Health professions and risk of sporadic Creutzfeldt-Jakob disease, 1965 to 2010.

In 2009, a pathologist with sporadic Creutzfeldt-Jakob Disease (sCJD) was reported to the Spanish registry. This case prompted a request for information on health-related occupation in sCJD cases from countries participating in the European Creutzfeldt Jakob Disease Surveillance network (EuroCJD). Responses from registries in 21 countries revealed that of 8,321 registered cases, 65 physicians or dentists, two of whom were pathologists, and another 137 healthcare workers had been identified with sCJD. Five countries reported 15 physicians and 68 other health professionals among 2,968 controls or non-cases, suggesting no relative excess of sCJD among healthcare professionals. A literature review revealed: (i) 12 case or small case-series reports of 66 health professionals with sCJD, and (ii) five analytical studies on health-related occupation and sCJD, where statistically significant findings were solely observed for persons working at physicians' offices (odds ratio: 4.6 (95 CI: 1.2-17.6)). We conclude that a wide spectrum of medical specialities and health professions are represented in sCJD cases and that the data analysed do not support any overall increased occupational risk for health professionals. Nevertheless, there may be a specific risk in some professions associated with direct contact with high human-infectivity tissue.

[Dynamics of the incidence of Creutzfeldt-Jakob disease in Slovakia in 1975-2008]. / Dynamika výskytu Creutzfeldtovej-Jakobovej choroby na Slovensku v rokoch 1975-2008.

The paper reports on Creutzfeldt-Jakob disease (CJD) occurrence in Slovakia in years 1975-2008. Changes in the incidence of this most important human prion disease, occurrence of individual forms of the classical CJD variant and the unique, unusually high proportion of genetic CJD are documented. Endo- and exogenous risk factors are analyzed, gaps in the prevention of iatrogenic infection are pointed out and the prophylaxis of genetic CJD is discussed.

CSF analysis in patients with sporadic CJD and other transmissible spongiform encephalopathies.

Patients with suspected Creutzfeldt-Jakob disease (CJD) often have routine cerebrospinal fluid (CSF) analysis performed to exclude treatable inflammatory conditions; however, little information is available about the range of results obtained for CSF tests in patients with sporadic CJD and other transmissible spongiform encephalopathies (TSE). Data from 450 patients with sporadic CJD and 47 patients with other TSEs were collected as part of an EC-supported multinational study. Raised white cell counts of >5 cells/microl were found in three of 298 patients with sporadic CJD, with two cell counts of 7 cells/microl and one of 20 cells/microl. Total protein concentrations of >0.9 g/l were found in five of 438 patients with sporadic CJD, although none had a concentration of >1 g/l. CSF oligoclonal IgG was detected in eight of 182 sporadic CJD patients. Of the patients with other TSEs, six had elevated cell counts ranging from 6 to 14 cells/microl but none had total protein concentrations of >0.9 g/l and one patient had detectable oligoclonal IgG. None of the patients with sporadic CJD or other TSEs had abnormalities in all three tests.

Determinants of diagnostic investigation sensitivities across the clinical spectrum of sporadic Creutzfeldt-Jakob disease.

To validate the provisional findings of a number of smaller studies and explore additional determinants of characteristic diagnostic investigation results across the entire clinical spectrum of sporadic Creutzfeldt-Jakob disease (CJD), an international collaborative study was undertaken comprising 2451 pathologically confirmed (definite) patients. We assessed the influence of age at disease onset, illness duration, prion protein gene (PRNP) codon 129 polymorphism (either methionine or valine) and molecular sub-type on the diagnostic sensitivity of EEG, cerebral MRI and the CSF 14-3-3 immunoassay. For EEG and CSF 14-3-3 protein detection, we also assessed the influence of the time point in a patient's illness at which the investigation was performed on the likelihood of a typical or positive result. Analysis included a large subset of patients (n = 743) in whom molecular sub-typing had been performed using a combination of the PRNP codon 129 polymorphism and the form of protease resistant prion protein [type 1 or 2 according to Parchi et al. (Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O, Zerr I, Budka H, Kopp N, Piccardo P, Poser S, Rojiani A, Streichemberger N, Julien J, Vital C, Ghetti B, Gambetti P, Kretzschmar H. Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 1999; 46: 224-233.)] present in the brain. Findings for the whole group paralleled the subset with molecular sub-typing data available, showing that age at disease onset and disease duration were independent determinants of typical changes on EEG, while illness duration significantly influenced positive CSF 14-3-3 protein detection; changes on brain MRI were not influenced by either of these clinical parameters, but overall, imaging data were less complete and consequently conclusions are more tentative. In addition to age at disease onset and illness duration, molecular sub-type was re-affirmed as an important independent determinant of investigation results. In multivariate analyses that included molecular sub-type, time point of the investigation during a patient's illness was found not to influence the occurrence of a typical or positive EEG or CSF 14-3-3 protein result. A typical EEG was most often seen in MM1 patients and was significantly less likely in the MV1, MV2 and VV2 sub-types, whereas VV2 patients had an increased likelihood of a typical brain MRI. Overall, the CSF 14-3-3 immunoassay was the most frequently positive investigation (88.1%) but performed significantly less well in the very uncommon MV2 and MM2 sub-types. Our findings confirm a number of determinants of principal investigation results in sporadic CJD and underscore the importance of recognizing these pre-test limitations before accepting the diagnosis excluded or confirmed. Combinations of investigations offer the best chance of detection, especially for the less common molecular sub-types such as MV2 and MM2.

Creutzfeldt-Jakob disease risk and PRNP codon 129 polymorphism: necessity to revalue current data.

The polymorphism at codon 129 (M129V) of the prion protein gene (PRNP) is a recognized genetic marker for susceptibility to Creutzfeldt-Jakob disease (CJD) in the Caucasians. The distribution of this polymorphism in healthy individuals provides an important starting point for the evaluation of CJD risk in the general population. Early studies of reference population cohorts demonstrated that methionine/valine heterozygosity was the most frequent genotype. These studies were performed in relatively small numbers of control subjects and do not correspond with the findings of more recent investigations. In this study, we present an analysis of the codon M129V distribution in 613 corneal donors, representing one of the largest control groups examined to date. Methionine homozygotes represented 48.1%, valine homozygotes 8.7% and methionine/valine heterozygotes 43.2%. While age-related difference was not significant, differentiation according to the gender showed significant difference. The observed highest proportion of methionine homozygotes and statistically significant difference between genders as well as comparison with results obtained in other countries underline the need to re-evaluate the generally used reference data on M129V, including consideration of the gender, age and geographical distribution.

Increased incidence of genetic human prion disease in Hungary.

The authors performed analysis of the prion protein gene (PRNP) in 27 out of 109 confirmed prion disease patients between 1994 and 2004. E200K mutation was found in 17 cases. Another 10 patients, lacking PRNP analysis, showed positive family history. The mean annual incidence (0.27/million) and proportion (25.6%) of genetic prion disease is unusually high in Hungary and might be related to the migration of ancestors from the Slovakian focus.

Mortality from Creutzfeldt-Jakob disease and related disorders in Europe, Australia, and Canada.

BACKGROUND: An international study of the epidemiologic characteristics of Creutzfeldt-Jakob disease (CJD) was established in 1993 and included national registries in France, Germany, Italy, the Netherlands, Slovakia, and the United Kingdom. In 1997, the study was extended to Australia, Austria, Canada, Spain, and Switzerland. METHODS: Data were pooled from all participating countries for the years 1993 to 2002 and included deaths from definite or probable CJD of all etiologic subtypes. RESULTS: Four thousand four hundred forty-one cases were available for analysis and included 3,720 cases of sporadic CJD, 455 genetic cases, 138 iatrogenic cases, and 128 variant cases. The overall annual mortality rate between 1999 and 2002 was 1.67 per million for all cases and 1.39 per million for sporadic CJD. Mortality rates were similar in all countries. There was heterogeneity in the distribution of cases by etiologic subtype with an excess of genetic cases in Italy and Slovakia, of iatrogenic cases in France and the UK, and of variant CJD in the UK. CONCLUSIONS: This study has established overall epidemiologic characteristics for Creutzfeldt-Jakob disease (CJD) of all types in a multinational population-based study. Intercountry comparisons did not suggest any relative change in the characteristics of sporadic CJD in the United Kingdom, and the evidence in this study does not suggest the occurrence of a novel form of human bovine spongiform encephalopathy infection other than variant CJD. However, this remains a possibility, and countries currently unaffected by variant CJD may yet have cases.

Predictors of survival in sporadic Creutzfeldt-Jakob disease and other human transmissible spongiform encephalopathies.

A collaborative study of human transmissible spongiform encephalopathies has been carried out from 1993 to 2000 and includes data from 10 national registries, the majority in Western Europe. In this study, we present analyses of predictors of survival in sporadic (n = 2304), iatrogenic (n = 106) and variant Creutzfeldt-Jakob disease (n = 86) and in cases associated with mutations of the prion protein gene (n = 278), including Gerstmann-Sträussler-Scheinker syndrome (n = 24) and fatal familial insomnia (n = 41). Overall survival for each disease type was assessed by the Kaplan-Meier method and the multivariate analyses by the Cox proportional hazards model. In sporadic disease, longer survival was correlated with younger age at onset of illness, female gender, codon 129 heterozygosity, presence of CSF 14-3-3 protein and type 2a prion protein type. The ability to predict survival based on patient covariates is important for diagnosis and counselling, and the characterization of the survival distributions, in the absence of therapy, will be an important starting point for the assessment of potential therapeutic agents in the future.

Creutzfeldt-Jakob disease with E200K mutation in Slovakia: characterization and development.

Creutzfeldt-Jakob disease (CJD), the most important human prion disease, occurs in sporadic, iatrogenic and familial form. Except Slovakia and Israel, the recorded familial cases have never exceeded 10-15%. In the Slovak CJD group 95 out of 136 CJD cases (74.2%) carried a CJD-specific mutation in the prion protein gene (PRNP) at codon 200 (mutation E200K). All CJD(E200K) patients carried a heterozygous E200K mutation within the alelle with methionine at codon 129. No more than 53.7% were typical familial cases. The penetrance of the E200K mutation in 1975-2000 was 59.5%. The distribution of codon 129 polymorphism showed 78.6% of methionine-homozygous and 21.4% of methionine/valine-heterozygous patients. Genetic analysis performed on 278 CJD patient relatives demonstrated the E200K mutation in 97 (34.8%) of healthy relatives tested. The E200K mutation carriers were methionine-homozygous in 64% and methionine/valine-heterozygous in 36%. The relatives without the mutation showed a 54.9% methionine homozygosity, 10.4% valine homozygosity and 34.7% methionine/valine heterozygosity. Analysis ofthe E200K carriers provided evidence that the methionine homozygosity is a CJD risk factor, more efficient in CJD patients than in asymptomatic relatives. Th influence of both the E200K mutation and methionine homozygosity at codon 129 was evident in the duration of the clinical stage of CJD and in the immunoreactivity pattern of PrP resistant to proteases (PrP(res)). In the CJD(E200K) methionine-homozygous patients the mean duration ofthe disease was significantly shorter (3.7 +/- 2.0 months) than in the methionine/valine-heterozygous patients (7.84 +/- 7.3 months). Comparison of the PrP(res) positivity in the cerebellum of familial and sporadic CJD using specific polyclonal and monoclonal antibodies (MAbs) to PrP showed less conspicuous immune reaction in CJD(E200K) cases. Methionine-homozygous CJD patients were characteristic mainly by synaptic pattern of staining, while methionine/valine-heterozygous patients by PrP(res) granules and plaque-like structures. Most of numerous plaque-like PrP(res) deposits were found in sporadic valine/valine-homozygous cases. Potential professional risk was excluded in health facility workers. The percentage of professions related to farming was significantly higher in CJD(E200K) (48%) and sporadic CJD (44%) cases as compared to the employed population (9%).

Creutzfeldt-Jakob disease in health professionals in Slovakia.

Creutzfeldt-Jakob disease (CJD) is the most important human transmissible spongiform encephalopathy (prion disease), recognised in sporadic, genetic but also iatrogenic forms. The identification of 8 health care workers in a group of 114 definitive CJD patients in Slovakia suggested the possibility of professionally acquired CJD and induced the investigation of potential endo- and exogenous risk factors. In CJD-affected health professionals special attention was paid to a detailed occupational history, including a possible professional contact with CJD patient and to the findings characteristic for iatrogenic CJD: early cerebellar symptomatology, long duration of the disease, absence of typical EEG finding and homozygosity of PRNP gene at codon 129. Analysis of epidemiological, clinical and molecular biological data in investigated group of CJD-affected health professionals gave no evidence of an occupational risk for CJD.

Creutzfeldt-Jakob disease risk in Slovak recipients of human pituitary growth hormone.

UNLABELLED: Creutzfeldt-Jakob disease (CJD) is a transmissible, fatal degenerative disorder of the CNS. CJD is known in a sporadic, familial and iatrogenic form. Iatrogenic form has been accidentally induced through corneal and dura mater transplantation or surgical procedures. The largest number of iatrogenic CJD developed in patients who had received human growth hormone (hGH). The minimal incubation period appears to be 4-15 years, the maximal 21-30 years after receiving hGh treatment. An increasing number of new CJD cases in hGH recipients in France, providing evidence of unusually long incubation period and an occurrence of genetically controlled (mutation E200K carrier) CJD-risk group in Slovak population induced this second investigation of hGh treated patients. The aim of this study is to verify whether the absence of CJD in hGH recipients in Slovakia reflects the actual epidemiological situation or a lack of informations. The objective of the study was to investigate signs of clinical manifestation of CJD and to perform molecular genetic study on prion protein (PrP) gene in hGh recipients. PATIENTS AND METHODS: 32 hGH treated patients (23 men and 9 women) at the age of 17-38 years were investigated. The occurrence of codon 200 (E200K) mutation and polymorphism at codon 129 of PrP gene was studied. RESULTS: Neurological, including cerebellar signs of CJD, intellectual or psychological changes were not observed in investigated patients. The shortest duration of hGH treatment was 2 years, the longest 9 years. The time interval since the beginning of hGH administration was 12-19 years. Restriction endonuclease analysis of the PrP gene revealed one patient with E200K mutation, 8 patients homozygous for methionin, 2 patients homozygous for valin and 16 heterozygous patients at codon 129. CONCLUSION: No evidence of CJD has been observed in investigated group of hGH recipients. Considering the long incubation period of hGH-induced CJD and the obtained results, clinical and genetic investigation on the whole relatively small group of Slovak hGH recipients is recommended. (Tab. 2, Fig. 1, Ref. 22.)

Descriptive epidemiology of Creutzfeldt-Jakob disease in six European countries, 1993-1995. EU Collaborative Study Group for CJD.

After the occurrence of bovine spongiform encephalopathy (BSE), there has been concern that transmission of BSE to the human population might result in a change in the epidemiological characteristics of Creutzfeldt-Jakob disease (CJD). A collaborative study of CJD in the European Union was performed from 1993 to 1995, to compare data from national registries for CJD in France, Germany, Italy, The Netherlands, Slovakia, and the United Kingdom. Five hundred seventy-five patients with definite or probable CJD died in the study period with an overall annual mortality rate of 0.71 cases per million. The incidence rates for CJD were similar in all participating countries despite variations in postmortem rates, and age-specific incidence rates were also relatively consistent, with the exception of an increased incidence of CJD in patients younger than 39 years of age in the United Kingdom. In relation to etiological subtypes of CJD, 87% of cases were sporadic, 8% genetic, and 5% iatrogenic. Genetic forms of CJD comprised 80% of all cases in Slovakia, and iatrogenic forms of CJD occurred most frequently in France and the United Kingdom. The statistical data reported here do not provide evidence of a causal link between BSE and CJD in Europe as a whole. However, the study has established baseline epidemiological parameters for CJD in participating European countries, which may be important in the assessment of any future change in the characteristics of CJD as a result of the epidemic of BSE.

[Transmissible spongiform encephalopathies: neuroinfections with unconventional immune reactions]. / Prenosné spongioformné encefalopatie: neuroinfekcie s nekonvencnými imunitnými reakciami.

Transmissible spongiform encephalopathies (TSE) as well as the properties of the major component of the infectious agent-prion, and the most important human and animal prion diseases are characterized. Considering the recent biochemical and molecular biological data, possible explanations of natural resistance, species barrier and lack of the immune response to the unconventional infectious particles are presented. Finally the importance of immunoblotting and immunostaining as the most specific confirmation of TSE diagnosis is underlined. (Ref. 11.)

SSPE in Slovakia: immunocytochemical study.

In a retrospective study of two patients from Slovakia with clinical, virological and histopathological diagnosis of subacute sclerosing panencephalitis (SSPE), measles virus antigen was detected by immunocytochemical labelling studies. The formalin fixed, paraffin-embedded thin brain sections labelled with anti-measles antibodies and avidin-biotin complex peroxidase were counterstained with haematoxylin. Only a single area of brain was examined in each patient: cerebellum and parietal lobe. Viral antigen positive reaction was identified within Purkinje cells and extending along dendritic processes in cerebellum, and also in oligodendrocytes of subparietal white matter.

Creutzfeldt-Jacob disease associated with the PRNP codon 200Lys mutation: an analysis of 45 families.

200Lys mutation in the human PRNP coding region has been identified in 45 of the 55 CJD-affected families thus far presented to our NIH laboratory. These codon 200Lys families have a total of 87 patients, and originate from 7 different countries: Slovakia, Poland, Germany, Tunisia, Greece, Libya, and Chile. Forty-seven patients were neuropathologically verified, and brain tissue from 14 patients transmitted disease to experimental primates. The mutation was found by direct sequencing in 4 patients, and it was detected by restriction endonuclease analysis with BsmA 1 and/or the single nucleotide extension reaction in 36 other patients and 45 of 109 first degree relatives (1 parent, 14 siblings, and 30 children). The mutation is associated with all known geographical clusters of CJD (Slovakia, Libyan Jews, Chile) in which the annual mortality rate is tens or hundreds of times higher than the world average of 1 per million. All patients originating from the cluster areas carried the mutation, but it was seen in only 1 of 103 unrelated control individuals from the same areas, and in none of 102 controls from other areas, indicating a strong association between the mutation and disease. The penetrance of the mutation was estimated to be 0.56. Branches of some families migrating from cluster areas to other countries continue to have CJD over several generations, suggesting that CJD in these families is a genetic disorder, in which the 200Lys mutation is responsible for the disease.

Some new aspects of CJD epidemiology in Slovakia.

Descriptive epidemiological and genealogical data obtained by prospective and retrospective studies on CJD in Slovakia and in patients emigrating from CJD clusters were analysed. Observations contradictory to an exclusively genetic etiology of temporo-spatial accumulation of CJD are presented. Data indicating a genetically increased susceptibility to the disease and its coincidence with environmental risk in clustering patients are discussed.

"Clusters" of CJD in Slovakia: the first statistically significant temporo-spatial accumulations of rural cases.

A space-time analysis of clustering among 78 definite CJD cases who died in Slovakia (75) and an adjacent part of Hungary (3) during 1972-1991 is presented. Two geographical rural accumulations of sporadic and familial CJD patients in the north and south of Central Slovakia were found. There was evidence of two significant clusters when spatial and temporal neighborhoods were defined by distances of 2,4,5 and 7 km within 1.5 and 2 years. Involvement of genetic mechanisms in the clusters was demonstrated, and the possible role of environmental (zoonotic) risk factors are considered.