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.

Compassionate use of quinacrine in Creutzfeldt-Jakob disease fails to show significant effects.

Quinacrine has been reported as an antiprion agent and proposed as an immediately applicable treatment for Creutzfeldt-Jakob disease (CJD). The authors report the results of an open compassionate procedure to which 32 CJD patients had access. In some genotypic subgroups, a slight but nonsignificant increase in survival was observed, likely due to biased inclusion of long-term surviving patients. There was no pathologic evidence of a beneficial effect of quinacrine treatment.

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.

A French cluster of Creutzfeldt-Jakob disease: a molecular analysis.

We report the molecular and phenotypic analysis of a French cluster of three cases of Creutzfeldt-Jakob disease (CJD), two of them occurring in 1998 in the same village and the other in 1995 in a neighboring village. Analyses of the occurrence of these events in a close area with less than 3000 inhabitants over the 1992-1999 notification period confirmed that they are rare. This could be explained either by a common source of contamination or by the coincidental occurrence of either sporadic or genetic CJD. We applied genetic analysis and brain PrPres typing to explore these CJD cases. The three patients did not carry any mutation in their prion protein gene coding sequence. All were homozygous for methionine at the polymorphic codon 129. Brain tissue was available from two cases that died in 1998. The two patients showed different PrPres profiles on Western blot and distinct clinico-pathological features. These findings do not support the conclusion that in these three cases, CJD was acquired from a unique source of contamination and suggest that concurrent occurrence of sporadic CJD accounted for this CJD cluster.

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.

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.

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.

Trends in mortality from sporadic Creutzfeldt-Jakob disease in France 1992-7.

This study examined trends in mortality from sporadic Creutzfeldt-Jakob disease in France for 1992-7 by age, genotype at the codon 129 of the prion protein gene, and geographical area. Case ascertainment was based on notifications by neurologists, neuropathologists, and laboratories; 324 deaths from definite or probable Creutzfeldt-Jakob disease were registered during the study period. The yearly number of deaths increased significantly between 1992 and 1997. The rise was higher for older age groups. It was also higher in those who were homozygous for valine compared with other genotypes. Eighteen departments (geographical administrative areas) out of 95 showed a significant increase in the number of deaths from sporadic Creutzfeldt-Jakob disease. Intensive epidemiological surveillance is a likely explanation for the apparent increase in the number of sporadic cases of Creutzfeldt-Jakob disease over the 1992-7 period, particularly in older age groups and in departments with low mortality rate at the beginning of the study period. Intensive surveillance may also have led to a better identification of atypical valine homozygous cases.

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.

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.

Prominent psychiatric features and early onset in an inherited prion disease with a new insertional mutation in the prion protein gene.

In five generations of the French M-E kindred, 11 members are now known to be or have been affected by a form of spongiform encephalopathy previously recorded as Gerstmann-Sträussler-Scheinker disease. Mean age at onset was 28 years (range 21-34 years). In six instances, these patients were hospitalized in psychiatric institutions with various diagnoses, the most frequent being mania or mania-like symptoms. Dementia occurred progressively after a lengthy course. Histological studies showed atrophy of the cerebellar molecular layer, which contained kuru and multicentric plaques labelled with anti-prion protein antibodies. Spongiosis was not prominent and remained largely limited to the periphery of plaques; it was more marked in the thalamus, where plaques were scarce. A 192 base pair (bp) insert (eight extra repeats of 24 bp) in the octapeptide coding region of the prion protein gene (PRNP) within a codon-129 methionine allele was found in four symptomatic subjects. Early age at onset, the prominence of psychiatric symptoms and the long course of the disease are noticeable clinical features in this family with an inherited prion disease due to a new insertional mutation in PRNP.

[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.

14-3-3 protein, neuron-specific enolase, and S-100 protein in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease.

We explored simultaneously 14-3-3 protein, neuron-specific enolase (NSE), and one astroglial protein, S-100, recently proposed as Creutzfeld-Jakob disease (CJD) markers, in the cerebrospinal fluid (CSF) of 129 patients with suspected CJD. Cutoff values for NSE and S-100 were established at 25 and 2.5 ng/ml, respectively. The highest sensitivity was observed for S-100 (94.2%) followed by 14-3-3 (89.8%) and NSE (79.7%), while the highest specificity in CJD diagnosis was obtained with 14-3-3 protein (100%) as compared with NSE (91.5%) and S-100 (85.4%). No influence of sex, genotype at codon 129 of the prion protein gene, time between sampling, and death or disease duration has been found. Based on 90 cases initially referred as 'probable' or 'possible' CJD, with 14-3-3, NSE, or S-100 we could correctly discriminate between 'CJD' or 'non-CJD' categories in 94.4, 86.5, and 90% of the cases, respectively. When limited to 'possible CJD' cases, diagnosis based on one of the three CSF proteins was accurate in 98, 90.7 and 87.3%, respectively. In view of the fact that the CSF 14-3-3 protein test alone has the highest specificity and good sensitivity, it appears that there is no additional advantage at the moment to include NSE and/or S-100 protein in the exploration of clinically suspected CJD cases.

Multiple sclerosis in North African migrants to France.

Among some 7500 respondents with known place of birth who had completed a nationwide questionnaire survey for multiple sclerosis (MS) in France in 1986, there were 260 born in former French North Africa (Algeria, Morocco, Tunisia). They had migrated to France between 1923 and 1986, but 66% came between 1956 and 1964. Two-thirds were from Algeria, where virtually the entire European population had emigrated in 1962 at the end of the Algerian war for independence. The migrants were younger at prevalence day (mean 43.4 years) and at onset (29.4 years) than the French-born MS (46.6; 31.3 years). Eight migrants lacked age information. The 225 migrants with onset more than 1 year after immigration presumably acquired their MS in France. They provided an age adjusted (US 1960) MS prevalence rate 1.54 times that for all France. If the latter is taken at 50 per 100,000 population their estimated adjusted rate is 76.8 with 95% confidence interval of 67.1 to 87.5. The other 27 with presumed acquisition in North Africa gave an estimated adjusted prevalence of 16.6 per 100,000 (95% CI 10.9-24.1). For those migrants with acquisition in France there was a mean interval of 13 years between immigration or age 11 and clinical onset, with a minimum of 3 years. This series provides further support for the theses: 1) that MS is primarily an environmental disease acquired after childhood; 2) that acquisition requires prolonged or repeated exposure (here 3 years for these medium-to-high MS risk migrants) followed by a prolonged latent or incubation period between acquisition and symptom onset (here 10 years); and 3) that this disease is most likely a widespread but unknown persistent infection which results in clinical MS in only a small proportion of those affected.

[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.