From the Field – Page 11

The Global Stroke Burden

By Sarah Song, MD, MPH

Sarah Song

Stroke is a devastating and debilitating disease. It is the second leading cause of death in the world, comprising approximately 10 percent of all deaths and killing 5.5 million people each year, with 44 million disability-adjusted life-years (DALYs) lost.^1,2 In 2010 alone, there were 16.9 million strokes worldwide, of which 70 percent occurred in low- and middle-income countries; this trend is expected to increase over the next 20 years.^1,3

Presently, low- and middle-income countries account for more than 85 percent of the global stroke mortality.⁴ Stroke mortality rates are especially high in Africa and Asia, where the burden of preventing and treating communicable diseases may shift resources away from cardiovascular disease and stroke.⁵ However, the burden from chronic and non-communicable diseases is likely to exceed the burden from communicable diseases in low- and middle-income countries in the near future.

A global focus on reducing mortality and morbidity from cardiovascular disease and stroke is more urgent than ever. Major problems shared by many countries are a lack of infrastructure, inadequate systems of care, effective programs to address cardiovascular risk factors, financial difficulty and shortage of trained health care workers.^3,6 Advocacy efforts, partnerships between countries, efficient and cost-effective targeted interventions and allocated funding and resources are necessary to tackle the worldwide stroke burden.

Stroke began to be tracked globally via surveillance systems in 1968 with the World Health Assembly, after which data including incidence, mortality and case-fatality was tracked. In more recent years, a more sophisticated stepwise approach to stroke surveillance has been recommended by the World Health Organization to include not only individuals with non-fatal events in the community, but also those admitted to the hospital.

Stroke risk factors are also tracked using a stepwise surveillance approach, including demographic and self-reported data, physical examination and objective laboratory results.¹ These measures have helped to show the great disparity between low- and middle-income countries and high-income countries, with national per capita income being the highest predictor of stroke burden, exclusive of cardiovascular risk factors.⁷

Overall, between the countries with the highest stroke mortality and the lowest stroke mortality, a tenfold difference in age-adjusted mortality rates and DALYs lost was observed.⁷ Globally, the highest at-risk countries are in Eastern Europe (with Russia having the highest stroke mortality rate), Asia and Africa, along with some in the South Pacific and the Carribbean.⁷

The economic impact of stroke has also been severe. For example, in 2005 it was estimated that the losses to gross domestic product due to vascular diseases was nearly $1 billion in China and India. This economic disparity is expected to increase in the near future in low- and middle-income countries.¹

Health systems of care for stroke require financing, staffing and structure in order to produce results. For example, the administration of intravenous alteplase (IV tPA) has been seen to significantly improve outcomes after acute ischemic stroke. However, giving IV tPA appropriately to eligible patients requires infrastructure and organization. Several countries have successfully developed systems to administer IV tPA (e.g., Brazil, Argentina, China and India), but there are still many barriers in low-income countries where medical services may be scarce and not easily accessible due to geography or human resources, and IV tPA may be prohibitively expensive.

In addition, funding is not proportional to economic and patient burden. For example, in 2011, funding for three of the major infectious diseases (HIV/AIDS, tuberculosis and malaria) was 35 times greater than funding for all non-communicable conditions combined.³ Therefore, besides the need for much greater funding in the realm of stroke and cardiovascular diseases, it has been suggested that community interventions and a focus on primary care might be the most cost-effective and efficient approach to stroke on a global level.^3,6,7

Although stroke burden is significant regardless of cardiovascular risk factor burden, the overall risk factor burden is increasing in low- and middle-income countries.⁶ For instance, hypertension is held accountable for approximately 54 percent of global stroke burden; this could be especially important as a target for intervention in countries such as China, where rates of hypertension are increasing.¹ As many of the population in low- and middle-income countries with stroke are working age (41-65) adults, more smoking has been seen in working-age adults than in other age groups.

The obesity epidemic continues to rise (with an estimated 10 percent of children globally considered overweight). The three-year INTERSTROKE study, based in 84 centers in 22 countries, confirmed that 88 percent of strokes were attributable to 10 risk factors: hypertension, smoking, waist-to-hip ratio, diet risk score, physical activity, diabetes mellitus, alcohol intake, psychosocial factors (including depression and stress), cardiac causes and the ratio of apolipoprotein B to apolipoprotein A1.⁴ The study, published in 2011, noted that targeting these risk factors on a primary care level, and focusing on healthy lifestyles, could substantially improve the global stroke burden.⁶

Other targets for low-cost, high-efficacy interventions could include educational campaign programs, such as the Go Red for Women Campaign and World Heart Day, which have been effective in spreading education and increasing disease awareness.⁶ In addition, cost-effective interventions such as the polypill, which incorporates three medications into a single pill, could help reduce costs and improve compliance with medications.^{6, 7}

It also may be beneficial to incorporate new and innovative, yet still cost-effective, techniques to address the global burden of stroke. Some innovative approaches to address primary stroke prevention, namely by using smartphone technologies, have been suggested and are being tested. Researchers from New Zealand have developed the Stroke Riskometer app, which assesses responses to a short questionnaire and determines the five- and 10-year risk for stroke using a validated algorithm similar to the Framingham risk score.⁸ It also incorporates education, comparison with similar individuals and an opportunity to share risk assessment results with others. An update of this app allows for participation in an international epidemiological research study (the Reducing the International Burden of Stroke Using Mobile Technology, or RIBURST study), which involves more than 160 countries.

Besides the interventions on a patient and community level, countries with high rates of stroke mortality must set priorities that are attainable and commensurate to resources. Better definition of stroke traits and determinants in low- and middle-income countries are needed to develop culturally-specific stroke prevention strategies. International agencies must work together to develop more novel strategies to attack the stroke epidemic. The UN General Assembly already has attempted to do this by setting a goal of reducing mortality from non-communicable diseases by 25 percent by the year 2025.³ Collaboration, vision and innovation are needed to reduce the global stroke burden and the stroke disparities that exist between countries.

References

Mukherjee D, Patil CG, “Epidemiology and the Global Burden of Stroke,” World Neurosurg, 76 (2011): S85-90.
Deresse B, Shaweno D, Epidemiology and In-hospital Outcome of Stroke in South Ethiopia, J Neurol Sci, 355 (2015):138-42.
Berkowitz AL, Stroke and the Noncommunicable Diseases: A Global Burden in Need of Global Advocacy, Neurology, 84 (2015):2183-4.
O’Donnell MJ, Xavier D, Liu L, et al, Risk Factors for Ischemic and Intracerebral Hemorrhagic Stroke in 22 Countries (the INTERSTROKE Study): A Case-control Study, Lancet, 376 (2010):112-23.
Kim AS, Johnston SC, Global Variation in the Relative Burden of Stroke and Ischemic Heart Disease, Circulation, 124 (2011):314-23.
Fuster V, Voute J, Hunn M, et al., Low Priority of Cardiovascular and Chronic Diseases on the Global Health Agenda: A Cause for Concern, Circulation, 116 (2007)1966-70.
Johnston SC, Mendis S, Mathers CD, Global Variation in Stroke Burden and Mortality: Estimates From Monitoring, Surveillance and Modeling, Lancet Neurol, 8 (2009):345-54.
Feigin VL, Krishnamurthi R, Bhattacharjee R, et al., New Strategy to Reduce the Global Burden of Stroke, Stroke, 46 (2015):1740-7.

Sarah Song, MD, MPH, is an assistant professor in the Section of Cerebrovascular Disease, department of neurological sciences, Rush University Medical Center, Chicago, Illinois.

Dementia: A New Perspective

By Vladimir Hachinski, MD

Vladimir Hachinski

As dementia rises in prevalence, new approaches must be adopted in the treatment of the condition and efforts to prevent it.

Dementia means the loss of brain capacity severe enough to result in the loss of self-sufficiency. The incidence of dementia, which is rising globally, is largely driven by the aging population. Although dementia increases with age, it is not inevitable with age. Dementia represents the end stage of several processes, for which some are treatable and preventable.

Brain blood vessels (vascular) and Alzheimer’s disease represent the two most common pathologies leading to dementia. The changes of Alzheimer’s disease are characterized by the deposition of amyloid protein plaques and of tau protein aggregation forming tangles in neurons. The changes that lead to Alzheimer’s disease begin about 20 years before any symptoms appear. Many elderly individuals die with plaques and tangles without having had any trouble in life as a result. Similarly, most vascular disease is insidious. For each stroke that affects the body, five affect the mind, usually with the person being unaware of them.

While Alzheimer’s and cerebrovascular pathology occur commonly with age, mostly without symptoms, the combination doubles the chances that the dormant pathologies will result in dementia. Although cerebrovascular disease is treatable and preventable, scant attention has been paid to this component, present in 80 percent of Alzheimer’s patients.

Instead, the declared intention is to find a cure or disease-modifying drug by 2025. The idea of giving one drug to an amalgam of pathologies broadly defined as Alzheimer’s disease may prove as disappointing as the litany of failed trials that took place in the late 1990s and early 2000s aimed at stopping the damage that follows a stroke with a single drug. Since dementia has multiple causes, one must try multiple therapies, including addressing the one component that can be treated and prevented: the vascular one.

Dementia is not a threshold but a continuum. The process begins decades before any symptoms appear, a phase termed the “brain-at-risk stage.” The earlier the risk factors are recognized and treated, the better the chance of success.

Knowledge accrues in pieces, but is understood in patterns. Specialization fosters fragmentation and fiefdoms. It turns out that all major brain diseases result from different combinations of half a dozen mechanisms. By integrating this knowledge, researchers may discover that drugs developed for one purpose in one field may have application in another. If we only knew what we already know.

The Need for Multiple Therapies

The diagnosis of Alzheimer’s disease is notoriously imprecise, mainly because most patients harbor multiple pathologies. Even if a drug were 100 percent effective in blocking amyloid deposition, its effect might be obscured or overwhelmed by concomitant pathologies, for example brain vascular disease and its interactions, such as inflammation, if not treated at the same time. This calls for multiple therapies and new methodologies, such as platform trials to evaluate multiple therapies simultaneously. The lack of precision in diagnostic categories can be overcome by identifying specific contributing mechanisms leading to dementia and treating them. It is now possible to image vascular disease, amyloid and tau protein deposition and inflammation in the brain. Each of these mechanisms can be treated individually or in combination.

The evaluation of drugs can be accelerated by developing protocols in close reciprocal interactions with experimental work in a few advanced centers. These would continue with extensive protocols and thorough evaluation of patients. Once experience has been gained, a protocol could be simplified so that large numbers of patients could be enrolled. At predetermined intervals, statistically valid samples of patients following the simplified protocol would be studied by those following the extensive study protocol to make sure that they were similar.

In the era of big data and electronic records, it may be possible to do more sophisticated post-marketing surveillance and gain real-world knowledge of the effectiveness of different treatments.

Unhealthy diets, physical inactivity and tobacco and alcohol addiction represent identifiable risks for stroke and dementia and other non-communicable diseases targeted by the United Nations resolution of September 2011. In order to succeed, a three-step approach is required:

Information
Motivation
Enablement

Good information is essential, but by itself is no more effective than New Year’s resolutions. Motivation matters but is seldom addressed. Healthy lifestyles require a healthy environment, and policymakers have a particular role in creating it. They also have a leadership role in introducing legislation to curb tobacco and alcohol use and limit the consumption of unhealthy foods. They also have a major role in ensuring that our air is breathable. Air pollution can harm the lungs, damage the heart and afflict the brain. What happens in Beijing matters at Schloss Elmau: We share the same biosphere. Policymakers can follow the lead of Finland in considering health in all policies. Public health could be enhanced considerably through the leadership of non-governmental organizations. Additionally, policymakers can get help from international brain organizations, which can provide expertise and patient support groups, and can help to mobilize the public toward healthier lifestyles and risk-factor control, which may prevent or postpone major chronic diseases, including dementia.

Conclusions

Dementia results most often from a combination of Alzheimer’s and cerebrovascular pathologies and their interaction. Cerebrovascular disease is both treatable and preventable.

The diagnosis of dementia is imprecise, but it is now possible to identify and target the different mechanisms leading to brain deterioration. This will require multiple interventions and new clinical trial methodologies.

Dealing with the challenges of dementia will require not only new resources, but new thinking and different approaches as well.

Vladimir Hachinski, MD, is the Distinguished University Professor at Canada’s University of Western Ontario. With John W. Norris, he founded the world’s first successful acute stroke unit. With David Cechetto, he discovered the role of the brain’s insula in sudden death, and, joined by Shawn Whitehead, they established a treatable link between Alzheimer’s disease and stroke. He has authored, co-authored or co-edited 17 books and more than 600 widely cited publications. He was president of the World Federation of Neurology from 2010 to 2013 and the founding and past chair of the World Brain Alliance.

Article originally published in G7 Germany: The Schloss Elmau Summit. www.g7g20.com.

A Continuum Course in Vietnam

By Nguyen Huu Cong

Nguyen Huu Cong

Through the aid of the World Federation of Neurology (WFN) and the American Academy of Neurology (AAN), the continuum courses have been carried out for many years in Vietnam. The courses are conducted one to two times a year, with the topics chosen by members of the executive committee of the Ho Chi Minh City Neurological Association, based on the issues delivered annually by the WFN and AAN. These courses are usually organized in Ho Chi Minh City, the largest city in Southern Vietnam. On May 6, the course took place for the first time outside Ho Chi Minh City in the Mekong Delta.

The Tien Giang Neurological Association (TNA) was founded one year ago in My Tho, a beautiful small town in the Mekong Delta and the capital of Tien Giang Province. It now has 60 members. Most of them are neurologists from the surrounding provinces in the Mekong Delta, but some are internists working in rural areas without neurologists. Dr Nguyen Van Thanh, chief of the department of neurology at Tien Giang Hospital and president of the Tien Giang Neurological Association, is actively working and running the association.

The Vietnamese Association of Neurology and the Ho Chi Minh City Neurological Association have been assisting the TNA by sending our experts to attend lectures there. This year’s continuum course, held at Tien Giang General Hospital, covered the topics of epilepsy, as presented in Continuum: Lifelong Learning in Neurology, Vol. 19, Issue 3, June 2013. The lecturers were Prof. Pierre Jallon, former professor of neurology at the University of Geneva; Le Van Tuan, MD, PhD; and Tran Quang Tuyen MD, from the Ho Chi Minh City Neurological Association. The lectures focused on these articles:

The 2010 Revised Classification of Seizures and Epilepsy
Antiepileptic Drug Treatment: New Drugs and New Strategies
EEG and Epilepsy Monitoring

Prof. Pierre Jallon presented the old and new definitions, compared previous to revised classifications and analyzed the advantages of new terms and concepts and their limitations. Then the professor also talked about the differential diagnosis, especially in difficult cases from the features of syncope convulsions, hypoglycemia and psychogenic nonepileptic seizure. Subsequently, Dr. Le Van Tuan introduced the article, “Antiepileptic Drug Treatment: New Drugs and New Strategies,” speaking about the targets of epilepsy treatment, classical AEDs and newer medications available in our country. He also showed how to select antiepileptic drugs appropriate for each types of seizure. The topic of AED treatment fascinated all of the attendees, and they started a fervent conversation with the lecturer. Dr. Tran Quang Tuyen introduced the usefulness of video EEG in supposing epilepsy diagnosis. On this occasion, Drs. Le Van Tuan Tran Quang Tuyén, took turns to report on the situation of using EEG in Vietnam for epilepsy monitoring. Once again, many questions related to clinical practice were asked of the lecturers. After the presentations, attendees were encouraged to discuss the contents of the articles, “Patient Management Problem” and “Patient Management Problem — Preferred Responses.”

The discussion lasted past the fixed hours. At the end of the course, Dr. Nguyen Van Thanh, president of the TNA, expressed the gratitude of the Tien Giang Association members to the lecturers, AAN and WFN. The participants showed their gratitude in kind and suggested similar educational courses in the Mekong Delta in the future.

The CME course with Continuum — Lifelong Learning in Neurology has contributed to improving the knowledge of epilepsy in our neurologists in Tien Giang and the surrounding provinces.

The issues of the Continuum: Lifelong Learning in Neurology, with articles written by experts from the American Academy of Neurology, are useful for our neurologists, especially young members of our associations in Vietnam. We are planning to organize one additional course in August 2015 on “Peripheral Nervous System Disorders.” We believe that afterward we will continue to have the assistance of the World Federation of Neurology.

Nguyen Huu Cong is an associate professor; deputy chairman of the neurological department at Pham Ngoc Thach University of Medicine, lecturer of the neurological department of Ho Chi Minh City University of Medicine and Pharmacology; president of the Vietnam Association of Electro Diagnostic and Neuromuscular Medicine; and vice president of the Neurological Association of Ho Chi Minh City.

Longtime INPC Continues in Croatia

By Vida Demarin, MD, PhD, FAAN, FAHA, FESO

55th INPC Opening Ceremony.

The 55th International Neuropsychiatric Congress (INPC) May 27-30 in Pula, Croatia, was held under the auspices of the president of the Republic of Croatia, her excellency Kolinda Grabar Kitarovic.

The organizer of the congress is the Society for Neuropsychiatry, and the co-organizers are the department of medical sciences of the Croatian Academy of Sciences and Arts and the Central and Eastern European Stroke Society.

The Congress was endorsed by the World Federation of Neurology (WFN), European Academy of Neurology, WFN Applied Research Group on the Organization and Delivery of Care, European Psychiatric Association and Croatian Stroke Society. The main sponsors of the congress were the Ministry of Science, Education and Sports of the Republic of Croatia, City of Graz, City of Pula and Istria County. There were more than 350 participants from Austria, Albania, Bosnia and Herzegovina, Montenegro, Kosovo, the Czech Republic, Croatia, China, Greece, Iran, Italy, Ireland, Hungary, Macedonia, Germany, Poland, Romania, Russia, South Korea, Slovenia, Serbia, Thailand, Ukraine, United Kingdom and the United States.

From left: Prof. Hrvoje Hecimovic; Prof. Vida Demarin, INPC president; and Prof. Raad Shakir, WFN president.

The congress kicked off with an academic lecture on “WFN: The Way Ahead,” given by our special guest, Prof. Raad Shakir, president of the WFN. The main theme was “Highlights in Neurology — What Have We Learned in the Last 55 Years” in stroke, post-stroke depression, multiple sclerosis, epilepsy, headache and pain and neurorehabilitation, presented by experts in the field, Professors Franz Fazekas, Kurt Niederkorn, Francesco Paladin, Wai Kwong Tang, Vesna Å eric and Vida Demarin.

Main topics in psychiatry were “Evolutionary Perspectives in Psychopathology” and “Controversies and News in Psychiatry,” organized by Prof. Karl Bechter and Francesco Benedetti. There were also numerous symposia, in particular: Challenging Child and Adolescent in Modern Society, Fourth European Summer School of Psychopathology, International Sports Psychiatry Meeting, Eighth International Symposium on Epilepsy, Fourth Symposium on the Interface Providers in Neurorehabilitation, Symposium on the Activities of the Association of Public Health Andrija Å tampar, and symposia about stress management and acute stroke treatment.

Joint meetings with Alps-Adria Neuroscience Section, WFN Applied Research Group on the Organization and Delivery of Care, and Central and Eastern European Stroke Society, chaired by Professors Leontino Battistin and Vida Demarin on the current status of stroke management in the region and on perspectives and new approaches in neurorehabilitation, also were organized as a part of the INPC. Prof. Anna Czlonkowska from Warsaw gave a special lecture on Wilson’s Disease, with original data from their registry.

During the congress, there were 66 lectures within 14 symposia, which were given by 55 lecturers from around the world, and a poster session with many interesting posters. Awards for best posters were given by the City of Graz and by INPC Kuratorium.

We are proud of this unique congress, being one with the longest traditions in the world. During the past 55 years, INPC has become a beloved place of meeting, a venue for continuing education in topics of neurology, psychiatry and related disciplines, and a point of scientific and professional exchange of experience for a large number of scientists and professionals from all over the world, continuing on the original idea of sciences and humanity. We hope to keep this success in the upcoming years.

Vida Demarin, MD, PhD, FAAN, FAHA, FESO, is president of the INPC.

Armauer Hansen: The Controversy Surrounding his Unethical Human-to-Human Leprosy Transmission Experiment

By Douglas J. Lanska, MD, MS, MSPH, FAAN

Douglas Lanska

In 1873, Norwegian physician Gerhard Armauer Hansen (1841-1912) [below]discovered rod-shaped bodies — Mycobacterium leprae — in leprous nodules. Initially unable to stain these bodies, he only tentatively suggested that they resembled bacteria, which led to a later priority dispute with Albert Neisser (1855-1916) when Neisser was able to stain the organisms and then claimed priority for the discovery. Although Hansen was convinced that leprosy was an infectious disorder, he was unable to cultivate the organism and unable to transmit the disease to animals, despite 12 failed attempts to transmit the disease to rabbits by inoculation.

In 1875, Hansen had been appointed as medical officer of health for leprosy in Norway and as the resident physician at the Bergen Leprosy Hospital. After corresponding with German physician and pioneering microbiologist Robert Koch (1843-1910) in Breslau, Hansen decided to attempt human-to-human inoculations, and specifically to inoculate leprous tissue from a patient with lepromatous (multibacillary) leprosy into patients with tuberculoid (paucibacillary) leprosy [below right] to determine whether he could produce manifestations of lepromatous leprosy.

Robert Koch. Public domain. Courtesy of the U.S. National Library of Medicine.

While Hansen had already achieved some professional renown for his studies of leprosy, his patients found him aloof and high-handed. On Nov. 3, 1879, while on rounds at the Bergen Leprosy Hospital, Hansen instructed a 33-year-old patient with the “anesthetic type of leprosy,” Kari Nielsdatter Spidsøen, to accompany him to his office as he indicated he wanted to speak to her. There, she saw that he had a sharp-cutting instrument in his hand which he brought up to her eye, while she held him off with her arms. After she was calmed down by one of the other doctors in the room, Hansen succeeded in his goal of inoculating leprous material from another patient under the conjunctiva of her eye with a cataract knife.

Gerhard Armauer Hansen. (Public domain. Courtesy of the U.S. National Library of Medicine)

The patient reported this to the hospital pastor, Pastor Grönvold, who in turn forwarded the complaints to legal authorities who charged him with causing bodily harm to an innocent patient. According to the transcript of the court proceedings, Hansen “admitted that he was not justified in carrying out the operation as he had neither obtained her permission in advance, nor told her of his aim in doing it. He had omitted seeking informed consent for the procedure “as he took for granted that the [patient] would not regard the experiment from his point of view, and if something happened [e.g., a lepromatous lesion developed that might threaten her vision], he was sure he could get the affection under control.”

Despite the criminal complaint against him, Hansen boldly expressed to the court his self-righteous belief that he was justified in these actions: … even if the subject should have some pain, because he had chosen a subject who had suffered from leprosy for many years, and therefore would not be exposed to a new disease. He was quite sure that there was no risk of loss of vision, even if the inoculation should have resulted in a nodule. He himself had several times extirpated nodules from eyes without any trouble, and had succeeded in saving the eyesight. … The great scientific and national importance of finding the answer to the question [of the transmissibility of leprosy] had therefore forced him to act as he did.

Maculo-anesthetic (tuberculoid or paucibacillary) leprosy (left) and lepromatous (multibacillary) leprosy (right). Tuberculoid leprosy is characterized by hypopigmented skin macules and anaesthetic patches from damaged peripheral nerves, while lepromatous leprosy is characterized by symmetric skin lesions, nodules, plaques and thickened dermis with detectable nerve damage typically late in the illness. (From Walker, 1905)

Although Hansen’s colleagues supported him with various post hoc justifications, it was clear to the court (with Hansen’s own admission) that, in his zealousness to prove the infectious nature of leprosy, he had misused his position of authority by trying to intentionally transmit a disease to a patient placed in his care without the patient’s consent.

Hansen was convicted and in consequence lost his post at the Leprosy Hospital in Bergen, but in a legal-political compromise he retained his position as chief medical officer for leprosy in Norway. The case had little effect, though, on Hansen’s professional reputation, and he continued with his scientific studies. Nevertheless, as Norwegian microbiologist and historian Thomas M. Vogelsang (1896-1977) concluded, the legal decision emphasized “that even a celebrated scientist is bound to obey the law of the land, and that it is the court’s duty to protect every citizen also against encroachments from more influential persons.”

Douglas J. Lanska, MD, MS, MSPH, FAAN, is with the Veterans Affairs Medical Center, Great Lakes Veterans Affairs Healthcare System, Tomah, Wisconsin.

Peter J. Koehler is the editor of this history column. He is neurologist at Atrium Medical Centre, Heerlen, the Netherlands. Visit his website at www.neurohistory.nl.

References
Blom K. Armauer Hansen and human leprosy transmission: Medical ethics and legal rights. Int J Lepr 1973;41:199-207.
Lock S. Research ethics – a brief historical review to 1965. J Intern Med 1995;238:513-520.
Marmor MF. The ophthalmic trials of G.H.A. Hansen. Survey Ophthalmol 2002;47:275-287.
Vogelsang TM. Gerhard Henrik Armauer Hansen: 1841-1912: The discoverer of the leprosy bacillus. His life and his work. Int J Lepr 1978;46:257-332.
Walker NP. An Introduction to Dermatology. Third edition. Philadelphia: William Wood and Co.

Worldwide Variations in Brain Death Declaration

By Torrey Boland, MD

Torrey Boland

Despite the publication of evidence-based practice parameters for the declaration of brain death by the American Academy of Neurology (AAN) in 1995 and updated in 2010, there remains much variation worldwide in how the actual determination of brain death is performed. Not only does the practice, but also the perceptions of brain death, vary widely across countries.

In 2002, an international review identified significant variations in the practice of determining brain death. However, studies such as this have reported primarily on higher-income regions.

Earlier this year, several researchers reported in Neurology the results of the largest study to date attempting to assess and characterize both the practices in determination of brain death worldwide as well as the perceptions of brain death among countries. This study aimed to gather data not only from high-income countries, but to gather a comprehensive worldwide dataset. It confirmed that significant variations continue to exist worldwide in both the perception and practice of declaration of brain death. This lack of agreement could become challenging as organ transplantation networks are becoming increasingly internationalized, and supports the need for a stronger international consensus on brain death.

The authors conducted an electronic survey, which was distributed to individuals who practiced medicine and had interactions with patients who could become brain dead. The target participants comprised physicians in 123 countries. The survey sought to query individuals with knowledge and expertise in brain death within each country. Included in the survey were members of the Neurocritical Care Society; country representatives of the World Federation of Neurology, who were asked to either complete the survey or forward it to appropriate colleagues, authors of publications on brain death; and international personal contacts of the authors. Responses were tallied from 91 countries, including the African, Eastern Mediterranean, European, Pan-American, Southeast Asian and Western Pacific World Health Organization regions.

The findings of the study showed that there remains significant variability in both the perception of brain death as a concept as well as dissimilarity in the practice of the declaration of brain death. Most countries noted a legal provision (70 percent) and an institutional protocol for the declaration of brain death (77 percent), but high-income countries were significantly more likely to have an institutional protocol than low-income countries.

In addition, the majority of countries in Africa lacked institutional brain death guidelines. Legal provisions for brain death were more likely in countries with organized transplant networks, even when adjusting for income. This may be related to advances in medical technology, which has led to an increase in organ transplantation in more middle- and low-income countries. This rise in transplantation indicates a corresponding need for understanding of the concept of brain death.

A small portion of countries (14 percent) reported a lack of brain death declarations in their hospitals, citing a lack of intensive care or advanced technology, lack of expertise in brain death, and uncertainties regarding the concept of brain death. This may represent a need for further
medical education in some areas of the world. Interestingly, 57 percent of respondents disagreed with the statement that brain death equates to cardiac death. This response did not appear to be associated with country income level, which may reflect variations among individuals related to personal or cultural beliefs. Nearly all physicians from countries with designated transplant networks agreed that brain death was an established concept at their hospitals.

Variations in the practice of declaring brain death were noted as well. While the majority (66 percent) of respondents reported that an attending physician trained in neurology, neurosurgery or intensive care must make the determination of brain death, 25 percent of those polled stated that a resident-level trainee could independently declare brain death. Discrepancies were noted in the clinical examination, with more than half of the countries citing an institutional protocol that was discordant with the 2010 American Academy of Neurology criteria. Apnea testing was another area in which much variability existed, with differences in blood gas requirements, number of tests required and equipment.

There did not seem to be an association between the use of ancillary testing and country income level. The authors hypothesized that this finding may be explained by the increased use of ancillary tests by physicians who are unfamiliar with brain death, as the AAN practice parameter does not require ancillary testing in straightforward cases.

While this study depended on the responses of individuals, there may be a bias in the nature of self-reported perceptions and practices. The results may not reflect each country as a whole, and there may be regional differences within each country that were not assessed. In addition, the survey was presented in English only, which may have led to some misinterpretation in the questions by responders. In the lowest income countries, the need for a policy surrounding the declaration of brain death may be irrelevant as there are more urgent public health issues. Overall, however, this study represented a large, diverse and worldwide sample.

Variations in brain death declaration both in practice and as a concept persists despite advances in communication and education worldwide. This study identifies the challenges in developing a worldwide consensus on the determination of brain death. It is unclear whether creating an international standard for brain death is a feasible goal. In addition to variations in medical education, cultural beliefs and legal codes worldwide, there are also individual differences in practice and beliefs, as evidenced by variations in practice within the United States, which may be related to individual biases and opinions. This study highlights the need for the international community to work together to create a more uniform approach to brain death, especially as the practice of organ donation continues to expand.

Torrey Boland, MD, is an assistant professor in the department of neurosciences at Rush University Medical Center, Chicago.

Reference
Wahlster S, Wijdicks EFM, Patel P, et al. Brain death declaration. Neurology 2015; 84:1870-1879.

EAPS 2014 Welcomes Six European Pediatric Societies

By Tamar Ediberidze

Tamar Ediberidze

The fifth Congress of the European Academic Pediatric Societies (EAPS) 2014, was held Oct. 17-21, 2014, in Barcelona, Spain. The Congress was organized by the three societies, the European Academy of Pediatrics, European Society for Pediatric Research and European Society of Pediatric and Neonatal Intensive Care (ESPNIC), including the Nurses Section of ESPNIC.

In addition, for EAPS 2014, six other important European pediatric societies accepted the invitation to join as collaborating societies: the European Pediatric Neurology Society, Pediatric Assembly of European Respiratory Society, Association for European Pediatric and Congenital Cardiology, Union of European Neonatal & Perinatal Societies, European Society for Pediatric Gastroenterology, Hepatology and Nutrition, and European Society for Pediatric Infectious Diseases.

It was an honor and pleasure to attend the congress and present the poster with the preliminary results of our research, “Sleep Complaints Among the Neurologically Impaired Children: Questionnaire Based Study.” We had the great opportunity to receive remarks and advice from experts and colleagues from Europe about the study design and data interpretation.

In addition, I want to point out that I attend the congress with my colleague, Nino Gogatishvili, MD, who also was awarded a World Federation of Neurology travel grant. She also had an excellent poster presentation during the poster session. As I know you received her thanksgiving letter in 2014. Overall, we feel our participation was successful for our delegation.

Urban Air Pollution in Children and Young Adults

Environmental Neurology, Neurodegeneration, Air Pollution and Young Urbanites

By Lillian Calderón-Garcidueñas, MA, MD, PhD, and Jacques Reis, MD

Ambient air pollution is a key disease risk factor producing detrimental health effects on millions of people, particularly children and young adults, across the global community. The neurological effects associated with sustained exposures to concentrations of outdoor air pollutants above the current international air quality standards are an important issue for people living in megacities and small towns around the world and those involved in high-risk occupational settings. Outdoor air pollutants are complex mixtures of particulate matter (PM), gases, and organic and inorganic compounds emitted directly into the air from combustion of fossil fuels, such as gas, oil, coal and fires.

New York; Toronto; Salt Lake City; Fairbanks, Alaska; Provo, Utah; the Los Angeles-South Coast Air Basin; Paris; La Oroya, Peru; Santiago, Chile; New Delhi; Beijing; Karachi, Pakistan; Krakow, Poland; Venice, Italy; Frankfurt, Germany; Brussels; and Mexico City residents share their main sources of pollution: transport, industry and heating. Particulate matter fine particles larger than 100 nm and smaller than 2.5 Î¼m (PM_2.5) and ultrafine PM <100 nm are target sizes for brain effects, and their main sources are road traffic and industrial emissions.

The detrimental impact of air pollution upon the brain in development is critical, as are the long-term potential neurodegenerative consequences upon children and young adults. Air pollution also is a risk factor in multiple sclerosis. We will discuss these topics in our T 20 Thursday, Nov. 5, 2015, Environmental Neurology XII Congress of World Neurology in Santiago, Chile.

Oxidative stress and brisk inflammatory responses are important features present in animal models and in humans exposed to polluted environments with diverse particulate matter chemistry as well as high concentrations of criteria pollutants.

Neuroinflammation is a key component of air pollution exposures. Megacity children exhibit significant frontal lobe imbalance in genes essential for inflammation, innate and adaptive immune responses, oxidative stress, cell proliferation and apoptosis. The up-regulation of potent inflammatory mediators involves supra and infratentorial regions and cranial nerves, including olfactory bulb, frontal cortex, substantia nigrae and the vagus.

Breakdown of the nasal, olfactory, gastrointestinal, alveolar-capillary and the brain-blood barriers has been extensively documented. There is evidence the GI tract barrier also is compromised in the air pollution setting, and recent research links inflammatory bowel diseases, changes in gut microbiome and abdominal pain with air pollution. The GI breakdown likely impacts neuronal enteric populations, and PM could reach the vagus and the brainstem. We suggested that damage to epithelial and endothelial barriers associated with air pollution exposures is a robust trigger of tight junction and neural antibodies.

Early dysregulated neuroinflammation, brain microvascular damage, production of potent vasoconstrictors, and perturbations in the integrity of the neurovascular unit are seen in children and young adults exposed to urban air pollution. The accumulation of misfolded hyperphosphorylated tau, alpha-synuclein and beta-amyloid coincides with the anatomical distribution observed in the early stages of both Alzheimer’s and Parkinson’s diseases.

Major depressive episodes are linked to neuroinflammation and systemic markers of inflammation. Epidemiological, cognitive, structural, and functional neuroimaging and mechanistic studies into the association between air pollution exposures and the development of neuroinflammation and neurodegeneration in children are of pressing importance for public health.

Air pollution has become a key issue in public health and in environmental sciences.

What can we do? Knowledge of the issue is imperative. Improvement of air quality is a must, and neuroprevention should be at the core of our efforts as health care providers.

Lillian Calderón-Garcidueñas, MA, MD, PhD, is with the University of Montana, Misoula, and Jacques Reis, MD, is with the University Hospitals of Strasbourg, France.

Conclusion Report on the Congress of PAUNS and the Saudi Neurology Society Meeting

From left: Prof. El Tammawy, previous president of the Pan Arab Union of Neurological Societies (PAUNS) president; Prof. Bohlega (current PAUNS president); and Prof. Adnan Awada, Lebanese Neurology Society president, at the Gala Dinner.

The 14th Congress of the Pan Arab Union of Neurological Societies (PAUNS) and the 22nd Saudi Neurology Society Meeting was held from Jan. 22-24 at the Hilton Jeddah in Saudi Arabia. The great success of the last PAUNS meeting in Egypt in March 2013 paved the way to move the flag to Saudi Arabia with the hope that all would enjoy the highly scientific and learning social activities planned for the event. The theme for the congress was “Broadening the Horizon of Neurology in the Arab World.”

PAUNS aims to organize a unique and important neurology conference in order to present the latest surgical techniques, research and management strategies in neurology. In addition to the presentations by thought leaders from around the world, the conference brings physicians and other clinicians together in networking opportunities that allow them to share their insights. The purpose of the conference also is to share state-of-the-art technology and techniques with clinicians in an effort to improve patient outcomes. It also provided a forum for experts and opinion leaders to share their findings and showcase the latest technologies and innovations in the field, as well as highlight the importance of advancements in neurology and medicine.

The 14th Congress of PAUNS and the 22nd Saudi Neurology Society Meeting explored the latest surgical techniques, research and management strategies in neurology.

Neurological societies from the Arab world exchanged knowledge and experience about practice, education and academic endeavors for a brighter future. One session was devoted to address neurology in the Arab world. In this session, Prof. Raad Shakir, of the United Kingdom and president of the World Federation of Neurology, presented “Burden of Neurological Disorders in the Arab World.” Other talks included “Neurology Research in the Arab World: Opportunities and Challenges.” There were joint symposia with European Academy of Neurology, and speakers from Europe and the Middle East took turns presenting and addressing queries from the participants. A number of ongoing research results also were presented.

The meeting was open to all registrants (854 attendees) to ensure adequate exposure to the workshops for the delegates. Distinguished guest speakers and world-renowned neurologists also were in attendance, including as Prof. Gunther Deuschl, Germany and president of European Academy of Neurology; Prof. Dirk Dressler, Germany; Prof. Aziz Shaibani, United States; Prof. Sean Hill, Switzerland; Prof. Helmuth Steinmetz, Germany, Prof. Dieter Schmidt, Germany; Dr. Edward Cupler, United States and Saudi Arabia; Prof. Messoud Ashina, Denmark; Dr. Hamidon Basri, Malaysia; Dr. Suhail Alrukn, United Arab Emirates; Prof. Bassem Yamout, Lebanon; Prof. Maurice Dhadaleh, Jordan; and many more.

The scientific program consisted of workshops on headache, neurophysiology, movement disorder, transcranial doppler and long-term EEG monitoring), satellite symposia and abstract presentations. Two well-known neurologists from the Middle East, Prof. Aziz Shaibani, who is now based in Houston, and Prof. Hani T.S. Benamer, who is based in the United Kingdom, were given recognition for the successful books they have written:

A Video Atlas of Neuromuscular Disorders, by Prof. Aziz Shaibani
Neurological Disorders in the Arab World, by Prof. Hani T.S. Benamer

The PAUNS Board Meeting was held to elect the following new board members:

President: Saeed A. Bohlega, Saudi Arabia. Secretary General: Waleed Khoja, Saudi Arabia. Vice-Presidents: Mostafa El Alawi Faris, Morocco; Mohammad Abdul Ghani, Egypt; Abdallah Younes, Jordan; Rashad Abdul-Ghani, Yemen; and Chakir Khamis, Lebanon. Treasurer: Adel Al-Jishi, Bahrain.

The Gala Dinner was held at the Park Hyatt Hotel garden facing the famous King Fahad Fountain, the highest man-made fountain in the world.

The success of these events would not have been possible without the vision and hard work of the of the Organizing Committee, our colleagues, strong support of our sponsors, and, of course, King Faisal Specialist Hospital and Research Centre with the institution’s leadership headed by Chief Executive Officer His Excellency Dr. Qasim Al Qasabi.

Cognitive Aging: A Report From the Institute of Medicine

By Dan G. Blazer, MD, MPH, PhD, Kristine Yaffe, MD, and Jason Karlawish, MD
Review and Commentary by Rita A. Shapiro, DO, FAAN, FACP

There is intense individual and public concern over cognitive decline in aging. What may seem like minor forgetfulness when young can result in intense fear of progressive cognitive decline and loss of independence for older individuals. In the U.S. and throughout most of the world, human life expectancy and the number of older adults continues to grow. Ongoing analysis and planning, including inventions that promote healthy aging and cognition, are crucial. Cognitive decline impacts individuals and families as well as society. Treatment and supportive measures consume a high portion of health care dollars and resources by health care providers, social and other services, and public health.

The Institute of Medicine convened a committee in 2014 chaired by Dr. Dan Blazer, a renowned geriatric psychiatrist, of 16 experts from a wide range of disciplines to study and make recommendations regarding the public health aspects of cognitive aging (CA). Dr. Blazer authored the report. By design, the committee did not focus on Alzheimer’s disease or other dementias or on basic science. The authors distinguished CA from cognitive impairment.

The CA report was written for a broad audience, including the general public; health care and human services providers; local, state and national policy makers; researchers; foundations and nonprofit organizations. The 2015 full report and a briefer version can be viewed at: http://iom.nationalacademies.org/Reports/2015/Cognitive-Aging. The multifaceted recommendations included definitions and terminology for CA, epidemiology and surveillance, prevention and intervention opportunities, education of health professionals and the public, as well as increasing public awareness.

Terminology for cognition is variable and not yet standardized. The authors defined cognitions as “the mental functions involved in attention, thinking, understanding, learning, remembering, solving problems and making decisions that are needed for individuals to successfully negotiate the world.” They point out that cognition is multidimensional and involves more than memory alone. CA is a lifelong process of “gradual, ongoing, yet highly variable changes in cognitive functions that occur as people get older.” Cognitive health was “exemplified by an individual who maintains his or her optimal cognitive function with age.”

Key features of CA are:

Inherence in humans and animals
Occurs across the spectrum of individuals
Highly dynamic variable process within and between individuals
Biology is just beginning to be understood but involves structural and functional brain changes.

CA is “not a clinically defined neurological or psychiatric disease such as Alzheimer’s disease and does not inevitably lead to neuronal death and neurodegenerative dementia (such as Alzheimer’s disease). Risk and protective factors include health and environmental factors throughout the lifespan influencing cognitive aging; modifiable and nonmodifiable factors (genetics, culture, education, medical comorbidities, acute illness, physical activity and other health behaviors) and the influence of development (beginning in utero, infancy and childhood) on cognitive aging. The recognition of developmental influences on cognition later in life is a newer concept.

The authors discuss the shortcomings of normative data and recommend the development of better tools to assess CA and cognitive trajectories. “Cognitive aging is not easily defined by a clear threshold on cognitive tests since many factors, including culture, occupation, education, environmental context and health variables (e.g., medications, delirium) influence test performance and norms.” The authors explained that for an individual, comparing cognitive performance is best assessed at several points in time.

Cognitive aging also was characterized by an impact on daily life:

Day-to-day functions, such as driving, making financial and health care decisions, and understanding instructions given by a health care professional, may be affected.
Experience, expertise and environmental support aides (e.g., lists) can help compensate for declines in cognition.
The challenges of cognitive aging may be more apparent in environments that require individuals to engage in highly technical and fast-paced or times tasks, in situations that involve new learning, and in stressful situations … and may be less apparent in highly familiar situations.

The potential impact of CA on driving, decision-making and understanding health care instructions is discussed.

The report aids in rectifying some common incorrect assumptions about older adults such as “it’s all downhill” or that cognitive decline is inevitable, although only a small minority of older adults develop dementia. The authors note the wide heterogeneity among older adults and variability with CA. Some cognitive functions show decline (e.g., speed of information processing, some aspects of attention and memory), others are relatively stable (e.g., sustained attention, crystalized intelligence), and some may improve (e.g., wisdom, expertise, life satisfaction).

Subsequent chapters address the important issue of risk factors and what is known about prevention and intervention for cognitive decline. Information is provided on each known modifiable factor, including lifestyle, physical environment, education, intellectual engagement, social engagement, diet, exercise, vitamins and supplements, toxins and substance abuse. An extensive section is devoted to health and medical factors, including control of cardiovascular risk factors.

Two important, often preventable factors include adverse effects of medications to be avoided in elders (revised Beers Criteria) and delirium (preventable 30 percent to 50 percent of the time). Particular mention is made about benzodiazepine risks and drugs with anticholinergic properties, including antihistamines, which are over-the-counter in many products and often taken to induce sleep. The authors explain additional measures to help prevent hospital association delirium, which is associated with adverse outcomes and can have significant residual effects.

People are worried about cognitive decline and emphasis is given to public education about cognitive aging, including measures to maintain cognitive health. The need for additional research and better understanding is a recurrent theme for each topic about CA.

The committee reviewed the existing evidence for a variety of interventions, some which have been commercially promoted, including cognitive training, medications, supplements and transcranial direct current stimulation. The authors recommend the development of policies and regulatory review of cognition-related products. Advertising may be misleading, and products costly for the involved individual.

It is proposed that core competencies and curricula in CA be developed and implemented for health professionals and that cognitive health be promoted during medical visits. Effects of CA on driving, health care, financial and consumer decisions are addressed with recommendations to help older adults “avoid exploitation, optimize their independence, improve their function in daily life, and aid their decision-making.” Driving resources are provided to help promote safe driving or aid in deciding if it is time to stop driving.

Although additional study is needed, the report also contains information about what can be done now. Consistent with the title, the report concludes with Opportunities for Action. The recommendations involve a wide audience, including individuals and families; communities; health care professionals, associations and systems; public health agencies; organizational, media and consumer groups; researchers and funders; policymakers; regulators; consumer advocacy groups and the private sector. The concluding remarks advised the continued strengthening of efforts in Alzheimer’s disease and other degenerative dementias, while still attending to the vast majority of older adults who may experience cognitive decline without a neurodegenerative disease and who want to maintain cognitive health. The committee “hopes that a commitment to addressing cognitive aging by many sectors of the society will bring about further effective interventions, greater understanding of risk and protective factors, and a society that values and sustains cognitive health.”

Reviews and Commentary

Rita A. Shapiro

The action guide for individuals and families contained excellent information and advised talking to their health care providers about risk factors and prevention of cognitive decline. However, it did not appear to promote discussion of cognitive symptoms with the provider for diagnostic assessment. The potential exists for older individuals and families to attribute all symptoms to cognitive aging even when significant impairment is present. Although concepts of CA, mild cognitive impairment and preclinical neurodegenerative disease are changing, and boundary areas are discussed well in the full report, the action guide for patients and families does not contain recommendations to “talk to your doctor” (or other health care provider) about all cognitive symptoms to make sure they are compatible with cognitive aging.

The shortcomings of current norms are extensively discussed, along with the need for better norms. Current norms affect clinical diagnosis, particularly when applied to a single individual at one point in time. Concepts likely will be refined better in future clinical criteria, but for 30 years ones relevant to Alzheimer’s disease (NINCDS-ADRDA 1984, NIA/AA and DSM5) have required significant impairment in social or occupational functioning or when functional independence is compromised. Additional comments about how the authors reconciled the concept of functional impairment would be helpful to the office clinician trying to make a clinically accurate diagnosis. The report is well-referenced and offers extensive recommendations in each chapter and in the conclusion. They are not prioritized, and each professional group or sector will need to decide which are most important to initiate.

Overall, this published report on cognitive aging “Progress in Understanding and Opportunities for Action” was true to its title and the first of its kind to comprehensively address the topic. The knowledge base of human cognition continues to expand, and there likely will be future refinements. The summary and chapter on “Characterizing and Assessing Cognitive Aging” stands alone as current and thorough for physicians and neuropsychologists. Cognitive aging is an important public health issue, and this report is unique in its scope and call to action. It will be considered a valued resource for many.

Rita A. Shapiro, DO, FAAN, FACP, is an assistant professor in the department of neurological sciences at Rush University Medical Center, Chicago.

References

Cognitive Aging: Progress in Understanding and Opportunities for Action, Institute of Medicine of the National Academies, Committee on the Public Health Dimensions of Cognitive Aging, Dan G. Glazer, Kirstine Yaffe, and Catharyn T. Liverman, Editors, 2015

JAMA. Published online April 15, 2015. doi:10.1001/jama.2015.4380