Amplification techniques and diagnosis of prion diseases.

Protein misfolding cyclic amplification assay (PMCA) and real-time quaking-induced conversion (RT-QuIC) are two amplification techniques based on the ability of PrPsc to induce a conformational change in PrP allowing the detection of minute amounts of PrPsc in body fluids or tissues. PMCA and RT-QuIC have different ability to amplify PrPsc from sporadic, variant and genetic forms of Creutzfeldt-Jakob disease (CJD). PMCA readily amplifies PrPsc from variant CJD (vCJD) tissue while RT-QuIC easily amplifies PrPsc from sporadic CJD (sCJD) patient tissues. In terms of diagnosis, this implies the possibility of distinguishing vCJD from sCJD and explains the wider use of RT-QuIC given the respective frequencies of vCJD and sCJD. The sensitivity values of RT-QuIC for the diagnosis of sCJD are comparable or higher than those of the other tests (EEG, MRI, detection of 14-3-3 or tau proteins in cerebrospinal fluid) but with a specificity close to 100%. These new diagnostic methods could also be useful for the diagnosis of other neurodegenerative diseases.

[Is Parkinson's disease a prion disease?]. / La maladie de Parkinson est-elle une maladie à prion?

The accumulation of a specific protein in aggregated form is a common phenomenon in human neurodegenerative diseases. In Parkinson's disease, this protein is α-synuclein which is a neuronal protein of 143 amino acids. With a monomeric conformation in solution, it also has a natural capacity to aggregate into amyloid structures (dimers, oligomers, fibrils and Lewy bodies or neurites). It therefore fulfils the characteristics of a prion protein (different conformations, seeding and spreading). In vitro and in vivo experimental evidence in transgenic and wild animals indicates a prion-like propagation of Parkinson's disease. The sequential and predictive distribution of α-synuclein demonstrated by Braak et al. and its correlation with non-motor signs are consistent with the prion-like progression. Although the triggering factor causing the misfolding and aggregation of the target protein is unknown, Parkinson's disease is a highly relevant model for the study of these mechanisms and also to test specific treatments targeting the assemblies of α-synuclein and propagation from pre-motor phase of the disease. Despite this prion-like progression, there is currently no argument indicating a risk of human transmission of Parkinson's disease.

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.

[Prion diseases or transmissible spongiform encephalopathies]. / Les maladies à prions ou encéphalopathies spongiformes transmissibles.

Prion diseases or transmissible spongiform encephalopathies (TSEs) are human and animal diseases naturally or experimentally transmissible with a long incubation period and a fatal course without remission. The nature of the transmissible agent remains debated but the absence of a structure evoking a conventional microorganism led Stanley B. Prusiner to hypothesize that it could be an infectious protein (proteinaceous infectious particle or prion). The prion would be the abnormal form of a normal protein, cellular PrP (PrPc) which will change its spatial conformation and be converted into scrapie prion protein (PrPsc) with properties of partial resistance to proteases, aggregation and insolubility in detergents. No inflammatory or immune response are detected in TSEs which are characterized by brain damage combining spongiosis, neuronal loss, astrocytic gliosis, and deposits of PrPsc that may appear as amyloid plaques. Although the link between the accumulation of PrPsc and the appearance of lesions remains debated, the presence of PrPsc is constant during TSE and necessary for a definitive diagnosis. Even if they remain rare diseases (2 cases per million), the identification of kuru, at the end of the 1950s, of iatrogenic cases in the course of the 1970s and of the variant of Creutzfeldt-Jakob disease (CJD) in the mid-1990s explain the interest in these diseases but also the fears they can raise for public health. They remain an exciting research model because they belong both to the group of neurodegenerative diseases with protein accumulation (sporadic CJD), to the group of communicable diseases (iatrogenic CJD, variant of CJD) but also to the group of genetic diseases with a transmission Mendelian dominant (genetic CJD, Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia).

Quantification of surviving cerebellar granule neurones and abnormal prion protein (PrPSc) deposition in sporadic Creutzfeldt-Jakob disease supports a pathogenic role for small PrPSc deposits common to the various molecular subtypes.

AIMS: Neuronal death is a major neuropathological hallmark in prion diseases. The association between the accumulation of the disease-related prion protein (PrP(Sc) ) and neuronal loss varies within the wide spectrum of prion diseases and their experimental models. In this study, we investigated the relationships between neuronal loss and PrP(Sc) deposition in the cerebellum from cases of the six subtypes of sporadic Creutzfeldt-Jakob disease (sCJD; n=100) that can be determined according to the M129V polymorphism of the human prion protein gene (PRNP) and PrP(Sc) molecular types. METHODS: The numerical density of neurones was estimated with a computer-assisted image analysis system and the accumulation of PrP(Sc) deposits was scored. RESULTS: The scores of PrP(Sc) immunoreactive deposits of the punctate type (synaptic type) were correlated with neurone counts - the higher the score the higher the neuronal loss - in all sCJD subtypes. Large 5- to 50-µm-wide deposits (focal type) were found in sCJD-MV2 and sCJD-VV2 subtypes, and occasionally in a few cases of the other studied groups. By contrast, the highest scores for 5- to 50-µm-wide deposits observed in sCJD-MV2 subtype were not associated with higher neuronal loss. In addition, these scores were inversely correlated with neuronal counts in the sCJD-VV2 subtype. CONCLUSIONS: These results support a putative pathogenic role for small PrP(Sc) deposits common to the various sCJD subtypes. Furthermore, the observation of a lower loss of neurones associated with PrP(Sc) type-2 large deposits is consistent with a possible 'protective' role of aggregated deposits in both sCJD-MV2 and sCJD-VV2 subtypes.

Updated clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease.

Several molecular subtypes of sporadic Creutzfeldt-Jakob disease have been identified and electroencephalogram and cerebrospinal fluid biomarkers have been reported to support clinical diagnosis but with variable utility according to subtype. In recent years, a series of publications have demonstrated a potentially important role for magnetic resonance imaging in the pre-mortem diagnosis of sporadic Creutzfeldt-Jakob disease. Magnetic resonance imaging signal alterations correlate with distinct sporadic Creutzfeldt-Jakob disease molecular subtypes and thus might contribute to the earlier identification of the whole spectrum of sporadic Creutzfeldt-Jakob disease cases. This multi-centre international study aimed to provide a rationale for the amendment of the clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease. Patients with sporadic Creutzfeldt-Jakob disease and fluid attenuated inversion recovery or diffusion-weight imaging were recruited from 12 countries. Patients referred as 'suspected sporadic Creutzfeldt-Jakob disease' but with an alternative diagnosis after thorough follow up, were analysed as controls. All magnetic resonance imaging scans were assessed for signal changes according to a standard protocol encompassing seven cortical regions, basal ganglia, thalamus and cerebellum. Magnetic resonance imaging scans were evaluated in 436 sporadic Creutzfeldt-Jakob disease patients and 141 controls. The pattern of high signal intensity with the best sensitivity and specificity in the differential diagnosis of sporadic Creutzfeldt-Jakob disease was identified. The optimum diagnostic accuracy in the differential diagnosis of rapid progressive dementia was obtained when either at least two cortical regions (temporal, parietal or occipital) or both caudate nucleus and putamen displayed a high signal in fluid attenuated inversion recovery or diffusion-weight imaging magnetic resonance imaging. Based on our analyses, magnetic resonance imaging was positive in 83% of cases. In all definite cases, the amended criteria would cover the vast majority of suspected cases, being positive in 98%. Cerebral cortical signal increase and high signal in caudate nucleus and putamen on fluid attenuated inversion recovery or diffusion-weight imaging magnetic resonance imaging are useful in the diagnosis of sporadic Creutzfeldt-Jakob disease. We propose an amendment to the clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease to include findings from magnetic resonance imaging scans.

[Epidemiological surveillance of Creutzfeldt-Jakob in France]. / Le réseau de surveillance de la maladie de Creutzfeldt-Jakob.

INTRODUCTION: Transmissible spongiform encephalopathies (TSE) have been under epidemiological surveillance in France and in Europe since the early 1990s. The observation of iatrogenic Creutzfeldt-Jakob disease (CJD), the outbreak of bovine spongiform encephalopathy (ESB) and its probable transmission to many species gave rise to the surveillance which remains warranted by the emergence of a variant of CJD (vCJD), in 1996. STATE OF ART: In France, epidemiological surveillance is coordinated by the InVS which receives input from cases notifications addressed to INSERM Unit 708 directly by clinicians or more often following requests for 14-3-3 detection in CSF. All suspected cases are followed up until a final diagnosis is established. Thanks to the effectiveness of the French network of neuropathology, autopsies are performed in more than half of patients who die with a diagnosis of suspected CJD. Diagnostic criteria allow comparison of the incidence of the different forms of the disease in all countries with a system of surveillance. Sporadic CJD is the most frequent form of the disease with more than 80% of the cases. Its origin remains unknown. To date, cases of iatrogenic CJD referred to the French surveillance network have been caused by dura mater grafts or human growth hormone treatments administrated in the 1980s. Ten percent of TSE are of genetic origin with an autosomic dominant transmission of a mutation or an insertion located on the PRNP gene. The most recent form of the disease is vCJD which is a new form, first described in the United Kingdom in 1994. PROSPECT AND CONCLUSION: Active epidemiological surveillance remains a timely issue, particularly in France, because of the development of new cases of iatrogenic CJD after human growth hormone treatment. It is of importance in France and worldwide because of the emergence of post-transfusional cases of vCJD and the possible appearance of vCJD in persons with valine-valine or methionine-valine genotypes at codon 129.

Tonic spinal cord stimulation as therapeutic option in Parkinson disease with axial symptoms: Effects on walking and quality of life.

Spinal cord stimulation (SCS) is an effective surgical therapy used for the treatment of chronic neuropathic pain. Tonic SCS is safe and improve not only gait disorders, motor symptoms, but also quality of life in Parkinson patients even with dopa-resistant symptoms with or without associated deep brain stimulation.

Mixing pro- and antisaccades in patients with parkinsonian syndromes.

Prosaccades and antisaccades were investigated in three groups of patients with parkinsonian syndromes, Parkinson's disease, corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), and in a control group. Saccade tasks were performed in single-task blocks (i.e. either blocks of prosaccades or blocks of antisaccades) and in mixed-task blocks (i.e. in blocks of randomly interleaved pro- and antisaccades). Saccade latencies and directional errors (misdirected saccades) were analysed in each subject, and we concentrated more specifically on the comparison of error rates in single tasks and in repeated trials of mixed tasks (i.e. mixing costs). The performance of each group in single tasks was largely consistent with previous studies, with normal antisaccade error rates in Parkinson's disease and CBD patients and increased antisaccade error rates in PSP patients. In contrast, a double dissociation was observed in mixed tasks. Parkinson's disease and CBD patients showed a marked increase in prosaccade and antisaccade error rates in repeated trials of mixed tasks, illustrated by increased mixing costs, whereas PSP patients showed similar error rates in single and repeated trials of mixed tasks, i.e. normal mixing costs. These results demonstrate that: (i) antisaccade performances may be differentially affected in mixed tasks and single tasks; (ii) the region of the dorsolateral prefrontal cortex which is crucial for reflexive saccade inhibition does not seem to be involved in the additional processes required in mixed-task conditions; (iii) the study of interleaved pro- and antisaccades may increase the accuracy of the differential diagnosis between these parkinsonian syndromes.

Desafíos y estrategias para mantenerse físicamente activo ante la pandemia de Covid-19: Revisión del tema / Challenges and strategies to stay physically active in the face of COVID-19 pandemic: A review

SUMMARY The pandemic caused by the COVID-19 has influenced peoples' lifestyles. Home-confinement scenario might impair physical activity practice, resulting in new challenges for maintaining health during the pandemic of the COVID-19. The aim of this study was to present the current context of COVID-19 pandemic, its impact on the practice of physical activity, and the strategies available to remain active during home-confinement according to international recommendations. The narrative review was conducted based on studies that analyzed themes related to physical activity and COVID-19. Virtual Health Library (VHL), CINAHL, Cochrane, PsycINFO, PubMed, ScienceDirect, Scientific Electronic Library Online (SciELO), Scopus, SPORTDiscus, and Web of Science databases were searched for relevant papers. Although an increased number of experimental studies are still necessary, people should devote more time to physical activity during social isolation. Guidelines were adjusted by international entities in order to encourage people to remain active, through practice regular physical activity, using alternative strategies such as fitness program applications, exergames, online exercise classes, and even chores. Reduction of prolonged sedentary behavior could contribute to maintain health and improve quality of life during the COVID-19 pandemic.

La pandemia provocada por la Covid-19 ha influido en los estilos de vida de las personas. El escenario de confinamiento domiciliario podría perjudicar la práctica de actividad física, generando nuevos desafíos para el mantenimiento de la salud durante la pandemia de la Covid-19. El objetivo de este estudio fue presentar el contexto actual de la pandemia de Covid-19, su impacto en la práctica de actividad física y las estrategias disponibles para mantenerse activo durante el confinamiento domiciliario según las recomendaciones internacionales. La revisión narrativa se realizó con base en estudios que analizaron temas relacionados con la actividad física y la Covid-19. Se realizaron búsquedas de artículos relevantes en las bases de datos Virtual Health Library (BVS), CINAHL, Cochrane, PsycINFO, PubMed, ScienceDirect, Scientific Electronic Library Online (SciELO), Scopus, SPORTDiscus y Web of Science. Aunque todavía es necesario un mayor número de estudios experimentales, las personas deberían dedicar más tiempo a la actividad física durante el aislamiento social. Las pautas fueron ajustadas por entidades internacionales para alentar a las personas a mantenerse activas, mediante la práctica de actividad física regular, utilizando estrategias alternativas como aplicaciones de programas de acondicionamiento físico, exergames, clases de ejercicios en línea e incluso tareas domésticas. La reducción del sedentarismo prolongado podría contribuir a mantener la salud y mejorar la calidad de vida durante la pandemia de Covid-19.

Neuropsychological Assessment of Older Adults With Virtual Reality: Association of Age, Schooling, and General Cognitive Status.

The development of neuropsychological assessment methods using virtual reality (VR) is a valid and promising option for the detection of cognitive impairment in the older people, focusing on activities composed of tasks of multiple demands. This study verified the association of age, schooling, and general cognitive status on the performance of neurologically healthy older adults in ECO-VR, a VR task of multiple demands for neuropsychological assessment. A total of 111 older adults answered a sociodemographic questionnaire, the Mini Mental State Examination, the Vocabulary subtest of the Wechsler Intelligence Scale for Adults (third edition), and the ECO-VR. Correlation analyses, multiple linear regression, and comparisons between groups (effects by age and schooling groups) were used to evaluate the results. The ECO-VR total score was significantly associated with age, years of education, MMSE, and Vocabulary subtest. The linear regression models identified that age was the main predictor for total score and rule breaking of ECO-VR. According to the univariate analysis, it was identified the main effect of age group and schooling group in the total ECO-VR score, but there was no interaction effect. The results are discussed in order to understand the role of sociodemographic characteristics in the performance of older adults in a VR task of multiple demands. It was also verified the possibility use of VR for neuropsychological assessment of older adults.

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.

[Effects of Parkinson's disease on quality-of-life patients' spouses: a qualitative survey]. / Impact de la maladie de Parkinson sur la qualité de vie des conjoints de patients. Une étude qualitative.

INTRODUCTION: Spouses play a major role as care givers for their partners with Parkinson's disease. This de facto part of family nursing turns out to be so demanding that they often feel isolated. While spouses may have access to financial and technical aids, but no specific psychological support is available to assist them in coping with the difficulties they have to face. Supporting and educating spouses thus appears today to be a real need. METHODS: Wishing to create an appropriate support program responding to the needs and expectancies of spouses of Parkinson's disease, we conducted a study designed to measure the effects of Parkinson's disease on spouses' quality-of-life and identify the priority needs in terms of information and support. This study included the spouses of 14 patients who participated in semi-directive individual interviews and a focus group. RESULTS: The data collected shows that spouses experience great disarray when faced with the disease. Their perception of Parkinson's disease has a strong anxiogenic effects. Caring for their spouse on a day to day basis creates a permanent atmosphere of stress with an insecure feeling generating tensions and major frustrations. Most of the spouses do not allow themselves any break and are overwhelmed with ambivalent feelings. They experience a kind of hostility towards their spouse and at the same time feel guilty for their attitude and also for their helplessness. The disease also leads to an impoverishment of the couples' social network, due to reduced autonomy and fear of other people's way of looking at them. CONCLUSION: Our study confirms the usefulness of organizing an educational support program for these spouses who often feel very lonely and helpless when confronted with their partner's disease.

[vCJD epidemiology in France]. / Epidémiologie de la variante de la maladie de Creutzfeldt-Jakob en France.

Variant Creutzfeldt-Jakob disease (vCJD) is the only form of prion diseases linked to bovine spongiform encephalopathy (BSE). The disease was first described in the United-Kingdom (UK) and France is the second affected country with 21 cases. Clinical, genetic and neuropathological features are the same in both countries. Comparison of the total number of cases in France and in the UK, according to dates of onset, shows that, in France, the maximum incidence seems to be five years delayed and that, in the UK, the number of vCJD cases regularly decreases since 1999. Delayed exposure to contaminated beef products in France compared to the UK could explain this temporal gap. Three cases of vCJD after transfusion of labile blood products were observed in the UK. No such of cases were observed in France but three patients developing signs of vCJD in 2004 were blood donors. A total of 42 recipients were identified with 17 recipients still alive.

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.

What is the accuracy of the clinical diagnosis of multiple system atrophy? A clinicopathologic study.

BACKGROUND: The presentation of symptoms for multiple system atrophy (MSA) varies. Because there are no specific markers for its clinical diagnosis, the diagnosis rests on the results of the neuropathologic examination. Despite several clinicopathologic studies, the diagnostic accuracy for MSA is unknown. OBJECTIVES: To determine the accuracy for the clinical diagnosis of MSA and to identify, as early as possible, those features that would best predict MSA. DESIGN: One hundred five autopsy-confirmed cases of MSA and related disorders (MSA [n=16], non-MSA [n=89]) were presented as clinical vignettes to 6 neurologists (raters) who were unaware of the study design. Raters identified the main clinical features and provided a diagnosis based on descriptions of the patients' first and last clinic visits. METHODS: Interrater reliability was evaluated with the use of kappa statistics. Raters' diagnoses and those of the primary neurologists (who followed up the patients) were compared with the autopsy-confirmed diagnoses to estimate the sensitivity and positive predictive values at the patients' first and last visits. Logistic regression analysis was used to determine the best predictors to diagnose MSA. RESULTS: For the first visit (median, 42 months after the onset of symptoms), the raters' sensitivity (median, 56%; range, 50%-69%) and positive predictive values (median, 76%; range, 61%-91%) for the clinical diagnosis of MSA were not optimal. For the last visit (74 months after the onset of symptoms), the raters' sensitivity (median, 69%; range, 56%-94%) and positive predictive values (median, 80%; range, 77%-92%) improved. Primary neurologists correctly identified 25% and 50% of the patients with MSA at the first and last visits, respectively. False-negative and -positive misdiagnoses frequently occurred in patients with Parkinson disease and progressive supranuclear palsy. Early severe autonomic failure, absence of cognitive impairment, early cerebellar symptoms, and early gait disturbances were identified as the best predictive features to diagnose MSA. CONCLUSIONS: The low sensitivity for the clinical diagnosis of MSA, particularly among neurologists who followed up these patients in the tertiary centers, suggests that this disorder is underdiagnosed. The misdiagnosis of MSA is usually due to its confusion with Parkinson disease or progressive supranuclear palsy, thus compromising the research on all 3 disorders.

Accuracy of the clinical diagnoses of Lewy body disease, Parkinson disease, and dementia with Lewy bodies: a clinicopathologic study.

BACKGROUND: Whether Parkinson disease (PD) and dementia with Lewy bodies (DLB) represent 2 distinct nosologic entities or are diverse phenotypes of Lewy body disease is subject to debate. OBJECTIVES: To determine the accuracy of the diagnoses of Lewy body disease, PD, and DLB by validating the clinical diagnoses of 6 neurologists with the neuropathologic findings and to identify early predictors of the diagnoses. METHODS: Six raters who were unaware of the neuropathologic diagnoses analyzed 105 clinical vignettes corresponding to 29 cases of Lewy body disease (post hoc analysis of 15 patients with PD and 14 with DLB) and 76 patients without PD or DLB whose cases were confirmed through autopsy findings. MAIN OUTCOME MEASURES: Sensitivity and positive predictive value (PPV) were chosen as validity measures and the K statistic as a reliability measure. RESULTS: Interrater reliability for the diagnoses of Lewy body disease and PD was moderate for the first visit and substantial for the last, whereas agreement for diagnosis of DLB was fair for the first visit and slight for the last. Median sensitivity for diagnosis of Lewy body disease was 56.9% for the first visit and 67.2% for the last; median PPV was 60.0% and 77.4%, respectively. Median sensitivity for the diagnosis of PD was 73.3% for the first visit and 80.0% for the last; median PPV was 45.9% and 64.1%, respectively. Median sensitivity for the diagnosis of DLB was 17.8% for the first visit and 28.6% for the last; median PPV was 75.0% for the first visit and 55.8% for the last. The raters' results were similar to those of the primary neurologists. Several features differentiated PD from DLB, predicted each disorder, and could be used as clinical pointers. CONCLUSIONS: The low PPV with relatively high sensitivity for the diagnosis of PD suggests overdiagnosis. Conversely, the extremely low sensitivity for the diagnosis of DLB suggests underdiagnosis. Although the case mix included in the study may not reflect the frequency of these disorders in practice, limiting the clinical applicability of the validity measures, the raters' results were similar to those of the primary neurologists who were not exposed to such limitations. Overall, our study confirms features suggested to predict these disorders, except for the early presence of postural imbalance, which is not indicative of either disorder.

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.