Workshop Report: Michael Forum: Dresden, Germany: September 18–20, 2008

The Michael Foundation was established “to promote research in seizure diseases and the most appropriate methods of treatment as well as the combat of their individual and social consequences.” The Michael Prize (now supported by UCB Pharma) is the most widely known product of the Foundation. The prize, first awarded in 1963, has since then recognized more than 60 researchers from 12 nations (see: http://www.stiftung-michael.de/e_fpreistraeger.html). Since 1987, the Michael Foundation has also organized regular workshops, called the Michael Forum, for the current and past prize winners to discuss research developments. The most recent Forum took place in Dresden in September 2008, and was devoted to the topics of seizure genesis and spread, development of new treatments, and translational aspects of epilepsy research. A brief summary of this Forum is presented below. Erwin Speckmann (University of Muenster, Germany) presented electrophysiologic data and optical recordings obtained in living slices of amygdalae from patients undergoing epilepsy surgery. Restriction in the spread of activity from ventromedial to dorsolateral sites was accompanied by a broad increase in neuronal activity, probably reflecting γ-aminobutyric acid (GABA)ergic mechanisms within the lateral amygdala (an “inhibitory focus”). Marco deCurtis (Istituto Nazionale Neurologico, Milan, Italy) discussed “focal ictogenesis” as reproduced in the isolated guinea pig brain preparation. Fast activity recorded in the entorhinal cortex at the onset of seizure-like events correlated with activation of interneurons and fast inhibitory potentials in principal cells. Istvan Mody (UC Los Angeles, CA, U.S.A.) explored further the possibility that enhanced GABAergic inhibition in the neocortex could be proepileptogenic. In recordings from neocortical pyramidal neurons in vitro from mice carrying mutant alleles of α4 subunit of the nicotinic acetylcholine receptor (nAChR) [associated with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)], there was a large selective increase in nicotine-evoked GABAergic inhibition; seizures in vivo were blocked by subconvulsive doses of the GABAA receptor antagonist picrotoxin. Massimo Avoli (MNI, Montreal, Canada) presented evidence for decreased tonic inhibition in a model [fmr1 knockout (KO) mice] of fragile X syndrome (FXS), in which there is region-specific altered expression of some GABAA receptor subunits. Tonic GABAA currents were down-regulated, and GABAA receptor subunits α5 and δ were underexpressed, in subicular neurons from fmr1 KO mice compared to wildtype neurons; no significant differences were observed in phasic GABAA events. Charles E. Ribak (UC Irvine, CA, U.S.A.) examined astrocytic [glial fibrillary acid protein (GFAP)–labeled] and microglial (Iba1-labeled) changes in the hippocampus during the first few days after pilocarpine-induced seizures in rats. Electron microscopy confirmed astrocytic hypertrophy and demonstrated astrocytic cell bodies in the location where glial end feet normally appear on capillaries. Differential response patterns of astrocytes and microglia may signify their roles in neuroinflammation after seizures. Wolfgang Loescher (TIHO, Hannover, Germany) critically reviewed cell replacement and gene therapies in acute and chronic models of epilepsy. Although substantial seizure suppression can be obtained with cell grafting, the anticonvulsant effect was restricted to a few weeks in most rodent studies. Stimulation of neurogenesis did not necessarily promote normal function in the epileptic brain. In contrast, in vivo gene transfer using adeno-associated virus (AAV) vectors offered more sustained effects on seizure suppression, but this effect remains to be demonstrated in animal models of chronic epilepsy. Heidrun Potschka (LMU, Munich, Germany) focused on the regulatory cascade of P-glycoprotein. Exposing isolated rodent brain capillaries to glutamate increased P-glycoprotein expression and transport activity, an effect blocked by the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 and by the selective cyclooxygenase (COX)-2 inhibitor celecoxib. In a pilocarpine status epilepticus rat model, seizure-induced increases in capillary P-glycoprotein expression were attenuated by administration of the nonselective COX inhibitor indomethacin or the COX-2 inhibitors celecoxib and NS-398. Alon Friedman (Ben-Gurion University, Beer-Sheba, Israel) evaluated the frequency, extent, and functional correlates of blood–brain barrier (BBB) permeability changes in human epileptic patients, and explored the mechanisms involved in epileptogenesis under disturbed blood–brain communication. Using novel imaging methods, he showed that BBB damage was significantly more frequent in posttraumatic epileptic patients compared to trauma patients who did not develop epilepsy. In a rat model for prolonged BBB disruption, regional hyperexcitability developed within a few days and lasted for weeks. Epileptogenesis was also observed following direct exposure of the neocortex to serum albumin; albumin uptake (into astrocytes) and epileptogenesis could be blocked by blocking activation of the transforming growth factor β (TGF-β) pathway. Christophe Bernard (INSERM, Marseille, France) performed a longitudinal study using the rat pilocarpine model to assess time course and underlying mechanisms of cognitive decline during epileptogenesis. Spatial memory was altered immediately after the status epilepticus (well before onset of spontaneous seizures), and spatial deficits correlated with a decrease in the power of theta oscillations in the hippocampal CA1 region. Reorganization of hippocampal circuitry resulting in impaired hippocampus-dependent memory functions may be dissociated from the process that leads to epilepsy itself. Friedrich Woermann (Bethel Epilepsy Centre, Germany) discussed whether the shift of language dominance is a consequence of structural damage close to language areas or whether functional disturbances (e.g., frequent interictal activity) might play an additional role. In patients with left-sided temporal lobe epilepsy (TLE) and hippocampal sclerosis, a shift of language dominance was associated with frequent interictal epileptiform activity. Jeff Noebels (Baylor College of Medicine, Houston, TX, U.S.A.) emphasized the increased (3-fold) incidence of epilepsy is in Alzheimer’s disease (AD). In an Aβ overexpression AD mouse model, there is dentate granule cell axonal sprouting, loss of calbindin, and ectopic neuropeptide Y (NPY) expression. These mice present with frequent interictal discharges and spontaneous generalized nonconvulsive seizures. Aβ protein alters several membrane currents that control intrinsic neuronal membrane excitability and neurotransmitter release, perhaps leading to abnormal network synchronization and seizures. Gregory L. Holmes (Dartmouth-Hitchcock Medical Center, Lebanon, U.S.A.) investigated whether neurologic deterioration in epileptic encephalopathies is attributable to very frequent or severe seizures, or severely abnormal electroencephalography (EEG), or both. In rats, interictal spikes were associated with a pronounced decrease in action potential discharge, suggesting that frequent and widespread interictal discharge can impair cognitive abilities. Impaired oscillatory rhythms, which occur in the epileptic encephalopathies, can also dramatically impair single-cell firing patterns and thus temporal coding of information. Michael Segal (Harvard Medical School, Boston, MA, U.S.A.) described patients with attention deficit disorder whose exacerbations could be triggered and prevented in the same ways as those of the muscle channelopathy hypokalemic periodic paralysis. The similarity of this phenomenology to a known channelopathy, and its resistance to a sodium-channel antagonist applied in the periphery, suggests that a peripheral nervous system channelopathy can produce the clinical picture of attention deficit disorder through a mechanism involving sensory overstimulation. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Disclosure: None of the authors has any conflict of interest to disclose. UCB supported the Forum with an unrestricted educational grant, but did not have any influence on the program of the meeting or the contents of this report.

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