The overall aim of our research projects is to improve quality of life in all epilepsy patients sustainably. In this regard we combine clinical, experimental and translational research with high-quality patient care. The network Epilepsy-Center Berlin-Brandenburg comprises the Department of Epileptology and the Institute of Diagnosis of Epilepsy at the Evangelisches Krankenhaus Königin Elisabeth Herzberge, the Epilepsy-Clinic Tabor in Bernau and the Clinical and Experimental Epilepsy Group at the Department of Neurology at the Charité – Universitätsmedizin Berlin. This network structure is an ideal prequisite to realise our research aims and to cooperate with other Charité-based, national and international neuroscience research groups. The different areas of our research are supported either directly or on the basis of grants by the “Friedrich von Bodelschwingh Endowed Professorship for Epileptology”, Deutsche Forschungsgemeinschaft, Stiftung Charité and Volkswagen-Stiftung, and by various industry cooperations.
Our clinical research projects concentrate on retrospective, cross-sectional and prospective longitudinal epidemiological studies on epileptic seizures and epilepsy. Beyond data on seizure outcome, parameters on quality of life and other social aspects are assessed. Using an interventional approach, one of our projects analyses efficacy and safety of deep brain stimulation in patients with difficult-to-treat epilepsies.
Epilepsy and haedache
We interview patients with epilepsy regarding additional interictal and/or periictal headache. In addition, we explore risk factors for headache in epilepsy patients. First results indicate that interictal headache and in particular migraine are not more frequent in patients with epilepsy compared to the general population challenging the concept of cormorbidity of these two conditions.
Epilepsy and alcohol, nicotine and illicit drugs
In this cross-sectional study we investigate frequency and amount of alcohol, nicotine and illicit drug consumption in epilepsy patients. We address the question whether alcohol consumption increases the risk for prompt occurrence of epileptic seizures in this population. Furthermore, we analyse how physicians advise their patients on use of alcohol.
Biological sex and sociocultural gender differences in patients with epilepsy
In collaboration with the Institute of Gender in Medicine at the Charité – Universitätsmedizin Berlin, we investigate differences in seizure type and frequency, epilepsy syndrome, aetiology, kind and dose of antiepileptic medication, and potential adverse events in men and women with epilepsy. Another focus is gender-dependent perception of and coping with the chronic condition. Surprisingly, there are large deficits in research on these aspects of epilepsy so far.
Long-term outcome in idiopathic generalised epilepsies
The former director of the Department of Neurology at the Free University of Berlin, Prof. Dr. Dieter Janz, established a large archive of charts of patients suffering from all subtypes of idiopathic generalised epilepsy, beginning in the mid-50ies of the last century. Based on this archive, we assess prognosis in terms of seizure freedom, prescription of antiepileptic drugs and social aspects in patients with absence epilepsies, juvenile myoclonic epilepsy and epilepsy with grand mal on awakening, all lasting more than 20 years. In all three subtypes, patients included into the studies have a mean duration of epilepsy of 40 to 45 years. First results indicate that the majority of patients has been free of seizures for at least 5 years prior to the interview.
Outcome in new-onset seizures and epilepsy
In this study, we examine the further course of disease in patients with new-onset acute-symptomatic and unprovoked epileptic seizures as well as with new-onset epilepsies for the next 1 to 3 years. The study population consists of subjects treated with first seizures at the Department of Neurology at the Charité – Universitätsmedizin Berlin. Using a standardised questionnaire, patients are interviewed with respect to seizure recurrence, antiepileptic medication, potential side-effects and social aspects. This retrospective analysis is a pilot study for a prospective register of patients with new-onset seizures and epilepsies in Berlin and Brandenburg, aiming for a follow-up of at least 15 to 20 years.
Deep brain stimulation
Collaboration Project with the Department of Stereotactic Neurosurgery, University Hospital Magdeburg
Patients with pharmacologically intractable epilepsy who do not qualify for resective epilepsy surgery – due to bilateral seizure foci or overlapping of epileptogenic and eloquent brain structures – may benefit from electrical stimulation of cortical or subcortical neuronal networks enhancing inhibitory mechanisms. A recent randomised controlled trial (SANTE trial) demonstrated that electrical stimulation of the anterior thalamus results in seizure freedom in 10 to 15% of patients for at least 6 months and in a significant reduction of seizure frequency in temporal lobe epilepsy in particular. In a collaboration project with the Department of Stereotactic Neurosurgery, University Hospital Magdeburg, we investigate antiepileptic efficacy and tolerability of electrical stimulation of the nucleus accumbens in addition to the anterior thalamus. Apart from assessment of clinical data, we analyse local field potentials from the above mentioned brain structures with and without concurrent electrical stimulation in order to improve our pathophysiological understanding of the underlying neurobiological mechanisms.
Experimental and translational research
Our experimental research projects comprise in vitro analyses in brain slices and in vivo studies in whole animals (rodents). Both model systems focus on unsolved problems in clinical practice regarding pathophysiological understanding of epilepsies and search for new therapeutic approaches. Results of our experimental findings aim for direct or indirect translation into patient care.
Intrinsic optical signals (in vitro): Analysis of onset and propagation of epileptic activity
In brain slices of rats and humans (specimen from resective epilepsy surgery), we deploy optical methods in addition to electrophysiological measurements in order to provide a better understanding of pathophysiological mechanisms of ictogenesis (i.e. generation of seizures). By use of intrinsic opical signals, i.e. activity-dependent alterations of optical properties of brain tissue, onset and propagation of epileptic activity can be visualised and analysed subsequently. In previous works, we were able to demonstrate significant differences in epileptic activity in juvenile or senile neuronal tissue and during epileptogenesis following status epilepticus. Furthermore, we currently assess epileptiform discharges and seizure patterns in brain slices of chronic epileptic animals by means of high-resolution voltage sensitive dye imaging.
Deep brain stimulation (in vivo)
Based on the model system of electrically induced self-sustaining status epilepticus, we developed an approach to induce single limbic epileptic seizures in naïve and chronically epileptic rats by 20 Hz stimulation of the perforant path for 5 sec. Using this methodological approach, pharmacological and non-pharmacological treatments can be tested in naïve animals first (“screening”) and, if successful, afterwards may be translated to the chronic condition characterised by spontaneous seizures. Using this new technique, we currently assess various parameters of deep brain stimulation (DBS) in well-defined brain areas. Beyond the direct anti-seizure effect, we analyse DBS-mediated alterations of excitation and inhibition in mesio-temporal structures working with the paired-pulse paradigm. Stimulation sites and parameters that are successful in animal models, may be translated to neurostimulation in patients with intractable epilepsy.
Novel treatments in status epilepticus (in vivo)
We analyse the anticonvulsant properties of pharmacological and non- pharmacological treatment approaches using the model system of self-sustaining status epilepticus. At an early stage, we were able to demonstrate the strong anticonvulsant effect of the anaesthetic propofol, but also that of the loop diuretic furosemide. Furthermore, we investigate the impact of various degrees of hypothermia on status epilepticus and thus collected experimental data for clinical use of cooling in patients with refractory status epilepticus.
Pathophysiology and preventive approaches in epileptogenesis (in vivo)
The current concept in the „treatment“ of epilepsy is prevention of further seizures. Formally, this is a secondary prophylaxis. So far, epilepsy itself cannot be treated pharmacologically, the only causal therapeutic approach is surgical removal of the seizure focus. The aim of this project is to prevent development or at least to decrease the extent of epilepsy following acquired brain lesions. However, the prerequisite for this is a better pathophysiological understanding of epileptogenesis (i.e. the development of epilepsy). Many drugs that are given to prevent further seizures have been tested regarding their antiepileptogenic properties, but all failed to prove efficacy. A research grant from the Deutsche Forschungsgemeinschaft enables us to investigate antiepileptogenic effects of hypothermia applied subsequent to status epilepticus.
Cellular and network mechanisms of cerebral excitability (in vitro)
Ion channel proteins are decisive for generation and propagation of epileptic activity. Ion channels are membrane proteins that transport charged compounds between the intracellular and the extracellular compartments and thus majorly contribute to signal conduction and excitability of neurons. Pharmacological impact on ion channel activity may suppress epileptic seizures, and is currently one out of many mechanisms in the treatment of epilepsy. To improve understanding of the mechanisms involved and thus to develop new treatment approaches, we study electric properties of single cell and neuronal networks by use of high-resolution electrophysiological methods (patch-clamp technique). In this regard, we apply specific pharmaceutical substances that have the capability to interfere with the activity of well-defined proteins. We work on brain slices of rats and mouse models in which single ion channel proteins are knocked out or altered regarding their function. By knocking out a specific subunit of the potassium channel, we were able to demonstrate that, in contrast to all other subunits, this is not involved in epileptogenesis, but that it enhances inhibitory neuronal processes. Currently, we investigate if knock-out of the potassium channel subunit also has protective properties in chronic epilepsy.
- Prof. Dr. Douglas Coulter (Children’s Hospital of Philadelphia, USA)
- Prof. Dr. Uwe Heinemann (Institut für Neurophysiologie, Charité, Berlin)
- Prof. Dr. Thomas Jentsch (Max Delbrück Center for Molecular Medicine, Berlin-Buch)
- Dr. Julia Matzen, Dr. Friedhelm Schmitt (Klinik für Neurologie, Universität Magdeburg)
- Dr. Lars Büntjen, Prof. Dr. Jürgen Voges (Klinik für Stereotaktische Neurochirurgie, Universität Magdeburg)
- Dr. Sabine Oertelt-Prigione (Institut für Geschlechterforschung in der Medizin, Charité – Universitätsmedizin Berlin)
- Prof. Dr. Michael Sperling (Jefferson Comprehensive Epilepsy Center, Thomas Jefferson University, Philadelphia, USA)
- Prof. Dr. Matthew Walker (Institute of Neurology, University College London, UK)