MICHAEL FORUM REPORT

The Michael Prize was initiated in 1975 to stimulate and support research in epileptology. Beginning this year, the Michael Forum and Prizes are supported by UCB. The prize is meant to recognize scientists in the early stages of their research career because it is awarded to those below the age of 45 years. It has become one of the most highly regarded international awards in epilepsy research. The prize has gone to individuals and groups in Austria, Brazil, Britain, Canada, Germany, Hungary, Israel, Italy, Poland, Switzerland and the USA. The past winners include many current leaders in the field of epilepsy. A complete list can be obtained from the web site of the Michael Foundation, http://www.stiftung-michael.de/e_inhalt.html. The Michael Forum represents the biannual meeting of the Michael Prize winners, both present and those of past years, to discuss recent developments in epileptology in a two-day, open discussion symposium. This year's meeting was held in Potsdam, just outside of Berlin, and the following short report summarizes the talks on clinical aspects, imaging, and basic science. In a medico-historical perspective, Dr. Dieter Janz delineated epileptic prodromi in Dostoievsky's novel “The Idiot,” pointing out that early clinical reports are scarce and that the literary description of Prince Myschkin's seizures is likely the most detailed one available. According to Dr. Janz, the mood and behavioral alterations—described in more than 20 pages—can be summarized diagnostically as a depressive paranoid state preceding one seizure, and an euphoric loquacious state preceding the other seizure. Dr. Janz points out that Dostoievsky himself doubted whether it could ever be determined definitely which of the two was decisive: “the underlying nervousness of biological nature or the psychologically motivated excitement.” Discussing these descriptions in the clinical context, Dr. Janz concluded that data on premonitory symptoms (different from auras) are scarce, but that taking the reports of patients and the observations of caretakers together, their frequency is 39%. They seem to occur more frequently before generalized tonic-clonic seizures than other seizure types and are more frequent in focal than in generalized epilepsies, and have a high predictive value; in 59% of the cases, prodromi are followed by seizures. In his presentation, Dr. Joszef Janszky focused on age at epilepsy onset (AEO) as one crucial determinant not only of idiopathic, but also of symptomatic epilepsies. To address the question which factors may influence AEO in these cases, he and his group investigated mesial temporal-lobe epilepsy (MTLE) patients who exclusively had hippocampal sclerosis (HS) and childhood febrile convulsions (CFC). He demonstrated that symptomatic epilepsy (MTLE) with a single etiological factor (CFC) can be divided into different AEO groups, with a trimodal age distribution, peaking at ages 5.5, 15.3, and 26.7 years. Remarkably, the adolescent and childhood peaks in MTLE shown in this study correspond well with AEO peaks of the most common idiopathic (genetic-related) epilepsies, suggesting that epilepsy caused by a single etiological factor such as by a genetic defect (absence epilepsy) or by early childhood injury (CFC+HS) shows a similar AEO distribution, with a childhood and an adolescence peak. This prompted him to hypothesize that other, most probably genetic, factors may play a role in AEO, which additionally modify the primary etiological factors. In MTLE, he further found that in the adolescent AEO group, family history of epilepsy occurred more frequently and the age at CFC was earlier than in the childhood AEO group. In her talk, Dr. Heidrun Potschka reported on new strategies to overcome pharmacoresistance. She stressed the importance of multidrug transporters at the blood–brain barrier (BBB) as crucial mechanisms of multidrug resistance. One possible strategy that was proven to be efficacious in experimental settings is the modulation of transporter function by co-administration of transporter inhibitors. Initial clinical data also indicate that inhibition of efflux transporter function may be one means to improve therapeutic success. However, in view of the general protective role of efflux transporters, complications of such a modulation might be expected, i.e., as discussed in the removement of Alzheimer plaques. As an alternative, Dr. Potschka reported on current efforts to develop a method to selectively deliver small interfering RNA (siRNA) to BBB endothelial cells in order to downregulate multidrug transporters. By encaspulating siRNA in liposomes, siRNA was protected from degradation and was successfully delivered to BBB endothelial cells. Another strategy is to bypass efflux transporters, leaving the function and expression of transporters completely unaffected. This technique involves intranasal administration of compounds to the brain via olfactory nerve pathways, thereby bypassing the BBB. Preliminary microdialysis experiments indicated excellent brain penetration rates of intranasally administered phenobarbital in rats. A third approach is to prevent seizure-induced upregulation of efflux transporters. In this context, Dr. Potschka is currently studying the molecular cascades that are upregulated by seizures in order to identify targets for resistance prophylaxis. Initial experiments point to the involvement of glutamate and of inflammatory mediators. In a strategy paper, Dr. Wolfgang Löscher reported on recent advances in antiepileptogenic drug development. Considering that there is no clear evidence that AEDs alter the underlying epileptogenic process, the development of new AEDs that prevent epileptogenesis or treat epilepsy (and not just seizures) is an important goal. It is likely that antiepileptogenic drugs will have mechanisms of action distinct from traditional AEDs, as the molecular mechanisms underlying epileptogenesis (the process of developing epilepsy, i.e., alterations that make the brain susceptible to spontaneous recurrent seizures) and ictogenesis (the processes involved in initiation, amplification, and propagation of seizures) probably differ. From a conceptual standpoint, there may be at least four strategies for the modulation of epileptogenesis: (1) Initial insult modification: by reducing the severity or duration of the initial brain insult, such as status epilepticus, the long-term consequences of the insult can be reduced. (2) Neuroprotection: Although recent data with neuroprotective drugs demonstrate that epileptogenesis and neurodegeneration are not causally related, neurodegeneration such as occurring in TLE may be important for the behavioral and cognitive problems associated with epilepsy. Thus, neuroprotective drugs, even if not preventing spontaneous recurrent seizures developing after brain insults, may prevent or reduce behavioral or memory deficits. (3) Antagonism of epileptogenesis: Although various drugs have been tested (both experimentally and clinically), no drug has yet been identified that prevents epilepsy when given shortly after a brain insult. Further design and implementation of antiepileptogenic drug screens are needed. (4) Disease modification: Disease-modifying drugs alter the process of epileptogenesis in such a way that epilepsy that develops is milder, easier to treat, nonprogressive, and without cognitive decline and drug resistance. For example, the antiepileptic drug levetiracetam has been shown to cause enduring effects on kindling development that outlast the presence of the drug in the body. Dr. Brian Meldrum reviewed the methodology and molecular targets appropriate to the search for antiepileptogenic drugs. He concluded that since there is no positive anti-epileptogenic drug, we have no means of validating any animal model. The kindling model in his view is as valid as any other proposed model but it has been wrongly interpreted. Treatment with the test drug prior to stimulation studies only results in modification of the symptoms (e.g., shortening of afterdischarge duration or reduction of Ca++ entry). Post-treatment is necessary to study antiepileptogenesis. Possible molecular targets were discussed. Nerve growth factors and their receptors in this context were seen as intriguing. Dr. Friedrich Wörmann discussed the advantages and disadvantages of fMRI in determining the lateralization/localization of primary motor cortex, language, and memory areas prior to epilepsy surgery. As advantages, he pointed out that, fMRI is noninvasive, free from ionizing radiation, widely available, and relatively inexpensive. Although “clinical fMRI” is still in the process of demonstrating that it can be used in the majority of epilepsy patients (including children), fMRI acquisition and assessment appear to be easy and reproducible. In a critical appraisal, Dr. Woermann pointed out that fMRI in the presurgical evaluation of individual patients with epilepsy differs from neuroscientific fMRI group studies where simple tasks are performed, and more importantly, a baseline condition can be monitored. Further, visualizing functional networks, arbitrary statistical thresholding may result in false positive identification of activated areas. Whether these statistically pinpointed activation areas and their extent are of clinical relevance and carry essential parts of cognitive and motor functions is often unclear. For clarification, fMRI results have to be correlated with deactivating methods. Currently, fMRI can be seen as part of a sequence of pre-surgical tests. fMRI's contribution to the overall validity of this sequence still needs to be determined. Dr. Matthias Koepp provided new information on using brain imaging to analyze brain connectivity. Diffusion tensor tractography is fast becoming an application of great scientific and clinical interest. In combination with other imaging modalities and electrophysiological techniques, it promises to increase our understanding of functional connectivity in both normal and disease states. Initial results have shown that the technique can be applied in pre-surgical planning of resection strategies in epilepsy patients in order to minimize damage to eloquent cortex and connections that affect language, vision, and memory regions. Furthermore, by the utilization of fractional anisotropy and tract volume measures, tractography in concert with fMRI can also be used to delineate atypical language organization. Dr. Esper Cavalheiro reported on the characteristics of a novel animal model in which to study anticonvulsant mechanisms. Proechimys caeyannensis (PC; previously known as Proechimys guyannensis) is a spiny rodent species living in the Amazonian region. This species shows a markedly reduced susceptibility to different epileptogenic treatments (amygdala kindling, pilocarpine, and intrahippocampal kainic acid). Among the possible reasons for this resistance are differences in GABA and opioid binding distribution in the brain of PC animals compared to Wistar rats; 3H-muscimol and 3H-flunitrazepam binding in various brain areas are reduced, while differential changes (increases and decreases) are observed for 3H-DAMGO binding. In in vitro preparations, signs of hypoexcitability were evident; although typical evoked orthodromic population spikes (PS) could be obtained, the voltage threshold for PS was significantly higher for PC when compared to Wistar rats. In contrast to Wistar rats, PC hippocampal slices were also less susceptible to bicuculline, more sensitive to elevated K+, and less sensitive to low Mg2+. Dr. Uwe Heinemann presented recent work done together with Dr. Alon Friedman from Beersheva, Israel. They studied effects of BBB opening in relation to epileptogenesis. Blood–brain barrier opening is a common event during status epilepticus, brain trauma, neuroinflammation, and often accompanies brain tumors—all conditions that frequently lead to later epilepsy. Focal opening of the BBB in parietal cortex, by detergent bile salts, leads with a delay of some days to a focus of hyperexcitability without a priori induction of neuroinflammation and cell death. Induction depends on extravasation of plasma proteins such as albumin. Albumin itself was able to induce a hyperexcitable focus. An early event of albumin treatment (or BBB opening) is activation of astrocytes, which is seemingly dependent on albumin uptake into these cells. The activated astrocytes lose their capability to buffer extracellular potassium, leading to abnormal potassium accumulation and transiently facilitated activation of NMDA receptors for glutamate. Prevention of albumin uptake into astrocytes prevents activation of astrocytes and later generation of an epileptic focus. In his contribution, Dr. Massimo Avoli focused on the role of nonhippocampal limbic structures, including the subiculum, entorhinal cortex, and amygdala, in the establishment of hyperexcitable neuronal networks in temporal lobe epileptic patients. His findings confirmed that: (1) in chronically epileptic mice and rats, status epilepticus (SE) induced in vivo causes cell damage and neuronal hypoactivity in the hippocampus proper, (2) these anatomical and functional changes alter the interactions between hippocampus and entorhinal cortex, and in particular the process of ictogenesis, (3) reverberant entorhinal cortex–subiculum interactions are capable of sustaining ictal discharges, (4) subicular neurons in hippocampal-entorhinal cortex slices of epileptic rats are hyperexcitable when activated by hippocampal or entorhinal cortex inputs, and generate spontaneous postsynaptic potentials at higher frequencies than cells in nonepileptic control tissue. In addition, GABAA receptor-mediated inhibitory postsynaptic potentials have more positive reversal potentials in epileptic tissue. These electrophysiological data from entorhinal cortex and subiculum correlated in the epileptic subiculum with (i) reduced levels of mRNA expression and immunoreactivity of the neuron-specific potassium chloride cotransporter 2; (ii) decreased number of parvalbumin-positive cells; and (iii) increased synaptophysin (a putative marker of sprouting) immunoreactivity, thus identifying an increase in network excitability within the subiculum of epileptic rats, with a reduction in inhibition as an underlying mechanism. (5) Finally, the lateral nucleus of the amygdala of pilocarpine-treated, epileptic rodents also shows a downregulation of inhibitory mechanisms, which plays a role in the increased excitability. In his paper on the electrophysiological functional characterization of the human amygdala in vitro, Dr. Erwin Josef Speckmann focused on synaptic network activity and spontaneous epileptiform discharges. He demonstrates that the amygdala shows a preference in the spread of (stimulated) activity from dorsolateral to ventromedial sites, and that this preferential spread is under the control of the GABAergic system. Further, spontaneous epileptiform discharges observed in vitro are not only mediated by glutamatergic, but also by GABAergic synaptic processes, suggesting that GABA plays an important role in shaping the physiological as well as presumed pathological activity within this structure. Dr. Charles Ribak discussed his recent studies that showed rapid neuroplastic changes in the adult rat dentate gyrus during the first five days following pilocarpine-induced seizures. These changes related to the seizure-induced increase in the rate of neurogenesis. Doublecortin (DCX) immunocytochemical preparations were used to quantify the number of DCX-labeled cells as well as to determine the percentage of DCX-labeled cells with hilar basal dendrites found at daily intervals from 1–5 days after seizure induction. In addition, DCX/Ki-67 double-labeling was used to quantify the number of type 3 progenitor cells at these same timepoints, and hilar basal dendrites were examined for synapses. From the first day after seizures, there were increases in the number of DCX-labeled cells and the percentage of DCX-labeled cells with basal dendrites. DCX/Ki-67 cells increased in number as well during this period. Also, developing synapses were observed on hilar basal dendrites beginning at 4 days after seizures, indicating that these dendrites become incorporated into excitatory circuitry in the dentate gyrus shortly after seizures. These findings demonstrate that DCX-labeled newborn granule cells rapidly display neuroplastic changes after seizures. Dr. Rüdiger Köhling probed the role of the basement membrane protein nidogen in shaping neuronal network excitability, and possibly epilepsy. Mice with mutated alleles of the NID-1 gene showed signs of neurological impairment with hindlimb weakness and seizure-like behavioral activity, substantiated by epileptiform spikes in the EEG. Further, in hippocampal slices of these animals, spontaneous as well as evoked epileptiform potentials were observed, as well as a shift of the input–output curve (upon afferent stimulation), suggesting increased excitability. The paired-pulse ratio in NID1−/− brains increased and dentate gyrus LTP decreased.

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