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.

Identification of three novel mutations (E196K, V203I, E211Q) in the prion protein gene (PRNP) in inherited prion diseases with Creutzfeldt-Jakob disease phenotype.

Inherited prion diseases are characterized by mutations in the PRNP gene encoding the prion protein (PrP). As the other sporadic or infectious prion disease forms, they are almost all characterized by the accumulation in the brain of an abnormal misfolded form of the patient's PrP. Brain extracts can often transmit the disease once inoculated in a recipient animal. Inherited prion diseases with Creutzfeldt-Jakob disease (CJD) phenotype are autosomal forms, although sporadic cases have been reported. We report three novel mutations of the PRNP gene in unrelated patients with clinical and histopathologic features of CJD. The three mutations were missense: c635G>A (E196K), c656G>A (V203I) and c680G>C (E211Q). Familial history of neurologic disorders was evidenced for patients carrying the E196K and E211Q mutations. E196K would be predicted to have more severe effects on protein stability than V203I and E211Q. These mutations expand the spectrum of mutations in PRNP and reduce the proportion of CJD patients in whom genetic alterations have not been found.

Diagnosis of Creutzfeldt-Jakob disease: effect of clinical criteria on incidence estimates.

OBJECTIVE: To assess the effect of usage of three different versions of Creutzfeldt-Jakob disease (CJD) diagnostic criteria on estimates of CJD incidence. METHODS: A total of 428 patients referred for suspected sporadic CJD between 1991 and 1997 were classified according to different criteria to be compared after analysis of medical records. Specificity, sensitivity, and positive and negative predictive values were calculated for each set of criteria in the subgroup of patients with a postmortem examination. Positive and negative predictive values of the clinical diagnosis were applied to cases without postmortem examination. Subsequently, the true number of cases of CJD among the referred cases was estimated. RESULTS: By comparison with the French and European study criteria, the Masters' criteria showed higher sensitivity but lower specificity and positive predictive value. Comparison with an estimate of the true total number of CJD cases showed that Masters' criteria overestimated the incidence by 7%, whereas the French and the European study criteria led to an underestimate of 12%. Detection of the 14-3-3 protein in CSF, considered as an additional diagnostic criterion for clinically probable CJD, resulted in a slight increase in the estimated incidence when the French or European study criteria were applied. CONCLUSIONS: Different diagnostic criteria could lead to an under- or overestimation of the true incidence of CJD. Therefore, comparisons of CJD incidence in different countries should rely on diagnostic classifications using identical criteria. Taking into account 14-3-3 protein detection as a criterion for probable CJD will result in a small increase in the estimated CJD incidence.

Molecular genetics of prion diseases in France. French Research Group on Epidemiology of Human Spongiform Encephalopathies.

Human prion diseases are characterized by the accumulation in the brain of an abnormal form of the prion protein. Prion protein polymorphisms seem to play a key role in the pathogenesis of these diseases, probably by enhancing the amyloidogenic properties of the protein. We performed prion protein gene (PRNP) coding sequence analysis in 57 French subjects with Creutzfeldt-Jakob disease (CJD) and found a mutation of the PRNP coding sequence in nine subjects (15.8%); the mutation corresponded with a known family history of CJD in only three of these subjects. In 41 definite and probable cases without known PRNP mutations, codon 129 genotyping revealed an excess of the homozygous 129Met/Met genotype corresponding to a 3.4-fold increased risk of developing CJD when compared with the two other genotypes. We also found that the 129Val/Val genotype, which mainly governs susceptibility to iatrogenic CJD, does not seem to predispose to sporadic CJD.

Sporadic Creutzfeldt-Jakob disease and surgery: a case-control study using community controls.

BACKGROUND: The cause of sporadic Creutzfeldt-Jakob disease (CJD) is unknown. Previous studies found a link with a history of surgery but had methodologic problems. OBJECTIVE: To help elucidate medical and associated risk factors for sporadic CJD as part of the 1993 to 1995 European Union collaborative studies of CJD. METHODS: Medical and associated risk factors from 326 patients with sporadic CJD, taken from population-based studies performed between 1993 and 1995 in France, Germany, the Netherlands, and the UK, were compared with 326 community controls recruited by telephone in 2000. RESULTS: A history of surgery was significantly associated with the risk of sporadic CJD (odds ratio [OR]: 1.8; 95% CI: 1.2 to 2.6), which was not dependent on the number of surgical procedures, and was stronger in females (OR: 2.5; 95% CI: 1.5 to 4.0). Gynecologic (OR: 1.5; 95% CI: 1.0 to 2.3) and "other" operations (any operation other than neurologic, eye, ear, gallbladder, gastrointestinal, and gynecologic operations, tonsillectomy, and appendectomy) (OR: 1.5; 95% CI: 1.1 to 2.1) were associated with risk of CJD. Tonsillectomy (OR: 0.3; 95% CI: 0.2 to 0.5) and appendectomy (OR: 0.6; 95% CI: 0.4 to 0.8) were observed less frequently in cases. An increased risk was also found with a history of ear piercing in females (OR: 1.6; 95% CI: 1.1 to 2.5) and psychiatric visit(s) (OR: 2.6; 95% CI: 1.5 to 4.3). CONCLUSIONS: These results support the hypothesis that cases of sporadic CJD may result from hitherto unrecognized surgical contamination events. However, because of the limits of the study design, the rarity of the disease, and the potential for bias, the results should be interpreted with caution.

Neuropathologic variants of sporadic Creutzfeldt-Jakob disease and codon 129 of PrP gene.

OBJECTIVES: To determine the contribution of methionine/valine (Met/Val) polymorphism at codon 129 of the prion protein (PrP) gene in the neuropathologic pattern and mechanisms of lesion development in sporadic Creutzfeldt-Jakob disease. BACKGROUND: Creutzfeldt-Jakob disease is a transmissible spongiform encephalopathy characterized by a conformational change of PrP and a variety of PrP deposits in the brain, some of which aggregate into amyloid plaques. METHODS: The authors semiquantitatively assessed neuropathologic lesions and performed PrP immunolabeling in 70 patients (39 Met/Met, 11 Met/Val, 20 Val/Val) who had died in France between 1994 and 1998. RESULTS: Met/Met cases (mild lesions mostly involving the occipital areas, low PrP load, few focal PrP nonamyloid deposits, no amyloid plaques) contrasted with Met/Val cases (marked lesions especially in the parahippocampal gyrus, high PrP load, numerous amyloid plaques) and with Val/Val cases (younger patients, longer course of disease: 11.5 +/- 3 months, and distinct neuropathology: severe lesions heavily involving the hippocampal formation and basal ganglia, high PrP load, numerous focal nonamyloid deposits, rare amyloid plaques). The course of Val/Val patients younger than age 55 was particularly long (19.9 +/- 7 months), and the isocortex bore the brunt of the pathology, suggesting a distinct variety. CONCLUSIONS: Polymorphism at codon 129 modulates the phenotype of sporadic Creutzfeldt-Jakob disease. The Val genotype enhances the production of proteinase-resistant PrP, and the Met/Val genotype facilitates its aggregation into amyloid plaques.

Dementia with Lewy bodies in a neuropathologic series of suspected Creutzfeldt-Jakob disease.

Discriminating Creutzfeldt-Jakob disease (CJD) from dementia with Lewy bodies (DLB) may be clinically difficult to achieve. The authors describe 10 patients with DLB initially referred to the French Network of Human Spongiform Encephalopathies as having suspected CJD. In a series of 465 autopsied cases, DLB ranked second among degenerative alternative diagnoses to CJD. The authors analyzed the factors that contributed to misleading the diagnosis, and suggest that the detection of 14-3-3 protein in CSF may be useful to distinguish CJD from DLB.

Analysis of EEG and CSF 14-3-3 proteins as aids to the diagnosis of Creutzfeldt-Jakob disease.

OBJECTIVE: To improve diagnostic criteria for sporadic Creutzfeldt-Jakob disease (CJD). METHODS: Pooled data on initial and final diagnostic classification of suspected CJD patients were accumulated, including results of investigations derived from a coordinated multinational study of CJD. Prospective analysis for a comparison of clinical and neuropathologic diagnoses and evaluation of the sensitivity and specificity of EEG and 14-3-3 CSF immunoassay were conducted. RESULTS: Data on 1,003 patients with suspected CJD were collected using a standard questionnaire. After follow-up was carried out, complete clinical data and neuropathologic diagnoses were available in 805 cases. In these patients, the sensitivity of the detection of periodic sharp wave complexes in the EEG was 66%, with a specificity of 74%. The detection of 14-3-3 proteins in the CSF correlated with the clinical diagnosis in 94% (sensitivity). The specificity (84%) was higher than that of EEG. A combination of both investigations further increased the sensitivity but decreased the specificity. CONCLUSIONS: Incorporation of CSF 14-3-3 analysis in the diagnostic criteria for CJD significantly increases the sensitivity of case definition. Amended diagnostic criteria for CJD are proposed.

European surveillance on Creutzfeldt-Jakob disease: a case-control study for medical risk factors.

Medical risk factors for Creutzfeldt-Jakob disease (CJD) were analyzed in a prospective ongoing case-control study based on European CJD surveillance. Detailed data on past and recent medical history were analyzed in 405 cases and controls matched by sex, age, and hospital. Data were correlated with polymorphism at codon 129 of the prion protein gene. Our analysis did not support a number of previously reported associations and failed to identify any common medical risk factor for CJD. Although not statistically significant, brain surgery was associated with an increased risk of CJD. A detailed medical history should be obtained in every suspected CJD case in order to identify iatrogenic sources of CJD.

Sleep, snoring and smoking in high school students.

The relationship between snoring, sleep and smoking was investigated in young students from a survey by self-administered questionnaire on sleep habits, conducted in high schools in the educational district of Lyons (France). Our sample consisted of 11,417 boys and 13,265 girls between 15 and 20 years of age. We found that 28.4% of girls and 38.8% of boys reported that they snored. In both sexes, snoring was associated with short (<7 h) and long (>10 h) sleep length, nocturnal awakenings and daytime sleepiness. Smoking was a risk factor for snoring. Multiple logistic regression showed that the odds-ratio for habitual snoring increased when tobacco consumption increased from a 1.30 (moderate smokers) to 2.26 (heavy smokers) in girls and from 1.38 to 2.09 in boys. This dose-effect relationship between smoking and snoring suggests that a substantial proportion of snoring cases is attributable to tobacco consumption in young students.

[Familial Alzheimer's disease: a study of HLA markers]. / Alzheimer familial: étude des marqueurs HLA.

We have studied HLA markers in family with 2 "Probable" and 2 "possible" cases of Alzheimer disease over 3 generations. Three of them (two brothers and the father) present A29 C-B12 DR2 haplotype. It seems that it exists an association between HLA system and Alzheimer disease but we cannot define the character of this genetic linkage; the study of many families and sporadic cases will allow to define it.

Scrapie in France: some possible predisposing factors in the naturally-acquired disease of sheep.

A nationwide survey of the occurrence of scrapie in France during the 12-year period 1968-1979 has shown the disease to be more widespread than previously thought. The data suggest that certain sheep raising practices, such as transhumance (nomadic grazing), pen and pasture alternations, and use of animals for milk production, may play a possible role in disease prevalence.

[Epidemiology of human diseases caused by unconventional transmissible agents]. / Epidémiologie des maladies humaines à agents transmissibles non conventionnels.

Human unconventional viruses infections are scarcely found with a worldwide occurrence below 1/million inhabitants. The disease would be induced by an interaction between the patient's genetic characteristics and environmental factors. No link has been found between the occurrence of the disease in man and the presence of the animal form of the disease, i.e. scrapie. The professional risk has been pointed out for people working with animals or in the medical sector. Most iatrogenic cases are subsequent to a growth hormone treatment. The other cases are associated with different medical and surgical acts. But the transmission by blood transfusion remains questionable and must be clearly demonstrated.

[Incidence of Creutzfeldt-Jakob disease in France, 1992-1995]. / Incidence de la maladie de Creutzfeldt-Jakob en France, 1992-1995.

BACKGROUND: Recent developments in animal and humans transmissible spongiform encephalopathies have motivated a study on incidence and risk factors of Creutzfeldt-Jakob disease (CJD) in France and 4 other European countries. METHODS: CJD cases were ascertained through a national network including 250 neurological departments or neuropathological laboratories. CJD cases were classified as definite, probable or possible. Overall incidence rate and age-standardized incidence rates by department were computed. Standardized incidence ratios and their 95% confidence intervals were computed for comparing observed and expected number of CJD cases in each department. RESULTS: Between 1992 and 1995, 216 CJD cases were registered (mean incidence rate: 0.87 per million inhabitants). The distribution of CJD cases was heterogeneous (p < 0.007). Nevertheless, the distribution of standardized incidence ratios fitted quite well a Poisson distribution. The observed number of CJD cases was significantly higher than expected in 4 departments and lower in 1 department. CONCLUSION: Incidence of CJD in France is similar to that observed in other European countries. Analysis of distribution of CJD cases by department showed a few significant differences which can be due to random fluctuations.

[Familial predisposition to multiple sclerosis]. / La prédisposition familiale à la sclérose en plaques.

Seven families were studied to evaluate the influence of genetic factors in MS and its transmissibility. The disease was associated with some B7 and/or DR2 alleles in relation to the susceptibility gene in all but one case. This association was always transmissible conjointly. The carrier haplotype conditions disease manifestations and its prognosis, favorable in this series, but it is not sufficient to promote the onset of the disease. This requires a triggering factor with sometimes disorders affecting 3 generations as demonstrated by the analysis of one family. Therefore there is not a genic heredity but a predisposition heredity. Possible associations of MS with other morbid states such as insulin-dependent diabetes must be considered when counselling families.

[A note on the epidemiology of Creutzfeldt-Jakob syndrome]. / Le point sur l'épidémiologie de la maladie de Creutzfeldt-Jakob.

The annual incidence of sporadic Jakob-Creuzfeldt disease has been stable for the last 30 years. The new variant affecting young adults which appeared in the United Kingdom (20 cases) and France (1 case) in 1994 is due to the same infectious agent which causes bovine spongiform encephalopathy. Epidemiological data are still insufficient for a precise prediction of epidemics of the new variant mainly due to the duration of the incubation period of the disease.

[Creutzfeldt-Jakob disease: diagnostic value of protein 14-3-3 and neuronal specific enolase assay in cerebrospinal fluid]. / Maladie de Creutzfeldt-Jakob: valeur diagnostique de la détection de la protéine 14-3-3 et du dosage de la NSE dans le liquide céphalo-rachidien.

We studied the diagnostic value of detecting protein 14-3-3 and of assaying neuronal specific enolase (NSE) in the cerebrospinal fluid of 150 patients with suspected sporadic Creutzfeldt-Jakob disease registered in an epidemiology research program between 1991 and 1996. Sensitivity and specificity of these two tests were high. This study confirms results reported earlier and authorizes a new definition of Creutzfeldt-Jakob disease which gives protein 14-3-3 the same diagnostic value as EEG recordings for classifying sporadic cases.

[A study network of human spongiform encephalopathies: 1st results]. / Réseau d'études des encéphalopathies spongiformes humaines: premiers résultats.

Several French teams including clinicians and researchers have created a group within the European network for the study of Creutzfeldt-Jakob disease and other human spongiform encephalopathies. The main objectives are to monitor the incidence of the disease and to search for possible risk factors with a case-control study. The diagnosis is based on neuropathological studies or the identification of an abnormal protein prion in cerebral fragments. The sequence of the gene encoding for the prion protein has was studied from blood or cerebral samples. The early results indicate that the incidence, mortality and clinical presentation remain relatively constant compared with earlier studies. Studying the expression of the 129 codon of the prion protein gene has led to the verification that homozygous methionine/methionine forms predominate in sporadic forms.

[Diseases transmitted by non-conventional agents ("prions"): nosology and diagnosis]. / Les maladies à agents transmissibles non conventionnels ("Prions"): nosologie et diagnostic.

Transmissible non conventional agents are currently called "Prions". This is not a neutral terminology: the attractive Prion hypothesis (the infectious agent being a protein able to replicate in the absence of DNA or RNA) due to Stanley Prusiner is the prevalent one, and has shown to be heuristic, but has not been formally proven and does not easily explain all the data, unless modified and expanded. No simple account has been given for the very unusual physical, chemical, and biological properties of non conventional agents. These infectious agents are associated with degenerative diseases of the nervous system that are either the consequence of a genetic mutation or develop spontaneously in apparently normal individuals, and then can be transmitted to various susceptible hosts, including man. Thus, non conventional agents cannot be considered only as fascinating biological enigmas. They constitute a challenge for public health. The changing characteristics of prion-associated diseases has led to a renewing of their clinical and neuropathological diagnostic criteria. A brief survey of the nosology and neuropathology of prions diseases, with emphasis on new data and on difficulties, is provided. A simple classification based on the familial, sporadic or infectious variety of the disease is suggested. Familial diseases can be named according to the genetic disorder. Sporadic and infectious diseases can be classified following the main clinical symptoms and signs, and the presence or absence of amyloid plaques in the brain, until new tools (analysis of the glycosylation pattern of PrP, strain recognition) allow a more precise nomenclature. The new epidemiology of Prion disorders allowed by these new approaches relies on a full study of Prion diseases affected patients, which necessarily involves their genetic study, and the analysis of brain tissue. This, for practical and ethical reasons, is better achieved by autopsy.

[Epidemiology of multiple sclerosis]. / Epidémiologie de la sclérose en plaques.

Multiple sclerosis is unevenly distributed throughout the world. Its prevalence depends on latitude: it decreases in each hemisphere from pole to equator. France is situated in a high prevalence zone, with 40 cases for 100,000 inhabitants. The prevalence of multiple sclerosis is modulated by risk factors unrelated to latitude; genetic susceptibility factors (HLA, Gm), as well as environmental, occupational, nutritional and infectious (notably viral) factors have been identified, but no conclusion can be drawn concerning their role in the aetiology and pathogenesis of the disease. Among the hypotheses that could put an end to this deadlock, the heterogeneity of multiple sclerosis must seriously be considered, and it might serve as a basis for further epidemiological studies benefiting from recent technological developments such as molecular genetics and magnetic resonance imaging.