Stichting Epilepsie Instellingen Nederland

Zwolle, Netherlands

Stichting Epilepsie Instellingen Nederland

Zwolle, Netherlands
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Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2007-1.2-3 | Award Amount: 9.09M | Year: 2008

We aim develop in-vivo imaging biomarker of multidrug transporter function as a generic tool for the prediction, diagnosis, monitoring and prognosis of major CNS diseases, as well as to provide support and guidance for therapeutic interventions. Multidrug transporters actively transport substrates (including multiple CNS drugs) against concentration gradients across the blood-brain barrier (BBB). Overactivity of these efflux transporters results in inadequate access of CNS drugs to their targets and hampers the build up of adequate tissue levels of these drugs in the brain, greatly limiting their therapeutic efficacy. As such, this transporter hypothesis of drug resistance is applicable to a broad range of CNS drugs and patients with a variety of CNS diseases who critically depend on these drugs. Efflux transporters may also influence brain elimination of A, the hallmark of Alzheimers disease (AD). Impaired multidrug transporter function with reduced clearance of A could lead to accumulation within the extracellular space, contributing to the pathogenesis of AD. We will determine the contribution of multidrug transporters to impaired brain uptake of drugs for the prediction of therapeutic responses, or the contribution of impaired transporter function to reduced clearance of toxic substances for the early in-vivo diagnosis of AD. Circumvention of pharmacoresistance, or increasing clearance, may involve inhibitors of multidrug transporters or sophisticated alternative therapies, but demonstration of overexpression or underactivity of transporter function is an essential and necessary first step. An in-vivo imaging biomarker of multidrug transporter function is essential for identifying altered transporter activity in individual patients. If a relation between overexpression and therapy resistance, or underactivity and AD, can be demonstrated, such a biomarker will provide the means for predicting treatment response, or early diagnosis, in individual patients.

Koppert M.,Stichting Epilepsie Instellingen Nederland | Kalitzin S.,Stichting Epilepsie Instellingen Nederland | Velis D.,Stichting Epilepsie Instellingen Nederland | Velis D.,University of Amsterdam | And 3 more authors.
International Journal of Neural Systems | Year: 2013

We aim to derive fully autonomous seizure suppression paradigms based on reactive control of neuronal dynamics. A previously derived computational model of seizure generation describing collective degrees of freedom and featuring bistable dynamics is used. A novel technique for real-time control of epileptogenicity is introduced. The reactive control reduces practically all seizures in the model. The study indicates which parameters provide the maximal seizure reduction with minimal intervention. An adaptive scheme is proposed that optimizes the stimulation parameters in nonstationary situations. © 2013 World Scientific Publishing Company.

Koppert M.,Stichting Epilepsie Instellingen Nederland | Kalitzin S.,Stichting Epilepsie Instellingen Nederland | Velis D.,Stichting Epilepsie Instellingen Nederland | Velis D.,University of Amsterdam | And 3 more authors.
International Journal of Neural Systems | Year: 2014

In this study, we investigate the correspondence between dynamic patterns of behavior in two types of computational models of neuronal activity. The first model type is the realistic neuronal model; the second model type is the phenomenological or analytical model. In the simplest model set-up of two interconnected units, we define a parameter space for both types of systems where their behavior is similar. Next we expand the analytical model to two sets of 90 fully interconnected units with some overlap, which can display multi-stable behavior. This system can be in three classes of states: (i) a class consisting of a single resting state, where all units of a set are in steady state, (ii) a class consisting of multiple preserving states, where subsets of the units of a set participate in limit cycle, and (iii) a class consisting of a single saturated state, where all units of a set are recruited in a global limit cycle. In the third and final part of the work, we demonstrate that phase synchronization of units can be detected by a single output unit. © 2014 World Scientific Publishing Company.

Koppert M.M.J.,Stichting Epilepsie Instellingen Nederland | Kalitzin S.,Stichting Epilepsie Instellingen Nederland | Kalitzin S.,University Utrecht | Lopes Da Silva F.H.,University of Amsterdam | And 2 more authors.
Journal of Neural Engineering | Year: 2011

In previous studies we showed that autonomous absence seizure generation and termination can be explained by realistic neuronal models eliciting bi-stable dynamics. In these models epileptic seizures are triggered either by external stimuli (reflex epilepsies) or by internal fluctuations. This scenario predicts exponential distributions of the duration of the seizures and of the inter-ictal intervals. These predictions were validated in rat models of absence epilepsy, as well as in a few human cases. Nonetheless, deviations from the predictions with respect to seizure duration distributions remained unexplained. The objective of the present work is to implement a simple but realistic computational model of a neuronal network including synaptic plasticity and ionic current dynamics and to explore the dynamics of the model with special emphasis on the distributions of seizure and inter-ictal period durations. We use as a basis our lumped model of cortical neuronal circuits. Here we introduce 'activity dependent' parameters, namely post-synaptic voltage-dependent plasticity, as well as a voltage-dependent hyperpolarization-activated current driven by slow and fast activation conductances. We examine the distributions of the durations of the seizure-like model activity and the normal activity, described respectively by the limit cycle and the steady state in the dynamics. We use a parametric γ-distribution fit as a quantifier. Our results show that autonomous, activity-dependent membrane processes can account for experimentally obtained statistical distributions of seizure durations, which were not explainable using the previous model. The activity-dependent membrane processes that display the strongest effect in accounting for these distributions are the hyperpolarization-dependent cationic (I h) current and the GABAa plastic dynamics. Plastic synapses (NMDA-type) in the interneuron population show only a minor effect. The inter-ictal statistics retain their consistency with the experimental data and the previous model. © 2011 IOP Publishing Ltd.

Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2011.1.1-2 | Award Amount: 7.84M | Year: 2011

The purpose of the project is to identify genome-based biomarkers for use in clinical practice to individualise treatment of epilepsy, and stratify patients for clinical trials, aiming to avoid chronicity, prevent relapse and reduce adverse drug reactions (ADRs). The need for improved treatments in epilepsy is undoubted. Epilepsy is affects 50,000,000 people of all ages worldwide. Epilepsy is serious, increasing morbidity across all aspects of life, including a high risk of premature mortality. Over 20 antiepileptic drugs (AEDs) are licenced for its treatment. Seizures can be effectively controlled by AEDs in ~70% of people. Control of seizures leads to risk reduction for most of consequences of epilepsy, improves quality of life, permits social re-integration and leads to direct economic benefits. However, in 30% of patients, currently-available AEDs do not control seizures recurrent seizures threaten life and impair its quality in these patients, and account for much of the 15.5 billion annual cost of epilepsy in the EU alone; there is currently no way to predict which patients will not respond to any or all AEDs; even in the 70% who do respond, only 47% respond to the first AED whilst the correct drug is being sought, risks from seizures continue we need to be able to predict the right drug for an individual from the outset; unrelated to responder status, AEDs can cause serious ADRs a biomarker exists for only one ADR; there is a clear need for novel means of discovery of new AEDs existing AEDs are anti-seizure drugs, not disease-modifying drugs. We will use genome-wide analyses, including next-generation sequencing, in large, well-phenotyped patient cohorts to identify genome-based biomarkers, to improve use of current AEDs and identify new therapy targets. SMEs, which are central to this project, will be able to take the data forward for development of clinical tests; data will also be invaluable for industry seeking to develop new treatments.

Van Houdt P.J.,Epilepsy Center Kempenhaeghe | Van Houdt P.J.,VU University Amsterdam | Ossenblok P.P.W.,Kempenhaeghe | Boon P.A.J.M.,Epilepsy Center Kempenhaeghe | And 4 more authors.
Human Brain Mapping | Year: 2010

EEG correlated functional MRI (EEG-fMRI) allows the delineation of the areas corresponding to spontaneous brain activity, such as epileptiform spikes or alpha rhythm. A major problem of fMRI analysis in general is that spurious correlations may occur because fMRI signals are not only correlated with the phenomena of interest, but also with physiological processes, like cardiac and respiratory functions. The aim of this study was to reduce the number of falsely detected activated areas by taking the variation in physiological functioning into account in the general linear model (GLM). We used the photoplethysmogram (PPG), since this signal is based on a linear combination of oxy- and deoxyhemoglobin in the arterial blood, which is also the basis of fMRI. We derived a regressor from the variation in pulse height (VIPH) of PPG and added this regressor to the GLM. When this regressor was used as predictor it appeared that VIPH explained a large part of the variance of fMRI signals acquired from five epilepsy patients and thirteen healthy volunteers. As a confounder VIPH reduced the number of activated voxels by 30% for the healthy volunteers, when studying the generators of the alpha rhythm. Although for the patients the number of activated voxels either decreased or increased, the identification of the epileptogenic zone was substantially enhanced in one out of five patients, whereas for the other patients the effects were smaller. In conclusion, applying VIPH as a confounder diminishes physiological noise and allows a more reliable interpretation of fMRI results. © 2009 Wiley-Liss, Inc.

PubMed | Kempenhaeghe, Stichting Epilepsie Instellingen Nederland and TU Eindhoven
Type: | Journal: Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology | Year: 2017

Diagnostic value and efficacy of re-interpretation of previous EEGs in 100 patients admitted to a tertiary epilepsy center with EEG results conflicting with the clinical diagnosis after the first visit.EEGs were reclassified. A matched control group was included to assess the efficiency of the re-interpretation process. Efficacy was assessed by questionnaires and costs as number of technician hours needed.In 85 patients the previous EEG conclusion was known. In 43 the conclusion was altered. In 23 the epileptic activity changed from positive to negative (17) or the reverse (6). In 15 the focus changed (7 originally classified as generalized epileptic activity). In 5 the syndrome changed. 57% of the re-interpretation group needed no extra EEG afterwards. 96% of the re-interpretations were considered useful by requesting and 72% by not involved neurologists. The average time per EEG technologist per patient was 8,81h in controls and 5,40 in the re-interpretation group.In 43 from the 85 patients (51%) re-interpretation of controversial EEGs led to a different opinion. The re-interpretations were useful and less time consuming, compared to new EEGs in controls.Re-interpretation of controversial EEGs is useful and cost effective.

Bos M.J.,Stichting Epilepsie Instellingen Nederland
Nederlands tijdschrift voor geneeskunde | Year: 2011

Behavioural episodes of staring in children are difficult to distinguish from epileptic seizures, especially in children with developmental disorders such as ADHD, autism spectrum disorders and intellectual disabilities. We discuss two patients with staring episodes who were using anti-epileptic drugs. In both patients, EEG with video monitoring showed that the staring was non-epileptic. The first is an 8-year-old boy, who developed severe motor problems and ataxia during treatment with valproate. His staring episodes were behavioural, caused by his intellectual disability, and the motor problems resolved after discontinuation of valproate. The second patient is a 10-year-old boy with known autism, ADHD and infantile seizures, who developed staring for which he was using valproate. Again, video-EEG monitoring during staring showed no abnormalities and in this case the staring was caused by his intellectual disability and autism. We discuss the differential diagnosis of staring episodes in children with developmental disorders and present the pitfalls of the diagnostic process.

Blad H.,Stichting Epilepsie Instellingen Nederland | Lamberts R.J.,Stichting Epilepsie Instellingen Nederland | Dijk J.G.V.,Leiden University | Thijs R.D.,Stichting Epilepsie Instellingen Nederland | Thijs R.D.,Leiden University
Neurology | Year: 2015

To describe the combination of tilt-induced vasovagal syncope (VVS) and psychogenic pseudosyncope (PPS) and aid its clinical recognition. Methods: We identified people with tilt-induced VVS/PPS from 2 tertiary syncope referral centers. For each case, 3 controls with tilt-induced VVS were selected at random from the same center. Clinical characteristics were compared between both groups adjusting for multiple comparisons. Results: Of 1,164 tilt-table tests, 23 (2%) resulted in VVS/PPS; these 23 cases were compared with 69 VVS controls. VVS and PPS coincided more often than chance would predict: 2% vs 0.6%, p < 0.001. Typical VVS prodromes and triggers were reported in all people with VVS/PPS and in controls with VVS. Attack frequency was significantly higher in the VVS/PPS (2 per month, range 0.1-60) than in the VVS group (0.25 per month, range 0.02-4; p < 0.001). Delayed recovery of consciousness was more frequently reported in the VVS/PPS group (likelihood ratio [+LR] 8.14, 95% confidence interval [CI] 3.94-16.84), as well as episodes without prodromes (+LR 5.57, 95%CI 2.53-12.26), atypical triggers (+LR 5.00, 95%CI 2.04-12.24), eye closure (+LR 3.75, 95%CI 1.68-8.35), and apparent loss of consciousness > 1 minute (+LR 2.86, 95% CI 1.98-4.13). Conclusions: VVS/PPS presents with a complex phenotype. High attack frequency, delayed recovery of consciousness, apparent loss of consciousness > 1 minute, ictal eye closure, atypical triggers, and the absence of prodromes may serve as indicators that PPS coincides with VVS. © 2015 American Academy of Neurology.

PubMed | University Utrecht and Stichting Epilepsie Instellingen Nederland
Type: Journal Article | Journal: Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology | Year: 2017

To detect determinants for photoparoxysmal EEG response (PPR) in SCN1A-related Dravet syndrome (DS).Data were studied from nationwide medical histories and EEGs of DS-patients (n=53; 31 males, age 2-19years). Detailed questionnaires on visual stimuli were completed by parents (n=49).PPR was found in 22 patients (42%; median age 1.25yr), and repeatedly in 17%. PPR (17% of 249 intermittent photic stimulation (IPS)-EEGs) occurred more often with optimal IPS protocols (OR 2.11 [95%CI 1.09-4.13]) and in EEGs showing spontaneous epileptiform abnormalities (OR 5.08 [95%CI 2.05-12.55]). PPR-positive patients tended to be younger at first (p=0.072) and second seizure (p=0.049), showed severe intellectual disability (p=0.042), and had more often spontaneous occipital epileptiform abnormalities (p<0.001). Clinical sensitivity was reported in medical files in 22% of patients and by parents in 43% (self-induction 24%). Clinical or EEG proven visual sensitivity was detected in 65% of cases.Sensitivity to visual stimuli is very common in DS and more often noticed by parents than confirmed by EEG. Detection of PPR improves with repetitive tests using accurate IPS protocols.Photosensitivity is an important feature in DS and seems to be a marker of the severity of the disorder. Therefore repeated standardized IPS should be encouraged.

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