(Coordination: Wolfgang Löscher)  

Epilepsies belong to the most frequently occurring illnesses of the brain and are characterised by spontaneous, recurring occurrence of convulsive or non-convulsive epileptic seizures (paroxysms). Frequently in addition psychiatric disturbances such as fear, depression or psychoses and learning and memory defects occur, which can be a result of typical neurodegenerative changes in the limbic system of some types of epilepsy. The causes of epilepsies are varied and are only partly understood. A number of familiar forms of idiopathic epilepsies derive for example as a result of ionic channel changes. Further CNS- illnesses with paroxysmal (occurring in attacks) symptoms are myoclonus, paroxysmal headache syndromes such as migraine, restless leg syndrome, paroxysmal dystonia, paroxysmal dizziness as well as ionic channel diseases with episodically occurring disturbances in muscle excitation or nervous system excitation such as episodic ataxia, myotonia and paroxysmal lameness.  

 

The ZSN focus “Epilepsy and other paroxysmal disturbances: pathophysiology and new therapeutic approaches” was formed to promote the cooperation and linking-up of those neuroscientific groups in Hannover working on this theme. In order to intensify this focus the Bethel Epilepsy Centre (Director Dr. Alois Ebner), which has many years of experience in conservative and operative treatment of epilepsy patients, was associated with the ZSN.  

 

Those groups in Hannover and Bethel are involved in this main focus work with in-vitro-models, animal models and with patients in order to improve understanding of pathophysioloy of paroxysmal illnesses and thereby to obtain the basis for new therapeutic approaches. Approximately 30% of all epilepsy patients do not respond to the currently available antiepileptic drugs, so that the investigations into mechanism of pharmacoresistance in the last years have become extremely important. The group of W. Löscher (Pharmacology of the TiHo) is investigating cellular and molecular mechanisms of antiepileptic resistance on animal models in which both resistant and responsive animals are selected from large groups of epileptic rats and are used for neuropathological, neurochemical and neurophysiological investigations. These models also form a central point of an EU-promoted collaboration (EURIPIDES) in which 14 groups in Europe are investigating the significance of “multi-drug transporters” such as P-glycoprotein for pharmacoresistance by means of positron-emission tomography (PET) in animal models and patients. The role of such an efflux transporter is also the focus of a cooperation of the group of W.  Löscher with the Bethel Epilepsy Centre. Clinically applicable new strategies for improved therapy of pharmacoresistant epilepsies can be clinically tested in cooperation with the Bethel Epilepsy Centre. At present the most important alternative to pharmacotherapy for pharmacoresistant patients is epilepsy surgery, one of the main focuses of the Bethel Epilepsy Centre.  

 

A further focus of the working group of W.  Löscher is the prevention of symptomatic epilepsies which can occur after brain insults such as brain tumours, ischemia or infections. Various pharmacological approaches are being pursued in animal models in which mechanisms of epilepsy development (epileptogenesis) are studied. In a cooperation between the  group  of W. Löscher and the group of  M. Gernert (Pharmacology of the TiHo) with Bethel (PD Dr. Hans) and Neurology of the MHH (Prof. Petri, PD Krampfl) the possible role of a disturbed GABAergic transmission of substantia nigra pars reticulata (SNr) in the case of epilepsies in humans is being investigated.  

 

The group  of M. Gernert is investigating the pathophysiologcal significance of basal ganglia for epilepsies. In this connection investigations not only on cellular but also on network levels are in the foreground. A further focus of the group of M.  Gernert is research into the therapeutic potential of deep brain stimulation in epilepsies. Cooperation with Neurosurgery of the MHH (Prof. Krauss, PD Schwabe) is in preparation. A further non-pharmacological approach to epilepsy therapy is neurotrasplantation in an animal model which is being investigated by the group of Löscher/Gernert in cooperation with USA groups.  

 

Epilepsies occur not only in humans but belong in veterinary medicine (above all in dogs) to the most frequently occurring neurological illnesses. In the group of A. Tipold (Small Animal Clinic of the TiHo) in cooperation with the group of W. Löscher the diagnosis of small animals has been partly improved (image-guided technique, electrodiagnostic) and new antiepilepic drugs are being clinically investigated in epileptic dogs. Research into possible prevention of epilepsies after head  trauma in dogs is planned.  

 

The group  of C. Fahlke (Neurophysiology, MHH) is concerned with molecular pathophysiology of genetic illnesses in which ionic channels and ionic transporters are affected. These include myotonia and certain forms of hereditary epilepsies. By means of a combination of electrophysiological, microscopical and biochemical techniques the effects of mutations causing illnesses on the function and the subcellular division are being investigated.  

 

Epileptic attacks can also be the result of a degenerative destruction of the myelin sheath of central nervous system axons, for example occurring in multiple sclerosis. The  groups  of M. Stangel (Neurology of the MHH), W. Baumgärtner (Pathology of the TiHo) and W. Löscher are investigating the incidence and pathogenesis of epileptic attacks in demyelinisation models.  

 

Antiepileptic drugs are not only used in treating epilepsies but also in therapy of other paroxysmal illnesses (e.g. migraine and paroxysmal dystonia), bipolar disorders and neuropathic pain (see Rogawski and Löscher, Nature Medicine 10, 685692, 2004). The group  of S. Kästner (Small Animal Clinic of the TiHo) is investigating the analgesic effectivity of the antiepileptic drugs gabapentin and pregabalin in neuropathic pain in dogs. The group of G. Haeseler (Anaesthesiology of the MHH) is concerned with developing new or modified pharmacological intervention possibilities in the therapy of chronic post-inflammatory and neuropathic pain. Those substances developed in this case are of interest for epilepsy therapy. The projects of the group  of G. Haeseler are cooperation projects with the Department for Neurology and Clinical Neurophysiology of the MHH (Prof. Dengler and PD Krampfl) and the Department for Cellular Chemistry of the MHH (Prof. Gerardy-Schahn and Dr. Mühlenhoff) of the ZSN.  

 

At the Department for Neurology and Clinical Neurophysiology of the MHH (Prof. Dengler) investigations are being carried out on clinical neurophysiological as well as on molecular physiological levels in the case of paroxysmal muscle illnesses with myotonia. With the help of electromyography, muscle functions in affected patients are thereby characterised, with molecular physiological approaches fundamental ionic channel changes and pharmacological therapy approaches are being worked on.