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.

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%).

Antibodies to axonal neurofilaments in Creutzfeldt-Jakob disease and other organic dementias.

Antibodies reacting with neurofilament proteins were detected by indirect immunofluorescence in the sera from 6 out of 10 patients with verified Creutzfeldt-Jakob disease (CJD), in 4 out of 8 cases of Alzheimer's disease (AD), in a variable percentage (29.4-42.8%) of sera from patients (n = 46) with other dementias of organic or infectious origin and in 5 out of 30 asymptomatic relatives of CJD patients. The occurrence of this antibody did not correlate with the duration or with any other clinical manifestation of CJD. The applicability of the test as differential-diagnostic marker appears limited. The later development of CJD and mental or nervous disease in 3 of 5 asymptomatic relatives with positive serological reaction suggest that the method although nonspecific, may be of certain value in the search for persons at higher risk to develop a degenerative disorder of CNS.

Phenothiazine-induced alterations of immune response in experimental tick-borne encephalitis: morphological model analysis of events.

The depressive effect of trifluoperazine (TFP), a phenothiazine derivative, on the morphology of the development of immune response (IR) (humoral and cell-mediated component) was studied in mice given tick-borne encephalitis (TBE) virus, sheep red blood cells (SRBC) or the BCG vaccine. This effect was manifested by a decrease in the mitotic activity of lymphocytes and in the number of blastic transformations after antigenic stimulation. In virus-infected and TFP-given mice, lowered levels of specific virus neutralizing antibody (VNA), together with a pronounced reduction of the inflammatory response in the brain were found. No signs of cytotoxicity following administration of the drug were observed. The mechanism of the immunodepressive action of TFP are discussed.

A live vaccine against tick-borne encephalitis; integrated studies, H. Histopathology of mice peripherally immunized with E5 "14" virus and challenged with virulent virus.

Histopathological changes in the central nervous and lymphoid systems were semiquantitatively analyzed in subadult mice (M) peripherally immunized with the live, highly attenuated E5 "14" virus from the tick-born encephalitis (TE) complex and in immunized M subjected to virulent challenge. The E5 "14" clone possesses an exceedingly restricted neuroinvasivity. A study of the sc marker, refined and extended by microscopic examinations seems to present a more relevant approach for comparative investigations on TE virus virulence. Morphological findings in immunized M given immunosuppressive doses of cyclophosphamide (CPA) suggest that the high efficiency of live vaccines may be related to the prolonged antigenic stimulation.

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.

Transmissible virus dementia. II. Neurohistology of three, geographically clustered cases of Creutzfeldt-Jakob disease.

Histopathological findings in three temporo-spatially linked cases of Creutzfeldt-Jakob disease (CJD) are reported. The patients were males, unrelated and without positive family history. Their mean age at the onset of the disease was 52.3 years. The mean duration of the illness was 6.6 months; the clinical symptomatology differed considerably. Neurohistology revealed in all patients a neuronal loss, intracyoplasmic vacuolation, spongiosis and astrocytosis. Besides the cortical regions, basal ganglia and cerebella were severely affected. All cases were pathologically suggestive of the cortico-striato-cerebella variant of CJD. Attention is drawn to this apparent topical similarity of most pronounced lesions. The possible significance of the pathoanatomical consistency, observed in the cases studied, for the unusual pattern of natural occurrence of CJD is considered.

Autoantibodies against neurofilaments in Creutzfeldt-Jakob disease: immunofluorescence in sections of human caudate nucleus.

Heterospecific autoantibodies to axonal neurofilaments of neurons in sera from five patients with Creutzfeldt-Jakob disease were detected with the use of cryostat section from normal human brain caudate nucleus. The antibody, visualized by the indirect immunofluorescence technique, was shown to bind complement. This allowed to achieve brighter staining either by the anticomplementary method alone or by a combination of both anti-C3 and anti-IgG conjugates

Transmissible virus dementia. I. An unusual space and time clustering of Creutzfeldt-Jakob disease and of other organic presenile dementia cases.

A peculiar grouping of Creutzfeldt-Jacob disease (CJD) and of other organic presenile dementia (OPD) cases in a small, prevalently rural area in Czechoslovakia to the east of 19 degrees 35' E and to the north of 48 degrees 15' N was studied. Between August, 1972 and November, 1976, three histologically proven CJD cases, bearing no sporadic of familial patterns, were observed. The distance between their dwellings was 13--17 km. In addition, seven cases of OPD were detected in the same area, two of them being suspected as possible CJD according to clinical evidence.

Early intrathecal production of specific IgM and IgG antibodies and alpha-interferon in herpes simplex virus encephalitis.

A complex approach was used in order to establish non-invasively the aetiology in three cases of encephalitis presumptively caused by herpes simplex virus (HSV). As indicative of brain HSV infection was considered the lowered serum to cerebrospinal fluid specific antibody ratio, which also assessed the humoral immune response within the CNS. For this purpose, during ongoing brain tissue infection, the early intrathecal (ITH) production of IgG and IgM antibodies was analysed by a differential enzyme-linked immunosorbent assay (ELISA) along with changing levels of complement-fixing (CF) antibodies in the serum and cerebrospinal fluid (CSF). Antiviral antibody (AA) response was markedly preceded by the appearance of alpha-interferon (IFN) in the serum and CSF. From the CNS biopsy and autopsy specimens one HSV-1 and one HSV-2 strain were recovered.

[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.)

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.)