Human prion disease surveillance in Spain, 1993-2018: an overview.

In Spain, human transmissible spongiform encephalopathies (TSEs) have been undergoing continuous surveillance for over 25 years. In 1995, the system was launched as an EU Concerted Action, with EU surveillance network procedures being incorporated from 2002 onwards. The aim of this report was to describe performance and outcomes of this surveillance system across the period 1993-2018. Neurology and public health specialists from every region reported cases to a central hub at the Carlos III Health Institute, Madrid. In all, eight accidentally transmitted cases and five definite variant Creutzfeldt-Jakob disease (vCJD) patients were reported. All vCJD cases were diagnosed between 2005 and 2008. Two of these were family/dietary-related and spatially linked to a third. Yearly incidence of sporadic CJD per million was 1.25 across the period 1998-2018, and displayed a north-south gradient with the highest incidence in La Rioja, Navarre and the Basque Country. Genetic TSEs were observed to be clustered in the Basque Country, with a 4-fold incidence over the national rate. A total of 120 (5.6%) non-TSE sporadic, conformational, rapidly progressing neurodegenerative and vascular brain disorders were reported as suspect CJD. We conclude that TSEs in Spain displayed geographically uneven, stable medium incidences for the sporadic and genetic forms, a temporal and spatial family cluster for vCJD, and decreasing numbers for dura-mater-associated forms. The vCJD surveillance, framed within the EU network, might require continuing to cover all prion disorders. There is need for further strategic surveillance research focusing on case definition of rapid-course, conformational encephalopathies and surgical risk.

Risk of transmission of sporadic Creutzfeldt-Jakob disease by surgical procedures: systematic reviews and quality of evidence.

BACKGROUND: Sporadic Creutzfeldt-Jakob disease (sCJD) is potentially transmissible to humans. OBJECTIVE: This study aimed to summarise and rate the quality of the evidence of the association between surgery and sCJD. DESIGN AND METHODS: Firstly, we conducted systematic reviews and meta-analyses of case-control studies with major surgical procedures as exposures under study. To assess quality of evidence, we used the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Secondly, we conducted a systematic review of sCJD case reports after sharing neurosurgical instruments. RESULTS: Thirteen case-control studies met the inclusion criteria for the systematic review of case-control studies. sCJD was positively associated with heart surgery, heart and vascular surgery and eye surgery, negatively associated with tonsillectomy and appendectomy, and not associated with neurosurgery or unspecified major surgery. The overall quality of evidence was rated as very low. A single case-control study with a low risk of bias found a strong association between surgery conducted more than 20 years before disease onset and sCJD. Seven cases were described as potentially transmitted by reused neurosurgical instruments. CONCLUSION: The association between surgery and sCJD remains uncertain. Measures currently recommended for preventing sCJD transmission should be strongly maintained. Future studies should focus on the potential association between sCJD and surgery undergone a long time previously.

Etiologic Framework for the Study of Neurodegenerative Disorders as Well as Vascular and Metabolic Comorbidities on the Grounds of Shared Epidemiologic and Biologic Features.

BACKGROUND: During the last two decades, protein aggregation at all organismal levels, from viruses to humans, has emerged from a neglected area of protein science to become a central issue in biology and biomedicine. This article constitutes a risk-based review aimed at supporting an etiologic scenario of selected, sporadic, protein-associated, i.e., conformational, neurodegenerative disorders (NDDs), and their vascular- and metabolic-associated ailments. METHODS: A rationale is adopted, to incorporate selected clinical data and results from animal-model research, complementing epidemiologic evidences reported in two prior articles. FINDINGS: Theory is formulated assuming an underlying conformational transmission mechanism, mediated either by horizontal transfer of mammalian genes coding for specific aggregation-prone proteins, or by xeno-templating between bacterial and host proteins. We build a few population-based and experimentally-testable hypotheses focusing on: (1) non-disposable surgical instruments for sporadic Creutzfeldt-Jakob disease (sCJD) and other rapid progressive neurodegenerative dementia (sRPNDd), multiple system atrophy (MSA), and motor neuron disease (MND); and (2) specific bacterial infections such as B. pertussis and E. coli for all forms, but particularly for late-life sporadic conformational, NDDs, type 2 diabetes mellitus (T2DM), and atherosclerosis where natural protein fibrils present in such organisms as a result of adaptation to the human host induce prion-like mechanisms. CONCLUSION: Implications for cohort alignment and experimental animal research are discussed and research lines proposed.

Guillain-Barré syndrome following the 2009 pandemic monovalent and seasonal trivalent influenza vaccination campaigns in Spain from 2009 to 2011: outcomes from active surveillance by a neurologist network, and records from a country-wide hospital discharge database.

BACKGROUND: Studies have shown a slight excess risk in Guillain-Barré syndrome (GBS) incidence associated with A(H1N1)pdm09 vaccination campaign and seasonal trivalent influenza vaccine immunisations in 2009-2010. We aimed to assess the incidence of GBS as a potential adverse effect of A(H1N1)pdm09 vaccination. METHODS: A neurologist-led network, active at the neurology departments of ten general hospitals serving an adult population of 4.68 million, conducted GBS surveillance in Spain in 2009-2011. The network, established in 1996, carried out a retrospective and a prospective study to estimate monthly alarm thresholds in GBS incidence and tested them in 1998-1999 in a pilot study. Such incidence thresholds additionally to observation of GBS cases with immunisation antecedent in the 42 days prior to clinical onset were taken as alarm signals for 2009-2011, since November 2009 onwards. For purpose of surveillance, in 2009 we updated both the available centres and the populations served by the network. We also did a retrospective countrywide review of hospital-discharged patients having ICD-9-CM code 357.0 (acute infective polyneuritis) as their principal diagnosis from January 2009 to December 2011. RESULTS: Among 141 confirmed of 148 notified cases of GBS or Miller-Fisher syndrome, Brighton 1-2 criteria in 96 %, not a single patient was identified with clinical onset during the 42-day time interval following A(H1N1)pdm09 vaccination. In contrast, seven cases were seen during a similar period after seasonal campaigns. Monthly incidence figures did not, however, exceed the upper 95 % CI limit of expected incidence. A retrospective countrywide review of the registry of hospital-discharged patients having ICD-9-CM code 357.0 (acute infective polyneuritis) as their principal diagnosis did not suggest higher admission rates in critical months across the period December 2009-February 2010. CONCLUSIONS: Despite limited power and underlying reporting bias in 2010-2011, an increase in GBS incidence over background GBS, associated with A(H1N1)pdm09 monovalent or trivalent influenza immunisations, appears unlikely.

Drivers: A Biologically Contextualized, Cross-Inferential View of the Epidemiology of Neurodegenerative Disorders.

BACKGROUND: Sutherland et al. (2011) suggested that, instead of risk factors for single neurodegenerative disorders (NDDs), there was a need to identify specific "drivers", i.e., risk factors with impact on specific deposits, such as amyloid-ß, tau, or α-synuclein, acting across entities. OBJECTIVES AND METHODS: Redefining drivers as "neither protein/gene- nor entity-specific features identifiable in the clinical and general epidemiology of conformational NDDs (CNDDs) as potential footprints of templating/spread/transfer mechanisms", we conducted an analysis of the epidemiology of ten CNDDs, searching for patterns. RESULTS: We identified seven potential drivers, each of which was shared by at least two CNDDs: 1) an age-at-exposure-related susceptibility to Creutzfeldt-Jakob disease (CJD) and several late-life CNDDs; 2) a relationship between age at onset, survival, and incidence; 3) shared genetic risk factors for CJD and late-life CNNDs; 4) partly shared personal (diagnostic, educational, behavioral, and social risk factors) predating clinical onset of late-life CNDDs; 5) two environmental risk factors, namely, surgery for sporadic CJD and amyotrophic lateral sclerosis, and Bordetella pertussis infection for Parkinson's disease; 6) reticulo-endothelial system stressors or general drivers (andropause or premenopausal estrogen deficiency, APOEɛ4, and vascular risk factors) for late-life CNDDs such as dementia/Alzheimer's disease, type-2 diabetes mellitus, and some sporadic cardiac and vascular degenerative diseases; and 7) a high, invariant incidence ratio of sporadic to genetic forms of mid- and late-life CNDDs, and type-2 diabetes mellitus. CONCLUSION: There might be a systematic epidemiologic pattern induced by specific proteins (PrP, TDP-43, SOD1, α-synuclein, amyloid-ß, tau, Langerhans islet peptide, and transthyretin) or established combinations of these.

Comparative Incidence of Conformational, Neurodegenerative Disorders.

BACKGROUND: The purpose of this study was to identify incidence and survival patterns in conformational neurodegenerative disorders (CNDDs). METHODS: We identified 2563 reports on the incidence of eight conditions representing sporadic, acquired and genetic, protein-associated, i.e., conformational, NDD groups and age-related macular degeneration (AMD). We selected 245 papers for full-text examination and application of quality criteria. Additionally, data-collection was completed with detailed information from British, Swedish, and Spanish registries on Creutzfeldt-Jakob disease (CJD) forms, amyotrophic lateral sclerosis (ALS), and sporadic rapidly progressing neurodegenerative dementia (sRPNDd). For each condition, age-specific incidence curves, age-adjusted figures, and reported or calculated median survival were plotted and examined. FINDINGS: Based on 51 valid reported and seven new incidence data sets, nine out of eleven conditions shared specific features. Age-adjusted incidence per million person-years increased from ≤1.5 for sRPNDd, different CJD forms and Huntington's disease (HD), to 1589 and 2589 for AMD and Alzheimer's disease (AD) respectively. Age-specific profiles varied from (a) symmetrical, inverted V-shaped curves for low incidences to (b) those increasing with age for late-life sporadic CNDDs and for sRPNDd, with (c) a suggested, intermediate, non-symmetrical inverted V-shape for fronto-temporal dementia and Parkinson's disease. Frequently, peak age-specific incidences from 20-24 to ≥90 years increased with age at onset and survival. Distinct patterns were seen: for HD, with a low incidence, levelling off at middle age, and long median survival, 20 years; and for sRPNDd which displayed the lowest incidence, increasing with age, and a short median disease duration. INTERPRETATION: These results call for a unified population view of NDDs, with an age-at-onset-related pattern for acquired and sporadic CNDDs. The pattern linking age at onset to incidence magnitude and survival might be explained by differential pathophysiological mechanisms associated with specific misfolded protein deposits.

Towards an age-dependent transmission model of acquired and sporadic Creutzfeldt-Jakob disease.

INTRODUCTION: Sporadic Creutzfeldt-Jakob disease (sCJD) might be transmitted by surgery. The purpose of this study was to investigate potential susceptibility to sCJD from surgery at juvenile age and in early adulthood. METHODS: From Danish and Swedish national registries we identified 167 definite and probable sCJD cases with onset from 1987 through 2003, and 835 age-, sex- and residence-matched controls along with their surgical histories. Main, anatomically or etiologically classified surgical procedures followed by a ≥20-year lag were analyzed using logistic regression, and stratified by age at first-registered surgical discharge. RESULTS: The risk of having a diagnosis of CJD depended strongly on age at first surgery with odds ratio (OR) of 12.80 (95% CI 2.56-64.0) in patients <30 years, 3.04 (95% 1.26-7.33) in 30-39 years, and 1.75 (95% CI 0.89-3.45) in ≥40 years, for anatomically classified surgical procedures. Similar figures were obtained for etiologically classified surgical procedures. CONCLUSIONS: Risk of surgical-acquired sCJD depends on age at exposure; this pattern is similar to age-specific profiles reported for CJD accidentally transmitted by human pituitary-derived growth hormone and susceptibility curves for variant CJD estimated after adjustment for dietary exposure to bovine spongiform encephalopathy. There might be an age-at-exposure-related susceptibility to acquire all CJD forms, including sCJD from routine surgery.

Sensitivity to biases of case-control studies on medical procedures, particularly surgery and blood transfusion, and risk of Creutzfeldt-Jakob disease.

BACKGROUND: Evidence of risk of Creutzfeldt-Jakob disease (CJD) associated with medical procedures, including surgery and blood transfusion, is limited by susceptibility to bias in epidemiological studies. METHODS: Sensitivity to bias was explored using a central-birth-cohort model using data from 18 case-control studies obtained after a review of 494 reports on medical procedures and risk of CJD, systematic for the period January 1, 1989 to December 31, 2011. RESULTS: The validity of the findings in these studies may have been undermined by: recall; control selection; exposure assessment in life-time periods of different duration, out of time-at-risk of effect, or asymmetry in case/control data; and confounding by concomitant blood transfusion at the time of surgery. For sporadic CJD (sCJD), a history of surgery or blood transfusion was associated with risk in some, but not all, recent studies at a ≥10 year lag time, when controls were longitudinally sampled. Space-time aggregation of surgical events was not seen. Surgery at early clinical onset might be overrepresented among cases. Neither surgical history nor blood transfusion unlabelled for donor status, dental treatments or endoscopic examinations were linked to variant CJD (vCJD). CONCLUSIONS: These results indicate the need for further research. Common challenges within these studies include access to and content of past medical/dental treatment records for diseases with long incubation periods.

Producción científico-profesional española sobre discapacidad según el modelo CIF. Revisión de la literatura, 2001-2011 / Scientific-professional production on the ICF disability model in Spain. A literature review (2001-2010)

Objetivos: Cuantificar la utilización de la Clasificación Internacional del Funcionamiento, Discapacidad y Salud (CIF) en España a partir de publicaciones, y compararla con la de otros países europeos. Métodos: Revisión de la literatura relativa a publicaciones periódicas nacionales e internacionales con participación de investigadores españoles, desde mayo de 2001 hasta junio de 2010. Resultados: Se encontraron 47 publicaciones, con un incremento anual reciente de las de lengua inglesa. Predominaron las publicaciones periódicas teóricas (53,1%) y las especialidades de revistas de salud mental, rehabilitación y discapacidad, con medio o bajo factor de impacto. El 27,6% utilizan el instrumento WHODAS-II. Son más frecuentes los estudios en adultos con enfermedad mental. En relación a otros países europeos, y por referencias Medline, España ocupa el quinto lugar. Conclusiones: Esta revisión sugiere que la aplicación efectiva de la CIF en España es limitada, aunque rápidamente creciente la de carácter científico, referida sobre todo al marco conceptual y diagnóstico en distintos contextos clínicos, de rehabilitación y poblacionales, con escasa aplicación en servicios y una considerable incardinación internacional (AU)

Objectives: To quantify the use of the International Classification of Functioning, Disability and Health (ICF) in Spain on the basis of published reports, and to compare this use with that in other European countries. Methods: We reviewed the scientific literature published by, or with the participation of, authors having Spanish institutional affiliations in Spanish or international journals between May 2001 and June 2010. Results: A total of 47 papers were identified, with a recent annual increase in those published in English. There was a predominance of theoretical journals (53.1%) and those specializing in mental health, rehabilitation and disability, with a medium or low impact factor. The World Health Organization-Disability Assessment Schedule (WHODAS-II) was used in 27.6% of publications. Most studies addressed adult populations with mental illness. Spain ranked midway in the table of European countries (fifth by Medline references). Conclusions: This review suggests that the effective application of the ICF in Spain is limited but is increasing and is internationally co-ordinated. The main fields of application are theoretical and diagnostic, in various clinical, rehabilitation and population-based contexts and, to a much lesser extent, in health services (AU)

[Scientific-professional production on the ICF disability model in Spain. A literature review (2001-2010)]. / Producción científico-profesional Española sobre discapacidad según el modelo CIF. Revisión de la literatura, 2001-2011.

OBJECTIVES: To quantify the use of the International Classification of Functioning, Disability and Health (ICF) in Spain on the basis of published reports, and to compare this use with that in other European countries. METHODS: We reviewed the scientific literature published by, or with the participation of, authors having Spanish institutional affiliations in Spanish or international journals between May 2001 and June 2010. RESULTS: A total of 47 papers were identified, with a recent annual increase in those published in English. There was a predominance of theoretical journals (53.1%) and those specializing in mental health, rehabilitation and disability, with a medium or low impact factor. The World Health Organization-Disability Assessment Schedule (WHODAS-II) was used in 27.6% of publications. Most studies addressed adult populations with mental illness. Spain ranked midway in the table of European countries (fifth by Medline references). CONCLUSIONS: This review suggests that the effective application of the ICF in Spain is limited but is increasing and is internationally co-ordinated. The main fields of application are theoretical and diagnostic, in various clinical, rehabilitation and population-based contexts and, to a much lesser extent, in health services.