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What is Global mental health? - read full article

By: Samuel Okpaku

Global health and global mental health are shifts in paradigm that are in response to the globalization process. Meanwhile, there is a shift in the definition and portfolio of health to include for example human rights and climate change. Many rich nations are beginning to include health policies within their foreign policies. Many stakeholders share the international vision of equity to all. We are in this together. This presentation will give a history of global mental health. It will present a definition of global mental health along 5 criteria. This definition as will be useful for research and scholarship. The presentation will highlight what some of the rich countries are contributing to global health, and what more they can do. It will also highlight the reciprocal benefits not only in terms of cultural and friendship benefits, but also potential education, research, and training benefits. It will define global mental health as the range of activities concerned with health that meets five principal criteria: universal and trans universal criterion; public health criterion; stakeholder's criterion; problem ownership criterion; and team criterion. This definition distinguishes it from community mental health and it allows for us likely to facilitate scholarship and research. Global mental health like the overarching process of globalization is not without any criticism. There is a vocal group that challenges the westernization and over medicalization of mental health. The role of such group as a watch dog will also be presented.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L1

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How is health across borders? - read full article

By: Gustavo Carona

The personal perspective of a doctor who has worked in some of the worst areas in terms of humanitarian need of our days. Medicine assumes a completely different role, although the aim is the same no matter where: save lives and improve the quality of life. Our task as a doctor and as an human being should always be seen as citizens of the world, because health issues has no borders.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L2

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What is global for medical students? - read full article

By: Alberto Silva

Medical students have a strong say on Mental Health globally. Mental Health still remains a neglected area of health worldwide. Although neuropsychiatric conditions constitute the highest cause of global disability, access to treatment is limited by the availability of services, affordability of services and treatment, and the stigma attached to mental health conditions. Medical students worldwide support their role as international advocates for mental health. This may be through undertaking overseas electives in psychiatry, championing the mental health needs of all patients in all clinical settings and involvement with mental health charities both at home and abroad. IFMSA considers the elimination of stigma towards neuropsychiatric disorders to be everybody’s business. Medical schools and student psychiatry societies must be instrumental in leading the way for their students by encouraging such activities.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L3

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Temperament and Creativity - read full article

By: M. Luísa Figueira

In the present communication we explored the relationships between temperament and creativity across bipolar disorder, with the specific goal of understanding which temperamental traits are most strongly related to creativity. The bipolar– creativity association may be related to temperamental differences, such as increased cyclothymia that contributes to enhance openness to experience, increase of consciousness, intense activity, heighten of perceptive skills and sensibility. We will focus our presentation in the musical and painting creativity taking as example several artists with excessive temperamental traits and will review prospective studies of non-eminent creativity in mood disorder patients. These are limited in size, scope, and number, but include findings complementing those in eminent creators, suggesting that some facets of bipolar disorder, but not the disorder itself, may confer advantages for creativity.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L4

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The sexuality in dictatorship time - read full article

By: António P. Palha

The author analyses aspects of legislative, social and cultural nature which characterize the fascist period in Portugal, particularly in the decades 30, 40 and 50. The total dependence of girl and woman respectively on father and husband’s authority is evidenced. The virtues of that dependence, exalting the values of conservative femininity according to both catholic religious patterns and political ideals imprinted in legislation, are widely shown through texts, quotations and iconographic symbols.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L5

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From ancient times to Technology - read full article

By: Luiz Gamito

The knowledge about human mind comes from Philosophy to Science through Psychiatry and Neurosciences. Last decades brought to us a marvellous new world of Technologies of Information and Communication (TIC), nowadays each more used on the diagnostic and treatment of mental diseases and dysfunctions. Virtual Reality is a good example about the possible linkage between the pathways of Technologies and Psychiatry in order to improve progress in Medicine. The author, according his self experience, introduces some principles of cyberdiagnose and cybertherapy and discuss concepts around clinical practice.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L6

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Neuroscience based Nomenclature - read full article

By: Joseph Zohar

Current psychopharmacological nomenclature remains wedded to earlier period of scientific understanding, failing to reflect contemporary developments and knowledge, does not help clinicians to select the best medication for a given patient, and tending to confuse patients as they are being given a drug with a different name compared to their identified diagnosis (e.g. "Antipsychotic" for depression). Four major colleges of Neuropsychopharmacology (ECNP, ACNP, Asian CNP, and CINP together with IUPHAR) proposed a new pharmacologically-driven nomenclature focusing on Pharmacological Target and Mode of Action. It includes also 4 dimensions of additional information: 1—Approved Indications; 2—Efficacy and side effects; 3—Practical note; and 4—Neurobiology. Several surveys in four different continents were conducted in order to examine satisfaction with the current psychopharmacological nomenclature, as well as test the NbN. A significant proportion of the participants in the surveys were in favor of the proposed nomenclature. It seems that clinicians found the available nomenclature system dissatisfactory and many times confusing for them and the patients. The proposed nomenclature seeks to up-end current usage by placing Pharmacology and Mode of Action rather than indication as the primary driven force. In the session examples of using the NbN in key medications will be presented and discussed.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L7

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A multidimensional approach to depression - read full article

By: Vicent Balanza

Major depressive disorder (MDD) is a prevalent condition associated with potential disability. Given that monoamine-based antidepressant therapies fail to address many important needs and associated side effects may be burdensome, more effective and safe interventions are needed. Omega-3 polyunsaturated fatty acids (PUFAs) may be one such option and there is growing interest for nutritional supplements worldwide. Several lines of evidence suggest that diminished omega-3 PUFA concentrations are associated with MDD. The shift away from traditional dietary patterns, including fish and seafood rich in omega-3 PUFAs, has been associated with increased rates of depression. Patients show lower levels of omega-3 PUFAs in body tissues. In addition, supplemental omega-3 PUFAs have shown efficacy to improve depressive symptoms and proven to be a very safe and well tolerated treatment. At the molecular level, Omega-3s have shown anti-inflammatory, antioxidant and neuroprotective effects, which are strikingly similar to those of conventional antidepressants, and might explain their clinical benefits in mood disorders. The active antidepressant component from omega-3 PUFAs is eicosapentaenoic acid (EPA). The reason why EPA is more effective than docosahexaenoic acid (DHA) in the treatment of MDD is not yet elucidated, but one of the mechanistic underpinnings may involve anti-inflammation. Increasing evidence suggests that inflammation plays an important role in the pathophysiology of MDD. For instance, elevated levels of pro-inflammatory cytokines have been consistently shown in MDD patients and the induction of a pro-inflammatory state facilitates ‘sickness behaviour’ resembling depressive symptoms. EPA has a stronger anti-inflammatory effect than DHA. This presentation will critically update the clinical evidence for the use of omega-3 PUFAs in MDD, with a focus on inflammation. The potential preventative and therapeutic efficacy of these compounds will be considered.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L8

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EFPT International Brain Drain Study - read full article

By: M. Pinto da Costa and EFPT Brain Drain Research group

Introduction: Migration of mental health professionals is an important phenomenon influencing mental health services of host and donor countries. Data on medical migration in Europe is very limited, particularly in the field of young doctors and psychiatry. To research this hot topic, the European Federation of Psychiatric Trainees (EFPT) conducted the EFPT Brain Drain Survey.

Objectives: To identify the impact of previous international experiences on migration, and to understand the characteristics, patterns and reasons of migration, as well as what is an attractive job for psychiatry trainees and what needs to be improved in psychiatry.

Methods: In this cross-sectional European multicentre study, data were collected from 2281 psychiatric trainees across 33 countries. All participants answered to the EFPT Brain Drain Survey reporting their attitudes and experiences on migration.

Results: Two-thirds of the trainees had not had a short-mobility experience in their lifetime, but those that went abroad were satisfied with their experiences, reporting that these influenced their attitude towards migration positively. The majority of the trainees has considered leaving the country they currently live in. Flows showed that Switzerland and United Kingdom are within the main host countries, whereas countries as Romania highlights from the main donor countries. ''Pull factors'' were mostly personal reasons, whereas typically ''push factors'' were mainly financial reasons. Indeed, trainees that wanted to leave the country were significantly more dissatisfied with their income. There is nevertheless an atypical pattern of migration worth to be further analysed.

Discussion: The possibility to endorse this discussion in a symposium on workforce and human resources, presenting and discussing the findings from the EFPT Brain Drain study, may raise awareness on the current trends, help to elucidate the underlying issues and recommend possible systems of support.

Conclusions: Migration within psychiatry will probably to a certain extent continue, being therefore essential to enhance support to those who migrate, and actually influence the mental health care provided internationally.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L9

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Views from donor countries - read full article

By: Ana Giurgiuca, M. Pinto da Costa, and EFPT Brain Drain Research group

Introduction: Migration of highly skilled professionals to a better working and living environment is widely referred to as 'brain drain'. This phenomenon is currently influencing the mental health care professionals living in Europe by leading them to relocate towards higher income countries within the EU. This work force migration highly influences the mental health services of donor countries..

Objectives and Methods: To identify migration attitudes and their underlying reasons among psychiatric trainees living in the donor countries in Europe, as identified in the Brain Drain research study, led by European Federation of Psychiatric Trainees in Albania, Bulgaria, Cyprus, Ireland, Latvia, Romania and Ukraine..

Methods: This presentation will focus on the Brain Drain results from the donor countries.

Results: Past mobility experiences of psychiatry trainees seem to influence their attitude in favor of migration and increase the chances to leave their country of origin in the future. The most significant push factor is the financial one, whilst personal reasons seem to influence most trainees towards remaining in their country of origin. Trainees that express their intension to leave are significantly less satisfied with their income. Specific characteristics, patterns and reasons for migration of psychiatric trainees will be compared between the 7 donor countries.

Conclusion: Psychiatry trainees from donor countries display a positive attitude towards migration and similar patterns can be identified regarding their motives. However, some reasons seem country specific and heterogeneity occurs regarding the push and pull factors for migration.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L10

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Views from host countries - read full article

By: Kevin Holmes, M. Pinto da Costa, and EFPT Brain Drain Research group

The EFPT Brain Drain Project involved surveying psychiatry trainees within x countries across Europe to understand the attitudes to and experience of migration. Following analysis of the results it became clear that some countries appeared to be net donors whereas a few appeared as net hosts for psychiatry trainees. Our results showed that Sweden, Switzerland and the UK were all significant net hosts. One of the main contributors as a ‘pull’ factor, assessed through the Brain Drain results, was unsurprisingly salary. It is notable that all three host countries were within the top two highest wage brackets within our survey. The percentage of immigrants varies from 28% in the UK to 70% in Switzerland. Presented are the individual host country results, looking at common themes that appear to attract trainees to migrate to these countries. In addition, the attitudes and experiences of individual trainees are discussed to try to draw some conclusions from our survey sample. These results are then considered within the overall political and financial landscape to make some concluding remarks.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L11

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Health workers for all - read full article

By: Giulia De Ponte

Mobility of is a right of every individual: like other professionals, health workers have the right to choose the place where they wish to live and work. In a public health perspective, however, health systems have also the duty to ensure that mobility of professionals does not translate into brain drain, and into inequality of access of citizens to health services. Which are the policies put in place at European and global level to ensure that both the right to mobility and the right to health are protected? The impact of austerity measures on mobility of health workers across Europe will be taken into account; cases of specific countries will be briefly presented; actions at European and local level will be illustrated.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L12

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Joint action on health workforce planning and forecasting - read full article

By: Eszter Kovács

Health workforce mobility is a crucial factor when considering long-term strategic health workforce monitoring, planning and forecasting activities. The increased movements of health professionals have been investigated in the last few decades, when the EU enlargement and the economic crisis as significant macro-factors fostered the migration and altered some trends. Data collection and analyses were performed in the Joint Action on European Health Workforce Planning and Forecasting (JA EUHWF 20122201) project. Quantitative and qualitative methods were employed to map available mobility data in EU Member States, and to reveal the different ways how mobility is considered in health workforce planning. The findings showed that the availability of mobility data is highly fragmented. Even the most advanced health workforce planning systems frequently experience the lack of reliable and valid quantitative data for mobility. Different mobility indicators, mostly proxy indicators or estimates are in use, thus the precise numbers are still vague. The minimum planning data requirements for health workforce planning should contain health professionals’ in- and outflows, based on a standardized formula. Qualitative data collections might support to overcome the gaps and to complete quantitative information. Several initiatives attempt to track mobility of health professionals, however an integrated approach is needed within Europe, international data collections - such as WHO, OECD, Eurostat – should focus more significantly on mobility data. Collecting data on licensed and practicing foreign health professionals and a strengthened, more automatic information exchange between Member States would facilitate having a deeper understanding and a more exact overview of the situation. Since some popular destination countries highly rely on foreign human resources in their domestic labor force, doubtlessly necessary to calculate their volume for the future. On the other hand, countries with significant shortages also need to gain clarity of the current and future trends in order to ensure the sustainability of their health systems. Not only the numbers, but also the skills – and skill-mix – of the future health workforce should be taken into account in planning, so mutual recognitions and equivalences in trainings, or continuous professional development might be monitored among the activities.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L13

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European early career psychiatrists - read full article

By: O. Andlauer, N. Jovanovic, K. Koelkebeck, O. Kazakova, and M. Pinto Da Costa

The European Psychiatric Association has had a dedicated Early Career Psychiatrists Committee for more than 5 years. Its aim is to involve Early Career Psychiatrists (ECP) in the association, and develop training activities. Its four task forces focus on research, publications, associations and professional development. The dedicated scientific programme during the EPA Congress gathers ECPs from all around the world, and provides scholarship, travel grants, and social activities during the Congress and throughout the year. It contributes in creating an identity to European Psychiatry.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L14

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Young Psychiatrists’ Network - read full article

By: Raphael Psaras

The Young Psychiatrists’ Network (YPN) - www.ypsnet.org - is a rapidly growing network of Early Career Psychiatrists and Psychiatric trainees. Its aims include, global development of psychiatry through close collaboration of Young psychiatrists worldwide, expanding knowledge and sharing experiences, and facilitating the evolution of YPs from different parts of the world and improvement of their knowledge, skills and abilities. The Young Psychiatrists’ Network was born in 2009 as ”Young Psychiatrists Eastern Europe” due to an initiative from the – no longer active - Swedish Eastern Europe Committee, and the 1st international meeting was organized in Vilnius, Lithuania in 2010. But the Network evolved, involving psychiatrists from more and more countries, and organizing three more very successful conferences, in Riga, Minsk, and Wroclav. Other projects of the YPN include Scientific collaboration, Research collaboration, and Regional meetings. The 5th Young Psychiatrists’ Network Meeting will take place between 30 September to 3 October 2015, in Porto Heli, Greece. The annual YPN Meeting always combines the exceptionally interesting scientific program with the rich daily social program and the rare opportunity of creating friendships with Young psychiatrists from more than 30 countries.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L15

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What patients want from Psychiatrists? - read full article

By: Pedro Montellano

Scientific knowledge has its own pace. It doesn’t happen when the scientists want and, in many occasions, when mankind most needs. The advances on mental health science that had a significant translation on patient’s care have been very rare in the last decades. It cannot be said that an innovative treatment or a new therapeutic approach has seen the light of the day. Some improvements have occurred in some psychiatric medicines but they still present several side effects that are responsible for dysfunction and are an obstacle to the patient’s integration in the community. Considering the document with the conclusions of the meeting of the EU Ministers of Health, in 2005, Helsinki, has Psychiatry, as a science and a treatment discipline, been able to provide to patients treatment outcomes that allow them to pursuit the vision expressed in the document, namely in what concerns the full integration in the society of people with mental health problems? Were the Psychiatrists in this past ten years opened to accept the changes of its papers and to promote the changes needed in the health care systems? What was the context for the Psychiatrists during this period? Considering that the complexity of the brain makes the improvements in Psychiatry science even more difficult than for the majority of sciences, the apparent disinterest of the pharmaceutical industry to develop new medicines for CNS and the limitations of health care systems, what can psychiatrists and patient do overtake this difficult situation?

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L16

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Is it a burden for families? - read full article

By: Filipa Palha

This presentation has two main objectives: 1) to introduce the European Federation of Families of People with Mental Illness (EUFAMI), a European non-profit organisation that primarily advocates on behalf of families and family carers. Founded in 1992 after a meeting where members from all over Europe "shared their experiences of helplessness and frustration when living with someone with severe mental illness"; 2) to present preliminary results of an international survey carried out in 2014 and 2015 in more than 20 counties to get a clearer picture of the experiences, well-being and needs of family caregivers for persons with a severe mental illness. This study focuses on family caregivers of people with schizophrenia in different Western countries. 431 family caregivers filled in a questionnaire about experiences, well-being, and needs, and data from 7 countries (Australia, Canada, France, Germany, Italy, Spain and United Kingdom) will be discussed.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L17

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How is mental health in international missions? - read full article

By: Maria Palha

Many times when we talk about mental health our mind wrongly traps us with examples like “the angry neighbour that shouts to her kids”, “that friend who has awkward behaviour or committed suicide”, “The crazy ex boy Friend who was paranoid” or “the main Psychiatric ward”. In fact all this assumptions are included in the vast area of mental suffering and not mental health. If we stick to the concept of mental health we access a world of harmony and well being that all of us desire to achieve. Nowadays science and information are available about physical and mental health, but it seems we have favouritism for our Physical health and a prejudice when it comes to Mental health. Why? We know that a sedentary life has impact in the quality of our sleep; we know that the excess of sugar in a daily basis is not good and we also know that cholesterol can damage our health. Living in an on-going stressful context can affect our well-being; A diet with vitamins deficiency can influence our memory, concentration and the way we perceive others and the world that surrounds us. For this reasons I believe it’s urgent to integrate Mental and Physical health without favouritism. If we are aware of its advantage I think we shouldn’t do differently and especially because we have a holistic and integrated condition as human being. Once we are conscience about ourselves and the impact that reality has in us, we can become experts in adjusting and surviving to all contexts where we live. By developing and getting self-knowledge about the way the reality impacts us we will also be able to monitor and regulate our emotions adjusting our answers to reality and others. When it comes to crisis situations, like humanitarian crisis, wars, natural disasters or even a big change of life, once we know what can happen to our mental and physical health, we will be able to identify our general needs and we will also be able to react and reduce the impact of this unexpected situations, that requires a fast and adapted response. This is the main benefit of a mental health Intervention when it comes to a crisis situation. Mental health will not only prevent mental suffering and mental chronicle conditions, like depressions, generalized anxiety, schizophrenia or psychosis, but will also support the medical programme when it comes to community approach and understanding. Generally during crisis situations people get scared about the symptoms they began to express, like insomnias, angriness, emotions instability, confusion or hair loss. They also get more suspicious about each other and especially about foreign support. Many times people begging to think that they are getting crazy, tend to get angrier and isolate themselves, facts that will increase what is a normal stress reaction into a severe condition or a chronicle condition (like Post traumatic stress disorder for example). As soon as the population get the information about what services are available to support them as well what can be a normal stress reaction, will also understand what is going on with them and begin to learn how to take care of themselves, understanding what can be health and unhealthy ways of copping. Studies show that as soon as the population has information about their normal stress reactions they are resilient to recover by themselves in 80%, only 20% will need individual support. This will also prevent the medical services obstruction and contribute to a traumatic social recovery. Form this 20% only around 1% will require a long-term intervention, due to development of Pathologies. I must admit that I became excited with this studies, because is very good news when it comes to generational trauma in countries in war. With Efficient Mental health intervention we can interrupt the traumatic transgenerational cycle.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L18

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Medical writing and publishing – Acta Médica Portuguesa - read full article

By: Rui T. Marinho

Medical editing and publishing is a key issue in medical activity. Is very important for the medical CV as well for the development of medical science. Is part of our preparation and task in order to give better care to our patients. To publish in a medical journal with good impact factor should be one of our most important goals to have in mind. Is good for us, for our Department, for our Hospital, University, Institute, country…. And for our patients and the modern society. So, it is very useful to know “How to Do”. Publish or Perish. Teaching of all the mechanisms to write, publish, review, etc must begin in early years of medical course. Is a difficult task with a lot of defeats. We must be prepared to be resilient. Never, never, never, never give up. In this presentation we present Acta Médica Portuguesa as a case study of a modern medical journal. Acta Médica Portuguesa is in the section of Internal Medicine and General in the position 132 in 150, of Web of Science. It is receiving around 1000 papers each year. We explain the flux of a paper, the process of review, how to use graphics and figures, how to convince the editor-in-chief, how to use facebook, twitter, www. Becoming an editor-in-chief is a specialized task, time consuming and certain times like a referee in soccer: we need them but we hate them all.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L19

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Medical writing and publishing – International Journal of Clinical Neurosciences and Mental Health - read full article

By: João Massano

Scientific writing and publishing is important at all stages of medical education, postgraduate training, and also throughout the professional career. Publications may be the product of original research or the critical evaluation of routine clinical activity, and any of these contribute to the improvement of critical thinking, scientific knowledge and, ultimately, clinical skills. Publications are also important indicators of academic and scientific achievement, which contribute decisively to secure grants and to career progression. Learning how to design, write and review a paper should be formally taught in medical schools, thus providing young medical students and doctors with the right tools to critically appraise and successfully write a scientific paper. The talk will approach the fundamental aspects of scientific writing and publishing, including basic authorship rules, and the trajectory of a paper submitted to a scientific journal. The audience will also be given a few tips and tricks for manuscript improvement, in order to increase the quality of papers and the chance of publication. Acknowledgments: talk given on behalf of the Editor-in-chief of the International Journal of Clinical Neurosciences and Mental Health.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L20

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Intervention in first-episode psychosis - read full article

By: Sofia Brissos

Early intervention in psychosis is based on the assumptions that psychosis is a (neuro)degenerative illness and that its progress can be arrested or reversed by treatment. These assumptions suggest that it may be possible to detect people who will develop psychotic illness in the future and prevent transition to psychosis (the ultra–high-risk paradigm), that reducing the duration of untreated psychosis in people with frank psychotic illness will improve outcomes (the duration of untreated psychosis paradigm), and that more intensive treatment starting at the time of detection of psychosis will improve outcomes (the early intervention paradigm). Around 20% of patients with a first psychotic episode will have no further episodes; this means, however, that symptoms do recur in the great majority of patients. Studies have demonstrated that individuals who receive early intervention including guidance on how to improve their adherence to treatment, insight into their illness and self-management and how to minimise substance use have a better course. Further, early intervention services with an outreach component may reduce hospital admission, relapse rates and symptom severity, and improve access to and engagement to treatment. This is of utmost importance, since non- or partial adherence to treatment is frequent in the critical period, and may have a profound impact on prognosis. In fact, the critical period of the disease (the first 5 years) is a relatively reliable indicator of the long-term course of the disease. In this sense, earlier detection is expected to lead to quicker access to the effective treatment that is necessary during the 'critical period' and is one of the main incentives for setting up early intervention in psychosis (EIP) services. Overall, it seems that interventions carried out as early as possible, namely psychosocial interventions adjunctive to pharmacotherapy, may contribute to symptomatic and functional recovery, and improve prognosis and quality of life in these patients.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L21

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The future of Social Psychiatry - read full article

By: Stefan Priebe

It has been suggested that psychiatry as an academic and medical discipline is in crisis. In many countries, it is difficult to recruit young psychiatrists, and the profession struggles to show what specific skills they have. For more than 30 years, there has been hardly any progress in developing more effective treatment methods. Subsequently there is a debate about the future of psychiatry with suggestions to focus on neurosciences. The presentation will argue that it is essential for psychiatry to embrace social psychiatry as central to its thinking and practice. This involves social values, social approaches to care, and a social perspective in research. Concepts of social psychiatry are not new. Yet, the future cannot be a mere reference to successful periods in the past. So, how can we build on what has been achieved and advance the field? What may be the new ideas and the new approaches? The presentation will argue that future social psychiatry may be guided by three general principles: 1) that mental distress is understood as a phenomenon on a continuum of potential behaviours in a given social context (rather than a dichotomous biomedical illness); 2) that changes to the social context, e.g. in families and communities, influence experience and behaviour; and 3) that personal and community resources are primarily available in social relationships. Pursuing these ideas may require a radically different description of mental distress and a new terminology. Risks and benefits will be outlined, and potential research approaches briefly discussed.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L22

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Integration of mental health into primary care - read full article

By: Tiago V. Pinto

As we all know, mental disorders affect hundreds of millions of people and, if left untreated, create an enormous toll of suffering, disability and economic loss. Despite the potential to successfully treat mental disorders, only a small minority of those in need receive even the most basic treatment. Mental health is central to the values and principles of the Alma Ata Declaration. So, it appears to be logical that integrating mental health services into primary care seems the most viable way of closing the treatment gap and ensuring that people get the mental health care they need. But how to do this? For sure it is essential that primary care workers are adequately prepared and supported in their mental health work. In fact, certain skills and competencies are required to effectively assess, diagnose, treat, support and refer people with mental disorders. For this purpose, we need education and training on mental health care for all students and health professionals training to work in family health and other areas of community oriented primary care. From an European point of view, there is no single best practice model that can be followed by all countries. Rather, successes have been achieved through sensible local application of broad principles. Again, how? Well, it is a fact that integration is most successful when mental health is incorporated into health policy and legislative frameworks and supported by senior leadership, adequate resources, and ongoing governance. Numerous low- and middle-income countries are successfully making the transition to integrated primary care for mental health, such as United Kingdom, Netherlands, Sweden, France, Ireland, Estonia and Portugal. Others, like Italy, Belgium, Poland, Romania and Spain are still making their development mainly on secondary mental health care institutions. In this presentation we will do both the update and the broad perspective of the current situation of the integration of mental health into primary care in the different countries across Europe, with a deeper explanation of the state of the art in Portugal.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L23

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Community intervention on first psychotic episodes - read full article

By: Teresa Maia

The author will describe an Early Intervention Program in Psychosis (PSIC) community based and integrated in a general adult psychiatry service. Early Intervention in Psychosis Programs (EIP) seek to help people who are in the early stages of their psychotic illness, through the prompt provision of comprehensive phase-specific interventions, with focus on recovery, in order to improve outcome. This program has been developed since 2001. The main goals of the Programme are: (1) early diagnosis and treatment of Ultra High risk and first psychotic episode patients; (2) treatment of primary symptoms and reduction of secondary comorbidity; (2) decrease of the frequency and severity of relapses; (3) decrease in the number of drop-outs; (4) decrease of family burden; and (5) promotion of psychosocial integration and development. The PSIC´s protocol include: (1) psychopharmacological treatment; (2) a psychiatric consultation within 2 weeks after referral, (3) Family Intervention; (4) cognitive evaluation (ACECF) on admission; (5) cognitive remediation (including cognitive remediation treatment [paper and pencil cognitive exercises] and ReHACOM [computer based cognitive exercises]); (6) psychomotor therapy; (7) occupational therapy; (8) social Cognition training using SCIT; and (9) socio-professional rehabilitation.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L24

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Social Impact Initiative - read full article

By: Irena Stojadinovic

The Social Impact Initiative is the newest EFPSA team and the only team representing one of the main goals of EFPSA—using psychology knowledge to make a positive impact on society. The first project chosen to be the representative of this team and its vision is the ‘Mind the Mind—to Combat the Stigma of Mental Disorders’ campaign. After thorough research about this topic, it was decided to make an educative workshop for high school students and make a positive impact on society by changing the way they perceive mental disorders and the associated stigma. The first wave of the campaign started in October 2014 and will finish in June 2015. The campaign was carried out in 19 European countries/regions. In each country there were between one and three Local Coordinators, one trainer, approximately 20 volunteers and between 300 and 1500 participants that were high school students involved. Both the Local Coordinators and the volunteers provided feedback and an analysis of this showed great results. The volunteers’ experience in both training and workshop delivery was very positive, the overall impression of students’ interest and engagement was very high and the workshops were mainly estimated as successful. The most difficult challenges volunteers faced were time management and keeping participants focused throughout the workshop. The next steps in the campaign are: revision of all the materials according to the feedback analysis, the experts’ check of the workshop, ensuring some sort of professional support for the project and development of the questionnaire measuring the campaign’s impact. The second wave of the campaign will start in September 2015 with a great potential of having an even bigger impact on society. The future plans for Social Impact Initiative are finalising the ‘Mind the Mind’ package and producing a report on all of this work, reestablishing the partnership with IFMSA on the topic of Mental Health and approaching other similar organisations to initiate new partnerships, as well as starting new campaigns on other sensitive and highly relevant topics for society.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L25

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The real pathology of depression - read full article

By: André F. Joubert

Depression is described as a disorder rather than a disease. This notion gradually needs to be challenged as we try to demystify depression and bring it into the realms of biological medicine. Using some of the accepted biological mechanisms describing depression, one is able to demonstrate the “whole body” nature of depression as a disease. More specifically, there is a difference between the neurotransmitter deficits and the underlying core biological deficits in the pathology behind depression, including the inflammatory hypothesis, the role of BDNF and neurogenesis, and other biological hypotheses. The deficits that underscore the “real pathology” of depression may pose new implications for treatment and treatment response.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L26

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The Profile of a Psychiatrist - read full article

By: Marc Hermans

The UEMS published in 2005 “The Profile of a Psychiatrist”. Although declared due for revision in 2009, the document has never been subject to such a process. The EFPT, represented by its president, Mariana Pinto da Costa, has been volunteering to revise this document on one of its scientific meetings. A workshop open to all trainees interested, seemed to be the most appropriate format to work on this document. Attendants working on it are expected to have read the document. They shall have the opportunity to give their suggestions during this workshop in order to eliminate elements no longer relevant, to keep necessary elements in the existing document, and to add elements that might have gained interest during the last few years.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L27

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First and second generation of cognitive-behavioural therapies: why the third was needed? - read full article

By: Serafim Carvalho

The first generation of behaviour therapy, which can be dated as far back as the 1920s, sought to modify problematic behaviour by the application of basic principles of classical or respondent conditioning à la Pavlov; and/or operant conditioning, in which behavior change is linked to reinforcing consequences. The potential contribution that language and cognition played in initiation, maintenance, exacerbation and improvement of abnormal behaviour could be acknowledged, while at the same time it could be largely ignored. The need to somehow incorporate language-based processes within behaviour therapy become obvious. In the 1970s cognitive therapy emerged as a distinct approach in response to this challenge, along with related efforts to create cognitive behavioural modification/therapy hybrid by combining cognitively based processes and techniques (e.g., cognitive restructuring), with existing respondent and operant conditioning principles and strategies. Despite clear technical and some conceptual differences between the first and the second generation of behaviour therapy, they still shared a common objective of focusing on what can be regarded as a strategy of first-order change, that is, attempting to alter the form, the frequency, and or content of abnormal behaviour. By the start of the 2000s, empirical limitations as well as philosophical reservations about the second wave of behaviour therapy, gave rise to the third generation approaches emphasizing a second-order change agenda, in which focus is shifted from altering the form or content of abnormal behaviour to the context in which it occurs. It is not easy to change the contextual factors as they are socio-verbal (language) and ubiquitous. The third wave therapies focus on aspects such as how language affects our experience, the concept of mindfulness, self as context, acceptance, commitment to values, compassion and therapeutic relationship. Some of third generation therapies presented at this workshop were: Acceptance and Commitment Therapy, Compassion Focused Therapy, and Mindfulness. The third wave comes to make behaviour therapy more comprehensive, depth and concerned in establishing a relationship with human problems in a broader sense.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L28

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Training our minds in compassion: an introduction to compassion-focused exercises and mindfulness skills - read full article

By: Paula Castilho

This presentation offers an outline of a basic approach to thinking about the nature of, and value of, developing compassion in our lives. In the other hand, explores some exercises that we practice to try to stimulate our own compassionate mind. (Self)Compassion is the heart of mindfulness. It is warm-hearted, connected presence during difficult moments in our lives. Thus, compassion can be thought of as a skill that one can train in, with increasing evidence that focusing on and practicing compassion can influence neurophysiological and immune systems. Compassion-focused therapy refers to the underpinning theory and process of applying a compassion model to psychotherapy. It is an integrated and multimodal approach that draws from evolutionary, social, developmental and Buddhist psychology, and neuroscience. First, we will explore how our brains work and what we mean by compassion. We are going to start by looking at a couple of challenges that life presents us with and that we all experience. Second, we will examine how the therapist help the client experience safeness in their interactions with him, to tolerate and feel safe with what is explored in the therapy, and to replace self-criticism with self-kindness. Empirical research suggests that a specialized affect regulation system (or systems) underpins feelings of reassurance, safeness and well-being. Compassion-focused therapy focuses on the development of the social safeness system in the therapy through the training of compassion and mindfulness exercises.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L29

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Acceptance and commitment therapy: an overview - read full article

By: Inês Guimarães

Acceptance and Commitment Therapy (ACT), is described as a third wave cognitive-behavioural therapy that is based in Relational Frame Theory (RFT). ACT is a psychotherapeutic approach that emphasizes the learning of acceptance and mindfulness skills as means to intervene in the psychological processes that underlie psychopathology, such as cognitive fusion and experiential avoidance. The aim of this communication is to provide an overview of ACT, covering briefly its theoretical foundations (Functional Contextualism and Relational Frame Theory), and to explain the psychological flexibility model that underlies ACT in its conceptualization of human suffering and psychopathology. The core therapeutic processes of ACT (mindfulness, acceptance, cognitive defusion, self-as-context, values and commited action) will be described, and given the experiential nature of many of the ACT interventions, these will be illustrated through experiential exercises and metaphors.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L30

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Complaints, litigation and malpractice: how to survive as a psychiatrist - read full article

By: Julian Beezhold

This informal user-friendly highly interactive course is aimed at addressing the ever-increasing tide of complaints and litigation faced by psychiatrists in their daily clinical work. All content is designed for an international audience working in a variety of different legal and regulatory environments. The course will provide a broad overview of the context, including data on complaints and litigation. We will then examine in greater detail the areas of medical error, complaints, litigation and medical misconduct. Discussion will highlight the situations and actions that more commonly lead to concern. There will be a focus throughout on actual real-life cases. We will explore the theory and practice of the prevention and minimization of the number and severity of adverse events in psychiatry. This will include looking at practical tips for individual practice as well as the gains that can be achieved by a systems approach to reducing medical error. This course aims to help improve the confidence and skills of participants in dealing with adverse events such as complaints and litigation; and also enhance participant’s ability to prevent things going wrong in the first place.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L31

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Suicidal risk assessment - read full article

By: Marco Sachiapone

The World Health Organization estimates that approximately 1 million people die each year from suicide; during the 2012 annual global mortality rate was about 11.4 per 100,000 and it is estimated that 1,500,000 will die from suicide in 2020. The suicidal behaviour is a complex and multi-determined phenomenon, determined by the action of several bio-psycho-social factors. Due to its complexity, it is not possible to absolutely predict if and when a suicidal behaviour will take place, but it’s possible to take into account the presence of certain risk factors and especially their coexistence. The main risk factors for suicide include mental disorder (depression, anxiety, personality disorder, use/abuse substances, schizophrenia), personality traits (aggression/impulsivity), the presence of familiar history of suicide and childhood trauma, some physical illnesses (neurological disorders, cancer, HIV infection), some specific socio-cultural characteristic. Even if the early diagnosis and an adequate treatment are keys to suicide prevention to date, there are not tools that allow an overall assessment of these dimensions. During the CME Course the Suicide Risk factors Check – List will be illustrated. This Check-list can be administered by mental health professionals and aims to allow a prompt and early screening of person at risk for suicide, integrating psychometric and anamnestic data and creating a check-list of the presences of risk factors.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L32

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Treatment of suicidal patients - read full article

By: Vladimir Carli

The need to have valid and effective treatments of suicidal behavior is as important as the early screening of the individuals at risk. However, the treatment of suicidal behaviour is complicated by a series of factors, since there aren't shared pharmacological therapeutic strategy available; an environment characterized by high stress and anxiety; the need of multi-disciplinary therapeutic interventions. Despite these difficulties the professionals who work with people with suicidal risk, have the general principles to refer for the treatment of these cases. The treatment of suicidal behaviour is based on some main concepts, as the importance of adequate communication between doctor and patient and the integration of pharmacological, psychological and social treatment. During the Course, these concepts basics of treatment as well as the important issue of hospitalization of the patient at risk of suicide will be illustrated.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L33

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Psychiatric Interview – subjectivity in the diagnosis - read full article

By: Luis Madeira

The scope of psychopathology as a discipline and its ability to (1) shape what is disturbed or normal and (2) to be assessed in the mental state examination has always been central to Psychiatry. For more than a century the increase of clinical workload, strict insurance policies and the request of objectivity and reliability for research have enforced categorization and operationalization of psychopathological phenomena. This move has been blamed as having led psychopathology into a dead end, undermining research and clinical diagnosis. The search for objectivity was spearheaded by the belief that standardization would (1) help increase its ever-low reliability, (2) diminish the exposure of Psychiatry to scientific criticism and most of all (3) restore the reputation of psychiatrists for they were reckoned as lacking scientific validity. Yet psychiatry seem to have dismissed the relational proxies of meaning (overlooking the conversational structure of the inquiry) accepting checklists of symptoms as proxies of patient’s rapport even if performed by untrained interviews, in uncanny settings (e.g. telephone or email). The clinical impression together with all pre-reflexive appraisal inputs was lost in the operationalization. The nature of phenomena we are accessing and studying are different from the symbols we learnt in psychopathology. Moreover the validity of the symbols we are learning have for long been overlooked as we are short of conceptual research . The quality of the rapport is contingent to the type of relation established and the acquaintance with intricateness of psychopathological symbols. Making such training a relevant feature of medical education might increase the quality of assessments and therefore improve diagnosis and research.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L34

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Statistical methods in psychiatric research - read full article

By: Corália Vicente

This course aims to present and discuss statistical methods in order to create a proper database, select appropriate statistical methods in the analysis of Psychiatric Research studies, use different types of designs having in account the pros and cons of each of them, present findings of a statistical analysis in a clear, concise and understandable way, identify the strengths and weaknesses of a research study and assess the usefulness and validity of the research findings. To attain these objectives case studies will be debated. After the course the participants will be able to appreciate the role of statistical methods in epidemiology, develop skills in presenting quantitative data, appreciate the sampling variation and the role of statistical methods in quantifying variation and testing hypotheses, use appropriate statistical methods in the analysis of datasets, interpret outputs and present findings from the statistical analysis. This will be a course intended for students with just a basic knowledge of the common statistical methods used in medical research. Previous computing experience is not required although it would be helpful.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L35

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Past and future of Training, Investigation and Intervention in CAP - read full article

By: Pedro Monteiro

Child and Adolescent Psychiatry is among the most fascinating fields of medicine. One of the most attractive factors in the rewards of working with children and families is the satisfaction of helping them to return to a healthier developmental stability. Mental health problems are expected to increase and psychiatrists are at the forefront of helping society to engage in best solutions. As we are at the front line of many problems and pathologies of children and adolescents we are in a unique position for intervention. According to this I have selected two main topics to discuss: (1) The early identification of children and adolescents at risk for schizophrenia and the Duration of Untreated Psychosis (DUP); (2) The psychotherapies. Progress in Child and Adolescent Psychiatry is based on the developments of psychology and neuroscience in a way that involves non-confrontational integration of biomedical and biopsychosocial models. This uses a combined practice of psychotherapy and psychopharmacology; we must continue to distinguish our practice from that of a “neurobiological prescriber” so as to prevent our discipline from merging with neurology.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L36

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The role of Child and Adolescence Psychiatry in Paediatric Oncology - read full article

By: Zulmira Correia

Children in oncology units face death. Many adults have the wrong idea that children don´t think about their own death. The most difficult moment is that of a relapse when a child thinks he is being punished . The role of child and adolescent psychiatrist concerns children, parents, siblings and other professionals involved in treatment. Mostly how to communicate bad news, but also how to return to normal life. When there is nothing we can do there is always something to do.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015.

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L37

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Health planning in Portugal - read full article

By: F. Parra da Silva

The Joint Action on Health Workforce Planning and Forecasting is working towards: (1) better understanding of terminology; (2) better monitoring of the HWF by access to timely data; (3) updated information on mobility and migration trends in the EU; (4) guidelines on quantitative and qualitative HWF planning methodology; (5) increased quantitative and qualitative planning capacity; (6) estimation of future skills and competencies needed in the health workforce; (7) a platform of cooperation to find possible solutions on the expected shortage of HWF; and (8) a higher impact of HWF planning and forecasts on policy decision making. 
Portugal, with this project, aims to: (1) improve the planning of medical specialists; (2) improve planning of HWF in less attractive and more needed areas; and (3) improve the methodology for identifying the needs of health professionals.
Portugal has already a database characterizing the existing stock of health professionals in the NHS. We are trying to complete the database with information from the private sector (a specific law has already been approved in general, in the Parliament, and is now being in specialty analysis).
For doctors and nurses we are trying to: (1) anticipate imbalances (supply vs demand) for medium and long term; (2) improve the knowledge on mobility of professionals within the EU; and (3) build tools that allow managing and adjusting the training capacity.
For dentists and pharmacists the scope of the pilot project considers measuring the current stock. 
This project considers the stakeholders within the Ministry of Health and the external ones, like others ministries, universities and professional associations.
About the involvement of stakeholders, we’ve had a first meeting, beginning 2014, and are planning a new one, next month. This aims at involving them in the planning process consistent with our own characteristics. 
And then, at the end of the pilot project (March 2016) we to measure the improvements in the period of the project.
The Pilot Study is working on a fixed term project to support national authorities in the implementation of models, procedures and tools, following the handbook produced in the framework of the Joint Action on Health Workforce Planning and Forecasting.

From the 23rd EFPT Forum, Porto, Portugal. 22–27 June 2015

International Journal of Clinical Neurosciences and Mental Health 2015; 2(Suppl. 1):L38


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Egas Moniz: the man and his work - read full article

By: Victor Oliveira

Egas Moniz was a Portuguese neurologist (1874-1955) with a multivariate scope of interests and remarkable interventions in Portuguese society: formerly as politician and later as physician, investigator and writer. Internationally he is recognized after his contributions to the advance of medicine. He was the founder of Portuguese Neurology and gained international recognition because of the development of cerebral angiography and later, because the surgical attempt to treat some psychiatric diseases: the so called Leucotomy. He was awarded with Noble Prize in 1949 shared with the Swiss psychologist Walter Hess. Egas Moniz was graduated at the University of Coimbra 1899 and begun his carrier in 1900 joining an academic position at that University of Coimbra with a place at the Portuguese monarch parliament. Soon after (1902) he directed his curiosity to Neurology and during his summer holidays he was able to spare a couple of weeks to visit La Salpétrière were some members of the golden era of the French and world neurology worked, such as Babinski who became close friend of him. After quitting a delusive political career where he was minister of foreign affairs and president of the Portuguese delegation to the peace conference at Versailles “with more sorrows than good remembrances” as he used to say, he dedicated his whole energies to medicine and the scientific talent of Egas Moniz was revealed. Angiography. The knowledge of brain circulation and though this, the brain pathology, namely tumors and other intracranial abnormalities along with cerebrovascular pathology became possible after his discovery in 1927 which is still performed everyday in large hospitals worldwide. Vascular structures like carotid siphon owe its name after him. Leucotomy. In an era of no effective treatment for psychiatric diseases forcing many patients to remain institutionalized for live, the idea of a surgical procedure to calm agitated patients allowing them to return to community was attractive. His experimental attempts by causing small lesions in both frontal lobes showed promising results. Driving these experimental ideas into an unwise massive practice as Walter Freeman in USA, did, (the so called lobotomy) launched much controversy and discredit. Egas Moniz never performed any of these procedures (either angiography or leucotomy): he was a man of ideas and as he used to say: he was the brain and his surgical colleagues, their hands. After retirement in 1945 he dedicated to writing and his private practice at downtown Lisbon. He received many international awards in recognition of his role in the development of Medicine, including the Noble prize in 1949. He died in Lisbon in December 1955 at 81 years of age.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L1

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Trinucleotide repeats - read full article

By: Sandra Macedo-Ribeiro

Trinucleotide repeat (TNR) expansions are present in a wide range of genes involved in several neurological disorders, being directly involved in the molecular mechanisms underlying pathogenesis. The molecular mechanisms that correlate TNR expansions with disease are multifactorial and divergent depending on the affected gene. In fact variations in TNR can alter either gene expression and/or the function of the RNA or protein it encodes. This talk will present an overview of TNRs, with a particular emphasis on CAG repeat expansions that are translated into polyQ repeats in the affected proteins. Detail will be given to the interplay between polyQ repeat expansions and flanking regions in modulating the protein dynamics, self-assembly and aggregation of the carrier protein, which culminates in neuronal toxicity and cell death.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L2

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Hysteria, simulation and functional disorders: from Charcot to Charcot - read full article

By: Julien Bogousslavsky

Jean-Martin Charcot (1825-1893) is at the origin of the modern “rebirth” of concepts on hysteria and related functional disorders. While Charcot never was interested in mental disease and what was called “alienism” at the time, his career at La Salpêtrière over 30 years was marked by the development of huge group of pupils which gathered around the study and management of hysteria. When Charcot took office at the beginning of 1862, hysteria was a no-man’s-.land, since neither the alienists, nor the internists beared a significant interest on it. At La Salpêtrière, these patients were largely left to themselves, before one of the first Charcot’s interns, Désiré Bourneville, stimulated and convinced his chief to care for them. Charles Richet’s 1875 article on somnambulism subsequently was the trigger for Charcot to introduce hypnotism in the management of hysterics. Later on, the studies of Charcot with Richer, Babinski, Gilles de la Tourette, Sollier, Janet and many others allowed to address the condition in detail. During his short stay with Charcot in 1885-6 Sigmund Freud, a young neuropathologist at the time, became fascinated by hysteria, an interest which was the main start point of his interest in psychology, and probably the origin of psychoanalysis a few years later. Charcot indeed emphasized mental – including “sexual - factors in hysteria long before Freud, along with the concept of a “dynamic” lesion, which accounted for the lack of neuropathological findings in all studies. While Charcot’s concepts on hysteria and hypnotism were criticized after his death even by former pupils, such as Babinski, recent findings from functional MRI studies show how accurate and often visionary Charcot’s thinking was in this field. In 1908, a “quarrel of hysteria” opposed several Charcot’s pupils, where Babinski was considered victorious against Charcot’s successor Raymond, despite the weaknesses of his theory on “pithiatism” (i.e.“curable by persuasion”), which erased the border between hysteria and simulation. During World War I, there was a new surge of interest in hysteria associated with war psycho-neuroses, and several students of Charcot became involved in medical-military care (Sollier, Babinski, Ballet, Souques). Babinski’s pupil Clovis Vincent developed a treatment called torpillage (torpedoing) against war hysteria, associating painful galvanic current discharges with “persuasion”, but which was dismissed after the rebellion of soldiers, who considered it as torture. After World War I, the neurological and psychiatric interest in hysteria again faded away, and this condition largely went back to the neither neurological nor psychiatric no-man’s land, where it had been before Charcot. Today, the boomerang thrown by Charcot is rightfully coming back, since current studies support most of his observations and theories, with reference to differences and similarities between hysteria, hypnotism, simulation, and organic dysfunction.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L3

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Exosomes/miRNA as nano-neurological therapy mediate recovery after stroke and neural injury - read full article

By: Michael Chopp

The ability to regulate and modulate intercellular communication may provide the basis for the treatment of neurological injury, neurodegenerative diseases and stroke. Exosomes are small (30-100 nm) endosomal generated particles consisting of a complex lipid membrane and contain proteins, RNAs,mRNAs and microRNAs (miRNAs). Nearly all cells generate exosomes, and these small lipid containers are ubiquitous in biological systems and provide an intercellular communications network which regulate cellular function. Exosomes mediate intercellular communication by transferring proteins, lipids, and genomic materials including mRNAs and miRNAs between source and target cells. In this presentation, I will describe our work on the treatment of stroke, traumatic brain injury and diabetic peripheral neuropathy with exosomes, with a focus on the transfer of microRNA (miRNA) content within the exosomes to recipient cells. miRNAs are 20-25 nucleotide non coding RNA which regulate gene translation . They act as major molecular switches and are post transcriptional regulators of protein production, and they can simultaneously impact multiple molecular pathways and signaling within cells. We have found that cell-based therapies promote neurological recovery and promote neurovascular remodeling by transferring exosomes to recipient cells. Thus, we have harvested exosomes by means of ultracentrifugation or using biochemical methods from a variety of cells, and directly employed these exosomes by intravenous administration for stroke and TBI to promote neurological recovery . By labeling the exosomes with fluorescent markers we have shown that intravascular administration of these exosomes pass the blood brain barrier and enter into parenchyma cells. The content of these exosomes , as noted , consists of proteins, miRs and mRNAs. Downstream molecular targets of specific miRs known to be transferred into parenchyma cells have been shown to affect their molecular targets, thus demonstrating that the harvested exosomes transfer miRs to parenchyma cells and thereby affect the molecular downstream targets. In vitro studies using microfluidic chambers can be employed to give insight into how exosomes promote neurological recovery. Microfluidic chambers are compartmental structures where neuronal soma and axons are located in separate compartments. The microfluidic device permits distal axons to grow into the axonal compartment after passing 450?m long microgrooves that connect the cell body and axonal compartments. We demonstrate that exosomes placed either on the somal or the axonal compartment significantly promote axonal outgrowth. This exosome enhanced outgrowth can also be inhibited by using siRNA to block Argonaut proteins, such as Ago2. Ago2 protein is a component of the RNA induced silencing complex (RISC), and is the key regulator of miRNA function by mediating the activity of miRNA-guided mRNA cleavage or translational inhibition. The majority of miRNAs in exosomes are bound to Ago2. Reduction of Ago2 in exosomes abolishes axonal outgrowth. Very importantly, the content of exosomes can be tailored to contain specific miRNAs. By transfecting exosomes source cells with specific genes or using siRNA on exosomal parental source cells, we can respectively, upregulate or reduce miRNA content within exosomes derived from parental cells. Using microfluidic chambers and vascular angiogenic experiments we demonstrated that targeting specific miRs will impact specific physiological events. For example, when parental mesenchymal stromal cells (MSCs) were transfected with a miR-17-92 cluster plasmid, exosomes harvested from the MSCs exhibited enriched levels of the miR-17-92 cluster. Applying these exosomes to either the somal or axonal compartments of the microfluidic chamber significantly increased neurite outgrowth. Thus, tailored exosomes can deliver their selective cargo miRNAs into and activate their target signals in recipient neurons. We have performed extensive preclinical studies on the therapeutic use of exosomes for stroke, traumatic brain injury, diabetic peripheral neuropathy, multiple sclerosis and dementia. For example , our data demonstrate that treatment of embolic stroke with exosomes derived from MSCs or other progenitor cells one or more days after stroke onset significantly promotes neurological recovery compared to control populations. Treatment with exosomes also concomitantly enhanced neurovascular plasticity, promoted neurogenesis, angiogenesis, and oligodendrogenesis. Similarly, treatments of experimental traumatic brain injury, peripheral neuropathy, and neurodegenerative models using exosomes harvested from a variety of cells, as well as harvested exosomes tailored to contain specific miRs, were shown to enhance neurological recovery along with neurovascular plasticity. Thus, we are developing a novel therapy, nano-neurological therapy, utilizing the body`s nano-lipid containers, exosomes, which contain and can be loaded with proteins, miRs and genetic instructions , to promote neurological recovery.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L4

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Post-stroke cerebral reorganization - read full article

By: J.P. Mohr

In 1898 the Scottish neurologist Byron Bramwell described “A Unusual Case of Aphasia” an autopsy-documented infarct affecting Broca’s area in the hemisphere dominant for speech and language. His case had aphasic syndrome of brief duration. Few examples were reported prior to 1973. Thereafter, the short clinical course has become well-recognized, especially with modern brain imaging. At first considered exception to the rule, then as examples that Broca aphasia is less important than the Wernicke syndrome, criticisms have slowly faded as a similar short-lived syndrome can occur from focal infarcts for Wernicke aphasia as well. Sensory and motor syndromes from circumscribed infarcts are also now well-known. In large clinical trials the sensory component frequently has a short clinical course. Focal motor syndromes may present with a functionless limb, appearing normal on examination weeks later. For larger Rolandic infarcts or from war wounds, the classical syndrome of dystonic hemiparesis slowly emerges regardless of whether the injury is high or low in the rolandic system. These disparities in outcomes suggest a certain layering function in the Rolandic motor system, the major injuries allowing more primitive motor function to emerge, the perilesional functions or functional reorganization being prevented by the large size of the injury. By hemispheral functional magnetic resonance imaging of unilateral rolandic infarcts provides further support for perilesional activation: a focus of activation predicts functional improvement within 30 days in some patients; why only in some remains unknown. Arguments still exist whether focal infarction in the calcarine cortex itself can be associated with improvement in the visual fields, but there is little argument that a short clinical course may follow anopia from precuneus infarction. The classical disconnection model for alexia now seems established as a volumetric effect, by disruptions of trans-callosal and ipsi-hemispheral pathways. Formerly-acceptable simplistic explanations of peri-lesional edema may have been satisfactory when autopsy documentation was the limited data source. But high-quality modern imaging now also prevents speculation of extremely superficial cortical infarction, or absence of penetration of the lesion into the white matter. In retrospect many of von Monakow’s cases described as ‘diaschisis’ were among these syndromes. If by diaschisis he meant disturbance and remote structures from those damaged, he may have underemphasized the importance of functional reorganization tissue surviving a focal infarct. Focal tissue disruption from infarction or trauma is but one model testing functional reorganization: Transcranial magnetic stimulation maps of Rolandic convexity areas serving a limb to be surgically excised has demonstrated the area post-surgery to have shifted its function serve adjacent body parts. Ingenious studies of local limb anesthesia from arterial blood pressure cuff causing temporary ischemia has demonstrated the cortical reorganization begins almost immediately, and re-establishes its prior organization after blood flow is restored and the anesthesia fades. Not merely perilesional function, but regional cerebral blood flow (rCBF) alterations may create the appearance of focal syndromes. Infarcts in the capsular genu has interrupted neurotransmitter pathways important for frontal lobe responses, creating a blunting of behavior characterized as “strategic infarct dementia”. A dysphasic syndrome has also occurred from pulvinar infarction, blunting rCBF responses over the ipsilateral parietal lobe. For many generations, clinicians have been taking credit for the improvement following focal lesions, assuming it related to our interventional efforts. More attention to the occurrence of what appeared to be compensatory mechanisms could allow insights into their control and augmentation. We could take our inspiration from the knowledge by designers of Voyager 2, allowing them to reprogram some of the hardware with the spacecraft well beyond Pluto. We can look forward to the day when we may achieve similar restoration of performances to allow the brain to achieve its maximum potential after focal injury.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L5

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The meeting of informatics with brain medicine: a vision for the future from the perspective of the human brain project - read full article

By: Richard Frackowiak

We now know that a single human gene mutation may present with any of multiple phenotypes, and vice versa, that a range of genetic abnormalities may cause a single disease phenotype. These observations lead to the conclusion that a deeper understanding is needed of the way changes at one spatial or temporal level of brain organisation integrate and translate into others, eventually resulting in behaviour and cognition or their abnormalities. The basic idea is that it is now possible to look for rules underlying the functional and structural organisation of the human brain, exhaustively, at all spatial scales, and eventually perhaps at all spatio-temporal scales. The methodological approach is to federate and integrate existing knowledge from bottom up using recent advances in information technologies, notably supercomputing and distributed and interactive data basing. The theory is that rules and constraints determining a particular structural and functional organisation at one level will limit what organisational principles are possible at the next. It has, for example, been shown that one can construct in silico models that look and behave remarkably like their ex vivo counterparts, up to the level of the cortical mini-column. The ambition therefore is to link genetic and proteomic levels by determining the rules that govern the segregation of protein expression. From protein expression we can start to extract rules that determine cellular morphology, which in turn predicts connectivity, and so on, until the mechanisms of emergent properties are discovered by a constructive process of reconstruction and predictive simulation, not as isolated modules but as interacting biological entities. Materials scientists discovered that the apparent simplicity of matter emerges from complex statistical combinations of subatomic particles and waves and have generated a rich theory to situate and interpret all new experimental results. They have done so by means of systematic deconstruction based on experimental hypothesis refutation—the classical reductionist approach. So it is perhaps unsurprising that in the case of the human brain, a similar approach has generated a mass of knowledge but no overarching theory explaining emergent behaviour. The response of brain scientists has been to generate more knowledge, hoping that a theory will eventually reveal itself. We argue that the degree of complexity represented by organic matter warrants an additional, complementary set of tools—tools that federate, integrate mine and simulate those data, thus discovering new patterns and rules that govern its organisation. The application of such tools is justified, we think, by one simple fact: every organic object, however complex, is generated from just four building blocks, the four base pairs of DNA. The HBP’s goal is to generate a draft blueprint that describes how the brain is constructed across all levels. The blueprint will provide a framework within which new and old theories can be tested and new hypotheses generated. An immediate aim is to create a federation of hospital databases, whilst respecting the imperatives of security and privacy of individuals. To this end the Medical Informatics Platform of the Human Brain Project brings together scientists and engineers from multiple domains including computer science, informatics, statistics, mathematics, clinical science, neurologists, psychiatrists, neuro-imagers and the like. We have specified and built together software that provides an Open Source distributed platform for use by European and other clinician scientists, population health scientists, epidemiologists, health economists and the like. All these and other health care related disciplines should in the long run be able to benefit from the very large, constantly accruing masses of clinical data that reside, currently grossly underused, in hospital databases. The federation will be distributed, eschewing the need for data warehousing and guaranteeing local control of access to data by every hospital, as presently. Another critical medicine-related research aim of the federated platform will be to use big data techniques and algorithms to fill the multi-dimensional brain disease space, which ranges from psychiatry through behavioural disorders to neurological diseases, with groups of like patients characterised by combinations of homogeneous features. We call such a group of specific features a “disease signature”. A disease signature brings together, in a systematic way, clinical features (phenomenology) and the results of genetic, biological, physiological and anatomical test results (biology). This reclassification should in the long-term supplant the symptom and syndrome based DSM and ICD disease catalogues by ones based on the same clinical features supplemented by patterns of abnormal investigations. This strategy has as its primary aim the definition of more precise diagnoses that reduce error variance in diagnostic categories for construction of clinical trial cohorts. A biological underpinning of phenomenological features may in combination with improved understanding of the functional and structural organisation of the human brain emanating from other parts of the Human Brain Project facilitate other aspects of brain medicine, such as identification of biological treatment targets, planning of potential benefits, risks and side effects of proposed treatments, as well as considerable reduction of clinical cohort sizes associated with more precise disease signature based definition of diagnosis and prognosis.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L6

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Redefining Neurodegenerative Diseases through Epigenetics - read full article

By: Tiago Fleming Outeiro

Neurodegenerative disorders, such as Alzheimer’s (AD) and Parkinson's disease (PD), are highly complex conditions that affect a growing number of patients worldwide, due to the aging of the human population. These disorders have a multifactorial origin, depending not only on genetic but also on environmental factors. Several genetic risk factors have already been associated with both AD and PD, but the precise mechanisms through which the environment contributes to neurodegeneration are still unclear. Recently, epigenetic mechanisms, such as DNA methylation, chromatin remodelling or miRNAs, which induce alterations in gene expression, have been implicated in various neurodegenerative conditions. Given that epigenetic modulation is present from pre-natal stages and throughout life, and that it depends on lifestyle conditions and environmental factors, it might provide new insights into the molecular basis of neurodegeneration, opening novel avenues for therapeutic intervention.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L7

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Is AD caused by viral infection? - read full article

By: Ruth F. Itzhaki

There are now about 100 experimental studies by several groups (including some 40 or so from RFI's group), using diverse approaches, which explicitly suppor—directly or indirectly—the hypothesis that herpes simplex virus type 1 (HSV1) is involved in AD. HSV1 is a neurotropic virus which infects 80-90% of humans by the age of about 60. Once infected, a person harbours the virus for life. It resides in latent form (i.e., dormant) in the peripheral nervous system (PNS) in the trigeminal ganglia but can reactivate under circumstances such as stress and immunosuppression, and in some 25% of infected people it then causes cold sores (herpes labialis). In very rare cases (~1-3/106), it causes the severe brain disease, herpes simplex encephalitis (HSE) The first relevant study, in 1991, revealed by PCR that HSV1 DNA is present in latent form in a high proportion of elderly brains, including those of AD patients. It was subsequently found that HSV1 in brain of carriers of an APOE-e4 allele confers a major risk of AD. The presence of HSV1 DNA in many elderly normal brains as well as in AD brains does not invalidate a role for HSV1; many microbes infect far more people than they affect, so "controls" might be infected but are asymptomatic; i.e., 'infect' does not necessarily mean 'affect'. Later, studies on intrathecal antibodies in the elderly (which are known to be long-lived after HSE), confirmed viral presence in brain, and showed also that HSV1 reactivation from latency can occur in brain (as well as in the PNS), quite probably recurrently; thus, HSV1 is not just an inert passenger in the aged brain. The main concept is that HSV1 reactivates periodically in brain under certain conditions such as stress, immunosuppression, peripheral infection etc. Reactivation leads to a productive infection, which causes both direct and also inflammatory damage, and viral spread. Repeated reactivation would cause cumulative damage - perhaps a limited, localised type of HSE, culminating in the development of AD in APOE-?4 carriers. (Significantly, APOE-e4 is a risk factor for cold sores.) HSV1 DNA presence in human brains has been confirmed by 5 other groups, another confirmed the HSV1-APOE-?4 association in AD, and yet another showed a trend. Further, studies on HSV1-infected APOE-transgenic mice found that APOE-e4 transgenic animals display a greater potential for viral damage. Diverse approaches—cell biological, genetic, epidemiological and virological—have subsequently been used to investigate the role of HSV1 in AD. These indicate that HSV1 does indeed reactivate in human brain and that it induces AD-type damage. Data on HSV1 DNA in CSF, which remains for only one week post-HSE (unlike long-lived HSV1 antibodies), suggest that reactivation of the virus is far more frequent than expected merely from the frequency of HSE. Other CSF studies have shown that biomarkers of AD are more similar to those of HSE patients than are those of patients with other brain infections. Also, in immunosuppressed leukaemic patients, brain specimens revealed HSV1 DNA in those who were seropositive, but not in those who were seronegative, nor in non-immunosuppresed subjects. HSV1 infection of a wide variety of cells in culture, including human neuronal-type, causes accumulation of beta amyloid (A?) and of abnormally phosphorylated tau (P-tau)—the main components respectively of the characteristic amyloid plaques and neurofibrillary tangles seen in AD brains. The increase in A? probably occurs via activation of PKR and de-repression of BACE1 expression. Implicating HSV1 further in AD is the finding that HSV1 DNA is very specifically localised in amyloid plaques in AD brains. This association of viral DNA with plaques does not prove causality, but considered together with the HSV1-induced formation of A?. It suggests that HSV1 is a major cause of A? formation in brain and of its toxic oligomers. Several genome-wide association studies (GWAS) have examined genetic links between HSV1 and its host cells. They show that a limited number of genes, when combined, are strongly associated with AD, even though the effect of any single gene or SNP is very weak. Possibly these genes code for proteins that interact in various processes, leading to a synergistic effect on AD pathogenesis. Also, HSV1 might bind to many cell proteins, thereby modulating their expression, including many encoded by susceptibility genes for various neurological diseases, including AD. Epidemiological studies have examined serum IgG and IgM, also IgG avidity index, and serological data relating to several different microbes; all show association between HSV1 reactivation and AD development, and between infectious burden and cognitive decline, with HSV1 particularly implicated. Cytomegalovirus (CMV) has been implicated also, possibly influencing immune response to other pathogens, thereby triggering the immune dysregulation involved in some age-related diseases, and suggesting specifically reactivation of HSV1 with CMV action and age. There is evidence that A? has anti-bacterial action, as part of the innate immune system, and recently it has been shown to have specifically anti-HSV1 action; however, it is likely that if eventually over-produced, it becomes toxic. Other relevant, harmful effects of infection include dynamic interactions between HSV1 and amyloid precursor protein (APP), the precursor of A?, which would facilitate viral transport and interfere with normal APP transport and distribution; induction of toll-like receptors in HSV1-infected astrocyte cultures, which has been linked to the likely effects of reactivated HSV1 in brain; infection-induced acute or chronic inflammation in triple-transgenic mice, which would exacerbate tau pathological features, further supporting the triggering of inflammation by infectious agents in brain, leading to cognitive impairment via effects on tau. Only 2 papers, 12 and 14 years ago, have challenged the data—specifically on viral presence in brain. No other opposing studies have since been published. One can conclude that there is overwhelming supportive evidence that HSV1 in brain of APOE-e4 carriers confers a major risk of AD.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L8

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Beyond the horizon in dementia - read full article

By: George Perry and R. Castellani

Our nearly 35 year journey in Alzheimer disease (AD) began with the linkage of senile dementia to AD and the molecular dissection of genetics and proteins that revealed the central players. How could a cure or even effective therapy have eluded us for so long? Studying AD is like walking through the looking glass, for while everything is the same--e.g., there is no novel gene expression—it is also different in quantitative and qualitative relationships leading to endless studies suggesting therapeutic strategies. Do endless abnormalities mask the one distinct initiator or is the countless change instead the disease: possibly a single condition but made up of thousands of components that are touched by the key risk factor of AD—age—for we find the same changes in aged normal people. Could it be the same changes of aging are AD because they are what maintains normal function with aging but are insufficient in AD to maintain physiology. Removal of these changes has not restored normal function and could do harm. In Alois Alzheimer’s time treatments revolutionized medicine by curing most diseases from the outside, infections and injury, and corrected many of defect (mutations) but since then we have made but modest impact in diseases of normal aging, degenerative diseases. Instead progress has been made when we address the underlying issues: lifestyle, inflammation, and others, instead of eliminating the reactive changes. We might consider the same for AD as we work on more effective therapy.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L9

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Beyond the horizon in neuropathology - read full article

By: Lea T. Grinberg

Neuropathology is a relatively old discipline known for still using methods developed over a century ago. Difficulties in procurement and examination of clinical specimens, the advent of high-throughput—omics, and advances in animal models with their ability to provide insight into the mechanisms of a disease process, led to a waning of interest in neuropathology that has been rendered obsolete. My talk will focus on the transformation of neuropathology into a 21st-century science on the forefront of advances in neurology. By incorporating elements of molecular biology, improved microscopy, advancing graphics, and technology to deal with big data in the study of human brain specimens, neuropathology is transforming biomarker discovery and treatment development in several areas of neurology and rapidly reinstating itself as a valuable player in the contemporary neurological research.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L10

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Close encounter on chromosome 14 - read full article

By: Sergiu C. Blumen, Itzhak Braverman, and Tamar Ben-Yosef

Since the discovery of the large cluster of Oculopharyngeal Muscular Dystrophy (OPMD) among Uzbek (Bukhara) Jews, we noticed that some OPMD homozygotes had significantly reduced vision due to pigmentary retinopathy. Recent investigations in a newly identified OPMD homozygote, as well as in several Uzbek OPMD heterozygotes, revealed in this population, a high prevalence of a novel, autosomal recessive, mutation producing, adult onset, progressive visual loss in homozygotes; vision is not affected in heterozygote carriers. This mutation, occurring on chromosome 14q, in close proximity to PABPN1, was found neither among Uzbeks with two normal [(GCN)10] PABPN1 alleles nor in OPMD patients belonging to another ethnic group. We conclude that, during history, two founder mutations occurred on 14q in Uzbek Jews and they are closely linked.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L11

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Effect of Glatiramer Acetate on Peripheral Blood Brain-Derived Neurotrophic Factor and Phosphorylated TrkB Levels in Relapsing-Remitting Multiple Sclerosis - read full article

By: Buzoianu Anca Dana, Vacaras Vitalie, Major Zoltan Zsigmond, Muresanu Fior Dafin, Krausz Ludovic Tibor, and  Marginean Ioan

Glatiramer acetate (GA) is one of the most widely used disease-modifying drugs for the treatment of relapsing-remitting multiple sclerosis; is assumed to have inductor effects on neurotrophic factor expression. One of these neurotrophic factor systems is the brain-derived neurotrophic factor (BDNF)/receptor tyrosine kinase B (TrkB) pathway. Peripheral blood is thought to contain soluble BDNF, and some blood cells express TrkB. We attempted to determine whether GA treatment leads to changes in plasma BDNF levels and TrkB activation. Such a phenomenon are relapsing-remitting multiple sclerosis patients is significantly reduced; GA treatment is not influencing peripheral BDNF levels, after one year of sustained therapy, not from the point of view of total free BDNF nor the phosphorylated TrkB.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L12

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Does the diagnosis of AD implies immediate revocation of driving license? - read full article

By: Sokratis Papageorgiou

Successful driving requires various physical and mental capacities to: judge distances, simultaneously manage multiple incoming stimuli, maintain attention for long periods of time, perform sequencing skills, demonstrate immediate reaction in case of adverse events and succeed proper interpretation of traffic signs and signals. While patients with moderate to severe dementia should stop driving, some patients with mild Alzheimer’s Disease (AD) seem still capable to drive without an increased risk of accidents compared to healthy elderly. Performance on tests of visuospatial and attentional abilities, executive functioning and memory is associated with the ability to drive safely in these patients. However, due to the moderate relationships of the cognitive tests with driving measures and individual variability, relying only on these tests for making recommendations for restrictions in driving is not adequate and combination with other measures such as findings from neurological assessment is warranted. Research findings indicate that patients with Mild Cognitive Impairment (MCI) are at risk for driving difficulties although their performance on driving testing was not consistently found worse than that of healthy elderly. Nevertheless, cognitive measures appear to be associated with driving performance in patients with MCI. Our research results suggest that measures of information processing speed, visuospatial memory, psychomotor vigilance and also motor measures of balance and movement coordination (e.g. tandem walking test) as well as measures of quality of sleep and emotional state could serve as useful predictors of driving performance in individuals with MCI as they predict various indexes of driving performance: number of crashes, reaction time, average driving speed, lateral position variation, and headway average time. Finally, compared to healthy elderly, mild AD and MCI patients are more sensible to distraction while driving (e.g. use of mobile phone and conversation). Definition of successful predictors of driving ability in patients with mild AD or MCI will allow the development of thoughtful guidelines and national policies to improve public road safety.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L13

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Lecture


Should Vascular Dementia be treated with Cholinesterase Inhibitors? - read full article

By: Babek Tousi

holinesterase inhibitors are considered to be the first-line cognitive enhancer for Alzheimer's disease, but they do not have regulatory approval for treatment of vascular dementia in the United States and most of the Europe. There have been multiple studies of cholinesterase inhibitors in patients with vascular dementia over past decade. Cholinesterase inhibitors showed greater efficacy than placebo on ADAS-cog in some of these studies. However, these studies showed inconsistent benefit in global functioning of patients with vascular dementia. Eisai's applications (Manufacturer of Aricept) for regulatory approval of donepezil for vascular dementia in 2002 and 2003 were rejected both in the United States and Europe. The development for this indication stopped. Donepezil has been studied frequently for patients with vascular dementia. One of the largest studies on donepezil, sponsored by the manufacturer, was a combined analysis using 2 identical randomized trial, 24-week period7. Patients were randomized to receive donepezil 5 mg/day or 10 mg/day, after brief titration or placebo. Both donepezil groups showed significant improvements in cognition compared with placebo (ADAS-cog, MMSE, p < 0.01). There was inconsistency in the global benefit. The 5 mg/day group showed benefit on the CIBIC-plus and the 10 mg/day group showed benefit on CDR-SB. The authors concluded that donepezil improved cognition, global function and ability to perform IADL in patients with vascular dementia and was well tolerated. Kavirajan and Schneider did a meta-analysis of randomized controlled trials of cholinesterase inhibitors in vascular dementia from 1996-2006. Eight studies including the above double blind RCT studies comprising 5183 patients met their selection criteria. Their meta analysis attenuate the global effects of the 5 mg dose reported by published data. The Alzheimer’s Disease Assessment scale was significantly improved for all drugs but only 5 mg daily donepezil had an effect on the Clinicians’ Global Impression of Change scale. There was no behavioral or functional benefits on any of these drugs, except for 10 mg daily donepezil on the Alzheimer’s disease Functional Assessment and Change Scale. They concluded that Cholinesterase inhibitors produce small benefits in cognitive abilities in vascular dementia but the clinical significance is uncertain. As previous studies of Donepezil in vascular dementia showed inconsistent benefit in global functioning of patients with vascular dementia, the manufacturer sponsored another trial to further evaluate the potential benefits of donepezil in VaD. The participants were randomized only to donepezil 5 mg or placebo once daily. They achieved their previous results that patients treated with donepezil 5 mg/d had significant improvement in cognitive, but they did not show any improvement in global function. A double-blind trial of Donepezil in patients with subcortical vascular cognitive impairment (CADASIL) failed to show any effect on the primary endpoint, which was change from baseline in the score on the vascular AD assessment scale cognitive subscale (V-ADAS-cog) at 18 weeks. Some improvements on few measures of executive function did not reach the clinical significance. These initial studies used the now-outdated NINDS-AIREN criteria for probable VaD and the NINCDS-ADRDA4 criteria for possible AD, coupled with a requirement for radiological evidence of significant cerebrovascular disease for mixed dementia. Mixed dementia is now known to be very common. Both these criteria were prepared before this was recognized. When these criteria were prepared, small amounts of CVD were routinely ignored when seen in conjunction with what was otherwise thought to be AD. NINDS-AIREN criteria require an Alzheimer-like dementing process coupled with the presence of cerebrovascular disease. As such, these criteria are probably better criteria for mixed dementia than they are for VaD, There is some evidence from the both the galantamine and donepezil studies of a therapeutic effect for acetylcholinesterase inhibitors in VaD, or mixed AD and VaD, although in reality both studies are probably studies of mixed disease. When different sets of diagnostic criteria for Vascular dementia (ICD-10, DSM-IV and NINDS-AIRENS) have been compared against pathological findings as the gold standard, their sensitivity and specificity (in differentiating AD from VaD) are highly variable. These sets of criteria cannot be used interchangeably either. The overall design of efficacy trials in vascular dementia is questionable. A randomized, double-blind, placebo-controlled, parallel-arm design seems to be the most appropriate for AD with gradual worsening clinical course but a similar design may not be appropriate for vascular dementia. On current evidence, an acetylcholinesterase inhibitor could reasonably be considered for a patient with a spectrum of AD mixed with vascular disease. It is more important to emphasize the importance of early identification of cases with a vascular component to their cognitive decline, as these patients can benefit from prevention rather than just symptomatic treatment. Since many patients with Vascular dementia also suffer from cardiovascular disease, a potential drug–drug interactions between cholinesterase inhibitor and the medications used to treat heart conditions in these patients is alarming. The potential inconsistent mild benefit of a cholinesterase inhibitor should be weighed against the harms likely to be caused to patients with vascular dementia.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L14

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Nanotechnology in early diagnosis and treatment of dementia - read full article

By: Jerzy Leszek

The lack of effective treatment for Alzheimer’s disease(AD) stems mainly from the incomplete understanding of AD causes. Currently there are several hypotheses which try to explain the early molecular mechanisms of AD pathogenesis. The current pathophysiologic approach is based on a number of common mechanisms of neurodegeneration, including accumulation of abnormal proteins(tau and ABeta), mitochondrial dysfunction, oxidative stress, impaired insulin signaling, calcium homeostasis dysregulation, imbalance of neurotransmitters, early synaptic disconnection and late apoptotic cell death. Considering that AD is a multi-factorial disease with several pathogenic mechanisms and pathways, a multifunctional nanotechnology approach may be needed to target its main molecular culprits. There are still no effective treatments to prevent, halt, or reverse AD. To very early diagnosis of AD we need to have an affordable, ultra sensitive and selective molecular detection methods. Nanomedicine as a biomedical and pharmaceutical application of nanotechnology for making nanocarriers for instance dendrimers has shown great potential not only for diagnosis but the treatment of many CNS diseases such AD. Ultra-low concentrations of protein biomarkers( eg. ADDL- amyloid-Beta-derived diffusible ligands) which have been implicated in the pathogenesis of AD, is possible to detect ,owing to carrier dendrimers. Dendrimers are polymeric molecules chemically synthesized with well defined shape size and nanoscopic physicochemical properties reminiscent of proteins. Recently an increasing number of studies have been focused on the potential of dendrimers to prevent aggregation and fibrillation of proteins involved in neurodegenerative disorders such as AD. Some of dendrimers were demonstrated to cross blood-brain barrier, which legitimized research on these compounds as potential drugs for neurological disorders. Recent our studies have revealed that dendrimers possess the intrinsic ability to localize in cells associated with neuroinflammation(activated microglia and astrocytes) and thus can be used in neuroinflammation therapy. Above/mentioned findings may be significance in the context of potential application of dendrimers as drug carriers or active compounds per se. According to the opinion the author’s of this presentation ,they are promising macromolecules for further investigations on their applicable in neurodegenerative disorders, for instance AD.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L15

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The CGRP story and its role in migraine pathophysiology - read full article

By: Lars Edvinsson

Migraine is a painful, debilitating neurological disorder that manifests as a debilitating headache associated with altered sensory perception, having a huge impact on individual and public health. In a survey about years lived with disability, migraine was ranked on the third place. Although evidence suggest no increase in migraine prevalence in a ten year period, the cumulative lifetime incidence is very high (43% in women, 18% in men), affecting especially young adults. Great progress has been made in understanding the pathophysiology of migraine. However, there are still some questions regarding the origin of migraine pain and on its chronification. The neuropeptide calcitonin gene-related peptide (CGRP) is now firmly established as a key player in migraine. The first evidence was presented already 1984, showing that sensory nerves on cerebral arteries store calcitonin gene-related peptide (CGRP) using immunohistochemistry, performed surgical denervation and quantification of CGRP, did in vivo work and defined the trigeminovascular reflex with CGRP as the main molecule. In 1988, we observed upon operation of patients with trigeminal neuralgia that CGRP was released into the jugular venous blood and at the same time there was unilateral flushing. This was the start of our migraine project. CGRP was found to be released in acute migraine and cluster headache attacks and correlated with the pain, and that both pain and increased CGRP levels were aborted by a triptan. Thus, CGRP is a key molecule in primary headache disorders. Subsequent work provided a wealth of preclinical and clinical data in support (Ho et al, Nature Rev Neurol 2010). Industry picked up the idea and started developed CGRP blockers 10-15 years ago. After the first proof-of-concept study (2004) several trials using small molecules that could be given orally, revealed positive effects both in acute migraine attacks and in a prophylaxis study with gepants (Edvinsson & Linde, Lancet Neurol 2010). Due to liver toxicity this program was halted. However today this has been followed by 4 different companies using antibodies towards CGRP or the CGRP receptor and they have revealed positive results in phase 2 trials. It is expected that CGRP blockers may reach the market in about 2-3 years. The preliminary data show compared to placebo no significant side effects and good efficacy. Despite this progress in the clinical arena, the details of the mechanisms and involvement of CGRP in migraine pathophysiology remain unclear providing room for further research.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L16

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Cortical Integrative Therapy: application of non-invasive brain stimulation in the treatment of pediatric brain injury and brain-based disorders - read full article

By: Victor M. Pedro

Cortical Integrative Therapy (CIT) is successful in treating a wide range of neurological conditions including traumatic and acquired brain injury as well as developmental disorders and learning disabilities. CIT utilizes the spatial and temporal specificity of sensory stimulation and motor signaling to initiate neuronal re-synchronization, restore hemispheric balance in functions, and drive neuronal plasticity so that long-term positive changes are implemented and maintained. CIT stimulates the brain by using a patient-specific set of simulative treatment therapies (visual, auditory, vestibular), physical exercises, and nutritional counseling. The purpose of this presentation is to illustrate the effectiveness of CIT in the treatment of pediatric and adult brain injury. We will introduce a conceptual framework of CIT, describe typical treatment modalities, and report patient outcomes.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L17

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Development of the international pediatric acquired brain injury plain (iPABI plan) - read full article

By: Patrick B. Donohue

Pediatric acquired brain injury (PABI) is the leading cause of death and disability for American youth up to 25 years of age and is an international public health crisis. Over 765,000 American youth enter an Emergency Department each year with a new brain injury, over 80,000 are hospitalized and over 11,000 die annually. There is currently no evidenced-based system of care to prevent, identify, treat or cure PABI. The International Pediatric Acquired Brain Injury Plan (iPABI Plan) is developed from the $2.9 billion, seven-year National Pediatric Acquired Brain Injury Plan (PABI Plan) by the International Advisory Board of The Sarah Jane Brain Foundation. The PABI Plan develops a seamless, standardized, evidence-based system of care that is universally accessible for the millions of American families who have a child with a brain injury. This presentation will explain Who, What, Where, Why, When and How about the iPABI Plan.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L18

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Can Neurology Solve the Free Will Paradox? - read full article

By: Mark Hallett

ne definition of a paradox is a proposition that arises from apparently sound premises leads to a conclusion that seems logically unacceptable. The paradox that arises in relation to free will is that studies of motor control do not obviously reveal the operation of free will, and there is a general view that people do have free will. Free will is a perception that people have that they choose to make (most of) their movements. This perception includes both a sense of willing the movement and self-agency that their act of willing was responsible for the movement that was made. Intrinsic to the perception of willing is the sense that the willing itself drives the movement. It is important to recognize that perceptions are purely passive. A critical question is whether there is any evidence for a “free will force” that plays a role in movement selection. The basic challenge to a relevant free will force is the experiment of Libet et al. (1983) that showed EEG activity well before the time of perception of willing (called W). A series of other experiments, less reliant on subjective and retrospective perceptions confirm this result. Moreover, the timing of W can be influenced by events, such as TMS, after the movement is made. The probable explanation of this is that perceptions must occur after physical events in the real world—consciousness is in the past. Evidence from neuroimaging and brain stimulation studies reveal that the sense of willing likely arises from regions in the brain including the temporoparietal junction area and supplementary motor area. Neuroimaging and brain stimulation studies have also been done investigating the sense of agency and similar regions appear relevant. Physiological studies of movement generation give a fairly clear account of how movement is produced, and a free will force has not been identified nor does it seem necessary. Much of what the brain does is unconscious and only some of its activity becomes passively experienced in consciousness. The brain event underlying the sense of willing is not a driving force. The paradox is solved with the recognition that a person “is” his/her brain. Then free will can be considered to exist if a person’s brain is functioning normally without coercion.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L19

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Trophic factors for Parkinson's Disease: facts and dreams - read full article

By: Jose Martin Rabey

Since the discovery of the trophic effects of nerve growth factor by Nobel laureate Rita Levi-Montalchini in the 1970's numerous studies have demonstrated that many trophic factors can prevent neuronal degeneration and increase the function of both intact and degenerating nerve cells. Moreover trophic factors show great promise in laboratory studies as potential therapies for PD. However multiple double—blind clinical trials have failed to show benefits in comparison to a placebo control. With respect to developing a therapy for PD patients, the GDNF family of ligands (GFLs) that include glial cell-derived neurotropic factor (GDNF) and neurturin (NRTN) have received the most attention. Lin (1993) first discovered GDNF and demonstrated that it supports the viability of dopaminergic midbrain neurons in tissue culture. We will review in our presentation the scientific rationale for testing trophic factors in PD , the result of the different clinical trials that have been performed and the possible explanations for these failed outcomes. Future directions will be also considered.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L20

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Clinical features and the natural history - read full article

By: T. Klockgether

Machado-Joseph disease/spinocerebellar ataxia (MJD/SCA3) is worldwide the most common autosomal dominantly inherited ataxia disorder. MJD/SCA3 is a multisystem disorder characterized by degeneration of spinocerebellar tracts, dentate nucleus, brainstem nuclei, and basal ganglia. In MJD/SCA3 mutation carriers, ataxia usually starts around 35 years with large variability that partly depends on the repeat length. The clinical syndrome is characterized by prominent cerebellar ataxia in combination with supranuclear gaze palsy and peripheral neuropathy. In addition, patients may present with pyramidal signs, basal ganglia symptoms, such as parkinsonism or dystonia, restless legs syndrome, urinary dysfunction, and mild cognitive dysfunction. As part of the EUROSCA study we followed a cohort of 139 MJD/SCA3 patients over a period of 8 years. The severity of ataxia at baseline, as measured by the Scale for the Assessment and Rating of Ataxia (SARA), was determined by repeat length and disease duration. Longer repeats and earlier age of onset were associated with the occurrence of pyramidal signs, whereas higher age was associated with clinical signs of peripheral neuropathy. SARA progression data were best fitted with a linear model. Annual SARA score increase was 1.56 (SE 0.08). We did not identify factors that affected progression of the SARA score. Progression rate in MJD/SCA3 was slower than in SCA1, but faster than in SCA6. Other than the SARA score, the increase of the number of non-ataxia signs reached a plateau.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L21

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Machado-Joseph Disease—single center experience from Central Portugal - read full article

By: Cristina Januário, Joana Afonso Ribeiro, Ana Margarida Novo, Luciano Almendra, Anabela Matos, Luís Negrão, and João Lemos

We report on a series of 80 spinocerebellar ataxia type 3 (SCA 3) patients from 39 unrelated families followed in our clinic, focusing on novel clinical findings and phenotypical diversity. Demographic, clinical (scale for the assessment and rating of ataxia (SARA), Montreal Cognitive Assessment, clinical Total Neuropathy Score-cTNS scores), and genetic features were recorded. Neurophysiological evaluation included nerve conduction studies, needle electromyography and cutaneous sympathetic skin response (SSR). Functional imaging using the radioactive tracer 123I-ioflupane was performed to assess dopamine deficiency, exclusively in parkinsonian patients. Neuro-ophthalmological assesment including strabismus evaluation, and the use of binocular video-oculography video-horizontal head impulse test (vHHIT) were further performed. Patients’ median age was 53+/-14 years, mean duration of disease was 15 (± 8) (3 – 38) years, median SARA score was 15.4 +/-6, median number of CAG repeats was 71+/-8, and median MoCA score was 25 (18 -29). Three cases presented initially as a levodopa responsive parkinsonian syndrome, and one of them underwent successful deep brain stimulation. Peripheral neuropathy is frequent in our population (>50%), showing predominant sensory involvement. The presence of peripheral neuropathy positively correlates with age but not with triplet expansion size. Strabismus was a universal finding, particularly esotropia at near. Vestibular ocular reflex loss positively correlated with SARA score. A novel saccadic intrusion has been found. In our series we have identified potential oculomotor biomarkers of disease.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L22

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Magnetic resonance imaging in Machado-Joseph disease - read full article

By: Marcondes C. França

Machado-Joseph disease (SCA3) is the most frequent spinocerebellar ataxia worldwide and caused by abnormal (CAG) expansions within the 10th exon of the MJD1 gene located at chromosome 14q. It is typically an adult onset ataxic syndrome, but there is remarkable phenotypic heterogeneity. Patients often present pyramidal signs, movement disorders (particularly dystonia) and peripheral manifestations. Current research efforts in SCA3 are directed towards understanding the pathophysiology of the disease and also to identify robust biomarkers for clinical trials. In this scenario, magnetic resonance imaging (MRI) emerged as a promising tool. It is a widely available and non-invasive technique that enables the evaluation of structural and functional changes related to the disease. Most available MRI-based studies focused in cerebral abnormalities and employed volumetric techniques. These studies revealed cerebellar (predominantly vermian) and brainstem atrophy in SCA3. More recently, studies using cortical thickness measurements also identified precentral, temporal and occipital volumetric reduction. Diffusion tensor imaging (DTI) is a MRI sequence that enables the evaluation of white matter integrity in the brain. In patients with SCA3, DTI-based studies essentially revealed damage to cerebellar and brainstem tracts, including the cerebellar peduncles. Spinal cord is another neural structure known to be affected in SCA3 from pathological reports. Current high-field scanners and protocols now enable adequate evaluation of the cord in vivo using MRI. Indeed, two reports showed cervical atrophy in the disease, and interestingly the extent of atrophy correlated independently with clinical severity. Overall, these results indicate that SCA3 is associated with multifocal damage to the central nervous system that goes far beyond the cerebellum and connections. It seems, however, that damage distribution is not homogeneous in every single patient. Some recent reports tried to compare MRI findings in patients with different phenotypes, such as dystonic vs non-dystonic. Results indicate that cerebellum is compromised in both situations, but the pattern of cortical and basal ganglia damage is clearly different. There are very few longitudinal MRI data in SCA3. Reetz et al reported progressive caudate and putaminal volumetric reduction after 2 years, but it did not correlate with clinical decline. In summary, MRI-based studies greatly improved our knowledge about disease mechanisms and genotype-phenotype correlation. The use of MRI parameters as clinical biomarkers for SCA3, however, still needs further studies with a longitudinal design. We strongly believe that DTI might prove more sensitive than volumetric techniques to detect subtle changes in the short-term.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L23

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Mutational origins of Machado-Joseph disease - read full article

By: Sandra Martins

Machado-Joseph disease (MJD) is the most frequent dominant ataxia worldwide, but de novo mutational events (i.e. expansions from normal or intermediate to the pathological range of (CAG)n alleles) do not seem to explain disease relative high frequency and diffusion into many populations. Previously, we have identified two SNP lineages, each underlying an independent MJD origin: the most ancient and worldwide spread Joseph (TTACAC) lineage, originated probably in Asia more than 6000 years ago; and the more recent Machado (GTGGCA) lineage, predominant in families of Portuguese extraction. Interestingly, these two lineages display different repeat instability biases upon paternal transmission of expanded alleles. Taking into account that the CAG repeat size is the parameter that better explains age-of-onset and disease severity, the identification of MJD lineages becomes even more important at the clinical level. More recently, we have been studying families from more remote and isolated communities in order to discern whether the presence of MJD in these populations is due to new mutational events or to the introduction of expanded alleles from other populations. A total of 20 SNPs flanking the expanded repeat was analysed in Australian aborigines and African families. No new mutational origins have been identified, but a “Joseph-derived” lineage shared by Australian aborigines and 9 Asian families suggested an introduction of the mutation in this community via Asia. By inferring a phylogenetic tree from genetic distances, we estimated that the Australasian Joseph-derived lineage dates back to more than 100 generations.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L24

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Planning and feasibility of clinical trials - read full article

By: T. Klockgether

Clinical trials in Machado-Joseph disease/spinocerebellar ataxia (MJD/SCA3) with neuroprotective drugs, such as lithium, or symptomatic drugs, such as varenicline have been performed, however with negative results. In the majority of recent clinical trials in ataxia, the Scale for the Assessment and Rating of Ataxia (SARA) is used as a primary outcome measure. The SARA score is highly correlated with activities of daily living, and it is a major determinant of health-related quality of life underlining the clinical relevance of SARA. SARA progression in MJD/SCA3 is comparably slow so that neuroprotective clinical trials require large numbers of patients. Based on the 8 year longitudinal data of the EUROSCA study, we calculated that more than 500 patients will be required to detect a 30% reduction in progression of the SARA score in a trial with a power of 80%. Before embarking on such large trials, smaller proof-of-concept trials are desirable. In such trials, biomarkers are used to provide evidence of target engagement and to indicate possible efficacy. Currently, however, validated biomarkers that could be used in MJD/SCA3 trials are lacking. To overcome some of these problems, we are launching the European Spinocerebellar Ataxia Type 3/Machado-Joseph Disease Initiative (ESMI) that aims at setting up a trial ready cohort by bringing together 7 European cohorts and 1 US cohort. ESMI plans to integrate the existing data in a common database and to apply standardized and quality-controlled clinical assessment, MRI and biobanking protocols. A major part of ESMI will be the development and validation of innovative assessment instruments and disease markers, including a new highly sensitive motor test battery, ambulatory sensor-based activity measurement, automated MRI volumetric evaluation, diffusion tensor imaging (DTI), and blood as well as CSF markers based on transcript profiling and disease protein (ataxin-3) measurement.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L25

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Ataxin-3 phosphorylation decreases neuronal defects in spinocerebellar ataxia type 3 models - read full article

By: Carlos Andrade Matos, Clévio Nóbrega, Susana R. Louros, Bruno Almeida, Elisabete Ferreiro, Jorge Valero, Luís Pereira de Almeida, Sandra Macedo-Ribeiro, and Ana Luísa Carvalho

Different neurodegenerative diseases are caused by aberrant elongation of repeated glutamine sequences normally found in particular human proteins. Although the proteins involved are ubiquitously distributed in human tissues, toxicity targets only defined neuronal populations. Changes caused by an expanded polyglutamine protein are possibly influenced by endogenous cellular mechanisms, which may be harnessed in order to produce neuroprotection. Here, we show that ataxin-3, the protein involved in Spinocerebellar ataxia type 3, also known as Machado-Joseph disease, causes dendritic and synapse loss in cultured neurons when expanded. We report that S12 of ataxin-3 is phosphorylated in neurons and that mutating this residue so as to mimic a constitutive phosphorylated state counters the neuromorphologic defects observed. In rats stereotaxically injected with expanded ataxin-3- encoding lentiviral vectors, mutation of serine 12 reduces aggregation, neuronal and synapse loss. Our results suggest that S12 plays a role in the pathogenic pathways mediated by polyglutamine-expanded ataxin-3 and that phosphorylation of this residue protects against toxicity.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L26

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Models of disease: C. elegans - read full article

By: A. Teixeira-Castro, A. Jalles, L. da Silva Santos, M.D. Costa, S. Oliveira, S. Vasconcelos, R.I. Morimoto, and P. Maciel

Caenorhabditis elegans has been successfully used to model neurodegeneration in vivo, mainly due to the conservation of basic cellular mechanisms such as neuronal signaling, cell death/survival, proteostasis and aging. Despite having relatively few neurons, C. elegans exhibit complex behaviors that can be assayed to monitor neuronal dysfunction, which can be combined with biophysical assays to examine protein aggregation in live neurons of interest. Here, we describe how the use of a C. elegans model of Machado-Joseph disease (MJD) pathogenesis allowed the identification of novel genetic modifiers of disease and promissing cellular targets for therapeutical intervention. Pan-neuronal expression of mutant ATXN3 led to a polyQ-length dependent, neuron subtype-specific aggregation and neuronal dysfunction. Wild-type ATXN3 is irreversibly recruited into polyQ-containing cellular aggregates, aggravating the animals’ motor dysfunction. Aging influenced the ATXN3 phenotypes which can be suppressed by lifespan increasing mutations in C. elegans. A drug repurposing screen identified pharmacological modulators of neurotransmission as potential treatment for MJD. Chemical genetics and validation in higher organisms will help to shed light into its mode-of- action in MJD.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L27

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Potential Treatment on SCA3/MJD Drosophila Models and patients - read full article

By: Hong Jiang, Zhe Long, Qinghua Li, Jiping Yi, Dandan Jia, LIfang Lei, and Beisha Tang

We used several SCA3/MJD Drosophila models through which we determined that heat shock protein 22 (Hsp22), lithium chloride, and valproic acid (VPA) are potential therapeutic agents for the treatment of SCA3/MJD. Hsp22, a member of the small heat shock protein (sHsp) family, plays a significant role as chaperone. In the SCA3 Drosophila model, expression of the MJDtr-Q78 transgene—containing an expanded polyglutamine tract—showed a greater loss of cell integrity, and the pigmentation of adult flies was faded and showed black, point-like necrosis. Findings showed that Hsp22 expression impacted eye depigmentation, growth restriction, ability for eclosion, and average lifespan. We examined the effect of VPA and Li chloride (LiCl) in a Drosophila SCA3 model. We expressed the MJDtr-Q78 transgene both in the developing eyes and in neurons. Expression of the MJDtr-Q78 protein produced deleterious phenotypes including faded eye pigmentation, impaired climbing ability, and decreased mean lifespan, similar to the characteristics of human SCA3. To test the therapeutic potential of VPA and LiCl in vivo, a series of daily doses of VPA as well as LiCl were administered to SCA3 flies before cross-breeding. Results showed that long-term use of VPA and LiCl at an optimal dose partly prevented eye depigmentation, alleviated climbing disability, and extended the average lifespan of SCA3/MJD transgenic flies. Additionally, we performed a randomized, double-blind, placebo-controlled, dose-controlled study evaluated the safety and efficacy of multi-dose VPA in 36 SCA3/MJD patients and found VPA is a potentially beneficial agent for the treatment of SCA3/MJD.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L28

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A transgenic zebrafish model of Machado-Joseph disease to test potential disease treatments - read full article

By: M. Watchon, K. Yuan, N. Mackovski, T.S. Becker, G.A. Nicholson, and A.S. Laird

Machado Joseph disease (MJD), also known as spinocerebellar ataxia-3 (SCA3) is a hereditary neurodegenerative disease that affects muscle control and coordination. The disease is caused by an extended trinucleotide repeat region (CAG) in the gene ATXN3/MJD1, encoding a polyglutamine (polyQ) region within the ataxin-3 protein. Whilst the wild-type (WT) ataxin-3 protein contains 12-44 glutamine residues, as many as ninety glutamines are found in the ataxin-3 protein of MJD patients. We have successfully established the first transgenic zebrafish model of MJD. These zebrafish express human ataxin-3 containing either 19Q (WT) or 84Q (MJD). Immunoblot analysis of protein lysates extracted from our transgenic SCA-3 zebrafish revealed the presence of ataxin-3 cleavage products similar to those found in MJD patient samples. These fragments were present at all ages examined from three days post fertilization (dpf) through to 12 months old. We identified a marked motor phenotype developed in ataxin-3-84Q zebrafish from 4 months old, with ataxin-3-84Q zebrafish swimming slower than ataxin-3-19Q fish. A more sensitive behavioural test (escape response during darkness) detected reduced swimming speeds in ataxin-84Q zebrafish than ataxin-19Q as early as 6dpf. This motor phenotype provides a useful readout for drug screening assays because it is easily quantified and occurs at an age that zebrafish larva can be treated in small multi-well plates. Our results indicate that our transgenic zebrafish model of MJD is relevant to the human disease and will be a valuable tool for testing potential disease treatments.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L29

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Humanized SCA3 knock-in mouse: progress in identification of new deregulated molecules by high throughput NGS and proteomic studies - read full article

By: Maciej Figiel, Malgorzata Kurkowiak, Kalina Wiatr, Pawel M. Switonski, Lukasz Marczak, Agnieszka Zywert, Marek Figlerowicz, Pawel Wojciechowski, Rafal Ploski, Malgorzata Rydzanicz, and Luiza Handschuh

Humanized SCA3 knock-in ataxin-3 mouse model (Ki91) contains the following hallmarks of the disease: instability of the CAG mutation, ataxin-3 positive inclusions, astrogliosis, purkinje cell degeneration and early transcriptional changes. To provide a more holistic view of the neurodegenerative process in SCA3 Ki91 knock-in model we proposed to identify the deregulated molecules using transcriptome, proteome, phosphoproteome and ubiqiutome profiling by NGS and mass spectrometry. The homozygous k300 knock-in animals containing the CAG repeats without Ataxin-3 protein were also included in NGS transcriptome studies. The NGS of cerebellum and cortex of pre-symptomatic Ki91 (mut/mut) 8-week old animals has shown deregulation of several genes on mouse chromosome 12 and 19. Serpina3n which is located at chromosome 12 was deregulated in both Ki91 and K300 mouse. The induction of Serpina3n in both models increased when both alleles contained CAG repeat tract. Moreover the increased expression of Serpina3n was identified in astrocytes but not in granular cell neurons in the cerebellum. The enrichment and profiling of phosphoproteins was performed in pre-symptomatic Ki91 (mut/mut) 8-week old animals and identified number of deregulated phosphoproteins. Among deregulated proteins the GO analysis identified RNA binding, axon and dendrite development, regulation of synaptic transmition, learning, regulation of cytoskeleton organization. Summarizing young presymptomatic homozygous Ki91 animals reveal limited number of transcriptional changes predominantly clustering on mouse chromosome 12 and 19 and show greater scale of phosphoproteins deregulation in cerebellum and cerebral cortex.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L30

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Nuclear localization and transport: a critical pathomechanism in Machado-Joseph disease - read full article

By: Thorsten Schmidt

Machado-Joseph disease (MJD) or Spinocerebellar ataxia type 3 (SCA3) is caused by a polyglutamine expansion in the ataxin-3 protein. In controls, ataxin-3 is predominantly located in the cytoplasm but forms protein aggregates in the nucleus of neurons in MJD/SCA3 patients. We recently demonstrated in vivo that the toxicity of expanded ataxin-3 is linked to its intracellular localization: Targeting ataxin-3 to the nucleus gave rise to a strong phenotype with a high number of protein aggregates. Purely cytoplasmic ataxin-3, however, even with a highly expanded polyglutamine repeat (148 glutamines), was not able to induce a phenotype and even did not aggregate. Only nuclear ataxin-3 gave rise to a phenotype. Purely cytoplasmic ataxin-3, however, even with a highly expanded polyglutamine repeat, remained harmless. In addition, we identified and characterized intracellular transport signals (two nuclear export signals, NES, and one nuclear localization signal, NLS) within the coding sequence of ataxin-3. Therefore, it is evident that proteins involved in the nucleocytoplasmic transport machinery recognize these localization signals, control the intracellular localization of ataxin-3, thereby influence the toxicity and aggregation of Ataxin-3 and, thus, the pathogenesis of MJD/SCA3. We further dissected the nucleocytoplasmic transport mechanisms of ataxin-3 and identified a transport protein whose critical importance for the nuclear import of ataxin-3 we confirmed in vitro and in vivo: Knocking down this protein alleviates the symptoms induced by expanded ataxin-3 both in transgenic Drosophila and mouse models. As pathologically ataxin-3 remains harmless as long as it is kept in the cytoplasm, we further anticipated the intracellular localization of ataxin-3 as a target for a possible therapeutical intervention. For this reason, we generated an assay allowing us to easily monitor the intracellular localization of normal or expanded ataxin-3, screened a library of FDA-approved compounds and indeed identified compounds impacting the nuclear translocation of ataxin-3 and validated them in vivo. As the compounds we identified are already FDA-approved and on the market, they could be transferred to the clinics comparatively fast. We believe that our results will improve the understanding of pathological mechanisms influencing the progression of the disease and are an important contribution towards a treatment of SCA3.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L31

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Transcriptional dysregulation in SCA3 - read full article

By: Bernd Evert

Ataxin-3 (ATXN3) the disease protein in spinocerebellar ataxia type 3 (SCA3) can act as a transcriptional repressor through inhibition of histone acetyltransferases (HATs) and blocking access of HATs to histone acetylation sites suggesting that transcriptional dysregulation contributes to SCA3 pathogenesis. Indeed, cell models of SCA3 showed differential expression of several genes encoding transcription factors, inflammatory cytokines and cell surface proteins prior to cell death. Also, in cerebella of transgenic SCA3 mice, altered expression of genes involved in glutamatergic and calcium signalling, GABA receptor subunits, transcription factors and heat shock proteins regulating neuronal survival and differentiation occurs before the onset of neurological symptoms. On the one hand, transcriptional dysregulation in SCA3 may be caused by depletion of transcriptional components into nuclear inclusions formed by mutant ATXN3. On the other hand, polyQ expansion in ATXN3 may alter its normal function in transcriptional regulation. Previously, we found that ATXN3 binds to target genes and represses transcription by interaction with transcriptional corepressors and histone deacetylation whereas mutant ATXN3 has a reduced ability to form deacetylating repressor complexes at target genes. Moreover, ATXN3 interacts with specific transcription factors and synergistically enhance transcription of target genes in response to oxidative stress compared to a reduced capability of mutant ATXN3 to activate transcription at target genes. These findings suggest that ATXN3 apart from its role in protein quality control is a component of transcriptional complexes regulating the activity of specific genes in response to different stimuli. To identify target genes of ATXN3, we undertook chromatin immunoprecipitation sequencing of genomic fragments bound by ATXN3 using induced pluripotent stem cell-derived neurons from control and SCA3 patients. Currently, we are analyzing identified ATXN3-bound genomic regions to distinguish genes and pathways modulated by normal and mutant ATXN3.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L32

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Regulation of translation of Ataxin-3 by Ataxin-2 - read full article

By: Clévio Nóbrega, Sara Carmo-Silva, David Albuquerque, Ana Vasconcelos- Ferreira, Udaya-Geetha Vijayakumar, Liliana Mendonça, Hirokazu Hirai, and Luís Pereira de Almeida

In polyglutamine disorders, proteins carrying abnormally long polyglutamine tracts interact aberrantly with other proteins contributing to neurodegeneration. In this work we focus on Machado-Joseph disease (MJD), a disorder associated to the polyglutamine-expanded ataxin-3 (Atx3MUT). Aiming at clarifying the mechanism of neurodegeneration we investigated the interaction of Atx3MUT with wild-type ataxin-2, a protein recently involved in ALS and PD pathogenesis, and whose mutated form causes spinocerebellar ataxia type 2. Using cell and animal models of MJD, we found that Atx3MUT aggregation in the cell nucleus leads to re-location of Atx2 to the nucleus and a downregulation of its mRNA and protein levels. Importantly, our results suggest a role of Atx2 in translational regulation of specific transcripts, by reducing the protein synthesis through interaction with PABP. Accordingly, abnormal reduction of Atx2 cytoplasmic levels, by freeing its natural interactor and translation activator PABP, leads to an overactive protein translation of specific transcripts, particularly of Atx3MUT. Conversely, the restoration of Atx2 levels represses Atx3MUT translation and rescues neuropathological MJD-related abnormalities, due to interaction with PABP through PAM2 motif. These data indicate a clear function of Atx2 in the regulation of the translation of specific mRNAs, particularly ataxin-3 and point to a key physiological role of ataxin-2 in MJD pathogenesis opening a new avenue for therapeutic intervention in this and potentially other polyglutamine disorders.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L33

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Mechanisms of disease: proteolysis of ataxin-3 - read full article

By: Jonasz Jeremiasz Weber

Proteolytic cleavage of disease-causing proteins is a widely discussed mechanism in neurodegenerative disorders, which gives rise to toxic fragments and thus may amplify the formation of protein aggregates. This molecular model - known as the toxic fragment hypothesis - was also proposed to play a crucial role in Machado Joseph Disease (MJD) and several studies have reported on the proteolysis of polyglutamine-expanded ataxin-3, the causative protein in MJD. Hitherto two classes of enzymes, caspases and calpains, were linked with the proteolytic processing of ataxin-3, triggering neurotoxicity and cell death. Inhibition of protease activity and mutation of caspase or calpain cleavage sites within mutant ataxin-3 was shown to reduce toxicity and neuronal death in cell and animal models of MJD. Our better understanding of proteolytic events in MJD has opened new possibilities to identify therapeutic targets as a treatment for this fatal disorder.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L34

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Drug discovery for MJD—Low molecular weight drugs - read full article

By: Patrícia Maciel

Machado-Joseph disease or spinocerebellar ataxia type 3 is a late-onset neurodegenerative disorder caused by expansion of a polyglutamine tract within the protein ataxin-3, for which there is no effective treatment. We have developed transgenic animal models expressing the mutant human ataxin-3 cDNA for the study of this disorder, in the mouse (CMVMJD135) and in the nematode Caenorhabditis elegans. These models show marked neuronal dysfunction, with loss of motor coordination, and the typical pathological feature of ataxin-3 aggregation, and can be used both to study the mechanisms of disease and to test therapeutic strategies in vivo. In this presentation I shall discuss our drug discovery efforts and most recent findings using hypothesis-based as well as unbiased hypothesis-free approaches (drug repurposing screenings), in these transgenic models. We have identified hsp90 inhibitors and serotonin signaling modulators as promising candidates for pharmacotherapy in MJD, but also discovered the beneficial impact of neuroprotective compounds such as tauroursodeoxycholic acid (TUDCA) and creatine in delaying disease onset and progression. The results of such preclinical studies inform us on the therapeutic efficacy of specific compounds but also provide important clues to the key aspects of pathogenesis that are amenable to therapy. Translation of the most promising findings to the clinic is challenging but also warranted.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L35

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Trehalose reverses the phenotype of Machado-Joseph disease models - read full article

By: Magda M. Santana, Susana L. Paixão, Teresa Silva, Janete Cunha-Santos,Cláudia Cavadas, Hagar Greif, and Luís Pereira de Almeida

Machado–Joseph disease (MJD), also known as spinocerebellar ataxia type 3, is the most common of the dominantly inherited ataxias worldwide and is characterized by mutant ataxin-3 misfolding, intracellular accumulation of aggregates and neuronal degeneration. No treatment able to modify the disease progression is available. In the present study, we evaluated whether trehalose, a natural occurring alpha-linked disaccharide, could rescue the disease phenotype of cell and mouse models of MJD. N2A cells, stably expressing human mutant ataxin-3, were treated with trehalose (1 mM and 10 mM) for 24h, 48 h and 72 h. By western blot, we observed a clearance of mutant ataxin-3 protein after 48h and 72 h treatment with trehalose (10 mM). Furthermore, MJD transgenic mice were orally treated with 2% trehalose for a period of 30 weeks. Motor behavior was measured at different time points during lifetime and neuropathological features were evaluated after sacrifice. We observed that trehalose treatment significantly improved the motor and coordination behavior in both males and females MJD transgenic mice. Moreover, trehalose effects on behaviour were associated with a reduction of the MJD-associated neuropathology as MJD transgenic mice treated with 2% trehalose presented a reduced atrophy of cerebellar layers and a decrease in the size of protein aggregates in Purkinje cells. In conclusion, we show that trehalose induces the clearance of mutant ataxin-3 in N2A cells and alleviates motor impairments and neuropathological features in a mouse model of MJD, suggesting that trehalose is a promising pharmacological drug for therapy of this disease.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L36

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Blood-based trancriptional biomarkers of Machado-Joseph disease - read full article

By: Mafalda Raposo and Manuela Lima

Whereas Machado-Joseph disease (MJD) remains an untreatable disorder, disease-modifying compounds have begun being tested in the context of clinical trials; their success is dependent on the sensitivity of the methods used to measure subtle therapeutic benefits. Thus, efforts are being made to propose a battery of potential outcome measures, including molecular biomarkers (MBs), which remain to be identified. MBs are particularly pertinent if trials are expected to enrol preclinical subjects. Our group has been investigating MJD-specific expression patterns, with the aim to identify novel MBs, studying patients in distinct stages of disease severity, as well as asymptomatic and preclinical subjects. Results of an exploratory whole-genome expression microarray allowed us to identify a set of genes whose expression was deregulated in patients blood samples (Raposo et al., 2015). Data from this array was combined with information from the literature concerning molecules whose levels were described as altered in the presence of mutated ataxin-3. In this candidate study we were able to confirm, using quantitative real-time PCR, that levels of HSPB1 and BCL2 were found to be significantly deregulated. We have further performed a pilot longitudinal study, using patient’s samples collected at two moments of disease progression. BCL2 and DNAJB14 adjusted mRNA levels were found to be significantly different between the baseline and the second moment. In an additional microarray experiment, in which different stages of disease progression were included, a set of deregulated genes, currently being analysed, was identified. Candidate MBs will have to be further tested by analysing independent cohorts of patients and evidencing the correlation with clinical as well as imaging data.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L37

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The Lithium clinical trial - read full article

By: Jonas Alex Morales Saute and Laura Bannach Jardim

In a recent phase II clinical trial in Machado-Joseph disease/Spinocerebellar ataxia type 3 (MJD/SCA3), a disorder without specific therapy, no significance on primary efficacy outcome —NESSCA score—was obtained. However, after 48 weeks of double-blind observation, possible benefit of lithium carbonate therapy appeared on secondary outcomes related to ataxia—SCAFI and CCFS. These apparently conflicting results may suggest that the study protocol should be revisited before ongoing on further studies. Therefore, unplanned subgroup analysis of this data was performed, as hypothesis generating technique for future studies. Treatment response modifiers and metric properties of clinical scales were also done. Sixty-two MJD/SCA3 patients had been randomly assigned (1:1) for the 48 weeks, single center (Hospital de Clínicas de Porto Alegre, Brazil), double-blind, placebo-controlled trial. We performed additional analysis with the subscores of the Neurological Examination Score for the Assessment of Spinocerebellar Ataxia (NESSCA) and the Scale for the Assessment and Rating of Ataxia (SARA) and with the subgroup of patients with independent gait. Potential interactions of clinical/molecular findings with treatment response; minimally important differences (MID); and sample size estimations (with placebo data) of NESSCA, SARA, Spinocerebellar Ataxia Functional-Index (SCAFI) and Composite-Cerebellar Functional-Score (CCFS) were evaluated. Interventions were Lithium carbonate (target serum level of 0.5- 0.8 milliequivalents per liter) or placebo tablets. Cerebellar NESSCA (range: 0-7 points) differed between groups 0.64 points (95% CI 0.23 to 1.05, p<0.001) over the whole 48 weeks of study, favoring lithium. NESSCA (p=0.010) and SCAFI (p=0.015) differed between groups in the subgroup of patients able to perform the 8-meters walking-time, favoring lithium. Estimated sample sizes with the evaluated scales were provided for future trials with lithium or other candidate drugs. Lithium efficacy on cerebellar NESSCA and on SCAFI and CCFS in the primary analysis suggests lithium efficacy on cerebellar features of MJD/SCA3. The interaction of disease severity with treatment response on SCAFI and NESSCA indicates that early stages patients should be preferentially recruited in future studies. We suggest that SCAFI should be utilized as the primary outcomes for phase 2 studies. SARA data from this phase 2 study with positive results on SCAF should provide sample size estimations for phase 3 trials with the same intervention, where SARA should be the primary outcome. The inclusion of independent walking patients only (according to 8MW) is advisable. And finally, taking SARA MID and SARA progression in the placebo group as references, we suggest that future phase 3 studies should be planned for lasting at least 18 or 24 months.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L38

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Preliminary results of intravenous trehalose for the treatment of Spinocerebellar Ataxia type 3 (SCA3) - read full article

By: C.R. Gordon, R. Zaltzman, C. Klein, H. Greif, I. Gliko-Kabir, and Z. Argov

Background: Trehalose is a disaccharide with protein stabilizing and autophagy enhancing properties. It showed efficacy in reducing abnormal protein aggregation in animal models of several human poly A- and poly Q- mediated hereditary neurological disorders. In animal models of SCA3, oral trehalose showed reduction of lesion size in a lentivirus model and improved motor function in an ongoing study in transgenic animals. The safety and pharmacokinetics of high dose IV trehalose in humans was recently studied in patients with Oculopharyngeal Muscular Dystrophy (OPMD). Objective: To report preliminary results of a phase 2 trial of trehalose 9% IV in SCA3 patients. Design and Methods: This is a proof of concept, phase 2 study to determine and compare the safety, tolerability and efficacy of 52 weekly IV administration of Trehalose 9% IV solution, 13.5 gr vs 27 gr in SCA3 patients. Primary endpoints will be the SARA score with several secondary endpoints (NESSCA scale, 9 hole peg test, 8 meters walk). Safety and tolerability is assessed by various clinical and laboratory tests. Results: We have recruited 15 clinically and genetically confirmed SCA 3 patients who are currently under treatment. No drug-related adverse events were noted. This is in accordance with the reported safety profile of our OPMD study. Efficacy data is very limited data and at the moment is not reportable. Conclusions: Based on these preliminary findings, trehalose 9% IV solution seems to be safe in humans. A further planned phase 2b multi-center clinical trial in SCA3 will be discussed.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L39

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TTR amyloidosis: a scientific journey - read full article

By: Maria João Saraiva

Mário Corino de Andrade described in 1952 in the journal “Brain” the first form of an hereditary amyloidosis, Famlial Amyloidotic Polyneuropathy, FAP—affecting the peripheral nervous system, also known as Andrade´s disease. In 1939, Andrade observed different patients complaining of loss of sensitivity to temperature and pain and suspected the clinical symptoms were peculiar and belonged to a rare hereditary disease. To understand in depth what he considered a new endemic clinical entity, he asked the collaboration of experts in different fields, such as biochemistry, genetics, pathology, who confirmed the genetic nature of the disease and the presence of systemic amyloid deposits, that we know since 1984 to be constituted by mutant transthyretin (TTRV30M), particularly in the peripheral nervous system. Explosion of molecular biology tools provided identification worldwide of more than 100 TTR mutations, most of them associated with amyloid neuropathies and cardiopathies as well as perspectives for their clinical improvement. Molecular and cellular in-depth studies are underway in several laboratories to dissect underlying ethiopathogenic mechanisms in TTR related amyloidoses; in particular: (1) consequences of protein aggregation on peripheral nerve and other organs and tissues; (2) development of improved/alternative therapies in pre-clinical models; (3) biomarker identification for therapy follow-up.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L40

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TTR-FAP: diagnosis of familial and sporadic cases - read full article

By: Isabel Conceição

Transthyretin-related familial amyloid polyneuropathy (TTR-FAP) is a rare, autosomal- dominant, adult-onset, systemic disease caused by mutations in the transthyretin (TTR) gene that lead the TTR protein to misfold and deposit as insoluble amyloid fibrils in peripheral and autonomic nerves, the heart, gastrointestinal tract, kidneys, eyes, and connective tissue of the transverse carpal ligament. Initial clinical symptoms may appear between the second and ninth decade of life and, without treatment, TTR-FAP leads to death on average within 10 years of symptom onset. The disease can be difficult to recognize due to extreme phenotypic heterogeneity and nonspecific clinical symptoms. Because of the late onset and low penetrance of TTR mutations in some areas, TTR FAP can present as sporadic cases leading to frequent misdiagnosis. As a result of such misdiagnoses, definitive diagnosis can be delayed for as much as 2–6 years, postponing adequate management and genetic counseling and leading to possible irreversible damage.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L41

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Molecular aging: a primary or secondary trigger in late onset myopathies? - read full article

By: Vered Raz

The genetic cause for OPMD is an alanine expansion in PABPN1. PABPN1 encodes for RNA binding protein, involved in multiple steps of RNA processing. The protein is ubiquitously expressed but symptoms in OPMD start only from midlife onwards, and initially are limited to only few muscles. This enigma is not fully understood. Recent data correlating molecular and pathological changes with symptoms reveals the most prominent affected molecular pathway in OPMD and key regulators that cause muscle weakness in OPMD. A better understanding of OPMD pathology could lead to better therapeutic developments.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L42

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OPMD therapy progress - read full article

By: Aida Abu-Baker

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset muscular dystrophy caused by a polyalanine expansion mutation in the first exon of the poly (A) binding protein nuclear 1 (PABPN1) gene. It is characterized by progressive eyelid drooping, swallowing difficulties and proximal limb weakness. Currently there is no effective treatment for OPMD. Here, we will highlight the current translational research research advances in the treatment of OPMD. Both In vitro and in vivo OPMD disease models will be described. We will discuss different experimental therapeutic approaches for OPMD including gene editing, RNA molecules, and drug therapies.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L43

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Disease modifying therapy should be stopped in secondary progressive MS - read full article

By: Abhijit Chaudhuri

Point of view: Yes
Disease modifying therapies (DMT) are not effective in non-relapsing secondary progressive multiple sclerosis (SPMS). Despite the recent progress in the treatment of relapsing remitting multiple sclerosis during the past two decades which has seen the introduction of several drugs, similar success has not been achieved for SPMS. This is primarily due to the intrinsic neurodegenerative process that drives the accumulation of disability in SPMS which is independent of focal inflammatory changes where DMT seem more effective. The underlying pathology in the progressive formof the disease is not unitary and neurodegeneration in SPMS is considered to be multi-factorial, diffuse and significantly influenced by metabolic neuroaxonal changes. One of the characteristic features of SPMS is the involvement of normal-appearing cerebral white and grey matter which worsens in severity with disease progression over time. Current selection of DMT does not influence the wider pathology in SPMS, which is attested by the failure of treatment benefit in several completed randomised controlled clinical trials. These trials have involved over 6000 patients since 1988 and included immunosuppressive agents (Azathioprine, Ciclosporin, Cyclophosphamide, Sulfasalazine, Linomide, Mitoxantrone and Cladribine), first line DMT (Interferon beta 1-a, 1-b, and Glatiramer Acetate), human IVIg, anti-CD20 monoclonal antibody (Rituximab), Myelin Basic Protein and Cannabinoid (Dronabinol). The European and North American placebo-controlled study of interferon beta-1b in SPMS showed divergent results in the primary outcome measure (sustained EDSS progression), while treatment effects were similar on relapse and MRI-related endpoints, confirming the dissociation between disease progression, relapse and MRI markers of inflammation (Enhancing and T2 lesions). There was no clinical benefit of Alemtuzumab in a small trial of SPMS and despite a reduction in inflammatory activity,with no benefit in terms of EDSS progression or rate of brain atrophy in MRI. Fingolimod, an oral DMT approved in relapsing remitting MS (RRMS) for patients failing first line DMT, was not shown to be effective in a large trial of patients with primary progressive multiple sclerosis (PPMS) which shares the disease pathology of SPMS. The clinical trial of Siponimod, an oral S1P superagonist similar to Fingolimod, in SPMS patients is expected to be completed in 2016, and the trial of Rituximab in SPMS will finish in 2017. An interim result of Ocrelizumab, a humanised anti-CD20 monoclonal antibody, found treatment benefit in younger (<55 years) ambulatory PPMS patients with MRI evidence of disease activity (enhancing brain lesions). Several other clinical trials in SPMS are currently ongoing, but very few of these trials are testing currently approved DMT with the exception of Natalizumab (ASCEND trial, estimated completion date in 2017). There is clearly an unmet need of effective treatment in SPMS. This is largely due to the incompleteness in our understanding of the progressive disease pathology in MS. By the exacting standards of “no evidence of disease activity (NEDA), the goal is achieved at best in about 45% of RRMS patients in the clinical trials of DMT and in 15% of placebo-treated patients; the relative size of the difference (30%) is small compared to the size of relative risk reduction of relapse with DMT. This implies that despite the huge success of current DMT with containment of MS relapse, a larger proportion of disease pathology still remains untouched and contributes to the disability progression and transition to SPMS. There is thin evidence, little therapeutic benefit and no cost-effectiveness to support the continuation of existing DMT in patients with established SPMS. A small subgroup of patients with so called progressive-relapsing phenotype with MRI evidence of enhancing or new lesions may in theory continue to experience some benefit from current DMT but this number is small and the presumed treatment benefit in this subgroup should not be extrapolated to all SPMS patients. The recommended stopping criteria for disease modifying therapy (DMT) in patients currently receiving treatment for relapsing remitting disease are: walk for reasons other than MS; which would imply an EDSS score >6.5, and (sustained disease progression) over a 6-12 month period. The disability progression is reflected in MRI as progressive loss of brain volume and cervical spinal cord atrophy without evidence of lesion enhancement. Many patients develop psychological dependence on DMT after having taken it for many years, and feel apprehensive when advised to stop treatment. SPMS patients meeting stopping criteria should be counselled and withdrawn from treatment gradually over a period of 3-4 months to avoid the risk of “rebound” and pseudorelapses; these patients should ideally be offered the opportunity to enrol in new treatment trials of SPMS. Quite appropriately, new treatment trials in SPMS are moving away from the immune-inflammatory focus and aiming at neuroprotection, mitochondrial function, neuroaxonal metabolic reserve and ion transport function with promising early results reported in clinical trials of Simvastatin and Biotin. Such treatments are likely to be introduced early in the future, possibly in combination with DMT in RRMS, to arrest disease progression and conversion to SPMS.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D9

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Statins: friend or foe? - read full article

By: Davide Carvalho

Statins (HMG-CoA reductase inhibitors) are drugs of choice for lipid lowering in patients at increased risk for cardiovascular disease (CVD) and for those with established atherosclerotic VD (secondary prevention). CV risk using risk calculators should be assessed prior to initiation of a statin for most patients being treated for primary prevention of atherosclerotic CVD. Guidelines vary regarding threshold for using statins for primary prevention: the American College of Cardiology/American Heart Association recommends statin therapy for patients in the following groups: patients with a 10-year risk of CVD >/=7.5% with consideration at risk 5% to 7.5%; patients with low-density lipoprotein (LDL) cholesterol >/=190 mg/dL; patients aged 40-75 years with diabetes (type 1 or 2) and LDL cholesterol >/=70 mg/dL. The National Institute for Health and Care Excellence recommends statin therapy if 10-year risk of CVD >/=10%. The European Society of Cardiology/European Atherosclerosis Society recommends statin therapy if estimated 10-year risk of first fatal atherosclerotic event >/=10%. Use of statin in intermediate-risk population also resulted in a significantly lower risk of CV events. Statins are well tolerated, but various statin-associated symptoms (SAS) might occur, including statin-associated muscle symptoms (SAMS), diabetes mellitus (DM), and central nervous system complaints. These SAS are rare in clinical trials, making their causative relationship to statins unclear. SAS are, nevertheless, important because they prompt dose reduction or discontinuation of these life-saving drugs. SAMS is the most frequent SAS, and mild myalgia may affect 5-10% of statin users. Clinically important muscle symptoms are rare, including rhabdomyolysis and statin-induced necrotizing autoimmune myopathy (SINAM). Antibodies against HMG-CoA reductase apparently provoke SINAM. Good evidence links statins to DM, but evidence linking statins to other SAS is not clear. The highest risk for incident diabetes with statins was found in older patients, independently of BMI at inclusion and changes in LDL cholesterol. The preventive effect on cardiovascular events did not change according to changes in HbA1c levels. These observations do not justify any change in clinical practice, except perhaps for a closer follow-up of HbA1c levels after initiating statin therapy. Management of SAS requires making the diagnosis, changing or adjusting the statin treatment, and using alternative lipid-lowering therapy.

Special Issue on Stroke. From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 7–8 June 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 2):L1

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Stroke mimics and stroke chameleons - read full article

By: Carlos Andrade

Stroke is one of the major causes of death and morbidity worldwide and carries an important economic impact. The diagnosis is still a clinical one, supported by brain imaging. However, up to 30% of suspected stroke presentations, have a different diagnosis. In these cases, two scenarios must be considered: a false positive diagnosis, or “stroke mimic”, and a false negative or “stroke chameleon”. Although a sudden onset of a neurological deficit usually represents a stroke, other conditions such as seizures (especially if Todd´s palsy is present), syncope, hypoglycaemia, migraine, brain tumours and functional disorders represent the bulk of the differential diagnosis. The accuracy of their recognition depends on context (primary care vs paramedics vs emergency department vs stroke specialist). Even the stroke specialists may have up to 15% of misdiagnoses. Brain imaging is a powerful helper. Non-contrast CT scanning has become the primary imaging modality in the initial assessment, mainly due to its wide availability, rapid execution and lack of major contraindications (such as pacemaker). It detects fairly easily an acute haemorrhagic stroke or a non-vascular structural cause of stroke mimic (such as a space-occupying lesion). However, the majority of strokes are ischaemic, and the initial CT-scan may be negative. Brain MRI, on the other hand, and in particular diffusion weighted imaging (DWI), have 88-100% sensitivity and 95-100% specificity for early ischaemia. A variety of other neurological conditions may be DWI positive, and so, clinical context must be considered. DWI negatives are rare, mainly associated with small lesions in the brainstem, and, as described more recently, are overcome by associating perfusion-weighted imaging. Nevertheless, MRI is time consuming and may not be immediately available, and therefore most clinicians still administer thrombolytic therapy base on clinical evaluation and non-contrast CT-scan. Inadvertently but inevitably, stroke mimics also receive this treatment. Although inadequate, it is relatively safe, with a low likelihood of complications (<1%). Stroke can have an unusual presentation and can often not be immediately recognized. Although rare, vertigo may be a manifestation of stroke. A thorough neurological examination, particularly focusing on the head impulse test, evaluation of nystagmus and skew deviation, can properly distinguish a peripheral lesion from a vertebrobasiIar stroke. Other findings, such as monoplegia or delirium, may infrequently be the sole manifestation of stroke. In conclusion, the identification of stroke can be difficult. The full workup (including MRI) of all patients that may have a stroke is probably not feasible, and an initial clinical evaluation is still an important screening tool. In the future, the development of blood biomarkers of cerebral ischaemia may further help the accurate detection of this common diagnosis.

Special Issue on Stroke. From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 7–8 June 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 2):L2

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Achy breaky brain: discussing headache and stroke - read full article

By: Ricardo Soares dos Reis

Headache and stroke are both fairly prevalent conditions, and their association could be deemed coincidental. However, the interaction of these conditions is far more complex. Headache may either be a cause or consequence of stroke and, then again, headache syndromes can mimic stroke and vice versa. Discussion of these issues is further complicated by the diversity of headache and stroke sub-types. Overall, up to 34% of stroke patients present with headache. While the brain is largely devoid of sensation, mechanical insults or inflammation of other cranial structures (the dura and dural sinuses, skull base and meningeal arteries and selected cranial nerves) are likely to elicit pain. Thus, it can easily be understood why headache is classically associated with haemorrhagic stroke. In fact, severity of headache has been studied as a prognostic factor in symptomatic intracerebral haemorrhage. Furthermore, subarachnoid haemorrhage, clinically characterized by thunderclap headache, has the highest association with headache (>90% of cases). On the other hand, ischaemic stroke (IS) presents with headache less frequently (up to 25% of cases). The headache is usually non-pulsatile and ipsilateral to the lesion. The likelihood of headache is higher when the infarct is large and when it affects the insular cortex or the posterior circulation. The likelihood is lower in lacunar syndromes. In the setting of IS, headache may point the clinician to an arterial dissection or to a migrainous infarction, among others. The latter is said to occur in a patient with typical aura lasting more than one hour and neuroimaging-confirmed ischaemia. Other cerebrovascular disorders such as cerebral venous thrombosis, reversible vasoconstriction syndrome, posterior reversible encephalopathy syndrome and vasculitides also present with headache and will be briefly mentioned. In conclusion, headache is a non-specific, albeit clinically useful, sign in acute stroke. Thus, this complex relationship should be kept in mind when considering the differential diagnosis of acute neurological deficits.

Special Issue on Stroke. From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 7–8 June 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 2):L3

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Imaging modalities in acute stroke - read full article

By: André Cunha and Manuel Ribeiro

Recently, multiple randomized controlled trials demonstrated a high degree of efficacy for endovascular treatment with stent-retriever in strokes caused by large-vessel occlusions. In these trials, the benefit of endovascular therapy was directly related to baseline imaging markers, such as identification of a large artery occlusion, existence of a small infarct core, documentation of adequate collateral circulation and estimation of a target mismatch. In this new era of acute stroke therapy, controversy persists about the optimal approach to patient selection based on brain imaging. The reduction of the time from onset of symptoms to reperfusion is crucial for a favourable long-term outcome in stroke patients – “time is brain” – therefore we need an imaging strategy to avoid any important delay. A CT-based imaging approach is the mainstay of acute stroke imaging. Several studies demonstrated the same quality of MRI when compared to a combination of non–contrast-enhanced CT (exclusion of intracranial haemorrhage and measure of early ischemic changes), CT Angiography (identifying the target thrombus) and CT Perfusion Imaging (tissue at risk), in detecting and quantifying signs of cerebral ischemia due to large artery occlusion. Nevertheless, MRI is more sensitive than CT in detecting small lesions and/or posterior fossa ischaemic lesions. In our practice, we are focused on minimizing delays to reperfusion, providing fast imaging paradigms with the essential information necessary for decision-making. The combination of the clinical assessment, non–contrast-enhanced CT and CT Angiography, supports the selection of suitable patients for endovascular revascularization. We are moving from a rigid time-based to a physiology-based decision, selecting patients for treatment beyond the 6-hour window if there is evidence of a significant imaging/clinical mismatch. Imaging has, therefore, a key role in medical and endovascular treatment decisions, overtaking time as the single surrogate marker of brain physiology.

Special Issue on Stroke. From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 7–8 June 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 2):L4

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Pharmacological revascularization in acute stroke - read full article

By: Pedro Castro

Intravenous fibrinolytic therapy has been used for acute ischemic stroke with wide acceptance for more than 15 years. The aim of this presentation is to review the literature, clinical protocols and some common dilemmas regarding pharmacological revascularization in acute ischemic stroke. The story starts with the NINDS trial (1996) which supported the efficacy of recombinant tissue plasminogen activator (rtPA) not only in early neurological recovery but also in better functional outcome at 3 months. The protocol included the use of 0.9 mg/kg intravenous rTPA to a maximum of 90 mg within 3 hours of symptom onset. Afterwards, the ECASS III trial (2008) stretched the time window to 4.5 hours. The major risk of intravenous rtPA treatment remains symptomatic intracranial haemorrhage which occurs in 2-6% of patients. The SITS-ISTR (Safe Implementation of Thrombolysis in Stroke – International Stroke Thrombolysis Register), the largest community registry, reported that in 11 865 patients treated with rTPA, 56% of them were independent at 3 months. The last chapter in the rTPA saga was the meta-analysis published in 2012, which depicts the safety of rTPA across all age groups. Common dilemmas in clinical practice are patients presenting with minor or fluctuating deficits, on oral anticoagulants and other items of an extensive and cumbersome contra-indication list. Other pharmacological agents and Transcranial Ultrasound Fibrinolysis Augmentation will be shortly reviewed. In conclusion, timely given rtPA remains the primary treatment in acute ischemic stroke, but recent advances in mechanical revascularization may challenge this mainstream paradigm. The epilogue remains, thus far, unwritten.

Special Issue on Stroke. From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 7–8 June 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 2):L5

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Mechanical revascularization in acute stroke - read full article

By: Tiago Parreira

The year of 2015 was a hallmark for the treatment of acute stroke. The publication of the MR CLEAN trial elicited a cascade of positive results from six additional stroke randomized controlled trials: ESCAPE, EXTEND-IA, REVASCAT, SWIFT PRIME, THERAPY and THRACE, which were halted prematurely for efficacy. The cumulative evidence from these studies shows an overwhelming benefit from the endovascular treatment of intracranial large artery occlusions. The published trials led to guideline changes in the USA and Europe, which reflect the major common factors amongst studies, but the need for clinical judgment remains significant, especially in patients who do not neatly fit the patient population enrolled in the trials, but who probably also benefit from this treatment. All studies (with the exception of THERAPY) involved new generation devices, namely stent retrievers. Although most of the technical approaches, with some variations, are relativity standardized, many uncertainties remain for specific situations such as tandem occlusions or intracranial stenosis. The decision to use general anaesthesia or conscious sedation has also been the topic of much debate. Early studies showed worse outcomes associated with general anaesthesia but were confounded by indication, that is, medically unwell patients with poorer prognosis were more likely to undergo general anaesthesia. The MR CLEAN trial addressed this issue, and treatment effect was clearly greater in those treated under conscious sedation. The concern regarding thrombectomy costs has also been addressed. The studies concluded that, although the upfront costs of thrombectomy are high, the potential quality-adjusted life year gains mean this intervention is cost-effective.

Special Issue on Stroke. From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 7–8 June 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 2):L6

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When to perform thrombophilia screening - read full article

By: Luciana Ricca Gonçalves

Identifying the stroke mechanism is a crucial aspect of secondary prevention. However, no stroke etiology is identified in 30-40% of patients. Cryptogenic stroke is the term used to refer to strokes for which no definite cause can be identified. Thrombophilia is defined as a predisposition to form clots inappropriately, and can be inherited or acquired. The inherited thrombophilias include deficiency of natural anticoagulants, such as protein C, protein S or antithrombin, and factor V Leiden or prothrombin G20210A gene mutation. The most important acquired thrombophilias are antiphospholipid syndrome and cancer. Thrombophilia is an important risk factor for venous thromboembolism, but its role in arterial thrombosis is not well defined. The presence of thrombophilia has been accurately investigated in this setting, obtaining controversial results. Multiple case-control studies and a meta-analysis failed to show an association between inherited thrombophilia and stroke. The only strong association found was with the presence of antiphospholipid antibodies, both in retrospective and prospective studies. Plasma levels of antiphospholipid antibodies were elevated in young adults who suffered a stroke compared with controls, and these patients presented a higher risk of recurrent thrombotic events. Before performing these tests, all other causes must be ruled out. There are many doubts if the information obtained in thrombophilia screening is sufficiently relevant to change clinical decision, regarding secondary prevention. As a consequence, there is no consensus about the clinical utility and cost effectiveness of thrombophilia screening in arterial thrombosis.

Special Issue on Stroke. From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 7–8 June 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 2):L7

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Inherited Metabolic Disorders and Stroke - read full article

By: Paulo Castro Chaves

Recent data show that stroke is one of the main causes of death and the main cause of neurological disability in the adult. It is also a major cause of dementia and age related cognitive decline. Conventional cardiovascular risk factors explain a significant percentage of stroke risk, but an important part of that risk remains without explanation. Additionally, different individuals have different outcomes when exposed to the same risk factor. This means that genetic factors have an important role in stroke risk determination. Unlike other cardiovascular diseases, stroke is a heterogeneous disorder and genetic factors can affect stroke pathophysiology at different levels. Taking this into consideration, we can identify several inherited metabolic disorders, usually with multisystemic presentations, that can have stroke as one of their phenotypic expressions. We have disorders that express themselves as small- or large-vessel disease patterns, as cardioembolic causes or other kind of profiles (for instance, stroke-like in MELAS). This group of disorders, although individually rare, are collectively frequent and they can appear at any age, from the newborn to the elderly. Due to their rarity, they are frequently not recognized or taken into account in diagnostic flowcharts, although for a significant number of them we have specific treatments that can improve prognosis significantly.

Special Issue on Stroke. From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 7–8 June 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 2):L8

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Etiologic and diagnostic workup in transient ischemic attack and ischaemic stroke in young adults - read full article

By: Carolina Lopes

The incidence of ischaemic stroke and transient ischaemic attack (TIA) in young adults is increasing, and this implies a great early death risk compared with the general population. A wide range of different etiologies is found in this group, and a careful anamnesis, physical examination and workup is essential for its diagnosis and proper management. Standard risk factors are still prevalent in this age group, and they should be considered in the initial evaluation. Special emphasis should be given to cervical artery dissection, right-to-left shunts and hypercoagulable states in young stroke patients. A wide variety of rarer causes should also be considered when the remainder of the workup is negative. In this protocol, we propose a methodical diagnostic approach to TIA and ischaemic stroke in young adults.

Special Issue on Stroke. From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 7–8 June 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 2):L9

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When to anticoagulate and when to resume anticoagulation after stroke - read full article

By: Filipa Gomes

Ischaemic strokes are attributed to a cardioembolic cause in approximately 20% of cases and atrial fibrillation (AF) is the most common cardioembolic source. AF is also associated with larger, more disabling and higher case fatality strokes which highlights the major importance of primary prevention with oral anticoagulants (OAC). Identifying patients with AF and other cardiovascular risk factors for starting these drugs is as important as evaluating their bleeding risk. CHA2DS2-VASc and HAS-BLED are two important tools, with the first helping deciding who to anticoagulate and the second serving as a guide to reduce modifiable bleeding risks (not to determine whether to offer anticoagulation or not). If starting anticoagulation is becoming more common for primary prevention, the resumption of this therapy after ischaemic and haemorrhagic stroke is sometimes delayed or avoided. However, several studies have already shown that resumption is important to decrease stroke recurrence and all-cause mortality, outweighing the major concern - intracranial bleeding. Resuming OAC may be contraindicated in some cases, for example when a lobar haematoma is associated with cerebral amyloid angiopathy. Still, the most difficult decision is not usually whether or not to start anticoagulation, but the ideal timing to do it. There are not enough data about this topic, although many observational studies have shown positive results with starting OAC between 36h to 90 days after the event. In clinical practice, the timing often depends on the indication for anticoagulation and on the thrombotic risk associated with the disease. Decision must also take in consideration the size of the ischaemic lesion, the location and dimension of the intracranial hematoma and the adequate control of hypertension, which are the main risk factors for (re)bleeding.

Special Issue on Stroke. From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 7–8 June 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 2):L10

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Embolic stroke of undetermined source: what to do? - read full article

By: João Sargento Freitas

Upon the diagnosis of an embolic stroke, the absence of significant arterial pathology in the symptomatic vessels, major cardiac sources of emboli and “other specific causes of stroke” will allow the formal classification of an embolic stroke of undetermined source (ESUS). And what is there to do then? Firstly, we should critically review the diagnostic work-up performed. Were all causes of embolic stroke really excluded? Regarding arterial pathology, occasionally the source of embolus is in less frequent locations that should be kept in mind. Complex atherosclerotic plaques in the aortic arch, distal extracranial or proximal intracranial vessels are locations often neglected. Moreover, attention should be paid to arterial pathology without hemodynamic impact, such as some cases of dissection or vasculitis, that may be overlooked, requiring specific exams. A routine ECG and 24-hour ECG monitoring excluding the presence of a potentially embolic arrhythmia may be enough for the formal classification of ESUS. However, they should not reassure the attending physician. Longer cardiac monitoring through implantable and non-implantable devices has been demonstrated to improved diagnostic labelling. The remaining critical question is what thromboprophylaxis strategy to use. Considering the medical equipoise at this time point of knowledge, the logical answer, whenever possible, can be only one: randomize! In case no trial is available for a specific patient, the decision should, like always, be shared by physician and patient after careful consideration. In sum, ESUS patients require a specific diagnostic and therapeutic approach that will surely be progressively reconsidered during the following years.

Special Issue on Stroke. From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 7–8 June 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 2):L11

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Cognitive Rehabilitation in Stroke - read full article

By: Vítor Tedim Cruz

Cognitive dysfunction of vascular origin may be defined as any type of cognitive or behavioural impairment that results from nervous system damage and neuronal loss caused by cerebrovascular disease. It may be slowly progressive, in relation with vascular risk factor exposure, or of sudden onset after stroke or even transient ischaemic attack. At least one third of stroke patients show cognitive impairment 3 months after the acute phase, with the most affected domains being attention, executive functioning and processing speed. These deficits contribute to overall functional impairment and may even lead to dementia, but they also interfere significantly with rehabilitation programs. However, there are very limited pharmacological treatment approaches for the management of cognitive impairment after stroke. Therefore, cognitive interventions are an increasingly common approach in stroke rehabilitation programs, either isolated or combined. If we consider the non-motor aspects of the human brain, cognitive training must be understood in a similar manner as physical therapy for motor deficits. Despite the continuum between cognitive, behavioural and motor functions, the former are more complex and supported on memory and other distributed neural systems, which presents specific challenges for the design of effective interventions. These may be defined as a group of non-pharmacological interventions, specifically conceived with the purpose of improving cognitive and behavioural performance in stroke patients. During this lecture, we will review the indications, methods and recent scientific evidence on the effects of specific neuropsychological interventions in cognitive dysfunction of vascular origin and after stroke.

Special Issue on Stroke. From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 7–8 June 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 2):L12

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Aetiology and diagnosis of intracerebral haemorrhage - read full article

By: Andreia Veiga

Spontaneous, non-traumatic intracerebral haemorrhage (ICH) remains a significant cause of morbidity and mortality, as it is the second most common cause of stroke. High blood pressure and age are the most important risk factors. However, the investigation should include a search for other causes including use of anticoagulants or antiplatelet agents, coagulopathy and other comorbidities such as dementia, epilepsy, cancer or hepatic disease. The CT scan remains the gold standard for diagnosis in emergency care. On the other hand, brain magnetic resonance angiography should be performed in the case of single/multiple lobar haemorrhages. These can be secondary to amyloid angiopathy, rupture of an aneurism or an arteriovenous malformation, cavernous angioma or tumour haemorrhage. Radiological evidence suggestive of vascular abnormalities as causative for ICH can include the presence of subarachnoid haemorrhage, enlarged vessels or calcifications along the margins of the ICH, hyperattenuation within a dural venous sinus or cortical vein along the presumed venous drainage path, unusual hematoma shape, presence of oedema out of proportion to the time of presumed installation, an unusual location, and the presence of other abnormal structures in the brain (such as a mass). Magnetic resonance venography and catheter angiography can be performed in specific situations.

Special Issue on Stroke Updates. From Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 7–9 June 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 2):L13

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The medical management of intracerebral haemorrhage - read full article

By: João Pinho

Intracerebral haemorrhage (ICH) accounts for 10-25% of all strokes, and despite its incidence, associated disability and mortality have been decreasing in high-income countries. Nevertheless, it is associated with a high one-month mortality, which may reach up to 40%. Medical management of ICH patients in the hyperacute and acute phases is a challenge, which requires continuous monitoring and up to date therapeutic interventions, even in patients who need surgical treatment. The ABCD approach is discussed as a guideline for a systematic and quick evaluation of ICH patients in the emergency department, as it is able to address priority concerns in these patients, namely airway management and indication for tracheal intubation, blood pressure management, neurological evaluation and reversal of antithrombotic medication. Patients with ICH should be preferentially admitted in acute stroke units or dedicated neurocritical care units, which have shown to improve mortality and disability. General management of practical issues such as timing of out-of-bed mobilization, timing of nutrition, measures for prevention of infections, deep vein thrombosis prophylaxis and epileptic seizure prevention are also discussed.

Special Issue on Stroke. From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 7–8 June 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 2):L14

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Aneurysms and arteriovenous malformations: When and how to treat? - read full article

By: António Vilarinho

When to treat? The answer to this question depends on the diagnosis and clinical presentation, which may be with or without rupture. Vascular lesions [aneurysms or arteriovenous malformations (AVM)] with haemorrhage should be treated as soon as possible, and this is particularly true when dealing with aneurysms. In the last years, there has been a change in the paradigm of timing to treat aneurysms with sub-arachnoid haemorrhage (SAH). Initially, treatment was postponed until after the risk period for vasospasm has passed. Later on, the patients started being treated earlier (in the first 72 hours after the SAH). Nowadays, there is a tendency for even earlier treatment (less than 24 hours after SAH). How to treat? Concerning aneurysms, there are two treatment modalities: surgery or endovascular treatment. As for AVMs, apart from the options of surgery and endovascular treatment, there is also the option of radiosurgery. In this case, treatment can be complementary, with two or three modalities possibly being used in the same patient. In aneurysms, the treatment modality depends on their location, morphology, vascular tree features, age and neurological status. In cases where both surgery and embolization are feasible, embolization should be chosen, as it is the least invasive. Even though initially all patients underwent surgery, endovascular treatment has evolved and has progressively expanded its indications. Nowadays, treatment decisions are the result of a multidisciplinary discussion between Neurosurgery and Neuroradiology, balancing the best immediate care with long term results.

Special Issue on Stroke. From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 7–8 June 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 2):L15

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Scales in stroke patients: the National Institutes of Health Stroke Scale (NIHSS) - read full article

By: Marta Carvalho

The National Institutes of Health Stroke Scale (NIHSS) is an assessment tool used worldwide to quantify neurological deficit in people with stroke. It is simple and easily administered in all clinical settings, including the emergency department, wards and out-patient clinics. This scale is composed of 15 items based on different parts of the neurological examination such as the level of consciousness, language, neglect, visual-field loss, extra-ocular movement, motor strength, ataxia, dysarthria, and sensory loss. The observer rates the patient’s ability to answer questions and perform activities so that each item is scored from 0 (normal) to a maximum of 2 to 4, according to the item tested. It takes less than 5 minutes to complete by trained people, and its reliability among health care providers is high. It is useful not only in evaluating the severity of stroke and in assessing the evolution of deficit over time, but also helps in the decision of treatment and in predicting patient outcome. This workshop aims at providing training skills in applying the NIHSS to patients with different neurological deficits due to stroke.

Special Issue on Stroke. From Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 7–8 June 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 2):L16

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Scales in stroke patients: the ABCD2 score, the TOAST classification and the Hunt and Hess scale - read full article

By: Diogo Fitas

arious stroke scales have been developed. They are useful to guide diagnostic accuracy, treatments, monitoring neurologic deficits and to predict outcomes. The ABCD2 and, most recently, the ABCD3 or ABCD3-I score, have been developed to predict the stroke risk after transient ischaemic attack. They may also assist in selecting out non-cerebrovascular diagnoses if the score is low. The Hunt and Hess scale describes the severity of subarachnoid haemorrhage based on the patient's clinical condition and is used as a predictor of outcome. The TOAST classification is a system for categorization of subtypes of ischaemic stroke mainly based on etiology. All these scales will be covered during the workshop.

Special Issue on Stroke. From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 7–8 June 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 2):L17

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Tricks to manage resistant hypertension in the clinical practice - read full article

By: Jorge Polónia

Definition and prevalence: Hypertension has been defined (ESH/ESC guidelines 2013) as resistant (RH) to treatment when it is not controlled after a therapeutic strategy that includes adequate lifestyle measures plus a diuretic and two other anti-hypertensive drugs from different classes at adequate doses. Its prevalence is about 5-30% in hypertensive patients, and there is clear evidence that RH associates with abnormally high cardiovascular and renal morbidity and mortality. In Portugal, as shown by the Physa study, RH occurs in 8% of all treated hypertensive subjects with a prevalence of 5-10% in general practice and 25-30% in hypertension clinics. HR is more common in elderly people as well as in the obese, people with sleep apnoea, high salt intake, diabetes, renal disease, secondary hypertension, among others. Strategy: Before RH is diagnosed, one must exclude resistance due to doctors and resistance due to patients. Resistance attributable to doctors includes: a) incorrect blood pressure (BP) measurements (non-adapted devices, cuffs, no BP evaluation in both arms and legs, Osler maneuverer…), b) inadequate regimens (incorrect combinations, low doses particularly of diuretics, furosemide given wrongly only once a day, inertia…), c) failure to identify white coat hypertension or white coat effect with 24h ambulatory BP monitoring (ABPM), d) no detection of drug interactions and potential pro-hypertensive drugs, e) failure to detect renal disease; f) failure to detect secondary hypertension (most prevalent forms are renal disease, primary hyperaldosteronism and sleep apnoea). Resistance due to patients includes: a) high salt intake (measurement of 24-h urinary sodium excretion is mandatory), high alcohol intake, low potassium intake, b) use of non-prescribed potential pro-hypertensive drugs; c) non-compliance to therapy (drug intake under surveillance and evaluation with ABPM is recommended). After all these items have been evaluated, further administration of mineralocorticoid receptor antagonists (e.g. spironolactone 12.5-25 mg/d) as a 4th drug has been shown to provide adequate BP control in a large percentage of suspected RH patients. If all these procedures fail to reverse or control RH, renal artery denervation or carotid sinus stimulation may be considered providing that there are no technical, anatomical or medical contraindications to these procedures.

Special Issue on Stroke. From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 7–8 June 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 2):L18

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Silent cerebral infarctions: not so silent after all - read full article

By: Henrique Costa

As the availability and quality of imaging techniques improve, doctors are identifying more patients with no history of transient ischaemic attack or stroke in whom imaging shows brain infarcts. Until recently, little was known about the relevance of these lesions. Silent brain infarcts are common not only in selected patients but also in the general population of elderly people. They are far more common than stroke, both with respect to their prevalence and incidence. Cardiovascular risk factors known to increase the risk of stroke are also associated with silent brain infarcts, with hypertension being, by far, the strongest modifiable risk factor identified to date. Therefore, silent brain infarcts might differ from symptomatic infarcts only by the lack of acute stroke-like signs. However, they do present as subtle deficits in physical and cognitive function that commonly go unnoticed. Moreover, the presence of silent infarcts more than doubles the risk of subsequent stroke and dementia.

Special Issue on Stroke. From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 7–8 June 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 2):L19

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New Oral Anticoagulants: “everyday clinical practice” experience - read full article

By: Pedro Abreu

Introduction: New oral anticoagulants (NOACs) were shown, when compared to warfarin in a randomized controlled trial setting, to be effective in reducing the risk of stroke and systemic embolism in non-valvular atrial fibrillation (NVAF) patients. 
Objectives: This presentation will assess, with special emphasis on rivaroxaban, efficacy, safety and persistence/adherence in an “everyday clinical practice” population of drug-naïve NVAF patients treated with NOACs. 
Methods: A PubMed® database non-systematic search of the latest articles published on efficacy, safety and persistence/adherence outcomes of NOACs as used in “everyday clinical practice” was performed. 
Results: Efficacy, safety and persistence/adherence outcomes of NOACs in an “everyday clinical practice” population of drug-naïve patients with AF were consistent with the results of previous randomized controlled trials across a wide range of “real life” patients.

Special Issue on Stroke. From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 7–8 June 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 2):L20

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The new stroke code protocol—a metropolitan inter-hospital collaboration - read full article

By: Elsa Azevedo

Once the time window for acute stroke revascularization treatments is narrow, a finely tuned stroke code strategy is mandatory to achieve good functional neurological results. In 2015, new trials on mechanical thrombectomy lead to new European recommendations (ESO, 2015) on acute stroke treatment, in addition to the already established intravenous thrombolytic treatment. While thrombolytic treatment can be provided in many hospitals that have computed tomography and a stroke team/unit, mechanical thrombectomy requires specialized neurointervention teams, which are available mostly in tertiary hospitals. Aiming to provide thrombectomy treatment to a larger population, a metropolitan inter-hospital collaboration now allows a continuous availability of this treatment (24h/7d). The pre-hospital emergency medical service delivers the suspected stroke patients (according to FAST – face, arm, speech, time) to the nearest hospital with a stroke team/unit in a 6-hour window after symptom onset. At these hospitals, thrombolysis may be administered, when indicated, within 4.5 hours of symptom duration. Whenever a large artery occlusion is suspected, it is diagnosed with non-invasive imaging, whenever possible. If this is the case, and the patient is not recovering with intravenous thrombolysis or has contraindications for this treatment (e.g. anticoagulation), the on-call neuroradiologist is contacted and the patient is sent for endovascular treatment up to 6 hours after symptom onset. Patients with unknown time of symptom duration are evaluated with multimodal imaging and treated accordingly. As the treatment time window for acute basilar artery occlusion is not well established, an individualized decision usually takes place, taking in consideration the clinical and imagiological potential for reversibility. Most importantly, the decision to undertake mechanical thrombectomy is made jointly by a multidisciplinary team comprising, at least, a stroke physician and a neuroradiologist.

Special Issue on Stroke. From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 7–8 June 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 2):L21

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Scales in stroke patients: the modified Rankin Scale - read full article

By: Luís Braz

The modified Rankin Scale (mRS) is a 7-level ordered categorical scale, which captures levels of patient functional independence following a stroke, with scores ranging from 0 (fully independent) to 6 (dead). The mRS has been reported to be a valid and reliable endpoint in randomized clinical trials and, as such, it is a common and recommended outcome measure in acute ischaemic stroke studies. In clinical practice, the mRS offers an easy and rapid assessment of the effect of a patient’s stroke on their activities and participation in a social context. Furthermore, its everyday use generally goes beyond stroke disability and broadens to global patient functional (in)dependence, aiding in several decisions concerning patient management. The application of a structured interview helps to classify patients in a more reliable way and improve inter-rater reliability. Since the interpretation and application of this scale is so important to those who manage or conduct research on stroke, a focused workshop is provided, including pitfalls as well as practical use recommendations.

Special Issue on Stroke. From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 7–8 June 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 2):L22

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Spasticity and stroke: pathophysiology and management rules - read full article

By: Maria José Festas

Introduction: Stroke is a common cause of morbidity and mortality. In fact, it is the leading cause of disability in the elderly. Spasticity occurs in up to 27% of patients in the acute phase of stroke and in up to 46% three months after the event. 
The Central Nervous System (CNS) and intentional movements: The CNS is a coupling of increasingly complex systems regulated by themselves. Higher centres usually command lower centres, which, in turn, control the automatic and primitive behaviours, postural and tonic reflexes, associated reactions and balance. 
Spasticity: Spasticity is an increase in tone (elastic hypertonia) that arises from pyramidal tract/upper motor neuron (UMN) injury, by the absence of its inhibitory action on the spinal reflexes and by a low threshold for myotatic activity. Lance (1980) put forward the most frequently accepted definition: spasticity is a motor disorder characterised by a velocity dependent increase in tonic stretch reflexes (muscle tone) with exaggerated tendon jerks, resulting from hyperexcitability of the stretch reflex. Spasticity is not only velocity-dependent, but it is also length-dependent. For example, in the quadriceps, the tonic stretch reflex is greater when the muscle is short, than when it is long. It is indeed a component of the UMN syndrome (UMNS), but functional limitations after stroke are more closely related to overall neurological deficits, other than spasticity. The UMNS includes positive signs, such as spasticity, hyperreflexia, clonus, muscle spasms, Babinski reflex, synergistic movement patterns, antagonist-agonist co-contraction, spastic dystonia and associated reactions; and negative signs, such as muscle weakness, dexterity decrease and fatigability. How does an UMN lesion cause spasticity? Each patient has injuries that affect different routes to varying extents, leading to adaptations in neural networks of the spinal cord. However, in all of them normal cortical-spinal tract functioning is absent. Different spinal mechanisms, such as membrane potential, reciprocal inhibition and presynaptic inhibition, may have different roles in different patients. Spasticity is likely to be caused not by a single mechanism, but by a complex chain of interrelated changes in different networks. Changing the balance between the above inhibitory spinal routes and excitatory pathways in the spinal cord, leading to a disinhibition of the stretch reflex. Spasticity appears only days to weeks after a central neurological injury. This delay between the acute lesion and the onset of spasticity is more than a phenomenon of mere disinhibition and suggests plastic changes in the CNS. An initial period of shock is followed by a transition period with the return of reflexes, not yet hyperactive. There appears to be a rearrangement, corresponding to neuronal plasticity in the spinal cord, and probably in the brain. Afferent fibres can grow and transform inhibitory and excitatory synapses. There is denervation hypersensitivity due to the upregulation of receptors. Furthermore, changes in the rheological properties and in the contractile soft tissue and musculoskeletal system (intrinsic hypertonia) are often associated with chronic spasticity and, in turn have been associated with increased spasticity. 
Signs and symptoms of spasticity: Spasticity signs include muscle stiffness or spasm, muscle spasms, clonus, pain, difficulty performing voluntary movements or deformity of the limbs (cosmetic or functional concerns). Spasticity symptoms include the resistance to passive movement, twitching, co-contraction of agonist and antagonist muscles, spastic dystonia, decreased range of passive movement, abnormal posture and/or limb deformity. 
Spasticity pattern of cerebral origin: This pattern observed after a stroke differs from spinal-origin spasticity as found in spinal cord injury and in multiple sclerosis. Cerebral-origin spasticity is characterized by a postural stereotype involving antigravity muscles: the upper limb presents a flexor pattern: depression of the scapula, internal rotation and adduction of the shoulder, forearm pronation, elbow, wrist and fingers flexion; the lower limb presents an extensor pattern: extension, adduction and internal rotation of the thigh, knee extension, plantar flexion and foot inversion. Spasticity is often classified according to the distribution of the affected body areas as focal, multifocal, regional or general. It is important to identify the distribution of spasticity since it has definite implications for treatment. 
Rules of spasticity management: Spasticity does not always need to be treated. In fact, it may aid the patient to walk or perform other activities of daily living (ADL), maintain muscle mass and bone mineralization, and decreased oedema and the risk for deep vein thrombosis. However, it can interfere with mobility, exercise and range of motion, reducing the support and swing of gait and lead to contractures. It can also interfere with ADL and patient care, including hygiene. Moreover, pressure sores and sleep disturbance occur and can cause pain. In the treatment of spasticity, we may consider factors such as a chronical status, spasticity severity and distribution, location of the central lesion, patient comorbidities and caregiver availability. Treatment of spasticity should include three major classes of goals: technical (increasing the range of motion, reducing the tone or reducing spasm), functional (improving ADL, reducing pain, facilitating care, improving limb positioning and gait), and preventive (preventing contracture, skin maceration, and skin ulcers). Spasticity treatment should be performed by a multidisciplinary team that includes physiatrics, neurologists, nurses and caregivers, therapists, and should be always based on the person as a whole. 

Special Issue on Stroke. From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 7–8 June 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 2):L23

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Application of cardiovascular risk scores - read full article

By: Pedro Von Hafe

There are a number of scoring systems used to determine an individual's risk of cardiovascular disease. Apart from giving an estimate of the risk of having a cardiovascular event or dying from a cardiovascular cause within, in general, ten years, they also indicate who is most likely to benefit from prevention. Therefore, these risk scoring systems are useful for the patient and for the clinician in deciding preventive medical treatment. The Framingham Risk Score, the first scoring system, estimates the cardiovascular risk of having an event at 10 years. Individuals with low risk have 10% or less coronary heart disease (CHD) risk at 10 years, with intermediate risk the value is 10-20%, and with high risk it is20% or more. The vast majority of younger adults are considered to be at “low risk” because of the weight of age and of the 10-year risk window, and thus the importance of addressing multiple moderate or single elevated risk factors for long-term CHD prevention. With these tools, we must recognize that age is the strongest predictor of cardiovascular risk. Almost all persons aged 70 and over are at >20% ten year cardiovascular risk and almost nobody aged under 40 is at >20% ten year cardiovascular risk. In the situation of young individuals with an extremely elevated risk factor, as is the case of cholesterol in familial hypercholesterolemia, the scoring system postpones treatment inadequately. Another problem with the majority of risk scoring systems is that they do not take into account factors like family history of cardiovascular disease, poverty and ethnicity. To measure the performance of a scoring risk system we should use: sensitivity/specificity/predictive value, discrimination, area under the Receiver Operating Characteristic (ROC) curve and the C statistic, calibration, positive and negative likelihood ratios and reclassification – the Net Reclassification Index (NRI) and the Integrated Discrimination Improvement (IDI).

Special Issue on Stroke. From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 7–8 June 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 2):L24

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New recommendations for the prophylaxis of venous thromboembolism in stroke patients - read full article

By: Elsa Azevedo and Carlos A. Molina

Deep venous thrombosis (DVT) is one of the most important, potentially preventable, causes of death and morbidity. Stroke confers a high risk of DVT (8-20%) in the absence of prophylactic treatment. Magnetic resonance studies show DVT in 40% of stroke patients, and in 18% of patients within 3 weeks of stroke. Colour Doppler ultrasound (CDU) reveals asymptomatic DVT in 18% of stroke patients. Guidelines advise the routine assessments of risk of DVT on hospital admission for stroke, and initiation of prophylaxis especially in high-risk patients. Risk factors for DVT after stroke are the stroke severity, whenever imobility is present, as well as some comorbilities such as cardiac heart disease, cancer, increased body weigth index, and the presence of elevated D-dimers. A review of 22 trials with low molecular weight heparin (LMWH) in ischemic stroke showed that, per 1000 patients, it can avoid 9 deaths, 3 pulmonary embolism (PE), 1 symptomatic DVT, although causing 6 major bleedings. In intracranial hemorrhage (ICH), a meta-analysis of anticoagulant drugs for thromboprophylaxis that included 1000 ICH patients from 4 trials (2 randomized), revealed that the early use of enoxaparin or heparin (from 1 to 6 days after admission) could reduce PE (1.7% versus 2.9%), having a non-significant effect on mortality reduction (16.1% versus 20.9%), hematoma enlargement (8.0% versus 4.0%) or DVT (4.2% versus 3.3%). Non-pharmacological measures aiming prophylaxis of venous thromboembolism (VTE) in stroke patients have been investigated in the last years. In CLOTS Trial 1, 2518 immobile stroke patients were allocated thigh-length graduated compression stockings or not, and, in CLOTS Trial 2, 3014 to thigh-length or below-knee graduated compression stockings. In both trials there were no statistically significant differences in VTE events and compression stockings increased the risk of skin breaks. Allocation to thigh-length graduated compression stockings was associated with a nonsignificant increased hazard of death in the first 6 months. Intermittent pneumatic compression (IPC) has been developed to prevent DVT in stroke patients. A sequential compression allows increasing venous flow through the deep veins of the leg to reduce the likelihood of thrombosis, while it stimulates release of intrinsic fibrinolytic substances. In a randomized trial of 151 ICH patients, IPC plus elastic stockings reduced asymptomatic DVT compared with elastic stockings alone (4.7% versus 15.9%). CLOTS Trial 3 aimed to establish whether or not the routine application of IPC to the legs of immobile stroke patients, additionally to routine treatment, reduces their risk of DVT and PE. If providing robust estimates of the effectiveness of IPC in stroke patients, this could be extrapolated to other groups of medical patients at high risk of VTE. CLOTS Trial 3 primary outcome was DVT in the popliteal or femoral veins within 30 days of randomisation, either asymptomatic as detected on the first or second CDU performed as part of the trial protocol, or symptomatic DVT confirmed on imaging (either CDU or venography). The compression system used in this trial delivered a sequential circumferential compression and incorporated a venous refill technology so that the frequency of compression was tailored to the individual patient. The trial included 2876 acute stroke patients, 376 with ICH. Patients were allocated in a 1:1 basis to routine treatment or routine treatment plus IPC. The routine treatment included in each group 17% patients receiving prophylactic dose and about 14% patients receiving full-dose of anticoagulants. The IPC group had 3.6% less absolute risk of DVT (12.1% vs 8.5%), and a 34% risk reduction when adjusting for confounding factors. This effect was particularly prominent in ICH patients (6.7% versus 17.0% DVT cases). The Cox model showed a reduced probability for death up to 6 months after randomisation in those allocated IPC. In secondary analyses from CLOTS 3, namely regarding cost-effectiveness of ICP, it was shown that IPC is inexpensive, prevents deep vein thrombosis, improves survival but not functional outcomes, and does not lead to a significant gain in quality-adjusted survival. The current European Stroke Organization (ESO) recommendations to improve outcome and reduce the risk of DVT in immobile patients with intracranial hemorrhage are against short or long graduated compression stockings, and in favor of IPC; it is pointed that there is insufficient evidence from randomized controlled trials to make strong recommendations about how, when, and for whom anticoagulation should be given to prevent DVT or improve outcome. Concerning ESO guidelines for prophylaxis of VTE in immobile patients with acute ischaemic stroke, it is also recommended that graduated compression stockings should not be used, while IPC (thigh-length, sequential) and prophylactic-dose anticoagulation can reduce the risk of VTE in those patients, the strongest evidence being for IPC. IPC should not be used in patients with open wounds on the legs and should be used with caution in those with existing DVT, heart failure, severe peripheral vascular disease or confusion where attempts to mobilise when unsupervised could lead to falls and injury. Prophylactic anticoagulation with unfractionated heparin (5000U, 2 or 3 daily), LMWH or heparinoid should be considered in patients whom the benefits of reducing the risk of VTE is high enough to offset the increased risks of intracranial and extracranial bleeding associated with their use. ESO guidelines stat that further research is required to test whether neuromuscular electrical stimulation is effective. Additionally, it is highlighted that better methods are needed to define which stroke patients are at high enough risk of VTE acutely, or during later phases of care, to warrant prophylaxis, as well as to stratify their risk of bleeding on anticoagulants.

Special Issue on Stroke Update. From Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 7–9 June 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 2):L25

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The most efficacious strategies for tobacco cessation - read full article

By: Ricardo Moreira

During recent years, there have been many advances in different types of pharmacological and non-pharmacological tobacco cessation treatments. Varenicline, Nicotine Replacement Therapies (NRT) and Bupropion, are the most supported ones, and, in combination with educational strategies, seem to have better results. Although the safety of these pharmacologic treatments for smoking cessation in patients with cardiovascular (CV) disease has yet to be definitively established, until now, studies suggest that there is no significant increase in CV risk.

From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 20–21 June 2017.

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 2):L1

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What is the current role of the new antiplatelet agents or double antiplatelet therapy in stroke prevention? - read full article

By: Paulo Castro Chaves

Stroke is one of the main causes of death and neurological disability and is also a major cause of dementia and age-related cognitive decline in the adult. Guidelines recommend urgent assessment and treatment of stroke patients, including risk factor control, carotid endarterectomy or stenting, and immediate oral anticoagulation for documented atrial fibrillation or aspirin therapy for most other cases. The International Stroke trial (IST) found that acute ischemic stroke patients who received 300 mg of aspirin within 48 h of experiencing symptoms had significant reductions (3.9% vs 2.8%) in recurrence of ischemic stroke as evaluated over a period of 14 days. Emerging studies suggest that early administration of dual antiplatelet therapy may be better than monotherapy for prevention of early recurrent stroke and cardiovascular outcomes in acute ischemic stroke and transient ischemic attack (TIA). There is also ongoing research on novel antiplatelet agents, with the aim of decreasing recurrent stroke rates as well as bleeding events. In fact, few randomized trials have tested aspirin directly against other antiplatelet agents for the treatment of ischemic stroke or TIA in the acute period. However, in the SOCRATES trial of over 13,000 subjects with acute ischemic stroke or TIA, ticagrelor monotherapy was not significantly better than aspirin monotherapy (both started within 24 hours of symptom onset) for the 90-day composite endpoint of stroke, myocardial infarction, or death. There are new developments expected in the shortcoming that address future possibilities for antiplatelet treatment for ischemic stroke and that may ultimately contribute to risk reduction. All these aspects will be reviewed in the current presentation.

From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 20–21 June 2017.

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 2):L2

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Intracranial atherosclerosis: what’s new? - read full article

By: Marta Carvalho

Intracranial atherosclerosis is a major cause of stroke worldwide, especially in Black, Asian and Hispanic populations. It affects more often the middle cerebral and basilar arteries and may coexist with cervical atherosclerosis. Modifiable risk factors are common to other locations of atherosclerosis, namely hypertension, diabetes mellitus, hyperlipidaemia, smoking, metabolic syndrome, and physical inactivity. The possible mechanisms for stroke related to intracranial atherosclerosis are artery-artery embolism or in situ occlusion due to thrombosis over a pre-existing atherosclerotic plaque; distal hypoperfusion; and/or occlusion of the origin of small perforating arteries. It is necessary to establish a correlation between clinical syndromes and infarct patterns in neuroimaging in order to understand the underlying mechanism, since they have different recurrence rates and responses to treatment. Although the gold standard for diagnosis is cerebral angiography, non-invasive or minimally invasive methods such as transcranial Doppler, computed tomography angiography or magnetic resonance angiography, are usually enough in clinical practice. High–resolution magnetic resonance imaging may be useful in the identification of high-risk atherosclerotic plaques. The risk of stroke recurrence in patients with intracranial atherosclerosis is very high, especially in the first month and for stenosis between 70-99%. Although endovascular treatment has been widely used, clinical trials have shown that medical treatment alone, consisting of antiplatelet drugs and aggressive modification of vascular risk factors, is more efficient in reducing the risk of stroke recurrence and mortality. Physical exercise should be particularly encouraged. In recently symptomatic stenoses, the combination of aspirin with clopidogrel should be used for 3 months followed by antiplatelet monotherapy. Despite aggressive medical treatment, some patients still have a high risk of stroke recurrence, and, currently, there are still many uncertainties concerning the management of these patients.

From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 20–21 June 2017.

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 2):L3

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Reversal of anticoagulation of NOACs in patients with acute stroke - read full article

By: Luciana Ricca Gonçalves

Management of patients taking Novel Oral Anticoagulants (NOACs) and acute stroke is challenging. The risk of intracranial haemorrhage (ICH) is reduced in patients treated with NOACs compared with patients treated with vitamin K antagonists (VKAs). However, the prognosis of ICH associated with anticoagulation is always poor, with high mortality rate, especially in patients with haematoma expansion. The occurrence of ICH requires prompt interruption of anticoagulation, regardless of the underlying thromboembolic risk of the patient. The coagulation status of patients receiving NOACs with ICH must be evaluated and corrected as soon as possible. The current treatment of an acute ICH occurring during treatment with factor Xa inhibitors (FXaI) – apixaban, edoxaban, rivaroxaban - is based on experience with ICH associated to VKAs: administration of coagulation factors concentrates, namely as prothrombin complex concentrate (PCC), activated PCC, activated factor VII. However, the efficacy and safety of coagulation factors are not well documented. Andexanet alfa, an FXaI reversal agent, is currently being evaluated in patients with acute major bleeding, including ICH. In patients treated with dabigatran, idarucizumab, a specific reversal agent for dabigatran, is recommended as first line therapy. If not available, coagulation factor concentrates should be administered. Haemodialysis can also be considered in patients with dabigatran-associated ICH and renal insufficiency, as a rescue therapy. If the last intake of NOAC was less than 6 hours ago, oral activated charcoal can be given to reduce absorption. In patients with acute ischemic stroke (AIS), systemic thrombolysis is the most effective medical therapy, though associated to a significant increase in ICH rate. Prior anticoagulation is a contra-indication for thrombolysis. The last recommendation of AHA states that thrombolysis should not be administered to patients who take NOACs, unless sensitive tests are normal and the patient took the last dose >48 hours prior. However, since the approval of idarucizumab, several reports have been published about its use in patients taking dabigatran with AIS before systemic thrombolysis and the results are very promising. Mechanical thrombectomy can be an option for some anticoagulated patients with AIS.

From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 20–21 June 2017.

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 2):L4

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Anticoagulation after stroke: how soon is too late? - read full article

By: Ricardo Soares-dos-Reis and Pedro Castro

Anticoagulation is the mainstay of long term therapy for the primary and secondary prevention of cardio-embolic ischaemic stroke. However, when the patient presents with an ischaemic or haemorrhagic stroke, and is a candidate for long-term anticoagulation, the issue of when to start anticoagulation arises. The delicate balance between the risk of a new embolic event and the risk of haemorrhage of an ischaemic lesion/new haemorrhage shifts as time from the index event passes. Therefore, there should be an optimal cut-off point, where the risk of a new event clearly offsets the risk of bleeding and where introducing anticoagulation would be clearly advantageous. Unfortunately, there is no good-quality evidence regarding the optimal timing of anticoagulation in acute stroke therapy. 
Current atrial fibrillation guidelines favour decision on a case-by-case basis. Regarding ischaemic stroke, factors such as presenting National Institutes of Health Stroke Scale (NIHSS), infarct extension on computed tomography (CT) images, perceived recurrence risk, clinical stability, age, blood pressure control and need for surgery should be taken into account, together with repeat CT before starting anticoagulation, preferably with a novel oral anticoagulant. Anticoagulation can generally be introduced 1 to 12 days from stroke onset [1 day for transient ischaemic attack, and 3, 6 or 12 days for mild (NIHSS<8), moderate (NIHSS 8-15) or severe (NIHSS>15) stroke, respectively]. On the other hand, for haemorrhagic stroke, the factors leading to bleeding, such as blood pressure control, anticoagulant dosing and blood levels, embolic risk, alcohol consumption and prior bleeding history, should be carefully examined to decide whether the patient is a candidate for resuming anticoagulation. If so, anticoagulation can be started 4-8 weeks after stroke onset. 
At the time of writing, there are multiple ongoing clinical trial such as RASS, DATAS II, START, ELAN, RELAXED and APACHE-AF which are trying to compare early versus late initiation of anticoagulation after stroke, and will certainly provide better quality evidence supporting or disproving current guidelines. 

This lecture will cover current guidelines, observational data and ongoing clinical trials in an effort to answer the question of how soon is too late to start anticoagulation after stroke.

From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 20–21 June 2017.

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 2):L5

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Strategies for a new dynamic in stroke management - read full article

By: Elsa Azevedo

Although a significant improvement has occurred in stroke patient’s approach, it is still a heavy burden in the Portuguese public health. Along with the efforts regarding primary prevention measures, the acute stroke care must be a focus of health care organization. Recent advances in ischaemic stroke treatment, namely using mechanical thrombectomy, have allowed a significant increase in the number of stroke patients who are independent in their daily activities at 3 months after stroke. As the acute management with thrombolytic and thrombectomy treatment is only helpful if undertaken very early after symptom onset, a finely tuned organization is crucial to achieve the best results. All the steps of the chain of acute stroke care are important to its global efficacy, and therefore all of them should be optimized. The population should be better informed about the stroke alarm signals and instructed to dial 112 immediately. Both the pre-hospital and intra-hospital emergent pathways must increase their efficacy to allow stroke patients to be identified and timely treated. With the development of the interventional neuroradiology centres a new challenge emerged with the necessity to easily and rapidly communicate and transfer CT scan images, and to transfer patients from other hospitals to these centres. A better organization of this system is urgent. The inclusion criteria for stroke code activation, for intravenous thrombolysis and for mechanical thrombectomy must be standardized among all the institutions with a role in acute stroke management. Telemedicine has been proven to enhance stroke treatment efficiency, helping the development of stroke teams in smaller hospitals and allowing an increase in the number of patients treated with more effective approaches. It is time to also implement telemedicine in our region. With the multiplicity of professionals and institutions involved in the stroke code chain and given its huge importance for population healthcare, it is indispensable to have a robust database behind a platform with epidemiologic and logistic indicators that allow quality evaluation and monitoring, and to implement measures to optimize the results. The parameters should be automatically collected from the stroke code pathway, and therefore should be systematically registered. A feedback to the main professional agents of this stroke code pathway is essential. They should have access to the whole pathway data, and they should be active in their contribution to organizing these systems.

From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 20–21 June 2017.

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 2):L6

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Criteria for the endovascular treatment of brain vascular malformations - read full article

By: Luís Cardoso

Brain Arteriovenous Malformations (AVMs) are abnormalities of the intracranial vessels regarding a connection between the arterial and venous systems without an intervening normal capillary bed. Patients with AVMs are at a lifelong risk for haemorrhagic strokes (1.4% to 2% of all haemorrhagic strokes), but their natural history, especially for those unruptured, is still poorly understood. When symptomatic, they can present with intracranial haemorrhage, seizures, headaches or other focal neurologic deficits unrelated to haemorrhage that can be due to vascular steal phenomenon and/or venous hypertension. AVMs can be graded according to size, location and pattern of venous drainage. The gold standard for diagnosis of AVM is cerebral angiography; however, the evolution of non-invasive imaging has helped with the detection of AVMs and the proportion of AVMs diagnosed still unruptured has almost doubled over the past decades, which now brings new challenges regarding their management. Prior haemorrhage, deep AVM location, exclusively deep venous drainage and associated aneurysms constitute significant risk factors for AVM haemorrhage. Previous series demonstrated an overall annual haemorrhage rate of 3.0% for AVMs, the annual re-bleeding rate as 4.5% and at least 6% in the first year after haemorrhage. Today, different management options are available for AVMs, such as medical management alone, microsurgical resection, stereotactic radiosurgery and endovascular embolization. Management of these lesions is complicated by the fact that AVMs form a very heterogeneous group of lesions, with variable locations, morphologies and angioarchitecture, imparting different risk of haemorrhage for each patient and, thus, requiring individualized treatment decisions. Also, the risks associated with treating a given AVM patient vary and must be weighted individually against the natural history of haemorrhage anticipated in that particular patient. The appropriate management of patients with AVMs can therefore range from simple observation to aggressive multimodality approach aimed at total AVM obliteration.

From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 20–21 June 2017.

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 2):L7

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Mechanical thrombectomy: technique and results - read full article

By: Luís Augusto

Stroke is one of the leading causes of death and morbidity in industrialized countries. Diagnosis and treatment options have largely evolved in the last decades with the aim of rapidly restoring flow in the occluded vessels. The approaches to a mechanical resolution of the occlusion have also evolved. Following the 2013 “unhappy” trials, MR CLEAN has been the first randomized controlled trial to demonstrate the superiority of mechanical thrombectomy plus intravenous thrombolysis over the best medical treatment option. Many other trials have since done the same. Stent-retrievers are considered the preferred option for mechanical thrombectomy, although aspiration techniques are evolving becoming progressively more effective and important in this setting. These trials have also been the basis for the establishment of a consensus for the approach, management and treatment of patients with large vessel occlusions.

From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 20–21 June 2017.

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 2):L8

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“Should we stay or should we go now?” A brief guide to the most common doubts regarding mechanical thrombectomy - read full article

By: Marta Rodrigues and Manuel Ribeiro

Endovascular thrombectomy of large vessel occlusion, combined with best medical treatment, improves the outcome of appropriately selected patients with acute ischemic stroke. The positive results of randomized trials led to guidelines changes. However, despite the strong evidence, there are areas of uncertainty and the need for clinical judgment remains. Which patients should be treated outside the boundaries established by the randomized trials? Which stroke reperfusion technique should be used: aspiration or stent retriever? Do we really need rT-PA immediately before thrombectomy? These questions will be approached in our lecture.

From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 20–21 June 2017.

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 2):L9

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Mutual Help Groups after Stroke - read full article

By: António Conceição

Mutual help groups, social clubs, self-help groups, supporting groups... it might have several denominations, but its name is probably the least important concern! Groups for and with stroke survivors are the simplest form of action to answer, perhaps, the most serious problems for those who have suffered a stroke: isolation and closure in oneself and in their concerns. In fact, if not "fought against", these problems tend to become progressively bigger and are often accompanied by other problems, such as social self-exclusion, depression, among others. The social, architectural, professional and any other context often do not help. People have been fighting for many years for a progressive alteration of this panorama, and, slowly, something is being changed. But this is a fight that can only be won with the presence of the affected ones, the stroke survivors, who, with very rare exceptions, are not united and organized. Here too, groups, no matter how informal, can help! These groups are the cells in the basis of organizations (and of rights recognition!) that we often admire, and are found everywhere: in the United Kingdom (± 500 groups), Germany (± 480), United States, Canada, Australia, and even in other realities with a socioeconomic context similar to ours! The creation, maintenance and consistency of these groups are not easy tasks, but they are also not difficult: all it takes is will and minimal organization! Curiously, this time, the requirements are not the funds; it is rather some volunteer work!

From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 20–21 June 2017.

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 2):L10

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Paediatric Stroke - read full article

By: Cristina Garrido

Although stroke is often viewed as occurring mainly in adults, it also strikes children, adolescents and can also arise in foetal life. The incidence of paediatric stroke is estimated at 1.6 out of 100,000. The incidence rate increased in the last decades mainly due to more sensitive diagnostic tests such as magnetic resonance imaging and increased survival in previously lethal paediatric diseases that predispose to stroke (congenital heart disease, malignancies and sickle cell disease). Black children and those in the first year of life (particularly in the perinatal period) are at higher risk for stroke. Clinical presentation of childhood acute ischaemic stroke (AIS) differs from adults due to a great frequency of seizures and non-focal neurological signs (irritability, headache and altered mental state). Stroke risk factors for children are also different than those for adults. About half of the children presenting with a stroke had a previously identified risk factor (for example, sickle cell disease or congenital heart disease). Other risk factors for stroke in children include vasculopathy, infection, trauma and prothrombotic conditions. Arteriopathy, including focal or transient cerebral arteriopathy, primary angiitis of the central nervous system, arterial dissection, Moya-Moya syndrome and genetic arteriopathies are present in >50% of children with AIS. Therefore, vascular imaging is essential for accurate identification and classification of arteriopathy in children with stroke. Childhood stroke has a mortality of 5% to 10% and is among the top 10 causes of death in children, but may be declining. More than 50% of childhood stroke survivors have long-term moderate to severe neurological impairment or epilepsy. Stroke symptoms, risk factors, prevention strategies, and treatment differ between children and adults. However, as in adults, there is a need for timely diagnosis and treatment and age appropriate rehabilitation to minimize sequelae. In addition, more research is needed to better understand the unique aspects of diagnosing and treating stroke in children.

From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 20–21 June 2017.

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 2):L11

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Early management of paediatric patients with acute ischemic stroke - read full article

By: Ana Aires

Stroke is an acute neurological disease whose recognition in children is a challenge. When diagnosed, it is crucial to evaluate and treat it efficiently and correctly. Presently, information on urgent management of stroke in children has only been exposed in case reports, case series and hospital database documentation. Therefore, our purpose in this presentation is to propose a protocol for better approaching acute paediatric stroke. Common presenting signs of acute stroke in children include seizures, focal weakness and altered mental status. Considering possible etiologies, cardiac conditions, haematological disorders, trauma, vascular compression, infections, vascular malformations, vasculopathies, metabolic and genetic causes may account for stroke in this population. A differential diagnosis must be made with seizures due to another cause, infectious encephalitis, metabolic disorders and acute disseminated encephalomyelitis. Once a paediatric patient is admitted with a potential ischaemic stroke, the priorities are controlling vital signs and adjusting analytical and hemodynamic parameters. If a possible stroke is confirmed by a neurologist (who performed Paediatric NIHSS - National Institutes of Health Stroke Scale), the preferred imaging modalities to be executed are brain computed tomography (CT)/brain magnetic resonance imaging (MRI), CT/MRI angiography and perfusion weighted imaging. All clinical, laboratory and imaging data will then be taken into account to define the eligibility for treatment with tissue plasminogen activator (tPA), always considering the estimated evolution time, a persistent deficit and no tPA contraindications. The role of mechanical thrombectomy in the paediatric group is not clearly settled. However, it may be safe and effective for large vessel occlusions. During the whole process, neuroprotective measures can be executed and include glycaemia and blood pressure management, seizure control and decompressive hemicraniectomy in selected cases. This presentation proposes a clinical algorithm for assessment and management of paediatric acute stroke in order to encourage discussion about this subject.

From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 20–21 June 2017.

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 2):L12

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Stroke in women - read full article

By: Carla Ferreira

During most of their lifespan, men have a higher incidence of stroke than women. However, over the age of 85 years more women suffer strokes, leading to an excess of disability and mortality in older women. This disproportionate mortality rate in women is mostly because of the older age of women at stroke occurrence and the fact that women live longer than men. However, after controlling for baseline differences between men and women, women continue to have poorer functional outcomes after stroke. Women are more likely to present at hospitals with stroke chameleons (“non-traditional” stroke symptoms) and it has been noted that women suffer more cardioembolic strokes than men. Several studies suggest that women may be treated less aggressively for primary and secondary stroke prevention and acute stroke than men (women have longer waiting times once they arrive at the emergency room and receive less intensive treatment and therapeutic workup once they are admitted). Women also have a higher rate of depression and lower quality of life than men and are more likely to require assistance after a stroke, even when controlling for factors such as age and premorbid function.

From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 20–21 June 2017.

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 2):L13

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Differential diagnosis of Central Nervous System Vasculitides - read full article

By: Andreia Costa

Central nervous system vasculopathy refers to any process that affects central nervous system vessels. It includes either inflammation of the vessel wall (vasculitis) or other non-inflammatory etiologies. In the first group, primary central nervous system vasculitides are an uncommon and laborious diagnosis that must be remembered. Secondary causes of vasculitis include systemic vasculitis with central nervous system impairment, infectious causes and others. Non-inflammatory vasculopathies include a wide range of diseases where the reversible cerebral vasoconstriction syndrome should be emphasized due to its distinct presentation, treatment and clinical course. The challenge remains on precociously differentiating these entities to start the appropriate treatment earlier and thus impact prognosis. Some main differential diagnoses will be discussed in detail. A possible diagnostic algorithm will be presented.

From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 20–21 June 2017.

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 2):L14

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Guideline update on the management of subarachnoid haemorrhage - read full article

By: Pedro Castro

Subarachnoid haemorrhage (SAH) remains a significant cause of morbidity and mortality throughout the world. This oral presentation aims to provide a comprehensive review of the current guidelines and best practice in acute treatment of SAH. Oral nimodipine remains the only prophylactic drug that should be administered to all patients with SAH. After any aneurysm repair, immediate cerebrovascular imaging is generally recommended to identify remnants or recurrence of the aneurysm that may require treatment. The risk of early aneurysm re-bleeding is high and is associated with very poor outcomes. Acute diagnostic workup should include non-contrast head computed tomography, which, if non-diagnostic, should be followed by lumbar puncture. Digital subtraction angiography with 3-dimensional rotational reconstruction is indicated for detection of aneurysm. Before aneurism obliteration, systolic blood pressure should be kept under control (< 160 mm Hg is a reasonable cut-off). In addition to the size and location of the aneurysm and the patient’s age and health status, it might be reasonable to consider morphological and hemodynamic characteristics of the aneurysm when discussing the risk of aneurysm rupture. Transcranial Doppler is reasonable to monitor for the development of arterial vasospasm. Maintenance of euvolemia and normal circulating blood volume is recommended to prevent delayed cerebral ischemia (DCI). Induction of hypertension is recommended for patients with DCI unless blood pressure is elevated at baseline or cardiac status precludes it. Cerebral angioplasty and/or selective intra-arterial vasodilator therapy is reasonable in patients with symptomatic cerebral vasospasm, particularly those who are not rapidly responding to hypertensive therapy. Acute symptomatic hydrocephalus should be managed by cerebrospinal fluid diversion or lumbar drainage. Heparin-induced thrombocytopenia and deep venous thrombosis, although infrequent, are not uncommon occurrences. SAH patients should be managed in a fast-track fashion to achieve better outcomes.

From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 20–21 June 2017.

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 2):L15

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Spontaneous intraventricular haemorrhage - read full article

By: António Vilarinho

Intraventricular haemorrhage (IVH) comprises a very wide range of situations: from a minor deposition of blood in the occipital horns, to the complete filling of the ventricular system with a clot. Intraventricular blood can be caused by the drainage into the ventricular system of spontaneous intracerebral haemorrhage or, in case of subarachnoid haemorrhage, by the circulation of the blood together with the cerebrospinal fluid (CSF). The symptoms are similar to any haemorrhagic stroke: headache, vomiting, stiff neck, with or without altered state of consciousness. The main causes of IVH are arterial hypertension, rupture of arteriovenous malformations (AVMs) or aneurysms (for example, anterior communicant, anterior choroid or posterior inferior cerebellar arteries) and bleeding of sub-ependymal cavernomas or intraventricular tumours. Other causes are related to coagulation disorders such as hypocoagulation and use of toxic substances. There are also some IVHs of unknown cause. For diagnostic investigation, in addition to the evaluation of blood pressure and bloodwork with coagulation study, brain computed tomography and magnetic resonance imaging are performed. Angiography can also be requested when considered relevant in the etiological investigation. This research is essential for diagnosis and therapeutic orientation. As a consequence of IVH, intracranial hypertension or hydrocephalus may occur. This may be due to the disturbance of the CSF circulation or to the toxic effects of blood and its degradation products. Patients with hydrocephalus usually undergo external ventricular drainage (EVD), the main risks being infections (meningitis, ventriculitis, abscess) or iatrogenic lesions due to the introduction of the catheter. Fibrinolysis through EVD is also a possibility of treatment. However, the risk of EVD placement in patients with coagulation disorders or untreated AVMs and aneurysms increase, so the use of fibrinolytics is contraindicated in these cases. It is important to treat intracranial hypertension and/or hydrocephalus and correct etiological factors to prevent further bleeding.

From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 20–21 June 2017.

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 2):L16

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NurAiD-II in stroke recovery: scientific reasoning and real-world evidence - read full article

By: Carlos de la Cruz Cosme

Background: NurAiD-II is an herbal supplement designed to help in ischemic stroke recovery. Lack of products in this field makes it mandatory to review the available evidence to decide about recommending it to patients who have suffered a brain infarction. 
Methods: Review of related Medline literature and a primary stroke center experience were performed. 
Results: Neuroprotection and neuroregeneration are Nur-AiD properties as basic research demonstrates: It increases brain-derived neurotrophic factor expression, inducing neuronal proliferation and synaptogenesis, it enhances vascular endothelial growth factor and angiogenesis, and in this way, enhances brain recovery after ischaemia in different animal models. Recent clinical trials including the multicentric Chinese Medicine NeuroAiD Efficacy on Stroke Recovery (n=1,100) reported a delayed but significant benefit in stroke patients who used it for three months after infarction OR 1.49 (1.11-2.01) and NNT=13 for modified Rankin scale 0-1 at 6 months, adding a significant reduction in fatal stroke recurrences (0% vs 0.7% at 3 months, p=0.045) and demonstrating an excellent safety profile. Poor prognosis factors in the total population as age>60, baseline NIHSS 10-14, stroke onset to initiation of treatment >48 hours and female sex were found to be positive predictive factors to obtain benefit of NurAiD-II. Finally, a primary stroke centre cases series (n=20) confirmed safety profile and suggested a benefit in patients who other way were not expected to improve as much as they did. 
Conclusions: NurAiD-II enhances neurorestorative processes in preclinical models of stroke and clinically improves long-term functional recovery and reduces early vascular events after a stroke. A subgroup of patients with poorer prognosis factors is more likely to achieve a benefit. Although real-word experience seems to support these results, further registries are required to confirm them. Lack of other effective treatments to enhance rehabilitation-induced stroke recovery makes it reasonable to report the availability of NurAiD-II to patients and/or relatives.

From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 20–21 June 2017.

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 2):L17

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Lecture


Considerations regarding therapeutic interventions in post-stroke spasticity - read full article

By: Fernando Parada

Spasticity is a common complication that occurs in those patients that have suffered a stroke. It Is a functionally limiting disorder that may lead to disability and pain. Botulinum toxin type A is the recommended first line treatment for spasticity. Reducing the severity of spasticity and its long-term complications may be facilitated by early intervention, making identification of stroke patients at high risk for developing spasticity. Several predictors of spasticity post-stroke have been proposed, including development of increased muscle tone, greater severity of paresis, hypoesthesia and low Barthel index score. The definition of early treatment of spasticity is that it begins before the first three months after stroke. The results of all trials support the beneficial effects of botulinum toxin type A treatment on improving hypertonicity within 3 months post-stroke and emphasize the importance of concomitant neurorehabilitation therapy.

From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 20–21 June 2017.

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 2):L18

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Lecture


The neuroplasticity of speech and language early after stroke - read full article

By: Maria José Festas

More than ninety-five percent of people depend on the left hemisphere for language processing related to grammar, vocabulary, and phoneme construction. In the early phase of stroke, one third of patients have impairment of speech and language. Global aphasia, which is the complete loss of the ability to understand language, formulate speech, and repeat sentences, or the combination of Broca's, Wernicke's and conduction aphasias, is caused by lesions in the anterior frontal gyrus (Broca’s area), upper temporal gyrus (conduction), and posterior regions of language (Wernicke area). These patients almost do not produce speech and present a serious deficit of auditory comprehension, although they can fulfil properly contextualized commands. It is like "falling asleep" in Portugal and "waking up" in Japan. However, the ability to sing familiar songs is preserved, since musical areas are represented in the non-dominant hemisphere. Music therapy is a method to treat patients with non-fluent aphasia. Singing ability remains unchanged, with several studies showing that the right hemispherical regions are more active during singing. Nevertheless, Hebert in 2003 showed that singing does not facilitate articulation of words in non-fluent aphasia, suggesting there are two systems for vocal production. The main pathways for the recovery from aphasia in the small lesions of the dominant hemisphere of language are the recruitment of the perilesional cortex, but, in major lesions, the recruitment and training of rudimentary structures compatible with language in the non-dominant hemisphere is needed. Music therapy involving melodic elements is considered a potential treatment for non-fluent aphasia, since singing can activate the right hemisphere of patients, compensating the injured left hemisphere. Both music and language use different sound parameters for their hierarchical sound organization. In spite of their differences, singing and language have both syntactic organization and imply semantic understanding. In aphasia, the preserved ability to sing can result from a cerebral circuit reserved for this purpose, which suggests that singing and speaking involve different neural pathways in the human brain. Therefore, right hemisphere partial replacement of the injured left hemisphere is one of the possible mechanisms of music therapy in non-fluent aphasia. Stahl has shown that rhythm, rather than singing, is the key element of music therapy that benefits aphasic patients. Sonic identity is the set of energies, sounds, music and movements that characterize the individual, from his intrauterine life until stroke, providing him with a nonverbal interaction to open channels of communication, stimulating different functions and abilities. This is the basis of the first approach by the speech therapist, in early phase after stroke. Strategy includes melodic intonation therapy (MIT), brief sentences spoken in melodic sequences, or in recitative, with increasing levels of difficulty, in time and in rhythm, using only two musical tones, where the most acute syllable represents the naturally marked syllable in speech. Each chanted syllable is accompanied by a beat of the left hand to stimulate the right hemisphere. In chronic non-fluent aphasia, left hand movement is used to benefit the verbal articulation in aphasic patients, involving the neurological network that coordinates the movement of the hand and the articulatory movement of the speech in the patients' right hemisphere.

From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 20–21 June 2017.

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 2):L19

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Lecture


The acute inpatient rehabilitation process after stroke - read full article

By: Hugo Amorim, Maria-José Festas, and Fernando Parada

Introduction: Nowadays, the burden of stroke is still notoriously high. Stroke also has a significant impact in the quality of life of the patients. The rehabilitation process is usually long, and its acute phase is frequently paramount in its success. 
Purpose: The aim of this lecture is to provide an outline of the clinical practice in the acute inpatient rehabilitative care of adults recovering from stroke. 
Results: The best rehabilitation setting for stroke patients is often a difficult decision that takes multiple factors into account. Patients that have higher functional impairments after stroke and that, at the same time, are able to cooperate in an intense impatient rehabilitation program benefit the most from admission to an acute inpatient rehabilitation unit. In this setting, stroke rehabilitation requires a sustained and coordinated effort from a diverse team that includes the patient, family and caregivers, physicians, nurses, physical and occupational therapists, speech-language therapists, psychologists, and social workers. The coordination of these team members is vital in maximizing the effectiveness of the rehabilitation process. The main areas of intervention include gait training, upper limb rehabilitation, speech therapy, dysphagia rehabilitation, cognitive assessment, pain management and spasticity prevention. Medical complications also arise more commonly in the acute rehabilitation phase rather than later, and the rehabilitation team is responsible for identifying and treating them accordingly. The concept of function is omnipresent throughout the various interventions and the rehabilitation specialist should establish a functional prognosis according to all the variables involved. The social integration of the stroke survivor in society is usually a measure of the success of the rehabilitation process and the secondary prevention measures are also reinforced during this period of time. 
Conclusion: The acute phase rehabilitation of stroke survivors is a complex process that strives to maximize their vital and functional prognosis.

From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 20–21 June 2017.

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 2):L20

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Lecture


Workshop: neurological emergencies - read full article

By: Cláudia Marques-Matos, Carolina Lopes, and Marta Carvalho

Neurologists are probably the most required non-surgical specialists in the Portuguese adult Emergency Departments. Whenever neurologists are not available, the internal medicine specialists or the general practitioners face the challenge of correctly evaluating neurological patients, struggling to go through confusing, yet invaluable, clinical history taking, neurological examination and clinical reasoning. This workshop will address the most common neurological complaints in the Emergency Department. Acute stroke will be extensively reviewed, focusing on practical issues of management and on the updates of the stroke “fast track” in the era of thrombectomy. Acute vestibular syndromes and the not always straightforward differentiation between central and peripheral etiologies will also be addressed. The span of pathologies that may present as headache in the Emergency Department is vast and the emergency physician must soon learn to identify those patients that need a thorough investigation, without neglecting symptomatic relief. We will address the particularities of clinical history taking and red flags in the history and neurological examination, pointing towards the most worrisome not-to-miss diagnoses. We will then review the clinical approach to the patient with seizures, both new-onset and as a part of previously diagnosed epilepsies, and the management of convulsive and non-convulsive status epilepticus. Other causes of altered mental status and delirium will also be presented. To conclude, the topic of the patient presenting with acute neurological deficit not caused by stroke, with a focus on spinal cord lesions and Guillain-Barré syndrome, will be briefly discussed.

From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 20–21 June 2017.

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 2):L21

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Lecture


Mechanical thrombectomy – practical workshop - read full article

By: Luís Albuquerque, João Pedro Filipe, Tiago Parreira, and Ângelo Carneiro

Mechanical thrombectomy (with or without intravenous thrombolysis) has improved the outcome of patients with acute large vessel occlusion of the anterior circulation, with impressive results: successful recanalization (mTICI 2b or 3) – 59 to 88%; number needed to treat – 3 to 7. As recent trials have demonstrated the benefit of mechanical thrombectomy, there is a demand for an increased number of well-trained practitioners who are able to perform these procedures. Stent retriever (SR) technique is still the standard of care; however, aspiration techniques have emerged and they have been demonstrated to be as effective as SR. A thorough knowledge of the different arterial approaches, materials and techniques is mandatory in order to improve recanalization rates, decrease procedure times and avoid complications. Apart from the procedural skills required to manipulate multiple catheters and other devices, mechanical thrombectomy might offer other specific challenges, such as difficult vascular access, patient movement and partial visualization of the intracranial circulation. Thrombectomy scenario practice using simulators (with specific models and dedicated software) is a useful educational resource for trainees. These might contribute towards an easier, safer and faster training.

From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 20–21 June 2017.

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 2):L22

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Lecture


Workshop: Dysphagia management in stroke patients - read full article

By: Bárbara M. Cruz

Stroke is the major cause of neurogenic dysphagia. Incidence of dysphagia in stroke patients ranges from 20% to 70%, in the literature. Nevertheless, the majority of the authors state that the incidence of swallowing disorders in stroke patients is around 50%. Dysphagia is a major issue in the acute phase of stroke, but it tends to resolve in two weeks in 80% of the cases. About 15% of stroke patients will maintain swallowing problems after three months since stroke onset. Dysphagia is associated with poorer stroke outcome, less participation in rehabilitation and higher mortality. Complications described as associated with dysphagia are: death, pneumonia, malnourishment, dehydration, institutionalization, increased length of stay, depression and higher healthcare costs. Stroke patients with dysphagia have a 3-fold higher risk of having pneumonia when compared with stroke patients without dysphagia. If dysphagia is severe enough to result in aspiration, the risk of pneumonia is eleven-fold higher when compared to stroke patients without dysphagia. In order to prevent the complications and the bad outcomes associated with swallowing disorders, it is extremely important to screen for dysphagia, with formal evaluation, and to treat it properly.

From the Porto University Center of Medicine Stroke Update Course, Porto, Portugal. 20–21 June 2017.

International Journal of Clinical Neurosciences and Mental Health 2017; 4(Suppl. 2):L23

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