Abstracts of the 1st Congress of the European Academy of Neurology, Berlin, Germany, June 2015.

© 2015 European Journal of Neurology, 22 (Suppl. 1), 1–20

Symposia Saturday, 20 June 2015

SYMP1-2 WORK-UP OF INTRA-CEREBRAL HAEMORRHAGES

EAN-ESO Symposium: Spontaneous intracerebral haemorrhage

Rustam Al-Shahi Salman

Edinburgh, United Kingdom

EUROPEAN JOURNAL OF NEUROLOGY

SYMP1-1 CAUSES AND CLINICAL COURSE OF SPONTANEOUS INTRACEREBRAL HAEMORRHAGES Valeria Caso

Perugia, Italy

The terms intracerebral and parenchymal haemorrhage describe spontaneous extravasation of blood into brain parenchyma. This clinical entity is present in 10 to 15% of all stroke cases and is also associated with a higher mortality rate than either ischemic stroke or subarachnoid haemorrhage. Moreover, there are trends towards a rising incidence of intracerebral haemorrhage (ICH) in an ageing population. Although early case fatality after spontaneous intracerebral haemorrhage has not changed over the past two decades, brain imaging has illuminated the pathophysiology of intracerebral haemorrhage and its various causes, such that the term primary intracerebral haemorrhage now seems antiquated. The SMASH-U classification takes into account the following predefined criteria as structural vascular lesions (S), medication (M), amyloid angiopathy (A), systemic disease (S), hypertension (H), or undetermined (U). This classification has proven to be feasible and is also associated with survival prognosis. In fact, patients with structural lesions tend to have the smallest haemorrhages and best prognosis, whereas anticoagulationrelated ICHs tend to be largest and with the worst prognosis. Regarding clinical course, ICH are commonly characterised by haematoma expansion and early neurological deterioration within the first few hours of onset. Thus, a rapid management including diagnostic work up needs to be performed in patients with intracerebral haemorrhage. Disclosure: Advisory boards & speaker fees (< 3 years): BMS, Boerhinger-Ingelheim

Objectives: I will provide an evidence-based review of the utility of diagnostic tests for identifying the treatable underlying causes of spontaneous intracerebral haemorrhage (ICH). Results: There are several systematic reviews of the diagnostic test accuracy of computed tomography angiography (CTA) compared to a reference standard of intra-arterial digital subtraction angiography (IADSA), which find 95% sensitivity and specificity of CTA for identifying underlying intracranial vascular malformations. However, there is an appreciable yield of repeat IADSA, when initial IADSA has been negative, so a negative CTA provides insufficient reassurance. Younger patients, patients with lobar ICH, and patients without a past history of systemic arterial hypertension appear to be more likely than other patients to harbour an underlying treatable cause of ICH; prediction algorithms may help target investigation to optimise their yield, but they still risk missing some treatable underlying causes. The diagnostic utility of brain MRI is under investigation. Conclusion: Rational diagnostic algorithms for the investigation of ICH may target investigations to optimise their yield, but they are not failsafe. Disclosure: Nothing to disclose

© 2015 EAN

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MICROBLEEDS, SMALL VESSEL DISEASE AND INTRACEREBRAL HAEMORRHAGES

TREATMENT AND CURRENT PERSPECTIVES

Charlotte Cordonnier

Daniel Hanley

The clinical and epidemiological scenario of intracerebral haemorrhages (ICH) has been changing in the last decades. Despite an overall stable incidence of ICH, the incidence among people older than 75 years has increased and the incidence among people younger than 60 years has decreased, with a larger proportion of lobar ICH, suggesting that vasculopathies more strongly associated with the elderly, particularly cerebral amyloid angiopathy, represent an increasing proportion within the etiological distribution of ICH. Brain microbleeds as well as superficial siderosis are interesting biomarkers both from diagnostic and prognostic perspectives. Indeed, the presence of lacunes, white matter hyperintensities, deep cerebral microbleeds, recent small subcortical infarcts, and brain atrophy may suggest deep perforating vasculopathy while the presence of lobar cerebral microbleeds, cortical superficial siderosis, predominant posterior white matter hyperintensities visualised on T2-weighted or fluid-attenuated inversion recovery MRI sequences, cortical microinfarcts seen on MRI DWI sequences, and subcortical enlarged perivascular spaces seen on axial T2-weighted images are suggestive of cerebral amyloid angiopathy. These radiological biomarkers are becoming surrogate markers for clinical trials and they may eventually help tailoring therapeutic strategies to prevent ICH recurrences and functional decline. Disclosure: Nothing to disclose.

Intracerebral haemorrhage is an important public health problem leading to high rates of death and disability in adults. Over a million haemorrhages occur world-wide each year, with little recent change in mortality or morbidity. Results of clinical trials suggest that early control of blood pressure and specialty care are associated with lower mortality than is typical community practice. Development of brain-specific treatment goals for surgery and critical care may improve outcome after intracerebral haemorrhage. Specific treatments supported by guidelines now include early diagnosis and aggressive management of blood pressure. Clinical trial investigations of minimally invasive surgical techniques to remove clot, as well as techniques to remove intraventricular blood and manage intracranial pressure, are nearing completion and will provide much needed data to support (or not) change in current practices. These approaches could improve clinical management of patients with intracerebral haemorrhage and appear to promise reduced mortality and increased functional survival. Disclosure: Nothing to disclose.

Lille, France

Baltimore, United States


Symposia 3

Epilepsy and the injured brain: causes and consequences

SYMP2-2

SYMP2-1

Martin Holtkamp

THE ROLE OF INFLAMMATION – ANIMAL AND CLINICAL DATA

Within the first days of acute brain injuries and acute systematic disturbances, epileptic seizures may occur, which are thought to be causally related to the event and thus are termed acute-symptomatic seizures. Brain injuries comprise cerebrovascular accidents, traumatic brain injury, intracranial surgery, and CNS infections, and seizures are defined to be acute-symptomatic when they occur within 7 days or during the active stage of infection. Strokes provoke acute seizures in 5-10% of cases, and haemorrhages are more proconvulsive than ischaemic infarctions. Interestingly, the majority of acute seizures following stroke occur within the first 24 hours. Seizures attributed to systemic disturbances have to manifest within 24 hours of the active stage of metabolic disturbances, within 7 to 48 hours of alcohol abstention (in abusers), and within 7 days of global hypoxia. Pharmacological management, i.e. conceptually a secondary prophylaxis, depends on acute and long-term seizure recurrence risk. Reliable data on the acute recurrence risk are available only for seizures in alcohol withdrawal syndrome which is estimated to be between 25 and 60%. A randomised controlled trial has demonstrated that 2mg intravenous lorazepam, administered after the first seizure in alcohol withdrawal, reduces recurrence risk almost by factor 10. The acute recurrence risk in other aetiologies is less clear, but commonly seizures due to acute systemic disturbances are treated with benzodiazepines for a couple of days while seizures due to acute brain injuries are treated with antiepileptic drugs for a couple of weeks. The 10-year-risk to develop an unprovoked seizure after an acute-symptomatic seizure due to brain injury is 15-30% arguing against long-term antiepileptic treatment in the majority of patients. Disclosure: Nothing to disclose

Annamaria Vezzani Milan, Italy

There is evidence of the activation of the innate and adaptive branches of the immune system, and the related inflammatory processes, in epileptic disorders. Experimental data support a putative pathogenic role of specific inflammatory processes developing in the brain in seizure generation and neuronal and glial cell pathology. Major challenges in this field remain a better understanding the key inflammatory pathogenic pathways activated in during epileptogenesis, and how to counteract them efficiently without altering the homeostatic tissue repair function of inflammation. Gaining insight into the intricate role of inflammation in the generation and exacerbation of epilepsy should yield novel molecular targets for the design of anticonvulsant, as well as disease modifying therapies that might prevent or abrogate this common and sometimes devastating brain disorder. Disclosure: Nothing to disclose

MANAGING SEIZURES AND SEIZURE RISK IN THE ACUTELY INJURED Berlin, Germany


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SYMP2-4

PREDICTING EPILEPSY RISK AFTER ACUTE BRAIN INSULTS

PREVENTING EPILEPSY FOLLOWING AN ACUTE BRAIN INSULT - FACT OR FICTION?

Torbjörn Tomson

Stockholm, Sweden

Objectives: This lecture will discuss risk factors for developing epilepsy after stroke and traumatic brain injury (TBI), the two most common causes of epilepsy, together accounting for at least 20-25% of all cases of epilepsy. Methods: Cohort studies have indicated a risk of developing epilepsy over 3-10 years after stroke ranging from 3-17%. The risk of unprovoked seizures after TBI ranges from 1-10% over 5 years after the TBI and from 2-17% over 30 years. The range in the risk depends on the type and severity of the insult as well as on the duration of follow-up. For stroke as well as for TBI the greatest risk of developing seizures is during the first year after the insult, but still elevated more than 10 years after. Results: Cohort- and case-control studies have analyzed risk factors for developing epilepsy after stroke and TBI. For stroke, cortical involvement and stroke severity have been identified as risk factors for epilepsy whereas it remains controversial if intracerebral hemorrhage carries a greater risk than infarction stroke. The severity of the insult is also a risk factor after TBI where in particular the combination of brain contusion and intracranial hemorrhage has been associated with a very high risk of developing epilepsy. Conclusion: Patients with particularly high risk of developing epilepsy after acute brain insults can thus be identified based the severity and characteristics of the brain injury. Disclosure: Nothing to disclose

Matthew C. Walker

London, United Kingdom

Our present drugs for epilepsy treat the symptom (i.e. the seizures) rather than the underlying disease process (i.e. epileptogenesis), and none have been shown to prevent epilepsy following an acute brain insult. Epileptogenesis results from structural and functional changes in neuronal networks that occur following an insult; these changes eventually result in the occurrence of spontaneous seizures (epilepsy). These processes have been modelled in animals (usually following status epilepticus), and, as a result, a number of promising targets have been identified to prevent epilepsy following an acute brain insult. However, these processes may also serve an important role in brain recovery and so antiepileptogenic treatments could have a detrimental effect on neurological recovery. There are also considerable obstacles in translating the findings from animal models to human disease, possibly explaining why potential antiepileptogenic treatments have failed. Moreover, adequately powered clinical trials of anti-epileptogenic treatments are problematic, partly due to their size, but also due to the risks of unnecessary treatment for large numbers of people who will not develop epilepsy. Such calculations emphasise the importance of biomarkers for informing such trials. Although there are many challenges facing the development of antiepileptogenic therapies, advances in gene therapy may offer alternative approaches that could perhaps more easily translate to disease modifying treatments. Disclosure: Mattew Walker has received speaker and consultancy fees from UCB pharma and Eisai, and has received grant funding from Vitoflo.


Symposia 5

Modern molecular genetics in clinical myology SYMP3-1 OVERVIEW IN EPIDEMIOLOGY AND CLASSIFICATION IN MYOLOGY Zohar Argov

Jerusalem, Israel

The epidemiology of neuromuscular disorders in Europe is not well studied, prevalence estimates cite about 160 per 100,000 total, hereditary myopathies contributing about 25:100,000. In some ethic clusters specific ‘rare’ conditions have been identified with high frequency, especially recessive conditions in closed societies. Examples of such conditions are the LGMD2A (calpainopathy) in the Basque population or the GNE myopathy in the Roma people (mainly in Bulgaria). With some conditions the prevalence is almost exclusive to certain countries, like the Welander distal myopathy in Sweden (due to a mutated RNA binding protein TIA1) and the tibial muscular dystrophy (titin mutations) in Finland. With other disorders the overall frequency may not be exceptionally high but founder mutations have been identified in certain populations. This is exemplified in the fukutin-related protein myopathy (LGMD2I) with a specific prevalent European mutation (C286A) or the calpain mutation (del550A) in limb girdle dystrophy in Croatia and neighboring ‘Slavic’ countries. One should also be aware of the ‘immigrant’ mutations, people coming to Europe from areas with known high frequency of mutations of specific myopathies (e.g. the Middle Eastern M743T mutation in the quadriceps-sparing GNE myopathy). On the other hand European immigrants have ‘established’ clusters of disorders in other areas of the world mainly in North America (e.g. the OPMD in FrenchCanadians and the LGMD2I north European mutation in Hutterite people). Knowledge of the geographical distribution of disorders may help in the diagnostic evaluation of patients and may simplify the genetic testing in the single subject. Disclosure: Nothing to disclose.

SYMP3-2 MYOTONIC DYSTROPHIES AND UPCOMING THERAPIES Benedikt G.H. Schoser Munich, Germany

Objectives: Myotonic dystrophy types 1 and 2 (DM1/ DM2) are progressive disorders characterised by progeric muscle weakness, myotonia, cognitive alterations and other multisystem facets. For Europe, is it estimated that within a population of 733 million Europeans about 150.000 DM1 and DM2 patients are living. By their pathogenesis both types belong to the growing group of repeat expansion disorders. DM1 is caused by repeat expansion of a

trinucleotide sequence (CTG) in the 3’-untranslated region of the myotonic dystrophy protein kinase (DMPK) gene which, when transcribed into CUG-containing RNA, forms aggregates of mutant transcripts that sequester RNAbinding proteins and cause abnormal splicing of downstream effector genes. DM2 is caused by expansion of a complex repeat motif (TG)n(TCTG)n(CCTG)n in the first intron of the CNBP (cellular nucleic acid-binding protein; previously ZNF 9, zinc finger protein 9) gene. A similar molecular mechanism of widespread cellular alterations of mRNA splicing has been proposed. Furthermore, beyond this important RNA toxicity mechanism, other effects on protein translation and turnover, and activation of cellular stress pathways are evident. Methods: A summary of the current state-of-the-art supervision and treatment inlcuding new molecular strategies of both diseases will be given. Results: A first large European study („Observational Prolonged Trial In Myotonic Dystrophy type-I to Improve Stamina, a Target Identification Collaboration”, OPTIMISTIC: Clinical Trials.gov Identifier: NCT02118779) collects prospectively longitudinal data on phenotype, natural history, fatigue, cognition and biomarkers of 280 DM1 patients of four European countries till end of 2015. DM1 patients receive randomised cognitive behavioural therapy or physical training for improving their fatigue, and general activity levels incl. quality of life. Besides, recent advances in molecular mechanisms opened avenues for new specific and hopefully effective molecular treatment strategies for DM1 and DM2. The development of targeted molecular treatments, like antisense oligonucleotide (ASO) therapy, has reached realization in-vitro and in animal models. Now it is time to translate this base of knowledge into first human clinical trials. For example, systemic administration of ASOs caused a rapid knockdown of CUG(exp) RNA in skeletal mice muscle, by correcting parts of the physiology, histopathology, and transcriptome of the disease for up to 1 year. In first in menstudies, ASOs, incorporated to human myotonic dystrophy type-1 tibialis anterior muscle, verified categorised changes that associated with ankle dorsiflexion weakness. Conclusion: Myotonic dystrophies are the most prevalent but variable adult multisystem muscular dystrophies and still associated with high morbidity and premature mortality. We still have no substantial treatment; however our improved knowledge on patient’s supervision has significantly reduced morbidity and mortality. New therapy avenues integrating modern molecular pathogenesis will help to elucidate a more promising disease editing in the long run. Disclosure: Nothing to disclose


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SYMP3-4

DYSTROPHINOPATHIES: FROM STEROIDS TO MOLECULAR THERAPY

THE VALUE OF NEXT GENERATION SEQUENCING IN DIAGNOSING NEUROMUSCULAR DISORDERS

Corrado Angelini Padova, Italy

Objectives: Duchenne muscular dystrophy (DMD) is a progressive disorder affecting primarily skeletal and cardiac muscle, due to loss of dystrophin. DMD patients lose ambulation by 7-12 years (average 10 years). In DMD progressive loss of respiratory function begins in the second decade and progresses to respiratory failure requiring nocturnal ventilation. Methods: Patients who met the following criteria were included between 5 and 18 years of age, diagnosed with DMD by lack of dystrophin and could cooperate with either GSGC test or 6MWT. Information on steroid or molecular treatment was offered by multidisciplinary team to patients and their families. The boys treated with Deflazacort were given oral supplements of vitamin D and calcium. Clinical examinations included independent clinical evaluation by physician, monitor and psychologist. Body weight increase was monitored regularly. Results: Corticosteroids, particularly Deflazacort (0.9 mg/ kg) or Prednisone (0.75 mg/kg), are the only method to preserve muscle function and have been used extensively in various countries. A general consensus is that they should be offered while boys are still ambulating. Molecular drugs are Ataluren (at two different doses) and antisense oligonucleotides (Disapersen), which have been studied in phase 2b/3 trials in about the 10% children either with stopcodon mutations or exon 51 deletion. There was a modest increase in 6MWT. Cardio-protection could be another issue in DMD, which is reached through beta-blockers and ACE inhibitors. Recently, Eplerenone has been shown by a radio nucleotide imaging technique to be efficacious against placebo. Also body weight control as well as fructose diet appear to be useful in DMD. Conclusion: All these interventions have a very significant impact on health, quality of life for DMD boys and their families, associated to few side effects. Disclosure: Support by Genzyme Registry. Supported by Grant from Telethon n. GUP13013 and AFM-

Volker Straub

Newcastle upon Tyne, United Kingdom

Neuromuscular diseases (NMD) have a wide phenotypic spectrum, show an enormous genetic heterogeneity, are usually incurable and are associated with a recurrence risk for the families affected. In the past 25 years the strategies and methods applied have allowed us to identify neuromuscular disease genes mainly in larger families and for more frequently occurring genetic conditions. Using cost- and time-intense step-by-step single gene approaches only the most frequent genetic causes and patients with characteristic phenotypes are normally being tested, leaving many patients with very rare and clinically unspecific NMD without a precise diagnosis. Depending on the health system and local access to diagnostic tools, between 30-80% of neuromuscular patients in Europe remain undiagnosed. As a precise genetic diagnosis is a prerequisite for the monitoring of disease complications, the counselling of families and therefore the overall quality of life and life expectancy of a patient, it is a major challenge to identify the genetic cause for all patients with NMD. The use of next generation sequencing technologies (NGS), namely exome and genome sequencing, has turned out to be an enormously powerful tool to identify causative mutations in single families, cohorts of few well characterized independent patients, single consanguineous patients or even single sporadic cases. Sequencing of trios (parents and patient) allows a fast identification of potential de novo mutations which seem to be more frequent than expected even among neuromuscular diseases. It is anticipated that whole exome or even whole-genome sequencing will soon be routinely used in diagnostics and current NGS research projects are laying the foundation for implementing standardized routine diagnostics for NMD and other rare neurological diseases. The increase in availability of targeted genetic testing for mutations linked with a high predictive value for positive and negative test results will decrease the uncertainty and fear for patients which are often associated with an undiagnosed condition. In addition to the identification of disease genes, NGS will also contribute to an improved understanding of underlying disease pathomechanisms and the development of biomarkers. These additional benefits of NGS will rely on strong bioinformatics expertise, data sharing policies and willingness for networking. Two such networking projects will be introduced: Neuromics and MYO-SEQ. Neuromics is an EU-funded (FP7, 2012-305121) translational research project, which has the primary aim of greatly improving understanding of neuromuscular and neurodegenerative diseases. The project studies 1,100 exomes and aims to discover disease causing and disease modifying genes, develop new therapies, undertake deep phenotyping of patients, increase patient cohorts for clinical trials and


Symposia 7

develop new biomarkers for clinical application. The MYOSEQ project is exploring 1,000 exomes of patients with limb girdle weakness of unknown origin across more than 40 European sites. Results from both projects will be presented. The projects are already showing that the identification of novel NMD genes can facilitate personalized medicine, advance and standardise NGS diagnosis, reduce ineffective interventions and burdensome investigations, improve standards of care for patients and the development of target–driven therapies. Disclosure: • I am or have been a principal investigator for trials sponsored by Genzyme, GSK, Prosensa/Biomarin, ISIS Pharmceuticals, and Sarepta. • I received speaker honoraria from Genzyme, a Sanofi company. • I am a member of the international Pompe advisory board of Genzyme, a Sanofi company, and have been on advisory boards for Acceleron Pharma, Audentes, Italfarmaco S.p.A., Nicox, Pfizer, Prosensa, Santhera and TrophyNOD. • I have a research collaboration with Ultragenyx and Genzyme/Sanofi


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Symposia

Sunday, 21 June 2015

PLEN1-2

Presidential Plenary Symposium: Hot topics in neurological sciences

THE CONCEPT OF HYPO- AND HYPERDOPAMINERGIC DYSFUNCTION OF THE BASAL GANGLIA Jens Volkmann

Würzburg, Germany

PLEN1-1 TRANSLATIONAL RESEARCH FOR BIOMARKERS IN MULTIPLE SCLEROSIS Xavier Montalban Barcelona, Spain

Multiple sclerosis (MS) is a complex disease characterized by a high degree of heterogeneity in clinical, radiological, and pathological features, and in the therapeutic response. In this scenario, biomarkers that reliably capture these different aspects of disease heterogeneity are strongly needed, and may aid to better understand MS pathogenesis, diagnosis, and prognosis; to predict response outcome to treatments; and to develop new treatments. Despite the many biomarkers proposed in different studies, large gaps still remain between exploratory biomarkers, validated biomarkers, and clinically useful biomarkers. This talk will focus, among other aspects, on current hurdles for integration of biomarkers into routine clinical practice and future perspectives of biomarkers studies, including (i) current clinical endpoints used in MS clinical trials, eg. relapse rate to assess disease activity or EDSS to evaluate neurological disability, and the need to develop more sensitive and clinically relevant outcome measures which can be used as surrogate endpoints to provide information on MS prognosis or treatment response earlier than the outcome of interest; (ii) the current scenario of MS treatment with many different options to treat patients, and the necessity of a personalized therapy that offers the right treatment to the right patient with a low risk of developing adverse drug effects; (iii) the need for studies to integrate different types of data (clinical, radiological, and biological information) into pan-disease predictive models that might allow to estimate the prognosis of a particular MS patient at any time during the disease course. Correction of the obstacles that prevent the clinical use of biomarkers will help to move forward from bench to bedside, and will certainly aid to bring personalized medicine to MS patients. Disclosure: not received

Chronic high-frequency stimulation of the subthalamic nucleus has evolved into a routine treatment for motor fluctuations, dyskinesia and medically refractory tremor in Parkinson’s disease. The most striking clinical effect of STN-HFS is the alleviation of akinesia, which matches the benefit induced by a suprathreshold dose of levodopa. In recent years, however, a variety of non-motor effects of STN-HFS has been described either by clinical observation of patients during the postoperative course or by using STN-HFS as a “reversible lesioning technique” to study experimentally the behavioral effects of focal basal ganglia deactivation. These studies confirm the functional connectivity of the STN to extensive frontal cortical regions, which subserve motor, cognitive, limbic and even autonomous functions. Moreover, using appropriate neurophysiological and neuroimaging techniques, the functional connectivity of the STN and brainstem motor areas could be probed and linked to specific motor symptoms of Parkinson’s disease, such as gait or balance disturbances. From these studies a much more complex picture of basal ganglia function has evolved than previously suggested by the prominent motor symptoms of basal ganglia disorders. They have helped to disentangle DBS effects on motor and non-motor symptoms of Parkinson’s disease into those related to extranigral neurodegeneration, medication induced sensitisation and hypo- or hyperdopaminergic basal ganglia function. This lecture summarizes the clinical and experimental data on motor and non-motor effects of STN-DBS and discusses the complex interaction between medication and stimulation in their origin. The concept of a „U-shape“ dose-response relationship for medication and stimulation is introduced, which may explain various behavioral effects of STN-DBS in the motor and non-motor domains, if applied to the functionally segregated basal ganglia loops, which are differently affected by the dopaminergic denervation in PD. Suggested readings: Volkmann, J., C. Daniels and K. Witt (2010). Neuropsychiatric effects of subthalamic neurostimulation in Parkinson disease. Nat Rev Neurol 6(9): 487-498. Castrioto, A., E. Lhommee, E. Moro and P. Krack (2014). Mood and behavioural effects of subthalamic stimulation in Parkinson's disease. Lancet Neurol 13(3): 287-305. Disclosure: not received.


Symposia 9

PLEN1-3 IMMUNISATION STRATEGIES FOR NEURODEGENERATIVE DISEASE Bruno Dubois Paris, France

The ‘chance’ of the therapeutic research in Alzheimer’s disease (AD) was that symptomatic drugs showed only limited efficacy, partly because of widespread neuronal damage in AD. As a consequence, this has promoted a massive engagement of pharmaceutical companies upstream in the disease cascade. The starting point of the cascade is still not known although it certainly implies a complex algorithm combining genetic risk factors that facilitate an intervention of multiple epigenetic environmental agents. Whatever the algorithm, the cascade involves some identified biological pathways (such as amyloid and tau) that are today considered as characteristic of the disease mechanisms. Given the poor impact on symptoms of the neurochemical replacement and the high number of neuronal systems involved in AD, it was natural to try to intervene at the level of the supposedly specific biological mechanisms of AD, and particularly of amyloidosis, which was promoted by the human autosomal-dominant genetic model of AD. Interestingly, the treatments developed against amyloidosis do work. This is particularly the case of monoclonal antibodies (MAB), which are acting against the brain lesions as demonstrated in animal models (transgenic mice) and also in humans affected by the disease (in postmortem and neuroimaging studies). However, MAB work on brain lesions but not on symptoms, which are the only and ultimate aim. Some of the reasons of these negative results are well known: the duration of the trials may have not been long enough to allow a significant reversal of the clinical symptomatology; the patients included in the trials were too advanced or partly misdiagnosed. These arguments are well established: all available data on therapeutic research on AD have been obtained in patients with a massive disorganization of their brain neuronal network for a long period of time (may be more than 20 years); a severe burden of amyloid lesions as shown in amyloid-PET studies; and a high rate of false diagnosis (up to 36% of the patients in a recent clinical trials). Under these conditions, it may not be surprising that “disease modifier” trials may turn all negative. However, these negative results may also signify that amyloidosis has nothing to do with the onset of the disease or of the symptoms; The new research criteria recently proposed are changing the rules as they allow to investigate treatments at an early prodromal stage of the disease with a higher diagnostic accuracy than before, thanks to incorporation of biomarkers. Studies are just starting with such designs. Efficacy on neuronal lesions also validates new approaches in cognitively normal individuals who are carriers of autosomal AD monogenic mutations (DIAN study): these normal subjects can be considered as presymptomatic. MAB will also be tested in asymptomatic at risk who are biomarker positive (A4 study) although we do not know if and when they will convert to a

clinical disease; and new approaches against other biological agents (anti-tau) have also started. Disclosure: not received

PLEN1-4

BIOMARKERS FOR EPILEPSY. WHAT IS BECOMING CLINICALLY USEFUL? Annamaria Vezzani Milan, Italy

Epilepsy is a brain disorder affecting over 50 million people worldwide, and around 6 million in Europe alone. It is associated with elevated mortality, significant comorbidities, unique stigmatization of affected individuals, and high social cost (~€20 billion/year in Europe). Current antiepileptic drugs (AEDs) provide only symptomatic relief from seizures, have multiple adverse effects, and are ineffective in up to 40% of people. This represents a major unmet clinical need. New anti-seizure treatments for epilepsy are unlikely to bridge this treatment gap and the next generation of therapies needs to possess diseasemodifying properties. Such drugs could potentially be used to halt or reverse the progression of epilepsy in people with an established diagnosis or to delay or prevent the onset of epilepsy in susceptible individuals. Development of disease-modifying agents for epilepsy would be greatly motivated by the identification of biomarkers that predict onset and progression of the disorder and its response to treatment; these are currently lacking. Ideally, such a biomarker should be sensitive and specific in terms of its association with prognosis and non-invasive and inexpensive in terms of the method of its measurement. It should also mirror the underlying pathophysiology of the disorder or, in this case, the mechanisms responsible for the generation and perpetuation of seizures, i.e. epileptogenesis. Epileptogenesis is a complex multifactorial process, characterized by either concomitant or sequential occurrence of various modifications in the brain, including neuronal network reorganization, glial cell activation, blood-brain barrier dysfunction, neuroinflammation (elicited by proinflammatory molecules generated by resident brain cells or invading blood cells), altered neurogenesis, genetic and epigenetic alterations, and acquired channelopathies. All of these changes may contribute to epileptogenesis, and ideally they might provide mechanistic biomarkers of the disease. There is an intense search for non-invasive biomarkers including EEG, brain imaging or serum investigations: they are as yet unavailable, although they are instrumental for stratifying patients for a preventive or disease-modifying clinical trial. In this frame, mechanistic biomarkers of neuroinflammation will be discussed in more detail by reporting both experimental and clinical data. Disclosure: not received


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Symposia

Monday, 22 June 2015

SYMP4-2

Preclinical Alzheimer’s disease

VALIDATION STATUS OF "ESTABLISHED" BIOMARKERS FOR PRECLINICAL DIAGNOSIS Philip Scheltens

SYMP4-1

Amsterdam, The Netherlands

TERMINOLOGY AND CURRENT CRITERIA Reinhold Schmidt Graz, Austria

Objectives: Review of the current definitions for preclinical AD in its asymptomatic and symptomatic stages. Review of literature on the prognostic potential of the various sets of criteria to predict conversion to Alzheimer’s disease (AD). Methods: Literature Search Results: The recent paradigm shift in the diagnostic conceptualization of AD based on evidence for structural and biological changes occurring already in preclinical stages of the disease resulted in the development of numerous criteria designed to determine the asymptomatic and prodromal AD stages. In the asymptomatic stages these include the International Working Group (IWG) criteria separating between asymptomatic at risk stages and presymptomatic AD and the National Institute on AgingAlzheimer’s Association (NIA-AA) criteria which distinguish 3 stages of preclinical AD and Suspected nonAD Pathophysiology (SNAP). The early symptomatic nondementia stages of AD are defined by the terms subjective cognitive decline, prodromal AD (IWG-1 and IWG-2), MCI due to AD (NIA-AA) and mild neurocognitive disorder due to AD (DSM-5). The differences between the various definitions are important as they are likely to identify different stages along the continuum of AD development. First short time follow-up data demonstrate reasonable prognostic accuracy of these criteria, but the relatively high number of subjects who convert to AD without fulfilling the criteria is of note. Conclusion: Current criteria to define pre-dementia AD are promising, but there are several issues that need to be further explored. These include long-term assessment of conversion risk, time to conversion, factors influencing conversion and information to be conveyed to individuals who meet given sets of criteria. Disclosure: I received honoraria from Axon Neuroscience for consultancy and speaker’s honoraria from Pfizer, Novartis, Takeda and Merz Austria

In the field of dementia there are now three established biomarkers for the diagnosis of Alzheimer’s disease: MRI, CSF and amyloid PET. These biomarker differ with respect to status of use in clinical practice, availability, costs, ease of utility, availability and level of diagnostic certainty especially in preclinical stages. As for validation, this holds true as well, although one needs to realise what is meant with the word validation. There is validation against pathology, against other markers, in terms of standardisation and operationalisation, as well as cross-cultural, and regulation issues. In this talk we will compare the biomarkers in terms of validation within the research and current practice standpoint, in other words how good they are for detecting preclinical stages of AD and how useful they are in research and practice. Disclosure: Nothing to disclose.


Symposia 11

Expanding fields in neurology

SYMP5-2 NEUROREHABILITATION

SYMP5-1

Stephanie Clarke

Lausanne, Switzerland

NEUROGERIATRICS Walter Maetzler

Tübingen, Germany

The relative share of elderly persons in Western societies is rapidly growing, leading to an increasing frequency of agerelated neurological diseases and functional impairments. While geriatric medicine is increasingly established as an important medical discipline for the prevention and treatment of diseases and disabilities in elderly persons, it is still often considered as an integral and evolving part of internal medicine. This development, however, does not sufficiently capture the fact that up to 70% of geriatric patients have neurological and psychiatric diagnoses and needs. I will demonstrate that neurology is an inevitable part of geriatric medicine (and vice versa), that is not subsumable merely under current internal medicine knowledge. Moreover, I will show that neurogeriatrics is not simply a transfer of neurological knowledge to the old patient, but should prompt a new, genuine focus in medical research and care. For example, neurogeriatrics focuses on the research, assessment and treatment of individual patterns of neurological dysfunctions and their interactions (e.g. the interplay between gait disorders, falls, cognitive and sensory impairments, and increased reaction and processing time), rather than on specific diagnoses and treatments of single syndromes and diseases. Moreover, I will outline how neurogeriatrics is conceptualized and implemented in different countries, taking into perspective the different methodological, socioeconomic and scientific background of these countries and health care systems. Reviewing both the progress and the current shortcomings of the development of this sub-specialty in each country will allow outlining future requirements and improvements to systematically advance and firmly establish this specialty. Disclosure: Not received

Cognitive neuroscience deals with the translation between cognition, the biological processes of the brain and computational modelling and includes clinically relevant fields such as neuropsychology, neuroimaging, neural plasticity and neurorehabilitation. The latter field benefitted substantially from cognitive neuroscience and should do so even more in near future. This point will be illustrated on the hand of three examples 1. Current models of speech and language processing changed our way of understanding classical aphasic syndromes and opened new vistas for rehabilitation. Based on these models new therapeutic interventions have been proposed and are investigated in clinical trials. Nevertheless, outcome prediction remains uncertain, partially due to the poor understanding we have of neural mechanisms underlying recovery of cognitive functions. The investigation of simpler models such as the dual-stream model for auditory processing, rather than the very complex networks involved in speech and language processing, may offer useful insights into postlesional plasticity and reorganization. Very interesting neurorehabilitation tools are behavioral interventions, such as prismatic adaptation in neglect, which enhance plasticity and change cognitive representations within the contralesional hemisphere. In summary, we are witnessing the development of new rehabilitation approaches. The understanding of the underlying neural mechanisms should help us to define more precisely the indications for these treatments and to carry out more focused randomized controlled trials. Reference: Clarke, Bindschaedler and Crottaz-Herbette (2015) The impact of cognitive neuroscience on stroke rehabilitation. Stroke, in press. Disclosure: Not received


12

Symposia

SYMP5-3

SYMP5-4

NEURO INTENSIVE CARE UNIT: POSTRESUSCITATION

NEUROLOGY AT THE EMERGENCY ROOM: STROKE MIMICS

Maxwell Simon Damian

Atte Meretoja

NeuroIntensive care is a rapidly growing field in most countries. Whereas the treatment of severe acute brain disorders was 20 years ago considered almost hopeless, recent advances in management of acute stroke and traumatic brain injury have demonstrated how outcomes can be improved, if diagnosis is prompt and correct treatment is instituted early. One common condition in which progress has been slower is post-resuscitation management after cardiac arrest. There is good knowledge on the pathomechanisms of hypoxic brain injury, and on how delayed neuronal injury develops, but accurate clinical assessment and treatment is not easy. In recent years, management and prognostic guidelines have been developed, but needed revision within a short space of time. The advent of therapeutic hypothermia (TH) in 2002 provided an evidence-based treatment option, but this also necessitated a rethink of accepted prognostic criteria. Since 2013, targeted temperature management (TTM) is often favoured, and this has again impacted on prognostic assessment. This lecture will give an overview of the scientific concepts underlying our understanding hypoxic brain injury and the evolution of neuronal damage, and discuss how this has informed clinical management. In addition, it will provide advice on best practice for postarrest management, and on prognostication in different clinical situations, and discuss current guidelines under development. Disclosure: Nothing to disclose.

With the discovery of multiple evidence-based interventions, our specialty is shifting from slow-stream diagnostics to ultra-rapid therapeutics. Some of the treatments, such as recanalisation of blocked arteries in ischaemic stroke, are highly time-critical. Ultra-fast diagnosis and treatment carry the risk of misdiagnosis. The talk will cover the typical clinical and imaging pitfalls of diagnosing stroke and stroke mimics, including the literature on thrombolysis mimic rates and associated risks. Finally, a case is made for stroke specialists to shift from a phone consultative service to active primary evaluation and management of stroke patients from the hospital door onwards. Disclosure: Stroke clinician and researcher in Finland and Australia. Lecture honorarium and travel costs from Siemens. World Stroke Organization board member.

Cambridge, United Kingdom

Hus, Finland


Symposia 13

Present and future treatment in movement disorders

SYMP6-2

SYMP6-1

Sarah J. Tabrizi

NEW THERAPIES IN PARKINSON’S DISEASE

The known genetic cause of Huntington’s disease (HD) has fueled considerable progress in understanding its pathobiology, and the development of therapeutic approaches aimed at correcting specific changes linked to the causative mutation. Among the most promising is reducing expression of mutant huntingtin protein (mHTT) with RNA interference or antisense oligonucleotides; human trials are now being planned. Zinc-finger transcriptional repression is another innovative method to reduce mHTT expression. These HTT lowering approaches will form the mainstay of my talk. Modulation of mHTT phosphorylation, chaperone upregulation and autophagy enhancement represent attempts to alter cellular homeostasis to favor removal of mHTT. Inhibition of histone deacetylases (HDACs) remains of interest; recent work affirms HDAC4 as a target but questions the assumed centrality of its catalytic activity in HD. Phosphodiesterase inhibition, aimed at restoring synaptic function, has progressed rapidly to human trials. Deranged cellular signalling provides several tractable targets but specificity and complexity are challenges. Restoring neurotrophic support in HD remains a key potential therapeutic approach with several approaches being pursued, including BDNF mimesis through TrKB agonism and monoclonal antibodies. An increasing understanding of the role of glial cells in HD has led to several new therapeutic avenues including kynurenine monooxygenase inhibition; immunomodulation by laquinimod; CB2 agonism and others. Many exciting therapeutics are progressing through the development pipeline, and combining a better understanding of HD biology in human patients, with concerted medicinal chemistry efforts, will be crucial for bringing about an era of effective therapies for HD. Disclosure: Sarah J Tabrizi receives Grant funding for her research from the EU FP7 health call, Medical Research Council UK, CHDI Foundation, Huntington Disease Association of the UK, Dementia and Neurodegenerative Disease Network UK, European Huntington’s Disease

Olivier Rascol

Toulouse, France

Recent clinical trials have been conducted to assess novel strategies to treat Parkinson’s disease (PD), including disease-modifying medications and dopaminergic or nondopaminergic drugs and non-pharmacological interventions to manage the motor and non-motor symptoms of the disorder. Disease-modifying trials have provided disappointing negative or inconclusive results during the last 3 decades. However, within the last couple of years, recent proof-of-concept studies have generated novel hopes, with the use for example of GLP1 analogs or iron chelators. Recent trials have also documented the interest of novel levodopa-carbidopa formulations to treat motor symptoms in PD, including intrajejunal infusions (duodopa), new extended-release formulations (IPX066), subcutaneous pump-patch (ND0612) or inhaled administration (CVT301). New COMT and MAO-B inhibitors (opicapone, safinamide) have been shown to improve OFF problems in PD patients. In parallel, original non-dopaminergic drugs have been tested to manage motor fluctuations and dyskinesia, although trials testing compounds like adenosine A2A antagonists (istradefylline, preladenent, tozadenent) or MGluR5 modulators (mavoglurant, diplaglurant) have not produced yet consistent positive results. New randomized controlled trials have demonstrated for the first time that dopamine and non-dopaminergic drugs can improve nonmotor parkinsonian symptoms: the dopamine agonists pramipexole and piribedil for depression or apathy; the opiate agonist oxycodone/naloxone for pain; the 5HT2A inverse agonist pimavenserin for hallucinations. Finally, a growing number of clinical trials have tested nonpharmacological interventions to treat PD, such as deep brain stimulation or physical exercise. However, at the moment, the quality of such trials remained usually insufficient to provide indisputable robust evidence. Disclosure: For the last 20 years O. Rascol has advised most drug companies developing new antiparkinsonian medications.

NEW THERAPEUTIC STRATEGIES IN HUNTINGTON’S DISEASE London, United Kingdom


14

Symposia

SYMP6-4 NEW TREATMENTS FOR ATAXIAS Thomas Klockgether Bonn, Germany

The ataxias (SCAs) are a clinically and genetically heterogeneous group of inherited and sporadic progressive ataxia disorders. To date, more than 50 genetically different recessive ataxias, approximately 40 different dominantly inherited spinocerebellar ataxias (SCAs) and many other non-genetic entities have been defined. Among the inherited ataxias, Friedreich’s ataxia (FRDA) and SCA3/MachadoJoseph disease are the most common. In the past ten years, sensitive clinical assessment instruments have been developed and validated in large cohorts including cohorts of individuals at risk for a dominantly inherited SCA. The natural history of the most common ataxias has been intensely studied. With this, large interventional trials are in ataxias are feasible. FRDA is due to partial loss of the mitochondrial protein frataxin caused by an intronic repeat expansion mutation in the encoding gene. Therapeutic research in FRDA concentrated on development of histon deacetylase (HDAC) inhibitors that increase frataxin expression. Another approach to increase frataxin levels is application of nicotinamide. In addition, major progress has been made in reversing FRDA cardiomyopathy in a mouse model by a gene therapy approach. Research in SCA3 concentrates on the development of antisense oligonucleotides that hybridize with the ATXN3 RNA transcript and target it for degradation or modification. As these approaches are disease-specific, there is an urgent need to develop in addition interventions that symptomatically improve ataxia irrespective of its molecular origin. Currently, a number of such trials are being performed of which results have to be awaited. Intense coordination training has been shown to have a relevant and lasting beneficial effect on ataxia. Disclosure: Nothing to disclose.


Symposia 15

Tuesday, 23 June 2015 Multiple sclerosis therapy moving forward/where is the truth? Hopes and hazards

Disclosures: Finn Sellebjerg has served on scientific advisory boards for Biogen, Genzyme, Merck Serono, Novartis and Teva; served as consultant for Biogen Idec and Lundbeck; received support for congress participation from Biogen Idec, Novartis and Teva; and received speaker honoraria from Biogen, Genzyme, Merck Serono and Novartis. His laboratory has received research support from Biogen, EMD Serono and Novartis.

SYMP7-1 MS PATHOGENESIS – WHERE IS IT HEADING NOW? Finn Thorup Sellebjerg Copenhagen, Denmark

Many of the fundamental aspects of MS have now been known for more than 100 years. Nevertheless, our understanding of the pathogenesis of MS is still incomplete. A popular concept states that disease activity in patients with relapsing-remitting MS is immune-mediated, whereas the slow deterioration observed in primary and secondary progressive MS may be due to neurodegenerative processes. The concept of relapsing-remitting MS being mediated by the immune system is readily compatible with the success of modern immunomodulatory and immunsuppressive treatment strategies. Furthermore, recent genetic studies have highlighted that many of the genetic variants now known to influence the risk of developing MS influence the function of immune cells. Exactly how immune activation and inflammation is linked to demyelination and axonal pathology is, however, still uncertain, but recent evidence suggests that oxidative damage and mitochondrial dysfunction may play a pivotal role in the pathogenesis. This may especially be the case in progressive MS. In the past few years several studies have indicated that immune activation and inflammation may also be crucially involved in the pathogenesis of progressive MS. First, genetic studies have failed to identify differences in genetic factors associated with the risk of developing the relapsingremitting and primary progressive subtypes of MS. Secondly, histopathology studies have indicated that immune activation is also associated with demylination and axonal damage in progressive MS, but that this inflammation is compartmentalized behind the blood-brain barrier. This is supported by studies of cerebrospinal fluid biomarker studies, which have indicated a clear correlation between inflammation and tissue damage even in progressive MS. Elucidating the precise mechanisms of tissue damage in relapsing-remitting MS and establishing the relative role of these processes in irreversible tissue damages in progressive MS are key aims of ongoing MS research. Hopefully this will lead to the development of treatments that can halt disease progression in MS and, eventually, to the development of regenerative treatment strategies.


16

Symposia

SYMP7-2

SYMP7-3

INJECTABLE FIRST-LINE THERAPIES IN MS (INF & GA) – DO THEY STILL HAVE A PLACE IN MS THERAPY?

CURRENT MS THERAPIES

Ludwig Kappos

Since the introduction of interferon-ß treatment for relapsing remitting MS some 20 years ago, clinical development of drugs for this disease has been remarkably successful. The second generation of disease modifying drugs entered the therapeutic arena in 2006 with the approval of natalizumab. 2011 the first oral agant, fingolimod, was introduced and the past 2 years have witnessed market access of 2 further oral medications, teriflunomide and dimethylfumarate as well as the monoclonal antibody alemtuzumab. Most recently, pegylated interferon-ß1a joined the group of injectables. Imminently emerging is the B-cell depleting monoclonal antibody ocrelizumab. Availability of this broadened repertoire has generated questions regarding the positioning of each drug and development of algorithms that taking into account regulatory constraints and local accessibility allows optimal management of patients. Individualized treatment approaches are governed by a multitude of factors. These include prognostic factors, disease and treatment history stage and activity, risk factors and perception, patient preferences amongst others. This will be reviewed in light of published pivotal trial data and post-approval experience. Disclosure: not received

Basel, Switzerland

Since the early nineties IFN & GA have been the mainstay of treatment for RR MS and CIS. Frequently dosed IFN beta is also used - with less and over time decreasing enthusiasm - in SP MS for patients who would not suffer from or tolerate the typical IFN associated flue like symptoms and did not qualify for intensive immuno suppression or experimental therapies. In the last 3 years, with the approval of more convenient oral drugs with manageable risks and at least equal or higher efficacy their role is being reconsidered along the lines of short-term and long term efficacy, convenience and risks and also costs. Direct head to head Phase III comparative trials against IFN exist in RR MS for Fingolimod (1y), Alemtuzumab (2y) and Daclizumab (>2 y) and have shown superiority. An unblinded parallel group comparison (2y) of DMF with GA did also indicate superiority. A small Phase II comparison of teriflunomide with high dose/frequency IFNb 1a failed to show superiority. Observational studies in patients switching therapies from IFN & GA to orals or more recently aproved injectables – per se more prone to methodological flows - also unisono report improvements. The place of IFNs & GA in the next years will be determined by 3 main factors: 1. Choice of treatment strategy: treatment escalation vs induction with or without maintenance treatment 2. Longer term experience with the respective risks of the new treatments 3. Better definition of specifically good responders to IFN & GA Comprehensive phenotypical characterization of large cohorts of patients by high-end clinical, imaging and laboratory measures and their inclusion in prospective observational studies must inform the development of personalized evidence based treatment algorithms. Disclosure: No personal compensation. Institution (University Hospital Basel) received in the last 3 years and used exclusively for research support: steering committee, advisory board and consultancy fees from Actelion, Addex, Bayer Health Care, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB, Xenoport; speaker fees from Bayer Health Care, Biogen, Merck, Novartis, Sanofi-Aventis, Teva; support of educational activities from Bayer Health Care, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, Teva; royalties from Neurostatus Systems GmbH; grants from Bayer Health Care, Biogen, Merck, Novartis, Roche, Swiss MS Society, the Swiss National Research Foundation, the European Union, and Roche Research Foundations

Hans-Peter Hartung

Düsseldorf, Germany


Symposia 17

SYMP7-4 THE FUTURE OF MS THERAPIES – HOW SOON, HOW FAR? HOW EFFECTIVE, HOW SAFE? Catherine Lubetzki Paris, France

Current approved multiple sclerosis disease modifying therapies, either immuno-modulators or immunosuppressants for first-line (interferon, glatiramer acetate, dimethylfumarate, teriflunomide) or second-line (mitoxantrone, natalizumab, fingolimod, alemtuzumab) therapy have considerably changed MS management. With different efficacy depending on the drug and the patient being or not responder, as well as with different safety profiles, these therapies reduce relapse rate, due to their impact, through different mechanisms, on the inflammatory component of the disease. However, despite a profound influence on the adaptive immune system, these drugs have not yet demonstrated a clear effect on accumulation of disability, which relates to irreversible neuronal/axonal damage and loss. This suggests that, in addition to an (early) immune-driven tissue damage that can be targeted through immuno-therapies and might influence relapse-related irreversible disability, a (late?) degenerative process, partially independent of active inflammation, takes place during the disease course, resulting in disability progression without relapses. Protecting or preventing this inflammationdependent and/or independent neuronal/axonal damage is currently the major challenge of MS therapeutic strategy. Concerning the inflammatory-driven tissue damage, several immuno-therapy trials are ongoing or have been recently completed (notably with laquinimod and the monoclonal antibodies daclizumab and ocrelizumab). Other strategies are still in their early phase of development, with the goal of improving the efficacy/safety balance. The optimal chronology of treatment (early aggressive treatment or secondary escalation for patients in therapeutic failure is still debated, and in this context, identifying factors that predict disease severity (which might result in early aggressive treatment) are crucially needed. Concerning non-acute, inflammation-independent tissue damage, several therapeutic avenues are actively studied. Many preclinical or early clinical studies are addressing neuroprotection (evaluating different compounds, among them ibudilast, phenytoin, amiloride, EPO, biotin…). Other preclinical strategies aim at reducing axonal degeneration through increased remyelination. Different remyelinating strategies are currently evaluated, either exogenous repair strategies through grafts (with different cell types, notably induced pluripotent stem cells) or strategies promoting endogenous myelin repair. For this latter strategy, several compounds have emerged recently, among them analogs of retinoic acid, olesoxime, antimuscarinic compounds …) which are still in their early phase of development or still in a preclinical phase. The anti-Lingo monoclonal antibody phase 2 studies (one study recently completed in patients with a first episode of optic neuritis and the other one still ongoing on relapsing remitting MS) are aimed at favouring

remyelination through accelerated oligodendrocyte maturation. The different questions concerning these future therapies: "How soon or how far, how effective and how safe?" have therefore no easy answer, but will ultimately depend on the type of strategy (immune versus neuroprotective strategy). Surrogate markers of the inflammatory component of the disease are available, resulting in easier development of therapeutic trials of immunotherapies. In contrast, availability of markers of neuroprotection (or damage) and remyelination (or persisiting demyelination) is still an unmet need, that further increases the complexity of designing therapeutic trials for strategies aimed at preventing neuro-degeneration and associated disability accumulation. Disclosure: not received


18

Symposia

Infections of the central nervous system: recent advances SYMP8-1 NEW DIAGNOSTIC TECHNIQUES IN CENTRAL NERVOUS SYSTEM INFECTIONS Israel Steiner

Petach Tikvah, Israel

Central nervous system infections present a diagnostic and therapeutic challenge. High index of suspicion is required to enable the early introduction of antimicrobial medication to reduce or prevent permanent neurological deficit. The confirmation of an infectious condition or a process that mimics infection is based on current histopathological, immunological and molecular technology. Available tools should be recognized and employed. The neurologist faced with such cases should also be aware of the disadvantages and pitfalls of these technologies. The talk will focus on the current diagnostic techniques, uses, abuses and limitations. Disclosure: not received

SYMP8-2 NEW ANTIMICROBIAL THERAPEUTICS IN COMMUNITY ACQUIRED AND NOSOCOMIAL MENINGITIS AND BRAIN ABSCESS Diederik van de Beek

Amsterdam, The Netherlands

Early antibiotic treatment improves outcome of patients with central nervous system infections, but the effectiveness of widely available antibiotics is threatened by global emergence of multidrug-resistant bacteria. New antibiotics could have a role in these circumstances, but clinical data to support this notion are scarce. Administration of empirical antibiotics for patients with bacterial meningitis and brain abscess should be based on local epidemiology, the patient's age, and the presence of specific underlying diseases or risk factors. Once a bacterial pathogen has been identified on Gram stain, or isolated and in-vitro susceptibility testing done, antibiotic therapy can be modified further for optimum treatment. Therefore, in patients with brain abscess, stereotactic aspiration of the purulent centre should be performed for the purposes of diagnosis and decompression unless it is contraindicated because of the suspected organism type or the patient's clinical condition. Optimisation of the delivery and effectiveness of antibiotics are two key therapeutic challenges in central nervous system infections. Penetration across the blood–brain barrier is important for successful treatment and depends on the amount of disruption of the barrier's integrity by inflammation, and the size, charge, lipophilicity, proteinbinding ability, and interaction with efflux pumps of the antibiotic. However, clinical efficacy also depends on the antibiotic cerebrospinal fluid concentration and its bactericidal activity against causative bacteria. Antibiotics need enough time to kill all the bacteria and prevent disease recurrence, but the timescale of this process varies widely and depends on the causative bacteria, disease severity, and antimicrobial agent used. The increasing prevalence of central nervous system infections caused by resistant bacteria has led to the consideration of new antimicrobial agents for therapy, although data describing their role are generally limited to extrapolations from experimental animal models and case reports. During this lecture, the options of new and old antimicrobial therapeutics will be discussed, highlighting the results of sparsely available clinical randomized studies in this area. Disclosure: Nothing to disclose.


Symposia 19

SYMP8-3 ADJUNCTIVE THERAPIES IN LIFETHREATENING CNS INFECTIONS Erich Schmutzhard Innsbruck, Austria

Acute bacterial meningitis, acute viral encephalitis, brain abscesses, acute protozoal diseases like cerebral malaria and acute helminthic diseases like eosinophilic meningoencephalitis due to Gnathostoma spinigerum or status epilepticus in neurocysticercosis may evolve into a potentially life-threatening course. Such a life-threatening course can be prevented by early diagnosis and earliest possible initiation of the appropriate antimicrobial chemotherapy, frequently necessitating adjunctive therapeutic measures to counteract secondary brain damage due to such an acute CNS infection, accompanying sepsis syndrome or secondary lesions due to complications like vasculopathy, sinus thrombosis, hydrocephalus/ pyocephalus, diffuse brain edema, cerebritis or abscess formation. Systemic manifestations of life-threatening viral, bacterial or protozoal infection may add to secondary brain damage, e.g. septic shock, hypo-, hyperventilation, hypo-, hypercapnia, blood sugar derangement, lactic acidosis, all of them need to be recognized, treated and - even better prevented. Acute bacterial meningitis being a disease of decreasing prevalence all over the world, will become eventually in the near future a rare disease, thus rendering its timely diagnosis even more difficult. Quickest possible initiation of antibiotic therapy is essential, at the best – if the bacterial pathogen is not yet known –the first dose of a third generation cephalosporin should be given - in a motor pump - over 2-4 hours. Dexamethasone should only be given – prior to the first antibiotic therapeutic dosage – if the patient most likely has acquired his/her acute bacterial meningitis in Europe and is older than 55 years of age, i.e. most likely suffers from pneumococcal meningitis. Dexamethasone is ineffective in children and in resource poor regions. The presence of decreased CSF/serum glucose ratio and increased cerebrospinal fluid lactate supports the likelihood of acute bacterial meningitis. The application of invasive neurointensive care measures, as external ventricular drainage, ICP-monitoring and CPP monitoring has been shown to decrease mortality from 30% to 10% in initially comatose patients (GCS 8). As in general critical care medicine, blood sugar management has been shown to be of crucial importance, the same applies to patients with acute bacterial meningitis, both hypo- and hyperglycemia need to be avoided. Continuous glycerol adjuvant therapy in adults has been shown to be detrimental, increasing overall mortality by almost 20%. Best possible management of accompanying septic shock requires early admission to a (neuro-)critical care unit. However, it needs to be stressed that the performance of adjunctive therapies in bacterial meningitis largely depends on the availability of neurocritical care medicine and, thus, on the local/regional circumstances. Aggressive therapeutic hypothermia in a non-sufficiently equipped environment might be deleterious

in patients with acute bacterial meningitis. Acute viral meningoencephalitis: Every patient with suspected viral meningoencephalitis should be given the benefit of earliest possible acyclovir therapy. Patients with acute viral meningoencephalitis need to be admitted to a neurointensive care unit, the major reasons are brain edema, anticonvulsive therapy in status epilepticus, the appropriate analgesia and sedation and optimal temperature management. In selected cases decompressive craniectomy in case of increased intracranial pressure may be lifesaving. It should be stressed that the knowledge of the ever changing epidemiology needs to be constantly updated and encephalitis may be considered as a sentinel for emerging infections. The neurological presentation is spectacular enough to be a good marker for the emergence of an agent in a new geographical area. This demonstrate the importance of close surveillance as, when implanted, these diseases are difficult to eradicate (e. g. tick borne encephalitis, rabies, West-Nile-virus-encephalitis, etc.). Very recently it has been shown that herpes simplex virus, even Varicella zoster virus, may trigger autoimmune encephalitides. Cerebral malaria: Per year more than 600,000 people still die from cerebral malaria worldwide. The cerebral malaria is preventable and curable and should be on the differential diagnostic agenda if a patient has a history of travelling to a malaria endemic country (in particular Sub-Saharan Africa) without having taking appropriate preventive measures. The diagnosis of cerebral malaria rests on history, the clinical syndrome of impairment of consciousness, severe prostration, epileptic seizures, focal neurological signs and symptoms, positive bloodsmear and fundoscopy showing the typical malaria retinopathy. The major pathophysiological basis for cerebral malaria is impairment of microcirculation and severe lesion of the endothelial cells of arterioles and capillaries. Every patient with suspected cerebral malaria needs to be started with the appropriate schizontozidal therapy, namely artesunate intravenously. Cerebral malaria is always part of a multiorgan malaria, thereby broad-based critical care measures are essential for survival. Dexamethasone has been shown to be deleterious in cerebral malaria, osmotherapy with mannitol is similarly contributing to increased morbidity and mortality. Every patient having survived a severe infection of the central nervous system, e. g. bacterial meningitis, viral encephalitis or cerebral malaria, needs an appropriate postacute management, including neurocognitive evaluation, audiometry and, if indicated, neuro-rehabilitation measures. Disclosure: No conflict of interest with respect to this topic.


20

Symposia

SYMP8-4 NEWS IN PREVENTION OF CNS INFECTIONS Timo Vesikari

Tampere, Finland

Successful control of meningococcal group C (MenC) outbreak in UK using a polysaccharide conjugate vaccine in 1999 was a major breakthrough and provided a model for prevention of meningococcal disease in general. The revised UK programme uses a trimmed back infant immunisation but with emphasis an adolescent immunisation to protect children through herd immunity. The same principle could be applied for use of MenACWY polysaccharide conjugate vaccines. Another major breakthrough is control MenA disease in the “meningitis belt” of sub-Saharan Africa using a monovalent MenA vaccine and mass vaccination of a target population of 315 million people. The most significant advance in the past years is development and licensure of two vaccines against MenB. A bivalent vaccine contains the subfamilies A and B of factor H binding protein (fHbp) produced as recombinants in E.coli. The vaccine was recently licensed in the USA as Trumenba® (Pfizer). Trumemba® is indicated for persons 10–25 years of age and given in a 3-dose series. A multicomponent vaccine 4cMenB was licensed in EU as Bexsero® (Novartis). The vaccine contains subfamily B of fHbp, Neisseria adhesin A, Neisseria heparin binding antigen NHBA and outer membrane vesicle OMV, and may be given to infants, children and adolescents. As the first country, the UK has recently adopted Bexsero into national immunisation programme. A truly universal meningitis vaccine would be a combination of the polysaccharide conjugate vaccine MenACWY and protein vaccine for MenB. Clinical trials of such MenABCWY vaccine are under way. Disclosure: Principal investigator of MenACWY conjugate vaccine trials of Novartis and GSK and MenB vaccine trials of Novartis and Pfizer. Received compensation for travel to present the results of the studies from each vaccine manufacturer.


Abstracts of the Joint Congress of European Neurology, 31 May-3 June, 2014, Istanbul, Turkey.

Abstracts from the 3rd World Congress on Vascular Access, WoCoVA 2014, 18-20 June 2014, Berlin, Germany.

Abstracts from the European Academy of Allergy and Clinical Immunology Congress, 7-11 June, 2014, Copenhagen, Denmark.

Abstracts of the Interventionell Radilogisches Olbert Symposium 2015, January 15-17, 2015, Berlin, Germany.

Abstracts of the 12th European Society for Pediatric Dermatology (ESPD) Congress, 12-14 June, 2014, Kiel, Germany.

European Academy of Neurology: The first steps.

Abstracts of the Annual European Congress of Rheumatology EULAR. June 12-15, 2013. Madrid, Spain.

Abstracts of the XXIV European Congress of Perinatal Medicine, June 4-7, 2014, Florence, Italy.

40th FEBS Congress, The Biochemical Basis of Life, Berlin, Germany, July 4-9, 2015.

Abstracts of the Joint Congress of European Neurology, May 28, 2014, Istanbul, Turkey.

Abstracts of the 11th European Congress on Epileptology, 29 June - 3 July, 2014, Stockholm, Sweden.

XXV Nordic-Baltic Congress of Cardiology. Tallinn, Estonia, June 4-6, 2015: Abstracts.

Drug addiction and AIDS: highlights of the 1st European Congress.

2015 american transplant congress abstracts.

Abstracts of the XXV Congress of the International Society on Thrombosis and Haemostasis, June 20-25, 2015.

Abstracts of the 21st International Congress of the European Association for Endoscopic Surgery (EAES), 19-22 June 2013, Vienna, Austria.

European Cancer Congress 2015.

Abstracts of the 10th Annual Congress of the European Cardiac Arrhythmia Society, March 23-25, 2014, Munich, Germany.

Abstracts of papers presented at the 39th European Organization for Caries Research (ORCA) Congress. Helsinki, June 24-28, 1992.

Abstracts of the Safe States 2015 Annual Meeting, April 29th–May 1st, 2015, Atlanta, GA.

The 50th Congress of the European Society for Surgical Research. June 10-13, 2015, Liverpool, United Kingdom: Abstract.

Abstracts of the 11th Annual Congress of the European Cardiac Arrhythmia Society, April 19-21, 2015, Paris, France.

[American Academy of Neurology, Washington, 18-25 April 2015].

22nd European Congress on Obesity (ECO2015), Prague, Czech Republic, May 6-9, 2015: Abstracts.