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1 Y.G. Weber , 2 A. Storch , 1 T.V. Wuttke , 3 K. Brockmann , 1 J. Kempfle , 1 D. Blazevic , 3 A. Pekrun , 1 M. Fauler , 1 F. Lehmann-Horn , 1 H. Lerche 11 University Ulm (Ulm, D) ; 2 University Dresden (Dresden, D) ; 3 University Gottingen (Gottingen, D)
Paroxysmal dyskinesias are characterized by attacks of involuntary movements classified as kinesiogenic, nonkinesiogenic or exertion-induced. The pathophysiology of these syndromes is still unclear. We describe a novel autosomal dominant syndrome in a three-generation family with four affected individuals presenting with a combination of a paroxysmal exertion-induced dyskinesia, hemolytic anemia and epilepsy. The syndrome was characterized by extensive clinical, genetic and experimental studies. Three individuals suffer from attacks of involuntary movements with dystonic and choreoathetotic components after heavy workload since early childhood. The two sons of the index case show mild neuropsychological deficits, mild permanent motor problems and a focal epilepsy with myoclonic and atonic seizures with status epilepticus in fasting state. A good response of the symptoms to glucose infusion and long term ketogenic diet was observed. Affected individuals presented with decreased CSF glucose, hemolytic anemia, and increased intracellular sodium and decreased potassium concentrations in red blood cells, which showed an increased percentage of echinocytes. Genetic investigation of SLC2A1 encoding the glucose transporter type 1 (Glut1) revealed a mutation in the pore region. Functional analysis in Xenopus laevis oocytes injected with wildtype or mutated cRNA revealed a decreased glucose uptake and a cation leak of the mutant transporter compared to the wild type. Erythrocytes analysis from patients and healthy controls confirmed the electrolyte rearrangement. The epileptic activity can be well explained by the energy deficit. In analogy to genetic defects of the anion exchanger of the erythrocyte membrane which can also induce deformed erythrocytes with intracellular ionic changes, the cation leak caused by the mutation may also explain the abnormal erythrocyte morphology and secondary hemolytic anemia. We propose that the dyskinesias are caused by a combination of a metabolic defect and an electrolyte shift in glial cells expressing the transporter. The cation leak may decompensate during prolonged exercise when not enough glucose as an energy source can be delivered across the blood–brain barrier.
1 T. Schmitt-Mechelke , 2 D. Bartholdi , 3 R. Touraine 11 Pediatric Clinic (Lucerne, CH) ; 2 Institute of Medical Genetics (Zurich, CH);3 Laboratory of Molecular Genetics (Saint-Etienne, F)
Background: Mutations of the ARX-Gene (aristaless-related homeobox gene, Xp22.11) have been observed in a variety of X-linked neurogenetic diseases: lissencephaly with ambious genitalia (XLAG), mental retardation with agenesis of the corpus callosum and ambiguous genitalia (Proud-Syndrome), mental retardation with progressive dystonia (Partington-Syndrome) and X-linked infantile spasms with mental retardation. We observed a male neonate with a myoclonic epileptic encephalopathy and a severe multisystem disorder due to a novel mutation in the ARX-gene.
Case Report: After an uneventful pregnancy and birth, a male term infant presented with myoclonic neonatal seizures on the first day of life. Physical examination showed an unilateral cryptorchism and was unremarkable otherwise; his head circumference was normal. Ultrasound and MRI showed an agenesis of the corpus callosum and a lissencephalic cortical migration disorder. The EEG showed an asynchronous burst-suppression pattern with frequent myoclonic and tonic seizures unresponsive to treatment with phenobarbital, vigabatrin or benzodiazepines equivalent to an early myoclonic epileptic encephalopathy (Ohtahara-Syndrome). The neonate developed hypothalamic dysfunction with temperature instability and an enteropathy with potassium-loosing secretory diarrhea. Considering the severely impaired prognosis, comfort care was offered and the patient died after 3 weeks.
Analysis of the ARX gene disclosed a 1414C>T mutation in exon 4 resonsible for a nonsense mutation R472X not described before. The mutation was not detected in DNA of the mothers leukocytes.
Conclusion: ARX-mutations can present as a neonatal epileptic encephalopathy with lissencephaly and agenesis of the corpus callosum without obvious genital malformation. The condition can affect the gastrointestinal tract and carries a poor prognosis. Prenatal diagnosis is feasible.
1 K. Jann , 1 M. Hauf , 1 J. Mathis , 2 K. Meyer , 1 T. Dierks , 1 T. König , 1 R. Wiest 11 University Berne (Berne, CH) ; 2 Bethesda Clinic (Tschugg, CH)
Purpose: Interictal combined EEG and fMRI is of gaining importance for the focus localization and understanding of the pathophysiology in epilepsies. We report on a new approach for the continuous acquisition of functional MRI data and EEG using an Independent Component Analysis (ICA) based technique.
Method: 18 patients, 14 with focal epilepsies (FE) and 4 with idiopathic generalized epilepsies (IGE) were examined with simultaneous 96-channel EEG-fMRI recordings in a 3 Tesla MR unit. ICA derived factors coding for time varying epileptiform activity were convolved with a hemodynamic response function (HRF) to predict the BOLD signal. Voxelwise correlations between the ICA-predictors and the BOLD signal were computed. Regions with significant correlations were interpreted as having been active during the time course of the interictal discharges.
Results: In 12 subjects with FE, the interictal focus was detected in accordance with previously and simultaneously recorded EEG sources and fitted the clinical semiology and structural lesions on high resolution MRI, if present. In three patients with IGE, symmetrical cortical (de-)activation patterns and bilateral thalamic changes were recorded, supporting the corticoreticular theory of epileptogenesis in IGE. Three patients had to be excluded due to uneventful EEG recordings or motion artifacts.
Conclusion: Our data suggest that simultaneous EEG/fMRI recordings are a safe, noninvasive and promising technique to provide additional information about the irritative zone in FE and different propagation patterns in FE and IGE.
With the support of the Swiss National Foundation (Grant no. 320000-108321/1).
1 M.T. Lutz , 2 C. Helmstaedter 11 Epilepsy Center Kleinwachau (Radeberg, D) ; 2 University Clinic of Epileptology (Bonn, D)
Purpose: One of the newest models of intelligence is the Cattell-Horn-Carroll model (CHC model). This model is a hierarchical framework of cognitive abilities and consists of different strata describing varying levels of generality. Performing a comprehensive evaluation of intelligence in addition to a neuropsychological testbattery for answering questions of diagnosis, prognosis, or outcome in patients with epilepsy, often surpasses available resources on time and manpower. Therefore we raised the question whether it would be efficient to deduce information about intelligence from a neuropsychological test battery. For that purpose, we analysed if data of a neuropsychological test battery can be described in the framework of the Cattell-Horn-Carroll model.
Methods: Testing of attention, visual and verbal memory, language, higher verbal and visual reasoning, and executive functions was performed in 190 healthy subjects recruited for a normative study and in 190 patients with refractory epilepsy. Both samples were derived from the University Clinic of Epileptology, Bonn, Germany. First, we contrasted alternative models of intelligence in the sample of healthy subjects using confirmatory factor analyses (CFA) and then we tested the factorial invariance of the best fitting model across the groups using multigroup CFA.
Results: The best fitting model in the sample of healthy volunteers was a reduced CHC-model with five broad cognitive abilities, namely crystallized intelligence, visual processing, long-term retention and retrieval, processing speed, and short term memory (goodness of fit characteristics: Chi-square = 206.48 (df = 140); CFI = 0.923). A g-factor was not included. Invariance of the measurement and structural model across groups could be demonstrated after erasing two test parameters. The fit characteristics of this multigroup CFA were good (chi-square = 344.98 (df = 228); CFI = 0.925).
Conclusion: This cross-battery study showed that the Cattell-Horn-Carroll model of cognitive abilities is suited for describing the data of a neuropsychological test battery. This holds true for healthy volunteers as well as for patients. The results add information about the factorial validity of the test battery and overcome out of date concepts of intelligence. Furthermore, the results show an economic way for combining the assessment of intelligence with neuropsychological diagnostics in presurgical patients with pharmacoresistant epilepsy.
1 K. Krakow , 2 F. Rosenow , 1 M. Sitzer , 1 C. Foerch 11 J.W.Goethe-University (Frankfurt, D) ; 2 University Hospital Giessen and Marburg GmbH (Marburg, D)
Background: Estimates of the rates of early epileptic seizures after stroke range from 2% to 33%. Aside from cortical location, no risk factors for poststroke seizures have been consistently demonstrated. In this study, we tried to identify predictors of acute poststroke seizures in different stroke subtypes.
Methods: We analyzed a large prospective hospital-based stroke registry with more than 100 hospitals enrolling stroke patients into this computerized database. Within a 7-year period (1999-2005), 58 954 patients with the diagnosis transient ischemic attack (TIA, n = 16 718), cerebral infarction (CI, n = 37 360), and intracerebral hemorrhage (IH, n = 4876) were documented, who were admitted within 24 hours after stroke onset. In multivariate analyses we adjusted for age, gender, neurological deficit at admission (Modified Rankin Scale, impairment of consciousness), type of stroke, arterial hypertension and diabetes mellitus.
Results: The mean age of the population was 72 ± 13 years. 50.1% were female. Acute poststroke seizures (defined as the occurrence of epileptic seizures during hospitalization) occurred in 0.8% of patients with TIA (mean duration of hospitalization 8 days), in 2.4% of patients with CI (11 days), and 5.1% of patients with IH (12 days). Multivariate analysis revealed that in patients with CI the risk of an acute symptomatic seizure decreases by 1.7% for each year of life (odds ratio (OR) 0.983 [0.977-0.989], p<0.001). Further predictors of acute seizures for all stroke subtypes were a severe neurological deficit and in particular diabetes mellitus (CI: OR 2.2 [95% CI 1.9-2.6], IH: OR 1.6 [1.2-2.2], TIA: 5.6 [3.8-8.3].
Conclusions: Beside young age and severity of the neurological deficit, diabetes mellitus is an independent risk factor for the occurrence of acute epileptic seizures after stroke. This effect is particularly strong in ischemic subtypes of stroke. Further studies are necessary to elucidate the mechanism of this association.
1 E. Rodin 1University of Utah (Salt Lake City, USA)
Purpose: Precise determination of seizure onset is essential for “non-lesional” epilepsy surgery. Yet this is at times difficult when conventional EEG frequencies of 0.5-75 Hz are used. Since it is known that slow baseline shifts accompany seizures, and can have lateralizing significance, infraslow activity (ISA) between 0.01-0.1 Hz was investigated.
Methods: The data from fifteen adult patients with partial complex seizures (N35) were compared with those from six children with classical 3 Hz Spike-Wave (SW) discharges accompanied by Absence seizures (N30). The adults were recorded on a Grass-Telefactor system and the children on a Nihon-Kodhen instrument. Data analysis was performed with the BESA program. When the low frequency filter was left open an offset was observed in a number of channels regardless which system was used. This disappeared when the low frequency filter was set at 0.01 Hz (6db forward). For the demonstration of ictal ISA a window of 30 seconds was used. It contained ten seconds prior to the conventionally determined seizure onset and 20 seconds of the beginning seizure. The data were then displayed in a topographic manner on a common average reference.
Results: In the adult patients two types of infraslow distributions were observed: 1) a clear propagation of activity within a given hemisphere with subsequent spread to the opposite side; 2) the ISA showed no appreciable latency differences between the two hemispheres. In these instances the frontal areas showed negative potentials while the posterior head regions were positive. At times both types of ictal ISA could be seen in different seizures from the same patient.
The 3 Hz SW pattern in the children was always accompanied by an ISA transient. It started several seconds before the seizure and subsequently outlasted it. The topographic distribution was identical in all seizures. There was synchrony throughout all channels with frontal negativity and posterior head regions positivity.
Conclusions: Ictal ISA can be clinically meaningful. Its major use may reside in the presurgical evaluation of medically refractory patients because it is likely that those who show the ictal ISA generalized topographic distribution may have a more guarded long-term prognosis when non lesional removal of cerebral tissue is performed. The data also suggest that when epilepsy monitoring units upgrade existing equipment that systems with the widest possible frequency range should be considered.
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Session: Cognition and epilepsy: from experimental studies to the patient
1 T. Kirschstein 1University Rostock (Rostock, D)
Patients with chronic temporal lobe epilepsy often suffer from persisting cognitive dysfunction in terms of declarative memory deficits. The fundamental molecular mechanisms of learning and memory in the central nervous system (CNS) have been recognized as different forms of synaptic plasticity. Depending on the intensity of the neuronal activity, synaptic strength can be potentiated or depressed, termed long-term potentiation (LTP) and long-term depression (LTD), respectively. Moreover, synaptic plasticity itself is modulated by the prior history of neuronal activity resulting in a higher-order plasticity termed metaplasticity. Thus, we asked how chronic epileptic seizures can influence synaptic plasticity in the chronically epileptic hippocampus. Following a prolonged status epilepticus induced by pilocarpine the rats developed spontaneous epileptic seizures, and long-term extracellular recordings were performed in the hippocampal brain slice. First, we studied NMDA receptor-dependent synaptic plasticity in the dentate gyrus. Whereas LTP in the medial perforant path was unaltered, we found a significant impairment of LTP in the lateral perforant path of epileptic rats. This lack of LTP could be rescued by D-serine bath application indicating NMDA receptor dysfunction in the epileptic lateral perforant path. Then we focused on NMDA receptor-dependent synaptic plasticity at the Schaffer collateral-CA1 synapses. Whereas LTD was unaltered in chronic epilepsy, we found an unexpected increase of LTP. As this discrepancy might be due to a differential expression of the most abundant NMDA receptor subtypes NR2A and NR2B, we went on to block these subtypes pharmacologically. We found that application of low micromolar zinc (1-10 μM), which primarily inhibits NR2A, virtually abolished LTP in controls, whereas epileptic rats still showed significant LTP. With a higher zinc concentration (100 μM) which blocks NR2A and NR2B, LTP was inhibited in both groups. In contrast, when a specific NR2B blocker was used, LTP remained inducible in controls, but was completely lost in epileptic rats. These results suggested a dominant role of NR2B in LTP induction in rats that have experienced status epilepticus. In conclusion, chronic epileptic seizures lead to a persistent alteration of synaptic plasticity in the hippocampus that can be seen as a kind of seizure-induced metaplasticity. These metaplastic changes could be in part involved in the cognitive impairment seen in many patients. A more precise understanding of the underlying mechanisms will be essential to develop new therapeutic strategies.
1 M.P. Richardson 1King's College London (London, UK)
Background: Temporal lobe epilepsy (TLE), usually caused by hippocampal sclerosis (HS), is a common disease which frequently fails to respond to antiepileptic drugs (AEDs). Hence, surgical removal of the epileptogenic zone, usually including the mesial temporal lobe (MTL), is an important treatment option and is usually curative. As a direct result of removal of MTL, however, memory is often significantly worse following surgery. Estimation of the risk for memory decline following surgery, and its severity, is therefore an important part of planning surgery in TLE. At the present time, there is no accurate tool established for this purpose. Functional magnetic resonance imaging (fMRI) of memory has recently shown great promise as a tool to predict memory decline following surgery in TLE, but considerable work is required to implement memory fMRI as a reliable clinical tool. Furthermore, although fMRI is widely used in neuroscience research, there is no existing methodology to facilitate a rigorous translation of “research-based” fMRI tools to the clinical domain.
Method: We studied 30 patients with mesial temporal lobe epilepsy (mTLE) and left HS, 12 of whom subsequently underwent surgery, and 13 normal control subjects. The patients who had surgery underwent neuropsychometric evaluation pre- and postoperatively. All subjects underwent a verbal memory encoding event-related fMRI study. First, we compared the pattern of verbal memory encoding activity in the group of patients with the group of normal controls, to establish typical patterns of activity for this task in normals and left HS patients. Secondly, we examined the group of patients who underwent surgery, to find the brain region(s) where preoperative memory encoding fMRI activity correlated with postoperative memory decline. This was assessed at the voxel level, using established methodology for examining group fMRI data. We also compared the predictive value of fMRI with established tools (structural MRI, neuropsychometry). Thirdly, we examined the data for each individual patient who underwent surgery, to establish a methodology to analyse data on a case-by-case basis, as would be required in a clinical setting. This approach used a new methodology to examine each case, to establish robust quantitative parameters of memory encoding activity which could be used prospectively to predict postoperative memory decline. Finally, in a qualitative manner only, we compared our approach with those of other groups who have also successfully implemented memory fMRI as a clinical tool in TLE.
Results: Verbal memory encoding involved activation of left hippocampus in normals, but was associated with reorganisation to right hippocampus and parahippocampal gyrus in the patients. In the patients who underwent surgery, a voxel-level analysis of the group showed that hippocampal memory encoding activity, measured from preoperative fMRI, provided strong prediction of postoperative memory change. Multiple regression analyses showed that fMRI provided the strongest independent predictor of memory outcome after surgery, compared with structural MRI and preoperative neuropsychometry. Examining individual patient data, visual inspection of individual patient activation statistic maps revealed noisy data that did not afford visual interpretation. Stepwise multiple regression analysis of predetermined regions of interest revealed left hippocampal activity was the strongest predictor of postoperative verbal memory outcome; greater left hippocampal activity predicted a greater postoperative decline in memory.
Conclusions: Preoperative memory fMRI provides a promising tool to evaluate hippocampal functional integrity prior to resective temporal lobe surgery in TLE. It is now essential to undertake studies to determine the clinical role of memory fMRI versus the intracarotid amobarbital test, and also to undertake studies comparing the different approaches to memory fMRI that have shown a clinical role in TLE.
1 J. Fell , 1 C.E. Elger 1University of Bonn (Bonn, D)
Background: Human declarative memory, i.e., the consciously accessible long-term memory for events and facts, crucially depends on two structures within the medial temporal lobe (MTL), the rhinal cortex and the hippocampus. But there had been no direct evidence for an interaction of both structures during memory formation. Transient coupling of neural assemblies may be accomplished by phase synchronisation of oscillatory activity, in particular gamma activity, i.e., EEG activity in the frequency range above 30 Hz.
Methods: In a group of 9 presurgical patients with unilateral MTL-epilepsies the event-related EEG was recorded with depth-electrodes during a word-memory task using common nouns as stimuli (1,2). In another group of 10 patients a similar memory task was performed contrasting common nouns with rare nouns (high versus low frequency of occurrence) (3). We compared the EEG-responses of the nonpathological MTL during word encoding of later remembered and forgotten words (subsequent memory effect). To address the question, whether the reduced facility to memorize dreams is associated with altered electrophyiological characteristics during sleep, all-night EEG was recorded in a group of 8 patients with depth- and scalp-electrodes (4). Moreover, 12 patients were awakened during REM phases and dream reports were inquired (5). Phase synchronization and spectral coherence within different frequency bands were quantified as measures of ongoing and stimulus-related neural connectivity between MTL substructures.
Results: We found that successful memory formation is accompanied by an initial stimulus-related increase of phase synchronization of gamma activity between rhinal cortex and hippocampus and a later decrease (1). These memory-related synchronisation changes are interindividually correlated with increases of rhinal-hippocampal theta (4-7 Hz) coherence (2). However, a pronounced broad-band rhinal-hippocampal coupling, including the gamma range, is only observed for words with a high frequency of occurrence (common words), but not for rare words (3). Compared to the waking state ongoing rhinal-hippocampal coherence decreases during sleep, most pronounced within the gamma-band (4). Finally, we detected that ongoing rhinal-hippocampal coherence is more than twice as large for patients with good dream memory compared to patients with poor dream memory (5).
Conclusion: Synchronisation of gamma oscillations may accomplish fast coupling and decoupling processes, which initiate and later terminate the information transfer between rhinal cortex and hippocampus (6). Moreover, early changes in synaptic plasticity may be triggered by synchronized gamma activity (7). Coherent EEG oscillations in the lower frequency range probably reflect a slowly modulated connectivity between rhinal cortex and hippocampus, which supports processes in the gamma range. However, a pronounced broad-band coupling, including the gamma range, may only occur, when significant semantic information is being processed within rhinal cortex, as is the case for common words. The reduced ongoing rhinal-hippocampal coupling during sleep may represent an indirect electrophysiological correlate of the diminished ability to encode memories during sleep. In accordance with this interpretation, ongoing rhinal-hippocampal connectivity was found to predict the memorization of dreams. Alltogether, these findings support the idea that ongoing, as well as stimulus-related rhinal-hippocampal synchronisation processes are crucial for successful declarative memory formation.
References: 1. Fell J, Klaver P, Lehnertz K, Grunwald T, Schaller C, Elger CE, Fernández G. (2001) Human memory formation is accompanied by rhinal-hippocampal coupling and decoupling. Nat Neurosci 4:1259–1264.
2. Fell J, Klaver P, Elfadil H, Schaller C, Elger CE, Fernández G. (2003) Rhinal-hippocampal theta coherence during declarative memory formation: interaction with gamma synchronisation?Eur J Neurosci 17:1082–1088.
3. Fell J, Fernández G, Klaver P, Axmacher P, Mormann F, Haupt S, Elger CE. (2006) Rhinal-hippocampal coupling during declarative memory formation: dependence on item characteristics. Neurosci Lett 407:37–41.
4. Fell J, Staedtgen M, Burr W, Kockelmann E, Helmstaedter C, Schaller C, Elger CE, Fernández G. (2003) Rhinal-hippocampal EEG coherence is reduced during human sleep. Eur J Neurosci 18:1711–1716.
5. Fell J, Fernández G, Lutz MT, Kockelmann E, Burr W, Schaller C, Elger CE, Helmstaedter C. (2006) Rhinal-hippocampal connectivity determines memory formation during sleep. Brain 129:108–114.
6. Fell J, Klaver P, Elger CE, Fernàndez G. The interaction of rhinal cortex and hippocampus in human declarative memory formation. Rev Neurosci 13:299–312.
7. Axmacher N, Mormann F, Fernández G, Elger CE, Fell J. Memory formation by neuronal synchronisation. Brain Res Rev 52:170–182.
1 M. Seeck 1University Hospital of Geneva (Geneva, CH)
Decrease of cognitive functions is a well known, unfavorable side effect of chronic epilepsy, due to the active epileptic focus and/or concomitant antiepileptic drug treatment. In the context of presurgical epilepsy evaluation, procedures using neuropsychological testing are applied to accomplish several tasks: to determine overall functioning, to localize the focus, or to determine vital cortex which needs to be spared when resecting cerebral tissue. More recent approaches which were developed to achieve these tasks are: fMRI based methods and postictal neuropsychological testing. They help to avoid invasive procedures, such as the intracarotid amytal test (IAT), in many patients. In a recent own study, postictal memory assessment was found superior in lateralizing memory performance compared to the interictal testing in patients with temporal lobe epilepsy. While there is a large body of fMRI studies on language lateralization, fMRI memory studies are few and lateralization of verbal/nonverbal memory with fMRI is less well established. Hopefully, lateralization and localization of cognitive functions will be carried out solely with non-invasive techniques, in particular since there is evidence that the corticography and IAT may not be the gold standard in every patient.
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1 S. Ruf , 1 I. Krägeloh-Mann , 1 M. Wolff 1University Children's Hospital (Tubingen, D)
Purpose: For many years ACTH and steroids have been used in the treatment of drug resistant childhood epilepsies, especially in children with West syndrome. However, severe side effects have been reported using ACTH and continuous treatment with steroids. We present efficacy and adverse effects of an alternative scheme using pulsatile steroids per os in outpatients.
Patients and methods: 20 patients with drug resistant epilepsies aged five months to 16 years were selected: West syndrome N = 11, Continuous spike and waves during slow sleep (CSWS) N = 5 (Landau- Kleffner syndrome N = 2, atypical benign focal epilepsy N = 3), focal epilepsy with secondary bisynchrony N = 2, and childhood absence epilepsy N = 2. The children were treated using a pulsatile steroid scheme per os (25mg/kg/d for three days once a week for four weeks followed by a variable tapering phase). Epilepsy and EEG data as well as adverse side effects were documented before treatment, after four weeks and at the end of the therapy.
Results: From the 11 children with West syndrome, six became seizure-free, and hypsarrhythmia disappeared in four of them. In three children seizure frequency was reduced > 50%. In the children with CSWS, EEG improved markedly in one child and slightly in two. In the two children with focal epilepsy and secondary bisynchrony no effect occurred. The two children with absence epilepsy became seizure free during follow up. There were no serious side effects in all of the children.
Conclusion: In this cohort of children with extremely pharmacoresistant epilepsies the pulsatile steroid therapy was partly effective. Severe side effects did not occur. Therefore, we suggest a broader and earlier use of steroids in pharmacoresistant childhood epilepsies.
1 G. Ramantani , 1 O. Wunderlich , 1 D. Friebel , 1 H. Ikonomidou 1Technical University Dresden (Dresden, D)
Encephalocraniocutaneous lipomatosis (ECCL), also known as Fishman syndrome, is a rare congenital neurocutaneous disorder comprising unilateral cranial lipomas, lipodermoids of the eye and brain abnormalities. Epileptic seizures and a consequent significant developmental delay are usually present. We report the clinical, electroencephalographic and neuroimaging findings over the years in a presently 6-year-old girl diagnosed with ECCL in the first months of life. The patient showed infantile spasms at the age of two months and remained seizure free over 2 years under vigabatrin treatment. At the age of 18 months, a mild spastic hemiparesis was diagnosed, which improved markedly with physical therapy. The cognitive development was estimated in the lower normal range. The cutaneous and ocular lesions remained unchanged over time. The EEG initially showed a burst-suppression pattern in the neonatal period, which evolved into an asymmetric activity with a continuous spike wave focus corresponding to the cerebral malformation. The MRIs showed a hemimegalencephaly with an enlargement of the lateral ventricle on the affected side, widening of the subarachnoid spaces, a lack of normal insular opercularisation, dysplastic cortex in the temporoparietooccipital region, corticopial calcifications, arachnoid cysts of the middle cranial fossa and thinning of the corpus callosum. The progressive enlargement of the lateral ventricle in the first years of life showed spontaneous regression, so that no ventriculoperitoneal shunt was necessary. Functional magnetic resonance imaging revealed transfer of motor functions to the unaffected hemisphere, in accordance to the hypothesis of functional reorganization. Furthermore, the results of functional imaging, including PET, SPECT and MR-Spectroscopy pointed towards an increased cerebral blood flow in the affected hemisphere, possibly due to intermittent ictal events. These features were consistent with ECCL. Most children with ECCL are reported to have a significant developmental delay; however in our case seizure control is associated with a considerable improvement in developmental outcome.
1 T. Gerstner , 1 D. Büsing , 1 E. Longin , 1 S.A. König 1University Children's Hospital (Mannheim, D)
Introduction: Valproic acid (VPA) is a commonly prescribed medication for generalized and focal epilepsy, migraine, neuropathic pain and bipolar disorder. The common side effects associated with VPA are typically benign, less common but more serious adverse effects may occur. These include hepatotoxicity, hyperammonemic encephalopathy, coagulation disorders and pancreatitis.
Method: We mailed a questionnaire to all 1200 members of the “German Section of the International League against Epilepsy,” containing questions about VPA-induced side effects from the years 1994 to 2003.
Results: We received 450 answers (37.5%) to our questionnaire. To our surprise 254 (56.4%) of the physicians never noticed any severe side effects of VPA.
31 cases of VPA associated-hepatotoxicity were seen by German physicians from 1994 to 2003, including nine cases of fatal liver failures and 22 reports of reversible hepatopathies, 44 cases of VPA-associated pancreatitis were reported, 27 cases of encephalopathy and 42 patients suffered of a VPA-associated coagulopathy. Additionally, one case of change of the hair colour and 10 events of massive weight gain (>15%) were reported.
Conclusion: In Germany 208,320 persons are under VPA-medication (date: November 2005). Due to this amount of patients, VPA-associated side effects should be recognized observant. Our query showed more than 50% of all questioned physicians never recognized any side effect, suggesting a very good tolerance of this drug. On the other hand, sever side effects (hepatotoxicity, pancreatitis and encephalopathy) are more likely as the literature supposed. Concomitant the outcome seemed to be better, if the side effect was recognized in time.
1 J. Dobesberger , 1 G. Brössner , 1 K. Seppi , 1 G. Walser , 1 R. Ehling , 1 I. Unterberger , 1 E. Schmutzhard , 1 E. Trinka 1Medical University Innsbruck (Innsbruck, A)
Purpose: Status epilepticus (SE) as well as seizure clusters are emergencies which require immediate and efficacious treatment. To date, intravenous (IV) benzodiazepines (BZD) as well as IV phenytoin (PHE) and IV valproic acid (VPA) are widely used antiepileptic drug (AED) therapies in these situations. This study aimed to investigate the effectiveness and tolerability of IV levetiracetam (LEV) in treatment of seizure clusters and SE.
Methods: All patients treated with IV LEV between August and December 2006 were retrospectively enrolled in our study. Indications for treatment, dosage, responsiveness and side effects were evaluated.
Results: 13 patients (six women and seven men, median age 60 ± SD 25 years) were consecutively treated with IV LEV. Indications for IV LEV were (1) nonconvulsive SE refractory to standard first-line therapy (i.e., BZD, PHE and VPA) in four patients, (2) IV LEV administration after successful treatment of nonconvulsive SE (i.e., BZD) in three patients and (3) seizure clustering triggered by AED reduction during video-EEG monitoring in six patients (rapid titration group). 10/13 patients suffered from focal epilepsies before study enrolment; 3/13 had no previous history of seizures. Dosage evaluation revealed that in 11 patients a bolus of 1000 mg IV LEV was initially administered and the two other patients were initiated with 500 mg IV LEV. All patients received oral LEV after treatment with IV LEV.
Outcome: Nonconvulsive SE was terminated with IV LEV in 3/4 patients after the initial dosage, one patient was resistant to all therapeutic advances. In the other 9 patients, IV LEV was effective in terminating SE/seizure clusters and no relapses occurred following treatment. No side-effects were observed.
Conclusions: These data suggest that IV LEV can be used as a safe alternative to standard AED therapies for acute treatment of seizure emergency situations, although larger studies are required to confirm these findings.
1 A. Reinshagen , 1 M. Holler , 1 H. Fritz , 1 F. Hoffmann 1Martha-Maria Hospital Halle-Dölau (Halle/Saale, D)
Purpose: Levetiracetam (LEV) is recently available as an intravenous (IV) formulation in Germany for use in patients unable to receive oral therapy. The use in status epilepticus (SE) is not yet reported; are there implications to improve status epilepticus therapy.
Method: We report on the use of IV LEV in six patients with different types of refractory status epilepticus, well documented why not to receive other anticonvulsive medication for status epilepticus.
Results: We present 1) the case of a of focal myoclonic SE due to a cortical ischaemic infarction in a 52 years old female with severe hepatopathy with coagulation disturbances, 2) the case of a complex-focal nonconvulsive status epilepticus in a male patient aged 41 years with symptomatic epilepsy and multiple sclerosis, who was on treatment with lamotrigine (LTG), 3) the case of a subtle status due to thrombopathia in a 80-year-old female, 4) the case of a 66-year-old male patient in persistent vegetative state with EEG-proved generalized SE on treatment with LTG, 5) a case of an ICU female patient, 81-year-old, with persistent myoclonic seizures and 6) a multimorbid ICU male patient aged 36 years with presumed vegetative state, but burst-suppression pattern EEG.
All of them were insufficiently treated with benzodiazepins and other anticonvulsive drugs before the decision for IV LEV (last case high dose LEV via gastrostoma) was made.
In 5 of 6 cases IV LEV stopped or helped stopping the refractory status with more or less well documented time courses, patient 1 after 30 min, patient 6 after at least 2 hrs. Patient 3 died without achieving consciousness, the patient (6) with high-dose LEV (6 g) experienced optical hallucinations after a long lasting coma.
Conclusion: There are poor data for SE therapy, for therapy of refractory status an aggressive treatment with sedation seems to be necessary. IV LEV appears to be a promising treatment for refractory status epilepticus without sedation and with no need for ICU as shown in the reported cases. There is need for more data and especially the time course of anticonvulsive effect of IV LEV in SE.
1 E. Gelpi , 1 L. Urak , 1 T. Czech , 1 H. Mayer , 1 G. Patzl , 1 M. Freilinger , 1 A. Dressler , 1 D. Prayer , 1 G. Kasprian , 1 J. Hainfellner , 1 M. Feucht 1Medical University of Vienna (Vienna, A)
Objective: To correlate clinical and radiolgical parameters with neuropathological findings of children with intractable seizures associated with abnormalities of cortical development.
Material and methods: Children <18 years who underwent surgery for refractory epilepsy associated with abnormalities of cortical development and other nontumorous lesions were selected for this study. Structural and functional brain imaging was performed in all patients. Clinical follow-up data were available for all patients. Neuropathological workup of surgical specimens was blinded to clinical and outcome data. Malformations caused by abnormalities of cortical development (MCD) were classified according to Palmini et al.
Results: Of a total of 93 children operated at the Medical University of Vienna, Austria, between 1996 and 2006, 21 (13 males, 8 females) met inclusion criteria. Mean age at onset of epilepsy was 2.3 years (range 1 day-9 years). Mean age at surgery was 7 years and 2 months (median 5y6m; range 3 months-23.4 years). Mean interval between onset of seizures and epilepsy surgery was 57.5 months (median 33 months; range 2-259 months). Lobar distribution was as follows: 8 temporal, 4 frontal, 1 postcentral, 2 occipital, 1 parietooccipital. 3 children showed hemimegalencephaly, 1 schizencephaly and polymicrogyria and 1 patient hemiatrophy. Surgery types comprised cortical resection, extended lesionectomy, and functional hemispherotomy. Neuropathological findings confirmed radiological interpretation in 18/21 cases. Histological diagnoses comprised: 9 focal cortical dysplasia (FCD) type II B according to Palmini's classification, 3 FCD type II A, 1 FCD IA, 1 FCD 1B, and 2 cases with mild MCD type II. Additionally, 2 cases showed diffuse astrogliosis and 3 cases normal grey matter. One patient had additionally polymicrogyria. Dual pathology (FCD type IIB and hippocampal sclerosis) was observed in only 1 case. Seizure free status after operation was achieved in 81% of patients. Postoperative outcome was class 1 in 17, class 3 in 2 and class 4 in 2/21 children according to Wieser's classification. Postoperative complications appeared only in 1 patient who developed an hygroma.
Conclusion: Epilepsy surgery in children with abnormalities of cortical development achieved excellent outcomes in term of seizure control and neurodevelopmental performance in the Austrian patient cohort. Early operation from onset of seizures and extended cortical resections yielded better outcome.
1 H. Clusmann , 1 O. Schijns , 1 C.G. Bien , 1 M. von Lehe , 1 H. Urbach , 1 M. Majores , 1 T. Kral , 1 J. Schramm , 1 C.E. Elger 1University of Bonn (Bonn, D)
Purpose: With the evolution of high-resolution MR-techniques signal alterations mainly in the area of the temporal pole are detected more frequently in patients with temporal lobe epilepsy (TLE). The impact of these findings, often accompanied by hippocampal sclerosis, is unclear.
Methods: We identified 370 patients undergoing different subtypes of temporal resection for TLE between 2000 and 2006 in a prospectively collected epilepsy data base. Radiological and histological reports were screened for the presence of temporo-polar gray-white matter abnormalities (GWMA).
Results: Abnormalities of “gray- and white-matter differentiation” were identified in 75 patients (rate 20%). Mean seizure onset was 7 (0,5-28) yrs, compared to 12 years (0.5-42) yrs in a matched control group without this feature, however preoperative epilepsy duration was similar. All patients underwent non-invasive video-EEG-monitoring and 28 patients (37%) had invasive EEG-monitoring with chronically implanted electrodes. Presurgical evaluation resulted in one of the following strategies: Of 58 patients with hippocampal sclerosis and presence of GWMA 29 patients underwent selective amygdalohippocampectomy (SAH), without resection of the area of GWMA. Another 29 underwent tailored temporal resections including the GWMA and the hippocampus. Seizure control was virtually equal (72–79% Engel Class I outcomes) with the two different approaches and compared to the matched controls without temporo-polar GWMA. In 17 patients GWMA was found to be the only pathology: only 58% of these patients had an Engel Class I outcome. If present, histological examination revealed gradual disturbances of gray- and white-matter differentiation in the majority of cases. There was no mortality and no permanent morbidity, except for expected visual field defects. Initial precipitating injuries (IPI) were predominantly associated with the presence of isolated hippocampal sclerosis.
Conclusions: Detailed presurgical evaluation enabled either limited or tailored resections with similar success rates, in patients with or without the presence of GWMA. Hippocampal sclerosis and concomittant temporo-polar abnormalities should be recognized and considered upon presurgical evaluation, however, the presence of GWMA does not exclude the use and potential benefit of limited resections.
1 M.A. Nitsche , 2 S. Thome-Souza , 2 S. Freedman , 2 K.D. Valente , 2 A. Pascual-Leone , 1 W. Paulus , 2 F. Fregni 11 Georg-August-University (Gottingen, D) ; 2 Harvard Medical School (Boston, USA)
Purpose: Transcranial direct current stimulation (tDCS) has been shown to be an effective noninvasive tool for inducing prolonged cortical excitability diminutions in healthy humans. Since cortical hyperexcitability is a critical condition for epileptic seizures in patients with cortical malformations, tDCS might diminish cortical epileptiform activity in these patients and reduce seizure frequency and severity. In this pilot study, we aimed to study the effects of cathodal DC polarization in patients with refractory epilepsy and malformations of cortical development (MCDs) as indexed by seizure frequency and epileptiform EEG discharges.
Methods: Nineteen patients with MCDs and refractory epilepsy underwent one session of DC polarization (20 min, 1 mA) targeting the epileptogenic focus. The number of epileptiform discharges (EDs) in the EEG and seizures were measured before (baseline), immediately after, and 15 and 30 days after either sham or active DC polarization. Seizure frequency after the treatment was compared with baseline.
Results: Active compared with sham DC polarization was associated with a significant reduction in the number of epileptiform discharges [mean ED reduction of −64.3% (95% CI, −122.5% to −6.0%) for the active treatment group and -5.8% (95% CI, −26.8% to 15.2%) for the sham treatment group]. A trend (p = 0.06) was noted for decrease in seizure frequency after active compared with sham treatment [mean seizure frequency decrease of −44.0% (95% CI, −95.0% to 7.1%) for the active treatment group and −11.1% (95% CI, −22.2% to 44.4%) for the sham treatment group].
Conclusions: This randomized, controlled study shows that cathodal DC polarization does not induce seizures and is well tolerated in patients with refractory epilepsy and MCDs. Furthermore, the results suggest that this technique might have an antiepileptic effect based on clinical and electrophysiological criteria.
1 J. Sperner , 1 J. Mertin , 1 H. Fiebelkorn , 1 H.J. Friedrich 1University Hospital Schleswig-Holstein (Lubeck, D)
Purpose: To investigate the immediate EEG changes during VNS on-time compared to VNS off-time in patients with pharmacoresistant epilepsy in correlation to VNS outcome.
Methods: 64 EEGs from 15 patients treated with VNS were investigated using quantitative automated, Fast-Fourier-Transformation-analysis (FFT). Routine scalp-EEGs (10-20-System) were analyzed to compare VNS on- (30 s) and off-time (3 or 5 min) in relation to output current and clinical outcome. FFT was applied in each EEG with at least 20 epochs (3 s duration) during on- and off-time. Changes of the power-spectra (amplitude2) and the gamma frequency band (20-32 Hz) during VNS on time were calculated for each of the 19 electrodes of the EEG.
Results: Eight patients (receiving 28 EEGs) were termed as VNS nonresponders because of seizure reduction less than 50%. Seven patients (receiving 36 EEGs) were termed as VNS responders. The overall significance of gamma-frequency increase was p = 0,001 (Mann-Whitney U test) in VNS responders. The differentiation into three classes of VNS output current revealed a significant increase of gamma frequency in the low (0,5-1,5 mA) and the medium (1,75-2,0 mA) current group, but no change in the high group (2,25-3,25 mA). This was taken as a striking argument, that the increase of fast EEG frequency band is not due to the stimulation artifact, but is a VNS induced, brain generated oszillation.
Discussion: These results clearly show quantitative EEG differences in VNS responders compared to nonresponders. The gamma frequencies are well known to originate from the locus coeruleus, which plays an important role in transmitting the anticonvulsive VNS effect in animal models of epilepsy. When the locus coeruleus is removed in experimental epilepsy models, the VNS therapy does not work any longer. Further studies are indicated to clarify the role of fast EEG frequencies during VNS therapy.
1 B. Huber , 1 M. Knoop 1Epilepsy Center Bethel (Bielefeld, D)
Purpose: Epilepsy patients who continue having seizures despite therapeutic efforts are at an increased risk of suffering injuries. Our aim was to collect data on the number, severity and circumstances of seizure-related injuries occurring in residential patients of an epilepsy centre. A further aim is to examine if part of the injuries can be avoided by protective measures.
Methods: Questionnaires were distributed and collected monthly over a period of 16 months in a defined part of the residential department for staff to report all injuries (requiring any kind of treatment) happening in the context of seizures.
Results: 273 injuries were reported; in 65 cases the relation to a seizure was uncertain – these were excluded from further evaluation. 122 injuries were mild (like abrasions, contusions, sprains), 80 were moderate (lacerations, cuts, one luxated shoulder), and 20 were severe (all fractures). No very severe events (like intracranial bleeding, other life-threatening conditions or permanent damage) were reported but one patient died from SUDEP. Head lacerations were the most frequent type of injury. More injuries occurred within the home (either in the patient's private room or in the common rooms) than at the workplace or out of doors. There appeared to be a core group of approx. 40 patients (out of 500 covered by this investigation) with repeated and/or severe injuries.
Discussion: Injuries remain a major burden for the person with therapy-resistant epilepsy. A majority of them happens at home – an environment that can be shaped by the person affected and his/her carers. In a second step of this project we are going to examine individually all of the patients of the above mentioned “core group” with respect to possible protective measures in their personal environment as well as for remaining medical therapeutic options.
1 M. Bergmann , 1 J. Ndayisaba , 1 W. Oberaigner , 1 G. Kuchukhidze , 1 E. Trinka 1University of Innsbruck (Innsbruck, A)
Introduction: Sudden unexpected death in epilepsy patientes (SUDEP) accounts for up to two third of fatalities in selected populations with drug resistant epilepsy. Incidence rates vary substantially between 0.3 and 10/1000 person years (PY) according to the design of the studies. The incidence of sudden unexpected death in epilepsy patientes (SUDEP) in Tyrol is unknown therefore we aimed to analyze SUDEP cases using a hospital based record linkage system.
Methods: All patients with definite epilepsy (n = 3334) treated at the outpatient epilepsy clinic of the Universitätsklinik für Neurologie, Innsbruck, Tyrol, between 1.1.1970 and 31.12.2000 were included in the study. Epilepsy diagnosis was based on the ILAE classification. Living or dead status was obtained from the Institut für Klinische Epidemiologie, TILAK, Innsbruck and the Landesstatistik Tirol using a specialized probabilistic record linkage. Patients were followed until death or 31.12.2003. A total of 48.595 person years were analyzed. All patients with ICD-9 codes G40.0-G41.9 (i.e., “epilepsy”) were further analyzed in detail (n = 43). Based on expert chart review we classified SUDEP cases as: definite, probable, possible and no-SUDEP cases. Incidence rates and proportional mortality of definite and probable SUDEP were calculated in relation to the total mortality of the cohort in the same time period.
Results: Five pts. had definite, 7 probable and 22 possible SUDEP. Eight pts had no SUDEP; (one of them was a near SUDEP case). In our cohort incidence rates of SUDEP (definite and probable) was 0.2/ 1000 person years. SUDEP (definite and probable) accounted 1.8% of all deaths caused by epilepsy in the Tyrol cohort.
Conclusion: SUDEP is a rare cause of death in the general epilepsy population. The results of Tyrol cohort reflect population based incidence rates and are compareable to population based studies about SUDEP.
1 A.C. Lang-Dullenkopf , 1 P. Weber 1University Children's Hospital Basel (Basel, CH)
Introduction: The hippocampal formation is an essential region in temporal lobe epilepsy. The development of hippocampal sclerosis is in discussion. The relevance of this gliosis for temporal seizures seems clear, if a hippocampal sclerosis could be developed due to seizures is unclear. Reversible posterior leukoencephalopathy syndrome (RPLS) is a brain disorder most commonly associated with malignant hypertension, toxemia of pregnancy, or the use of immunosuppressive agents. It is associated with an inflammation of the brain.
Case report: We describe a male patient with hippocampal sclerosis developing after RPLS. Normal development until the age of 5 years. Diagnosis of a leukemia at the age of 5 years. Initiation of chemotherapy according to study protocols after documentation of a normal EEG and brain MRI. Some days after the end of the first chemotherapy he developed visual hallucinations with small manikins walking at the wall. Some days later the boy suffered from 2 complex partial seizures on the right side with disorientation, yawning and speech difficulties. A therapy with phenobarbital and aciclovir intravenously was initiated. The MRI findings were consistent with RPLS. In the initial MRI the hippocampal formation was normal. Further on the patient developed seizures with swallowing and smacking. Therefore we started a medication with oxcarbazepin and later on with phenytoin. Two years later worsening of seizure frequency and new seizure types (epigastric aura, visual and psychomotoric phenomenons) developed. At this time chemotherapy was stopped according to study protocols. Now the MRI findings were consistent with a left hippocampal sclerosis. Now the patient is seizure free treated with lamotrigine 300mg/d.
Discussion: We assume that in this case a healthy boy without any preexisting neurological signs developed hippocampal sclerosis after inflammation and seizure activity. In animal studies it is described that hippocampal sclerosis can evolve after high seizure activity or after inflammation. In this case we cannot differentiate what was the origin of the new pathologic entity but we can properly show the development of hippocampal sclerosis.
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Session: Mitochondrial diseases in epileptology
1 W. Sperl 1Paracelsus Private Medical University (Salzburg, A)
Mitochondria are organelles of the cell with a key function in energy supply. Furthermore mitochondria play a role in apoptosis and can generate reactive oxygen species (ROS). These three components, energy deprivation, induction of apoptosis and radical damage have major input for pathophysiological processes. Mitochondrial dysfunction is usually gradual and may occur as metabolic disease but is also part of civilisation diseases and important in tumour formation and aging. Proper function of the mitochondrial energy metabolism requires more than 100 enzymes, including membrane transport, metal ion-, vitamin- and lipid metabolism, which highly complicates the diagnosis. Secondary disorders can occur by inhibition of various enzymes due to toxic metabolites or substances. Oxidative phosphorylation, the central part of the metabolism, consists of multisubunit enzyme complexes; parts of them are encoded on the nuclear, parts on the mitochondrial genome. Defects of the mitochondrial DNA only affect the energy metabolism and mitochondrial genetics differs in several aspects from nuclear genetics.
Mitochondrial dysfunction can affect various organs, especially those with high energy demand. Therefore diseases with (cardio-)muscular and CNS involvement have been found first (mitochondrial encephalomyopathies). Mitochondrial diseases usually affect more than one organ, however tissue-specific forms are also known. Some disorders do not present primarily with an affection of the neuromuscular system, e.g., mitochondrial hepatopathy, cardiomyopathy. A number of mitochondrial syndromes like MELAS, MERRF, NARP, KSS, Pearson, CPEO, LHON, MNGIE, Barth, Leigh, Alpers-Huttenlocher etc. have been defined. Some of them have a unique genetic cause but in some syndromes also defects in different enzymes can result in the same phenotype. Many patients do not fit into syndrome criteria and therefore diagnostics has to be performed stepwise. Lactate elevation in body fluids can be a hallmark for diagnosis, but can be unspecific and may be absent in several patients. Magnetic resonance imaging, spectroscopy and other organ investigations can point to a mitochondrial disease. In most cases the diagnosis can be made by functional biochemical analysis (functional investigations in isolated mitochondria from fresh muscle tissue and respiratory chain enzyme investigations including ATPase and PDHC) and histological and histochemical investigation of a tissue (muscle) biopsy. Genetic analysis of target genes proofs such a defect and is the basis for genetic counselling.
Therapy of disorders of the mitochondrial energy metabolism is limited in most cases. It is mainly based on the enhancement of remaining enzyme activities by increased cofactor supplementation. Furthermore, toxic radicals are tried to be reduced by antioxidant support. Pyruvate oxidation defects can be treated remarkably by ketogenic diet, which provides an alternative energy fuel for these patients. Gene therapy has only been tried in vitro till now.
In summary diagnostics of mitochondrial disorders is complex and requires an individually adapted diagnostic cascade performed in cooperation with highly experienced diagnostic centers with quality criteria and international cooperation. Randomized prospective multicenter studies are required to improve therapy.
1 S. Gallati , 1 A. Schaller 1University Berne (Berne, CH)
Hereditary mitochondrial disorders (MCDs) are caused by mutations in the mitochondrial DNA (mtDNA) or nuclear DNA, resulting in extremely variable single- or multisystem diseases with onset between birth and senescence. Even the same molecular defect can associate with diverse phenotypes. One of the most common mtDNA mutations, the A3243G transition in the tRNALeu(UUR) gene, is mainly associated with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), but also with various other types of multisystemic diseases such as progressive external ophthalmoplegia (PEO), diabetes and deafness.
Clinical and molecular genetic findings of three patients and family members carrying the A3243G mutation will be presented:
M.A. with epilepsy, admitted to the hospital because of sudden severe exacerbation, died two weeks later at the age of 11 years.
B.B. with diabetes and deafness, 3 spontaneous abortions, one son developing first symptoms (bilateral hearing loss, muscle weakness, seizures) at the age of 10 years.
G.W. with epilepsy, diabetes, hearing loss, progressive dementia, ataxia, brain atrophy, death at the age of 62 years. Although the noninvasive genetic testing of blood samples is common and successful in many cases, A3243G mutation levels are known to decrease in this tissue during ageing and to exist at consistently higher mutation levels in postmitotic tissues.
Patients M.A., B.B. and her son showed 64%, 20%, and 47% respectively of mutated mtDNA in blood, whereas the A3243G amount in muscle tissue from the son was 67%. For patient G.W. the mutation was only detectable in mtDNA isolated from brain parenchyma but not in muscle tissue and blood. This phenomenon may be explained by the fact that embryologically, muscle derives from mesodermal whereas CNS derives from ectodermal germ layers. Although, molecular genetic analysis of skeletal muscle is widely accepted as to be the ‘gold standard’ in routine diagnostics of patients with suspected MCD, our findings demonstrate, that testing of muscle mtDNA still includes the risk to yield false negative results.
In conclusion, our findings underscore the fact that phenotypic expression of MCDs depend on a threshold effect based on mitotic segregation and polyploidy on the one hand and on the nature and localization of a mutation, its tissue distribution as well as the energy needs of an organ on the other hand. Family members were provided with this complex information in the context of genetic counselling and the extreme difficulty to interpret testing results of at-risk individuals and to predict phenotypes and clinical courses was discussed. Moreover, the phenotypic presentation of the A3243G mutation, originally described as MELAS mutation, is extremely heterogeneous, meaning that, in fact, A3243G is associated with but not diagnostic for MELAS per se.
1 T. Dorn 1Swiss Epilepsy Centre (Zurich, CH)
Background: Mitochondrial cytopathies (MC) are a huge group of genetic diseases having respiratory chain dysfunction in common which causes dysfunction of tissues using oxydative phosporylation such as nervous system, muscles and heart. Epileptic seizures are a frequent symptom when cerebral cortex is involved. One subgroup of MC is caused or associated with mutations, deletions or rearrangements of mitochondrial DNA (mtDNA). These alterations of mtDNA, however, are usually not present in each mitochondrium, cell or tissue, i.e., they are heteroplasmic. Furthermore, the number of altered mtDNA copies usually increases during life time explaining the progressive nature of these entities with symptoms occurring after the number of altered mtDNA copies has exceeded a tissue specific threshold value. Thus, patients with the same mutations can differ considerably with respect to type, age at onset and severity of symptoms as well as with respect to velocity of disease progression. Despite these differences the involvement of different parts of the nervous sytem (especially occipital cortex, retina, n. opticus, inner ear), muscles and heart in course of disease progression often enables the suspicion of mitochondrial disease which should cause further diagnostic procedures including mtDNA analysis of cells of different tissues (usually blood and muscle). But one can assume that due to heteroplasmy patients with, for example, symptoms generated by only one part of the brain – at least at the beginning of their diesease – should exist. Therefore as epileptologists we have to ask whether there are MC patients with epileptic seizures as the outstanding symptom for a long time. If this is the case we have to clarify how MC can be diagnosed in these patients because in MC valproic acid being often used as initial monotherapy in generalized and focal epilepsies should not be used because of ist potential to cause fatal liver failure. In order to answer these questions two MC patients are presented with a predominat epileptological phenotype showing course of and difficulties in the diagnostic process.
Case Reports: Patient 1, female, born 1974 had a mother with a left branch bundle block and a father suffering from migraine. After a syncope 1986 a slowly progressive syndrome emerged with multifocal myoclonias, rare generalized tonic–clonic and frequent occipital seizures, headache, ataxia and slight neuropsychological impairment. Finally hypacusis was diagnosed in 1999. Most important paraclinical findings were giant visual and somatosensory evoked potentials, mild cerebellar atrophy in MRI, slightly elevated cerebrospinal fluid lactate levels and absence of ragged red fibres in muscle biopsy. 1995 analysis of lymphocyte mt-DNA showed no point mutation between positions 8167 and 9049, thus, MERRF was excluded. In 1999 a mutation in the EPM1 (CSB) gene had been excluded. However, a sensitive quantitative allele-specific PCR which was performed because of hypacusis revealed a heteroplasmic point mutation T3271C in lymphocyte mt-DNA. After the diagnosis of MC had been established the patient suffered from stroke like episodes for several times underpinning the diagnosis of MC. Patient 2, male, born1950 with partial seizures and sometimes myoclonic jerks since 1960, seizure freedom since 2000 under an antiepileptic polytherapy with oxcarbazepine, primidone and clobazam, normal MRI, mild left frontotemporal neuropsychological signs. Repeatedly observed slight increases of creatine kinase without clinical signs of myopathy led to an EMG which showed only mild neurogenic changes. An ophthalmological examination including VEP and perimetry because of increasing visual disturbances since 2001 disclosed optic nerve atrophy without ocular movement disorders. After exclusion of an autoimmune disease an extended analysis of mtDNA in blood cells demonstrated a homoplasmic polymorphism (T9582C) which was also found in his two asymptomatic brothers. Finally in mtDNA of a muscle biopsy which otherwise showed only mild neurogenic changes, no ragged red fibers and normal oxphos activity a heteroplasmic 7.4 kb deletion going beyond the Kearns-Sayr deletion was found.
Discussion/Conclusion: These two cases demonstrate that epileptological features can be predominant in the phenoptype of MC and be almost the sole symptom for a long time in the course or at least at the beginning of the disease. Thus, in each patient with first seizures we closely have to look for mild mitochondrial signs and symptoms, especially when treatment with valproic acid is planned.
1 W.S. Kunz 1University of Bonn (Bonn, D)
The specific pathophysiological significance of mitochondria in epilepsy is documented by the genetic association of mutations in mitochondrial tRNA genes with certain forms of myoclonic epilepsy. Frequent mitochondrial tRNA mutations which are relevant for routine genetic testing are the A8344G MERRF mutation in the tRNA lysin gene and the A3243G MELAS mutation in the tRNA leucin(UAA) gene. Recent investigations confirm also in Alpers syndrome, a myoclonic epilepsy in children, a direct mitochondrial cause. Here, mutations in the mitochondrial DNA polymerase gamma (POLG1) have been associated with the disease. Especially frequent are the pathogenic mutations A467T or W748S, which are met homozygeous or in the compound heterozygeous state with other rare POLG1 mutations in nearly all Alpers patients. These mutations lead by inhibition of replication of mitochondrial DNA in postmitotic tissues to multiple deletion of mitochondrial DNA or to the depletion of mitochondrial DNA. The functional consequences of depletion of mitochondrial DNA on mitochondrial oxidative phosphorylation are similar to the effects of pathogenic mitochondrial tRNA point mutations. It has to be noted, however, that in the Alpers patients the effects of depletion of mitochondrial DNA are especially severe in liver, which causes the extremely high toxicity of valproic acid.
Even in hippocampal tissue of patients with temporal lobe epilepsy and Ammons horn sclerosis local pathologies of mitochondrial respiratory chain were detected. In the hippocampal CA3 region a deficiency of mitochondrial respiratory chain complex I was shown which molecular cause is – similar to the Alpers syndrome – a depletion of mitochondrial DNA. The direct cause for this depletion of mitochondrial DNA is however not a nuclear mutation but a status epilepticus-associated increased oxidative stress leading to increased DNA turnover.
Thus it has to be concluded that pathologies of mitochondrial function appear to have a direct causal relationship to certain forms of epilepsy.
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Poster session 1.1. Clinical epileptology: new antiepileptic drug
1 G. Kuchukhidze , 1 M. Rauchenzauner , 1 T. Gotwald , 1 E. Haberlandt , 1 S. Felber , 1 E. Trinka 1Innsbruck Medical University (Innsbruck, A)
Purpose: Joubert syndrome (JS) is an autosomal recessive neurodevelopmental disorder characterized by molar tooth malformation on MRI and clinical presentation with neonatal hypotonia, episodic hyperpnea, ataxia, developmental delay, mental retardation and oculo-motor apraxia. Abnormalities of dentate nucleus are rare in JS and their clinical significance is poorly understood (Maria, 1999). Epilepsy found in concert with infratentorial dysplasias or in association with JS is also rarely reported.
We present three patients with JS, agenesis of dentate nucleus and epilepsy in an attempt to shed more light on this rare association.
Patients and methods: Patient 1, a 7-year-old, mentally retarded boy with an unremarkable family history of neurological diseases had muscular hypotonia, infantile spasms, mild ataxia and global developmental delay.
Patient 2, a 23-year-old woman suffering from symptomatic epilepsy with generalized tonic–clonic seizures, learning disability, convergent squint, mild gait ataxia and dysmorphic facial features. Her seizures began at the age of 12 and were poorly controlled by different anticonvulsants. Her family history was negative with regard to neurological diseases.
Patient 3, a 12-year-old boy with delayed developmental milestones, mental retardation, generalized epilepsy with tonic seizures and absences, hypoacusis, convergent squint and gait ataxia. His family history of epilepsy or other neurological diseases was unremarkable.
All patients underwent thorough clinical examination, EEG recordings, neurophychological testing and high resolution MRI (1.5 T). MRI sequences included T1-weighted gradient echo 3D MPRAGE with and without IV contrast application, axial and coronal T2-weighted turbo spin echo, T1 inversion recovery, T2-weighted fast FLAIR and diffusion weighted sequences.
Results: Three patients presented with typical clinical and MRI features of JS. Additionally all patients had agenesis of dentate nucleus on MRI and all suffered from symptomatic generalized epilepsies. Parents were not related in any case and patients were born after uneventful pregnancy and labor. Cerebellar foliation, basal ganglia, cerebral cortex and pituitary gland were normal. No white matter abnormalities were observed and MRI changes were not progressive over time.
Conclusion: Abnormalities of deep brain structures (brainstem and cerebellum) might contribute to the pathophysiology of symptomatic generalized epilepsies in patients with JS.
1 S. Dempewolf , 1 S. Bunten , 1 S. Happe 1Hospital Bremen East (Bremen, D)
Objective: Sleep deprivation (SD) is a commonly used method to increase the diagnostic yield of the electroencephalogram (EEG), especially in the evaluation of patients with suspected epilepsy. In different studies, the observed rate of epileptic activity achieved by SD is varying from 13% to 52%.
Patients and methods: We retrospectively studied all EEGs of patients aged 16 years or older examined in our department between January 2000 and June 2006, who, after having undergone an initial routine EEG recording, had been examined with a second recording after full-night SD (n = 831). Most of the patients were admitted to our hospital because of a loss of consciousness of unknown origin (n = 634). Forty-three patients were suffering from known epilepsy of unknown etiology. One hundred eight patients were referred to our department because of a focal neurological deficit and 46 patients because of other complaints.
Results: Altogether, routine EEG showed epileptic activity in 4.9% and EEG following SD in 14.6%. The percentage of occurrence of epileptic activity did not differ in routine EEG (1.9%) and EEG after SD (2.6%) in patients without epileptic symptoms (n = 313). In patients diagnosed a first epileptic seizure (n = 270), however, the proportion was 2.6% vs. 6.3%, in focal epilepsy (n = 153) 9.8% vs. 40.5%, in generalized epilepsy (n = 38) 31.6% vs. 73.7%, and in unclassified epilepsy (n = 31) 6.5% vs. 12.9%. Epileptic discharges were recorded in a routine setting in 3.8% and after SD in 7.7% in patients (n = 26) whose symptoms remained unexplained.
Conclusion: Our data confirm the diagnostic value of EEGs following sleep deprivation. In many cases, it is helpful to distinguish between epileptic and non epileptic seizures and to specify epileptic syndromes.
1 I. Unterberger , 1 R. Unterpertinger , 1 G. Bauer , 1 E. Trinka 1Medical University Innsbruck (Innsbruck, A)
Background: Familial myoclonic epilepsies are characterized by an adult onset of epileptic seizures [myoclonias, generalized tonic–clonic seizures (gtcs)], a family history of seizures and a benign course of the disease. Genetic heterogeniety could be demonstrated.
Aim: The aim of our study was to further characterize a large pedigree comprising 237 family members with a history of familial myoclonic seizures.
Results: Thirty-four family members could be studied. All of them underwent a detailed clinical workup including neurological exam, natural history, history of seizures, history of cognitive dysfunction or any movement disorder, family history and EEG. Probands were rated as “clinically affected,” if they exhibited a seizure history of myoclonias only, myoclonias plus gtcs, myoclonias plus febrile seizures (fs) or fs only. Fifteen alive patients (12 m, 3 w, mean age 38 yrs, mean age at myoclonia onset 39 yrs) fulfilled the criteria “clinically affected.” Five out of fifteen showed stimulus sensitive myoclonias, six had a history of myclonias plus gtcs, one exhibited myclonias plus fs, two suffered from fs only and two further described “ a sudden thrill or shaking of the body” in adolescence, which could not be further classified. Three patients showed mild dysmetria. Patients were members of basically three subfamilies within the large pedigree. All patients showed a benign, nonprogressive course of the disease with a good response to antiepileptic drug treatment.
Discussion: We present a family with a benign familiar myoclonic epilepsy with adult onset and possible autosomal dominant inheritance. Worldwide more than 50 families are described but confusingly different terms (e.g., beningn adult familial myoclonic epilepsy 1, autosomal dominant cortical myoclonus and epilepsy 2, familial adult myoclonic epilepsy 3, familial cortical myoclonic tremor with epilepsy 4) are used. A more standardized description would be helpful.
References: 1 Mikami et al. Am J Hum Genet 1998; 2 Guerrini et al. Brain 2001; 3 Labauge et al. Neurology 2002; 4 van Rootselaar et al. J Neurol 2002.
1 D.-M. Altenmüller , 1 J. Vesper , 1 V. Van Velthoven , 1 J. Zentner , 2 H.-J. Huppertz 11 Neurological Clinic of Freiburg (Freiburg, D) ; 2 Swiss Epilepsy Centre (Zurich, CH)
Pharmacoresistant focal epilepsies which are regarded as ‘cryptogenic’ because of normal findings of high resolution magnetic resonance imaging (MRI) often pose a particular diagnostic and therapeutic challenge.
In order to identify reliably the epileptogenic zone and its extension for epilepsy surgery, an invasive video EEG monitoring with implanted intracranial electrodes is frequently required.
A morphometric MRI analysis, i.e., postprocessing of the MRI data and comparison with a normal database regarding cortical gyration, cortical thickness and differentiation of the grey-white matter junction, may help to detect and delineate potential focal cortical dysplasias. This can decisively influence the planning of electrode implantation with respect to the precise location of subdural grid and strip electrodes and intracerebral depth electrodes.
Exemplarily, we report on a patient with cryptogenic focal epilepsy in whom the combined use of a morphometric MRI analysis and—for the first time targeted through this—invasive EEG including a depth electrode implanted stereotactically at the base of a left frontal sulcus in addition to a subdural grid on the overlying cortex permitted a stereo-EEG evalution of the primary epileptogenic area and allowed for a very circumscribed resection of a focal cortical dysplasia, which led to seizure freedom. Spatiotemporal EEG analysis and histopathologic findings confirmed that the depth electrode guided by morphometric MRI analysis was placed in the epileptogenic core of the focal cortical dysplasia.
1 H. Korall 1Center of Metabolic Diagnostics (Reutlingen, D)
Introduction: Clinical symptoms of many inborn errors of metabolism (IEOM) are partially unspecific like intractable grand mal and absence seizures, ataxia, muscular hypotonia, mental retardation and progressive extrapyrimidal movement disorders. For the clinician it may be difficult to decide which biochemical test may be useful to detect epilepsies based on a metabolic disorder. Using tandem mass spectrometry (TMS) we developed multiple disease categories screening analysis (MULTISCAN)—an advanced selective screening method in urine, dried blood spots and plasma for detecting inborn errors of metabolism (IEOM). This broadband screening method facilitates the diagnosis of epilepsies based on metabolic disorders.
Method: Urine metabolites were separated by a column and quantified by TMS. We show new applications with TMS screening for common and rare metabolic diseases by partially using keymetabolites for specific categories of IEOM. Plasma metabolites like homocysteine, phytanic acid and very long-chain-fatty acids (VLCFA) were detected, too. In most cases quantification of pathognomic metabolites is based on stable isotopes dilution technique as internal standards.
Results: In just a few minutes run all relevant aminoacids and additional pathognomic metabolites are detected. Key metabolites e.g., pipecolic acid are used for a urine preselection in peroxisomal disorders, guanidinoacetate and creatine for the diagnosis of guanidinoacetate methyl transferase deficiency (GAMT). GAMT-deficiency shows epileptic seizures, is automatically screened in each urine sample by TMS and may be treated with oral creatine substitution and additional dietary arginine restriction and ornithine supplementation. We made the diagnosis of 5 GAMT patients of 28 patients described worldwide. Fabry disease by quantification of globotriaosylceramides (GL-3) and disorders of purine and pyrimidine metabolism are screened, too. Peroxisomal disordes may be confirmed by quantification of phytanic acid and VLCFA in plasma. These disorders are not detected by extended newborn screening in dried blood spots. Furthermore by this applications we found new approaches in quick, reliable and adequate therapy control of IOEM.
Summary: Especially tandem mass spectrometry with MULTISCAN in dried blood spots, plasma and urine and gas chromatography are rapid, sensitive and reliable diagnostic tools for an effective, selective screening and therapy monitoring of IEOM associated with epilepsy.
1 R. Kraus , 1 B. Budig , 1 S. Klarmann , 1 M. Naumann 1Hospital Augsburg (Augsburg, D)
Objective: Myoclonic status epilepticus is rarely observed in patients with primary generalized idiopathic epilepsy. It is also uncommon in adult-onset idiopathic epilepsy or in senile myoclonic epilepsy described in patients with Alzheimer-type dementia. We present the case of an 87-year-old woman with typical myoclonic jerks and EEG features resemble juvenile myoclonic epilepsy to discuss whether a de novo impulsive petit mal status epilepticus may appear in an 87-year-old woman.
Methods and results: An 87-year-old woman was admitted to our hospital because of an acute disturbance of behavior and myoclonic jerks of her upper limbs occurring every ten seconds since several hours. She had the history of severe Alzheimer and vascular dementia. Epileptic seizures were never seen before. The myoclonic jerks were associated with brief bursts of generalized polyspike discharges of 9-10 Hz. Background EEG activity shows a diffuse slowing about 5 Hz. Random interictal spikes frontal were seen. The jerks were reduced after injection of 2.5 mg midazolam and completely abolished after intravenous administration of 1000 mg levetiracetam.
Discussion: Although the clinical and electroencephalographic findings at onset resemble classical impulsive petit mal status, we wonder whether de novo primary idiopathic epilepsy may appear in late age. Symptomatic myoclonic status associated with metabolic, toxic and post anoxic encephalopathies are much more common in this age. But these encephalopathic myoclonias usually are associated with absence of epileptiform discharges and are much more difficult to treat. Because of vascular cerebral lesions, we discuss the possibility of primary frontal lobe epilepsy with secondary bilateral synchrony. Furthermore the cortical and subcortical dysfunctions in Alzheimer disease itself could cause epileptic myoclonias. Myoclonic epilepsy is being increasingly recognized as a late-onset complication in patients with Alzheimer-type dementia. In series of patients with Alzheimer's disease 10% had seizures or myoclonus but they never occurred together. Interestingly in our case the bursts of polyspike waves on the first EEG were replaced by continuously periodic triphasic sharp waves occasionally occurring in patients with rapidly progressive Alzheimer dementia.
Conclusion: Some findings suggest that primary myoclonic status epilepticus can occur even in late age, but it needs further observations to distinguish them from symptomatic encephalopathic myoclonias.
1 H. Muhle , 2 C. Dreiwes , 2 R. Boor , 1 A. Van Baalen , 1 U. Stephani 11 University of Kiel (Kiel, D) ; 2 Northern German Epilepsy Centre Raisdorf (Kiel, D)
Introduction: In 1977 Jeavons described a photomyoclonic reflex epilepsy that manifests with 1. eyelid myoclonia (rapid blinking) immediate after eye closure (not occurring in the dark), 2. upwards deviation of the eyes, 3. accompanied by generalized spike-wave (sw) discharges in the electroencephalogram, and 4. independent brief absences (also accompanied by sw). All patients exhibited photosensitivity during intermittent photic stimulation (IPS). The “Jeavons syndrome” (eyelid myoclonia with or without absences, EMA) represents an idiopathic generalized epilepsy (IGE).
Eyelid myoclonia can be separated from myoclonic absences, where myoclonia occur more regular (3-4/s) and often synchronously with the spikes and waves but not associated with eye closure or photostimulation. Loss of consciousness is necessary for diagnosis.
Patients: We describe two children who both developed pure eyelid myoclonia (without loss of consciousness) after a period of time with myoclonic absences (with loss of consciousness) some years ago.
In patient 1 epilepsy started with myoclonic absences at age seven years. A tonic–clonic seizure appeared at age 13 years. At the age of 16 years, she showed eyelid myoclonia after spontaneous eye closure diagnosed as EMA. The family history includes several IGE and photosensitivity. Her brother exhibited juvenile myoclonic epilepsy with tonic–clonic seizures. The index patient, her mother, her epileptic brother, and two healthy siblings are photosensitive. The pedigree is shown below (dark quadrant = photosensitive).
Patient 2, a boy, exhibited idiopathic generalized epilepsy with myoclonic astatic seizures (Doose syndrome), tonic–clonic seizures and myoclonic absences. Later he developed epileptic eyelid myoclonia (without absences) and occasional pure absences. He was also photosensitive. A syndrome shift from Doose syndrome to EMA was diagnosed.
Conclusion: The accurate discrimination between epileptic eyelid myoclonia and myoclonic absences differentiates the Jeavons-syndrome from pyknoleptic and spanioleptic absence epilepsies. Therefore consciousness should be tested during the occurrence of sw. This is also important for distinguishing these epilepsies for genetic analyses.
1 M. Fischera , 1 K. Anneken , 1 C. Kellinghaus , 1 I.W. Husstedt , 1 S. Evers 1University Hospital Munster (Munster, D)
Objective: To determine the etiological and clinical aspects of seizures in patients with human immunodeficiency virus (HIV) infection.
Methods: The patient charts of all HIV infected patients with epileptic seizures who presented to the neurological clinic of the University Hospital of Muenster between 2004 and 2006 were enrolled. Seizure type was classified and seizure frequency as well as seizure cause was determined.
Results: 12 Patients infected with HIV (9 male, 3 female) suffered from epileptic seizures, mean age was 45 years (32–57 years). Ten patients had new onset of epileptic seizures. Two Patients suffered from epileptic seizures before diagnosis of HIV infection. Mean latency (±SD) between diagnosis of HIV infection and the first seizure was 4.5 (±4.7) years. Seizure etiology was progressive multifocal leukencephalopathy (PML) in four patients (33%), AIDS dementia complex in one patient, CNS toxoplasmosis in one patient, HSV encephalitis in one patient, concurrent etiology (PML and subarachnoidal haemorrhage / AIDS dementia complex and CNS toxoplasmosis / AIDS dementia complex and HIV associated encephalitis / AIDS dementia complex and benzodiazepine withdrawal) in four patients (33%) and unknown etiology in one patient. Seizures were generalized tonic-clonic in two patients (16%), partial motor in five patients (42%) and partial motor with secondary generalization in five patients (42%). One of them suffered from a focal status epilepticus with secondary generalisation. Recurrence of seizures was observed in 50% of patients in spite of anticonvulsive medication.
Conclusions: The majority of patients with HIV infection and seizures have secondary brain lesions as seizure etiology. Interestingly, 80% of patients with partial motor seizures suffered from PML. Special care should be given to the choice of the anticonvulsive medication considering the seizure type and the manifold interactions of anticonvulsants and antiretrovirals.
1 T. Polster , 2 S. Athanassopoulos 11 Epilepsy Center Bethel (Bielefeld, D) ; 2 Children's Hospital Bethel (Bielefeld, D)
Background: Munchausen-Syndrome-by-Proxy is an established differential diagnosis in difficult-to-explain medical situations. Although seizures are reported to be among the most common presenting symptoms, little attention is paid towards this topic in the literature on pediatric neurology or epilepsy.
Method: The case of a toddler is presented, who was repeatedly admitted in a pediatric hospital with a history of seizures followed by transient ataxia.
Results: 1. The use of a prescribed medication (diazepame) to induce the symptoms complicated the diagnostic workup. 2. The suspicion of a factitious disorder was proven by toxicological screening of a urine specimen with gas chromatography-mass spectrometry, that detected N-Methyl-3,4-methylenedioxyamphetamine (commonly referred to as MDMA or ecstasy). 3. This case of factitious disorder by proxy does not fulfill the criteria of Munchausen-Syndrome-by-Proxy.
Discussion: 1. Meticulous screening for toxic substances is mandatory in all cases of an unclear presentation of a seizure disorder in childhood. 2. The use of the terminology “factitious disorder by proxy” is helpful to describe a number of conditions with induced medical symptoms, Munchausen-Syndrome-by-Proxy being only the best known of them. The differentiated look at these conditions is a prerequisite for adequate diagnostic workup and therapy.
1 M. Sparmann , 1 P. Hopp , 1 T. Mayer 1Epilepsy Center Kleinwachau (Radeberg, D)
Introduction: Gaucher's disease is an autosomal-recessive inherited lipid storage disorder based on a deficiency of the lysosomal enzyme glucocerebrosidase and resulting storage of glucocerebrosides. Type 3a of Gaucher's disease is a subacute neuropathic form with myoclonic seizures.
Methods: We recently characterized a patient suffering from type 3a Gaucher's disease with specific interictal electroencephalographic pattern.
Results: This 36 year old woman developed at age of 33 years anemia, throbocytopenia and splenetic enlargement. The diagnosis of Gaucher's disease was established by bone marrow biopsy. Since youth the patient has very slow horizontal sakkades. She developped supranuclear gaze palsy, dysarthria, trismus, mild spastic and cerebellar symptoms. Initially the patient had brief myoclonic jerks triggered by emotional agitation. At the age of 33 years she had one seizure with fall and loss of consciousness. She also developped myoclonic seizures of both arms lasting up to one minute (1/month).
EEG examination revealed occipital predominant rapid polyspike activity which appeared after eye closure and increased by photic stimulation. In addition she had intermittent slow backround activity.
Conclusions: We suggest that clinical and the previously rarely discribed electrophysiological findings of this case are suggestive of type 3a of Gaucher's diasease.
1 C. Kurth , 1 B.J. Steinhoff 1Epilepsy Centre Kork (Kork, D)
Subject: Sleep deprivation and hyperventilation are well known provocation methods in routine EEG. In this study we examined the benefit of these techniques for video EEG monitoring of drug resistant epilepsy patients.
Method: Monitoring protocols of 107 patients (51 men, median age 34.5 years; minimum 18 and maximum 62 years) were evaluated. Occurrence of seizures within 2 hours after hyperventilation was determined. For those patients who had a partial sleep deprivation time between beginning of sleep and first seizure after sleep deprivation was examined. Seizure occurrence was compared to the distribution of the other seizures of the patients, too.
Results: 79 patients performed a hyperventilation. In one patient an epigastric aura occurred within a few minutes afterwards. In a second patient a series of 3 short tonic seizures was induced. 20 patients had a partial sleep deprivation. In 11 of them (no seizures before sleep deprivation) no seizure developed after a median latency of 88.5 hours (26-304 hours). 1 patient without previous seizures got seizures 75 and 87 hours after the provocation. 7 patients had a median seizure frequency of 2 (1–11) before sleep deprivation. They exhibited 2 seizures (1–5) in median after provocation with a median latency of 17 hours (8–29). In one patient with psychogenic seizure 3 of 6 seizures occurred before sleep deprivation, each of them around noon without clear relation to the provocation.
Discussion: Hyperventilation has almost no impact on occurrence of seizures in video EEG monitoring. In patients having no seizures before sleep deprivation, no seizures occurred after provocation without one exception. Median seizure frequency before and after sleep deprivation was comparable for those patients having seizures before provocation. Median latency was long. Therefore relationship between provocation and seizure occurrence is very questionable.
Conclusion: Benefit of hyperventilation and sleep deprivation seems to be little in presurgical video EEG monitoring of epileptic patients. But further investigations are necessary define subpopulations of patients in which provocation of seizures may be reasonable.
1 B. Feddersen , 1 C. Bernhard , 1 C. Stoyke , 1 J. Remi , 1 C. Vollmar , 1 S. Noachtar 1University Munich (Munich, D)
Introduction: Evaluation for temporal lobe epilepsy surgery aims to identify candidates for partial temporal lobe resection and needs to distinguish unilateral from bilateral temporal lobe epilepsy (TLE). We wished to investigate whether the analysis of seizure semiology and lateralising seizure phenomena helps to identify bilateral TLE.
Methods: We searched the data base of the University of Munich Epilepsy Monitoring Unit for the terms bitemporal and TLE. Twenty-one patients with seizures arising independently from either temporal lobe and the first consecutive 21 patients of our database with left and right temporal lobe epilepsy, who were seizure free after temporal lobe resection, were included in the study. Only patients with high quality MRI and EEG-video recordings were included. The analysis of seizure semiology was based on video recorded objective seizures. Thus, patients who only had auras were excluded.
Results: Patients with bilateral TLE had more often seizures with a different seizure semiology and seizure evolution than the patients with unilateral TLE (90% vs. 43%; p<0,05). We recorded a total of 450 lateralising signs. Patients with bilateral TLE had more often lateralising signs arising from both hemispheres than the patients with unilateral TLE (80% vs. 50%; p<0,05).
Conclusions: Seizure semiology provides clues as to whether a patient has unilateral or bilateral TLE.
1 B.J. Steinhoff 1Epilepsy Centre Kork (Kehl-Kork, D)
Purpose: Vigabatrin (VGB) may lead to permanent visual field defects in about 1/3 of patients. In patients treated with VGB regular perimetric controls are therefore recommended. However, we had the impression that in patient being treated with VGB for a longer period without visual field problems this devastating adverse event occurs almost rarely.
We therefore assessed the incidence of visual field defects in patients treated with VGB for more than three years.
Patients and methods: We addressed the percentage of patients who developed visual field defects after at least 3 years of VGB treatment. Patients were identified from our patient database. Only patients treated with VGB for at least three years were considered.
Results: We identified 27 adult patients from our database who were treated with VGB longer than three years. Six of them were severely mentally handicapped so that regular visual field controls could not get obtained. Thus, the data of the remaining 21 (mean 39.29 ± 10.7 years, range 21–59 years) were used. All of them still underwent regular ophthalmological and especially perimetric investigations beyond the treatment period of three years. The mean VGB treatment time was 12.1 ± 2.1 years, range 8–15 years). Since these patients were out-patients from all over the country they were advised to see the same ophthalmologist in their home area to ascertain that Goldmann perimetry was always performed according to the same standard.
Mean dosage was 2012 ± 943 mg, range 1000–4750 mg). Regular ophthalmological investigations revealed that no patient developed visual field defects.
Conclusions: We identified no patient who developed visual field defects after an uneventful VGB treatment time of three years. Some of our patients continued VGB for up to 12 years. Apparently in these subjects the necessity of regular ophthalmologic controls appears to be questionable. In patients being treated with VGB for more than three years without ophthalmologic problems the risk to develop visual field defects appears to be minor. VGB responders therefore should not be automatically withdrawn only due to the fear that this side effect could still occur. For safety reasons our data should not be misinterpreted. Regular ophthalmological controls should still be performed until bigger series may confrim our observations.
1 C. Brandt , 1 T.W. May , 1 E. Nieder , 1 B. Huber , 1 V. Böhme , 1 K. Witte-Bölt , 1 B. Pohlmann-Eden 1Epilepsy Center Bethel (Bielefeld, D)
Zonisamide (ZNS) was licensed as add-on treatment for partial epilepsy in adults in Germany in March 2005. Controlled clinical trials demonstrated that ZNS is an efficient and well tolerated antiepileptic drug (AED). The aim of this open label study was to evaluate efficacy and tolerability of ZNS in patients with refractory epilepsy under clinical conditions.
We included all patients of the Bethel Epilepsy Centre who started with ZNS between June 2005 and October 2006. Most of these patients suffered from severe refractory epilepsy. They were interviewed after 3, 6 and 12 months. However, due to the currently small number of patients with a follow-up of twelve months, data for a follow-up of six months will be presented. We assessed the (dis)continuation of ZNS, type of epilepsy, seizure type and frequency, comedication etc. The primary parameter for efficacy and tolerability was the retention rate of ZNS.
75 adult patients (aged 32.9 ± 15.1 years, range: 4.5 – 69.6) were treated with ZNS as add-on therapy, on average in combination with 2.1 AED. The mean observation period was 167 days. After six months, 60 patients were available for follow-up: 2% (n = 1) became seizure free, 19% were responders (≥ 50% reduction of seizure frequency), in 46% the seizure frequency remained unchanged or increased. In 34%, ZNS had been withdrawn, 66% (n = 40) remained on ZNS. Obviously, in addition to seizure frequency other aspects of outcome (e.g., tolerability, changes of severity of seizure) have had also an impact on continuation of ZNS therapy. Changes of the comedication have to be taken into account.
Reasons for withdrawal were: lack of efficacy (13.3%, n = 8), side effects (11.7%, n = 7) or both (8.3%, n = 5). Average weight loss was 1.6 and 2.9 kg after 3 and 6 months of treatment (p<0.01), respectively. Adverse effects most frequently mentioned by the patients were weight loss (18.3%, n = 11), tiredness (13.3%, n = 8), psychiatric (13.3%, n = 8), cognitive side effects (10%, n = 6), aggressive behavior (8.3%, n = 5) and agitation (6.7%, n = 4).
The retention rate of 66% after 6 months indicates that add-on treatment with ZNS is effective and well tolerated even in patients with refractory epilepsies, although the effect on total seizure frequency was less marked.
1 B. Huber , 1 E. Robertson , 1 M. Bocchicchio , 1 W. Wagner , 1 E. Feuerbaum , 1 E. Wilking , 1 T. Meinert , 1 H. Schorlemmer , 1 M. Seidel 1Epilepsy Center Bethel (Bielefeld, D)
Purpose: To gain information on the efficacy and tolerability of the novel antiepileptic drug pregabalin (PGB) in therapy-resistant patients with intellectual disability.
Methods: Retrospective evaluation of all inpatients started on PGB for epilepsy between December 2004 and July 2006. After 6 months of PGB treatment, seizure reduction was calculated comparing 3 months on PGB (4th–6th month on PGB) with 3 months baseline before PGB. In addition, efficacy was clinically judged using the Clinical Global Impression (CGI) scale. Unwanted side effects were evaluated using a list of the ten most frequently observed side effects in the regulatory studies. The CGI scale was also administered to judge tolerability.
Results: After 6 months, 24 of 32 patients included were still on PGB (75% retention rate). 6 patients (18,75%) were responders (50% seizure reduction and/or “moderate” or “very good” effect on CGI). 16 patients or their carers reported no side effects at all and 7 had only side effects that “do not impair essentially.” 8 patients/carers reported “side effects which impair essentially,” mainly sleepiness, lack of drive, mental slowing, loss of cognitive or daily life capacities, and one case of increased auto-aggression. Weight increase occurred in approx. one third of the patients. Other potential side effects out of the “list of ten” were rare.
Discussion: After 6 months of treatment, the efficacy of PGB proved to be moderate (18,75% responder rate). However, three out of four patients were still on PGB, so we assume that dose escalation or the adaptation of comedication was not finished yet. At a second time point of evaluation after one year the results may become more unequivocal.
Tolerability was good in the majority of patients. However, one quarter experienced impairing (mainly central-nervous) side effects.
1 E. Nieder , 2 T.W. May , 1 C. Brandt , 2 K. Witte-Bölt , 1 B. Pohlmann-Eden 11 Evangelisches Krankenhaus Bielefeld gGmbH (Bielefeld, D) ; 2 GfE – Gesellschaft für Epilepsieforschung (Bielefeld, D)
Pregabalin (PGB) was licensed as an add-on treatment for partial epilepsy in adults in Germany in September 2004. Controlled clinical trials demonstrated that PGB is an efficient and well tolerated antiepileptic drug (AED). The aim of this study (open label, mostly phone interviews) was to clinically evaluate the efficacy and the tolerability of PGB in patients with refractory epilepsy.
We included all patients of the Bethel Epilepsy Centre who started with PGB between September 2004 and December 2005. The patients' interviews were carried out after 3, 6 and 12 months. We assessed e.g., the rate of (dis)continuation of PGB, the type of epilepsy, seizure type and frequency, comedication. The primary parameter for both efficacy and tolerability was the overall retention rate of PGB.
In total, 111 adult patients (aged 37.5 ± 13.2 years) were treated with PGB in combination with 1 to 4 AED's (average 2.1). The patients had already been treated with a mean of 6 to 8 AED (range 1–14) in different mono- or combination therapies, before they received PGB as additional therapy. Twelve patients had a vagal nerve stimulator. The mean observation period was 224 days. 105 patients were available for 12 months follow-up, of which 5% became seizure free; 20% were responders (> 50% reduction of seizure frequency), in 14% the seizure frequency remained unchanged or increased and in 60% (n = 63) PGB was withdrawn. Accordingly, 40% (n = 42) of the patients remained on PGB.
Reasons for withdrawal were lack of efficacy (30%, n = 32), side effects (8%, n = 8) or both (20%, n = 21). Weight gain was the most frequently mentioned adverse effect (25%, n = 26). Average weight gain was 2.2, 3.7 and 4.1 kg after 3, 6 and 12 months of treatment, respectively. Other adverse effects mentioned by the patients included tiredness (17%, n = 18), dizziness/unsteady gait (12%, n = 13), cognitive (10%, n = 11) and psychiatric side-effects (10%, n = 10), and skin reactions/irritations (7%, n = 7).
The retention rate of 40% after 12 months indicates that add-on treatment with PGB is effective and well tolerated even in patients with refractory epilepsies.
1 V. Böhme , 2 B. Rambeck , 2 T.W. May , 2 R. Neb , 1 B. Pohlmann-Eden , 1 C. Brandt 11 Epilepsy Center Bethel (Bielefeld, D) ; 2 GfE – Gesellschaft für Epilepsieforschung (Bielefeld, D)
Introduction: Pregabalin (PGB), a recently licensed antiepileptic drug (AED), is rapidly absorbed and renally eliminated. In patients with normal renal function, its elimination half-life is about 6 hours. Therefore, considerable changes in serum concentration during the day are to be expected. However, only few pharmacokinetic data have been published for PGB so far. The purpose of this study was to measure the fluctuations of PGB serum concentrations during the day and to identify possible contributing factors.
Methods: We retrospectively examined the data of 16 patients with daily doses of PGB between 500 and 1000 mg (mean 702 mg) as an add-on AED. PGB serum levels were determined at hourly intervals for up to 5–9 hours after drug intake. All patients had normal renal function.
Results: During the day, PGB serum concentrations increased to 324 ± 109% of the baseline (morning value); the mean trough PGB concentration was 3.5 ± 1.3 mg/l (range: 1.3–6.3 mg/l), the mean peak PGB concentration was 10.5 ± 2.0 mg/l (range: 8.0–13.9 mg/l). The highest concentrations were found 2.3 hours after drug intake with a span from 1 to 5 hours. In accordance with the literature, the mean estimated elimination half-life of PGB was 5.7 ± 1.3 hours; however, the half-lives varied between 3.2 and 7.8 hours. In patients on enzyme-inducing comedication the half-life of PGB was shorter and the fluctuations of PGB concentrations were greater. Neither age nor PGB dose had an influence on half-lives or (percentage) fluctuations.
Discussion: As expected, marked fluctuations of PGB serum concentrations during the day were observed. However, fluctuations and half-lives of PGB were found to vary considerably among patients. Enzyme-inducing comedication might be a contributing factor, surprisingly enough in an AED with renal elimination. It has to be considered that the extent of fluctuations could actually affect clinical response. Due to limitations of our retrospective study (e.g, open-label study, relatively small number of patients) our results should be verified in a larger prospective study under standardized conditions.
1 T.W. May , 2 R. Schulz , 2 M. Hoppe , 1 B. Rambeck , 2 A. Ebner 11 GfE – Gesellschaft für Epilepsieforschung (Bielefeld, D) ; 2 Epilepsy Center Bethel (Bielefeld, D)
Levetiracetam (LEV), a new antiepileptic drug, is usually applied in dosages up to 3000 mg/day. Some studies indicate that the efficacy and tolerability of LEV is dose-dependent.
We present a case report of an adult woman (36 yr.) suffering from symptomatic, focal epilepsy treated with extremely high LEV dosages. The patient underwent epilepsy surgeries (1994 / 2004) due to therapy resistant epilepsy, but auras (in clusters) still remained. As the patient reported positive effects of LEV on frequencies of auras, LEV was stepwise increased up to 15000 mg/day (according to the patient's request and under closely clinical examination for side-effects). LEV concentrations up to 240 mg/l were measured without severe adverse effects.
A daily profile was performed in this patient on an extremely high LEV dosage in order to investigate pharmacokinetics of LEV and to examine whether side effects during the day (dependent on fluctuations of LEV) did occur.
A daily profile was performed in this patient for clinically reasons when she received a LEV dosage of 11000 mg/day t.i.d. (4000/3000/4000 mg). Blood samples were taken at 8:00, 9:30, 11:00, 14:00, 17:00, 20:00, 23:00 h and 8:00 h at the next day. Serum concentrations of LEV were determined by HPLC. The patient was asked to assess side effects during the day using a standardized questionnaire. Furthermore, body sway was investigated by posturography.
The LEV concentrations fluctuated markedly during the day (45.7-166.2 mg/l) in this patient on a LEV dosage of 11000 mg/day. However, even on the highest LEV concentrations no acute, adverse effects occurred and no or only slight complaints were reported by the patient. Body sway (posturography) was in the normal range and did not correlate with LEV concentrations during the day. The elimination half-life estimated from the daily profile was 5.7 h and clearance was 3.8 l/h in this patient. Thus, the pharmacokinetic parameters were comparable to published data.
In some extraordinary cases, LEV seems to be tolerated even in extremely high dosages (up to 15000 mg/day) and high LEV concentrations (up to 240 mg/l) without serious adverse effects over a long period (> 2 years). Pharmacokinetics of LEV does not seem to change at high LEV dosages.
This case demonstrates that LEV dosage and serum concentrations show considerable individual variability with regard to tolerability.
1 E. Korn-Merker , 1 A. Hofmann-Peters 1Epilepsy Center Bethel (Bielefeld, D)
Rational: In Japan zonisamide (ZNS) is admitted for the treatment of focal and generalized seizures in adults and children as mono- and add on-therapy since 1989. Since 2005 ZNS is available in Germany as add on-therapy for the treatment of focal epilepsies in patients older than 18 years. Because we treat children and adolescents with pharmacoresistant epilepsies mostly, we used ZNS off-label.
Method: 22 patients (6 girls, 16 boys) aged 2–19 years with mostly focal epilepsies (symptomatic 18, cryptogenic 2) but also 2 with IGE received ZNS add on-therapy. Mean dosage was 4,5 mg/kg BW/d (max. 7,9 mg/kg BW/d). Comedications have been VPA, OXC, CBZ, TPM, LEV, LTG, PB, BR, FBM, CLN and CLB. 2 patients had a Vagal-Nerve-Stimulator too. In mean all patients had had 9 antiepileptic drugs before without persisting effect. They have had different seizures types. First ZNS was titrated up to 5 mg/kg BW/d.
Results: 7 patients have had a seizure reduction of 75–90%. 2 children showed a reduction of 50-75%. 13 patients didn't benefit from ZNS, 2 of them have had an transient effect only. One female adolescent suffered from rheumatic pain, which disappeared after discontiunation of ZNS. One boy had repeating vomiting, which stopped some time after discontitnuation of ZNS according to the half life time. One boy who already suffered from attention deficit under several other anticonvulsant drugs before, showed the same symptoms with ZNS. We did not see any hyperthermia or kidney stones.
Conclusion: Nearly 41% of our patients had a benefit from ZNS-treatment. Regarding the pharmacoresistance, proofed before, this is an amazing effect. One girl with myoclonic absences benefit from ZNS since more than one year and now receives a ZNS-monotherapy. In 2 patients only we saw a transient effect.
1 M. Bacher , 1 B.J. Steinhoff 1Epilepsy Centre Kork (Kehl-Kork, D)
Objective: Assessment of long-term efficacy and tolerability based on retention rates of zonisamide (ZNS).
Patients and methods: Year-by-year ongoing assessment of clinical data files of all adult epilepsy patients treated with add-on ZNS since June to December 2005.
Results: We observed 57 adult patients most of them suffering from intractable focal epilepsy syndromes. The actual retention rate is 53% as compared to 75% one year ago. Long-term ZNS add-on treatment still appears to be not complicated. In most cases the tolerability was good with a satisfying efficacy profile.
Conclusion: Based on our experience ZNS is a favorable addition to our antiepileptic drug treatment options.
1 U.A. Kopp , 1 V. Gaus , 1 B. Wandschneider , 1 B. Schmitz 1University Hospital Charité (Berlin, D)
Objective: Adverse cognitive side effects have been reported for all major antiepileptic drugs (AED; Aldenkamp 2001). However, so far little is known about the impact of Levetiracetam (LEV) on cognitive performance. The aim of this study was to assess the effect of LEV, Carbamazepine (CBZ) and Valproate (VPA) on cognition after beginning an antiepileptic monotherapy in de novo patients.
Methods: We investigated cognitive performance in 15 patients of our outpatients department. Patients with newly diagnosed epilepsy were randomly assigned to monotherapy with LEV, CBZ or VPA respectively. Two of the patients with idiopathic generalized epilepsy (n = 4) were randomised to VPA, and 2 to LEV. Twelve patients had localisation-related epilepsies (CBZ n = 6; LEV n = 4; VPA = 1).
Neuropsychological assessment was performed at three points: prior to introduction of AED therapy, 6 weeks and 12 weeks after beginning of AED medication. Psychometric tests comprised attention (simple reaction time task, divided attention), short term and working memory (digit span forward and backward), learning and retention of verbal and non-verbal information (Rey-Auditory-Verbal-Learning Test and Rey-Osterrieth Complex Figure Test), planning abilities (Tower of London) and inhibition (Stroop Colour-Word-Interference Task).
Results: Multivariate analyses of variance were conducted for each cognitive variable separately. No significant effect of type of medication or time of assessment could be found.
Conclusions: There were no significant side effects on attention, memory, executive functions and overall intellectual abilities of monotherapy with LEV as compared to CBZ or VPA over a 12 week period. Thus, LEV appears to be a safe antiepileptic drug with respect to cognition. However, the sample examined so far is small so that continuing work is needed to consolidate these preliminary data.
1 C. Reinsberger , 2 T. Dorn , 2 G. Krämer 11 Julius-Maximilian-University (Wurzburg, D) ; 2 Swiss Epilepsy Centre (Zurich, CH)
Smoking has been shown to induce glucuronidation and therefore influence serumlevels of drugs metabolized by glucuronidation such as lorazepam and oxazepam. In this study a possible influence of smoking on lamotrigine (LTG), a widely used drug to treat epilepsies with simple- and complex-partial as well as generalized seizures that is metabolized by glucuronidation is examined for the first time.
LTG serumlevels of 43 patients with epilepsy treated with LTG in monotherapy were retrospectively examined. Fifteen of the patients (ten females & five males) were smokers (three cigarettes/month to three packages/day) and 29 (15 females, 14 males) nonsmokers. Patients who smoked more than three cigarettes per month were considered as smokers. Allowing repeated measurements in single patients, 204 samples were analyzed. All patients were recruited as in- or outpatients in our epilepsy center within two years. The statistical comparison between LTG serum levels was performed by one-factor ANOVA.
The comparison between LTG serumlevels revealed a highly significant (p = 0,00138) difference of the quotient of LTG serumlevel and dosage between smokers and nonsmokers. Analyzing only male patients, the same relationship with an almost equally high level of significance could be demonstrated (p = 0.008). Although there was no statistically significant correlation between the number of cigarettes per day and LTG serum level-to-dose ratio, there was a trend pointing to a dose effect of smoking on LTG serumlevels in the Pearson Correlation (r = -0,127 μmol/l*mg, p = 0,069).
Smokers showed a significantly lower LTG serumlevel-to-dose ratio than nonsmokers. Because our patients were examined on various occasions and daytimes and because a strict compliance, especially in the outpatients of our sample, cannot be generally assumed, this effect may even be underestimated. The inclusion of patients with a very mild consumption of cigarettes (three per month) into the group of smokers may also contribute to an underestimation of this effect. In addition, due to the relatively low number of smokers, possible dose effects of smoking could not have been detected with statistical significance. Whether this effect is of clinical significance and directly related to glucuronidation has to be confirmed by further prospective studies with a higher number of patients and a more detailed assessment of smoking habits.
1 J.-P. Ernst , 1 D. Neumann , 1 J. Fahrbach , 1 A. Wiemer-Kruel 1Epilepsy Centre Kork (Kehl-Kork, D)
Introduction: The rate of intractable epilepsies is high in specialized epilepsy centers. Besides the symptomatic focal epilepsies, West and Lennox-Gastaut syndromes, the severe myoclonic epilepsy (SMEI) and the myoclonic-astatic epilepsy (MAE) play an important role. The need for new antiepileptic drugs (AED) is high. Since December 2001 Stiripentol is available as orphan drug for the treatment of SMEI in combination with sodium valproate and clobazam. It is unrelated to other AED and belongs to the group of aromatic allylic alcohols. It has been shown to prevent the uptake of GABA and inhibits its metabolism. More important it improves the effectiveness of other AED by inhibition of several cytochrome P 450 isoenzymes.
Methods: In the year 2006 patients with refractory epilepsies, in whom all other available AED had failed, were treated with stiripentol add-on. The data were analyzed retrospectively.
Patients: 10 patients (2 female, 8 male) with a mean age of 10;3 years (5,5–16) received stiropentol add-on to a pre-existing therapy with 2 to 3 AED, mostly valproic acid, bromides, phenobarbitone and topiramate. Classification: Severe myoclonic epilepsy 5, myoclonic-astatic epilepsy 1, CSWS 1, symptomatic focal epilepsy 3.
Results: Seizure-free 1 (MAE), seizure-reduction > 90% 1 (SMEI), 50-75% 1 (SMEI). In all other cases we saw only transient, slight improvement. No one worsened. No serious events occurred.
Discussion: Stiripentol seems to be an effective drug in the therapy of severe generalized epilepsy of infancy and childhood. It should be introduced early, if valproic acid, bromides, phenobarbitone and topiramate have failed.
1 R. Besser , 1 M. Eckert 1Hospital Krefeld (Krefeld, D)
Purpose: The injectable Levetiracetam (LEV) formulation has been developed for intravenous (IV) use in epileptic patients, if oral administration is temporarily not possible. Fast infusion rates even in elderly epileptic patients are required for its use in the emergency situation.
Methods: 13 patients with and without previous antiepileptic medication other than LEV were treated with LEV IV 2000 mg for focal convulsive or nonconvulsive status epilepticus (SE) and generalized nonconvulsive SE. The infusion rate was 15 minutes in six patients and 5 minutes in seven. Consciousness, cardiovascular function and respiration were monitored. Blood samples were collected 30 to 60 minutes, 6, 12 and 24 hours later. The plasma was separated within 12 hours and LEV concentrations were determined by HPLC.
Results: The median age of the patients was 79 years ranging from 50 to 93 years. Despite higher age, all patients showed creatinin values within normal range. Following LEV IV, regardless the infusion rate, none of the patients developed additional clouding of consciousness. No alterations in cardiovascular function or respiration occurred. LEV plasma concentrations were available from 12 patients. Thirty to 45 minutes after LEV IV the mean plasma concentration was 48 mg/l ranging form 21-81 mg/l. Thereafter the concentration dropped in an exponential manner. The respective values for 6, 12 and 24 hours were 31 (14.5–54), 20 (8.5–46) and 17 (6.7–44) mg/l. Three patients had received an additional dose of LEV IV 500 mg before the last blood sample. Efficacy was inconsistent. LEV tended to be more effective in patients with repetitive seizures, than in those with generalized nonconvulsive SE.
Conclusions: LEV IV 2000 mg within 5 to 15 minutes was well tolerated in elderly epileptic patients and achieved high plasma concentrations for at least 12 hours.
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Poster session 1.2. -Clinical Epileptology (Therapy)
1 C. Tilz , 2 Y. Wang-Tilz , 2 A. Backof , 2 H. Stefan 11 Convent Hospital "Barmherzige Brüder” (Linz, A) ; 2 University of Erlangen-Nuremberg (Erlangen, D)
Objectives: According to the Chinese medical literature acupuncture is most effective in the treatment of generalized epilepsy. For years there is still a gap between the standardization of the treatment according to seizure type and an objective evaluation of the effects. In this study the effect of acupuncture as add-on therapy in the treatment of absence seizures was quantified during the monitoring of long-term EEG.
Methods: 6 outpatients suffering from primary generalized absence seizures based on the ILAE criteria (1981), who were referred to the epilepsy centre, University of Erlangen-Nuremberg, Germany, were enrolled. The whole study lasted 11 days and the concomitant antiepileptic drugs were maintained stable. After 48 hours long-term EEG monitoring the patients were randomised to either the real-points group or sham-points group to receive seven sessions of acupuncture treatment, daily 30 minutes at the same time. Immediately after the last session followed another 48 hours long-term EEG monitoring. The selection of the acupuncture points (acupoints), the treatment duration and the depth of the needle-insertion were based on Chinese literature and experts' experience from P.R China. A total of 11 acupoints were used in every session, including five scalp points and six extremity points. The parameter of effect was the changes of the number of spike-wave-complex before and after the seven-day acupuncture treatment.
Results: A total of six patients finished the study: 4 in the real-points group and 2 in the sham-points group. The age ranged from 4 yrs. to 63 yrs with a mean of 29 ± 19.73. Before acupuncture there were totally 14066 spike-wave-complexes in the real-points group (median 2125, ranged from 20 to 9795) and 10558 in the sham-points group (median 5279, ranged from 94 to10464) during the 48-hour long-term EEG recording. After the acupuncture the total number reduced to 6596 (53% reduction) in the real-points group with the median of 397 (range from 0 to 5802) and 9566 (8.4% reduction) in the sham-points group with the median of 4783 (range: 97 to 9488). Two patients in the real-points group were completely free from spike-wave-complexes during the post-acupuncture EEG monitoring.
Conclusion: This pilot study showed a preliminary effect of acupuncture in reducing the number of spike-wave-complexes in the EEG monitoring. But because of the small sample seize, further study with more patients are definitely necessary.
1 M. Rauchenzauner , 1 A. Griesmacher , 1 T. Tatarczyk , 1 G. Falkensammer , 1 L. Zimmerhackl , 1 G. Luef , 1 E. Haberlandt , 1 W. Högler 1University Hospital Innsbruck (Innsbruck, A)
Introduction: Valproic Acid (VPA) therapy causes weight gain and hyperleptinemia. Both, VPA and newer antiepileptic drugs (AED), have been associated with vitamin D insufficiency and increased bone turnover or even reduced bone mass.
Objective: To determine the influence of VPA and new AEDs on body composition, insulin resistance, leptin, vitamin D and novel markers of bone metabolism in children and adolescents.
Methods: This study included 142 non-institutionalized, ambulatory children >6 years with idiopathic epilepsy on chronic AED monotherapy. Body-Impedance analysis, HOMA-index, leptin, 25OH vitamin D, osteoprotegerin (OPG), soluble receptor activator of NF-kappaB ligand (sRANKL) and tartrate-resistant acid phosphatase 5b (TRAP5b) were determined.
Results: 87 children (mean age 12.3 ± 3.6) were on treatment with VPA and 55 (mean age 12.3 ± 3.1) on other AEDs, comprising the control group. VPA-treated children, vs. controls, had greater weight standard deviation score (SDS; 0.31 ± 1.3 vs. -0.65 ± 1.1, p<0.001), body-mass-index SDS (0.43 ± 1.3 vs. -0.44 ± 0.9, p<0.001), percentage body fat (22.6 ± 9.3% vs. 12.2 ± 6.6%, p<0.001), leptin concentrations (25.9 ± 19.7 vs. 7.2 ± 7.6ng/mL, p<0.001) and HOMA index (3.2 ± 2.0 vs. 2.2 ± 1.6, p = 0.008). No difference was found between groups in 25OH vitamin D (107.5 ± 63.8 nmol/l vs. 116.3 ± 77.2 nmol/l), OPG (2.8 ± 0.7 pmol/l vs. 3.0 ± 0.8 pmol/l), Trap5b SDS (0.48 ± 1.9 vs. 0.54 ± 1.9) with a tendency for higher RANKL concentrations in VPA treated children (0.47 ± 0.7 vs. 0.39 ± 0.9, p = 0.071). None of the children had Vitamin D insufficiency (<50nmol/L). No correlations between markers of bone turnover and anthropometric variables, leptin or HOMA index were found.
Conclusion: VPA therapy was associated with higher body weight, body fat and serum leptin concentrations as well as impaired glucose homeostasis. Neither the VPA nor the AED group showed evidence of vitamin D insufficiency. There was no significant effect of AED treatment, hyperleptinemia and high body fat on novel markers of bone turnover.
P. Borusiak , G. Kluger , G. Wohlrab , T. Bast for the “Valentinskreis pädiatrischer Epileptologen”
Objective: Idiopathic focal epilepsies generally are a benign condition. However in some children mental deterioration and difficult to treat seizures occur. Some authors suspect an aggravation by certain anticonvulsive drugs.
Methods: We performed an extensive literature review on the question of drug-induced electroencephalographical and/or seizure aggravation in idiopathic focal epilepsies with respect to carbamazepine, gabapentin, lamotrigine, levetiracetam, oxcarbazepine and sulthiame. These data were compared with the results of studies on spontaneous evolution of children with idiopathic focal epilepsies.
Results: One systematic retrospective study finds a probable association of seizure aggravation in 2/98 patients treated with carbamazepine. Otherwise only case reports exist for carbamazepine, lamotrigine and oxcarbazepine. Atypical course in the beginning of epilepsy, Landau-Kleffner-syndrome and bilateral sharp waves might be risk factors.
Conclusion: Given the variable spontaneous course we did not find any data for a systematic aggravation due to certain drugs in idiopathic focal epilepsy.
B. Schäuble , S. Wang , F. Wiegand for the EPMN-106/INT-28 Investigators
Objectives: Analyses of data on adolescent subjects from dose-controlled studies evaluating the efficacy and tolerability of topiramate as initial monotherapy.
Methods: Subset analyses of a previously published trial (Arroyo et al., 2005) including patients between 10-15yrs with newly diagnosed epilepsy or untreated patients with epilepsy relapse and ≥2 lifetime seizures and 1–2 partial or generalized tonic–clonic seizure during a 3 months retrospective baseline. The primary efficacy end point was time to first seizure; a secondary efficacy measure was the seizure-free rate at 6 months and 1 year. The safety population was pooled with patients receiving 50mg/day in a very similar pivotal trial (Gilliam et al., 2003).
Results: A total of 470 patients were included in the initial efficacy analysis, 114 patients between 10–15 years of age (50% female) are presented in this analysis. Kaplan-Meier survival analysis for time to first seizure in the adolescent subset of the IIT population favored 400mg/day (n = 57) over 50mg/day (n = 57) (P = 0.001). The probability of being seizure free at 6 months was 79% in those randomized to 50mg/day and 94% in patients randomized to 400mg/day (P = 0.001). Average daily dose of topiramate during the double blind phase was 43mg/day (0.92mg/kg/day) in the 50mg group and 335 mg/day (7.47mg/kg/day) in the 400mg/day group. Adverse events leading to study discontinuation were anxiety, chest pain and migraine in one patient in the 50mg arm. In the 400mg arm, 7 patients overall discontinued due to cognitive problems, fatigue and mood complaints. No treatment related serious adverse events occurred. Mean weight change from baseline to final visit in the double blind phase (6 months) were a 2.5% weight gain in the 50mg arm and a 0.7% weight loss in the 400mg arm.
Conclusion: The results of this analyses support the efficacy and safety of topiramate for initial monotherapy of partial-onset or generalized tonic–clonic seizures in adolescents with epilepsy.
B. Schäuble , P. Levisohn , K. Holland , F. Wiegand for the JME Capss-107 Investigators
Objective: Open label study (CAPSS-107) to evaluate the effectiveness of topiramate (TPM) in patients with juvenile myoclonic epilepsy (JME).
Method: Open-label study enrolling patients age 12-65 years with a confirmed diagnosis of JME (myoclonic jerks and PGTCS or an EEG with generalized epileptiform abnormalities consistent with a clinical diagnosis of JME), age of disease onset between 8–26 years. Patients had to have myoclonus and/or >1 PGTCS within the 3-month retrospective baseline. Eligible patients were randomized (2:1) to 26 weeks treatment with TPM (target 3–4 mg/kg/day; maximum, 9 mg/kg/day) or VPA (target 10 mg/kg/day; maximum 60 mg/kg/day or 750 mg/day if >16 years of age). Seizure frequency, tolerability, and patient and physician evaluations of response were recorded during each visit (Baseline and Weeks 4, 8, 14, and 26).
Results: 28 patients were randomized to TPM (N = 19; median age 15 years; range 9-42) or VPA (N = 9; median age 16 years; range 12-34). 12 patients had one baseline AED. 12/19 patients receiving TPM and 7/9 patients receiving VPA completed the study; mean dose among completers was 189 ± 78 mg/day and 897 ± 375 mg/day, respectively. At the end of the study, all patients but one patient achieved TPM (OXC) or VPA monotherapy. Reasons for discontinuation in the TPM group included adverse events (N = 2), patient choice (N = 1), or loss to follow-up (N = 1); two patients discontinued VPA due to adverse events or other reasons. During the 3-month maintenance phase, seizure-free rates were 47% with TPM and 33% with VPA. Seizure-free rates for myoclonic, PGTCS, and absence seizures in the TPM and VPA groups were 7/14 (50%) vs 6/9 (67%), 8/12 (67%) vs 3/4 (75%), and 2/2 (100%) vs 1/2 (50%), respectively. Physician and patient global evaluation of improvement, alertness, and improvement in seizure severity were similar in both treatment groups (TPM, 75%; VPA, 71%). Neurotoxicity scores over time were similar, but systemic toxicity scores were higher with VPA. Most TPM-treated patients lost (mean, -4.1 kg), while patients receiving VPA gained weight (mean, 5 kg); the between group difference was statistically significant (p<0.001).
Conclusion: TPM was effective in the treatment of patients with JME with less systemic toxicity compared to VPA. The results suggest similar effectiveness in seizure control, but because of the small sample size, clinically meaningful differences cannot be ruled out. These results are supported by recently published data from a randomized controlled trial [1, 2].
1 B. Schäuble , 1 A. Schreiner 1Janssen-Cilag GmbH (Neuss, D)
Objective: To evaluate quality of life (QUOLIE-10) and weight change of epilepsy patients transitioned from valproate (VPA) to topiramate (Topamax, TPM) monotherapy.
Methods: Multicenter, prospective, open-label, noninterventional trial (TOPMAT-EPY-403). Patients with epilepsy independent of seizure type ≥ 12 years of age and unsuccessfully treated with VPA due to lack of efficacy and/or lack of tolerability were eligible for this study. Patients were prospectively followed for 20 weeks after initiation of, and transition to a TPM monotherapy.
Results: Overall, 147 patients (59% women, mean age 41 ± 19 years) were enrolled. Reasons for transition from VPA onto TPM were side effects in 81% (mostly tremor, somnolence or cognitive symptoms) and/or lack of efficacy (61%). 23% of patients were seizure free at baseline. 84% of patients completed the study. Mean weight at baseline was 75.9 ± 17.9 kg and decreased on average by 3.7kg ± 4.5kg; mean BMI improved from 26.5 to 25.4 kg/m2. Seizure frequency significantly decreased after transition to TPM (p<0.0001 vs. baseline). QUOLIE-10 subscores mental health, role functioning and severity of epilepsy all improved significantly (p<0.0001 vs. baseline for all items). Tolerability of TPM was rated as ‘good’ or ‘very good’ in 83%. TPM was well tolerated with 14% of patients experiencing treatment-emergent adverse events (AEs). AEs >/= 3% were paraesthesia (4%) and weight decrease (5%). The only cognitive AE reported was speech disorder in 3% of patients.
Conclusion: Transition from valproate to topiramate monotherapy was associated with a substantial improvement in quality of life, a considerable weight decrease and a beneficial tolerability profile including few cognitive side effects.
1 B. Schäuble , 1 A. Schreiner 1Janssen-Cilag GmbH (Neuss, D)
Objective: To evaluate quality of life (QUOLIE-10), tolerability and weight change in patients with epilepsy after transition from carbamazepine (CBZ) or oxcarbazepine (OXC) to topiramate monotherapy (Topamax, TPM).
Methods: Multicenter open-label noninterventional trial (TOPMAT-EPY-405). Patients >/= 12 years of age with epilepsy unsuccessfully treated (due to lack of efficacy and/or lack of tolerability) with CBZ (72%) or OXC (28%) were eligible for this study. Patients were prospectively followed for 26 weeks after initiation of, and transition to, TPM.
Results: 140 patients (54% women, mean age 47 ± 18 years) were enrolled. Main reasons for CBZ/OXC discontinuation were side effects (80% of patients) and/or lack of efficacy (75%). At end point, median TPM dose was 100 mg/day. Mean seizure frequency decreased from 6/month at baseline to 1.4/month at endpoint (p < 0.0001). 81% of patients completed the study. All QUOLIE-10 items including subscores mental health, role functioning, and severity of epilepsy improved significantly (p < 0.0001 vs baseline for all items and subscores). Mean baseline BMI slightly improved from 26 to 25.5 kg/m2 at endpoint, mean weight decrease was –1.9 ± 3.7 kg. TPM was well tolerated: 26% of patients reported treatment-related adverse events (AEs). AEs >/= 5% were paraesthesia (9%), memory difficulties (5%) and weight decrease (8%). 12% of patients discontinued treatment due to an AE. The only additional cognitive side effect reported was speech disorder in 4% of patients. Tolerability of TPM was rated as ‘good’ or ‘very good’ in 80% by physicians.
Conclusion: Transition from CBZ or OXC to topiramate monotherapy was associated with a significant improvement in quality of life and was well tolerated.
1 A. Carius , 2 A. Schreiner , 2 B. Schäuble 11 University Hospital Freiburg (Freiburg, D) ; 2 Janssen-Cilag GmbH (Neuss, D)
Objective: To evaluate seizure frequency and tolerability in patients with epilepsy treated with topiramate (TPM, Topamax) transitioning from valproic acid (VPA)
Methods: Multicenter open-label noninterventional trial (TOPMAT-EPY-403) following patients ≥ 12 years of age with epilepsy previously unsuccessfully treated with VPA. Patients were prospectively followed for 20 weeks after transitioning to TPM. A 12-week retrospective seizure frequency was used as baseline.
Results: 147 patients (59% female; mean age 42 yrs (± SD 19)) were followed. Median duration of epilepsy was 9 yrs (range, 0-60 yrs). 77% had seizures during the 12-week retrospective baseline. 70% of patients were on TPM monotherapy at end point and 77% continued TPM therapy. Most frequent seizure types at baseline were generalized tonic–clonic (52%), complex partial (23%), and simple partial (12%). Main reasons for transition from VPA to TPM were insufficient efficacy (61%) and/or side effects (81%). Mean dose of VPA at time of first administration of TPM was 1286 ± 629 mg. Median TPM dose was 125 mg/day at endpoint. Mean (± SD) seizure frequency decreased significantly from 32 ± 248 seizures per month during the retrospective baseline to 3 ± 16 seizures/month during the maintenance period (p < 0.001). The responder rate (≥ 50% seizure reduction in patients with seizures during their retrospective baseline) during the last three months of observation was 75%, and 51% patients remained seizure-free during this period. 94% of the patients who were seizure-free at baseline continued to do so during the study. 16% of patients discontinued TPM, 8% due to an adverse event (AE), and 3% due to insufficient efficacy. 14% of patients reported treatment-emergent adverse events (TEAE). TEAE occurring in > 3% were paraesthesia (4%) and weight decrease (5%). The only cognitive adverse events was speech disorder occurring in less than 3% of patients.
Conclusion: In patients previously unsuccessfully treated with VPA, mono – or add-on therapy with topiramate was well tolerated according to patient's reports and was associated with a substantial reduction in seizure frequency and a high seizure-free rate.
1 B. Schäuble , 1 A. Schreiner , 2 H. Adam 11 Janssen-Cilag GmbH (Neuss, D) ; 2 Practice (Rostock, D)
Objective: To explore seizure frequency and tolerability in patients with epilepsy treated with topiramate (TPM; Topamax) transitioning from carbamazepine (CBZ) or oxcarbazepine (OXC).
Methods: Multicenter open-label noninterventional trial (TOPMAT-EPY-405) prospectively following patients with epilepsy ≥12 years of age who were previously unsuccessfully treated with CBZ (72.1%) or OXC (27.9%) for 26 weeks after transitioning to TPM. A 12-week retrospective seizure frequency was used as baseline.
Results: 140 patients (54% female; mean (± SD) age 47 ± 18 yrs) were enrolled. 72.1% of patients had unsuccessfully been treated with CBZ and 27.9% with OXC. Mean (± SD) duration of epilepsy was 14.3 ± 13.7 yrs and patients had had an average of 2.2 AEDs (range, 1–10) prior to observation. 84% had seizures during the 12-week retrospective baseline. Most frequent seizure types at baseline were generalized tonic–clonic (52%), complex partial (25%), and simple partial (16%). Main reasons for transition from CBZ/OXC to topiramate were insufficient efficacy (75%) and/or side effects (80%). Mean dose of CBZ at treatment initiation of TPM was 825mg ± 397mg/day and 1254 ± 555mg/day with OXC. At endpoint, the median TPM dose was 100mg/day. 73% of patients received TPM monotherapy by the end of observation. Mean (± SD) seizure frequency decreased significantly from 6 ± 21/month at baseline to 1.4 ± 5/month during the observation period. The responder rate (>/= 50% seizure reduction) during the last 3 months of observation was 91%, and 62% of patients remained seizure-free during this period. 19% of patients discontinued TPM, in 12% due to an adverse event (AE), and in 3% due to insufficient efficacy. The only treatment-emergent adverse events reported in ≥5% were paraesthesia (9%) and weight decrease (8%).
Conclusions: In patients previously unsuccessfully treated with CBZ or OXC, topiramate was well tolerated and associated with a substantial reduction in seizure frequency and a high seizure-free rate.
1 H. Stefan , 2 A. Schreiner , 1 F. Kerling , 1 B. Kasper , 2 B. Schäuble 11 Epilepsy Center – University Erlangen-Nuremberg (Erlangen, D) ; 2 Janssen-Cilag GmbH (Neuss, D)
Objective: To assess effectiveness of topiramate (Topamax, TPM) in different age groups of elderly patients (≥ 60) with epilepsy.
Methods: In this prospective, open label, multicenter phase IV flexible dose clinical trial (TOP-GER-13), elderly patients (60-64, 65-74 and ≥ 75 years (yrs)) with epilepsy irrespective of seizure type were included and followed for a median of 12 months. Doses of TPM and concomitant AEDs could be adjusted individually. Seizure frequency and adverse events were assessed at each visit.
Results: 107 patients (53% male, mean age 69 ± 7 years) were enrolled encompassing 32 patients 60–64yrs, 54 patients 65–74yrs and 21 patients ≥ 75yrs. 102 patients had at least one seizure during the retrospective 12-week baseline. Mean duration of epilepsy was 11.8, 9.7 and 5.5 years, respectively. Most frequent seizure types at baseline were generalized tonic–clonic (58%) and complex partial (25%) with the highest seizure frequency in the oldest group (9.3 ± 34.1 at baseline). Mean seizure frequency for all was 3.5 ± 14.6 at baseline and decreased to 1.6 ± 7.7 at endpoint (p < 0.0001). At endpoint, the mean TPM dose given as monotherapy was 98 mg/day and 153 mg/day if given adjunctively. Mean monotherapy dose was lowest in the oldest elderly group (86mg/day) and the percentage of monotherapy was highest in the oldest group. The proportion of responders (seizure reduction ≥ 50%) was highest in the youngest group (87% responders), and overall, 78% of patients were responders and 44% remained seizure-free throughout the study.
46 patients (43%) had at least one treatment-emergent adverse event (TEAE). The number of TEAEs was highest amongst the oldest elderly. TEAEs ≥ 5% were somnolence (9.4%), dizziness (7.5%), paraesthesia (5.6%), and memory difficulties 5.6%. Main reasons for study discontinuation (40% overall) were an TEAE (15.9%) or loss to follow-up (12.2%).
Conclusion: In elderly patients with epilepsy, TPM was well tolerated amongst all age groups, was associated with a significant decrease in seizure frequency, and was well tolerated. Doses used were slightly lower than the recommended target doses for adults.
1 A. Owega , 2 A. Schreiner , 3 K. Rettig , 2 B. Schäuble 11 Practice (Cologne, D) ; 2 Janssen-Cilag GmbH (Neuss, D) ; 3 G.E.M. (Meerbusch, D)
Objective: To describe differences in effectiveness and safety profile in patients treated with the most commonly prescribed AEDs in Germany transitioning to topiramate monotherapy (Topamax, TPM).
Methods: Multicenter, open label, observational study (TOPMAT-EPY-0001) examining patients ≥ 6 yrs diagnosed with epilepsy and prior insufficient treatment (lack of effectiveness and/or tolerability) with PHT, OXC, CBZ or VPA monotherapy and planned transition to TPM monotherapy. Patients were followed for 16 weeks after initiation of TPM.
Results: The ITT analysis included 407 patients (53% female, no significant difference between groups) including 148 patients on VPA, 168 on CBZ, 42 on OXC and 49 on PHT. Mean age (± SD) over all groups was 45.8 ± 16.8 yrs. Between-group comparisons were performed by the Chi2- or the Kruskal-Wallis-H-test. Patients on VPA or PHT were younger at diagnosis than patients on CBZ or OCX (p < 0.005), but epilepsy duration was longer in the PHT treated group (p < 0.001). BMI differences among patients were non-significant. The number of previous AEDs ranged from 1–10 (mean 2.4 ± 1.6), being highest among PHT patients (p = 0.018). Overall, 75% of patients transitioned to TPM due to lack of efficacy (no differences between groups) and 61% due to insufficient tolerability (Chi square- test: p = 0.067). Reason for switch were side effects listed most frequently for CBZ (64% somnolence) or VPA (55% weight gain). TPM median dose at endpoint was 100mg/day. Overall, seizure frequency decreased from 2.35 ± 5.4 per 4 weeks during the 12-weeks retrospective baseline to 1.14 ± 4.05 during the prospective observational period (Wilcoxon- test: p < 0.001). Regardless of the prior AED (OXC, CBZ, VPA or PHT), all patients showed a significant seizure reduction while transitioning. 64.2% of all patients had an at least 50% seizure reduction and 41.8% were seizure free during the entire documentation period. A total of 58 adverse events occurred in 38 patients and 51 of these AEs had at least a possible relationship to TPM treatment. Treatment-related AEs (≥ 3% out of 58 AEs) were: tiredness, nausea, weight loss, dizziness, lack of concentration, restlessness, ataxia, exanthem, and development of seizures.
Most common reasons (≥ 3%) for discontinuation of TPM (15.8% overall) were AE (3.1%) or “unknown” (8.9%). 87% of physicians rated the effectiveness of TPM “very good” or “good” regardless of previous AED and 91% considered the patient's situation as very much or much improved. The number of seizure related physician visits or loss of workdays decreased (p < 0.001). 82% of patients continued on TPM treatment.
Conclusion: Transitioning from PHT, VPA, CBZ or OXC to TPM was associated with a substantial seizure reduction and good tolerability regardless of the AED previously used. In addition, there was a significant reduction in seizure related physician visits and loss of workdays.
1 B. Huber 1Epilepsy Center Bethel (Bielefeld, D)
Introduction: VPA-associated liver failure most often affects severely handicapped young children (some with metabolic defects) on antiepileptic polytherapy. Most cases happen during the first half year of treatment.
We report on a case of fatal liver disease after the extraordinary long period of 21 years of VPA therapy.
History: The 54 year old patient suffered from epilepsy, moderate to severe intellectual disability, and physical handicaps due to pre- or perinatal brain hypoxia. He was seizure free since VPA had been added to his medication in 1985. Phenytoin and later barbexaclon (a phenobarbital-derivative) were gradually discontinued. Since 1991 he remained on VPA monotherapy (1200 mg/d continuously since 1996) with his seizures still completely controlled.
Clinical course: In autumn 2006 the patient developed jaundice, pruritus and loss of appetite. Liver enzymes (transaminases) were elevated (ASAT and ALAT in the range of several hundred, GGT > 1000; alcalic phosphatase approx. 3 fold of normal) while parameters of liver synthesis were normal. Thorough laboratory examinations showed no plausible cause of liver dysfunction. VPA serum concentration was low (35,4 μg/ml). Pancreatic enzymes were normal. Abdominal ultrasound was little informative due to obesity but CT did not show signs of extrahepatic cholestasis. There was no evidence of fever or infection preceding jaundice.
Histology obtained by liver puncture, although unspecific, was compatible with drug toxicity. VPA was discontinued and replaced with clobazam. Thereupon transaminases improved but bilirubin elevated to extremely high values. Only in this stage the patient became somnolent and later soporous. He developed high fever. Only then parameters of liver synthesis were reduced; ammonia was elevated twofold. A generalized tonic–clonic seizure had to be aborted with midazolam. He died from bilateral pneumonia and cardiac failure.
Discussion: Although our patient finally died from pneumonia, we believe that VPA hepatotoxicity was decisive in this fatal course (decrease of liver enzymes after stopping VPA; failure to determine any other cause). Concomitant medication was not known to be hepatotoxic. However, postmortem autopsy was not performed and thus the final cause of death could not definitely be established.
Our patient is unusual in several aspects: adult age, monotherapy and relatively long period with isolated jaundice. The most extraordinary feature, however, is the very long period of VPA therapy.
Conclusion: There is jeopardy of VPA hepatotoxicity to be overlooked or underestimated in patients who do not belong to the typical risk group, especially in long lasting treatment. VPA should be considered as a possible aetiology in every VPA-treated patient with unexplained hepatic disorder, including adult patients with long lasting VPA therapy.
1 G. Möddel , 1 P. Zwanzger , 1 R. Dziewas , 1 W.-R. Schäbitz , 1 C. Kellinghaus , 1 K. Anneken , 1 M. Fischera , 1 S. Kovac , 1 M. Dogan , 1 S. Evers 1University Hospital Munster (Munster, D)
Refractory status epilepticus (SE) comprises a therapeutic challenge and poses the question whether nonmedical treatment options are feasable. To date, eight cases of SE have been reported which were supposedly successfully terminated by electroconvulsive therapy (ECT). Here, we present three EEG-documented cases in which ECT was not effective in terminating SE.
Methods: Retrospective chart review and EEG analysis of all patients who received ECT for the treatment of SE at our institution between 2003 and 2006.
Results: Patient 1 was a 59-year old female with nonconvulsive SE due to bitemporal encephalitis. Despite repeated CSF analyses and lesion biopsy, no infectious agent was detected. The patient was treated with midazolam, propofol, phenytoin, valproate, levetiracetam, topiramate, oxcarbazepine, and lidocaine. SE was terminated three times but recurred after reduction of the anaesthetic dose. On days 62 through 69 after SE onset, three ECT were done, without effect on EEG status. Two weeks after ECT, SE ceased and did not recur. This was correlated with extensive bilateral cortical necrosis on MRI. Patient 2 was a 65-year old male with SE after resection of multiple left convexity meningeomas. SE was not terminated by lorazepam, phenytoin, propofol, valproate, levetiracetam, lamotrigine, topiramate, lidocaine, and thiopental. On day 40 after SE onset, the patient received one ECT without cessation of SE. Patient 3 was a 80-year-old female with SE due to right frontoparietal subdural hematoma. The patient was unsuccessfully treated with lorazepam, phenytoin, propofol, thiopental, levetiracetam, and valproate, and subsequently received three ECT, 28 days after SE onset. SE was not terminated. All three patients were finally in a persistent vegetative state and transferred to palliative care.
Discussion: ECT was not effective in terminating refractory SE in three out of three patients. In all three patients, functional outcome was bad. To date, there are eight cases in the literature that report termination of SE by ECT. Only one of these case reports  documents termination of SE by showing respective EEG recordings. Despite cessation of SE, outcome was bad in this patient as well. The previous positive case reports suggesting effectiveness of ECT in terminating SE are not exceeding anecdotic relevance. Further, scientifically based data is lacking.
Reference: Lisanby et al. ECT in the treatment of status epilepticus. J ECT. 2001 Sep;17(3):210-5.
1 G. Möddel , 1 W.-R. Schäbitz , 1 R. Dziewas , 1 F. Bösebeck , 1 C. Kellinghaus , 1 K. Anneken , 1 M. Fischera , 1 S. Kovac , 1 M. Dogan , 1 S. Evers 1University Hospital Munster (Munster, D)
Only few substances employed for the treatment of status epilepticus (SE) are used on the basis of controlled studies, i.e., lorazepam, diazepam, midazolam, phenytoin, and phenobarbital. Several substances are used on the basis of uncontrolled studies and case-series, such as valproate and propofol. The local anesthetic drug lidocaine, which acts as a sodium channel blocker like phenytoin, was first used in the treatment of status epilepticus in 1955. Until the late 1980s, approximately 150 cases were published, with the largest series comprising some 50 subjects. Since then, lidocaine has been used only sporadically, despite promising early data.
Methods: Retrospective chart review and EEG analysis of all patients with SE refractory to standard treatment who were treated with lidocain i.v. at our institution between December 2004 and August 2005.
Results: Six patients with refractory SE received lidocaine i.v. Lidocaine was applied as a continuous infusion (2-4 mg/kg/h). All patients had previously been administered standard doses of benzodiazepines and phenytoin. Five subjects had been intubated and received anesthetic doses of propofol and midazolam, two patients were additionally treated with thiopental narcosis. SE was terminated in three patients following lidocaine loading (etiologies: 1. ischemic MCA infarct, 2. hypoxic brain damage after delayed CPR, 3. inflammatory lesion secondary to AIDS CDC C3). Intubation was avoided in one patient (AIDS). In one patient, SE was terminated following lidocain infusion but recurred after dose reduction. In two patients (etiologies: hypoxic brain damage, and multiple left-hemispheric meningeomas, respectively), SE could be terminated by neither adequate doses of midazolam, propofol, phenytoin, valproate, and levetiracetam, nor by lidocaine and thiopental anesthesia. One of these patients died of multiple organ failure during hospitalisation, the other was transferred to palliative care in persistent vegetative state. In none of our patients treated with lidocaine at a maximum dose of 4 mg/kg/h, high-grade cardiac arrhythmias were noted. In none of the patients, significant lowering of blood pressure or increase of the necessary catecholamine dose occurred.
Conclusion: Lidocaine, a sodium channel blocker like phenytoin, may constitute an effective and safe alternative option for the treatment of refractory SE. Case series as this one are promising, however controlled trials are lacking so far.
1 G. Möddel , 1 C. Kellinghaus , 1 R. Dziewas , 1 K. Anneken , 1 M. Fischera , 1 S. Kovac , 1 M. Dogan , 1 S. Evers 1University Hospital Munster (Munster, D)
Status epilepticus (SE) is a neurological emergency with high mortality and morbidity. We present here our first experiences with the recently available intravenous (IV) formulation of levetiracetam (LEV).
Methods: We screened all patients admitted to our hospital between April and November 2006 with a diagnosis of either epilepsy or SE and retrospectively reviewed the records and EEGs of the patients found to have been treated with IV LEV.
Results: 7 patients had received IV LEV. 4 patients were treated for refractory SE after failure with standard doses of benzodiazepines and phenytoin. 3 were previously treated with valproic acid, 2 topiramate and 2 lidocaine; 3 patients were subsequently intubated and received propofol to induce EEG burst suppression. IV LEV was administered at 1500–9000 mg daily. SE was terminated in 2 (50%) patients; 1 with convulsive SE due to pre-existent focal epilepsy consequent to early hypoxic brain injury, one with nonconvulsive SE secondary to remote left MCA infarction. In 2 patients (50%) SE was not terminated; one patient had traumatic subarachnoid hemorrhage and left PCA infarction, the other had encephalitis of unknown etiology. IV LEV was generally well tolerated with no associated cardiovascular side effects. 1 patient experienced nausea and vomiting after receiving a 1500 mg IV LEV loading dose, resulting in mild aspiration pneumonia, successfully treated with antibiotics. 1 patient with remote right parietal infarction was admitted with generalised tonic–clonic seizures without regaining consciousness between seizures. After acute lorazepam administration this patient received 1000 mg IV LEV over one hour, followed by a 2000 mg/24 hr continuous infusion. Intubation was unnecessary and no complications occurred. 2 days after admission, the patient was discharged home in good condition on oral LEV. 2 patients with focal epilepsy were administered IV LEV in preference to oral therapy because of swallowing difficulties. There was no change in seizure frequency and no specific side effects.
Conclusions: IV LEV terminated refractory SE in 2 out of 4 patients with severe brain lesions, without cardiovascular side effects. IV LEV also appears well tolerated and effective when used to initiate antiepileptic therapy in clinical settings and as a replacement for oral antiepileptic drugs in patients with transient swallowing difficulties. Although further data are required, IV LEV may be a promising new treatment option for SE.
1 M. Steinert , 1 B. Henkel , 1 E. Korn-Merker 1Epilepsy Center Bethel (Bielefeld, D)
Rationale: Ketogenic diet (KD) is a therapy which is well established in the United States as a treatment option for children with pharmacoresistant epilepsies. In Europe, KD becomes more and more accepted, too.
In our tertial epilepsy center we treat children with difficult to control epilepsies. Since 2003 we established KD. We wanted to know whether different epilepsy syndromes respond different to KD and how many AEDs the patients took before the introduction of KD.
Method: Retrospective analysis of 14 patients who were treated with KD from 11/2003 until 12/ 2006. Responders were defined as patients with seizure reduction of at least 50%.
KD is always established as an inpatient setting. Usually, at least one member of the family is trained thoroughly during a 14 day hospital stay by our dietician. During the hospital stay blood gas analysis, glucose and ketones are monitored closely. Patients were discharged after two weeks only if ketone bodies were at minimum of 2 + in the urine and/ or > 2 mmol/l in the blood. Evaluation of KD took place with inpatient setting after 2-3 months.
Results: 14 Patients were treated with KD. 7 patients are responders, 7 are nonresponders. 3 of them quit KD because of noncompensated acidosis and /or recurrent severe hypoglycaemia during the first three days of KD.
Responders had the diagnosis of the following epilepsies: symptomatic focal (2), cryptogenic focal (1), idiopathic generalized (2) idiopathic epilepsy with generalized and focal signs (1), CSWS and myoclonic seizures (1). Mean age of this group was 8. 4 years (range: 3.4–13.2). The median of AEDs before the introduction of KD was 8 (range: 5–11).
Non-responder had the following epilepsy syndromes: symptomatic focal (4), cryptogenic focal (1), epilepsy with focal and generalized seizures (1) and Lennox-Gastaut syndrome (1).
Mean age in this group was 6.3 years (range:1.5–9.8). The median of AEDs before KD was 7 (range: 5–13).
Conclusions: According to our small series, we could not find a clear correlation between a specific epilepsy syndrome and positive effect of KD. Both groups are overlapping.
Responders as well as nonresponders took a lot of AEDs before KD was started. According to the current literature, KD should be offered as soon as 2 or 3 appropriate AEDs fail to control the epilepsy. But even if KD is started after multiple AED treatment attempts we can report of a responder rate of 50%.
1 S. Rupprecht , 1 K. Franke , 1 S. Fitzek , 1 O.W. Witte , 1 G. Hagemann 1Friedrich-Schiller-University (Jena, D)
Purpose: Nonconvulsive status epilepticus (NCSE) is not rare but certainly underdiagnosed. There is some debate about the sequelae of NCSE and how aggressively it should be treated, as high dose antiepileptic drugs (AEDs) may be an influential factor on prognosis especially in the elderly. We evaluate whether levetiracetam (LEV), a well tolerated highly effective AED may be a safe treatment option in complex partial status epilepticus (CPSE), one type of NCSE.
Methods: Retrospective analysis and follow-up of all patients with CPSE in a University Hospital treated with oral doses of LEV (8 patients) compared with conventional intravenous (IV) AEDs including valproate, phenytoin and benzodiazepines (11 patients) during a 5 year period. Both groups were statistically compared for age, hospitalisation time, time in intensive care unit and outcome. Follow-up was collected in both groups to assess seizure frequency and subjective quality of life.
Results: All 8 patients showed a marked clinical improvement with final cessation of ictal EEG-activity and clinical symptoms of NCSE after LEV initiation within 3 (mean 1.5) days. LEV was titrated from a starting dose of 500–1000 mg per day to a maximum dose of 2000 mg per day within 2 days. Conventional treatment in the control group was similarly effective but there were severe side effects (phenytoinintoxication (n = 1), toxic hepatitis after valproate (n = 1), valproate-induced hyperammonaemic encephalopathy with elevated ammonia levels (n = 3), whereas no relevant side effects in the LEV-treated group were reported. Long-term follow-up (6-36 months postdischarge) revealed 6 patients being treated with LEV achieved persisting seizure frequency reduction. One patient changed LEV medication because of inefficacy and the other died from causes other than epilepsy 2 months postdischarge. We found no significant differences in hospitalisation time, time in intensive care unit and outcome between the LEV group and the control group.
Conclusions: These data suggest that LEV may be a well tolerated, effective treatment option in NCSE and highlights the need for a prospective controlled study, particularly as an IV LEV formulation is now available.
1 K. Anneken , 1 M. Fischera , 1 C. Kellinghaus , 1 G. Möddel , 1 I.W. Husstedt , 1 S. Evers 1University Hospital Munster (Munster, D)
Introduction: About 5% of patients with HIV infection develop epileptic seizures. Anecdotal reports on antiepileptic treatment in HIV infected patients are available (1), however, systematic data is rare. We examined efficacy and safety of antiepileptic drug (AED) treatment in HIV infected inpatients with epileptic seizures.
Methods: The patient charts of all HIV infected patients admitted to the neurological inpatient clinic of the University of Münster, Germany, between 2004 and 2006 were analysed concerning the following items: demographic data, HIV related data, epileptic seizures, AED drug regime, efficacy and side effects of antiepileptic treatment.
Results: In this population, 12 out of 40 HIV infected patients (30%) had at least one epileptic seizure. All patients suffering from epileptic seizures received HAART and AED treatment, nine were put on AED monotherapy and three on AED polytherapy. Gabapentin was used in 11 cases, carbamazepine in 2 cases, and each of the following drugs in one case: lidocaine, levetiracetam, pregabalin, valproic acid, clonazepam, oxcarbazepine, and phenytoin. Nine patients had significant reduction (>50%) of seizure frequency, all of them were treated with gabapentin. Four patients suffered from side effects (SE), three of them received gabapentin. The most common SE was sleepiness. All SE were mild in nature.
Conclusion: Epileptic seizures are a relevant complication in HIV infected patients. Our data suggest that AED treatment with gabapentin is effective and safe in this population.
Literature: 1. Bhigjee AI, Rosemberg S. (2006) Optimizing therapy of seizures in patients with HIV and cysticercosis. Neurology 67:19-22.
1 S. Bunten , 1 B. Kroeger , 1 S. Dempewolf , 1 M. Lanz , 1 H. Rawert , 1 S. Happe 1Hospital Bremen East (Bremen, D)
Introduction: Multimorbid patients with status epilepticus are particularly challenging regarding treatment as they can present several problems when the common treatment measures are applied. Most recommendations start with intravenous lorazepam or another benzodiazepine followed by phenytoin or valproate. Administration of phenobarbital or primidone should come last as it can lead to respiratory problems and intubation.
Methods: Evaluation of multimorbid patients treated with levetiracetam due to EEG confirmed persisting status epilepticus and failure of initial treatment.
Results: Eight patients in status epilepticus were treated with levetiracetam after initial therapy failed. In six cases levetiracetam ended the status epilepticus after a treatment with lorazepam had failed. One patient received levetiracetam after an ineffective treatment with clonazepam. One patient was treated with a combination of valproate and phenytoin, another with valproate and lorazepam before the decision was made to alter the medication.
Seven times treatment took place due to nonconvulsive status epilepticus, once due to a series of generalized seizures. Twice, the medication was administered orally, seven times intravenously. All patients were multimorbid, two suffered from liver cirrhosis, two of the patients were treated with levetiracetam twice, each time with status epilepticus.
All patients profited by the decision to switch to levetiracetam as it ended the status epilepticus without causig the necessity of intubation and respiratory assistance.
Summary: Treatment of status epilepticus in multimorbid patients, in particular those with liver dysfunction, poses special problems that often lead to prolonged intensive care treatment. Levetiracetam may be a promising option in the treatment of status epilepticus and can help to minimize the risk of further liver dysfunction, prolonged intensive care or intubation as drugs such as valproate, phenytoin, phenobarbital or primidone can be avoided.
1 D. Neumann , 1 J.-P. Ernst , 1 P. Sager 1Epilepsy Centre Kork (Kork, D)
Evaluated are the datas from 40 children (18 female, 22 female) in the mean age of 5.9 y (0.8-18.8 y). The mean duration of epilepsy is 3.5 y (0.7-14 y). Before starting ketogenic diet they were treated with 9 (1–15) drugs in single or combination therapie.
20 children have a symptomatic epilepsy, for example complex malformation of the brain, or residual state after bleeding, infections and others.
20 children have an idiopathic epilepsy like Lennox-Gastaut-Syndrome, Grand Mal Epilepsy and others.
62.5% have generalized, 37.5% focal seizures.
67.5% of the children are doing classical 4:1 ketogenic diet. The were underlying a moderated John-Hopkins-protocoll, without fastning and with no restriction of liquid.
10% were without any other medication, 82.5% had 1 or 2 drugs under ketogenic diet. 37.5% have a comedication with valproin acid.
The children do ketogenic diet 18 weeks in the mean; the responder rate is 55% (n = 22). No effects were seen in grand mal epilepsy.
The 22 responder do ketogenic diet in the mean for 48 weeks (13–144 weeks). 30% with a seizure reduction over 50%, 17.5% over 90%, 3 children are complete seizure free.
Even after ending the ketogenic diet the responding children show a significant reduction of seizures.
The ketogenic diet can be used in the treatment of pharmacoresistent and inoperable epilepsies in childhood.
1 C. Wehinger , 1 P. Gallmetzer , 1 B. Mamoli 1Ludwig Boltzmann Institute for Epilepsy (Vienna, A)
Purpose: Photosensitivity is a common cause of seizure EEG pattern precipitation. Fixation-off sensitivity (FOS) which is suggested in routine EEG by abnormalities that consistently occur as long as the eyes are closed but not with eyes open is less common.
Results: A 66- year- old man with a known history of seizures and alcohol abuse was admitted to our department after three generalized tonic–clonic seizures (GTCS).He had been treated with oxcarbazepin (OXC) for three years following a single GTCS. Upon admission there was no visible seizure activity. A postictal confusionary state resolved within the first few hours. During the following days the patient showed an unimpaired mental state. Due to elevated hepatic parameters the patient was stepwise switched to gabapentin (GBP). A routine EEG performed on day 5 showed a generalized, 2 to 4 c/ s spike-wave and polyspike-wave pattern with complete suppression on eye opening and recurrence on eye closure. Intermittent photic stimulation (IPS) consistently elicited polyspike-wave complexes with a return to baseline activity in stimulation-free intervals. After switching to oral Levetiracetam(LEV) 500 mg bid and discontinuation of OXC and GBP treatment the EEG pattern completely resolved with only a slight amount of occipital polyspike activity following eye closure and no reaction to IPS.
Conclusion: LEV was effective in the treatment of nonconvulsive status epilepticus with FOS.
1 O. Debus , 1 H. Koch 1St. Marienhospital Vechta (Vechta, D)
Hypothalamic Hamartoma (HH) usually has a characteristic clinical course. Apart from polymorphic seizure types with typical gelastic seizures a psychomotor regression develops over the time. Mostly this epileptic syndrome is refractory to the currently available antiepileptic medications. Epilepsy surgery is chosen in rapidly deteriorating patients but its success is not predictable.
A 15-year-old girl suffering from severe psychomotor retardation is presented. Her seizure history began with a febrile status epilepticus in infancy. At the age of 3 she started with complex partial seizures followed by secondary generalized and gelastic seizures. A HH was diagnosed as the cause of the epilepsy which did not grow over the years. After multiple antiepileptic drug trials the situation was stable under a combination with lamotrigine, clobazam and sulthiame with only few and short complex partial seizures. The EEG showed sparce groups of bilateral precentrally commencing and rapidly generalizing spike wave and few tonic patterns. After the reduction of sulthiame the girl developed a clinical and electroencephalographical absence status that could be controlled by a reintroduction of sulthiame.
Clinical seizures and their EEG-correlate in HH can present as focal or generalized activity. The choice of an appropriate medication in this syndrome usually depends on the seizure type. Sulthiame is an antiepileptic drug commonly applied in focal epilepsies. Its introduction can be justified in generalized seizure types, when standard medications have been used unsuccessfully.
1 G. Krämer , 2 T.W. May , 3 B. Schmitz , 4 H. Stefan , 5 B.J. Steinhoff , 6 S. Stodieck , 7 E. Trinka 11 Swiss Epilepsy Centre (Zurich, CH) ; 2 Gesellschaft für Epilepsieforschung e.V. (Bielefeld, D) ; 3 University Hospital Charité (Berlin, D) ; 4 Epilepsy Center – University Erlangen (Erlangen, D) ; 5 Epilepsy Centre Kork (Kehl-Kork, D) ; 6 University Hospital of Neurology and Epileptology (Hamburg, D) ; 7 University Hospital of Neurology (Innsbruck, A)
Background: Even at the beginning of the 21st century carbamazepine and valproate remain the most commonly prescribed standard antiepileptic drugs (AEDs). Since the introduction of vigabatrin there have been eight other new AEDs with partial approval for monotherapy up to now. This has not only led to a broadening of the options of AED therapy but also to a kind of confusion for the prescribing physicians especially regarding the comparative value of newer AEDs. Because evidence based guidelines are mainly based on the regulatory studies and head-to-head comparisons are not available, these guidelines of neurological or other medical societies can only partially solve this problem. Therefore we adopted a questionnaire for experts which has already been used twice in the US (Karceski S, Morrell MJ, Carpenter D. Epilepsy Behav 2001; 2, Suppl.:A1-A50, and Epilepsy Behav 2005;7 Suppl 1: S1-64) to the situation in the three German speaking countries.
Methods: We sent a questionnaire to 45 experts in the field of adult epileptology (“opinion leaders”) in Germany, Austria, and Switzerland in the second half of December, 2006. All had been asked before whether they were willing to participate and had agreed. The questionnaire consisted of 28 case histories in the treatment of idiopathic as well as symptomatic or presumably symptomatic epilepsies. The experts were asked to give their opinion for 22 possible alternative treatments (in addition to all available AEDs as well ketogenic diet and vagus nerve stimulation) on a 9-point scale (with “9” most appropriate and “1” least appropriate). This should be done irrespective of the current approval status based on their personal experience and view.
Results and conclusions: Forty-three out of the 45 contacted experts answered until the end of January 2007. The statistical analysis of the results is currently ongoing. We expect the results to be of complimentary usefulness to existing guidelines for treatment of adult patients with epilepsy.
The study and the evaluation of the results was performed with unrestricted educational grants by (in alphabetical order) GlaxoSmithKline, Novartis, Sanofi-Aventis, and UCB. All analyses were done without any influence of any of these companies by the “Gesellschaft für Epilepsieforschung” in Bielefeld.
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Poster session 1.3. Epilepsy surgery and miscellaneous
1 C.G. Bien , 1 M. Szinay , 1 H. Urbach , 1 A. Becker , 1 J. Schramm , 1 C.E. Elger 1University of Bonn (Bonn, D)
Purpose: Presurgical workup in patients with nonlesional brain MRI is complex, intricate, and often unsuccessful. Surgically treated patients have an inferior outcome compared to lesional surgical candidates. It is therefore a matter of debate if presurgical evaluation is worthwhile in those patients. Only a few studies on the outcome of surgically treated cases have been published. A possibly even greater limitation lies in the fact that—to the best of our knowledge—there is no study available comparing the outcome of surgically treated non-lesional patients to those who have not been offered epilepsy surgery. The present was undertaken to provide such data.
Method: Review of the records of all patients undergoing presurgical assessment at this centre between 2000 und 2005 in whom high-resolution brain MRI on initial assessment was found to be negative for a potentially epileptogenic lesion. For all patients, the most recent available follow-up at our outpatient department or (if this was unavailable) through telephone interviews was noted.
Results: We identified a total of 176 patients. Twenty-one of them underwent resective surgery (12%). Between the surgery and the non-surgery groups, there were neither demographical differences nor such regarding the extent of noninvasive presurgical investigations.
Outcome after a mean follow-up of 2.2 ± 1.5 years was available for all operated and 121 nonoperated patients. Eleven (52%) of the surgery patients [histopathology: four FCDs, one cavernoma, four cases of mild hippocampal sclerosis Wyler I/II, and 12 with non-specific findings] vs. 19 (16%) of the non-surgery patients were seizure-free for at least one year (P < 0.001).
Supposing that no surgical treatment had been offered to anyone in the whole cohort, i.e., that the seizure-freedom rate of all patients with follow-up were that of the real nonoperated subgroup: The seizure-freedom rate of that fictive group (16%, 22/142) wouldn't have been inferior to that of the real one (30/142, 21%, P = 0.2).
Conclusion: The seizure-freedom rate of the operated patients was superior to that of their nonoperated counterparts. However, the seizure-freedom rate of the whole group was not significantly improved by the surgery subgroup. There is still need for reliable prognostic parameters to be applied in rejection and selection of nonlesional surgical candidates.
1 C. Bußmann , 2 H.-J. Meink , 2 H.H. Steiner , 3 W. Broxtermann , 4 C.G. Bien , 1 D. Rating , 1 T. Bast 11 Children's Hospital Heidelberg (Heidelberg, D) ; 2 University Hospital Heidelberg (Heidelberg, D) ; 3 Social Pediatric Center (Mosbach-Neckarelz, D) ; 4 University Clinic of Epileptology (Bonn, D)
Background: The therapeutic role of vagus nerve stimulation (VNS) in epilepsy was clearly demonstrated. We investigated the effects of VNS in a patient with epilepsia partialis continua (EPC), a condition usually refractory to antiepileptic treatment.
Case report: An 18-year-old male patient experienced EPC in the left foot, sometimes including the left leg/arm/face, which had lasted for 10 years. Epilepsy started at the age of 6 years with complex-partial seizures (CPS) with left sided cloni. At the age of 8 years epilepsy worsened acutely, including the onset of EPC and he developed a stable mild spastic hemiparesis. VNS was implanted at the age of 18 years (follow-up 24 months). Actual frequency of CPS was 6–8/month and he suffered from additional isolated and prolonged auras. Because of severe myoclonia of the left foot it took the patient up to three hours to fall asleep.
Diagnostic workup: MRI at the age of 13 years showed diffuse cerebral atrophy with right hemispheric maximum, which was progredient in further MRI controls, corresponding to the formal diagnostic criteria of Rasmussen encephalitis. FDG-PET showed a diffuse hypometabolism of the right hemisphere. Jerk-locked averaging of perimyoclonic MEG signals and source analysis revealed a right central generator with spikes.
Polygraphic neurophysiological investigations, including giant left tibialis SEP indicated a cortical myoclonus.
Follow-up: VNS reduced CPS frequency >50% and auras were shortened by magnet activation. EPC stopped when currents of 1mA were reached, although the patient still experienced several myoclonic jerks of the left leg per hour. However, the sleep problem was solved. Acute reduction of stimulation currents from 1.25 to 0.75 mA was necessary two times because of psychogenic panic attacks with sweating and dyspnea. EPC worsened after 6 to 12 hours. A prompt response was noted when currents were increased again 4 weeks after the first and 24 hours after the second episode.
Conclusion: The reported patient with Rasmussen encephalitis profits from VNS as former pharmacoresistant seizures are reduced. Especially the reduction of cortical myoclonus is a considerable improvement of quality of life. Therefore VNS may be an effective treatment in epilepsia partialis continua.
1 F. Kerling , 1 B. Fraunberger , 1 H. Stefan 1Epilepsy Center – University Erlangen (Erlangen, D)
Introduction: After successful epilepsy surgery, a discontinuation of antiepileptic drugs (AED) is desirable to achieve a state of complete seizure freedom without medication. However, prospective randomised trials of AED discontinuation are difficult because of their risk of seizure relapse. We report about a prospective withdrawal study with patients from our epilepsy centre.
Methods: All postsurgical patients were invited to follow up visits every year in the first five years after epilepsy surgery. Patients who were completely seizure free one year after surgery and without any severe EEG changes (frequent epileptiform discharges) participated in this study. The patients could decide whether medication should be discontinued (tapering group) or kept at the same dosage (control group). Discontinuation was realized in small tapering steps over a one year period for the first drug. When patients had more than one drug, the second drug could be discontinued in the next year and so on.
Results: Eighty-four patients could be included since 1997, 50 in the tapering group and 34 in the control group. Forty two patients in the tapering group and 31 patients in the control group already passed the two years follow up visit, 24 patients in the tapering group and 20 patients in the control group had passed the five years follow up visit.
93% (38 of 41) in the tapering group and 83% (26 of 32) in the control group were seizure free two years postoperatively. Five years after surgery, 83% (20 of 24 patients) in the tapering group and 60% (12 of 20 patients) in the control group were seizure free.
Conclusions: These preliminary data show no higher risk for discontinuation of antiepileptic drugs after successful surgery. Nevertheless, the number is small. We suggest to initiate a multicenter study with a standardised protocol.
1 S. Fauser , 2 T. Bast , 1 D.-M. Altenmüller , 1 J. Schulte-Mönting , 3 K. Strobl , 3 B.J. Steinhoff , 1 J. Zentner , 1 A. Schulze-Bonhage 1 University of Freiburg (Freiburg, D) ; 2 University of Heidelberg (Heidelberg, D);3 Epilepsy Centre Kork (Kehl-Kork, D)
Introduction: Focal cortical dysplasia (FCD) is a common cause of pharmacoresistant epilepsy in childhood and adulthood. Determination of prognostic factors for epilepsy surgery is important when counselling these patients.
Methods: 120 patients with histologically proven focal cortical dysplasia were retrospectively analysed. Multivariate logistic regression analyses were performed to assess the prognostic importance of the clinical variables duration of epilepsy, age at epilepsy surgery, age at epilepsy onset, location of FCD, and histology of FCD.
Results: Longer duration of epilepsy reduced the chance of becoming seizure-free after epilepsy surgery. One year postoperatively, 75% of the patients with epilepsy duration between 0 and 5 years were seizure-free, as compared to only 39% of patients with epilepsy duration > 20 years. This effect was independent of the duration of follow-up. Location or histological subtype of the FCD, however, had no statistically significant influence on the postoperative outcome.
Conclusion: This finding strongly suggests early consideration of epilepsy surgery in patients with FCD.
1 J. Wellmer , 1 F. von der Groeben , 1 C. Weber , 1 H. Urbach , 1 C. Schaller , 1 C.E. Elger 1University Hospital Bonn (Bonn, D)
Introduction: With the introduction of high resolution MRI into the presurgical work up of pharmacoresistant epilepsy patients, epilepsy surgery has become highly individualized. In this context, the chronic implantation of sudural grid electrodes may be considered to delineate the seizure onset from functionally relevant cortex. However, the decision for grid implantation has to be met in view of the risks that are linked to this procedure. We performed a retrospective evaluation of grid implantation-related complications.
Materials and methods: In the period from 2004 to 2006, 57 epilepsy patients (28 f; 3-60 ys, mean 34 ± 12) received grid electrodes. We defined grid electrodes as any electrode array with 16, 20, 32 or 64 electrode contacts which was inserted under sight via open craniotomy. With the exception of three patients, all patients had one grid. Two had two and one patient three grids (mean number of grid contacts: 44 ± 17). Additionally, one to eleven strip electrodes and one to two depth electrodes were implanted in 41 and 25 patients, respectively (total number of electrodes: 20 to 120, mean 60 ± 20). Complications occurring during the period of implantation (5 to 40 days, mean 16 ± 6) are classified as grade 1: complication visible on CT/MRI only; grade 2: clinically apparent complication, no surgical revision needed; grade 3: open revision or termination of invasive workup necessary.
Results: In 17 patients (30%) we observed the following complications: subdural or epidural hematoma (N = 11); brain swelling/edema (N = 5); cortical contusion (N = 5); interacerebal hemorrage (N = 3); olfactory nerve contusion (N = 1). Grade 1: N = 5 (9%); grade 2: N = 3 (5%); grade 3: N = 9 (16%). Following grade 3 complications, after hematoma evacuation the workup was continued in seven patients, removal of grids or other electrodes were necessary in one patient each. No patient exhibited a persistent neurological deficit. We found no correlation between the occurrence of complications and the number of implanted electrode contacts, grid size, or the duration of the implantation procedure. In all 57 patients invasive monitoring finally led to a definite result, either recommendation of surgery (N = 52) or rejection (N = 5).
Discussion: Invasive presurgical workup with grid electrodes is not free of complications. However, we did not observe implantation related permanent neurological deficits. The invasive workup with grid electrodes should be restricted to patients who can not be diagnosed otherwise.
1 J. Wellmer , 1 C. Weber , 1 F. von der Groeben , 1 C. Schaller , 1 C.E. Elger 1University Hospital Bonn (Bonn, D)
Introduction: Despite functional neuroimaging, invasive EEG recording and electrocorticostimulation (mapping) with subdural grid electrodes remain necessary tools in the presurgical workup of pharmacoresistant epilepsy patients. Because of higher risk of complication when compared with “acute” (intraoperative) electrocorticography, “chronic” grid implantation can only be justified by a gain of information relevant to planning and execution of surgery. To quantify usual efforts related to the creation of comprehensive surgical maps, we evaluated 57 extraoperative presurgical procedures.
Materials and methods: From 2004 to 2006, 57 epilepsy patients (28 f; 3-60 ys, mean 34 ± 12) received implantation of grid electrodes. We defined grid electrodes as any electrode array with 16, 20, 32 or 64 electrode contacts which was inserted under sight via open craniotomy. Indications for grid implantation were: localization of the epileptic focus (N = 57) and mapping eloquent cortex (N = 50). Depending on the grid location, we mapped for motor cortex, SMA, negative SMA, language (including counting, confrontation naming, repeating sentences, reading, token test and body commands), sensory functions, and visual phenomena. During mapping, all grid electrode contacts were stimulated at least twice in different bipolar relays.
Results: During a monitoring period of one to 36 days (8.0 ± 5.8) we recorded spontaneous seizures in 56 of 57 patients. Following reduction of antiepileptic drugs, first seizures occurred after one to 12 days (2.6 ± 2.7). Seizure onset was identified within the grid in 43 patients. The mapping period took one to six days (2.8 ± 1.4) or 30 to 850 minutes (252 ± 181), respectively. 77 distinct functions were found in 47 of 50 mapped patients. Despite performance under antiepileptic medication, electrostimulation elicited seizures in 21 patients. Grids remained implanted five to 40 days (16 ± 6). In all patients, sufficient information for the creation of comprehensive maps was collected.
Discussion: Creation of comprehensive and reliable maps is complex and tends to be time-consuming. Unlike acute electrocorticography and stimulation, extraoperative monitoring allows verification of doubtful results, adaptation of the examination velocity to the capacity of individual patients, and discontination of mapping in case of unpredicted events (such as seizures). From the neurosurgical point of view, preoperatively created maps allow for a natural work flow during surgery.
1 K. Strobl , 1 H. Mayer , 1 J.-P. Ernst 1Epilepsy Centre Kork (Kehl-Kork, D)
Introduction: Hypothalamic hamartomas with epilepsy still are a huge challenge in epilepsy surgery. Nowadays different strategies seem to solve this problem: Interstitial radiosurgery (ISR), LINAC- or gammaknife (GK)-radiosurgery and open or endoscopic microsurgery (MS) seem to compete for the best results.
Methods: We report about 8 patients treated in different centers with at least one of these methods:
1 open microsurgery (2x in the same patient) only,
1 ISR + open microsurgery,
1 ISR (twice) + LINAC + open microsurgery,
1 GK + endoscopic microsurgery,
Results: Overall the best outcome was seen in the 4 patients who were operated in the end (Engel IA 2x, Engel IIA 1x, Engel IIIA 1x). Two of these patients developed postoperative complications: obesity + hypogonadism or obesity + transient hemiparesis respectively.
There was only little positive effect on seizure frequency in the 4 patients with only radiotherapy until now (follow up more than one year). Some of them might have profited concerning behavior and cognitive parameters.
Conclusion: Looking for the best treatment for 8 children with hypothalamic hamartoma and epilepsy different strategies in different centers were used. In our very small group it looks like as if microsurgery is the most effective procedure, although there are also very encoureging results about gammaknife or interstitial radiosurgery in literature.
Besides this discussion about the best option we should give this small group of our patients a chance and start to offer them early a proper device and additional radiosurgical or microsurgical treatment.
1 T. Falkenstetter , 1 T. Benke , 1 J. Dobesberger , 1 I. Unterberger , 1 M. Ortler , 1 T. Fiegele , 1 E. Trinka 1University Hospital Innsbruck (Innsbruck, A)
Introduction: Analysis of seizure semiology may help to lateralize and localize the seizure onset zone and symptomatogenic zone, respectively, and may contribute to our knowledge regarding functional neuroanatomy. In temporal lobe epilepsy (TLE), early head turning, mostly ipsilateral, and late contralateral versive head movements have been described.
Eye movements, visuospatial attention and visuomotor integration are controlled by a cerebral network presumably involving areas in the frontal lobe (e.g., the frontal eye field) and in the parietal lobe (e.g., the parietal eye field, gyrus supramarginalis, other parietal sites). According to known studies, head and eye movements are functionally linked to the prefrontal area.
We report a case of contralateral nonversive head deviation induced by electrical stimulation at the temporoparietal junction.
Case report: A 45-year-old man suffered from pharmacoresistent non-lesional left sided epilepsy with a presumed posterior temporal seizure onset zone. He underwent invasive EEG recording and stimulation to further delineate the seizure onset zone and potentially involved eloquent areas. Frameless stereotactic implantation of two hippocampal depth electrodes as well as subdural grid-electrodes (left frontal, temporal and parietal lobes) and subsequent video-EEG allowed the localization of the seizure onset zone to the left superior temporal gyrus. Electrical stimulation at the left temporoparietal junction repeatedly elicited contralateral nonversive head deviation. The seated patient, performing language tasks, was not aware of his head turning. The involuntary head turns resembled head turns intentionally conducted to look for something or to pay attention to something, but occurred without any external lateralized stimuli being present. The evoked movements exactly resembled the semiology of early head turning, which was in this case contralateral to the side of stimulation. Early head turning was not found in the patient's habitual seizure semiology.
Discussion: We hypothesize that stimulating the area at the temporoparietal junction where head turning was induced had an effect on the cerebral network controlling eye movements and visuomotor integration. This finding reemphasizes the challenges in accurately interpreting the lateralizing and localizing value of different types and sequences of head turning. Special caution should be paid in analyzing non-versive head turns in posterior neocortical TLE.
1 K. Wagner , 1 L. Frings , 2 T. Maiwald , 1 A. Schinkel , 1 C. Lehmann , 1 A. Buller , 1 R. Everts , 1 A. Carius , 1 A. Schulze-Bonhage 11 University Hospital Freiburg (Freiburg, D) ; 2 Center for Data Analysis and Modeling (Freiburg, D)
In order to assess titration effects of levetiracetam (LEV) in patients with focal or generalized epileptic seizures, we applied a novel method that allows for temporally fine-grained monitoring of cognitive performance as well as subjective well-being using hand held computers.
Twenty patients recruited in the outpatient clinic of the epilepsy center took part in this pilot study, 10 were newly medicated with LEV, the other 10 patients served as a control group in which medication was held constant. Differences between groups were analyzed regarding self-rated cognitive condition, psycho-physical condition, aggressiveness, and cognitive test performance by applying a 2-back working memory task assessed 3 times a day (morning, early afternoon, evening) over the course of 6 days. The first day served as a baseline with no add-on medication, on the subsequent days LEV was introduced as follows: 250 – 0 – 250 mg (day 1), 500 – 0 – 500 mg (day 2), 1000 – 0 – 1000 mg (during days 3 to 5).
Results revealed a significant group difference in self-rated aggressiveness (p < 0.05), which was higher in the LEV group in the early afternoon across days. Furthermore, control patients' cognitive performance significantly improved in the morning over the course of days compared to LEV patients, in which morning test performance was rather stable. Beyond proving feasibility of this novel method of patient monitoring, we were able to detect early effects during titration of LEV on (1) subjective aggressiveness depending on time of day and (2) changes in working memory performance over the span of days. We hereby emphasize the unique opportunities for patient monitoring and counseling provided by this novel method.
1 A. Carius , 1 A. Schulze-Bonhage 1Epilepsy Centre – University Hospital Freiburg (Freiburg, D)
Purpose: It is well known that an increase of body temperature may trigger epileptic seizures.
There is only little information in the literature which effect an artificial hyperthermia by bathing in thermal springs, by having a sauna or during therapeutic hyperthermia, e.g., by infrared radiation may have.
Methods: We present a retrospective summary of casereports of outpatients in whom seizures occured while having a sauna.
Results: 11 of our adult patients (6 m, 22-57 years) spontaneously reported to have suffered from seizures during sauna use between 2003 and 2006; we saw about 120 outpatients monthly. 9 of the seizures have been doubtless of epileptic origin. Usually these seizures were habitual, but more than the half were of an extended duration. In 6 of these 9 patients a brain tumor was the cause of their epilepsy. 2 patients incured their first seizure while having a sauna, both have got a brain tumor. 7 of 11 patients were under a stable treatment with 1 to 3 antiepileptic drugs, which had not been changed during the weeks before the seizure occured. The seizure frequency of all patients was 0 (in 7 patients!) to 5 habitual seizures monthly, the mean was one seizure in one month before the seizure during sauna has happened.
Conclusions: These results suggest that artificial hyperthermia may facilitates the occurence of seizures in epileptic patients especially in symptomatic focal epilepsy due to a brain tumor. This information may be of importance for this patient group. If the first seizure of a patient occurs during saunaing a brain tumor should be ruled out carefully. More information is needed with regard to the degree to which the risk of seizures is increased and which mechanisms play a role in hyperthermia-induced seizures
1 K. Hattemer , 1 S. Knake , 1 W. Oertel , 1 H. Hamer , 1 F. Rosenow 1University Hospital Giessen and Marburg GmbH (Marburg, D)
Seizures related to alcohol are a common finding and are usually attributed to alcohol withdrawal or a neurotoxic effect of ethanol leading to seizures that are unrelated to acute alcohol consumption or withdrawal. There is increasing evidence for a third kind of alcohol-related seizures: alcohol-induced seizures.
We describe a 36 year old patient who during the years from 1996 – 2006 was admitted 27 times with alcohol-induced seizures that occurred during alcohol consumption. Excluding one documented withdrawal seizure, serum ethanol levels at admission were 3.24o/oo ± .67o/oo. There were no seizures unrelated to alcohol consumption.
This case report supports the evidence of a seizure-provoking effect of ethanol that should be considered in the diagnosis and treatment of patients with alcohol-dependency and seizures.
1 M. Hoppe , 1 U. Specht , 1 R. Thorbecke , 1 T.W. May , 1 A. Ebner , 1 B. Pohlmann-Eden 1Epilepsy Center Bethel (Bielefeld, D)
Rationale: Suspected seizure provocation due to conditions at the workplace probably contributes to the high rates of unemployment in patients with epilepsy. The diagnosis of epilepsy frequently leads to restrictions concerning workplaces with word processing personal computers (PCs), even in patients without photosensitivity. Current knowledge about photosensitivity does not suggest an increased risk of seizures from office work with PCs because of the high refresh frequencies (≥ 75 Hz) of modern PC screens; however, studies with EEG registration in patients working at a PC have not been performed.
Methods: Patients with a documented photoparoxysmal response (PPR), i.e., epileptiform EEG discharges (ED) provoked by intermittent photic stimulation (IPS), were included. They underwent a standardized EEG procedure with simultaneous video recording. It comprised three evaluation periods in randomized order, each lasting 10 minutes: 1) baseline period (resting condition), 2) PC-test period (reading and editing a text at a personal computer using a word processing program), 3) control period (reading and editing a similar text printed on a white paper). For the PC-test period, a commercially available personal computer with a 17 inches cathode ray tube (CRT) monitor display (resolution 800×600 dpi, refresh rate of 85 Hz) was used. The number and duration of ED during each of the evaluation periods were assessed by two blinded examiners. In addition, a standard IPS was performed in order to document present PPR.
Results: Twenty-five patients were examined. Eight did not show PPR on IPS and thus were excluded. All remaining 17 patients had idiopathic generalized epilepsy. In 8 of them (47%), ED occurred at least during one of the three evaluation periods. There was no statistically significant difference between the three conditions (p = 0.25). Pairwise comparisons even indicated that during PC-test period the duration of ED was marginally shorter compared to baseline period (p = 0.094) and to control period (p = 0.063). None of the 17 patients showed an increase in duration of ED during condition “PC-test” compared to condition “control.” No seizures were recorded during the study.
Conclusion: In accordance with other studies using IPS, our results do not give evidence for an increased risk of seizure precipitation in photosensitive patients when using a word processing program displayed on a 17” CRT PC screen. Thus, restrictions concerning PC workplaces for office work are not warranted.
The study was supported by UCB Pharma GmbH, Kerpen, Germany
1 I. Coban , 1 R. Kretz , 1 S. Eibach , 1 V. Gaus , 1 B. Schmitz 1Charité Campus Virchow-Hospital (Berlin, D)
Background: The treatment with antiepileptic drugs (AED) during pregnancy is associated with the risk of teratogenic effects for the foetus. The data with respect to the teratogenicity of the older AED are conflicting, mainly due to inadequate sample size and methodological shortcomings. The teratogenic potential of newer AED is even less known.
To address this problem, a prospective registry for pregnancies exposed to AED has been established.
Methods: EURAP is a prospective and retrospective observational study. Women taking AED at the time of conception are included within the first 16 week of gestation for a prospective risk assessment. Cases ascertained later in pregnancy are recorded retrospectively.
Evaluation: At present more than 750 physicians from 39 countries have contributed 8785 cases to the central registry (Interim Report 11/2006). 3749 prospective cases have completed the study including the one-year follow-up after birth (age 29.6 ± 5.1 years (mean ± SD), ranging from 15 to 45 years. Epilepsy syndrome: generalized 41.2%, localization-related 52.7%; monotherapy 80.3%).
3252 live births, 279 spontaneous abortions, 125 induced abortions, 62 stillbirths and 31 perinatal deaths have been reported. There were 232 major congenital malformations (MCM) which represent a malformation rate of 6.7% and 30 chromosomcal monogenic abnormalities.
In 166 out of 2726 pregnancies with AED monotherapy one or more birth defects were observed (6.9%), as opposed to 64 out of 655 pregnancies with AED polytherapy (10.6%).
Until January 2007 170 neurologists, gynecologists and pediatricians reported 810 cases (prospective 793 = 89.3%) in Germany. Regarding age, epilepsy syndrome and monotherapy there were no significant differences compared to the international database.
The most frequently used anticonvulsive monotherapies are lamotrigine (43.2%), valproate (22.1%) und carbamazepine (20.1%).
There have been 489 live births, including 45 (8%) preterm deliveries and 36.1% caesarean sections. Spontaneous abortions occurred in 33 cases (4.7%), induced abortions in 16 cases (2.3%), including 4 cases with fetal anomalies. Furthermore 4 (0.7%) stillbirths and 5 (1%) perinatal deaths were observed.
There were 25 MCM, including 3 induced abortions (monotherapy 3.6%, polytherapy 5.7%). 4 more cases are not yet classified.
With respect to specific AED the malformation rates were: valproate 8 (8.2%), lamotrigine 6 (3.8%), carbamazepine 3 (3.5%).
1 P. Ratzka , 1 I. Schäfer , 1 M. Bartl , 1 A. Reeh , 1 C.D. Reimers 1St. Ansgar Hospital (Höxter, D)
We present the case of a 49-year-old woman who was initially admitted to our internal medicine department to investigate drop-attacks exsisting over the last 2 years. Remarkably, the drop-attacks only occurred during walking. During a typical episode, she stereotypically falls on her knees without loss of conciousness. On physical examination at admission, she presented with massive bruises at both knees. The extensive syncope evaluation revealed no pathological findings and the patient was referred to our neurological department for further diagnosis to exclude an epileptic cause. On neurological examination no pathological findings were found except weak tendon reflexes of the m. quadriceps femoris on both sides. The past medical history included a NIDDM since 8 years and a bronchial asthma since 12 month. She reported to be postmenopausal. The EEG showed intermittent frontotemporal theta-delta-activity on the left hemisphere, however no signs of epileptic activity. Because of the typical history, a normal MRI of the brain and after ruling out all other causes, we initially decided on the diagnosis of cryptogenetic drop-attack in climacteric (“maladie des genoux bleus”).
However, a subsequent EMG surprisingly revealed myopathic changes. We then performed a MRI of the thigh muscles which indicated a chronic neuromuscular disease of the ventral portion of the muscles. In a subsequent muscle biopsy of the left m. vastus lateralis we found typical signs of polymyositis.
In our poster presentation, we discuss the differential diagnostic procedure of the “maladie des genoux bleus.”
1 K . Anneken , 1 M. Fischera , 1 C. Kellinghaus , 1 G. Möddel , 1 S. Evers 1University Hospital Munster (Munster, D)
Introduction: The brainstem is supposed to be a component of the epileptic circuit in cortical seizures. However, the role of subcortical areas as a generator of epileptic seizures is discussed controversely (1). Here we report a case of focal status myoclonicus in a patient with transient brainstem ischemia.
Case: A 58-year-old woman was admitted to the emergency unit because of myoclonic jerks of her right arm, vertigo, anisocoria, diplopic images and left sided hemipareses for four hours before admission. An EEG was normal. The focal myoclonic jerks could be terminated by successive application of 3 mg lorazepam, all other symptoms ceased spontaneously within 48 hours. MRI imaging of the brain and cerebral fluid analysis did not indicate an ischemic lesion or inflammation. The diagnosis of transient brainstem ischemia was made.
Conclusion: Our case of focal status myoclonicus associated with brainstem symptoms suggests that special subtypes of epileptic seizures may originate from subcortical regions.
Literature: 1 Mesiwala AH, Kutarani JD, Avellino AM, Roberts TS, Sotero MA, Ellenbogen RG. (2002) Focal motor seizures with secondary generalization arising in the cerebellum. Case report and review of the literature. J Neurosurg 97:190–196.
1 M. Pfäfflin , 2 T.W. May , 1 H. Sudbrock , 1 S. Urban , 2 R. Neb , 3 A. Übelacker , 4 H. Kießling , 4 D. Dennig , 3 B. Schmitz 11 Epilepsy Center Bethel (Bielefeld, D) ; 2 Gesellschaft für Epilepsieforschung (Bielefeld, D) ; 3 University Hospital Charité (Berlin, D) ; 4 Schwerpunktpraxis Epileptologie (Stuttgart, D)
Aims: Epilepsy affects multiple aspects of life including everyday life, social relations, work, and leisure activities. Thus, comprehensive care for patients with epilepsy includes support and counseling specific to patients' needs. In outpatient clinics and private practices nurses are key persons for patients. To improve nurses' skills for counselling and patient management a modularized educational program was developed for nurses working in an outpatient setting of epilepsy care. The efficacy of this educational program will be evaluated in a controlled study.
Methods: Nurses are trained on the job including workshop-like modules every three months. Topics include interactive skills, epilepsy specific knowledge, and emotional aspects of coping, counseling (including regulations), self-management and patient (case) management.
The efficacy of the educational program will be evaluated in a multi-center, prospective, controlled study with respect to, e.g., epilepsy knowledge of the patients, coping, treatment outcome, compliance, quality of life and especially contentedness of the patients with counseling and treatment. The patients were randomly assigned (either counseled by the nurse or not in addition to standard treatment) and answered questionnaires before and six months after counseling / respectively standard treatment. Three outpatient care units are included. The evaluation study has started in June 2006; up to now 254 patients have been included.
Results: The modules and the organization of the educational program are introduced. Experiences and first outcome results of the evaluation will be presented. The systematic evaluation will allow a more profound assessment of the efficacy of the educational program for epilepsy nurses and improvement of the program.
Conclusion: Preliminary feedback of patients and physicians indicate that epilepsy nurses play an important role in counselling of patients with epilepsy and improve the contentedness of the patients in an outpatient setting of epilepsy care.
The project is supported by an unrestricted grant of the UCB Pharma GmbH, Kerpen, Germany and the German Chapter of the International League Against Epilepsy (Deutsche Gesellschaft für Epileptologie e.V. Bielefeld, Germany).
1 A. Strzelczyk , 1 J.P. Reese , 1 R. Dodel , 1 H. Hamer 1Philipps-University (Marburg, D)
Objective: To give an overview on published cost of illness studies and their methodological approaches.
Background: Epilepsy imposes a substantial burden on individuals and society as a whole. The mean prevalence of epilepsy is estimated at 0.52% in Europe and according to the WHO Epilepsy Atlas peaks up to 1.0% in developing countries. Estimation of the health economic burden of epilepsy is of pivotal relevance to enable a rational distribution of society's resources. Even more as the introduction of new antiepileptic drugs, the marketing of the vagal-nerve stimulator and the intensifying of surgical treatment options may have caused a considerable increase in costs of therapy.
Methods: A systematic literature review was performed to identify studies that evaluated direct and indirect costs of epilepsy. Using a standardized assessment form, information on the study design, methodological framework, and data sources was extracted from each publication and systematically reported.
Results: We identified 21 studies on costs of epilepsy worldwide. The majority of the studies reflected the costs of epilepsy in Europe [UK (3), I (3), GER (1), NL (1), CH (1), F (1) and EU (1)] and the US (4), but also studies were available from India (2), Hong Kong, Oman, Burundi and Mexico. The studies utilize different frameworks to evaluate costs. All of them used a bottom-up approach, however only 12 studies (57%) evaluated direct as well as indirect costs. The range for the mean annual direct costs lay between 48 Euros (adjusted for PPP 2003) in rural Burundi and 4040 Euros in a German epilepsy center. Anticonvulsant medication was the main contributor to direct costs in recent years. The indirect costs ranged between 12% (I) and 85% (US) of the total annual costs.
Conclusions: A reliable comparison of the different cost of illness studies in epilepsy is currently not feasible as the evaluated studies had substantial limitations in respect to their patient selection criteria, diagnostic stratifications, but also regarding methods and evaluated costs. Most of the studies did not adhere to the guidelines for performing health economic evaluations. Therefore there is an urgent need for studies which evaluate direct and indirect costs in a comparable fashion.
1 S. Novak , 1 R.A. Sälke-Kellermann , 2 E. Martin , 1 G. Krämer 11 Swiss Epilepsy Centre (Zurich, CH) ; 2 University Children's Hospital Zurich (Zurich, CH)
Introduction: Endosulfan is a chlorinated hydrocarbon insecticide with a high toxicity on the central nervous system. It alters the serotoninergic system as well as the GABAergic and cholinergic systems and inhibits the calmodulin dependent Ca-ATPase. Though forbidden in many countries, it is still broadly used and constitutes an important cause of poisoning worldwide. Acute neurological symptoms after intoxication are tonic–clonic seizures, headache, dizziness, and ataxia.
Case report: We report on a previous healthy boy who at the age of 2 3/4 years accidentally ingested an insecticide containing about 10 ml of Endosulfan. Shortly after ingestion he had a syncope followed by a convulsive status epilepticus and a metabolic and respiratory acidosis. He was intubated and referred to a pediatric intensive care unit. The status was stopped with intravenous diazepam. The post-status EEG showed a severe nonspecific disturbance without epileptiform activity. CT-scan of the brain was normal. He recovered well and was discharged after five days. Three years later he presented complex-focal seizures with left sided temporal lobe semiology, increasing learning difficulties, and behavioral disturbances. MRI at this time showed left sided hippocampal sclerosis (HS). At the age of 7 years the neuropsychological assessment showed an organic amnestic syndrome. At this time MRI demonstrated the suspicion of bilateral pathology. Two years later bilateral HS was proved beyond doubt. He still suffered from refractory seizures at this time.
Discussion: In the literature it has been shown with serial MRI studies that central nervous system lesions associated with acute Endosulfan intoxication affect specific structures localised to the caudate nucleus, putamen, and occipital cortex. These lesions were bilateral and reversible. To our knowledge there are no reports of residual hippocampal lesions as sequel of an intoxication with Endosulfan. Harmful events in childhood as prolonged febrile seizures, convulsive status epilepticus, insults, or infections of the central nervous system, play an important role in the pathogenesis of HS.
Conclusion: The evidence available in this case, especially the convulsive status and the following latency period until the manifestation of epilesy, would suggest that the Endolsufan poisoning was not the primary cause of the chronic epilepsy and hippocampal sclerosis but rather that it was due to the Endosulfan-induced convulsive status epilepticus.
1 P. Gallmetzer , 1 B. Glawar , 2 J. Ferrari , 3 W. Lalouschek , 1 B. Mamoli 11 Ludwig Boltzmann Institute for Epilepsy (Vienna, A) ; 2 Convent Hospital "Barmherzige Brüder” (Vienna, A) ; 3 University Hospital of Neurology (Vienna, A)
Purpose: To assess the incidence and predictive factors of poststroke epilepsy in the elderly.
Methods: A total of 1265 patients (aged 65 to 98 years) with recent ischemic cerebrovascular event, were prospectively enrolled at 9 neurological departments. The follow up was 19 ± 9.5 month (mean, ± SD). Seizure patients were followed for 39 ± 12.7 month (mean, ± SD).
Results: Nineteen of the 1265 patients (1.5%) developed poststroke epilepsy. Persistent neurological deficit (NIHSS > 12) at day 7 after stroke (odds ratio [OR] 7.1, 95% CI 2.1 to 23.9), cerebral complications like cerebral edema and secondary hemorrhagic transformation (OR 18.5, 95% CI 4.8 to 71.1) and previous early poststroke seizures (OR 56.8, 95% CI 16.9 to 190.7) were independently associated with poststroke epilepsy. Diabetic comorbidity showed inverse correlation to seizure recurrence (OR 0.1, 95% CI 0.01 to 0.9).
Conclusion: Epilepsy is occurring in a minority of patients after ischemic stroke. A Persistent neurological deficit (NIHSS > 12), cerebral complications like edema and hemorrhagic transformation and previous early poststroke seizures were predictors of poststroke epilepsy, whereas diabetic comorbidity showed an inverse correlation to seizure recurrence.
1 C. Pollo , 2 M. Seeck , 2 C. Boex , 2 L. Spinelli , 1 E. Pralong , 1 G. Foletti 11 CHUV (Lausanne, CH) ; 2 HUG (Geneva, CH)
Background and purpose: High-frequency (HF) amygdalo-hippocampal stimulation (AHS) has recently been proposed as a therapeutic option for intractable temporal lobe epilepsy. Although preliminary results are promising, long-term efficacy of this technique as well as stimulation paradigms or implantable device are still under evaluation. We report the Lausanne-Geneva experience regarding the safety and effect of AHS on seizure control.
Material and methods: 6 patients with intractable epilepsy unsuitable for resective surgery were selected for unilateral AHS. All cases but one showed strictly unilateral epileptogenic zone located in the mesial temporal lobe, 3 were right sided, one left, one bilateral predominantly left.
The electrode was implanted through a posterior approach at the junction between the hippocampus and the parahippocampal gyrus with the distal contact located within the inferior aspect of the amygdala. External extension was provided to perform deep EEG recordings for 3-4 days. The stimulator was then implanted under general anesthesia. Initially, stimulation was delivered simultaneously through the 4 contacts at a frequency of 130 Hz, pulse width 450μs, and amplitude up to 1–2 V and subsequent refinement was performed according to deep EEG recordings.
Results: Stimulation was performed in the amygdala in 1/6 case, anterior hippocampus in 3/6 cases and posterior hippocampus in 2/6 cases. Follow-up from 5 months to 3 years shows a decrease of seizure frequency in all the patients (30-90%). No stimulation-induced side effects were noticed. The whole device was changed in 1 case following dysfunction of the electrode.
Conclusion: HF-AHS is safe and effective as an alternative treatment for medically intractable temporal lobe epilepsy in selected cases. Further controlled trials and fundamental research are needed for the assessment of long-term efficacy and a refined understanding of mechanisms of action of electrical stimulation.
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Poster session 2.1. Basic sciences and experimental epileptology
1 N. Gueler , 2 M. Kukley , 2 M. Nikoulina , 2 D. Dietrich 11 Swiss Epilepsy Centre (Zurich, CH) ; 2 University Hospital Bonn (Bonn, D)
Objectives: Presynaptic group II mGluRs modulate transmitter release at many glutamatergic terminals in the CNS but it is unclear which patterns of presynaptic neuronal activity leads to a relevant feedback inhibition. To determine the requirements for synaptic activation of group II mGluRs and to elucidate the factors regulating their physiologic activation by released glutamate.
Material and methods: Hippocampal slices were prepared from male wistar rats (20-40 days old). Field excitatory postsynaptic potentials (fEPSP) were recorded in the middle molecular layer of the dentate gyrus. Repetitive stimulation of presynaptic fibers was used to activate mGluRs. We varied the number of stimuli as well as the frequency of stimulation. In addition we used different post-tetanic intervals to assess how long mGluRs may remain activated. We employed the following protocols: 1, 3, 7, 14, 28, 56, 100, 200 stimuli @ 3, 5, 20, 100, 200 Hz and 0.03, 0.05, 0.2, 0.3, 0.8, 1, 3, 6, 20 sec post-tetanic interval. To evaluate the degree of synaptic activation of group II mGluRs we applied the antagonist LY 341495 (3μM) and analysed the resulting increase of the test fEPSPs following tetanic stimulation.
Results: Tetanic stimulation leads to a modest, but significant activation of group II mGluRs. The broad spectrum glutamate transporter blocker DL-TBOA (100μM) facilitates synaptic activation of mGluRs. The results show that synaptic activation of group II mGluRs is dependent on stimulation frequency, number of stimulation and post-tetanic interval. More stimulations and a higher stimulation frequency yielded a more pronounced activation of the group II mGluRs. Strongest inhibition of the test fEPSP was observed between 0.1 and 0.3 sec following the tetanus. GABA receptor antagonists (Bicucullin, CGP) did not alter the magnitude of the test fEPSPs after application of LY341495.
Discussion: In contrast to ionotropic glutamate receptors, synaptic activation of group II mGluRs occurs only after high frequency stimulation. The optimal stimulation protocol is most likely determined by an interplay of glutamate removal mechanisms, replenishment of releasable vesicles and the activation/deactivaton kinetics of mGluRs. We propose that the slow deactivation kinetics of metabotropic glutamate receptors may provide longer lasting effects.
1 M. Tomka-Hoffmeister , 1 R. Schulz , 1 A. Ebner 1Epilepsy Center Bethel (Bielefeld, D)
Objective: Earlier studies demonstrated the efficacy of levetiracetam given to patients who did not become seizure-free after epilepsy surgery. Does this also apply to patients who did not respond to levetiracetam before surgical intervention?
Method: We included patients meeting the following criteria:
had epilepsy surgery from 2003 to 2006
had no response to levetiracetam before the operation
were not given levetiracetam during and immediately after the operation
did not become not seizure-free after surgical intervention
were postoperatively readministreted levetiracetam
N = 9 (1 child und 8 adults)
Mean age at time of operation = 31 yrs. (Range 4.75 to 47 yrs.)
Gender: 6 male und 3 female
Comparison was made of the seizure-situation:
Taken into consideration was the dosage-level of levetiracetam (and comedication) before and after the operation.
Result: 6 patients became seizure-free despite lower doses of levetiracetam; 5 of these became completely free of auras and seizures and 1 had only auras. In 2 further patients there was improvement in frequency. Only in 1 case was a worsening observed.
Conclusion: Our results confirm other studies showing that levetiracetam is effective in patients who underwent surgery but did not become seizure-free after the operation. Furthermore we show that the majority of patients who did not respond to levetiracetam before surgery, did so after that surgery.
1 R. Trollmann , 1 J. Schneider , 1 D. Wenzel , 1 W. Rascher , 2 O. Ogunshola , 2 M. Gassmann 11 University of Erlangen (Erlangen, D) ; 2 University of Irchel (Zurich, CH)
Background: Hypoxia-inducible transcription factors (HIF), the most important mediators of the molecular response to hypoxia, are ubiquitously expressed in human and rodent tissues, including brain. By transcriptional activation of specific target genes HIF-regulated systems are critically involved in adaptive mechanisms to hypoxic-ischemic brain lesions. As the antiepileptic drug levetiracetam (LEV) reduces cellular degeneration in focal cerebral ischemia, we aimed to prove its effects on endogenous adaptive factors in developing hypoxic brain.
Objectives: To study effects of LEV on endogenous neurotrophic HIF-regulated factors (HIF-1alpha subunit, VEGF, iNOS) in developing mouse brain at different developmental ages (P0, P7) as well as effects of LEV on hypoxia-inducible, but HIF-independent, NOS isoforms (nNOS, eNOS).
Material and methods: Fetal C57BL/6 mice (P0, P7) were treated with saline or LEV (i.p.; 50 mg/kg) 1 h before exposure to normoxia (21% O2; N) or severe systemic hypoxia (8% O2, 6 h; H). Brains were dissected immediately without reoxygenation. HIF-1alpha protein accumulation was investigated by Western blot and immunohistochemistry (cerebral cortex, hippocampus). Gene expression was quantified by TaqMan RT PCR.
Results (mean ± SEM): Under normoxia, no significant changes of cerebral HIF-1alpha, VEGF and NOS gene expression were observed in LEV-treated (P0, n = 6; P7 n = 7) compared to control mice (P0, n = 6; P7, n = 7). Similarly, HIF-1alpha staining did not show remarkable differences of protein accumulation in hippocampus (HC) or cerebral cortex between saline- and LEV-treated animals. Systemic hypoxia itself led to prominent accumulation of HIF-alpha protein at P0 and P7 as well as significant up-regulation of VEGF at P0 (N, 0.022 ± 0.001, n = 6; H, 0.031 ± 0.003, n = 6) and at P7 (N, 0.096 ± 0.032, n = 7; H, 0.873 ± 0.069, n = 7; p < 0.001). Interestingly, a significant decrease of iNOS mRNA levels in hypoxic brains at P0 (N, 1.001 ± 0.057; H, 0.733 ± 0.048, p < 0.01) and at P7 (N, 1.364 ± 0.083; H, 0.319 ± 0.047, p < 0.001) was observed. LEV treatment did not affect HIF-1alpha accumulation in hypoxic cerebral cortex or HC (P0, n = 9; P7, n = 7) compared to controls (P0, n = 6; P7, n = 7), or substantially alter gene expression of VEGF, iNOS, eNOS and nNOS, except, a normalization of iNOS decrease in hypoxic P0 brains.
Conclusions: Severe systemic hypoxia differentially affects expression of HIF- regulated vasoactive factors in fetal mouse brain in vivo during acute hypoxia. No evidence of toxic effects of LEV on HIF-1alpha and vasoactive HIF target genes was observed. Under hypoxia, expression of HIF-1alpha protein, HIF-dependent and independent genes was not significantly altered by LEV-treatment (P0, P7) indicating no significant influence of LEV on crucial endogenous, HIF-regulated neuroprotective mechanisms.
1 L. Müller , 1 T. Tokay , 2 C. Rüschenschmidt , 2 J. Chen , 2 A. Becker , 1 R. Köhling , 2 H. Beck , 1 T. Kirschstein 11 University of Rostock (Rostock, D) ; 2 University of Bonn (Bonn, D)
Chronic temporal lobe epilepsy is often accompanied by cognitive dysfunction such as declarative memory deficit. In order to find promising strategies to address these deficits, we study fundamental molecular mechanisms of learning and memory such as long-term potentiation (LTP) and long-term depression (LTD). These are long-lasting changes of synaptic strength due to the history of prior neuronal activity. By using long-term extracellular recording techniques, we asked how chronic epileptic seizures influence synaptic plasticity in the hippocampal CA1 region in the rat pilocarpine-induced status epilepticus model. Synaptic plasticity can be induced by activation of either NMDA-type glutamate receptors or metabotropic glutamate receptors (mGluR). First, we investigated the mGluR-dependent form of LTD and observed a significant reduction of this type in epileptic rats. This was found to be due to a specific transcriptional down-regulation of the mGluR5 subtype. Then we focused on NMDA receptor-dependent synaptic plasticity. Whereas NMDA receptor-dependent LTD is unaltered in chronic epilepsy, we found an unexpected increase of NMDA receptor-dependent LTP. Therefore, we asked whether this discrepancy is due to differential alteration of the most important NMDA receptor subtypes NR2A and NR2B. We found that application of low micromolar zinc (1-10 μM), which primarily modulates NR2A, virtually abolished LTP in controls, whereas in epileptic rats significant LTP was still observed. At a higher zinc concentration (100 μM), LTP was inhibited in both groups. In contrast, when NR2B was specifically inhibited, LTP remained inducible in controls, but was completely lost after status epilepticus. These results suggested a dominant role of NR2B in LTP induction in epileptic rats which may be caused by post-transcriptional and/or post-translational modification of these NMDA receptor subtypes.
In conclusion, status epilepticus leads to persistent changes of various forms of synaptic plasticity in the CA1 region. These changes could be in part accountable for cognitive impairment seen in many patients. A more precise understanding of the underlying mechanisms will be essential to develop new therapeutic strategies.
1 H. Feldwisch genannt Drentrup , 1 B. Schelter , 2 J. Wohlmuth , 2 J. Nawrath , 2 A. Brandt , 1 J. Timmer , 2 A. Schulze-Bonhage 11 University of Freiburg (Freiburg, D) ; 2 University Hospital Freiburg (Freiburg, D)
Concerning the assessment of the predictability of epileptic seizures, a continuous and reliable analysis of neurophysiological recordings of epilepsy patients is necessary. Recent work has indicated that methods from nonlinear dynamics can detect significant preseizure changes in the EEG at least for some patients. As a mean to increase seizure prediction performance we tested whether or not two different kinds of combination of seizure prediction methods yield superior prediction results. In this study a bivariate phase synchronization index (PSI) and the univariate “Dynamical Similarity Index” (SIM) were adapted for seizure prediction. The analysis of these prediction methods was based on long-term intracranial EEG data with continuous recordings of 8 patients for 7-11 days including 124 seizures. Approaches to combine methods were applied and compared to the individual methods. All results have been validated by a statistical test procedure (Schelter et al., Chaos 2006; 16: 013108). By evaluating the EEG data continuously and without knowledge of ‘future’ events, a prediction situation analogous to an online application was possible. For a fixed set of parameters, significant prediction results could be observed for five (PSI) and four (SIM) patients by evaluating each method individually, with average sensitivities of 51% (PSI) and 49% (SIM). A combination of both methods using a logical “and” showed improved results, with a mean sensitivity of 64%. A combination of both prediction methods applied shows an increase in sensitivity of about 25%. These findings represent a next step towards a clinical application of seizure prediction.
1 A. Capurro , 1 A. Aertsen , 2 A. Schulze-Bonhage 11 University of Freiburg (Freiburg, D) ; 2 University Hospital Freiburg (Freiburg, D)
Purpose: To assess the evolution of high frequency (HF) content in afterdischarges (ADs) during kindling.
Methods: We recorded ADs evoked by short stimulus trains delivered to the right hippocampus of 10 Wistar rats. The recording electrodes were placed bilaterally in hippocampi and frontal neocortices (4 in the right dorsal hippocampus, 2 in the left dorsal hippocampus and 1 in right and left frontal neocortex each). A common reference electrode was placed above the cerebellum. The stimulus consisted of a 60 Hz train of biphasic rectangular pulses lasting 1.6 s. Each biphasic pulse lasted 0.4 ms with an amplitude of ± 0.5 mA. The stimulation was performed daily in each rat over a period of 5-10 days. EEG was recorded at 10.4 kHz sampling rate and signals were split into physiologically meaningful periods, e.g., control period before stimulus and various AD periods with different waveforms. For each period, spectra and spectrograms with an optimized window width were computed to assess the HF content.
Results: After the stimulus we recorded an AD at all recording sites. On the first day the AD started with a series of slow spikes. In the subsequent days, HF ripples (100-300 Hz) were superimposed to these slow waves, the total duration of the AD increased, and the HF ripples extended to the contralateral hippocampus. We often observed a 2nd phase of AD containing HF separated from the initial AD by a period with low amplitude rhythmic alpha or mixed frequency activity. During the 2nd phase of the AD a behavioral seizure was observed in some cases. The HF content of the EEG (consisting of ripples superimposed on slow waves of high amplitude) was observed before and during the seizure, but behavioral seizure manifestation was not accompanied by a clear change in the EEG pattern.
Conclusions: During the kindling process, afterdischarges occurred from the 1st day on. They were not limited to the site of stimulation but appeared in both, ipsilateral and contralateral hippocampus and neocortical areas. HF discharges developed over subsequent days and increased in duration and amplitude when behavioral seizures occurred, and were not limited to the kindling site but also extended to the contralateral hippocampus.
Supported by BMBF (Grant 01GQ0420 to BCCN-Freiburg). The authors thank to Martin Müller, Ute Haeussler, Ralph Meier, Armin Brandt and Michael Jachan.
1 B. Schelter , 1 H. Feldwisch genannt Drentrup , 1 J. Wohlmuth , 1 J. Nawrath , 2 A. Brandt , 1 J. Timmer , 2 A. Schulze-Bonhage 11 Center for Data Analysis and Modeling (Freiburg, D) ; 2 University Hospital Freiburg (Freiburg, D)
Objective: A reliable prediction of epileptic seizures would offer new therapeutic options for treating the severe disease epilepsy. An abnormal synchronization of neurons leading to epileptic seizures proposes multivariate time series analysis techniques detecting synchronized dynamics as a promising approach for seizure prediction when applied to invasive EEG recordings of epilepsy patients. The proper assessment of these techniques is a prerequisite for a seizure prediction device. Apart from statistical significance the clinical relevance is investigated.
Methods: A quantity measuring phase synchronization (Mormann et al., Physica D 2000;144:358-369) has been applied to an invasive EEG data pool of 14 patients with long term intracranial continuous EEG data of more than 100 days duration. The seizure prediction performance has been assessed for long intervention times of up to 4 hours and occurrence periods of up to 2 hours, which are not unusual in epilepsy research. The obtained results have been compared to the performance of an unspecific random predictor (Schelter et al., Chaos 2006;16:013108). Moreover, additional measures have been used to quantify the strain of especially false predictions on patients. Thus, the fraction of false predictions with respect to the total number of predictions as well as the time a patient is awaiting a seizure that will never occur have been investigated to quantify the clinical relevance of the prediction techniques.
Results: For several patients a prediction performance superior to a random predictor could be shown. Sensitivities of up to 75% were observed when allowing 2 false predictions per day. To achieve this promising result the patient is awaiting seizures for 15%, i.e., 3–4 hours every day that will never occur. This fraction is rather low compared to other published results, which is the benefit of subdividing the prediction horizon in intervention time and occurrence period. A fraction of false alarms with respect to the total number of alarms of more than 50% on average was observed.
Conclusions: Preictal changes in the synchronization of the EEG dynamics may offer a chance for epileptic seizure prediction. Besides statistical significance other parameters have to be taken into account quantifying the clinical relevance. Especially avoiding false predictions will reduce the strain on patients and, thereby, lead to a much higher clinical relevance.
1 M. Bechstein , 1 M.C. Müller , 1 M. Kirsch , 1 A. Flubacher , 1 S. Tinnes , 1 C.A. Haas 1University of Freiburg (Freiburg, D)
The widening of the granule cell layer (granule cell dispersion, GCD) in the dentate gyrus is a characteristic feature of Ammon's horn sclerosis which often accompanies temporal lobe epilepsy (TLE). The dispersion is considered to be a local migration defect, but the mechanisms underlying its development are rather unclear. We have recently shown that GCD formation is paralleled by the appearance of a radial glial scaffold in the dentate gyrus, observable in TLE patients and in a mouse model of TLE (Fahrner et al., 2006; Heinrich et al., 2006). In order to investigate the role of glial cells in GCD development, we used a mouse model of TLE and combined it with preactivation of astrocytes. To this end, we injected ciliary neurotrophic factor (CNTF), a potent activator of glial cells, into the hippocampus of adult mice 48 hours prior to the injection of kainate (CNTF preconditioning). Injection of kainate (KA) alone is known to induce focal epileptic seizures and GCD. At sixteen days after KA injection we measured the width of the granule cell layer (GCL) in cresyl violet-stained hippocampal sections of CNTF-preconditioned mice and in a control group treated with saline prior to KA injection. While these mice showed a mean increase in GCL width by 102 micrometers, in CNTF preconditioned mice the increase was only 27 micrometers. This corresponds to a reduction of the GCD by 74%. In order to verify CNTF-mediated activation of hippocampal astrocytes, GFAP mRNA expression was measured by real time RT-PCR analysis. Two days after CNTF injection we found a strong up-regulation of GFAP mRNA expression. The effect was noticable even 18 days after CNTF injection by GFAP immunohistochemistry. Taken together our results show that CNTF-mediated activation of astrocytes strongly reduces GCD formation.
(Supported by the DFG: Transregio SFB TR3 and SFB 505).
1 M. Osswald , 1 M.C. Müller , 1 S. Huber , 1 C.A. Haas 1University of Freiburg (Freiburg, D)
The impairment of neurogenesis in Ammon's horn sclerosis, which is often associated with temporal lobe epilepsy (TLE), has recently been described in the resected hippocampi of patients suffering from this neurological disorder (Fahrner et al., Exp Neurol 2007). Unilateral intrahippocampal injection of kainic acid (KA) in adult mice induces an epileptic focus associated with the major histopathological features of TLE including the observed loss of neurogenesis. In order to elucidate the molecular mechanisms involved in the regulation of neurogenesis we investigated potential changes in the expression of vascular endothelial growth factor (VEGF), a potent neurogenic and angiogenic molecule, in the KA-injected hippocampus. We performed a postlesional time course analysis at two, four, eight, twenty-one and eighty days after KA injection. Using in situ hybridization we found constitutive expression of VEGF mRNA in pyramidal cells of the cornu ammonis and in the granule cell layer of the dentate gyrus. This expression pattern did not change during the whole time period. However, we observed a transient up-regulation of VEGF mRNA expression in the ipsilateral hilus and molecular layer with a peak at eight days after KA injection. In order to identify the phenotype of these VEGF mRNA-positive cells, we performed fluorescence in situ hybridization (FISH) for VEGF mRNA combined with immunolabeling for NeuN (as neuronal marker) or GFAP (as astrocytic marker): Most of the newly appearing VEGF mRNA-expressing cells were double labeled with GFAP showing that reactive astrocytes synthesize VEGF mRNA in the epileptic hippocampus. Since VEGF is also a strong angiogenic factor, possible alterations in blood vessel distribution were studied by immunolabeling for CD 31, a marker for adult and embryonic endothelial cells. We observed a permanent increase in blood vessel density in subregions of the epileptic hippocampus. Taken together, we show that epilepsy triggers a de novo synthesis of VEGF in astrocytes. We hypothesize that VEGF does not play a role in the down-regulation of neurogenesis, but rather in vessel formation in the epileptic hippocampus. (Supported by the DFG: TR-3).
1 Y.G. Weber , 1 J. Kempfle , 1 D. Blazevic , 1 S. Maljevic , 1 H. Lerche 1University of Ulm (Ulm, D)
The syndrome of benign familial neonatal convulsions (BFNC) is characterized by clusters of epileptic seizures within the first days of life disappearing spontaneously after weeks to months. BFNC is caused by loss-of-function mutations in the voltage-gated potassium channels KCNQ2 or KCNQ3, which can explain the occurrence of epileptic seizures via membrane depolarization. However, the underlying mechanism of the transient phenotype of BFNC still remains to be elucidated. One possible explanation might be a change in the expression pattern of these channels during development. We therefore examined the expression and localization of KCNQ3 channels in the developing mouse brain.
We used 5-10 μm frozen sections of mouse brain at postnatal (P) days P0-P40 and performed immunofluorescence staining using a polyclonal rabbit antibody against KCNQ3. A specific S35-labeled KCNQ3-probe was used for the in situ hybridization.
KCNQ3 is ubiquitously expressed in brain with predominance in hippocampus, cortex and thalamus. In the hippocampus, staining of axon initial segments was observed in pyramidal neurons in the CA1 to CA3 region starting from P3, whereas in the dentate gyrus a specific KCNQ3 signal at axon initial segments was first detected at P15. The delayed appearance of the staining in the dentate gyrus was confirmed in the in situ hybridization, in which the KCNQ3 signal appeared at P8.
The analysis of KCNQ3 expression at different developmental stages in mice brain revealed a delayed staining of the dentate gyrus which might contribute to the age dependence of BFNC.
1 S. Kovac , 1 Y. Sirin , 1 C. Kellinghaus , 1 G. Möddel , 1 M. Fischera , 1 M. Dogan , 1 S. Evers , 1 E.-J. Speckmann , 1 A. Gorji 1University Hospital Munster (Munster, D)
In the present study, the effects of adenosine on stimulus-induced bioelectric activity were investigated in the rat hippocampus and neocortex under epileptiform (n = 17) and non-epileptiform (n = 16) conditions.
Spatio-temporal distribution of activities was studied by using a voltage-sensitive dye (RH795) and a fast optical recording system. Epileptiform activity was induced by omission of extracellular Mg2+ before adenosine (1, 10, 50 and 100 μmol/l) was added to the bath medium. In hippocampal slices, stimulus (with an intensity of 1, 5 and 10 μA) was given in Schaffer collaterals, and dye-related fluorescence signals were detected by a 464-element honey-comb shaped photo diode in CA1 regions. In neocortical slices, stimulus was given either in the border zone between white and gray matter (afferent fibre stimulation) or in layer I/II (stimulation of parallel fibres), and signals were detected in layer I-VI of the cortical motor regions.
In the hippocampus, adenosine led to a dose dependant reduction of stimulus-induced activity. The reduction was most effective when adenosine was applied in concentrations of 10 and 50 μmol/l and when stimulus was given with middle (5 μA) or low strengths (1μA). Furthermore, a significant reduction of signal amplitude was observed primarily under epileptiform conditions. In the neocortex adenosine showed no effect on stimulus induced signal amplitude neither in non-epileptiform nor in epileptiform tissues.
In conclusion, the results demonstrate a different regional effect of adenosine on stimulus-induced activity. The neuroinhibitory effect of adenosine is predominant in hippocampal tissues where adenosine receptors are found in high densities. Furthermore, data here indicate that adenosine exerts its modulatory effects via synaptic network activity especially when the tissues are highly excited.
1 F. Klinker , 1 D. Hering , 1 R. Koch , 1 M.A. Nitsche , 2 H. Potschka , 2 W. Löscher , 1 W. Paulus , 1 F. Tergau , 1 D. Liebetanz 11 University of Gottingen (Gottingen, D) ; 2 School of Veterinary Medicine (Hannover, D)
Purpose: Cathodal transcranial direct current stimulation (tDCS) is able to induce a lasting, focal depression of cortical excitability. This may be a promising tool for the treatment of focal cortical hyperexcitability leading to focal epileptic seizures. In this study, we evaluated the anticonvulsant potential of cathodal tDCS in a transcranial ramp stimulation model of focal epilepsy.
Methods: To determine the threshold for localized seizures (TLS), we designed a new model of transcranial ramp stimulation (TRS). TLS was determined in freely moving rats by applying a single train of rising bipolar pulses through a unilateral epicranial electrode and was defined as the minimum current strength leading to a unilateral forelimb clonus. The unilateral electrode montage permitted the focal application of both tDCS and TRS over the same cortical area without trepanation. After tDCS, TLS was determined repeatedly for 120 min at an interval of 15 min. The first group of animals received 2 sessions of cathodal tDCS at 100μA, one for 30 and one for 60 min. A third session consisted of 60 min of anodal tDCS. A second group received cathodal tDCS at 200 μA for 15 and for 30 minutes, as well as anodal tDCS for 30 min.
Results: After application of cathodal tDCS at 100 μA for 60 min a significant TLS increase could be seen for 120 min. When the intensity was increased to 200 μA, the duration needed to achieve a lasting TLS elevation was reduced to just 30 min. In contrast, anodal tDCS at identical stimulation durations and current strengths had no significant effect on TLS, proving the polarity dependency of the antiepileptic effect.
Conclusion: Cathodal tDCS is able to induce a lasting elevation of the threshold for localized seizures. The duration of tDCS needed to induce a lasting effect is dependent on the current strength of the stimulation. These results imply a possible therapeutic use of tDCS for the focal treatment of drug refractory partial epilepsy. Cathodal tDCS could be of particular therapeutic value in patients with epileptic foci at the surface of the hemisphere such as epilepsia partialis continua and focal or secondary generalized epilepsy resulting from cortical dysplasia.
1 T.V. Wuttke , 1 F. Lehmann-Horn , 2 W. Paulus , 3 J. Penzien , 1 K. Jurkat-Rott , 1 H. Lerche 11 University of Ulm (Ulm, D) ; 2 University of Gottingen (Gottingen, D) ; 3 Hospital Augsburg (Augsburg, D)
Benign familial neonatal convulsions (BFNC) is caused by mutations in the voltage-gated potassium channels Kv7.2 and Kv7.3, being expressed in CNS and PNS. BFNC is characterized by frequent unprovoked seizures, typically beginning within the first days of life and spontaneously disappearing after several weeks to months. Peripheral nerve hyperexcitability (PNH, neuromyotonia, myokymia) is characterized by muscle overactivity due to spontaneous discharges of lower motor neurons. Antibodies against or mutations within different types of voltage-gated potassium channels can cause PNH. PNH could only be linked to one single Kv7.2 mutation (R207W) so far, in a family with PNH and BFNC. Here we describe two new mutations within the Kv7.2 channel, leading either to BFNC (E119G) or myokymia (R207Q).
Genomic DNA was amplified and sequenced. WT and mutant Kv7.2 channels were heterologously expressed in Xenopus oocytes and functionally characterized using two-electrode voltage-clamping.
Electrophysiological studies of E119G demonstrated that this mutation induces a slight depolarizing shift of the voltage dependence of activation. The steady-state activation curves for E119G and all co-expressions of E119G with Kv7.2 and/or Kv7.3 wild type (WT) channels were significantly shifted compared to Kv7.2 or Kv7.2/Kv7.3. These shifts resulted in significant reductions of the relative current amplitudes for mutant channels in the subthreshold range of an action potential. Furthermore, the voltage dependence of the time constants of activation was shifted by about +10 mV revealing a significant slowing of the activation time course. In contrast, functional characterization of R207Q and R207W revealed large depolarizing shifts of the conductance-voltage relationships and marked slowing of the activation time course for R207W > R207Q compared to wild type channels. Coexpression of both mutant channels with wild type channels revealed a dominant negative effect, reducing the relative current amplitudes in the physiologically relevant subthreshold range by 70–90%.
Many of the known BFNC mutations result in haploinsufficiency, but as our results suggest, very subtle changes in channel gating are already sufficient to cause neonatal seizures. In contrast, only a distinct reduction of channel function by the voltage-sensor mutations R207Q and R207W seems to be able to affect PNS, suggesting CNS being more vulnerable than peripheral motoneurons.
1 C. Kurth , 2 A. Schulze-Bonhage , 1 B.J. Steinhoff 11 Epilepsy Centre Kork (Kork, D) ; 2 University of Freiburg (Freiburg, D)
Objective: FDG-PET is done frequently in preoperative monitoring work up of drug resistant epilepsy patients. Therefore we evaluated the impact of this functional imaging method on preoperative diagnostic and therapeutic decisions.
Method: In this retrospective study 38 patients (17 men, age 18-63, mean age 38,5) were analyzed, who underwent presurgical monitoring with video-EEG with surface electrodes, MRI of the skull, neuropsychological testing and FDG-PET. Neurosurgery prior to the monitoring was an exclusion criterion.
Results: 9 patients were nonlesional in MRI. Decisions for further invasive diagnostics were made in 4 of them on the basis of semiology and EEG. In the other 5 patients no option for further diagnostics was seen, due to semiology and EEG. PET scans showed hypometabolism in all 9 patients, but decisions could be made without these informations. 10 patients showed isolated unilateral hippocampussclerosis (HS) with or without increased signal in the ipsilateral temporal pole. In these patients selective amygdalohippocampectomy (AHE) or AHE and 2/3 resection of the temporal lobe was performed on the basis of MRI, EEG and semiology. PET showed multiregional hypometabolism in most patients and did not contribute to the presurgical decisions.
In 3 patients with bilateral HS bitemporal hypometabolism was found in PET. This finding was not helpful for the decision to plan invasive recording with bilateral hippocampal depth electrodes. In 1 patient with unilateral HS no further evalution was planed due to an extensiv temproal dysplasia in MRI. In 6 patients with pure extratemporal lesions in MRI PET findings were inconsistent. In 4 patients resetion of the lesion was recommended independent from the PET scan. In 2 patients invasive diagnostic was planned according to MRI and EEG. 5 patients showed complex lesional patterns in the MRI including temporal and extratemporal structures. Invasive recording depending on semiology, EEG and MRI was planed for these patients. PET did not contribute significantly to the final judgment. Only in one patient with fairly poor quality of the first MRI, PET scan was taken into considerations for further diagnostics – but only as long as no better MRI scan was available.
Conclusions: Routine PET scans had only little impact on decision in the presurgical work up of drug resistant epilepsy patients. Due to this finding further evaluations with a larger number of patients are necessary to determine reasonable indications for this method in presurgical epilepsy diagnostics.
1 J. Larch , 1 I. Unterberger , 1 J. Dobesberger , 1 N. Embacher , 1 G. Walser , 1 A. Auckenthaler , 1 G. Luef , 1 G. Bauer , 1 E. Trinka 1Medical University Innsbruck (Innsbruck, A)
Background: Juvenile myoclonic epilepsy (JME) is is a common age-related epilepsy syndrome. Under appropiate antiepileptic drugs (AED) up to 85% of the patients are seizure-free but after AED withdrawal more than 90% of patients will have a relapse. Hence JME is known as “easy to treat but hard to cure.” Several authors believe it is a lifelong disease. Only few studies have adressed the issue of long term seizure freedom. The aim on this study is to analyse seizure outcome in a large hospital based cohort.
Methods: Retrospective hospital-based study. All pts. with JME (n = 242) treated at the Universitätsklinik für Neurologie, Innsbruck, Austria (1975-2006), were screened. Inclusion criteria: (1) JME diagnosis (based on definition of ILAE) and (2) medical treatment >2 years in outpatient clinic. We included 175 pts. and analysed age, sex, seizure onset age, first and last documented seizure type, EEG, photosensitivity, MRI/CT, febrile convulsions (FC), family history, and AED response (seizure-free >2years).
Results: Population: 175 pts (111w/64m), mean age 38 years (range 14–87), mean observation 8 years (range 2–38). Four percent (7/175) had FC. Photosensitivity was present in 14% (24/175). Seizure Outcome: Fifty four percent (94/175) were seizure-free of all seizure types >2 years. Seventeen percent (16/94) of them without AED. Eight percent (15/175) were seizure-free for >1 year and < 2 years. Thirty-eight percent (66/175) were not seizure-free on appropriate AED. Fifty-seven percent were seizure-free between 2 and 5 years, 28% between 6 and 10 years and 15% for > 10 years. Seizure types: Pts. not seizure-free had significantly more often all three seizure types within the first year of their disease than those who were seizure-free at last follow up (11% vs. 3%, Chi-square = 4.679, df = 1, p = 0.031). Persisting seizure types were most often myoclonia with (Chi-square = 9.297, p = 0.002) or without grand mal on awakening (Chi2 = 3.987; p = 0.046), while absences tend to remitt.
Conclusions: We cannot confirm the assumption that JME needs lifelong treatment. A substantial proportion of JME patients remain seizure free with or without AEDs.
1 M. Dogan , 1 A. Gorji , 1 E.-J. Speckmann 1University of Munster (Munster, D)
Spread of excitation in the dentate gyrus and in the hippocampal CA3 region with stimulation of perforant path and of stratum granulosum was investigated. Data were sampled from fluorescence changes of the voltage-sensitive dye RH 795 incorporated into cellular membranes and recorded with a 464-photodiode array in a neuronal network in vitro.
The experiments show that stimulation of the crest of the stratum granulosum evoked activity in this entire layer and the hilus communicating with both ends of the stratum granulosum. The inner edge of the endal limb adjacent to the presubiculum was omitted. Maximal activity spread to the endal limb and the hilus within 6.3 ms and reached the ectal limb within 12.6 ms. Whereas activity evoked by stimulation of the stratum granulosum in the endal limb comprised the entire layer in this limb only the end of this stratum and a small region adjacent to the prosubiculum of the entorhinal cortex in the ectal limb were included. Again activity spread within 6.3 ms. Stimulation of stratum granulosum in the ectal limb did not only show higher level of activity but also the activity pattern was inverse: activity could be found in the whole layer of the ectal limb but only at its end of the endal limb. Unlike the stimulation in the endal limb the level of activity in the dentate gyrus was higher and activity reached the area around the crest within 3.78 ms. Stimulation of the perforant path at the crest mainly evoked activity in the whole ectal limb and only in the distal part of the endal limb- including stratum granulosum and moleculare in both cases. Activity spread within 12.6 ms.
In conclusion, the extent of activity in the hilus, at both ends of the stratum granulosum and in the region adjacent to the prosubiculum was always existent in the same extent independent of position and amplitude of the stimulus.
1 E. Ziegler , 1 M. Bodusch , 1 K. Krampfl 1Medical School Hannover (Hannover, D)
Gamma-aminobutyric acid (GABA) is the neurotransmitter at most of the fast inhibitory synapses within the mammalian brain whereas glycine plays a major role in fast inhibitory synaptic transmission in brain stem and spinal cord. GABAA receptor channels mediate fast inhibitory neurotransmission throughout the CNS while the expression of ionotropic glycine receptors is mainly restricted to spinal cord and brain stem. Neuroactive steroids are well known as positive allosteric modulators of GABAA receptors and there are data showing an interaction of neuroactive steroids with ionotropic glycine receptors. In our study, we compared the modulatory actions of androsterone and progesterone at human recombinant homoligomeric α1 glycine receptors, heterooligomeric α1β glycine receptors and α1β2γ2 GABAA receptors.
Recombinant α1 glycine receptors, α1β glycine receptors, or α1β2γ2 GABAA receptors were transiently expressed in human embryonic kidney cells (HEK) 293. The effects of androsterone and progesterone were studied using the whole-cell patch-clamp technique in combination with tools for ultrafast test solution exchange.
At α1β2γ2 GABAA receptors, not at ionotropic glycine receptors, a direct activation by androsterone was observed with a sigmoid dose-response relationship. Upon pulse-wise application of progesterone however, no direct activation of GABAA or glycine receptor channels was observed.
Androsterone enhanced currents elicited by submaximal (EC20) agonist concentrations at GABAAα1β2γ2 receptors and α1 glycine receptors in a concentration dependent manner. The dose response-relationship oft his positive allosteric modulation was tent-like with an increase of the relative peak current amplitude up to a concentration of 30 micromolar androsterone an a decrease of the relative amplitudes at upon coapplication of higher concentrations with an EC20 of GABA or glycine. Progesterone showed a similar effect but enhanced currents elicited by EC20 agonist concentrations at α1 glycine receptors, α1β glycine receptors and α1β2γ2 GABAA receptors to an extent minor than androsterone.
The data show the differential interaction of steroids with the most important fast inhibitory synaptic receptors, the ionotropic glycine receptor channels and the GABAA receptor channels. Different molecular mechanisms of interaction could be identified and quantitatively described. A major direct activation of inhibitory ionotropic receptors was observed with androsterone at GABAA receptors. A coactivation of currents elicited by nonsaturating agonist concentrations was observed with both compounds at glycine and GABAA receptors. At concentrations of 0.1 mM and higher, there were also hints to a channel block like mechanism.