygotes. Scholars such as Kobayashi reported that there are two normally occurring polymorphisms of the human PRNP gene, methionine (M)/valine (V) at codon 129 and glutamic acid (E)/lysine (K) at codon 219, that can affect susceptibility to prion diseases. Patients who are M/M homozygous at codon 129 are overrepresented among sCJD patients [26, 27]. In this study, Chinese sCJD patients were all M/M homozygous at codon 129 and more sensitive to PRNP. Therefore, we assume that Chinese people are more susceptible to sCJD.
Fig. 5. FDG-PET images of different PRNP diseases. a Decreased radioactive uptake in the occipital cortex of an sCJD patient. b Decreased radioactive uptake in the cerebellum of a GSS patient. c Decreased radioactive uptake in the thalamus of an FFI patient. FDG-PET, fluorodeoxyglucose-positron emission tomography; sCJD, sporadic Creutzfeldt-Jakob disease; PRNP, prion protein; GSS, Gerstmann-Sträussler-Scheinker syndrome; FFI, fatal familial insomnia.
In conclusion, this study retrospectively analyzed 104 patients diagnosed with sCJD pathologically and clinically. The characteristics of sCJD were summarized from the perspectives of demographic data and auxiliary examinations, and the results were compared with those from sCJD patients in other reports. This study may represent the characteristics of sCJD patients in China or even in Asia. In addition, PET-CT and PET-MRI examinations were important for the early diagnosis of sCJD due to their high sensitivity.
''In recent years, an increasing number of young sCJD patients have been reported as clinicians continue to understand the disease [7, 8]. In this study, there were 4 patients aged from 20 to 39 years. None of these patients had a familial gene mutation in the PRNP gene. However, we still consider that these young patients are in urgent need of special attention from neuroscientists.''
ZOONOSIS OF SCRAPIE TSE PRION
O.05: Transmission of prions to primates after extended silent incubation periods: Implications for BSE and scrapie risk assessment in human populations
Emmanuel Comoy, Jacqueline Mikol, Valerie Durand, Sophie Luccantoni, Evelyne Correia, Nathalie Lescoutra, Capucine Dehen, and Jean-Philippe Deslys Atomic Energy Commission; Fontenay-aux-Roses, France
Prion diseases (PD) are the unique neurodegenerative proteinopathies reputed to be transmissible under field conditions since decades. The transmission of Bovine Spongiform Encephalopathy (BSE) to humans evidenced that an animal PD might be zoonotic under appropriate conditions. Contrarily, in the absence of obvious (epidemiological or experimental) elements supporting a transmission or genetic predispositions, PD, like the other proteinopathies, are reputed to occur spontaneously (atpical animal prion strains, sporadic CJD summing 80% of human prion cases).
Non-human primate models provided the first evidences supporting the transmissibiity of human prion strains and the zoonotic potential of BSE. Among them, cynomolgus macaques brought major information for BSE risk assessment for human health (Chen, 2014), according to their phylogenetic proximity to humans and extended lifetime. We used this model to assess the zoonotic potential of other animal PD from bovine, ovine and cervid origins even after very long silent incubation periods.
*** We recently observed the direct transmission of a natural classical scrapie isolate to macaque after a 10-year silent incubation period,
***with features similar to some reported for human cases of sporadic CJD, albeit requiring fourfold long incubation than BSE. Scrapie, as recently evoked in humanized mice (Cassard, 2014),
***is the third potentially zoonotic PD (with BSE and L-type BSE),
***thus questioning the origin of human sporadic cases.
We will present an updated panorama of our different transmission studies and discuss the implications of such extended incubation periods on risk assessment of animal PD for human health.
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***thus questioning the origin of human sporadic cases***
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***our findings suggest that possible transmission risk of H-type BSE to sheep and human. Bioassay will be required to determine whether the PMCA products are infectious to these animals.
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***Transmission data also revealed that several scrapie prions propagate in HuPrP-Tg mice with efficiency comparable to that of cattle BSE. While the efficiency of transmission at primary passage was low, subsequent passages resulted in a highly virulent prion disease in both Met129 and Val129 mice.
***Transmission of the different scrapie isolates in these mice leads to the emergence of prion strain phenotypes that showed similar characteristics to those displayed by MM1 or VV2 sCJD prion.
***These results demonstrate that scrapie prions have a zoonotic potential and raise new questions about the possible link between animal and human prions.
***> Moreover, sporadic disease has never been observed in breeding colonies or primate research laboratories, most notably among hundreds of animals over several decades of study at the National Institutes of Health25, and in nearly twenty older animals continuously housed in our own facility. <***
SATURDAY, JUNE 23, 2018
CDC
***> Diagnosis of Methionine/Valine Variant Creutzfeldt-Jakob Disease by Protein Misfolding Cyclic Amplification
Volume 24, Number 7—July 2018 Dispatch
Monday, April 20, 2020
PRION2020 POSTPONED TO 2021 – DUE TO CORONAVIRUS (COVID-19)
MONDAY, AUGUST 26, 2019
Creutzfeldt Jakob Disease CJD, TSE, Prion, Surveillance Update August 2019
SUNDAY, MARCH 10, 2019
National Prion Disease Pathology Surveillance Center Cases Examined¹ Updated Feb 1, 2019 Variably protease-sensitive prionopathy VPSPr
***> In conclusion, sensory symptoms and loss of reflexes in Gerstmann-Sträussler-Scheinker syndrome can be explained by neuropathological changes in the spinal cord. We conclude that the sensory symptoms and loss of lower limb reflexes in Gerstmann-Sträussler-Scheinker syndrome is due to pathology in the caudal spinal cord. <***
***> The clinical and pathological presentation in macaques was mostly atypical, with a strong emphasis on spinal cord pathology.<***
***> The notion that CWD can be transmitted orally into both new-world and old-world non-human primates asks for a careful reevaluation of the zoonotic risk of CWD. <***
***> All animals have variable signs of prion neuropathology in spinal cords and brains and by supersensitive IHC, reaction was detected in spinal cord segments of all animals.<***
***> In particular the US data do not clearly exclude the possibility of human (sporadic or familial) TSE development due to consumption of venison. The Working Group thus recognizes a potential risk to consumers if a TSE would be present in European cervids.'' Scientific opinion on chronic wasting disease (II) <***
THURSDAY, JANUARY 30, 2020
Docket Number: FDA-2012-D-0307 Recommendations to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease by Blood and Blood Components; Draft Guidance for Industry Draft Guidance for Industry Singeltary Submission
FRIDAY, JANUARY 31, 2020
CJD TSE Prion Blood Products, iatrogenic transmission, Confucius is confused again, WHAT IF? Docket Number: FDA-2012-D-0307
Updated April 3, 2020
Year Total Referrals² Prion Disease Sporadic Familial Iatrogenic vCJD
1999 & earlier 381 230 200 27 3 0
2000 145 102 90 12 0 0
2001 209 118 110 8 0 0
2002 241 144 124 18 2 0
2003 259 160 137 21 2 0
2004 316 181 164 16 0 1³
2005 327 178 156 21 1 0
2006 365 179 159 17 1 2⁴
2007 374 210 191 19 0 0
2008 384 221 205 16 0 0
2009 397 231 210 20 1 0
2010 401 246 218 28 0 0
2011 392 238 214 24 0 0
2012 413 244 221 23 0 0
2013 416 258 223 34 1 0
2014 355 208 185 21 1 1⁵
2015 401 263 243 20 0 0
2016 396 277 248 29 0 0
2017 375 266 247 19 0 0
2018 309 223 204 18 1 0
2019 416 270 240 21 0 0
2020 84 56 21 2 0 0
TOTAL 73566 45037 40108 4349 13 4
1Listed based on the year of death or, if not available, on the year of referral;
2Cases with suspected prion disease for which brain tissue was submitted;
3Disease acquired in the United Kingdom;
4Disease acquired in the United Kingdom in one case and in Saudi Arabia in the other;
5Disease possibly acquired in a Middle Eastern or Eastern European country;
6Includes 14 cases in which the diagnosis is pending, and 19 inconclusive cases;
7Includes 42 (9 from 2019, 33 from 2020) cases with type determination pending in which the diagnosis of vCJD has been excluded.
8The sporadic cases include 3906 cases of sporadic Creutzfeldt-Jakob disease (sCJD), 69 cases of Variably Protease-Sensitive Prionopathy (VPSPr) and 35 cases of sporadic Fatal Insomnia (sFI).
9Total does not include 272 Familial cases diagnosed by blood test only.
Monday, February 3, 2020
Informing Patient Contacts About Iatrogenic Creutzfeldt Jakob Disease
terry
posted by Terry S. Singeltary Sr. at
11:49 AM
