Brain and other nervous system disorders across the lifespan - global challenges and opportunities.

This is an exciting time for scientific discovery that aims to reduce the frequency and impact of neurological, mental health and substance-use disorders. As it became increasingly clear that low- and middle-income countries have a disproportionate share of these disorders, and that many of the problems are best addressed by indigenous researchers who can seek context-sensitive solutions, the US National Institutes of Health and other research funders began to invest more in low- and middle-income country-focused research and research capacity-building to confront this significant public health challenge. In an effort to identify existing information, knowledge gaps, and emerging research and research capacity-building opportunities that are particularly relevant to low- and middle-income countries, in February 2014 the Center for Global Health Studies at the National Institutes of Health Fogarty International Center held a workshop to explore these issues with scientific experts from low- and middle-income countries and the United States. This evolved into the preparation of the Reviews in this supplement, which is designed to highlight opportunities and challenges associated with topical areas in brain-disorders research over the coming decade. This Introduction highlights some of the over-arching and intersecting priorities for addressing causes, prevention, treatment and rehabilitation as well as best practices to promote overall nervous system health. We review some brain disorders in low- and middle-income countries, while the Reviews describe relevant issues and the epidemiology of particular conditions in greater depth.

Costs explained by function rather than diagnosis--results from the SNAC Nordanstig elderly cohort in Sweden.

BACKGROUND: Because the prevalence of many brain disorders rises with age, and brain disorders are costly, the economic burden of brain disorders will increase markedly during the next decades. AIM: The purpose of this study is to analyze how the costs to society vary with different levels of functioning and with the presence of a brain disorder. METHODS: Resource utilization and costs from a societal viewpoint were analyzed versus cognition, activities of daily living (ADL), instrumental activities of daily living (IADL), brain disorder diagnosis and age in a population-based cohort of people aged 65 years and older in Nordanstig in Northern Sweden. Descriptive statistics, non-parametric bootstrapping and a generalized linear model (GLM) were used for the statistical analyses. RESULTS: Most people were zero users of care. Societal costs of dementia were by far the highest, ranging from SEK 262,000 (mild) to SEK 519,000 per year (severe dementia). In univariate analysis, all measures of functioning were significantly related to costs. When controlling for ADL and IADL in the multivariate GLM, cognition did not have a statistically significant effect on total cost. The presence of a brain disorder did not impact total cost when controlling for function. The greatest shift in costs was seen when comparing no dependency in ADL and dependency in one basic ADL function. CONCLUSION: It is the level of functioning, rather than the presence of a brain disorder diagnosis, which predicts costs. ADLs are better explanatory variables of costs than Mini mental state examination. Most people in a population-based cohort are zero users of care.

What does the developing brain tell us about neural diseases?

In a recently published report, the European Brain Council estimated that the annual cost of brain disorders is larger than the cost of all other disease areas combined, including cardiovascular diseases, cancer, and diabetes. The World Health Organization concluded that approximately one-third of the total burden of disease in Europe is attributable to brain disorders. Therefore, drug development for neural diseases should flourish and attract large pharmaceutical companies and smaller enterprises alike. However, this is far from being the case: industry is cutting down on research and investment in brain disorders in Europe. Political reasons may be contributing to this, but they do not constitute the only explanation. An important reason for the decreasing interest and investment is the lack of drug targets in neural diseases. In order to change this, greater efforts at understanding the etiologies and pathogenetic mechanisms of disorders of both the developing and the adult brain are required. We need to strengthen basic research to understand the brain in health and disease. A shift from translational to basic research is required to meet the need for drugs and therapies in the future. In support of this, I summarize some recent studies indicating that the developing brain has much to offer in this respect. The processes and genes involved in brain development are linked to the etiologies not only of neurodevelopmental but also of neurodegenerative diseases.

The economic cost of brain disorders in Europe.

BACKGROUND AND PURPOSE: In 2005, we presented for the first time overall estimates of annual costs for brain disorders (mental and neurologic disorders) in Europe. This new report presents updated, more accurate, and comprehensive 2010 estimates for 30 European countries. METHODS: One-year prevalence and annual cost per person of 19 major groups of disorders are based on 'best estimates' derived from systematic literature reviews by panels of experts in epidemiology and health economics. Our cost estimation model was populated with national statistics from Eurostat to adjust to 2010 values, converting all local currencies to Euros (€), imputing cost for countries where no data were available, and aggregating country estimates to purchasing power parity-adjusted estimates of the total cost of brain disorders in Europe in 2010. RESULTS: Total European 2010 cost of brain disorders was €798 billion, of which direct health care cost 37%, direct non-medical cost 23%, and indirect cost 40%. Average cost per inhabitant was €5.550. The European average cost per person with a disorder of the brain ranged between €285 for headache and €30 000 for neuromuscular disorders. Total annual cost per disorder (in billion € 2010) was as follows: addiction 65.7; anxiety disorders 74.4; brain tumor 5.2; child/adolescent disorders 21.3; dementia 105.2; eating disorders 0.8; epilepsy 13.8; headache 43.5; mental retardation 43.3; mood disorders 113.4; multiple sclerosis 14.6; neuromuscular disorders 7.7; Parkinson's disease 13.9; personality disorders 27.3; psychotic disorders 93.9; sleep disorders 35.4; somatoform disorder 21.2; stroke 64.1; and traumatic brain injury 33.0. CONCLUSION: Our cost model revealed that brain disorders overall are much more costly than previously estimated constituting a major health economic challenge for Europe. Our estimate should be regarded as conservative because many disorders or cost items could not be included because of lack of data.

Consensus document on European brain research.

Psychiatric and neurological diseases combined represent a considerable social and economic burden in Europe. A recent study conducted by the European Brain Council (EBC) quantified the 'cost and burden' of major brain diseases in Europe, amounting to €386bn per year. Considering that these costs will increase exponentially in the years to come due to ageing of the European population, it is necessary to act now in order to curb this increase and possibly reverse the trend. Thus, establishing a strong European platform supporting basic and clinical research in neuroscience is needed to confront the economic and social challenge posed by management of brain diseases in European countries. To setup a platform for discussion, EBC published in 2006 a Consensus Document on European Brain Research, describing needs and achievements of research in Europe and presenting proposals for future research programs. Since 2006, European research in neuroscience has advanced tremendously. The present document represents an update elaborated to reflect changes in research priorities and advances in brain research that have taken place since 2006. The same approach and format have been used here as in the previous version. Multinational and multidisciplinary teams have once again come together to express their views, not only on the current strengths in European research, but also on what needs to be done in priority, hoping that this update will inspire policy makers and stakeholders in directing funding for research in Europe.

Rapid, low-cost MR imaging protocol to document central nervous system and sinus abnormalities prior to pediatric hematopoietic stem cell transplantation.

Patients undergoing bone marrow transplant (BMT) are at risk for infectious complications, including those of the sinus. Central nervous system (CNS) abnormalities related to the chemotherapy or radiation that the patient received for the treatment of underlying malignancy or to transplant-related effects are also commonly seen. The only effective way to differentiate pre- and post-transplant causes is to have a baseline evaluation prior to the admission for transplant. The current method used to evaluate these patients is head CT. However, CT is not accurate to demonstrate CNS abnormalities and exposes the patient to radiation. MRI, despite better sensitivity for white matter abnormalities, has not been routinely used because of the higher cost and longer duration of the exam. Therefore, we designed a fast, low-cost and radiation-free MRI-based protocol to simultaneously evaluate sinus and brain abnormalities.

Electrolyte orders in the neuroscience intensive care unit: worth the value or waste?

BACKGROUND: To assess the value of the practice of obtaining frequent electrolyte measurements in patients with extended stay in a neuroscience intensive care unit (NICU). METHODS: We identified consecutive patients 18 years or older, admitted to the NICU between January 1 and July 31, 2009 with length of stay ≥ 5 days. We collected potassium, sodium, magnesium, ionized calcium, phosphorus laboratory measurements and hemoglobin levels, and recorded electrolyte replacement orders and red blood cell transfusions. Average laboratory costs were estimated. RESULTS: 93 patients were included in the study (54 men, mean age 54 years, range 18-85 years). Mean length of stay was 10.4 days (range 5-36 days). Sodium and potassium were the electrolytes most frequently measured (averages of 14.1 and 13.1 per patient, respectively). More than 75% of the results were within normal range for all electrolytes measured and critical values were extremely uncommon. The number of phlebotomies for electrolyte measurements was strongly associated with the degree of hemoglobin drop (P < 0.0001). Electrolyte panels were ordered much more often than individual electrolytes with average cost exceeding $2200 per patient. Replacing half of these electrolyte panels with single sodium or potassium orders would have resulted in savings greater than $100,000 in our population. CONCLUSIONS: Electrolytes measurements are very frequent in the NICU, but results are most often normal and only exceptionally critical. The phlebotomies required for these tests significantly worsen hemoglobin levels. A more conservative use of electrolyte measurements can result in reduction of blood loss and substantial cost savings.

Recent treatment patterns and variations for pediatric acute encephalopathy in Japan.

BACKGROUND: Treatments for pediatric acute encephalopathy are largely empiric with limited evidence to support. This study investigated recent trends in clinical practice patterns for pediatric acute encephalopathy at a national level. METHOD: Discharge records were extracted for children with acute encephalopathy for the fiscal years 2010-2015 using a national inpatient database in Japan. We ascertained the secular trends in medications, diagnostic and therapeutic procedures, healthcare costs, in-hospital mortality, and length of hospital stays (LOS), using mixed effect linear or logistic regression models. We also ascertained variations and clustering of the practice patterns across different hospitals using hierarchical cluster analyses. RESULTS: A total of 4692 eligible inpatients were identified. From 2010 to 2015, we observed increasing trends in hospitalization costs, corticosteroid and edaravone use and a decreasing trend in LOS. Despite changes in treatments, the rates of home respiratory support and in-hospital mortality were constant during the study period. Hierarchical cluster analyses showed that 6 hospital groups showed largely different therapeutic strategies to the same disease regardless of mortality rates. Hospitals with more intensive treatment practices were likely to have higher mortality, while hospitals with less intensive treatment practices were likely to have the lower mortality. However, hospitals in one group (group 1) had less intensive treatment practice even though they had the highest mortality. CONCLUSIONS: We provided novel insights into the recent trends in treatments for pediatric acute encephalopathy. Therapeutic strategies varied between hospitals, suggesting the importance of pursuing evidence-based treatment strategy and promoting standardized practices to pediatric acute encephalopathy.

Costs of brain disorders in Finland.

OBJECTIVE: To calculate the costs of brain disorders on the national level. METHODS: Electronic data bases, national registers and internet data. RESULTS: Any brain disorder was estimated to affect a fifth of the Finnish population. The three most common disorders were migraine, anxiety disorder and affective disorder. The total costs of brain disorders constituted 3% of the national gross product, or 45% of all the health-care costs. However, this is likely a conservative estimate, because not all chronic brain disorders and not all costs were included. Of the total costs of brain disorders, 32% were for direct health care, 23% for indirect medical care and 45% for indirect costs. Dementia was the most costly individual brain disorder followed by addiction and affective disorders. Most costly per case were brain tumours and multiple sclerosis. CONCLUSION: Brain disorders constitute a costly part of the population's health costs. Directed preventive measures are needed to counteract the population morbidity and to control the increasing cost pressure in health care.

Cost of disorders of the brain in Denmark.

The cost of brain disorders in Denmark is unknown and such information is important to decision makers. The aims of the study were to estimate the total number of subjects with brain diseases, and the associated direct and indirect expenses in Denmark. This was part of a larger pan-European study commissioned by the European Brain Council, which is an international collaboration of organizations within psychiatry, neurology, neurosurgery, neuro-research and patient organizations. The project provided the best possible estimates of the expenses for brain diseases based on available international scientific literature. The present study presents results for Denmark. There were an estimated 1.4 million Danish citizens who in 2004 had one of the selected 12 brain diseases, equivalent to one quarter of the total population. Anxiety disorders and migraine were the two most frequent diseases with 500,000 and 340,000 patients, respectively. The total expenses for all selected brain diseases were 37.3 billion DKR. Affective disorders, dependency, dementia and stroke were the most costly diseases. An estimated 12% of all direct costs in the Danish health system were spent on brain diseases; 9% of the total drug consumption was used for treatment of brain diseases. Expenses to brain diseases constituted 3% of the gross domestic product. Brain disorders are very prevalent in Denmark and they cause high societal and personal cost.

Neonatal encephalopathy and socioeconomic status: population-based case-control study.

OBJECTIVE: To investigate the association between maternal socioeconomic status and the risk of encephalopathy in full-term newborns. DESIGN: Population-based case-control study. SETTING: Washington State births from 1994 through 2002 recorded in the linked Washington State Birth Registry and Comprehensive Hospital Abstract Reporting System. PARTICIPANTS: Cases (n = 1060) were singleton full-term newborns with Comprehensive Hospital Abstract Reporting System International Classification of Diseases, Ninth Revision diagnoses of seizures, birth asphyxia, central nervous system dysfunction, or cerebral irritability. Control cases (n = 5330) were singleton full-term newborns selected from the same database. Main Exposures Socioeconomic status was defined by median income of the census tract of the mother's residence, number of years of maternal educational achievement, or maternal insurance status. MAIN OUTCOME MEASURES: Odds ratios estimating the risk of encephalopathy associated with disadvantaged socioeconomic status were calculated in 3 separate analyses using multivariate adjusted logistic regression. RESULTS: Newborns of mothers living in neighborhoods in which residents have a low median income were at increased risk of encephalopathy compared with newborns in neighborhoods in which residents have a median income more than 3 times the poverty level (adjusted odds ratio, 1.9; 95% confidence interval, 1.5-2.3). There was also a trend for increasing risk of encephalopathy associated with decreasing neighborhood income (P<.001). Newborns of mothers with less than 12 years of educational achievement had a higher risk of encephalopathy compared with newborns of mothers with more than 16 years of educational achievement (adjusted odds ratio, 1.7; 95% confidence interval, 1.3-2.3). Newborns of mothers receiving public insurance also had a higher risk of encephalopathy compared with newborns of mothers who have commercial insurance (adjusted odds ratio, 1.4; 95% confidence interval, 1.2-1.7). CONCLUSION: Disadvantaged socioeconomic status was independently associated with an increased risk of encephalopathy in full-term newborns. These findings suggest that a mother's socioeconomic status may influence the risk of encephalopathy for her full-term newborn.

[Cost of disorders of the brain in Austria in the year 2004]. / Die Kosten von "Gehirnerkrankungen" in Osterreich im Jahr 2004.

OBJECTIVES: The costs of twelve selected neurological, neuro-surgical and psychiatric disorders in Austria in the year 2004 will be presented. The present paper is part of the "Cost of Disorders of the Brain in Europe" study. METHODS: The data for the present calculations are based on systematic reviews of epidemiological and health-economic studies. For all European countries identical methods were applied. All economic data were transformed to Euros for Austria in the year 2004 ("Purchasing Power Parity adjusted"). RESULTS: The highest costs per case per disorder were caused by brain tumors (49,800 Euro) and multiple sclerosis (30,500 Euro). One-year-prevalence estimates (Austrian population 8.1 million) were highest for anxiety disorders (848,000 cases), followed by migraine (537,000 cases) and affective disorders (479,000 cases). The total costs (i.e. for all cases of a specific disorder in Austria) were highest for affective disorders and addiction (alcohol and illegal drugs). The total cost of all included disorders (addiction, affective disorders, anxiety disorders, brain tumours, dementia, epilepsy, migraine, multiple sclerosis, Parkinson's disease, psychotic disorders, stroke and brain trauma) was estimated at 8.8 billion Euros for Austria in the year 2004. Direct health care cost amounted to Euros 3.2 billion (37% of total cost), direct non-medical cost totalled Euros 1.5 billion (17%), and indirect cost Euros 4.1 billion (47%). DISCUSSION: Even when considering that such estimates based on international studies have methodological limitations, the total cost of the twelve included disorders is considerable. The total cost of these twelve disorders constitutes 4% of the gross national product of Austria. Taken together, these disorders cost each Austrian citizen Euros 1 090 per year.

Cost of disorders of the brain in Ireland.

The "Cost of Disorders of the Brain in Europe" (CBDE) study was conducted by the European Brain Council (EBC) to estimate prevalence and cost of the twelve leading disorders encountered in Neurology, Neurosurgery, and Psychiatry. The data for Ireland are presented here. Prevalence and costing information was obtained by structured review of published literature for each country. Where such information was lacking, figures were estimated from European data. Costs included direct medical, direct non-medical, and indirect costs. None of the costs presented here are directly from Irish data and the prevalence figures are mostly estimated from known European rates. In 2004, 1.1 million people in Ireland were affected by a disorder of the brain. Total cost of included disorders in Ireland was 3.0 billion Euro, representing 3% of gross national product, and costing each Irish citizen Euro 775 per year. Brain disorders are prevalent and pose significant economic burden in Ireland.

[The economics of mental health and health care- a blind spot?]. / Die ökonomische Bedeutung psychischer Erkrankungen und ihrer Versorgung- ein blinder Fleck?

Mental disorders are associated with an immense burden of disease for patients, their social environment and for society as a whole. Neuropsychiatric diseases have been estimated to account for 27% of disability adjusted life years (DALYs) in the Euro-A region and have thus more impact on the global burden of disease than cardiovascular diseases or neoplasms. In the population younger than 30 years even 65% of years lost due to disability are due to neuropsychiatric disorders. Moreover, the economic consequences of mental disorders pose a significant challenge on health care systems. For example, it has been estimated that 10% of direct health care costs in Germany were caused by mental and behavioural disorders in 2002. With limited available resources, it is becoming increasingly important to allocate health care budgets efficiently. It is therefore surprising that mental disorders as compared to other diseases are considerably underrepresented in the health economic evaluation of health care interventions. Health economic research has concentrated on the pharmacoeconomic assessment of new drugs so far while other interventions and alternative ways of care delivery, e.g., specialized day care, have rarely been subject to health economic evaluation and are thus systematically disadvantaged. Causes underlying the reservation towards mental disorders in health economics are being discussed and future perspectives are outlined.

Consensus document on European brain research.

Brain disease psychiatric and neurologic disease combined represents a considerable social and economic burden in Europe. Data collected by the World Health Organization (WHO) suggest that brain diseases are responsible for 35% of Europe's total disease burden. An analysis of all health economic studies of brain diseases in Europe, published by the European Brain Council (EBC) in June 2005, estimated the total cost of brain disease in Europe in 2004 to be Euro 386 billion. That burden is set to grow, mainly due to the fact that the European population is ageing. Investment in brain sciences does not match that burden now, let alone in the future. Brain research received only 8% of the life science budget in the European Commission's Fifth Framework Programme, which represents less than 0.01% of the annual cost of brain disorders for that period. Over the last decade, Europe has been losing ground to the USA and Japan in terms of both basic and clinical research. Many of Europe's young researchers are taking up posts in the USA and staying there. Big pharmaceutical companies are fleeing Europe for the USA, taking their drug development programmes with them. Research in the brain sciences now holds the promise of therapies that halt and even reverse neurodegeneration, of better diagnostic tools, neural prostheses for the paralysed and drugs for depression and anxiety that are tailored to the individual, thereby eliminating or reducing side effects. Our growing understanding of the normal brain could lead to better prevention of brain disease and to more effective teaching methods. The need for innovative treatments has never been greater, and Europe boasts clusters of excellent researchers in biotechnology who could collaborate with brain scientists and the pharmaceutical industry to realise this promise. But if Europe is to seize these opportunities and meet the challenge of brain disease, it needs to go forward on the basis of greater collaboration between countries, greater collaboration between industry, academia and patient organisations, and increased investment in the brain sciences. The EBC was formed in 2002 to bring together scientists, clinicians, the pharmaceutical industry, charities and patient organisations from all over Europe to campaign for these goals. It takes a novel, bottom-up approach to research policy, and in developing this consensus document, it aims to promote a greater and more focused effort in this area, to improve public understanding of the brain sciences and above all, to support brain research as a priority under the European Commission's Seventh Framework Programme (FP7, 2007-2013). The research programme outlined here was first conceived by the EBC board. An outline was sent to all member organisations and a number of individual experts for comments. Following that, a table of contents was developed. The 45 research themes were written by groups of experts from across Europe who represent a wide range of disciplines. Each one contains a proposal for future research on a specific brain-related theme which the EBC believes could form the basis of one or more integrated projects or strategic targeted research projects (STREP) funded under FP7. The EBC has deliberately focused on the major diseases and then described the basic research needed to understand and treat or perhaps even cure those diseases. The programme is therefore constructed "from man to molecule" and not the other way round, with equal importance attached to basic and clinical research. The EBC suggests that each of the proposed integrated projects or STREP should be awarded a budget in the order of Euro 10 to 15 million. In addition, brain research should be treated as an important element of many other parts of FP7, such as the European Research Council and research programmes on information technology and the causes of violence. Any research programme that concerns human behaviour should, by definition, take account of brain research. The EBC envisages that the priority for brain research it proposes at the European level will translate into higher priority for brain research at the national level, and this document may also serve as a starting point for the development of national consensus programmes. It seems likely that consensus conferences on brain research in Europe may further develop the themes and ideas discussed here. An EBC task force may also be established to further the consensus process. In general, increasing funding in the brain sciences would bring enormous economic returns by lightening the burden on healthcare systems and increasing the productivity of affected individuals-and might easily pay for itself. The human and social returns of such an investment are inestimable. And the time to act is now.

Cost estimates of brain disorders in Belgium.

This article presents the data on cost of the major brain disorders in Belgium which were retrieved from "Cost of Disorders of the Brain in Europe" study sponsored by the European Brain Council and performed by Stockholm Health Economics. The disorders selected were: addiction, depression, anxiety disorders, brain tumours, dementia, epilepsy, migraine and other headaches, multiple sclerosis, Parkinson's disease, psychotic disorders, stroke and trauma. Figures for prevalence of disorders and direct medical, direct non-medical and indirect costs are based on data coming from available electronic data bases, or when missing for Belgium, best possible estimates or extrapolated data were used. All economic data were transformed to Euro's for 2004 and adjusted for purchasing power parity (PPP). The results show that the total number of people with any brain disorder in Belgium amounts to 2.9 million in 2004, the most prevalent being anxiety disorders 1.1 million, migraine 860000, addiction (any) 800,000 and depression 500,000 cases. The total cost of all included brain disorders in Belgium was estimated at 10.6 billion Euros. Most costly per case are brain tumours, multiple sclerosis, stroke and dementia. Because of their higher prevalence, however depression, dementia, addiction, anxiety disorders and migraine have the highest total costs. Taken together brain disorders consume 4% of the gross national product and cost each citizen of Belgium 1029 Euros per year. The drug costs for brain disorders constitute only 10% of the total drug market in Belgium, and only 4% of the total cost of brain disorders in Belgium. This should be compared to the cost estimates and to a previous study which showed that brain disorders are responsible for 35% of the total burden of all disorders in Europe. This study suggests therefore that the direct healthcare resources, including expenses for drug therapies, allocated to brain disorders in Belgium are not leveled to the indirect costs and burden of these disorders. A comparison with data available from a direct prospective study in demented Belgian patients suggests that the mathematical estimates presented here reflect quite accurately the real average cost for dementia, although there are large variations depending on disease severity. As, in addition, subjects with brain disorders face collateral costs which have not been taken into associations, a complementary survey in the Belgian ecosystem to establish the cost profile of representative patients for the major brain disorders. Such a survey is being organized by a task force of the Belgian Brain Council.

Health problems due to long working hours in Japan: working hours, workers' compensation (Karoshi), and preventive measures.

Late in the 1970s, serious social concern over health problems due to long working hours has arisen in Japan. This report briefly summarizes the Japanese circumstances about long working hours and what the Government has achieved so far. The national statistics show that more than 6 million people worked for 60 h or more per week during years 2000 and 2004. Approximately three hundred cases of brain and heart diseases were recognized as labour accidents resulting from overwork (Karoshi) by the Ministry of Health, Labour and Welfare (MHLW) between 2002 and 2005. Consequently, the MHLW has been working to establish a more appropriate compensation system for Karoshi, as well as preventive measures for overwork related health problems. In 2001, the MHLW set the standards for clearly recognizing Karoshi in association with the amount of overtime working hours. These standards were based on the results of a literature review and medical examinations indicating a relationship between overwork and brain and heart diseases. In 2002, the MHLW launched the program for the prevention of health impairment due to overwork, and in 2005 the health guidance through an interview by a doctor for overworked workers has been enacted as law. Long working hours are controversial issues because of conflicts between health, safety, work-life balance, and productivity. It is obvious that we need to continue research regarding the impact on worker health and the management of long working hours.