European Journal of Neurology 2014, 21 (Suppl. 1), 1–17

Symposia Saturday, 31 May

Symp1-2

Post-stroke dementia

Amyloid, ischemia and inflammation in post-stroke dementia V. Hachinski

London, Canada

Symp1-1 Incidence and development of cognitive impairment after stroke D. Leys

Lille, France

Objectives: To determine the incidence of cognitive impairment after stroke and the underlying mechanisms. Methods: Literature review. Results: Dementia is one of the major causes of dependency in stroke patients. The prevalence of dementia in stroke patients is likely to increase in the future. The risk of dementia is doubled after stroke. Patient-related variables associated with an increased risk of dementia after stroke are increasing age, low education level, dependency before stroke, pre-stroke cognitive decline without dementia, diabetes mellitus, atrial fibrillation, myocardial infarction, epileptic seizures, sepsis, cardiac arrhythmias, congestive heart failure, silent cerebral infarcts, global and medial temporal lobe atrophy, and white matter changes. Strokerelated variables associated with an increased risk of dementia after stroke are severity, volume, location, and recurrence of stroke. Dementia in stroke patients may be due to vascular lesions, Alzheimer pathology, or summation of these lesions. The cause of dementia after stroke varies between studies according to the mean age of patients, ethnicity, criteria used, and duration of follow-up after stroke. In Western populations, the proportion of patients with presumed Alzheimer’s disease amongst those with dementia after stroke varies between 19% and 61%. Stroke patients with dementia have higher mortality rates, and are more often functionally impaired. Conclusions: Post-stroke cognitive decline is frequent and can be due to both Alzheimer pathology and stroke lesions. Disclosure: Nothing to disclose

Objectives: To discuss one of the mechanisms of cognitive deterioration after stroke. Methods: The experimental method involves a rat model of Alzheimer’s disease (amyloid deposition) and cerebral infarction.The clinical methods are the use of ligands for amyloid deposition and microglial activation in humans by positron emission tomography. Results: We found that an infarct in the presence of amyloid experimentally was larger and it grew as opposed to it being smaller and shrinking in control animals. Similarly inflammation was greater in the animals with amyloid in the brain and it flared, as opposed to settling down as it did in control animals. Treatment with anti-inflammatory and antioxidant agents resulted in the mitigation of the histological changes and behavioral consequences. Preliminary clinical studies suggest that there is a better correlation between the cortical amyloid deposition and the 6 month cognitive status than with the initial cognitive status and that there is a better correlation between white matter inflammation and cognitive status in 6 months than there is with the initial cognitive status. Conclusions: The interaction between ischemia, amyloid and inflammation offers an opportunity for a treatable mechanism to prevent or minimize post-stroke cognitive impairment. Disclosure: Nothing to disclose

© 2014 EFNS

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Symposia

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Symp1-4

Imaging morphologic, metabolic and molecular changes responsible for poststroke dementia

Therapeutic concepts to prevent or ameliorate cognitive impairment after stroke

W.-D. Heiss

D. Inzitari

Aging leads to a small loss of cortical neurons, but to a significant reduction of synapses, dendrites and myelinated fibers. These age-related changes may cause some cognitive impairment, brain atrophy and frontally accentuated diffuse decrease in metabolism. In pathological disorders leading to dementia, most frequently degenerative Alzheimer’s disease, cerebrovascular disease or a combination of both, the changes are more severe, affect predominantly specific regions and result in significant loss of neurons. The differential diagnosis of these disorders is based on symptoms of cognitive and memory impairment and is supported by results of neuropsychological tests and of imaging. Whereas computed tomography and magnetic resonance imaging are able to detect morphologic lesions, these modalities cannot determine functional consequences of the underlying pathologies. Positron emission tomography allows imaging of the localized and/or diffuse metabolic disturbances responsible for cognitive impairment and dementia, and is effective in differentiating vascular from degenerative dementia, as Alzheimer’s disease. It can also detect inflammatory changes and their interaction with amyloid depositions for the development of mixed dementias after stroke. Imaging of neurotransmitters and of synaptic function additionally yields insight into disease specific pathophysiology. Combined PET-studies of amyloid deposition and microglia activation as an indicator of neuroinflammation indicate that mainly cortical amyloid deposition, which is correlated with gray matter inflammation, predicts post-stroke cognitive impairment. In subcortical white matter amyloid deposition does not play a significant role for cognitive impairment in contrast to inflammation. Modulation of inflammation and / or amyloid deposition might open a way for prevention of cognitive impairment after stroke. Disclosure: Nothing to disclose

Stroke is associated with a substantially increased risk of subsequent cognitive impairment or dementia. A number of pre-stroke factors may contribute to Post Stroke Cognitive Impairment (PSCI), including older age, prior cognitive dysfunctions, previous stroke, recent infections, and selective risk factors such as hypertension, diabetes and Apoe 4 allele. Acute phase complications such as fever, hyperglycemia or seizures were also reported to be associated with PSCI risk. Concurrent chronic small vessel disease changes including white matter changes, silent infarcts, or microbleeds may interact with the effect of acute infarct lesions. Following the multi-infarct concept, the factor most strongly associated with PSCI risk is likely stroke recurrence. Among patients with atrial fibrillation risk of dementia after stroke proved over twofold increased. Consequently the best prevention of PSCI is logically based on the best prevention of recurrent stroke. Successful reperfusion after ischemic stroke, and the best patients management during the acute phase, may be important aiming at preventing PSCI. Regarding PSCI prevention or treatment to be started after stroke, BP lowering or control of other risk factors may contribute by slowing progression of concurrent small vessel alterations. Studies are in progress investigating comprehensive and adherent control of risk factors. There are clues suggesting that motor rehabilitation, specific domains interventions (against aphasia, spatial neglect, executive or attention dysfunctions), as well as physical activity combined with aerobic exercise might help ameliorating cognitive performances in stroke patients. No selective drug was proven conclusively as effective on improving cognitive performance after stroke. Disclosure: Grants for research: Bayer Italy S.p.A.

Cologne, Germany

Florence, Italy

© 2014 EFNS European Journal of Neurology 21 (Suppl. 1), 1–17

Symposia

Status epilepticus

Symp2-2

Symp2-1

Pharmacotherapy: initial & established status epilepticus

Definitions, epidemiology & outcome

H.R. Cock

E. Trinka

Salzburg, Austria

Status epilepticus is one of the most common neurological emergencies. With an incidence rate of 20-60/100,000/year and its mortality of around 20% emergency management and effective treatments are needed. The definition of status epilepticus has varied over time and can be defined as “the failure of the mechanism responsible for seizure termination leading to continue seizure activity that midely to long-term consequences including neuronal death, neuronal injury and alterations of neuronal networks, depending on the type and duration of status epilepticus”. It is important to emphasise that the duration, when a seizure is most likely to be prolonged, depends on the type of status. There is current evidence that a generalized tonic-clonic seizure exceeding 2-3 minutes is likely to go on into status epilepticus. Thus, the definition of 5 minutes has been widely accepted to designate a condition as status epilepticus and treated as such with all available emergency measures. The causes of status epilepticus may be divided in the common, and the uncommon ones. In the developed countries of the industrial world cerebrovascular accidents, traumatic brain injury, intoxication and epilepsies are the most common causes. In the developing world infections are the prevailing cause of status. The uncommon causes deserve special attention, because identification of the causes and its proper causal treatment is important for prognosis of SE. Uncommon causes, such as autoimmune encephalitides and inflammatory diseases might respond well to immunosuppressant, while rare infections and metabolic disorders must follow another treatment strategy. Most treatment protocols worldwide follow a staged approach for generalized convulsive status epilepticus, which includes benzodiazepines as first line agents, followed by intravenous antiepileptic drugs (levetiracetam, valproic acid, phenytoin and lacosamide). If seizures persist patients should be further treated in the neurological intensive care unit. Due to the lack of randomized controlled trials at this stage, pure empirical treatment is the predominant method used. Barbiturates, benzodiazepines, propofol and ketamine are widely used with different enthusiasm of intensivists and neurologist. The outcome depends on the duration of status and its cause. The main negative predictors are old age, symptomatic etiology, long duration and deep coma. Several scores to predict the negative outcome are currently under clinical evaluation. Disclosure: E. Trinka has acted as a paid consultant to Eisai, Ever Neuropharma, Biogen Idec, Medtronics, Bial, Lundbeck, and UCB. He has received research funding from UCB, Biogen-Idec, Sanofi-Aventis, FWF, Jubiläumsfond der Österreichischen Nationalbank and Red Bull. He has received speakers honoraria from Bial, Eisai, GL Lannacher, Glaxo Smith Kline, Böhringer, Viropharma, Actavis, and UCB.

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London, United Kingdom

After over 2 decades of largely retrospective and small case series, (with the noteable exception of the Treiman study of 1998) a drive towards evidence based treatment of convulsive status epilepticus (CSE) has gained considerable momentum in the last few years. Whilst age and etiology remain the primary predictors of outcome, prompt control (within 1-2h) now established as an important predictor. There is also now good evidence and agreement that Midazolam (buccal, in and out of hospital) and Lorazepam (intravenous) should be used in preference to diazepam in initial status, and that for 2nd line agents, there are several efficacious alternatives. Speed and adequacy of treatment, which in turn may be reflected in familiarity with the drug, are probably more important than which drug is used on current evidence, although both valproate and levetiracetam are gaining favour over (fos)phenytoin. This is despite CSE being an unlicensed indication, but reflects ease of use, better side effect profiles and what looks like at least equivalent efficacy (Yasiry & Shorvon Metaanalysis, Figure 1; HC review Figure 2). A long awaited adequately powered randomized controlled trial (ESETT) to provide good quality comparative efficacy and safety data is now in the late stages of development, pending confirmation of funding. International guidelines on both sides of the Atlantic reflect current evidence, yet considerable variation in practice still exists both between and within countries. Lacosamide is also emerging as a possible alternative. Newer initiatives include technological advances making the possibility of rapid EEG in the emergency department tantilizingly close, and a proposal to consider earlier intubation and anaesthesia than is currently typical. Neuroprotection, beyond that directed at the etiology, remains a relatively distant prospect, and there is still considerable work to be done on how best to implement evidence based practice more widely. Disclosure: Dr Cock has received hospitality and/or honorarium from the manufacturers of all currently licensed AEDs. Full disclosed over the last 5 years is at http://www.whopaysthisdoctor.org/

© 2014 EFNS European Journal of Neurology 21 (Suppl. 1), 1–17

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Symposia

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Immunity & inflammation in status epilepticus

Refractory & super-refractory status epilepticus (ICU management)

M. Seeck

A. Rossetti

In recent years, an increasing number of auto-antibodies (AB) are detected in the CSF and serum of patients with new onset epilepsy. Some of these patients develop status epilepticus (AB-SE), convulsive or non-convulsive, necessitating intensive care. From several case reports and few small series it became evident that AB-SE is a severe but often reversible condition. However, the delay of treatment effect of immune-modulating drugs or plasmapheresis is variable, and we do not yet know the optimal treatment algorithm. If AB-SE has a paraneoplastic origin, outcome appears to be better if the tumor can be successfully treated. We will review most frequent clinical presentations related to distinct antibodies, as well as relevant diagnostic and therapeutic approaches. AB-SE is probably still under-diagnosed. Only increased awareness will shorten the still considerable delay to diagnosis, and ultimately to treatment, hopefully related to an overall better prognosis of AB-SE. Disclosure: During the last two years, Dr Seeck received consultant fees from UCB & EISAI.

Status epilepticus (SE) not responding to an initial treatment with benzodiazepines and one antiepileptic drug defines the condition of refractory status epilepticus (RSE); it occurs in about 1/3 of patients with SE, and is related to a high morbidity and mortality. While there is a wide consensus on attempting a prompt control of RSE, scarce evidence is available to support the choice of specific treatments and strategies. In particular, the delicate balance between the aim of aborting ongoing seizures on the one side, and the risk of treatment-related side-effects on the other, represents a very challenging issue. Of note, age and etiology are the major independent outcome SE predictors (which should always be actively addressed), while existing studies are controversial regarding the specific prognostic impact of SE treatment. Most expert guidelines recommend that RSE treatment strategies should be adapted to the clinical situation: in order to minimize complications, focal RSE without major consciousness impairment should be approached without coma induction, at least initially; conversely, a rapid escalation towards pharmacological coma and EEG-verified seizure control should be undertaken in generalized-convulsive forms. For this purpose, midazolam, propofol or barbiturates represent the most popular compounds. Should RSE continue despite this step, the so-called super-refractory SE may be managed with several additional treatments, such as other anesthetics, further antiepileptic drugs, immunomodulatory agents, ketogenic diet, or non-pharmacological approaches (e.g., electroconvulsive treatment, hypothermia). Prolonged SE treatment lasting for weeks or months may sometimes still result in a good functional outcome; therefore, it is mandatory not to stop SE treatment unless a clearly irreversible brain damage is proven. Awaiting well-designed studies of these conditions, it seems reasonable to tailor the therapeutic management to the underlying biological background of each patient. Disclosure: Nothing to disclose

Geneva, Switzerland

Lausanne, Switzerland

© 2014 EFNS European Journal of Neurology 21 (Suppl. 1), 1–17

Symposia

Peripheral neuropathies: present and future

Symp3-2

Symp3-1

P.A. van Doorn

Genetic neuropathies: chances for treatment R. Martini

Würzburg, Germany

Genetic neuropathies of Charcot-Marie-Tooth type 1 are presently not treatable. Previous studies from our laboratory have shown that in models for three distinct forms of Charcot-Marie-Tooth neuropathy, phagocytosing macrophages mediate demyelination and perturbation of axons. One important mediator is monocyte chemoattractant protein-1 (MCP-1; Ccl2) which is expressed by mutant Schwann cells. Another important cytokine is colonystimulating factor-1 (Csf-1), expressed by endoneurial fibroblasts and essential for macrophage-mediated demyelination and axonopathy. Based on these findings, we considered the possibility that attenuating macrophagerelated peripheral nerve inflammation could be a putative option to ameliorate disabling symptoms associated with CMT-1. As a first approach, we orally treated three distinct CMT-1 models with a novel and highly selective Csf-1receptor (Fms kinase) inhibitor (provided by Plexxikon Inc.), which was tested in a phase 1 clinical trial for the treatment of rheumatoid arthritis. In all models investigated, a high concentration of the inhibitor led to a robust decline of macrophages in the peripheral nerves, accompanied by an alleviation of demyelination, as revealed by electron microscopy and electrophysiological recordings. However, at the doses initially applied, a reversible and subclinical reduction of the compound muscle action potentials (CMAP) was also detectable. By step-wise reduction of the inhibitor concentration, we could preserve CMAP while still substantially attenuating macrophage numbers in nerves and spinal roots. Studies are now under way which focus on the pathological and clinical outcome of respective long-term treatments. In another approach, we injected human adipose derived mesenchymal stem cells (MSCs) isolated from lipoaspirate into tail veins of Cx32-deficient mice, a model for CMT-1X. Single injection of these immune modulatory xenografts caused macrophage attenuation and mild preservation of myelin. Future experiments are designed to optimize the treatment regime in order to receive an even more robust and persistent treatment effect in the mouse model. Our experiments demonstrate that attenuating phagocytic macrophages in peripheral nerves might be a promising chance for treatment of inherited neuropathies of the CMT-1 type. Disclosure: Supported by German Research Foundation (DFG, MA 1053/6-1); Plexxikon Inc. (USA) and CMT Association, USA. A. v. H was an ERASMUS student from the University of Antwerp, Belgium (local co-supervisor: Vincent Timmerman).

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Immune-mediated neuropathies: how to optimise treatment? Rotterdam, The Netherlands

Guillain-Barré syndrome (GBS) in most cases is a post infectious and potentially life-threatening heterogeneous disease. The main characteristics are rapidly progressive symmetrical weakness of the extremities and low or absent tendon reflexes. About a quarter of patients develops respiratory insufficiency, many patients have signs of autonomic dysfunction and pain. Prognostic models are now available that help to accurately predict the chance that an individual patient will require artificial ventilation, and to predict the probability to walk unaided after half a year. These simple models are ready to use, at or soon after hospital admission, and may help making important clinical decisions. Additional models are under construction. Treatment is with intravenous immunoglobulin (IVIg) or plasma exchange. Despite this treatment, the prognosis is still cumbersome in a substantial proportion of patients. Therefore new treatment trials have been started. About 10 percent of GBS patients will have a treatment related deterioration (TRF), requiring a repeated treatment course. Other patients initially diagnosed as GBS will turn out to have acute-onset chronic inflammatory demyelinating polyradiculoneuropathy (A-CIDP). This condition may indicate a switch to maintenance IVIg or to steroid treatment. For CIDP is has been shown that steroids, IVIg and plasma exchange are effective. Recent trials evaluated pulse high-dose steroid treatment in comparison with IVIg. Follow-up studies in CIDP found some factors related to the initial IVIg treatment response and to the requirement of long-term treatment. These studies may help to further optimise treatment in these immune-mediated neuropathies. Disclosure: Nothing to disclose

© 2014 EFNS European Journal of Neurology 21 (Suppl. 1), 1–17

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Symposia

Symp3-3 Amyloid neuropathies: treatment D. Adams

Kremlin-Bicêtre, France

Amyloid neuropathies (AN) are progressive and lifethreatening sensorymotor and autonomic neuropathy. As amyloidosis are systemic diseases, each newly diagnosed AN case should be screened also for cardiological and nephrological impairment but also for ocular manifestations in transthyretin FAP (TTR-FAP) or hematological involvement for Light-chain amyloidosis (AL-amyloidosis). Treatment of AN includes anti-amyloid therapy, symptomatic therapy (i.e. for sensorimotor and autonomic neuropathy, visceral involvement), and treatment of endstage organ failure (cardiac, renal). Anti-amyloid therapy: i) For TTR-FAP, it includes liver transplantation (LT) to remove the main source of variant TTR, TTR-kineticstabilizers (tafamidis, diflunisal) to stabilize the tetrameric TTR and inhibit release of amyloidogenic monomers. Indications for these treatments depend on the stage of the neuropathy, the variant TTR, the age of the patient and severity of organ involvement. Pacemaker implantation should be discussed in case of significant conduction disorder. Heart or kidney transplantation must be discussed in endstage cardiac or renal failure in stage 1 neuropathy. LT has better results in early onset (

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

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