European Congress Proceedings

Epilepsicl, 35(Suppl 7):l-100, 1994 Raven Press, Ltd., New York 0 International League Against Epilepsy European Congress Proceedings

European Congress of Epileptology Oporto, Portugal, September 6-10, 1994

Topic I: Epileptogenesis Epileptic discharges represent a pathologic extreme of the emergent properties of neuronal networks. Excitatory connections between the pyramidal cells of neocortex and hippocampus Main Session (1OOOa-1OOOc) play a key role in initial synchronization of neuronal activity into epileptic discharges. Combined experimental studies and realis- Ionic Mechanisms of Epileptogenesis. U we Heinemann, A. Dra- tic computer simulations of a range of acute experimental epilepsies has led to detailed understanding of the necessary fea- guhn, and H. Luhmann (Department of Neurophysiology, Phys- iological Institute of the Charite, Humboldt University, Berlin, tures of the hippocampal CA3 region (J Physiol (Lond) 1993;461: 525-47): The divergence and efficacy of the connections between Germany)-lOOOa. pyramidal cells. Acute convulsants generally increase efficacy. For ictogenesis, the balance between excitation and inhibition Chronic models more closely parallel clinical epilepsies. One must be disturbed. This is organized on two levels: the synaptic such is the tetanus toxin model. lnitially (<4 weeks), synaptic and the cellular. On the cellular level, depolarizing inward cur- inhibition is disrupted by block of y-aminobutyric acid (GABA) rents must be balanced by hyperpolarizing outward currents. release. Subsequently, GABA release recovers, but the tissue Similarly, on the synaptic level, excitatory postsynaptic poten- remains epileptogenic (Neuroscience 1993;57:235-9; J Physiol tials (EPSPs) must be counteracted by inhibitory postsynaptic (Lon4 1993;465:595-614). During this late phase, inhibitory in- potentials (IPSPs). Consequently, changes in intrinsic membrane terneurons appear disconnected from the excitatory network, properties or synaptic organisation can contribute to epileptoge- consistent with the “dormant” interneuron hypothesis. Dormant nesis. Interfering with this balance induces epileptiform activity interneurons and the sprouting of new excitatory connections both in vivo and in vitro. Although interictal and absence type have each appeared in several chronic epilepsies, suggesting that seizures are not associated with major ionic changes in the ex- they have general significance for epileptogenesis. (Supported by tracellular microenvironment, such changes occur during sei- The Wellcome Trust.) zurelike events. The observed ionic changes are themselves ca- pable of inducing epileptiform activity and thus provide for feed- Molecular and Morphologic Changes in Epilepsy: A Process Lead- back mechanisms supporting seizure development. ing From Seizures to Neosynaptogenesis. A. Represa, H. Pollard, If an ictogenic agent is applied for some time to a cortical slice C. Marlangue, M. Khrestchatisky, J. Niquet, K. Bugra, and Y. such as the entorhinal cortex (EC) slice, the epileptiform activity Ben-Ari (INSERM U. 29, Paris, France)-lOOOc. may change both its appearance and drug sensitivity. This was particularly well documented for low Mg2+-induced seizurelike Seizures set in motion a cascade of complex molecular and events in EC. The transition from seizurelike events to late re- genomic changes, which may contribute to abnormally increased current discharges which are no longer sensitive to clinically neuronal excitability and be involved in maintenance of the ep- used anticonvulsants, and the transition to late recurrent dis- ileptic process. These changes may also be responsible for de- charges, is facilitated by K+ channel blockers such as TEA and velopment of seizure-induced neuronal lesions. Such modifica- by GABA receptor antagonists. Because in EC Kf channels tions have been well analyzed in experimental models of tempo- sensitive to TEA are metabolically regulated, increased energy ral lobe epilepsy in rats, but recent data already suggest that consumption and consequent downregulation of K currents may similar changes develop in human epilepsy. contribute to the transition from seizurelike events to late recur- Seizure-induced changes may be rapid and transient (from 30 rent discharges. With respect to GABA, we noted that the GABA min to 24 h after seizure onset). These changes include increased uptake blocker nipocotic acid blocked late recurrent discharges expression of transcription factors (i.e., c-fos and zif268), whereas barbiturates and benzodiazepines were ineffective. trophic factors (i.e., basic fibroblast growth factor), and neuro- Between seizures, brain, although predisposed to ictogenesis, transmitter receptors (glutamatergic receptors of the AMPA is stabilized, and a momentary disregulatory event will start the type). Such changes may also be delayed and long-lasting (from actual seizure. Such disregulation may occur under emotional 24 h after seizures; they may last for the life of the animal). conditions in which steroids interact with brain. Seizure onset During this phase, a persistent change in glutamate receptor ex- may be related to certain stimuli and to release of neuromodu- pression, development of neuronal death (by both necrotic and lators such as serotonin, norepinephrine, and histamine. The ef- apoptotic mechanisms), glial proliferation and hypertrophy, ac- fects of some of these agents were determined in our study. tivation of cytoskeletal proteins and, finally, reactive sprouting Through IA receptors, serotonin blocked epileptiform activity and neosynaptogenesis have been observed. Study of such pro- both in rat hippocampal slices and in EC. cesses may lead to better understanding of the consequences of The processes that underlie epileptogenesis are multifold. Im- seizures in brain as well as of the mechanisms underlying focal pairment of circuitry formation, hypoxia, and status epilepticus, epilepsy. as well as infection, induces lesions in brain; tumors and seizure- induced alterations in neuronal properties are most common. Evidence €or changes in cellular and synaptic properties can be Platform Presentation 1 (1001-1006) obtained in preparations from hypoxia-lesioned animals and in animals with a kindled as well as a tetanus focus. Whether changes in neuromodulatory activity can produce epileptiform activity in Effect of Cycloheximide Intraventricular Administration on Epi- these prelesioned animals still has not been well investigated. leptic Focus Development in Amygdala-Kindled Cats. J. Maj- kowski, A. Sobieszek and Jerzy Majkowski (Department of Neu- rology and Epileptology, CMKP, Warsaw, Poland)-1001 . Basic Mechanisms of Partial Epilepsies. John G.R. Jefferys (St. Mary’s Medical School, Imperial College, London, England)- Epileptic focus formation in a kindling model is an expression 1000b. of permanent synaptic plastic modification, which in turn is a

1 2 EUROPEAN CONGRESS PROCEEDlNGS result of neuronal protein synthesis. We studied the inhibitory ence between MAM-treated and control rats. The results suggest effect of the protein synthesis inhibitor cycloheximide on epilep- that some types of NMDs are not associated with a greater de- togenesis. Electrodes for kindling stimulation were implanted in gree of seizure-induced hippocampal damage in developing different cat brain structures, including amygdala. An osmotic brain. Alzet pump (2 ML4) containing 2 ml cycloheximide solution 50 pg/ml was then implanted subcutaneously. The pump was connected by a polyethylene tube to a cannula inserted in the lateral ventricle of the hemisphere. Cycloheximide was infused at a Pathogenic Clinical Mechanisms in Temporal Seizures. Gary W. constant rate for 28 days (2.5 pl/h). After pump insertion, Mathern, Thomas L. Babb, James K. Pretorius, and Barbara G. amygdala kindling was started. The control group of animals Vickrey (Division of Neurosurgery, RNRC, UCLA Medical received physiologic saline. Center, Los Angeles, CA, U.S.A.)-1004. Preliminary results show that epileptic focus formation in amygdala was decreased in animals receiving cycloheximide. In temporal lobe epilepsy (TLE), prolonged first seizures and Moreover, no epileptic seizures occurred. In contrast, control head trauma, termed initial precipitating injuries (IPI), have been cats receiving saline infusion developed seizures during a com- suggested to cause hippocampal sclerosis (HS). We determined parable time period. The protein synthesis inhibitor cyclohexi- the clinicopathologic associations between IPIs, HS, and seizure mide may have some inhibitory effect on amygdalar epileptoge- outcome in a cohort of 215 surgically treated TLE patients. The nesis in the kindling model of epilepsy. presence and type of iPI (independent variable) was compared with hippocampal (HC) neuron losses, mossy fiber (MF) sprouting, and seizure outcome (three dependent variables). For nonlesional TLE (n = 163), patients with IPis had greater HC loss (p Implication of Chemical Kindling for Drug-Resistant Epilepsy. = 0.0001), more MF sprouting (p = 0.0005), and better outcome Andrey Mazarati, Alexei Shandra, Leonid Godlevsky, and Val- (p = 0.0001) as compared with No-IPI patients. Of the IPi types, entin Kresyun (Department of Normal Physiology, Medical In- those with prolonged first seizures and head trauma had signifi- stitute, Odessa, Ukraine)-1002. cantly better outcome than types with birth injury or nonseizure cerebral infections (p = 0.0043). Of those with lesional TLE (n Antiepileptic drug (AED) resistance is an advantage of the = 52), 1PI patients (n = 13) had greater HC loss than No-IPI kindling model of epilepsy, but is a feature of electrical rather patients (p = 0.0005), and HC loss was also detected in lesions than chemical kindling. Furthermore, kindling comprises three adjacent to HC (p = 0.04). These data indicate that HS, MF states: seizure development, kindled seizures, and postkindling sprouting, and good seizure outcome are associated with lPIs in increased seizure susceptibility. We describe the peculiarities of surgically treated TLE, supporting the notion that the pathogen- action of AEDs, depending on kindling state, in rats kindled with esis of HC damage begins with the IPI and progressively devel- picrotoxin 1.5 mg/kg. Phenobarbital 2.5-10 mg/kg (increment 2.5 ops into HS. mg/kg) or diphenylhydantoin 10-100 mglkg (increment 10 mglkg) were injected either 24 h after the last kindling trial (kindling state) or after 14-day picrotoxin-free interval (postkindling state). Spatial and Temporal Evolution of Neuronal Stress and Death in When applied during kindling state, both drugs displayed dose- Lithium-Pilocarpine-Induced Status Epilepticus. Jacques E. dependent antiseizure effect, but they were ineffective during Motte, *Tallie Z. Baram, and *O. Carter Snead (CHU Reims, post-kindling state, when anticonvulsive action could be INSERM U398, Strasbourg, France; and *University of achieved only after AED administration in toxic doses (20 and Southern California School of Medicine, Los Angeles, CA, 150 mg/kg, respectively). Thus, with regard to AED efficacy, U.S .A.)--1005. kindling state can be considered a drug-sensitive model and postkindling state a drug-resistant model. Each model can be used in Injection of pilocarpine in rats treated with lithium chloride proper cases for preclinical evaluation of AEDs. produces sustained limbic seizures followed by generalized status epilepticus (SE) and widespread brain damage, To determine the mechanisms of this neuronal necrosis, we used the immunoreactivity for the nonconstitutive heat shock protein (HSP72) to Neuronal Migration Disorders and Epileptogenesis. I .M. Ger- determine cell stress and applied fuchsin acid stain to color dying mano, E.F. Sperber, L.K. Friedman, R.S. Zuckin, and S.L. neurons. Thus, the evolution of the pattern of stress and death Mosht (Department of Neurosurgery, Mount Sinai School of after different EEG-controlled durations of SE was studied. Af- Medicine, New York, and Department of Neurology and Neu- ter 40-50 min of SE, HSP72-labeled neurons were observed in roscience, Albert Einstein College of Medicine, Bronx, NY, the hilus of hippocampus and in sensorimotor cortex. After 100- U .S .A.)-1003. 120 min of SE, labeling was also noted in dorsolateral amygdaloid nuclei and anterior olfactory nuclei and weakly in piriform Neuronal migration disorders (NMDs) may increase the like- cortex. At 140-180 min, additional neurons in the ventral thala- lihood of seizure-induced hippocampal damage. We tested this mus, cingulate cortex, and other hippocampal regions were la- hypothesis in a molecular biologic study, treating pregnant rats beled. After 180 min, HSP72 positivity appeared throughout with the alkylating neurotoxin methylaxoxymethanol (MAM) to brain, but predominantly in sensorimotor and cingulate cortex, induce NMDs in the offspring. Control rats were injected with hilus and CA3, lateral amygdala, and anterior olfactory nuclei. saline. Status epilepticus was induced in 14-day-old rats by in- This pattern of neuronal stress differed from that of neuronal jection of kainic acid (KA 5 mg/kg intraperitoneally, i.p.). In situ death, as assessed by fuchsin acid staining. hybridization (n = 17) was used to measure glutamate receptor gene expression, GluR, subunit, which is linked to calcium im- permeability and protection from calcium-induced neuronal damage. Secondary Epileptogenesis After Initial Status Epilepticus. Hart- As compared with controls, MAM-treated rats studied before mut Meierkord, Eva Schielke, Udo Wieshmann, *Rainer Ba- KA-induced seizures showed a significant decrease in GluR, chus, and *Alexander Bock (Neurologische Klinik and mRNA expression in the zone of neuronal ectopia in the CAI *Abteilung fur Neuroradiologie, Universitatsklinikum Charitt, hippocampal area (p < 0.005). Twenty-four hours after status Berlin, Germany)-1006. epilepticus, GluR, mRNA expression was significantly decreased (p < 0.005) in the hippocampal pyramidal cell layer in Secondary epileptogenesis is a term used to describe the con- MAM-treated rats. However, histologic assessment of seizure- sequences of epilepsy that in themselves may cause epilepsy. induced hippocampal damage did not show a significant differ- Unequivocal evidence shows that the mechanism of secondary

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 3 epileptogenesis occurs in several experimental models, such as ences on neocortex were weakened by destruction of globus the kindling or tetanus toxin model in which mirror foci can be pallidus (GP) of substantia nigra pars reticulata (SNR), as ex- observed. In humans, however, the occurrence of secondary pressed in decrease of duration of epileptic activity (EpA) sup- epileptogenesis has been questioned and its existence is difficult pression under NC stimulation (p < 0.001), in decrease in speed to prove. of regression (p < 0.01) and increase in duration of EpA (p < We report a 23-year-old woman with no previous history of 0.01). Furthermore, after entopeduncular nucleus (EP) destruc- epilepsy or other neurologic disease, in whom secondary epilep- tion, the antiseizure caudatocortical influences were eliminated. togenesis occurred after status epilepticus (SE). The patient was Under these conditions, NC stimulation intensified EpA in neo- admitted to the hospital for diagnostic evaluation of a first tonic- cortex, inducing 13- to 15-s ictal discharges. clonic seizure. Apart from nausea and irritability, no other ab- We also studied the effects of destruction and activation of normalities were noted, and magnetic resonance imaging (MRI) GP, EP, and SNR. Results showed that pallidal segments and showed no abnormality. The patient then developed a cluster of SNR exerted mainly proepileptic effect on cortical EpA. Our tonic-clonic seizures merging into SE initially intractable to med- research showed that antiepileptic effects of NC stimulation can ication. She was treated on the intensive care unit with artificial be achieved by suppression of GP activity and destruction of EP ventilation, complete muscle relaxation, and balance of all met- and SNR, with resultant disinhibition of ventral anterior and abolic parameters. EEG monitoring showed ongoing SE for -10 lateral thalamus nuclei. days. Serial MRI studies showed bilateral edema in mesiotemporal regions on T,-weighted images; several days later pronounced cell loss was noted in the same regions. After termination of SE, the patient developed complex partial seizures despite treatment with several anticonvulsants. The cause of the Intermittent Vagus Nerve Stimulation Activates Brainstem Norad- patient’s SE has not yet been determined. To our knowledge, renergic Nuclei. Dean K. Naritoku, Wendy J. Terry, and Robert this is the first case of proven secondary epileptogenesis after W. Helfert (Departments of Neurology, Pharmacology, and Sur- initial SE. gery, Southern Illinois University School of Medicine, Spring- field, IL, U.S.A.)-1009.

Intermittent vagus nerve stimulation (VNS) is under study for treatment of intractable partial-onset epilepsy. Little is known Platform Presentation 2 (1007-1012) about the way in which stimulation of vagus afferents in brainstem exerts an antiepileptic effect on forebrain. Fos is expressed in several forebrain structures implicated in seizure initiation or regulation (Epilepsia 1993;34(supp16):8). We examined fos expression in brainstem noradrenergic and serotonergic nuclei to Buccal Ganglia of the Snail Helix pomatia: An In Vitro Model of determine if these structures are activated by VNS. Under pen- Focal and Multifocal Epileptic Activity. *Ulrich Altrup, *M. Wie- tobarbital anesthesia, leads were attached to the left vagus nerve mann, and *+Erwin-Josef Speckmann (*Institut fur Experimen- of adult Sprague-Dawley rats (n = 9) and stimulated electrically telle Epilepsieforschung and flnstitut fur Physiologie, Universi- (30 Hz, 1 mA, 500-p,s pulses, 30 s on, 5 min off) for 3 h. Control tat Munster, Munster, Germany)-1007. rats (n = 9) received electrode implantation without stimulation. Animals were perfused, and brain sections were incubated over- Foci of epileptic activity are detected in most of the epilepsies night with rabbit primary antibody against fos. Sections were resistant to drug therapy, but their establishment is still poorly stained by avidin-biotin method and scored blindly [scale 0 (no understood. Invertebrate nervous systems can be used as model staining) to 3 (intense nuclear staining)]. Moderate fos immuno- structures for the study of foci under in vitro conditions. We reactivity (median = 2) occurred in locus ceruleus and A5 nuclei isolated buccal ganglia of Helix pomatia and mounted them in an in rats receiving VNS, but not in unstimulated rats (p < 0.001). experimental chamber. Snail “Ringer’s” solution contained (in In contrast, no immunostaining occurred in raphe nuclei of stim- mM) NaCl 150, KCI 4.5,CaCI, 9, and Tris-C1 5. Several identi- ulated or nonstimulated rats. The data suggest that VNS may fied giant neurons were recorded intracellularly and simulta- exert its antiepileptic effect though noradrenergic projections to neously. Field potentials were recorded through glass pipettes. forebrain. Epileptic activity was induced by pentylenetetrazol (10-60 mM) or etomidate (ETO 0.1-1 .0 mM). With increasing concentration of an epileptogenic drug, epileptic activity appeared in differential networks of electrically coupled neurons. Epileptic activity appeared first in the B3- Is There Correlation Between Frequency Potentiation and Cortical network (ETO 0.5 mM), followed by the B1 and B2 networks Epileptic Afterdischarges? Pave1 Mares, Jifi Million, and Hana (ETO 0.7 mM) and by a motoneuronal network (ETO 1.0 mM). Kubovh (Institute of Physiology, Academy of Science, and 3rd Epileptic field potentials appeared in the high concentration Medical School, Charles University, Prague, Czech Republic)- range of epileptogenic drugs owing to synchronized epileptic ac- 1010. tivities in the rnotoneuronal network. Field potentials were asynchronous to epileptic activities in other networks. On the whole, Low-frequency stimulation (8 Hz) of rat cerebral cortex elicits increasing numbers of basically independent epileptic foci were an afterdischarge (AD) characterized by EEG spike-and-wave induced in isolated buccal ganglia of Helix pomatia with increas- rhythm in clonic seizures of facial and forelimb muscles. One of ing epileptogenicity (i.e., increasing concentration of epileptoge- the mechanisms of AD generation may be frequency potentia- nic drugs). tion, i.e. an increase in amplitude of responses during short trains of stimuli. We studied this possibility in young rats with implanted electrodes, using rats aged 25 days, in which frequency potentiation could be easily elicited, and 12-day-old rat Role of the Main Targets of Caudate Efferents in Realization of pups, in which frequency potentiation failed to appear under Antiepileptic Nucleus Caudatus Influences on Neocortex. Ruslan control conditions. Stimulation series consisted of 121 biphasic F. Makulkin, Serge A. Novitsky, and Tatiana V. Korneyenko rectangular pulses of 1-ms duration and 8 Hz frequency; inten- (Pirogov Medical Institute, Odessa, Ukraine)-1008. sity of stimulation was varied to record one series without AD and another that elicited AD. No substantial changes in fre- Using the strychnine application epilepsy model in Wistar rats, quency potentiation occurred at the beginning of the stimulation we determined that antiepileptic nucleus caudatus (NC) influ- series in 25-day-old rats in relation to generation of ADS. On the

Epilepsia, Vol. 35, Suppl. 7, 1994 4 EUROPEAN CONGRESS PROCEEDINGS contrary, the shape of evoked potentials changed toward the end stricted to the hippocampus, fully expressed 4MO min after of stimulation in connection with appearance of ADS in both age i.c.v. injection. Such activity lasts 120-180 min and is associated groups. with occasional episodes of “frozen” attitudes never followed by loss of consciousness. Carbamazepine and the Ca” antagonist nifedipine strongly reduced this EEG pattern (Epilepsia 1988;29:369-73). These observations suggest the possibility that Repetitive Transcranial Magnetic Stimulation in the Rat. Poul Jen- CRF may modulate the seizure threshold in certain types of con- num and H. Klitgaard (Department of Clinical Neurophysiology , vulsive pathology and that CRF epileptogenic effects might be Hvidovre Hospital, Hvidovre, Denmark)-lOl1. regarded euristically as a possible model of partial epilepsy and a promising avenue in interpreting some basic mechanism of the Repetitive transcranial magnetic stimukation (RTMS) is a new epileptogenesis . method in which magnetic pulses of short duration (S200 ws) are applied to the head with stimulus frequencies

Epilepsia, Val. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 5

Spatiotemporal Distribution of Intracellular Calcium Transients Receptors in Sprouted Human Hippocampal Epilepsy. Thomas L. During Epileptiform Activity in Guinea Pig Hippocampal Slices. Babb, Gary W. Mathern, and James K. Pretorias (Department of *tBirgit Albowitz and *Ulrich Kuhnt (*Department of Neurobi- Neurology, RNRC, UCLA Medical Center, Los Angeles, CA, ology, Max-Planck-Institute for Biophysical Chemistry, Gottin- U .S .A .)-I 0 17. gen; and tlnstitute for Experimental Epilepsy Research, Mun- ster, Germany)-l015 In human hippocampal epilepsy, “excitatory” mossy fibers (MF) and “inhibitory” GABA axons sprout in the supragranular region of fascia dentata (FD), possibly contributing to spontane- Many experimental data show that calcium ions are important ous seizures. Whether these aberrant sprouted terminals upreg- in generation of epileptic activity. Using a fast optical recording ulate postsynaptic receptors in the same supragranular region of method and a fluorescent calcium probe, we monitored the spa- the FD is not known. Adjacent sections of hippocampi were tiotemporal distribution of intracellular calcium concentrations processed to identify aberrant terminals for MFs, and glutamic during epileptiform activity across large parts of hippocampal acid decarboxylase (GAD); alternate sections were labeled for slices. the receptors glutamate Rl (GluRl), glutamate R2/3 (GluR2/3), Hippocampal slices (350 pm) were prepared from adult guinea GABA-A subunit-a, and GABA-A subunit+. In all 4 patients, pigs and stained with calcium-green-AM. Epileptiform activity receptor densities matched the type of sprouted aberrant termi- was induced either by adding bicuculline (BIC 20 p,M) to or by nals; i.e., MF sprouting differentially increased GluRl and removing magnesium from the perfusion medium and by single- GluR2/3 (the latter receptor was increased most). Similarly, both pulse electrical stimulation. Calcium-dependent fluorescent GABA-A receptor subunits increased with GAD hyperinnerva- changes were monitored by a 10 X 10 photodiode array. The tion, suggesting that sprouting of axons and formation of new system provided a spatial resolution of 60 pm and a temporal synapses causes remodeling of receptors at the target synapses. resolution of 0.4 ms. These new synapses are potentially functional and could contrib- In both model epilepsies, intracellular calcium concentrations ute to seizure genesis. reached larger peak amplitudes and decreased later to baseline as compared with control recordings. In contrast to BIC-induced epileptiform activity, peak amplitudes were reached later in low- Antisense Oligonucleotide Reduces Production of Fos-Like Immu- magnesium epilepsy. Calcium also decreased at a slower rate and noreactivity Induced by Partial Amygdala Kindling Seizures. Luisa frequently stayed at a plateau level for s200 ms. After APV was L. Rocha and *Daniel Kaufman (Instituto Mexican0 de Psiguia- added to the perfusion medium, calcium concentrations were tria, Mexico D.F.; and *UCLA School of Medicine, Los Ange- only slightly reduced during BIC-induced epileptiform activity les, CA, U3.A.)-1018. but were significantly reduced in low-magnesium epilepsy. Most of the calcium influx N-methyh-aspartate in low-magnesium Immediate-early genes such as c-fos are rapidly and tran- epilepsy is mediated by receptors and by other, possibly voltage- siently activated in amygdala and piriform cortex after partial gated, calcium channels in BIC-induced epilepsy. kindling seizures. We use antisense technology to reduce kindling-induced production of fos-like immunoreactivity . Male Wistar rats were implanted with a bipolar electrode and guide cannula in right amygdala. They were allowed to recover for 7 days. Antisense and sense phosphorothioate oligonucleotide to Membrane Conductances Underlying Different Firing Properties of c-fos mRNA (1.2 pg) were infused at 0.3 pgimin. Six hours after Rat Pyramidal Neurons. S. Franceschetti, G. Sancini, F. Pan- oligonucleotide administration, rats were connected to the EEG zica, *E. Guatteo, and G. Avanzini (Dipartimento di Neurofisio- and electrical stimulation apparatus and stimulated, for 1 s with logia, Instituto Neurologic0 C. Besta; and *Dipartimenti di Bio- 60-Hz, I-ms diphasic pulses, 400 pA peak to peak. This proce- chimica e Fisiologia, Generali Universita, di Milano, Milano, dure was repeated on 3 consecutive days. Thirty minutes after 1taly)-I 016. the last electrical stimulation, animals were transcardially perfused for c-fos immunohistochemistry: c-fos immunoreactivity was observed bilaterally in amygdala and piriform cortex in Experiments were performed on coronal slices obtained from sense-injected animals. In contrast, antisense oligonucleotide in- adult Wistar rats. Current clamp intracellular recordings were fusion virtually eliminated c-fos immunoreactivity in amygdala obtained from 92 pyramidal neurons in layer V. The following and piriform cortex ipsilateral but not contralateral to the site of neuronal populations were characterized. infusion. Antisense technology can be used to study the role of First, intrinsically bursting (IB) neurons tire single or repeti- immediate-early genes in specific brain areas during the kindling tive bursts of action potential (AP) when low-amplitude depolar- process. izing current pulses are injected intracellularly. Repetitive bursting is reversed to tonic firing when the membrane is maintained at a more depolarized level. In this condition, individual APs are Recent Data on Anticonvulsant Effects of Neurotropin. Alexei followed by a prominent depolarizing AP (DAP). Bursting is not Shandra, Leonid Godlevsky, Ruslan Vastyanov, and Andrey modified when prestimulus membrane potential (V,) is held 10- Mazarati (Department of Normal Physiology, Medical Institute, 20 mV negative to resting potential. Spike frequency adaptation Odessa, Ukraine)-l019. (SFA) is always absent. All IB neurons possess a powerful anomalous rectifying current that is blocked by extracellular Neurotropin is a nonprotein fraction of low-molecular weight Cs+ without affect on bursting behavior. Only simultaneous ad- substances formed by immune reaction and extracted from the ministration of CaZ+and Na+ channels blockers can extinguish skin of rabbits inoculated with Vucciniu virus. Neurotropin was burst and/or DAPs. previously shown to suppress seizures in various animal models Second, nonadapting regular spiking (RS,,) neurons also of epilepsy. mostly show IB neurons, DAPs that follow each individual APs We showed that intraperitoneal (i.p.) neurotropin suppressed potentials. Their physiologic character and responsiveness to kindled epileptic activity (EpA). This effect, as well as protective pharmacologic manipulations suggest that RS,,, differs from IB neurotropin action under conditions of chemical kindling, was quantitatively (i.e., strength of Ca2+ and/or Na+ persistent cur- blocked by systemic naloxone (1 .0 mg/kg). Neurotropin antisei- rents) rather than qualitatively. zure influences on acute picrotoxin-induced EpA were blocked Third, adapting RS neurons (RS,) show an increase in SFA by cycloheximide administration. Intracerebroventricular strength when depolarizing pulses are superimposed on a holding (i.c.v.) cerebro-spinal fluid (CSF) obtained 1 h after neurotropin hyperpolarizing current maintaining V, at -80 to -90 mV. i.p. injection raised the seizure threshold. This effect was Pharmacologic tests indicate that RS, cells possess a strong blocked after CSF incubation with pronase-E. High-performance CaZ+-dependent K+ current responsible for SFA. liquid chromatography of CSF detected peptide with a molecular

Epilepsia, Vol. 35, Suppl. 7, 1994 6 EUROPEAN CONGRESS PROCEEDINGS weight of 10 Kd. Neurotropin exerted antiepileptic action increase in TNF-a levels. Patients with and without medication through endogenous opioid system activation. One of the likely showed all these abnormalities. Epileptic patients both with or mechanisms of its protective effects is the appearance of endog- without medication exhibit immunologic abnormalities. enous peptide factors in CSF.

Capillary Prolactin Estimation After Seizures in Children with Ep- Peptides From Hybernated Brain: Antiepileptic Effects. Leonid ilepsy. D.T. Hindley, R.W. Newton, M.J. Noronha, and *J. Godlevsky, Alexei Shandra, Andrey Mazarati, and Igor Anderson (Royal Manchester Children’s Hospital *Withington Tkachenko (Department of Normal Physiology, Medical Insti- Hospital, Manchester England)-l023. tute, Odessa, Ukraine)-1020. Several studies have shown an increase in serum prolactin Administration in the lateral brain ventricles of both kyotor- concentration after epileptic seizures but not in nonepileptic phin (Tyr-Arg) and the related peptides, neokyotorphin (Thr-Ser- events, e.g., pseudoseizures, syncope, or breathholding attacks. Lys-Tyr-Arg) and ~-Ser-2-neokyotorphin(Thr-D-Ser-Lys- This observation has been limited as an objective discriminatory Tyr-Arg), all at a dose of 10 nmol, significantly attenuated the test for epilepsy by the need to obtain venous samples soon after severity of picrotoxin-induced convulsions in rats. Local micro- such episodes cease. injection of the peptides into CA3 hippocampus resulted in a We report the results of an investigation of changes in serum dose-independent seizure-protecting effect (within the dose prolactin with seizures in a group of children with an established ranges of 2.5-5.0 nmol) for neokyotorphin and ~-ser-2- diagnosis of epilepsy. All samples were obtained by fingerprick neikyotorphin, whereas kyotorphin displayed anticonvulsant ac- and applied to filter paper; postictal samples were obtained at tion only at a high dose (5.0 nmol). When administered in sub- home by parents. stantia nigra reticulata, neokyotorphin facilitated seizures at a Fourteen children provided 20 baseline/postictal paired sam- low dose (2.5 nmol) and attenuated convulsions at a higher dose ples. Baseline levels ranged from 31 to 295 IU/L (median 75.5 (10 nmol). ~-Ser-2-neokyotorphinhad anticonvulsive effect only IU/L). Postictal prolactin levels ranged from 69-755 IU/L (me- at the highest dose used (10 nmol). Kyotorphin administered dian 198.5 IU/L) (p < 0.001). In 13 of 19 children who showed a intranigrally did not affect seizures. Kyotorphin-related peptides postictal prolactin increase, the percentage of increase from possess antiepileptic activity that depends on peptide structure. baseline was >loo%. A questionnaire given to parents demonstrates that testing in the postictal period by this method is achievable, simple, and acceptable to families. Anticardiolipin Antibodies and Epilepsy. Lacramioara Perju- Dumbrava, and Dan Peju-Dumbrava. (Department of Neurol- ogy, University for Medicine and Pharmacy, Cluj-Napoca, Ro- mania)-l021. Callosotomy for “Generalized” Seizures Unveils Frontal Partial Seizures. Mark Rayport, Anthony T. Lassiter, Carolyn A. Schell, Anticardiolipin antibodies (ACL-A) are immunoglobulins of and Shirley M. Ferguson (Comprehensive Epilepsy Center, the IgG, IgM, or IgA class characteristically detected in patients Medical College of Ohio, Toledo, OH, U.S.A.)-1024. with systemic lupus erythematosus or related autoimmune diseases. Investigators have reported the presence of ACL-A in Incomplete generalized seizure control after callostomy (CCS) patients without autoimmune disorders, such as brain infarction, requires explanation. We hypothesize that partial seizures (PSz) transient ischemic attacks or amaurosis fugax, retinal infarction, arising in callosally connected cortex may have clinical and EEG transverse myelitis, vascular dementia, chorea, seizures, head- features of “generalized” seizures (GSz). Among 19 consecutive ache and subdural hematoma. Using a micropin enzyme-linked GSz patients with no indications for focal corticectomy, 9 had immunosorbent assay, we measured the levels of ACL-A in sera anterior CCS (aCCS) only, 10 had two-stage complete CCS, and of 43 unselected patients with epilepsy. Four patients had ACL- all were followed >2 years by the same multidisciplinary, team A, a prevalence of 9.3%. Two patients had IgG-ACL-A, 1 had (neurosurgery, neurology, and EEG, neuropsychiatry, neuro- IgM-ACL-A, and 1 had antibodies belonging to both classes. All psychology, nursing). Extracranial EEG (ecEEG) and closed- patients had a negative VDRL reaction, no evidence of lupus circuit TV/ecEEG long-term monitoring for spontaneous sei- erythematosus, and negative history of thrombotic events. There zures (LTMSS) were performed before and after aCCS; 1 patient was no difference with respect to serum immunoglobulin con- also underwent LTMSS with stereoelectroencephalography centrations between ACL-A-positive and ACI-A-negative pa- (SEEG) before aCCS, and 3 patients did so after aCCS. Before tients. Although much attention has been focused on ACL-A for aCCS, 9 patients had a mean of 3.2 seizure patterns (14 GSz, 14 > 10 years, their role and pathophysiologic effects have not yet PSz). All 9 had tonic-postural PSz. After aCCS, GSz incidence been elucidated. decreased from 14 to 7; 3 became free of GSz. Complex PSz decreased from 4 to 1, but tonic-postural seizures continued in 9 of 9. Before aCCS, ecEEG and LTMSS predominantly showed synchronous or independent bilateral discharges. After aCCS, Cytokines and Serum Immunoglobulins in Epileptic Patients. S. synchronous interictal and ictal discharge decreased and bilater- Bostantjopoulou, G. Kyriazis, 0. Hatzizisi, M. Kantaropoulou, ally independent discharge increased. A mesiofrontal regional or S. Karachristianou, and A. Kazis (3rd University Department of localized ictal onset was demonstrated in 5 of 8 patients, in 3 by Neurology, Thessaloniki, Greece)-1022. SEEG/LTMSS. Corticectomy of a supplementary motor area in 2 provided worthwhile improvement in seizure control and be- Serum immunoglobulins (IgG, IgA, IgM, IgE), IgG subclasses havior; 2 are surgical candidates. The hypothesis was sustained; (IgG,, IgG,, IgG,, IgG,), K and A light chains and p/A ratio, and the other 10 cases provide support. C, and C, complement component and cytokines [interleukin 1 (IL-la, IL-1 p) tumor necrosis factor (TNF-a, interferon-y)] were determined in 34 patients with epilepsy and in 20 controls. Twelve patients were receiving valproate, 11 were treated with Sympathetic Nervous System in Genesis and Treatment of Mi- carbamazepine, and 11 were receiving no medication. Patients graine and Epilepsy. Bernhard H. Landgrebe (San Antonio, TX with epilepsy had significantly lower concentrations of IgG, (p < U .S .A.)-l025. 0.01) and IgG3 (p < 0.001), but there was no difference in levels of total IgG, IgM, IgA, and p/A ratio. Furthermore, epileptic Migraine and epilepsy both with similar recurrent and parox- patients showed a slight decrease in IL-la and IL-Ip and a slight ysmal symptoms, autonomous dysfunctions, and psychological EUROPEAN CONGRESS PROCEEDINGS 7 and EEG changes, have been treated successfully with stellate focus than in those with extratemporal EEG foci. We could not ganglion blocks (SGB). SGB not only relieved severe migraine demonstrate any correlation among verbal, mimic, or ambula- but also reduced frequency and severity of seizures, often long- tory automatisms and EEG topography. lasting, even in patients with (partial myoclonic epilepsy and Our findings suggest a strong correlation among gestural or Lennox-Gastaut syndrome) refractory to conventional drugs. In eating automatisms and temporal EEG abnormalities, and pos- migraine, a hypoperfusion starting in the occipital area pro- sibly with temporal epileptogenesis, independent of etiology and gresses anteriorly throughout aura and headache phases. In ep- MRI topography. ilepsy, “adrenergic vasoconstriction” results in cerebral hypoperfusion and anoxia. The vasomotor changes are neuronal, resulting from disturbed cerebral metabolism, known as “spreading depression.” The sympathetic nervous system mediates neu- rogenic autoregulation, important in pathogenesis of both disor- Theoretical Approach to Contribution and Significance of Physio- ders. Nerves from superior cervical ganglia innervate logic Antiepileptic Systems in Clinical Manifestations of Epileptic intracerebral arteries. Blockade with lidocaine “increased cere- Symptoms. Peter Rajna (Department of Psychiatry, Semmelweis bral blood flow considerably.” Adrenergic drugs increase sei- University of Medicine, Budapest, Hungary)--1028. zure activity and intensify psychological symptoms. SGB has protective antianoxic and antiischemic effects. Ganglionectomy Despite a persisting epileptogenic cerebral lesion, and/or a failed to cure cryptogenetic epilepsy (Penfield and Jasper), prob- continuous interictal epileptic dysfunction (EDF), and even recognizable accidental provoking factors, the occurrence of clini- ably owing to “increased denervation hypersensitivity. ” The textbook assertion: “Since pain of M is due to vascular dilata- cal seizures is surprisingly rare. Why this is so has not been made tion, SGB would have no effect,” has been invalidated. clear by basic or clinical science. In the “two-factor’’ model (TFM) for clinical manifestations of EDF, the probability of clinical manifestation of epilepsy depends on continual balance of epileptogenic and antiepileptic Resistance of the Immature Rat Hippocampus to Nonneuronal Sei- systems. With the aid of TFM, many yet unsolved issues may be zure-Induced Damage. Ellen F. Sperber and Kurt Z. Haas (Al- satisfactorily explained: (a) the category of accidental/occasional bert Einstein College of Medicine, Bronx, NY, U.S.A.)-1026. epileptic seizures, (b) the paradoxical situation of 2 Family members with identical interictal epileptiform EEG activity (spike Kainic acid (KA) seizures, a model of temporal lobe epilepsy, and wave pattern), 1 of whom has seizures and the other of results in age-related hippocampal changes. Seizure-induced whom never has a clinical manifestation (“pattern holders”), damage in adult rats includes: neuronal degeneration, neuronal and (c) the great differences in epileptogenicity of a cerebral loss in the CA3/CA4 area, synaptic reorganization of mossy fiber lesion with identical locus and intensity experienced in (posttrau- axons in the dentate gyrus, and increased paired-pulse depres- matic, postoperative, postinfectious) patient populations. sion after perforant path stimulation. Parallel changes have not been observed in developing rats. Seizure-induced nonneuronal changes might occur in immature brain yet not be detected by this procedure. Whether seizure-induced damage can be observed in immature Topic 11: Genetics brain by use of a nonneuronal marker of damage was investigated. One type of glial cells, the astrocytes, proliferate in an area of damage. Five days after KA seizure, hippocampal sec- Main Session (2000a-2000d) tions from adult and 14-day-old rats were stained immunocy- tochemically for GFAP (glia fibrillary acid protein), a specific astrocytic protein. Results indicate positive GFAP staining in the CA3/CA4 hippocampal area of the KA-treated adult rats as compared with adult controls. There was no positive staining in im- Genetic Analysis of Epilepsy Syndromes: The Relevance of Pheno- mature hippocampus. These findings confirm results of previous typic Studies. D. Janz and G. Beck-Mannagetta (Abteilung fur studies indicating greater resistance of immature brain to sei- Neurologie, Universitatsklinikum Rudolf Virchow, Berlin, Ger- zure-induced damage. many)-2000a.

Genetic research in epilepsy depends largely on clinical definitions of epileptic seizures and epileptic syndromes in probands Localization-Related Value of Automatisms in Partial Complex as well as in affected relatives. The analytic approach recently Seizures. Vicente Bertol, Antonio Oliveros, M“Ange1es Cid, and led to remarkable results, but at the same time disclosed sub- Isabel Perez (Hospital Miguel Servet and Clinica Quirbn, Zara- stantial difficulties in methods used for ascertaining and inter- goza, Spain)--1027. preting data. A phenotype-based comparison within the syndromes of idiopathic generalized epilepsies (IGE) demonstrated Clinical and paraclinical findings in complex partial seizures concordance in monozygotic twins (Berkovic, 1991) and a rela- (CPS) may help improve our knowledge about different foci and tive specificity of syndromes iq affected family members (Beck- paths of local epileptogenesis. In 151 epileptic patients, with dif- Mannagetta and Janz, 1991; Bianchi, 1994). A syndrome-related ferent types of partial epilepsy, we analyzed the automatisms in comparison between families of probands within the spectrum of CPS, EEG (or video-EEG), neuroimaging, and other etiologic focal epilepsies is still lacking. data in an attempt to demonstrate an eventual correlation be- We report the analysis of epileptic syndromes in 250 families tween type of automatism and cerebral localization. On first re- of probands with IGE and 200 respective families of probands view, statistical analysis showed no correlation among any type with focal epilepsies. The relevance of phenotypic (absences, of automatism and etiology or topography of magnetic resonance photosensitivity) and biologic variables (age at onset, sex) was imaging (MRI) anomalies. investigated as a source of heterogeneity, and the possibilities of The relative frequency of automatisms was as follows: eating reverse genetics was considered. Analytic problems arise from automatisms, 30%; mimic, 11%; gestural, 35%; ambulatory, the impossibility of making absolutely strict distinctions between 19%; verbal, and 13%. A second review showed correlations syndromes (childhood absence epilepsy, juvenile absence epi- between type of automatism and EEG topographic findings with lepsy), from reduced reliability of data taken by third persons, a statistically significant difference: 12.3% more gestural and and from irretrievable loss of information on age-dependent EEG 43.7% more eating automatisms in patients with a temporal EEG findings such as photosensitivity and spike and wave discharges. 8 EUROPEAN CONGRESS PROCEEDINGS

A Juvenile Myoclonic Epilepsy Locus Proximal to HLA: The Value causing gene below HLA to chromosome 6p to a region spanned of Studying a Large Family. *?$A. V. Delgado-Escueta, *t$J. M. by chromosome 6p21.1-6p12.1 Pairwise analysis showed that Serratosa, *?$A. W. Liu, *IlM. T. Medina, and *OR. S. Sparkes three markers in this region (D6S272, D6S428, and D6S257), (*Comprehensive Epilepsy Program, Los Angeles; ?VA South- spanning 8.5 cM, were significantly and very tightly linked (Z,,, west Regional Epilepsy Center, Neurology and Research Ser- >3.0 with 0, = FO.OO1 to 0.00) to the JME phenotype and its vices, West Los Angeles DVA Medical Center; Departments of epileptogenic and epileptiform EEG paroxysms. Recombination $Neurology and $Medicine, UCLA, Los Angeles, CA, U.S.A., events in a clinically affected member and 2 unaffected members and "National University, Tegucigalpa, Honduras)-2000b. suggested that the JME-bearing haplotype includes the area spanned by TNF to D6S257. Recombinations in one clinically Approximately I .5-3 million Americans and 100-200 million unaffected member narrowed the JME-bearing haplotype further persons worldwide have recurrent seizures, making the epilep- to D6S269, D6S272, D6S294, D6S428, and D6S257. Interpreta- sies one of the most common neurologic conditions and a major tions of our data are tempered by the fact that the significance of public health problem. The common idiopathic convulsive syn- recombinations detected in normal individuals is always tenu- dromes of grand ma1 and juvenile myoclonic and nonconvulsive ous; such normal individuals could develop the disease later. childhood absence epilepsies account for almost 40% of all these However, JME rarely has onset after age 20 years and these disorders. Of these syndromes, juvenile myoclonic epilepsy normal individuals are now aged >20 years. Four-point analysis (JME) is the most frequent and thus most important cause of did not identify a best supported JME-marker order, possibly primary convulsive seizures. In JME, rapid 15-30-Hz multi- because of the few recombinations between the JME locus and spikes and slow wave complexes in the EEG produce myoclonic the three linked markers. and tonic-tonic-clonic convulsions beginning at age 8-20 years. Earlier linkage analysis suggested a gene on chromosome 6p (EJMl) that could determine one form of JME. In 1988, we first reported that EJMl may be linked to Bf-HLA on chromosome Progressive Myoclonus Epilepsies: Clinical and Genetic Correla- 6p, when clinically symptomatic and asymptomatic family mem- tions. P. Genton (Centre Saint Paul, Marseille, France)-2000c. bers with paroxysmal EEG abnormalities were considered affected. In 11 small JME families, 8 informative for Bf and 3 A sustained effort by clinicians, led by the Montreal and the informative for HLA, lod scores summed to 3.04 (0 M/F = 0.01, Marseille groups, led to new understanding of the complex 0.10), assuming autosomal recessive inheritance. Because we nosography of progressive myoclonus epilepsies (PMEs) just 4 noted no significant association with any specific alleles or hap- years ago. Four comparatively common groups stand out. First, lotype of HLA, we assumed that the locus might lie outside the Unverricht-Lundborg disease, well-described in Baltic and Med- HLA region. In 1991, Weissbecker et al. excluded tight linkage iterranean patients, was unified on clinical grounds before gene- to HLA, in agreement with our suggestions. They reported ticians confirmed the same linkage with a locus on chromosome summed lod scores of 3.11 (0 M = F 0.001 and 0.20) in 23 small 21 (band q22.3). The gene will probably be identified in the very families from Berlin, assuming autosomal dominant inheritance. near future. Second, Lafora's disease was identified as a char- In the same small Berlin families, Durner et al. reported tight acteristic entity in Holland 30 years ago; genetic research is in linkage to DNA markers in the HLA-DQ locus, assuming auto- progress. There is no linkage with the loci of other forms of soma1 dominant inheritance with peak lod scores of 3.9 at re- PME. Third, Neuronal ceroid-lipofuscinoses are a heterogenous combination fractions of 0.01 M = F, when all forms of idio- group. The early infantile type maps to the short arm of chro- pathic generalized epilepsies were considered affected. Tight mosome 1; the juvenile form maps to chromosome 16q22. linkage was not as evident (0 M = 0.1 and F = 0.3) when asymp- Fourth, Myoclonic epilepsy with ragged-red fibers is a mater- tomatic members with multispike wave complexes were consid- nally transmitted disease associated in most cases with a hetero- ered affected. Because 25 small JME families from England and plasmic mitochondria1 DNA A/G mutation in position 8,344. Sweden and 12 other Los Angeles families (7) do not segregate a Progress has been made in other, rare forms, especially in disease gene linked to HLA or other chromosome 6p markers, childhood Huntington's chorea (which maps to chromosome 4) genetic heterogeneity is suspected among this group of idiopathic and in dentato-rubro-pallido-luysian atrophy (with an unstable convulsive epilepsies. expansion of a CAG triplet on chromosome 12). After genetic linkage was suspected between JME and HLA, Rapid progress in understanding of the biochemical mecha- substantial effort was made to determine whether the locus is nisms is expected to result from the tremendous genetic efforts. outside or within the HLA region and to flank the disease locus Precise biochemical classification of these diseases may lead to with genetic markers. However, further studies were con- further nosologic revisions. founded by uncertain diagnosis, uncertain mode of inheritance, incomplete penetrance, failure to identify EEG multispike wave complexes in asymptomatic family members, and interfamilial genotypic heterogeneity. We report a relatively large JME kin- Identification and Characterization of the Tuberous Sclerosis Gene dred from Los Angeles and Belize with a clear mode of inheri- on Chromosome 16p: Clinical Implications. *Bart Janssen, tance, i.e., autosomal dominant inheritance with 70% pene- *Arienne Hesseling-Janssen, *Senno Verhoef, *Ans v.d. Ouwe- trance. We studied 48 members of four generations. To prevent land, *Dick Lindhout, *Dicky Halley, and the *t$$European misdiagnosis, closed-circuit TV-EEG was used to validate myo- Chromosome 16 TSC Consortium (*Department of Clinical Ge- clonias during rapid multispike wave complexes in the proband netics, Erasmus University and University Hospital, Rotterdam, and 3.5- to 6-Hz multispike wave complexes in affected mem- The Netherlands; ?Institute of Medical Genetics, University of bers. EEGs documented the normal states of clinically unaf- Wales College of Medicine, Cardiff, Wales; $MRC Molecular fected members and persons who married into the family. Five Haematology Unit, Institute of Molecular Medicine, John Rad- family members had JME and 4 clinical asymptomatic females cliffe Hospital, Oxford, England; and $Institute Human Genet- had epileptogenic diffuse 3.5-6-Hz multispike wave complexes ics, Leiden University, Leiden, The Netherlands)-2000d. in their EEGs. One female had transient neonatal convulsions from age 5 days to age 6 months; she has EEG epileptiform but Tuberous sclerosis (TSC) is an autosomal dominant multisys- nonspecific irregular spike-slow wave formations. Linkage anal- tem disorder, characterized by widespread development of ha- ysis with 146 short tandem repeat polymorphisms distributed martomata. Seizures occur in >80% of patients. Other common across the autosomal genome with an autosomal dominant mode symptoms include hypopigmented skin macules, facial angiofi- of inheritance with 70% penetrance classified clinically symp- bromas, ungual fibromas, and mental retardation. TSC is genet- tomatic and asymptomatic family members with epileptogenic ically heterogeneous, with one locus closely linked to the ABO EEG multispike wave complexes and epileptiform EEG multi- blood group locus on chromosome 9 and a second locus on chro- spike slow wave formations as affected and mapped the epilepsy- mosome 16.

Epilepsiu, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 9

Using pulsed field gel electrophoresis (PFGE), we recently “petit mal” status, and juvenile absences. Patients with CAE identified five TSC-associated deletions in a 120-kilobase (kb) were divided into two groups according to the presence of gen- region of 16~13.3from which four candidate genes were isolated. eralized tonic-clonic (GTC) seizures after psycholeptic absences. One gene (designated TSC2) was interrupted by all five PFGE The group with GTC seizures had a lesser degree of other famil- deletions, and closer examination showed several intragenic mu- ial cases, worse prognosis, and a greater number of patients with tations. The 5.5-kb TSC2 transcript is expressed in a wide range abnormal neurologic or intellectual status. Rigid exclusion crite- of tissues, and its protein product (designated tuberin) has a ria (photosensitivity, intellectual deficits, bad response to ther- region of homology to the Rap1 activator Rapl-GAP. A pre- apy, and persistence of abnormal EEG trait) limits the entire sumed function of tuberin in the Rap1 signaling pathway is in series to only 20 cases with present homogeneous clinical char- agreement with its proposed function as a tumor suppressor acteristics that diverge in part from the literature on CAE: a very gene. Since isolation of the gene, we have focused on construc- high prevalence in females (80%), high numbers of affected fam- tion of a full-length cDNA clone and generation of antibodies ily members (43%), seizure onset at age 6 years, and low fre- against fusion proteins and synthetic peptides. These will be quency of subsequent febrile convulsions (12%) and GTC (6%), used in studies of cellular localization, tissue distribution, and very good response to therapy, and subsequently normal EEG. (normal) function of tuberin. The cases of familial CAE that fulfill the same rigid criteria col- A clinical implication of our finding concerns molecular diag- lected in the multigenerational families of the Italian League nostics. About 50% of all patients have a TSC2 gene defect. Against Epilepsy databank show the same characteristics. Such More than 10% of these mutations can be detected with PFGE a form of epilepsy may therefore be considered the “pure” syn- and Southern analysis. We intend to improve this score by using dromic form of CAE. other techniques, such as RT-PCR, SSCP, and protein trunca- tion tests. In large TSCl and TSC2 families, diagnostics by linkage analysis of flanking markers can be obtained. Furthermore, we attempt to improve treatment of the disease by offering better Childhood Absence Epilepsy with Eyelid Myoclonia: A Syndromic understanding of the molecular cause. Subform. Amedeo Bianchi, *Giuliano Avanzini, *Simona Binelli, tDaniela Buti, Graziano Buzzi, $Carlo Cianchetti, OPasquale De Marco, ‘IPaola Giovanardi-Rossi, and $Dario Pruna (U.O. Neu- rologia Ospedale, Arezzo, *Milano, tFirenze, Kogliari, STrento, and llBologna,Italy)-2003. Platform Presentation 1 (2001-2006) Eyelid myoclonia with absences, described by P.M. Jeavons in 1977, are a form of seizures characterized by eyelid myoclonia with upward deviation of eyes and absences, with an EEG pat- Benign Infantile Familial Convulsions: Clinical Aspects. F. tern of spike-wave specifically activated by eye closure. This Vigevano, L. Fusco, M. Di Capua, S. Ricci, R. Sebastianelli, *P. seizure type may have an autonomous clinical character, may be Lucchini, tB. Dordi, $A. Chindemi, 10. Dulac, and IIA. associated with other forms of epilepsy, or may be a clinical Malafosse (Section of Neurophysiology , Children’s Hospital variant of photosensitivity. Bambino Gesu, Rome; *Treviso; tBolzano; $Bari, Italy; $Paris In the databank of families and twins of the Multicentric Study and I1Montpellier, France)-2001. of the Italian League against Epilepsy, we singled out 3 pairs of monozygotic twins with such a specific form and 3 families with In 1992, Vigevano et al. (Eur J Pediatr 1992;151:608-12), re- several cases of idiopathic epilepsy with the proband affected by ported 5 infants with an undescribed form of epileptic disorder this syndrome. Clinical characteristics of these caSes and of a characterized by partial seizures, onset between 4 and 7 months further series of 8 sporadic cases appear to be homogeneous with of age, no etiologic factors, normal psychomotor development, regard to seizure onset, clinical and prognostic outcome, and benign course, normal interictal EEGs, and family history of therapy. Analysis of the cases in families with other affected seizures with similar age of onset and course. They termed the members showed concordance for clinical form that is different disorder benign infantile familial convulsions (BIFC). and autonomous as compared with the other Italian families with In a multicenter study, we have now collected data on 17 a proband with childhood absences. Childhood absence epilepsy families: 15 Italian and 2 French. Thirty-one of first- and second- with eyelid myoclonia, in particular because of the important degree relatives exhibited BIFC. Seizures occurred in clusters in finding of three monozygotic twins, is an autonomous syndromic 16 patients. The most frequently reported semeiology was psy- subform of epilepsy and represents a useful model for molecular chomotor arrest, cyanosis, head-eye deviation to one variable genetic studies. side, tonic contraction, and bilateral clonic jerks. Interictal EEGs were normal. Ictal EEGs (available in 8 patients) were characterized by fast activity in the occipital and parietal areas of one hemisphere with subsequent involvement of the other side. Angelman Syndrome: Evolution of Epilepsy and EEG Findings. Follow-up data confirmed the benign course of this disorder. L. A. F. M. Laan, *W. F. M. Arts, tI. M. Buntinx, tH. Clinical and EEG features, together with the first results of ge- Stroink, $P. J. Willems, and 0. F. Brouwer (Department of netic study, suggest BIFC to be an epileptic disorder distinct Neurology, Division of Child Neurology, University Hospital, from benign neonatal familial convulsions. We believe that BIFC Leiden; *Department of Neurology, Westeinde Hospital, The is a new epileptic syndrome that should be included among the Hague, The Netherlands; ?Department of Medical Genetics, idiopathic forms. University of Antwerp, Antwerp, Belgium; and $Department of Neurology, University Hospital of Rotterdam, Rotterdam, The Netherlands)-2004

Childhood Absence Epilepsy: An Analysis of the “Pure” Syndromic Angelman syndrome (AS) is characterized by severe mental Subform. Amedeo Bianchi, Alessandro Tiezzi, Graziano Buzzi, retardation, lack of speech, inappropriate laughter, a wide-based Sauro Severi, and Paolo Zolo (Centro Epilessia, U.O. Neurolo- ataxic gait, dysmorphic facial features, and epileptic seizures. gia, Ospedale Arezzo, Arezzo, Italy)-2002. More than 60% of cases show deletion of chromosome 15q. Ep- ileptic seizures and specific EEG features in AS patients have Characterization of syndromic subforms within the idiopathic frequently been reported, but little is known about evolution of epilepsies is one of the fundamental fields of clinical genetic seizures and EEG findings. research. We studied a first series of 50 cases in childhood ab- We studied retrospectively the seizure types and EEGs of 18 sence epilepsy (CAE), excluding from the largest group of the AS patients with proven 15q deletion (10 males, 8 females) aged epilepsies with absences those absences with eyelid myoclonia, 2.5-39 years (mean 13.2 years). Follow-up ranged from 2 to 37

Epilepsia, Vol. 35, Suppl. 7, 1994 10 EUROPEAN CONGRESS PROCEEDINGS years (mean 11.4 years). Epileptic seizures occurred in 15 pa- High-voltage slow burst (HVSB) in the EEG was evident be- tients. Age at seizure onset varied from 5 months to 5 years. fore age 10 years in 12 patients; in 4 patients, it remained evident Most common initial seizure types were atypical absences (lo), until age 20 years, and in 1 patient was still apparent at age 29 tonic-clonic seizures (4), and myoclonic seizures (I). Six patients years. HVSB voltages were 60-150 pV rather than >200 pV. In still have epileptic seizures after age 10 years (atypical absences, 4 patients, EEGs never showed typical HVSB. With age, more myoclonic seizures). The most effective drug was valproate, diffuse and generalized spike-wave abnormalities appeared, but sometimes in combination with clonazepam. The most typical after age 10 years epileptic activity decreased in most patients. EEG pattern was almost continuously rhythmic triphasic 2- to 3-Hz delta activity of high amplitude (200-500 pV), mixed with spikes or sharp waves with a maximum over the frontal regions, and detected in 13 patients, all of whom had epileptic seizures; this is accordance with the findings of Boyd et al. (Eur J Pedialr Platform Presentation 2 (2007-20 12) I988 ;147508-1 3).

EEG Topographic Mapping in Angelman Syndrome. M. Elia, Misleading Aspects of the First Standard EEG in Juvenile Myo- S. A. Musumeci, R. Ferri, S. Del Gracco, C. Scuderi, and B. clonic Epilepsy. Maria de Socorro Gonzales, Pierre Genton, Dalla Bernardina (Oasi Institute, Troina, Italy)-2005. Michelle Bureau, Charlotte Dravet, and Amaha Saltarelli (Cen- tre Saint-Paul, Marseille, France)-2007. Angelman’s syndrome (AS) is characterized by dysmorphic facial features, profound mental retardation, speech delay, par- In genetic studies, atypical clinical or EEG presentations may oxysms of laughter, ataxic gait with jerky movements, and epi- complicate screening for juvenile myoclonic epilepsy (JME) pa- leptic seizures. A de novo 15q12 deletion of maternal origin is tients. Specific EEG markers are bursts of 3-5-Hz spike and detected in 60% of patients. EEG findings in AS have already wave or polyspike and wave (SW, PSW). To assess the sensi- been reported by many authors investigators. Recently, a pecu- tivity and specificity of EEG, we retrospectively evaluated the liar electroclinical pattern was described, characterized by un- first EEG performed in 56 consecutive JME patients first re- usual spike-and-wave (s-w) discharges, frequently diffuse and ferred between 1986 and I992 (26 males and 30 females aged correlated with subcontinuous mostly erratic myoclonias, remi- 12-53 years, mean 24.4 years) with onset at age 3-33 years (mean niscent of “myoclonic status” [Epilepsia 1993;34(suppl 2):71]. 14.3 years). The diagnosis was often confirmed only during fol- We analyzed the EEG spectral and topographic characteristics low-up. Standard EEG was recorded with at least 12 leads for 20 of the s-w discharges in AS. Eight subjects with AS (2 males and min and included hyperventilation (HV) and intermittent light 6 females) aged 4.58-20.17 years were admitted to the study. The stimulation (ILS). The first standard EEG was normal in 15 cases EEG was acquired by a Neuroscan system from 19 scalp elec- (27%), showing aspecific or misleading changes in 16 cases (28%) trodes referred to linked ears, using the International 10-20 sys- and typical changes in only 25 (45%). Baseline EEG was normal tem. In all but 1 subject, we were able to obtain the power in 25 (45%), atypical in II (20%), and typical of JME in only 20 spectra of at least ten 4-s artifact-free epochs of EEG containing (35%). HV and ILS yielded 37 and 39 normal, 10 and 7 aspecific, s-w discharges. In all subjects, s-w bursts were also analyzed by and 9 and 10 specific findings, respectively. A single standard serial topographic mapping of the amplitude of the paroxysms. EEG is inconclusive or misleading for diagnosis of JME in >50% The main peak of the power spectra of discharges always oc- of newly referred patients, and a single standard EEG will most curred -2-3 Hz. Field distribution of such paroxysmal activity probably be insufficient for reliable screening of clinically unaf- showed a maximum over the midline (Fz, Cz, or Pz) if both the fected relatives. spectral analysis and that of the potential amplitude are considered. This field distribution appears to indicate the activity of a radially oriented dipole. The interictal epileptiform abnormalities were often lateralized and showed focal distribution. Generally, Family Studies in Idiopathic Generalized Epilepsies. U. Sailer, *B. no changes occurred in field distribution of s-w activity during Schmitz, *T. Sander, ?G. Beck-Mannagetta, G. Bauer, and tD. the bursts. These findings appear to suggest a role (also in the Jam (Universitatsklinik fur Neurologie, Innsbruck, Austria; and electroclinical pattern of AS) of reverberating corticosubcortical *Departments of Psychiatry and tNeurology, Klinikum Rudolf circuits similar to those proposed for 3-Hz s-w activity during Virchow, Berlin, Germany)-2008. absences. Idiopathic generalized epilepsies with onset in childhood or adolescence display significant overlap of both clinical symp- Epilepsy in Angelman Syndrome. W. 0. Renier, C. J. A. M. van toms and EEG findings. The etiology of these syndromes most der Buret, and F. B. T. Zegers (University Hospital Nijmagen, likely is genetic, and a close linkage to a gene on the short arm of Nijmagen, The Netherlands)-2006. chromosome 6 could be established for juvenile myoclonic epilepsy. Findings from linkage studies have been equivocal, how- Type of seizures, onset, and evolution of epilepsy and EEG ever, and there is sufficient evidence for heterogeneity. To make abnormalities were examined retrospectively in 17 patients (10 molecular genetic research more efficient in identifying other males and 7 females) with genetically proven Angelman syn- genes involved in expression of age-related epilepsies differenti- drome (AS). Except for 1 boy aged 5 years, all patients had ating families on the basis of specific clusters of clinical symp- epilepsy. Mean age at onset of epilepsy was 33 months (11-55 toms and EEG criteria appears promising. months). Fourteen patients had atypical absences; in 7 patients We analyze clinical and EEG data from 60 multiplex families. these were the only type of seizures. Seven patients had one or We included probands with a definite diagnosis of childhood more episodes of status epilepticus (SE), mostly absence status. absence epilepsy, juvenile absence epilepsy (n = 30), or juvenile Other seizure types were myoclonic, partial, tonic-clonic and, in myoclonic epilepsy (n = 30) with at least one first-degree rela- 4 cases, febrile convulsions. After age 10 years, 8 of 11 children tive with nonsymptomatic, nonfebrile seizures. We aim to iden- manifested a decrease in seizure frequency. Five patients are tify familial clusters of clinical symptoms such as age of onset, seizure-free for >5 years. Only 3 patients have difficult-to-treat seizure types, and seizure combinations in relation to EEG fea- epilepsy, in 1 patient possibly due to more than one genetic tures such as different sw patterns and photosensitivity. Results defect. are and discussed with reference to the background of actual Twelve patients were initially treated with valproate (VPA); 7 etiologic concepts for the group of idiopathic generalized epilep- still are, 2 of whom are seizure-free. Eight patients received sies, with special emphasis on possible implications for strategies phenobarbital (PB); 6 still do, 2 of whom are seizure-free. in molecular genetic research.

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 11

Juvenile Myoclonic Epilepsy: Segregation Analysis in 28 Families 1993;1:99-110 in the probands of 30 families with juvenile myo- from Mexico City and LAIBelize. Sergio Cordova, Ma Elisa clonic epilepsy (JME) and 25 with childhood absence epilepsy Alonso, *$$Marc0 T. Medina, *t$Antonio V. Delgado-Escueta, (CAE). Genomic DNA was extracted from white blood cells. Francisco Rubio-Donnadieu, Jaime Ramos-Peek, *tManyee Overlapping primers were designed to amplify fragments of the Gee, *?$Joan Spellman, and *t$JosC M. Serratosa (National In- genes sequentially by polymerase chain reaction. Amplification stitute of Neurology and Neurosurgery, Mexico City, Mexico; products were screened using dideoxy sequencing, single- *California Comprehensive Epilepsy Program; tNeurology and stranded conformational polymorphism (SSCP), and heterodu- Research Service, VAMC, West Los Angeles; $Department of plex analysis. Neurology, UCLA, CA, U.S.A.; and $National Autonomous A base substitution in HBK2 of possible functional signifi- University, Tegucigalpa, Honduras)-2009. cance was detected in 1 family segregating for JME. Analysis of DRKl continues. Advances in molecular neurobiology and Segregation analysis of 55 Caucasoid Juvenile Myoclonic Ep- methods for mutational analysis have rendered candidate gene ilepsy (JME) Los Angeles (LA) families favored an incompletely analysis a feasible and powerful approach to investigation of the penetrant autosomal dominant model but could not reject a fully genetic basis of epilepsy. penetrant recessive model. Therefore, we studied 28 Spanish Mestizo families; 27 from Mexico City and 1 from LA/Belize. Families were ascertained through a proband with JME (13 males and 15 females). Twenty-five Mexico City families were HLA in Severe Epilepsy and Response to Intravenous Immunoglo- classified as “normal by normal” matings. Eight of 9 affected bin Treatment. K. van Rijckevorsel-Harmant and M. Delire sibs were males; 6 of 9 sibs had JME, 2 had tonic-clonic and (Centre Neurologique William Lennox, Ottignies, Belgium)- another had early childhood tonic-clonic epilepsies. For normal 2012. by normal watings, estimated segregation ratio (p) was 0.069 (SE 0.022), and for “normal by affected” matings, p = 0.1538 (SE The hypothesis that some aberrant immune function could be 0.100). In 2 sibships of the LAiBelize family, p = 0.38 (SE 0.171) involved in the etiopathogenesis of particular epileptic syn- for one normal by normal mating and p = 0.43 (SE 0.187) for one dromes is regularly evoked and still controversial. Sixty-six pa- normal by affected mating. Because 35 additional nonnuclear tients with intractable epilepsy (most of them with cryptogenic family members of the Mexico City families have epilepsy, our partial epilepsy) were analyzed for HLA, A, B, and C and 55 and preliminary results suggest that genetic factors that do not use HLA-DR groups and were compared with a control group. We Mendelian modes of inheritance best fit JME in Mexico City. An noted a decrease in HLA DR5 in epileptic patients (7.2%). The autosomal dominant form of JME with 7545% penetrance best patients were treated with intravenous immunoglobulins (IVIG) fits the LA/Belize family. (Supported in part by NIH Grant No. (Adv Epileptol 1989; 17:336-9; Infektionen und Autoim- NS21908.) rnunerkrankungen: Neue Therapeutische Ansatze mit Immun- glohulinen und deren Derivaten. Frankfurt; Verlag, 1991;8&94). For 30 patients, we compared HLA groups between responders (R, 18 patients) and nonresponders (nR, 12 patients) to IVIG Chromosome 4 Anomalies and Epilepsy. Helmut Fichsel and Bet- treatment. A2 was detected in 50% of R and 25% of nR, A28 in tina Sandgathe (Department of Neuropediatrics, University Chil- 5.5% of R and 41.6% of nR, and B7 in 16.670 of R and 50% of nR. drens Hospital Bonn, Bonn, Germdny)-2010. No R patients, but 25% of patients showed DR6. These findings provide support to the hypothesis that immunogenetic mecha- With respect to the role of genetic determination in occurrence nisms may play an active role in progression of determined ep- of epilepsies, chromosome anomalies allow us to determine in- ilepsies and in their responsiveness to immunomodulating treat- volved genetic areas. We analyzed data of 69 patients with anom- ments. alies of chromosome 4 from the world literature and our own observations. The frequency of epilepsies is very low in patients with ring 4 chromosome (in our series, 0%); moderate in patients with 4 q deletion, 4 q, and 4 p trisomies (20-38%); high (>SO%) in 4 q interstitial deletion and 4 p deletion; -90% in 4 p deletion; and Poster Session (2013-2031) nearly 100% in proximal 4 p deletion syndrome, if chromosome bands 4 p to 15.2-15.5 are involved. Chromosome area 4 p 15.2- 15.5 apparently plays an important role in the manifestation of epilepsies. Severe Myoclonic Epilepsy of Infancy Does Not Share the Haplo- type Segregating with Juvenile Myoclonic Epilepsy in a Large Ped- igree. *Jose M. Serratosa, *Antonio V Delgado-Escueta, *fMarco T. Medina, *Quanwei Zhang, and $Robert S. Sparkes Genetic Analysis of Voltage-Gated Potassium Channels in Patients (*California Comprehensive Epilepsy Program, UCLA and West with Idiopathic Generalized Epilepsy. Frances Elmslie, Michele Los Angeles VAMC, Los Angeles, CA, U.S.A.; tuniversidad Rees, *Olaf Pongs, ?William Whitehouse, SAnders Sundqvist, Aut6noma Nacional de Honduras, Tegucigalpa, Honduras; and and Mark Gardiner (University College London, London, En- $Division of Medical Genetics, UCLA School of Medicine. Los gland; *Zentrum fur Molekular Neurobiologie, Hamburg, Ger- Angeles, CA, U.S.A.)-2013. many; ?Birmingham Children’s Hospital, Birmingham, England; and $Sodersjvhuset, Stockholm, Sweden)-201 1. A member of an extended Los Angeles-Belize pedigree (family J-1) multiply affected with juvenile myoclonic epilepsy (JME) or Candidate gene analysis represents one approach to determin- the 3.5-6-Hz diffuse polyspike-wave EEG trait presented severe ing the molecular genetic basis of human idiopathic generalized myoclonic epilepsy of infancy (SMEI) as described by Dravet et epilepsies. Voltage-gated potassium channels play a central role al. in 1982. Linkage analysis restricted to 33 members of the G in controlling neuronal excitability and are therefore an impor- branch (6 clinically affected, 4 EEG affected) showed tight link- tant class of candidate gene for epilepsy. Candidate genes can be age to microsatellite markers centromeric to HLA in chromo- analyzed to detect a variation affecting protein structure or ex- some 6p. Maximum lod scores of 3.8 at 8 = 0.00 were obtained pression (VAPSE) (Genomics 1992;12: 1-6). for D6S272 and D6S257 in the 6~21.1-11 region (autosomal dom- We investigated the human brain voltage-gated potassium inant model with 70% penetrance). When a member of the G channel gene HBK2 EMBO J 1990;9:1749-56 and the delayed branch with neonatal convulsions was considered affected, lod rectifier potassium channel gene DRKl Receptors Channels scores for D6S272 and D6S257 increased to 4.0 at 8 = 0.00.

Epilepsia, VoL 35, Suppt. 7, 1994 12 EUROPEAN CONGRESS PROCEEDINGS

Recombinant events in one affected and 2 unaffected members Direct DNA Diagnosis in Juvenile Huntington's Chorea with Epi- reduced the EJMl region to an area spanned by D6S269, lepsy. Jorg Klepper, Hans-Michael StraRburg, and *R. Spiegel D6S272, D6S294, and D6S257. The haplotype segregating with (Universitats-Kinderklinik Wiirzburg, Germany; and *Genetis- EJMl was not present in the only epilepsy (SME1)-affected ches Institut der Universitat Zurich, Zurich, Switzerland)-2016. member of another 39-member branch (C branch), suggesting that the SMEI phenotype does not represent an allelic form of The genetic mutation underlying Huntington's disease (HD) the EJMl gene in this pedigree. (Supported in part by NIH Grant has been identified as expansion and instability of a specific No. NS21908.) CAG-repeat sequence in a gene (IT15) on chromosome 4. We describe a 12-year-old boy with symptoms ofjuvenile HD at age 5 years and onset of epilepsy with complex focal and secondarily Phenotypic Variability of Idiopathic Generalized Epilepsies in Ju- generalized tonic-clonic convulsions and myocloni at age 10 venile Myoclonic Epilepsy Families. Dieter Janz, Gertrud Beck- years. Mannagetta, *Thomas Sander, and ?Thomas Hildmann (Neurol- EEG showed theta-delta pattern and irregular spike-wave par- ogische Klinik and *Psychiatrische Klinik, THumangenetisches oxysms. With valproate, carbamazepine, sulthiame, and addi- lnstitut der Freien Universitat Berlin, Berlin, Germany)-2014. tional neuroleptic drugs, good control of seizures was achieved. Vigabatrin had only temporary effect. Is it possible that the clinical variance in juvenile myoclonic By direct DNA analysis with polymerase chain reaction, we epilepsy (JME) reflects different genetic mechanisms? To at- detected an extremely high number of CAG-trinucleotide- tempt to answer this question, we correlated the phenotypic vari- repeats (89-101) on the Huntington gene of our patient (normal ability in families of JME probands to criteria for homologous population 11-34). We proved that the gene was paternally trans- and heterologous transmission. We compared the occurrence of mitted, as described in 91% of cases ofjuvenile HD. This may be clinical signs with positive or negative family lod scores for link- a molecular-biologic explanation of onset and severity of HD. age with the EJM 1 locus. The study comprises 25 pedigrees. Similar links between neurologic diseases presenting with epi- From 108 relatives, clinical data including EEG recordings were lepsy and high trinucleotide-repeats have been described in the available. In 11 families, I additional family member in 8 families fragile X syndrome and in hereditary dentatorubral-pallido- 2 members, in 2 families 4 members, and in 1 family each 5 and luysian atrophy. 6 affected family members had an epileptic manifestation. In clinical genetic as well as molecular genetic aspects, some factors may with great caution be described as favoring linkage Exclusion of Linkage Between D20S19 and Idiopathic Generalized with the EJM 1 locus and some as not favoring linkage. Linkage Epilepsies in Families of Patients with Juvenile Myoclonic Epi- is promoted by large family size and several affected relatives, lepsy. *tT. Sander, tT. Hildman, tD. Janz, OL. A. Sandkuijl, when other close family members show JME as well, and pre- SH. Neitzel, tB. Schmitz, TG. Beck-Mannagetta, and "K. sumably by the additional occurrence of absence epilepsies in Johnson (*Departments of Psychiatry, ?Neurology, and $Human the family. A history of febrile convulsions and detection of sub- Genetics, UKRV, Freie Universitat Berlin, Germany; §Depart- clinical spike and wave discharges also appears to support link- ment of Clinical Genetics, Erasmus University, Rotterdam, The age. The less frequent observation of linkage in simplex families Netherlands; and I'Department of Anatomy, Charing Cross and may be conclusive because of the small family size. Other genes Westminster Medical School, London, England)-2017. may interact in the occurrence of photosensitivity and be responsible for genetic heterogeneity in JME with photosensitivity. Two previous linkage studies of families ascertained through patients with juvenile myoclonic epilepsy (JME families) localized on chromosome 6p21.3 a susceptibility locus predisposing Exclusion of Linkage Between Idiopathic Generalized Epilepsies to idiopathic generalized epilepsies (IGEs) (Epilepsia 1993;34 and HLA Restriction Fragment Length Polymorphism Markers in (suppl3):12-18; Neurology 1991;41:1651-5). However, evidence Families of Patients with Idiopathic Absence Epilepsies. *tT. for a complex inheritance and genetic heterogeneity of the com- Sander, $T. Hildmann, tD. Janz, TL. A. Sandkuijl, $H. Neitzel, mon lGEs suggests that more than one genetic locus contributes "A. Bianchi, §G. Bauer, PU. Sailer, 5K. Berek, tB. Schmitz, and to expression of IGEs in JME families. (Epilepsia 1994;35(suppl tG. Beck-Mannagetta (*Departments of Psychiatry, tNeurol- 1):29-40). An interesting candidate region for the presumed ad- ogy, and $Human Genetics, UKRV, Freie Universitat Berlin; ditional locus is that identified on chromosome 20q13.2 by tight §Department of Neurology, University of Innsbruck, Austria; linkage to D20S19, which strongly predisposes to the dominantly I'Genetic Collaborative Group of the Italian LEA; lIDepartment inherited benign neonatal familial convulsions and to human low- of Clinical Genetics, Erasmus University, Rotterdam, The Neth- voltage EEG (Epilepsia 35(suppl 1):2940; Nature 1989;337:647- erlands, and #VT. Sander, Psychiatric Klinik, UKRV, Berlin, 8; Genomics 1992;12:69-73). Germany)-20 15. In the present linkage study of 26 JME families (160 individuals) we determined whether this region on chromosome 20 con- Previous linkage studies of families ascertained through pa- tributes to expression of the common IGEs. Our results excluded tients with juvenile myoclonic epilepsy (JME) suggest that an linkage (lod score < - 2) between D20S19 and two IGE pheno- HLA-linked susceptibility gene on chromosome 6p, designated type models (model 1, IGEs, model 2, IGEs or bilateral synchro- EJMl , predisposes to a group of idiopathic generalized epilep- nous spike and wave discharges in the EEG) for recombination sies (IGEs) consisting of JME, absence epilepsies, and epilepsies frequencies ~2.5-14%under an autosomal dominant or autoso- with generalized tonic-clonic seizures. [Greenberg DA, Delgado- ma1 recessive mode of inheritance with reduced penetrance. Escueta AV. Epilepsia 1993;34(suppl 3):12-8; Neurology 1991; Therefore, we conclude that this candidate region on chromo- 41:1651-51. To evaluate the phenotypic spectrum of EJMl, we some 20 does not contribute to the complex inheritance of the performed linkage studies in 28 families with 234 individuals as- common IGEs in these JME families. certained by an index-case with childhood or juvenile absence epilepsy. Our analyses excluded linkage between two IGE phenotype models (model 1; IGEs; model 2, IGEs or bilateral synchronous spike and wave discharges on EEG) and restriction Ring Chromosome 18 in a Large Pedigree with Dysmorphic Fea- fragment length polymorphisms at the HLA-DQa locus on chro- tures and Epileptic Seizures. Maria Petridou and Aristidis Kazis mosome 6p. Lod scores < - 2 were obtained for recombination (Thessaloniki, Greece)-2018. frequencies c12% under both an autosomal dominant and an autosomal recessive mode of inheritance with reduced pene- Epileptic seizures may be included in well-known genetic syn- trance. These findings do not support evidence showing that dromes, some of them often associated with dysmorphic fea- EJMl participates in expression of a wider spectrum of IGEs. tures. We report a family with 6 affected persons (4 men and 2

Epilepsiu, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 13 women aged 42-57 years) who had dysmorphic characteristics, pairment and poor response to antiepileptic therapies. There- mental retardation, and generalized seizures. The proband, a fore, a more specific etiologic treatment is recommended. 52-year-old man, had macrocephaly, flat occiput, low-set ears, hypertelorism, macryglossia, dysarthria, long fingers, cryptor- chidism, sinus venosus, and mental retardation. He presented to us with status epilepticus and had had epilepsy since age 5 years. Epilepsy and fra(X)-Syndrome. Gerhard Kluger, Michael C. He has been an alcoholic since adolescence. His sibs (3 brothers Laub, and *Ingolf Borm (Neuropediatric Department, Behand- and 2 sisters) showed the same dysmorphic characteristics; all lungszentrum Vogtareuth, Vogtareuth; and *Labor Dr . Walde- them had had epilepsy and mental retardation since childhood. maier, Munich, Germany)-2021. Four of 5 sibs had sinus venosus. Alcoholism was a common feature in all, although none of the healthy members of the ped- Benign partial epilepsies of childhood, either typical or atypi- igree was an alcoholic. Computed tomography brain scans, rou- cal, are distinct epileptic entities with specific EEG abnormali- tine biochemical analysis, and endocrine analysis were normal. ties. Similar EEG findings are reported in patients with fra(X)- Karyotype analysis in the affected persons showed a ring chro- syndrome. We speculated that fra(X)-syndrome may be the un- mosome 18. We report this pedigree as a case of ring chromo- derlying disorder in at least some patients with this type of some 18, which does not include the typical dysmorphic features epilepsy. described in the literature, and which also was accompanied by We report 7 boys with fra(X)-syndrome and 2 of their sisters tonic-clonic seizures and alcoholism. with premutation status. In addition, we report molecular genetic findings regarding fra(X)-syndrome in 10 children with rolandic epilepsy and 6 children with atypical benign partial epilepsy. All 7 children with fra(X)-syndrome had focal centrotemporal or oc- Eyelid Myoclonia with Absence. Athanasios Covanis, Kostas Ski- cipital sharp waves, activated to discontinuous status during adas, Nomiki Loli, Andriani Ioannidou, Chris Lada, and Virginia sleep, but only from age 4 to 8 years. Two of their sisters with no Theodorou (Department of Neurology, The Children’s Hospital, clinical symptoms but with a premutation status with regarding “Agia Sofia,” Athens, Greece-2019. to fra(X) have short clusters of generalized spike waves. In all but 1 child with benign partial epilepsy, including atypical cases, Eyelid myclonia with absence (ELMA) has characteristic clin- neither fra(X)-syndrome nor premulation status could be de- ical features. Therapy is particularly difficult (Dev. Med. Child tected. Neurol. 1977;19:3-8; Epilepsia 1982;23:693-710). We report 25 Although EEG findings in children with fra(X)-syndrome and patients with ELMA or tonic clonic seizures. Eyelid jerking was in patients with benign partial epilepsy show striking similarities, obvious during clinical or EEG assessment. Age of onset was we noted no significant correlation to the molecular genetic 3-12.5 years. The ratio of females to males was 3.2:l. All pa- cause of the fra(X)-syndrome, including premutation status. On tients exhibited eyelid jerking, particularly on eye closure. the other hand, still-unknown proteins coded by fra(X)-gene may Twenty percent had myoclonic jerks, and 56% had tonic-clonic influence the disposition to epilepsy. seizures. Family history was positive for epilepsy in 24%. Spike polyspike-wave discharges and photosensitivity were detected in all patients, usually on eye closure. Monotherapy with valproate was successful in 14, of whom 7 discontinued treatment after a Spinal Muscular Atrophy and Bilateral Pachygyria: A Case Report. mean 5 f 1.3 years of treatment years; all relapsed. Three pa- P. Veggiotti, F. Beccaria, A. Berardinelli, L. Farinotti, F. Fazzi, tients who were not controlled with valproate responded to lam- and C. Resi (Divisione NPI, Fondazione “C. Mondino,” Pavia, otrigine. Italy)-2022. ELMA is a separate syndrome and should be included in the International Classification. Lamotrigine is a useful drug in myo- Syndromes characterized by association between neuronal mi- clonic seizures with or without photosensitivity. Prognosis of gration disorders and muscle involvement are well described in ELMA is similar to that of juvenile myoclonic epilepsy. the literature, but we found no reports of the relation between disorder of migration and spinal muscular atrophy. We report the clinical history of a 13-month-old child with epilepsy, development delay, and marked generalized muscular hypotonia. Brain Melas and Epilepsy: EEG Patterns and Therapeutic Considerations magnetic resonance imaging showed bilateral, frontoparietotem- in Three Cases. Marco Guidi, Osvaldo Scarpino, Giuseppe Pel- poral pachygyria. Electromyogram and muscle biopsy showed liccioni, Tommaso Rossi, and Maurizio Del Gobbo (Unit& di spinal muscular atrophy. Some EEG records documented differ- Neurologia, I.N.R.C.A., Ancona, ItaIy)-2020. ent seizure types (spasms and partial and tonic seizures) and status epilepticus with erratic myoclonus. We report this case We describe the EEG abnormalities in 3 subjects with MELAS because of its peculiarity and its clinical and nosographic inter- syndrome, the usefulness of EEG in monitoring the course of the est. (Brain and Dev 1991;13:1-8; Brain Dev 1993;15:242-4). disease, and therapeutic efficacy. In the first patient, during acute symptoms characterized by confusional state, cortical blindness, focal neurologic deficits, cognitive impairment, and myoclonic jerks, the EEG showed a periodic epileptic pattern of Bone Marrow Ultrastructure and Early Diagnosis Orientation in diffuse and synchronous diphasic sharp waves occurring at in- Neuronal Ceroid-Lipofuscinoses. Louis Vallee, *Marc Zandecki, tervals of 1-1.5 s. His clinical condition improved slowly, and tAnne Janin, *Martine Fournier, Jean-Christophe Cuvellier, EEG abnormalities changed in both morphology and recurrence $Jacques Motte, Jean-Pierre Nuyts, and Joseph Vamecq (The after the positive clinical evolution. North France Center for the Study of Childhood Epilepsy, Neu- The second and third patients had a quite similar course and rologie Infantile, HBpital B; *Laboratoire d’Hkmatologie A, and differ only in the severity of neurologic impairment. Both have tLaboratoire d’Anatomopathologie, Hspital Calmette, CHRU partial sensitive or complex seizures evolving at times to gener- de Lille, Lille; and $Service de Pkdiatrie, Memorial Hospital, alized tonic-clonic convulsions. Both had EEG abnormalities CHRU de Reims, Reims, France)-2023. characterized by sequences of diffuse slow waves mixed with sharp waves increased by hyperventilation. Recent advances in understanding of neuronal ceroid- All 3 patients first underwent antiepileptic treatment with phe- lipofuscinosis (NCL) includes the discovery of lysosomal storage nobarbital and carbamazepine, which did not effect clear clinical of subunit c (lipid-binding subunit) of mitochondria1 ATP syn- improvement or EEG pattern modifications; more specific etio- thase and the proposal of a new class of lysosomal storage dis- logic therapy was then introduced, with better results. eases: the proteolipid proteinoses (J Biol Chem 1989;264:5736- Mitochondria1 alteration can explain the diffuse neuronal im- 40). For most laboratories, appropriate biochemical and amino

Epilepsia, Vol. 35, Suppl. 7, 1994 14 EUROPEAN CONGRESS PROCEEDINGS acid sequence determinations of this type of proteolipid are cur- in siblings of patients with idiopathic GTC seizures (one parox- rently not available. Therefore, morphologic examinations in pa- ysm every 53 s) than in those of patients with the symptomatic tients with NCL still represent an alternative and convenient type (one paroxysm every 229.3 s). Genetics also play a role in procedure for diagnosis orientation. We compared the respective symptomatic GTC, but the seizure threshold is higher than that contributions of blood, bone marrow (BM), and conjunctiva cell of idiopathic GTC. Although no exogenous factors are necessary morphology to diagnosis of NCL in a series of 9 patients with to activate seizures in the idiopathic type, they are required in NCL. Light microscopy examination failed to detect NCL in 4, the symptomatic type. whatever the tissue studied. Electron microscope detection of specific structures characteristically detected NCL (i.e., granu- lar osmophilic dense deposits, curvilinear and fingerprint pro- Risk Factors for Partial and Generalized Epilepsies. Pave1 Temin, files) was actually positive in 9 of 9, 7 of 9, and 6 of 9 patients; *Konstantin Muchin, and Marina Nikanorova (Institute of Pedi- cell sources were BM, circulating blood, and conjunctiva, re- atrics, *Russian Medical University, Moscow, Russia)-2026. spectively. In 30 patients with initial clinical features evocative of NCL Of 157 epileptic patients aged 4-40 24 years, 63 had partial but not diagnosed as having NCL (patients with either progres- epilepsies (PE) (37 temporal, 12 frontal, 10 occipital, 4 benign sive encephalopathy or myoclonic epilepsy), no lysosomal stor- focal with centrotemporal spikes) and 94 had generalized epilep- age specific to NCL could be detected in BM cells by morpho- sies (GE) (21 juvenile myoclonic, 16 juvenile absence, 29 child- logic light and electron microscope examinations. BM electron hood absence, 15 with tonic-clonic seizures on awakening, 13 microscopy is suitable for early diagnosis orientation in NCL. other). Personal perinatal antecedents, febrile convulsions (FC) in infancy, family history for epilepsy, and FC were analyzed. Perinatal pathology was noted in 79% of patients with PE and 38% with GE. Prematurity and pre- and neonatal anoxiaischemia Relation Between Electroclinical Signs and Genetic Factors in a were the most significant factors; 33% of patients with PE and Population of Persons with Epilepsy. J. B. A. Keating, M. San- 10.6% with GE had FC in infancy. A positive family history for tiago, M. Sampaio, J. F. Rente, L. Sousa, and 0. Costa (De- epilepsy was noted in 24% of patients with PE and in 21% with partment of Neurological Sciences, University Hospital, Coim- GE. The incidence of FC among relatives was higher in patients bra, Portugal)-2024. with PE and in 21% with GE. The incidence of FC among relatives was higher in patients with PE as compared with patients In 1,490 patients of both sexes from our epilepsy consultation with GE: 20 and 5%, respectively. A combination of these fac- data bank, we used age of onset per 5-year interval, age <15 tors may constitute the highest risk for epilepsy. years, EEG type, generalized or focal, crisis type, generalized versus partial onset, neurologic examination normal versus hemiparetic, and presence or absence of “cause” as selection Clinical Genetics of Epilepsy: Epidemiologic Aspects. Igor Mihael criteria fed into a computer to identify patients with and without Rdvnik, Bogdan Lorber, Darja Paro, and Borut Peterlin (Depart- a family history of epilepsy. Relatives considered were grand- ment of Child Neurology, Centre for Epilepsy, Ljubljana, Slo- parents, parents, sibs, and children. Criteria were used either venia)-2027. alone or in combination. Eight symptomatic groups were identified by crisis type, EEG type, and neurological examination; A retrospective epidemiologic study of pediatric and adoles- number and percentage of patients with a family history were cent epilepsies in the Ljubljana Health District, Slovenia yielded measured in each category. Effect of cause and age of onset < 15 a cumulative incidence of 4,58 in 1,000 (neonatal epilepsy and years were measured in each group. The group with generalized single epileptic and febrile seizures excluded). The investigators EEG and crisis, normal neurologic examination, and no cause reported 16.5% of patients to have a positive family history for had a significantly higher proportion of patients with a family epilepsy; 17.8% were symptomatic, and 1.9% shared a familial history as compared with group 1. Those with partial crisis, focal and an organic factor. An unusual difference among the admin- EEG, hemiparesis, and cause showed 42.85 versus 17.70%, the istrative subunits of the district was noted (cumulative incidence lowest percentage of all groups (p < 0.028). Percentage of pa- range 1,5-6,75 in 1,000, not quite reaching statistical signifi- tients compared with age of onset was remarkably constant cance). (20%) until the sixth decade. Genetic factors presents as a fea- For a genetic study with the intention of selecting familial ture of the epileptic mechanism itself were observed in a variety epilepsy pedigrees with two or more affected members, we made of conditions as well as in well-known genetic epilepsies. Focus- an inquiry, starting with the epidemiologic database; 122 medical ing attention on very selected homogeneous groups poses the files were reexamined, and seizures and epilepsies were classi- potential danger of detecting a marker of some characteristic of fied. During family sessions, histories were taken in detail again that group and not of the epileptic condition itself. and EEGs were performed. Of 20 planned families for 1994 5 family pedigrees had been studied as of February 1994 according to the methodology of the group for Concerted Action on Genetic Analysis of Epilepsy. We Contribution to the Genetics of Idiopathic and Symptomatic Gen- are now assessing methodologic issues stemming from the work eralized Tonic-Clonic Seizures. R. Degen and H.-E. Degen (Ep- on the project as well as geographic epidemiologic aspects. ilepsy Centre Bethel, Bielefeld, Germany)-2025.

Waking and sleep EEGs were recorded in 133 siblings of pa- Prospective Cohort Study of Pregnancy Outcome. E. Bettina Sam- tients with idiopathic and symptomatic generalized tonic-clonic rCn, Dick Lindhout, C. M. Van Duijn, B. Hofman, G. Beck- seizures (GTC). There was a difference in family history of sei- Mannagetta, S. Koch, D. Janz, A. W. Deichl, H. Klepel, E. zures in the two groups (43 vs. 22.9%). The same rate of epileptic Gailey, V. K. Hiilesmaa, M. L. Granstrom, and A. H. Bardy activity (EpA) was noted in siblings of patients with both seizure (Department of Clinical Genetics, University Hospital and De- types (42 vs. 41%). EpA was observed in waking or waking and partment of Epidemiology and Biostatistics, Erasmus Univer- sleep in 22 and 22.9% and during sleep only in 20% (idiopathic) sity, Rotterdam, The Netherlands)-2028. and 18.1% (symptomatic). The type of EpA also was almost the same: In 40% (idiopathic) and 38.6% (symptomatic) generalized Use of antiepileptic drugs (AEDs) during pregnancy increases spike-wave complexes were recorded, and in 2 and 2.4% benign the risk of major congenital malformations (MCA). However, the spike foci were noted. In addition, photosensitivity was noted in specific risks associated with specific drugs are unknown. To 4.8% of siblings of patients with symptomatic seizures. There quantify the risk of MCA due to AED use in pregnancy, a joint was a striking difference between the groups, however: Counting European reanalysis of prospective studies from Berlin (data col- of the single epileptic discharges showed considerably more EpA lected 1976-1984), Helsinki (1976-1979), Magdeburg (1979-

Epilepsiu, Vol. 35, Siippl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 15

1987), and Rotterdam (1972-1990) was performed. The analysis nance of the previous epilepsy pattern are the relevant results of is based on 1,220 AED-treated pregnancies and 158 control preg- our study, indicating the importance of planning each pregnancy nancies not exposed to AEDs and matched during pregnancy. so that antiepileptic polytherapy may be avoided, as well as the Analysis of the data from Berlin and Magdeburg shows a sig- benefits of paying careful attention to both epileptic women and nificant increase in risk of MCA for offspring of women using their fetuses during pregnancy. valproate (VPA) (RR = 4.8) or carbamazepine (CBZ) (RR = 4.4) as compared with nonexposed pregnancies. The maternal epilepsy type could not explain differences in risk of MCA, nor Outcome of Pregnancy in Epileptic Women. M. Beaussart, J. could differences in maternal age, sex of the child, or parity of Beaussart-Defaye, J. M. Lamiaux, J. Goujard, and J. C. Grubar the mother. However, pooling of all data from Berlin, Magde- (Laboratoire de Psychologie Cognitive, Unite de Recherches sur burg, Helsinki, and Rotterdam and comparison of the risks of les Epilepsies, Universite Charles de Gaulle, Lille, France)- specific monotherapies and polytherapies showed no significant 203 I. differences between specific treatment regimens. Although the risk of MCA is increased for offspring of women Following our 1985 comparison of the children born to 100 treated with AEDs, our results suggest that the relatively in- epileptic women and 100 epileptic men, our new survey exam- creased risks of MCA in individual studies for some specific ined, among other variables, the outcome of pregnancy and the therapies such as VPA and CBZ may be explained by small children born to a group of 427 French women who had had at sample size or factors not yet analyzed, such as differences in least one pregnancy. We studied 1,055 pregnancies, considering dose regimen between studies. (Supported by CLEO/NEF Grant the influence of epileptic syndromes and symptoms, medica- No. A-90 and Klingenstein Foundation.) tions, neuropsychological aspects, and family factors of morbidity. Special attention was paid to the rank of the pregnancies in Epilepsy, Pregnancy, and Offspring of Women with Epilepsy in relation to distribution of spontaneous abortion, of malformation Israel. Michael Dublin and *Judith Manelis (Department of Pae- in new-borns, of still-birth, and of death infancy. Preliminary diatrics and *the Neurology Unit, Western Galilee Hospital, Na- results show the following pathologic consequences: peak of hariya, Israel)-2029. spontaneous abortions in the third pregnancy and a decrease in the number (37) of major malformations after the third preg- Ninety-four women with epilepsy with 215 live births were nancy. Among the different types of major malformations, the 2 followed up for a period of 1-10 years between 1980 and 1992. cases of spina bifida and 4 of the 5 cases of cleft lip occurred in Ninety-four healthy women with 273 children served as controls. first pregnancies. Consequently, the rank of the pregnancy ap- Of the women, 58% were Jewish, 22% were Muslem, 18% were pears to be a significant factor prognosis of risks for children of Druze, and 2% were Christians; one fourth of the Muslem and an epileptic parent. Druze women had married their relatives. Seventy-three women were receiving monotherapy, 13 were receiving two antiepileptic drugs (AEDs), and 2 were receiving more than two AEDs. Carbamazepine was used mainly. Seizure Topic 111: Epidemiology of Epilepsy rate increased during pregnancy in 21% of women with tonic- clonic seizures, in 40% with partial seizures, and in 83% with partial generalized seizures. Sixteen percent of all pregnancies of Main Session (3000a-3000d) women with epilepsy ended in spontaneous abortion as compared with 10% in the control group. Perinatal death rate was identical in both groups (1.85%). Neonatal asphyxia occurred in Multicentre Study of Early Epilepsy and Single Seizures. David 7% of the offspring of epileptic mothers (0.6 in the control Chadwick (Department of Neurological Science, Walton Hospi- group). Intrauterine growth retardation was noted in 17% of ba- tal, Liverpool, England)-3000a. bies born to epileptic mothers (9% in controls). There were six cases of minor and three of major malformations as compared Deciding when to start and when to stop treatment in epilepsy with a single minor malformation in the control group. Our reis difficult because of the very variable nature of epilepsy and its sults, in accordance with those of previous studies, indicate that prognosis. Clinicians need information to present to patients that women with epilepsy have a slightly higher but definite obstetric will identify risk factors for seizure recurrence and the effect of risk as compared with healthy women. treatment on such a risk. This will enable patients to make sensible informed decisions about initiation of treatment in a way that should encourage good compliance with treatment policies. Pregnancy and Teratogenesis in Epilepsy, An Epidemiologic In the United Kingdom, the Medical Research Council (MRC) Study. Elia Baeta, *Rui Choriio, tLuisa GuimarSes, $Isabel has provided financial support for a pragmatic multicenter study Luzeiro, §Jose Keating, "Rui Mota, lLuis Guerra, and #JosC that aims to compare immediate and deferred antiepileptic drug Pimentel (Department Neurology, *Hospital Garcia de Orta, Al- (AED) treatment in a population of persons with first seizures or mada; ?Hospital Santo Ant6nio and S. Joiio, Porto; Kentro early epilepsy. The methods of this pragmatic multicenter study HoSpitalar and §Hospital Universitario, Coimbra; "Hospital Dis- are based on those of the MRC's AED Withdrawal Study, which trital, Ponta Delgada; THospital Egas Muniz; and #Hospital de satisfactorily achieved its aims of defining prognostic factors for Santa Maria, Lisbcn, Portugal)-2030. seizure recurrence on discontinuation of AEDs and was able to develop a prognostic model that appears to be of practical use in An increasing number of women with epilepsy are either plan- patient decision making. We hope to recruit ~3,000patients in ning pregnancy or are already pregnant when they first visit a the next 3 years and would benefit greatly from collaboration doctor. Therefore, close neurologic, obstetric, and pediatric sur- with other European countries. veillance is needed to prevent or decrease the risk of pregnancy or labor disturbances and teratogenesis, events known to be induced either by seizures or antiepileptic drugs (AEDs). Diagnosis and Classification of a First Seizure. Pierre Loiseau, A national, multicentric, study of this condition is currently in JCrBme Loiseau, and Jean-FranGois Dartigues (Departments of progress in collaboration with the Portuguese League Against Neurology and Epidemiology, Bordeaux University Hospital, Epilepsy. Follow-up of pregnant women, type of AEDs and eval- Bordeaux, France)-3000b. uation of their serum levels, and folate therapy were in accordance with established guidelines. The absence of major preg- Diagnosis of an isolated paroxysmal event may be very diffi- nancy complications or newborn malformations and mainte- cult. Is it really an epileptic seizure? What sort of seizure? In

Epilepsia, Vol. 35, Suppl. 7, 1994 16 EUROPEAN CONGRESS PROCEEDINGS what proportion of patients is it possible to use the classification of recurrence, but it does not appear to influence the long-term of the International League Against Epilepsy? Using a syndro- prognosis of epilepsy. mic classification is easier, and harder. It is easier because at this time the cause of a seizure is more important than its precise signs. It is more difficult because several seizures are mandatory for many syndromic diagnoses. Platform Presentation 1 (3001-3006) These facts are exemplified by data from an epidemiologic survey of epileptic events in Southwest France. Of a cohort of 804 patients, 327 had experienced an acute symptomatic seizure, Case Register on Epilepsy: Why and How? Th. P. B. M. Suurmei- 125 were diagnosed with remote symptomatic seizures, and 12 jer, *A. P. Aldenkamp, *Th. W. H. Heisen, *J. Overweg, with symptomatic generalized epilepsy; 340 had an unprovoked tW. 0. Renier, and $0.G. Sie (Northern Centre of Health Care idiopathic or cryptogenic seizure. We analyzed in the last group, Research NCH, Department of Medical Sociology, University of after 5-year follow-up, what syndromes were identified from the Groningen, Groningen; *Meer en Bosch, Special Epilepsy Cen- outset (by history, clinically, by EEG, or radiologically), why tre, Heemstede; thterdisciplinary Centre of Child Neurology, some patients shifted from one syndrome to another, and when Academic Hospital, Nijmegen; and $Department of Neurology, (factors and time of recurrence, number of deaths and causes of Academic Hospital, Groningen, The Netherlands)-3001. death) and why patients were lost to follow-up. An epilepsy case register provides, among other things, the opportunity to obtain (a) more reliable and valid information on Natural History of Untreated First Seizure. J. W. A. S. Sander the epidemiology of the epilepsies and, based on further re- (Institute of Neurology, National Society of Epilepsy, Chalfont search, (b) better insight into use of healthcare facilities and (c) St. Peter, Bucks, England)-3MK)c. the quality of care provided, and (d) the secondary effects of epilepsy. Therefore, such an epilepsy case register was started in The orthodox viewpoint that single seizures should not be the province of Groningen, The Netherlands. equated with epilepsy originates from early hospital-based recur- Collection of cases has just begun. Based on recent Dutch rence studies indicating that a considerable proportion of pa- epidemiologic research, a prevalence rate of 0.07% is assumed, tients with a single seizure had no further attacks. The U.K. which corresponds to -4,200 patients with epilepsy in that prov- community-based National General Practitioners Study of Epi- ince. Large deviations from this estimation may be evident lepsy has provided comprehensive information on this issue; re- merely by taking the existence of institutions for the mentally currence rates were determined by actuarial analysis for 564 un- handicapped in the region into consideration. selected patients with nonfebrile seizures. In all, 67% of patients The next steps will be collection of further basic data on med- had recurrence s12 months after a first attack and 78% had ical and psychosocial functioning of the patients to make the recurrence after ~36months, Seizures associated with a neuro- register a more complete sample base, followed by fundamental deficit present at birth had a 100% rate of relapse, whereas sei- and applied medical and epidemiologic as well as psychological zures associated with a CNS lesion acquired postnatally had a and sociologic research on the secondary effects of epilepsy, risk of relapse of 75% by 12 months (85% by 36 months). patterns of use of health care facilities and on the relation be- The risk of a further seizure after a first attack is greater than tween the two. was previously accepted. This has implications for management of single seizures and also casts doubt on the value of distinguishing between single seizures and epilepsy. If it is meaningful Epidemiologic Survey of Epilepsy in Portugal. J. M. Lopes Lima, in an individual, it is so only when the time elapsed from the first R. Almeida, D. Alves, J. M. Calheiros, and J. Leal Loureiro. attack is known. (Consulta de Epilepsia, Neurology Service, Hospital G. S. An- tonio, Porto, Portugal)-3002.

Therapeutic Management of the First Seizure. Ettore Beghi for the Studies of prevalence and incidence in epilepsy are always First Seizure Trial Group (Clinica Neurologica, Ospedale S. Ger- difficult, mainly owing to the absence of an easy diagnostic ardo, Monza, Italy)-3000d. marker of the disease. Door-to-door inquiries generally overestimate the actual rates, including patients who are misdiagnosed Although the earlier the treatment of newly diagnosed patients as having the disease. On the other hand, review of the medical with epilepsy the better the long-term prognosis, it is still de- registries tends to underestimate since patients with less severe bated whether treatment should be started after the first seizure epilepsy are not included. or after seizure recurrence. The first seizure may be an isolated In 1992 and 1993, we attempted to review all persons sus- episode in up to 76% of patients with no recognized risk factors pected of having epilepsy among the population registered in the for seizure recurrence. This percentage tends to decrease to 35% list of general practitioners (GPs) throughout North Portugal- in patients with symptomatic epilepsy and EEG epileptiform ab- almost one third of the Portuguese population. These persons normalities. Observational studies report that the relapse rate of were discussed by the epileptologist team and the GPs; when the the first seizure is similar in patients given immediate treatment, diagnosis was in doubt, they were investigated thoroughly or, in as compared with those treated after seizure recurrence. Then, the more difficult cases, were reviewed in outpatient epileptic about 30% of the individuals treated with antiepileptic drugs ex- clinics. Whenever possible, charts available in the different hos- perience moderate to severe adverse treatment events leading to pitals of the same region of the persons identified were also treatment failure. After the positive results of a small random- reviewed. ized trial reporting carbamazepine to be effective in reducing the During these 2 years, 11 regional health centers were visited risk of relapse, a multicenter, randomized, clinical trial was con- regularly by the different teams of epileptologists (four teams; 13 ducted in Italy on patients at their first unprovoked tonic-clonic epileptologists). Each center made a contribution through 5-10 seizure; 218 subjects were randomly assigned to immediate treat- GPs, each center having an average 1,500 persons registered in ment and 208 to treatment after the first relapse. The cumulative the respective files. The population studied is a sample of time-dependent risk of relapse by 24 months was 25% among - 100,000 with a harmonious distribution through North Portu- treated patients and 51% among the untreated. However, the gal; >500 suspected cases were reviewed. This study will allow probability of 1-year remission was 82% in patients given imme- not only a rigorous estimate of the incidence and prevalence of diate treatment and 84% in those who were left untreated; the epilepsy in Portugal, but will also provide important information corresponding figures for 2-year remission were 60 and 59%, about the prevalent etiologies, relative frequency of the different respectively. Based on these findings, the immediate treatment types of seizures and epileptic syndromes, and even the trends of of the first unprovoked epileptic seizure seems to affect the risk therapy and social impact of the disease.

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 17

Descriptive and Comparative Study of Epilepsy in a Health District gray areas. In the United Kingdom, 53% (411 of 775) consultant of Genoa, Italy, with Evaluation of Medical and Social Aspects. geriatricians responded to a questionnaire exploring their ap- Paolo Tanganelli and Giovanni Regesta (Department of Neurol- proach to seizures in the elderly. ogy, Epilepsy Center, San Martino Hospital, Genoa, Italy)- One to 5 patients aged predominantly 75-85 years were re- 3003. viewed monthly; 70% of consultants undertook the investigations themselves. Biochemical and hematologic profiles were de- In the fourth health district of Genoa (73,494 inhabitants), we termined in 95% of patients, but EEG and computed tomo- identified all suspected cases of epilepsy from prescriptions of graphic scanning were requested in only 25%. antiepileptic drugs (AEDs). The subjects were examined and Fifty-eight percent of geriatricians managed the patients them- asked to compile an original questionnaire. The data were com- selves; 16% started treatment after a first seizure, 59% after a pleted by information from hospital registers and by interviews second, and 5% only after a third. Fifty-five percent chose phe- with practitioners. The diagnosis of epilepsy was ascertained in nytoin first for generalized tonic-clonic seizures and carba- 468 cases (prevalence rate 6.37%). Medical and social aspects mazepine for partial seizures. If control was not obtained, 67% were investigated. The onset of epilepsy is higher in the first 5 substituted another drug; 27% added one. Sixty percent moni- years of life, with a second peak after age 60 years; 17% have a tored anticonvulsant concentrations in patients with poor control family history of epilepsy and 27% have associated handicaps. or toxicity. Less than 3% of responders prescribed newer agents, Seizures are well controlled in monotherapy in 44% of cases. such as vigabatrin or lamotrigine. With regard to social aspects, we evaluated educational level, In the United Kingdom, elderly persons with epilepsy have employability, rate and type of employment, sport practice, and limited access to specialist investigations and little exposure to civil and social status as compared with relatives and with the newer antiepileptic drugs. Epilepsy clinics would encourage general population of the district. Military service and driver’s structured research into the many unanswered questions affect- licensing were also considered. Epileptic persons with no other ing the care of this patient population. handicaps may attend regular studies and obtain adequate employment. The percentage participating in sports was low (16.9%) as compared with the percentage of siblings who did so (45.6%); seizures rarely occurred during sports activities. Social adjustment is good, but the percentage of unmarried persons is Clinimetrics in Epileptology. M. W. Lammers, Y.A. Hekster, higher among epileptic persons in the general population. Re- A. Keyser, W. 0. Renier, and H. Meinardi (University Hospital, markable difficulties exist for subjects with epilepsy and other St. Radboud, Nijmegen, The Netherlands)-3006. handicaps both with regard to employment and social integration. We wish to improve the methods for concise and reproducible registration of outcome variables for assessment of epilepsy treatment. For our study, we adapted the VA Seizure Frequency and Severity Rating Scale. This composite rating scale allows for assessment of seizure frequency and severity and of toxicity Secular Trends in the Epidemiology of Epilepsy: A Population Re- caused by antiepileptic medication. A composite score of 350 visited. Oliver C. Cockerell, Isolde Eckle, Seema Gupta, Josemir was accepted as the criterion for unacceptable epilepsy control. W. Sander, and Simon D. Shorvon (Epilepsy Research Group, The adapted rating scale used in this study, the Composite Index The Institute of Neurology, Queen Square, London, and the of Impairments (CH), has been validated. We studied first the Chalfont Centre for Epilepsy, Chalfont St. Peter, Bucks, En- difference in CII scores between patients of secondary- and ter- gland)-3004. tiary-referral centers. The latter had the higher scores. Second, we compared the outcome of CII scores with physicians’ state- Treatment of epilepsy has changed dramatically in the last ments about whether they had achieved treatment objectives. decades, with newer and more effective use of antiepileptic C11 scores correlated well with clinicians’ opinions of patients’ drugs as well as other treatments such as neurosurgery and im- clinical state. Third, we compared two toxicity subscales to as- provements in treatment of status epilepticus and refractory ep- sess differences in toxicity in patients receiving mono- and poly- ilepsy. Evidence of the effects of such change on the prognosis of therapy with comparable antiepileptic drug dosage parameters. patients with epilepsy is scant, however, and whether epilepsy is No differences were evident in either frequency or severity of changing in incidence or prevalence is not known. The incidence side effects. A study of the sensitivity of the CII for changes in of epilepsy is suggested to be decreasing in children and the dosage or in serum levels is still in progress. likelihood of remission of epilepsy to be increasing in the last few years. We examined the time trends of the epidemiology of patients with epilepsy in a population of 6,000, an examination facilitated by a 1992 study that ascertained all patients with epilepsy in this population; records of these patients are still available. The number of new cases was highest between 1964 and Platform Presentation 2 (3007-3012) 1968 (n = 33), and then decreased: There were only 11 cases between 1984 and 1988. These results reflect the changing age structure in the United Kingdom, but do not exclude a decreasing incidence of epilepsy. No differences in 2- or 4-year remission rates were noted in patients diagnosed before 1970 or before Natural History of Epilepsy and Its Psychosocial Outcomes: Find- 1980 as compared with patients diagnosed after these dates. ings From a U.K. Community Study. Ann Jacoby, *GUS A. Baker, and *David W. Chadwick (University of Newcastle, Cen- tre for Health Services Research, University of Newcastle, Newcastle upon Tyne; and *Department of Neurosciences, Wal- ton Hospital, Liverpool, England)-3007. Management of Seizures in the Elderly: A Survey of U.K. Geria- tricians. Iwona H. Stolarek, Adam F. Brodie, and Martin J. Bro- As part of a large community study of epilepsy undertaken in die (Epilepsy Research Unit, University Department of Medi- one U.K. health region, adult patients with active epilepsy were cine and Therapeutics, Western Infirmary, Glasgow, Scotland) asked to complete postal questionnaires about the nature of their -3005. condition, their psychosocial functioning, and the medical care they received. The response rate to the postal questionnaires Although the incidence and prevalence of epilepsy increases was 75%. Of the 696 adults who responded, 20% had had their substantially into old age, investigation and management remain first seizure by age 10 years and just over half had had a first

Epilepsia, Vol. 35, Suppl. 7, 1994 18 EUROPEAN CONGRESS PROCEEDINGS seizure by age 20 years. Mean duration of epilepsy was 16 years; Mortality in the Outpatient Population of a Dutch Epilepsy Centre. 57% had had at least a 2-year seizure-free period, and 50% had J. A. P. van Parijs, G.-J. de Haan, R. Mantel, and P. Meijer had no seizures in the last year. Twenty-four percent reported (Instituut voor Epilepsie Bestriding, Heemstede, The Nether- currently having one or more seizures a month. lands)-30 10. Thirty-four percent of patients reported other long-term health problems in addition to epilepsy; 24% were clinically anxious As compared with the general population, mortality is in- and 10% were clinically depressed; and approximately one fifth creased among epileptic patients. The excess mortality risk is felt stigmatized by their epilepsy. The percentage of persons in highest in young adult male patients. Standard Mortality Ratios the sample living alone was higher than national U.K. figures. (SMRs) were determined for outpatients of the lnstituut voor The rate of employment in the sample was low, with high per- Epilepsiebestrijding, Heemstede, The Netherlands. According centages classified as unemployed or permanently sick. Even to the administrative database, 50 of 7,226 patients died in 1992. when seizures were well-controlled, patients reported significant The SMR was 1.9 for male patients and 1.7 for female patients. psychosocial problems related to their epilepsy. The excess mortality was most pronounced in the group aged 15-29 years.

Remission of Epilepsy: The Probability of Newly Diagnosed Epi- Population-Based Mortality of Persons with Epilepsy. Matti Lauri lepsy Achieving Three- and Five-Year Remission in the National Sillanpaa and *Markku Juhani Koskenvuo (Departments of General Practice Study of Epilepsy. Oliver C. Cockerell, Yvonne Child Neurology and *Public Health, University of Turku, M. Hart, Josemir W. Sander, and Simon D. Shorvon (Epilepsy Turku, Finland)-301 I. Research Group, The Institute of Neurology, Queen Square, London, and the Chalfont Centre for Epilepsy, Chalfont St. Pe- A representative population sample of 245 children with epi- ter, Bucks, England)-3008. lepsy was prospectively followed for 35 years to adulthood for medical and social outcome. At the end of follow-up, 91% of the Population-based studies suggest that between 60 and 75% of sample were still traceable. During follow-up, 44 (18.0%) had patients with epilepsy will enter a period of remission lasting 3-5 died. In a remarkable percentage, death was attributed to epi- years at some time in their lives. However, no prospective pop- leptic seizures. Mortality was higher in patients with both epi- ulation-based studies have followed patients with newly diag- lepsy and symptomatic etiology, abnormal neurologic status, or nosed patients from onset of their epilepsy, and several issues partial seizures. Standardized mortality ratios, detailed analysis remain to be clarified, including the effect of early seizure pat- of causes of death, and the role of epileptic seizures were eval- terns, the effect of underlying etiology, and the factors that lead uated. Ours is the only study based on prospective follow-up of to relapses after remission. Patients were identified in the United a nonselected population. Kingdom between 1984 and 1987 as part of the National General Practice Study of Epilepsy, which is the largest prospective community-based cohort study of newly diagnosed epilepsy; follow- Circumstances Surrounding Sudden Death in Epilepsy: Interviews up is now 9 years. The remission patterns were analyzed in 564 with Relatives. L. Nashef, S. Garner, D. Fish, J. W. A. S. patients with proven epilepsy and in 228 patients with possible or Sander, and S. D. Shorvon (The Epilepsy Research Group, In- probable epilepsy. Sixty percent of patients experienced a 3-year stitute of Neurology, London, England)-3012. period of remission after 5-year follow-up; this figure was not greatly influenced by etiology, seizure type, or age of onset. Twenty-two self-referred relatives of patients with epilepsy Detailed actuarial analysis, with 5-year remission rates, and ter- and sudden unexpected death were interviewed. Medical details minal remission rates was made. were substantiated by physicians and by death certificates and coroners’ and postmortem reports. Three patients were excluded (submersionddiagnostic doubt). All remaining 19 cases (12 males, 7 females) were coroner’s cases (mean age 27 years, range Epilepsy Mortality in Sweden. Magnus Olivecrona and Herbert 10-63 years). Epilepsy was localization-related in 5, idiopathic Silfvenius (Department of Neurosurgery, University Hospital, generalized in 8, and unclassified in 6. Only 5 had >lo0 lifetime Umei, Sweden)-3009. generalized seizures, 5 had

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 19 termine their type of epilepsy and its etiology. In 1,220 cases In 1987, 216, and in 1988, 225 children with febrile seizures (96.9%), the type of epilepsy could be classified. The highest (FS) were admitted to the Municipal Children’s Hospital or were percentage corresponded to partial epilepsies (symptomatic treated by outpatient pediatricians and child neurologists in three 32.3%, cryptogenic 42.4%), followed by secondary generalized districts of L6di (the child population aged 6 months to 5 years epilepsies (13.3%), idiopathic generalized epilepsies (7.0%), and was 35,967 in 1987, 36,102 in 1988). Twenty-eight children had other (4.1%). long-lasting (>30 min) attacks. We compared clinical features in The cause of epilepsy was determined in 44.6% of patients. children with long-lasting attacks with the entire group of chil- The most frequent were perinatal damage (18.2%), congenital dren with FS by prospective observation to at least age 7 years. malformations and metabolic encephalopathies (7.0%), vascu- The group with long-lasting attacks consisted statistically signif- lar disease (6.l%), postinfection (5.4%), degenerative lesions icantly more children with epilepsy (28 vs. 6%); 50% of them had (3.0%), tumorous lesions (2.5%), and traumatic injuries (2.4%). neurodevelopmental delay at time of disease onset. Prospective Joint preventive action by health practitioners might reduce the observation allowed us to diagnose the primary epilepsy attack percentages of precipitating causes of epilepsy. (precipitated by fever) in 40%. The average value of WISC was decreased only slightly (no statistical difference). In nearly all children (25 of 28) we noted disharmony in development of cognitive functions. Patients with epilepsy showed more specific Cause of Epilepsy in the Elderly. Mostafa Shirzadi and Hasan brain microdysfunctions than did patients without epilepsy and Zadmehere (Isfahan Medical School, Isfahan, Iran)-3014. had more changes in examination for visual- and sensory-evoked potentials. We evaluated the cause of epilepsy in 279 elderly patients (155 males and 124 females) to study the etiologic distribution of epilepsy with onset after age 60 years. Statistical studies showed increased frequency of seizure with increasing age. All patients were classified according to clinical findings, Late-Onset Epileptic Seizures: Review of a Neurologic Consulta- EEG, brain computed tomography scan, and magnetic reso- tion. Manuel GonCalves, Rita Almeida, J. Pinto Viana, Martinho nance imaging in a few patients into six etiologic categories. The Pimenta, and J. Cabral Biergo (Neurology Service, Hospital de frequency in each group was established for comparison with St. Ant6nio dos Capuchos, Lisbon, Portugal)-3017. other studies in the literature. Seizures were more common in males than in females. Vascular insult accounted for the largest Seventy-five patients with epilepsy (42 men and 33 women identifiable fraction (28.2%). Infections followed the vascular in- aged 22-78 years, mean 49 years), in whom the first seizure sult (12.5%). Tumors, toxic-metabolic causes, and head trauma occurred after age 20 years (mean 40 years), were selected during were next in order of frequency. Our results confirm the pre- a I-year follow-up period from a neurologic outpatient clinic. dominance of vascular disease as a cause of epilepsy occurring They were retrospectively investigated to explore clinical char- after age 60 years, followed by infections in our analysis, but acteristics, EEG and computed tomography (CT) findings, and cryptogenic epilepsy remained the major cause of epilepsy therapeutic response. (35.3%). Seizures were generalized in 45 patients and partial in 30. Their frequency was variable; 70% of the patients had had seizures in the last 3 years. Neurologic examination was abnormal in 23 patients; only 12 patients had focal signs. Seventeen pa- Epilepsy in Slovenia: Epidemiologic Consideration. Joie I. GroSeli tients had a history of alcoholism, and 16 had a history of cranial (Department of Psychiatry, Ljubljana, Slovenia)-3015. trauma. The EEG was abnormal in 55 patients, but only 40 showed focal changes. These changes were more often demon- We analyzed a sample of 511 patients attending the epilepsy strated in the group with partial epilepsy (25 of 30 cases) than in clinic at the outpatient psychiatry center in Ljubljana. The group the generalized epilepsy group; 27 patients had CT abnormali- comprised nearly equal proportions of women (50.3%) and men ties, but only in 18 were they focal. Fifty-five patients (73%) had (49.7%). Their average age was 42 years; 75% were aged 40 a good therapeutic response, with no differences between the years; 87% patients were Slovenians, 4.5% were Croats, 4% generalized and the partial groups. Seizure etiology could be were Serbs, 3% were Muslims, and 1.5% were of other nation- identified in 41 patients (55%): 9 related to alcoholism, 22 to ality. Forty-eight percent of patients had primary, 38% had sec- stroke, 6 to cranial trauma, and 4 to other factors (atrioven- ondary, and 8% had higher levels of education; 5% were illiter- tricular malformation, tumor, cerebral abscess). In 34 patients ate. Most patients (75%) lived within 50 km of the psychiatry (45%), no etiology could be identified. center. Analysis of diagnoses 65% with partial seizures, 24% with generalized seizures, and 11% with unclassified seizures. The most common clinical forms in the group were tonic-clonic seizures (49%), followed by complex partial seizures (23%) and simple partial seizures (12%). Factors Predicting the Risk of Relapse After Antiepileptic Drug The cause of epilepsy was unknown in 61% of the patients, Discontinuation in Children with Partial Seizures. Filippo Donati, trauma was implicated in 28%; brain tissue inflammation ac- *Ralf I. Hassink, Hans Jung, and *Franc0 Vassella (Division of counted for 8% and brain tumors for 3% of cases. A hereditary Clinical Neurophysiology , Department of Neurology, and *Di- predisposition, considered probable in 14% of cases, had been vision of Neuropediatrics, Department of Pediatrics, University rnled out in the remaining 86%; 47% had favorable clinical status Hospital of Berne, Berne, Switzerland)-3018. with absence of seizures; 47% showed psychic changes, mainly in the form of psychoorganic (21%) and neurotic disorders (15%). We wished to identify possible factors that could influence the Further studies are necessary to clarify the high prevalence of risk of relapse after discontinuation of antiepileptic drug treat- psychoorganic disorders observed in the group. ment (AED) in children with epileptic partial seizures. From our computerized database of >800 children with epilepsy, 155 patients with partial seizures (simple and complex) and with >5- year follow-up could be selected. In 82 of 155 children, the AED Occurrence and Follow-up of Long-Lasting Febrile Seizures in had been discontinued a mean of 4.70 years after the last epilep- Three Districts of Lodi. Janusz Wendorff, Izabela Indisow, and tic seizure; 24 of 82 had a relapse 1.20 years (mean) after AED Barbara WiSniewska (Polish Chapter of ILAE, and Department discontinuation (“group with relapse,” mean age 14.34 years, of Neurology, Polish Mothers’ Memorial Hospital, Lodi, Po- mean follow-up 9.61 years), and 58 of 82 had no relapse in the land)-30 16. last 3 years after AED discontinuation (“group without relapse,” 20 EUROPEAN CONGRESS PROCEEDINGS mean age 12.89 years, mean follow-up 9.39 years). We compared radiologic procedures (EEG, computed tomography, and brain the group with relapse and the group without relapse in relation magnetic resonance imaging). We compared our results with to possible risk factors. Abnormal neurologic findings (8 of 24 vs. those of other previously published studies. 8 of 58, p < 0.05, chi-square test), delayed psychomotor development (7 of 24 vs. 7 of 58, p < 0.05) at the last clinical control before AED discontinuation, and focal slowing (6 of 24 vs. 3 of 58, p < 0.01) in the last EEG before AED discontinuation were Epidemiology of Epilepsy in a Large Community Sample. Ann significantly more common in children who relapsed. However, Jacoby, *GUSA. Baker, *David Smith, and *David W. Chadwick no statistically significant differences between the two groups (University of Newcastle, Centre for Health Services Research, were noted concerning age at time of first epileptic seizure (4.28 Newcastle upon Tyne; and *Department of Neurosciences, Wal- vs. 5.44 years), duration of AED after the last seizure (4.51 vs. ton Hospital, Liverpool, England)-3021. 4.83 years), familial occurrence of epilepsies (6 of 24 vs. 12 of 58), background EEG abnormalities (6 of 24 vs. 17 of 58), and The Wellcome Study of Quality of Life and Care was a large focal epileptiform discharges (5 of 24 vs. 5 of 58) in the last EEG community study performed in one health region in the United before AED discontinuation. Our results suggest that the pres- Kingdom. Medical records of a random sample of 30 general ence of focal slowing in the last EEG before AED discontinua- practices were reviewed to identify patients with active epilepsy. tion, abnormal neurologic findings, and delayed psychomotor From a total practice population of 177,700, 1,347 patients with development are risk factors for relapse of seizures after AED epilepsy were identified, a prevalence rate of 0.8%. In 50% of discontinuation in children with partial seizures. patients, duration of epilepsy was >I0 years; 40% had been seizure-free for 2 years. The etiology of seizures was cerebrovas- cular in 22%, genetic epilepsy syndrome in 21%, head injury in 17%, perinatal insult in 13%, and brain malformation in 11%. Prognostic Factors at the Beginning of Partial Seizures in Children. Seizures were classified as tonic-clonic in 60% of patients, ab- Ralf I. Hassink, *Filippo Donati, *Regula Briellmann, and sence in 22%, complex partial in 19%, and simple partial in 17%. Franco Vassella (Division of Neuropediatrics, Department of Pe- Four percent of patients had never been treated with antiepilep- diatrics, and *Division of Clinical Neurophysiology, Department tic drugs (AEDs). Among those currently receiving AEDs, most of Neurology, University Hospital of Berne, Berne, Switzer- were treated with phenytoin, carbamazepine, valproate, and land)-3019. phenobarbital. Eighteen percent of patients were classified as having mental handicap and 15% as having a psychiatric disor- We wished to identify possible factors that could influence the der. Information collected from patients themselves indicated outcome after the first epileptic partial seizures in children. From that 25% were clinically anxious and 10% were clinically de- our computerized database of >800 children with epilepsy, 281 pressed. Approximately one fifth reported a seizure-related inpatients with partial epileptic seizures (simple and complex) and jury in the past year. with >3-year follow-up could be selected. Sixty-eight of 281 showed persistence of seizures under antiepileptic drug therapy (AED) (“group with seizures”). In 191 of 281 children, the epileptic seizures remitted under AED therapy after >I year Type-Specific Diagnostic Analysis of First Epileptic Seizure in (“group without seizures”). We compared the group with sei- Adults: Follow-up Investigations. Ulf Baumhackl, Richard Bil- zures and the group without seizures in relation to possible fac- leth, and *Martin Graf (Neurological Department, General Hos- tors influencing follow-up. Delayed psychomotor development pital, St. Polten; and *Neurological Department. Wilhelminens- (44 of 68 vs. 33 of 191, p < 0.001, chi-square test), abnormal pital, Vienna, Austria)-3022. neurologic findings (44 of 68 vs. 56 of 191, p < 0.001), focal EEG slowing (21 of 68 vs. 41 of 191, p < 0.01), background EEG Of 327 adult patients with a first epileptic seizure evaluated abnormalities (29 of 68 vs. 39 of 191, p < 0.001) before initiation with respect to underlying causes, most had had alcohol-related of therapy, and onset before age 3 years (41 of 68 vs. 73 of 191, seizures; in elderly patients, vascular pathology dominated. p < 0.001) were significantly more common in children with Stroke contributed in a high percentage of the elderly patients in persistent seizures. However, no statistically significant differ- our cohort and apparently is an increasing problem in manage- ences between the two groups were noted concerning familial ment of older patients. Remote symptomatic seizures give rise to occurrence of epilepsies (10 of 68 vs. 43 of 191), existence of the question of anticonvulsant therapy. febrile convulsions (2 of 68 vs. 10 of IYt), and focal epileptiform We have now observed 171 patients for >I year. Sixty percent discharges in EEG (26 of 68 vs. 80 of 191) before initiation of of patients with structural lesions (tumor, stroke, and brain therapy. The prognosis for remission of epilepsy with partial and trauma, n = 89) receiving anticonvulsants were seizure-free as complex seizures is poor if the following factors exist: onset of compared with 40% without anticonvulsants. This small number seizures before age 3 years, abnormal neurologic findings, de- does not allow valid conclusions concerning treatment, espe- layed psychomotor development, focal slowing, and background cially in patients with remote symptomatic seizures, but further EEG abnormalities. investigations appear to be justified and urgently needed.

Study of Epidemiology of Epilepsy. J. Acosta, E. Calderon, F. Coroners’ Autopsy Reporting of Sudden Unexplained Death in Ep- Guisado, J. Jimenez, P. Sanchez Ayaso, and M. J. Rio (Section ilepsy in the United Kingdom. Helen Coyle, Stephen W. Brown, of Neurology, Hospital Universidad Puerta Del Mar. Cadiz, and Nicholas Baker-Brian (The David Lewis Centre, Cheshire, Cadiz, Spain)-3020. England)-3023.

An epidemiology study has been made door to door in a coun- Sudden unexplained death due to epilepsy (SUDEP) is not try village of 12,770 inhabitants in Southwest Spain (Vejer- uncommon. The incidence may be difficult to ascertain owing to Cadiz), with research on other diseases of interest (extrapyramy- variations in reporting cause of death. To study this, we used a dal and degenerative disorders) performed by a team of neurol- cuttings service to identify all cases of SUDEP reported in the ogists and medical residents. A questionnaire was used for the U.K. press in 1992. These cases had been reported by different entire population to rule out or detect any seizure disorder in the pathologists and coroners. Postmortem reports, witness state- first phase. ments and other relevant information were examined in 40 cases. In the second phase, patients suspected of having epilepsy Inconsistencies were observed in the investigations performed were studied by neurologists. In the third and last phase, the and observations made at the time of death. In 70% of cases, patients were examined in our hospital by diagnostic or neuro- type of epilepsy was either not known or not referred to; incon-

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 21 sistencies were noted in details of medication, position of body, lesions and absent or subtherapeutic postmortem antiepileptic toxicology reporting, and detailed examination of organs, partic- drug (AED) levels. We retrospectively reviewed the 1,875 au- ularly brain. topsies performed between November 1985 and January 1992 at The wide variation in practice of individual coroners and pa- the Beaumont Hospital, Dublin, Ireland. Of 27 patients with a thologists in the investigation and registering of sudden deaths history of epilepsy, 13 met our criteria for SUDEP. raises issues of quality assurance. Because most SUDEPs are Age ranged from 9 to 54 years (mean 29 years). There were 7 not witnessed, we rely on these investigations and statements of males and 6 females. All were white. The most common autopsy officials involved in the process of registering deaths. If we are to findings were pulmonary edema (10) and aspiration of gastric build a profile of people at risk of SUDEP, epilepsy must be contents (3). Gross CNS examination showed transtentorial her- stated on the death certificate. Until this is done, many more niation (3), cavum septum pellucidum (2), previous temporal deaths will go unrecorded. lobectomy (2), and evidence of old cerebral injury (I). Gross neuropathologic examination was entirely normal in 6. Micro- scopic examination showed no other abnormality in 5, neuronal migration defects in 3, hypoxic ischemic changes in 2, mesiotem- Examinations After First Seizures: Clinical and EEG Data. Margit poral sclerosis in 1, and low-grade ganglioglioma in 1. Of 8 pa- R6zsavolgyi (Budapest, Hungary)-3024. tients tested, AED levels were absent in 5, subtherapeutic in 2, and therapeutic in 1. Clinical and EEG data after first epileptic seizures were stud- The exact etiology of SUDEP remains unknown. Potential ied in patients who had generalized seizures and who showed mechanisms include pulmonary edema and cardiac arrhythmia, generalized epileptic pattern on EEG. Provoked seizures (II/A) which may be directly related to an ictal discharge. As in previ- and seizures with generalized epileptic pattern on EEG (WB) ous studies, AED levels were often low or absent in our study. were separated. The latter group was divided into two subgroups: II/B/l, patients with a single seizure and with no repetition in I year; and II/B/2, patients with seizures recurring in 1 year. Control groups were patients with some seizures but no Therapeutic Management of Single Seizure: A Retrospective Study antiepileptic drug (AED) therapy (111) and those with a general- of 200 Patients. P. G. Garofalo, C. Durisotti, and C. Filati-Roso ized epileptic pattern on EEG, but no seizure (I). (Centro Epilessie, Neurologia, Ospedale Civile, Vicenza, It- Some clinical and EEG data that may predict recurrence of aly)-3027. epileptic seizures are young age, family history of epilepsy, unprovoked seizure, and frequency of generalized paroxysms on We examined 200 patients with a single seizure and with fol- long-term EEG. Careful examination after first seizure is of great low-up of at least 4 years and compared this group with a control importance in predicting need for AED therapy. population of 1,000 patients with more than one seizure to evaluate therapeutic management of the first seizure. A correlation was made between etiology, onset of disease, associated neurologic deficits, type of seizure, therapeutic regimen, and clinical Risk Factors for Ischemic Heart Disease and Cancer in Patients evolution for the two groups. The group of patients with a single with Epilepsy: A Population-Based Case Control Study. Oliver C. seizure had a clear prevalence of idiopathic and cryptogenic Cockerell, Seema Gupta, Simon Broadley, Josemir W. Sander, forms with onset at age 13 years, ther- who receive antiepileptic drug therapy may have an increased apy had not been initiated in most patients (1 of 6 patients risk of cancer and heart disease (lHD), but patients with epilepsy treated). may have more mundane risk factors for cancer, strokes, and IHD, i.e., smoking habits and other lifestyle factors. To address this possibility, we made a case control study at the community level of patients with epilepsy (n = 130) and matched these Comparison Between Males and Females in the Various Forms of patients for age and sex with the general population: 28% of Epilepsy. P. G. Garofalo, C. Durisotti, and C. Filati-Roso (Cen- patients smoked, 6% smoked >20 cigarettes a day, mean blood tro Epilessie, Neurologia, Ospedale Civile, Vicenza, Italy)- pressure was 127/78 mm Hg, and body mass index was 26.8. 3028. None of these measures, nor alcohol consumption, differed from those of the control sample; this did not vary by activity of We examined 1,372 cases of epilepsy with follow-up of at least epilepsy or etiology. Therefore, patients with epilepsy do not 2 years, excluding cases with a single seizure. A correlation was have a significantly greater number of risk factors, and other made between etiology, onset of disease, type of seizure, clinical explanations for their higher mortality rates must be sought. evolution, duration of disease, socioeconomic status, and profession. With regard to etiology, tumoral, vascular, and surgical lesions (75% of cases) and head trauma, correlation was greater (87% of cases) in male patients. With regard to disease onset, Sudden Unexplained Death In Epileptic Patients: A Regional Hos- there was a clear prevalence of female patients aged 3-12 years pital Experience. Richard L. Cristea, Selim R. Benbadis, J. Mau- and a prevalence of male patients aged 20-60 years. Idiopathic rice Hourihane, and Michael A. Farrell (Beaumont Hospital, generalized epilepsy with tonic-clonic seizures showed a pre- Dublin, Ireland, and Cleveland Clinic, Cleveland, OH, U.S.A.) dominance in females, corresponding to a prevalence of petit ma1 -3026. with tonic-clonic seizures in female patients (3 of 10). Female gender did not influence clinical evolution or disease duration. Sudden unexplained death in epileptic patients (SUDEP) is With regard to socioeconomic status, there was an obvious sig- well recognized. Previous studies have attempted to identify nificant prevalence of farmers and blue-collar workers in the high-risk groups, such as black males with structural cerebral male group and of housewives in the female group. 22 EUROPEAN CONGRESS PROCEEDINGS

Symptomatic Epilepsy: A Review of 100 Cases. A. Aradjo, M. J. of medical diagnoses of epilepsy varies. The advantage of a stan- Duarto, Costa Bandeira, H. Aguas, J. Guerra, D. Jardim, and dardized screening questionnaire is that it may be sent to large M. D. RojBo (Hospital St. Antonio de Capuchos, Lisbon, Por- numbers of persons in the community, thus avoiding costly tugal)-3029. house-to-house surveys. A two-step validity study and test-retest reliability study de- We reviewed 100 cases of patients with symptomatic epilepsy sign of a self-administered Epilepsy Screening Questionnaire in a admitted to the Neurology Service Hospital de Santo Antonio random 1:2 sample of a general practice (community-based) pop- dos Capuchos-Lisboa, in the last 10 years. All patients under- ulation of 12,000 people was used. Operational criteria for diag- went EEG and computed tomography (CT) scan. We analyzed nosis of active epilepsy were seizure in the previous 2 years etiology and localization of the lesions, type of seizures, alter- and/or treatment with antiepileptic drugs. Exclusion criterion ations in EEG, CT scan, magnetic resonance imaging, angiogra- was symptomatic seizures. The ESQ was mailed to the study phy and biopsy, treatment, and evolution, and correlated clinical population. Positive scorers were initially interviewed by tele- aspects, EEG changes, and CT scan Lesions. phone and/or in person to clarify the nature of positive replies. If the replies did not lead to exclusion, subjects and, when possible, a close relative or friend, were administered an Epilepsy History Schedule (EHS) by an epilepsy specialist. Possible Existence of Sex Risk Factor for Epilepsy in Multiple Scle- rosis Patients. A. Reggio, *R. Biondi, F. Patti, *V. Sofia, D. De Pascalis, *G. Nibali, and A. Grasso (Department of Neurology Sciences, M.S. Center, and Epilepsy Center, Catania, Italy)- Epidemiology of Infantile Spasms in a County in Western Norway. 3030. Anne-Lise Bjorke Monsen and Per Erik Waaler (Department of Pediatrics, Haukeland Hospital, Bergen, Norway)-3033. Epilepsy in patients affected by multiple sclerosis (MS), previously reported as episodic, occurs in 1-10% of the general A population-based study was made of 34 patients fulfilling population. Between October 1, 1992 and September 30, 1993, criteria for infantile spasms (IS), spasms, and hypsarrythmia we examined 102 MS patients (40 men and 62 women). Ten with or without mental retardation. Medical records were retro- patients (9 women and 1 man) had epilepsy, they constituting spectively reviewed, and a follow-up study included medical and 10.2% of the entire study population with secondary epilepsy of neuropsychological examination of the patients. known etiology. Eight patients were classified as having The incidence of IS from 1981 to 1992 in Hordaland County “chronic progressive” and 2 as having “relapsing-remitting” ep- varied from 0 to 0.78 in 1,000 live births per year (mean of 0.53). ilepsy. Seizures were the initial symptom in 2 patients; 1 of the 2 Annual sex-specific incidence rates (maximum value per 1,000 had partial epilepticus status (PES). The other patients had sei- live births) was 0.98 for girls and 1.52 for boys. Mean age at zures 1l.l.years after disease onset (1-21 years of disease dura- diagnosis was 6.5 months. Mean delay between seizure onset tion). Of them, 4 exhibited episodes of PES. Epilepsy may occur and diagnosis was 4.2 weeks. Twenty-four percent of patients in MS as onset symptom, and SE may occur with great fre- constituted the cryptogenic group, and 76% constituted the quently in MS patients (-50%). Particularly remarkable is the symptomatic group. Approximately 80% of patients received preponderance of women with epilepsy and MS (F/M ratio 9: I). high-dose ACTH alone or in combination with an antiepileptic drug. Of the 13 patients receiving ACTH alone, 12 responded. ACTH had no serious side effects. Electrocardiographic and Clinical Study of Sudden Unexplained Death in Epilepsy. S. J. Tavernor, C. Gifford, L. Owen, A. S. Medagoda, and S. W. Brown (The David Lewis Centre for Ep- Relation Between Mortality for Epilepsy and Rate of Use of Anti- ilepsy, Cheshire, England)-3031. epileptic Drugs in Vila Real. M. R. Silva, M. Correia, J. Ramal- heira, A. P. Correia, J. Lopes, J. Pinheiro, C. Silva, and J. M. Ten cases of sudden unexplained death in epilepsy (SUDEP) Lopes Lima (Consulta de Epilepsia, Neurology Service, Hospi- in patients who had undergone ambulatory EEG with coregis- tal G.S. Antonio, Porto, Portugal)-3034. tered electrocardiogram (ECG) before death were studied retrospectively. These cases were compared with an age- and sex- We evaluated the relation between mortality rates of the dif- matched control group of 10 patients, also with uncontrolled ferent regions of Vila Real district and the rate of antiepileptic epilepsy, from the same residential center. Clinical data analyzed drugs (AEDs) used in the same regions. The death certificates of included age of epilepsy onset, epileptic diagnosis, presence of the Ndcleo de Estatistica e Epidemiologk da AdministraGBo Re- cyanosis during seizures, duration of epilepsy, age at death, his- gional de Sadde do Distrito de Vila Real registry from 1984 to tory of febrile seizures, family history of epilepsy and cardiovas- 1991 were verified. Gross and specific sex mortality rates were cular disease, and medication at death. Interictal ECGs were calculated based on the national survey (census) of 1981. Male obtained in all patients, and a corrected QT interval for heart rate mortality rate was 3.1 in 100,000 (95% confidence limit 2.24.2), was calculated (QTc). On the average, interictal ECGs were ob- and the female rate was 1.2 in 100,000 (95% confidence limit tained 10.3 months (range 1-30 months) before death. QTc in- 0.7-2.0). The rate of AEDs (RAED) used was based on data terval was within the accepted normal range in all 10 patients supplied by Ciba-Geigy. There was a positive correspondence be- with SUDEP. tween mortality rates and RAED in the different regions studied. The mechanism of death in SUDEP remains unknown. QT prolongation has been shown to predispose to sudden death and may be a vulnerability factor in patients with SUDEP. Although the study was small, no patient showed prolonged QTc, suggest- Regional Distribution of Use of Antiepileptic Drugs in Portugal: ing that it is not a major risk factor in SUDEP. Considerations for Study of the Prevalence of Epilepsy Throughout the Country. J. Lopes, M. R. Silva, J. Ramalheira, M. Correia, H. J. Pereira, and J. M. Lopes Lima (Consulta de Epilepsia, Neurology Service, Hospital G.S. Antonio, Porto, Portugal)- Epilepsy Screening Questionnaire. D. Jadresic (The David Lewis 3035. Centre for Epilepsy, Cheshire, England)-3032. Use of antiepileptic drugs (AEDs) in the different regions of Epidemiologic studies that rely on existing medical records are the country can be used as an indicator of prevalence and mor- likely to exclude patients with epilepsy who have not reported bidity of the disease throughout the country. We used data sup- their seizures. Furthermore, the quality of medical records and plied by Ciba-Geigy (in millions of Portuguese escudos and in

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 23 unit&) and analyzed regional distribution of the different AEDs, seizures. Among partial seizures, temporal lobe seizure was con- basing data on the population registered in the 1981 national sidered in 37.5%, localization undetermined partial seizure in survey (census). 29.7%, and extratemporal lobe seizure in 24.7%. Correlation Use of AEDs was fairly homogeneous throughout the country, with EEG findings in these patients showed a disconcordance although there was a trend toward wider use in the interior re- rate of 34.6% in generalized seizure, of 17.7% in extratemporal gions of the country. The slight discrepancies detected do not lobe seizure, of 5.8% in temporal lobe seizure, and of 5.3% in suggest a different prevalence of epilepsy; rather, they can be localization-undetermined partial seizure. Structural lesions in explained by a different population structure. MRI were noted in 51.6%. Hippocampal atrophy was the most common lesion (59.4%), followed by focal encephalomalacia (18.4%), focal atrophy (4.2%), vascular malformation (4.2%), tumor (3.7%), granuloma (3.7%), and cyst (2.4%). Patients with Mortality of Epilepsy in Portugal. M. Correia, M. R. Silva, J. clinically judged temporal lobe seizure had the most common Ramalheira, A. P. Correia, J. Lopes, C. Silva, and J. M. Lopes structural lesions in MRI (59.2%). Of those with extratemporal Lima (Consulta de Epilepsia, Neurology Service, Hospital G.S. lobe seizures, in 50.6% had focal lesions, 50.5% had localization- Antonio, Porto, Portugal)-3036. undetermined partial seizures, and 23.1% had generalized seizure. Of 98 patients with hippocampal atrophy, 27 patients Study of the mortality rate of epilepsy and its evolution (27.6%) had dual pathology; focal encephalomalacia was the throughout the years can provide some clues regarding the im- most common. Eleven patients were suspected of having bilat- pact of the disease in society and of the capacity of health ser- eral hippocampal atrophy. Hippocampal atrophy was more com- vices to handle it. We used the data published by the Instituto mon in patients with a history of febrile convulsion and in pa- Nacional de Estatistica and evaluated the gross mortality rate tients with severe seizures. and specific rates for sex from 1980 to 1992, comparing the results with those of other countries. The gross mortality rate for epilepsy was highest in 1980 [2.07 in 100,000, 95% confidence limits (CL) 1.79/2.38]; the value was Epilepsy in the Preschool Period. Zvonka Rener Primec, Igor Mi- lowest in 1989 (1.02 in 100,000, 95% CL 0.8311.24). The specific hael Ravnik, and N. ZupanCiC (Centre for Epilepsy, Hospital for male mortality rate was highest in 1981 (2.92 in 100,000,95% CL Sick Children, Ljubljana, Slovenia)-3039. 2.46/3.45); lowest in 1990 (1.32 in 100,000 95% CL 1.01/1.71). The specific female mortality rate was highest in 1980 (1.64 in The outcome of epilepsy in 465 children from Ljubljana health 100,000, 95% CL 132.05); lowest in 1988 (0.78 in 100,000, 95% district (with first attack of seizures before age 12 years) was CL 0.55/1.06). Mortality rates tended to decrease between 1980 studied; 91% experienced remission or notable improvement, and 1992, probably owing to better mother and infant health with 47.7% having 3-year remission. Seizures recurred in 78 pa- care. tient (16.8%). Of the children, 370 followed a regular school program, 50 attended special schools, and 32 were incapable of schooling. Children with first seizure before age 3 years showed a higher incidence of neurologic involvement (p < 0.01) or men- Mortality Rate for Epilepsy and Infectious Diseases of the CNS in tal disability (p < 0.001) than those with later onset. A 3-year Vila Real From 1984 to 1991. M. R. Silva, M. Correia, J. Ramal- remission rate was lowest in the former group (40.8%), and high- heira, J. Lopes, A. P. Correia, J. Pinheiro, C. Silva, and J. M. est in the group aged 3-6 years (54%). Lopes Lima (Consulta de Epilepsia, Neurology Service, Hospi- Mental retardation, abnormal neurologic status, andlor myo- tal G.S. Antonio, Porto, Portugal)-3037. clonic seizures as assessed by the method of binary logistic regression are important independent negative prognostic factors We studied the relation between the mortality rate for epilepsy (p < 0.01): 3-year remission was achieved in only 1 of 3 mentally and infectious CNS diseases and the different health indicators in retarded children and in 1 of 4 children with neurologic impair- diverse regions of the Vila Real district, reviewing the death ment, respectively. Most epileptic children with severe mental certificates of the “Nucleo de Estatistica e Epidemiologia da retardation (IQ 48-68) had a first seizure before age 3 years; 54 of Administra@o Regional de Saude do Distrito de Vila Real from them had coexisting neurologic disorders. This group also con- 1984 to 1991. The population studied was that registered in the tained the greatest proportion of patients with intractable epi- 1981 national survey (census). The mortality rates of both dis- lepsy. eases were compared with other health indicators (medical doctor/population, neonatal mortality, global mortality, alcohol abuse). The mortality rate for epilepsy was 3.1 in 100,000 [95% confi- Use of an Algorithm for Management of Single Generalized Tonic- dence limits (CL) 2.2/4.2] for males and 1.2/100,000 (95% CL Clonic Seizure. karko MartinoviC and NebojSa Jovic (Depart- 0.7/2.0) for females, in the entire district. Of the different Con- ments of Neurology and Psychiatry for Children and Youth, celhos, the mortality rate was 0.9 in 100,000 in Chaves and 1.3 in Medical Faculty of Beograd University, Beograd, Yugoslavia)- 100,000 in Vila Real, (the two better Concelhos) as compared 3040. with the rates in Mesfio Frio (14.3 in 100,000) and Alij6 (9.3 in 100,000). These different rates were compared with those for the Many controversies in management of patients with a single other health-related indicators in the different regions of the dis- generalized tonic-clonic seizure arise from lack of reliable data trict, that would predict risk of seizure recurrence. Therefore, any rational approach should be based on (a) a thorough history and planning of investigations aimed at proving a symptomatic etiology, (b) assessment of preexisting states and seizure precipitat- Clinical, EEG, and Magnetic Resonance Imaging Findings in Ep- ing factors, and (c) estimation of risk of seizure recurrence. In a ileptic Patients Referred to the Epilepsy Clinic. Ok Jun Kim (De- prospective study of 103 patients (aged 3-21 years) mean follow- partment of Neurology, Severance Hospital, Yonsei University, up 3.8 years) with single generalized tonic-clonic seizure (unpro- College of Medicine, Seoul, Korea)-3038. voked in 71, provoked in 32), an algorithm was designed for patient monitoring and management. Magnetic resonance imaging (MRI), EEG, and clinical assess- The preexisting state of the patient (particularly mental retar- ment were conducted in 320 consecutive epileptic patients re- dation or decreased intellectual functioning) and the interictal ferred to the Yonsei Epilepsy Clinic from October 1, 1992 to EEG discharges characteristic of a definable epileptic syndrome February 28, 1993. Clinical assessment suggested that 91.9% of on EEG after sleep deprivation were contributory in predicting our patients had partial seizures and only 8.1% had generalized risk of seizure recurrence. Although use of the algorithm cannot

Epilepsia, Vol. 35, Suppl. 7, 1994 24 EUROPEAN CONGRESS PROCEEDINGS settle all problems arising in management of a single seizure, its of epilepsy onset, type of seizures, interval between seizure on- use is justified for making rational decisions at the present level set and hospital consultation, previous antiepileptic (AED) med- of our knowledge. ication, and remission of seizures were analyzed. Frequency of seizures (mean number of seizuresiyear), AED and EEG findings were evaluated for each patient during the entire hospital follow- up period. The 181 patients (89 males and 92 females) had a mean Risk of Recurrence After a First Generalized Tonic-Clonic Seizure age at seizure onset of 19 years; 110 had more than one seizure in Children and Adolescents. karko MartinoviC and NebojSa Jo- type. Idiopathic epilepsy was more frequent in patients aged <20 viC (Departments of Neurology and Psychiatry for Children and years (56%) and with a single seizure type. In 78% of patients, Youth, Medical Faculty of Beograd University, Beograd, Yugo- neurologic examination was normal. Thirty-seven percent of pa- slavia)-3041. tients had at least one period of remission (22 years seizure- free), with only 12% in present remission. The interval between A sample of 71 patients (32 females and 39 males) who had a first seizure and first observation at HGSA has been decreasing first unprovoked generalized tonic-clonic seizure at age 3-21 continuously with time, but remained a 2-year interval in the last years was studied prospectively. Duration of follow-up was 2-9 decade. There was a significant interval between seizure onset years (mean 4.9 years). A second seizure occurred in 71.8% (51 and specialized neurologic consultation, with previous irregular, of 71), most commonly (33 of 51, 64.7%) in the first 3 months and at times inadequate, treatment. Because recent data suggest after the first seizure. All but 2 of 12 patients with symptomatic that early and adequate AED treatment may be a definite prog- etiology had recurrence of seizures, as did 41 of 61 patients with nosis factor in epilepsy, general practitioners’ knowledge of such idiopathic first seizure. According to the physiologic state at the factors might allow earlier referral and ameliorate the prognosis time of first seizure, patients were divided into a sleep group and of at least some patients. an awake group. Seizure recurrence was significantly more common in the sleep group (34 of 38, 89.5%) than in the awake group (17 of 33,51.5%). The second seizure occurred in the same state, i.e., night sleep or awake in 86.3% (44 of 51) of patients. The Spectrum of Neurocysticercosis Epilepsy: A Long-Term Follow-up presence of epileptiform patterns in the first EEG in sleep or in of 143 Patients. Belina Nunes, *Luis Monteiro, *Jog0 Lopes, and EEG after sleep deprivation was also significantly associated ?Denise Mendonsa (Departments of Neurophysiology and *Neu- with highly increased risk of recurrence. Sleep state at the time rology, Hospital Geral Santo Ant6nio; and ?Population Studies of first seizure, epileptiform EEG findings, and etiology or the Department, Instituto de CiCncias Biomadicas Abel Salazar, preexisting state of the patient are important predictors of sei- Porto, Portugal)-3044. zure recurrence. In an epilepsy outpatient clinic of a general university hospital with a referral population of -1,700,000 inhabitants with neurologic conditions, we made a retrospective study of 143 patients Prevalence of Epilepsy in an Outpatient Headache Clinic. R. with seizures and neurocysticercosis (NCC) to evaluate the prog- Chorrio, J. Barros, J. Pinheiro, A. P. Correia, J. Lopes, J. Ra- nostic factors of seizures resulting from NCC. Demographic data malheira, P. Monteiro, and L. Lima (Headache and Epilepsy and the following characteristics were analyzed: type and mode Outpatient Clinics, Department of Neurology, Hospital St. An- of onset of seizures, duration of epilepsy, timing of antiepileptic tonio, Porto, Portugal)-3042. treatment, computed tomography (CT) and EEG findings, and correlation of some of these parameters with seizure control. Any type of epilepsy or epileptic syndrome may be associated Pearson chi-square test and Student’s f test were used for sta- with any type of idiopathic headache, but the prevalence and the tistical analysis. Mean age at epilepsy onset of the 143 patients etiologic relation of this association are not fully understood. (62 males and 81 females) was 29 years (range 2-71 and SD 17.7 Prospective study of the prevalence of the epilepsies in a popu- years), and mean duration of epilepsy was 16 years (range 1-58 lation of headache patients may enlarge our knowledge of this years). Mean follow-up was 5.2 years (range 1-18 years). Sei- problem. zures were generalized tonic-clonic seizures in 35% and partial in We analyzed the medical records of 508 patients in our head- 65% (3 of 4 secondarily generalized). Seizures were controlled in ache outpatient clinic chosen randomly from patients followed 64% of patients and noncontrolled in 36%. A single seizure was during the last 5 years, and then performed a prospective anal- observed in 24 (17%) patients. Epileptic status as the mode of ysis of a similar number of new patients. Our study population onset, generalized tonic-clonic seizures, higher age at epilepsy comprised 466 patients with idiopathic headaches (migraine, 167; onset, brief disease duration, antiepileptic treatment since first tension type, 271; cluster, 12; not classified, 16) and 5 patients seizure, and a single granuloma on computed tomography (CT) with epilepsy (9.8 in 1,000), 4 with idiopathic headache (8.6 in were the findings related to best prognosis. Complex partial sei- 1,000), and 1 with migraine (5.9 in 1,000). The data are equivalent zures, younger age at epilepsy onset, long duration of epilepsy, to those in available literature and will be compared with those and late-onset treatment correlated with the worst prognosis. obtained from the prospective study now in progress. EEG and CT findings (excluding the single granuloma) were of no prognostic significance. NCC causes a wide spectrum of epileptic disorders. Chronic Epilepsy: A Study of Prognostic Factors in 181 Patients with Complex Partial Seizures. Belina Nunes, *Cristina Alves, *Ana Paula Correia, and ?Carolina Costa e Silva (Departments Validation of a Questionnaire for Detection of Epileptic Seizures in of Neurophysiology, and *Neurology, Hospital Geral Santo An- Epidemiologic Studies. Esmeralda LourenCo, *Manuela Santos, tonio; and tPopulation Studies, Instituto de CiCncias Biomedicas tJ. M. Lopes Lima, $.Jose M. Calheiros, $.Maria Eduarda, and Abel Salazar, Porto, Portugal)-3043. tPereira Monteiro (ServiCo de Neurologia, Hospital de Smarlos, Braga; *Hospital Maria Pia; ?Hospital de St. Antonio, Porto; and Recently, there ha been renewed interest in the concept of SInstituto de Cihcias Biomedicas Abel Salazar, Porto, Portu- chronic epilepsy and a search for early specific markers related gal)-3045. to seizure intractability, especially because results of studies of epilepsy prognosis performed in the community or hospital have Placencia et al. validated a questionnaire for detection of ep- differed. Hospital Geral Santo Antonio (HGSA) is the neurologic ileptic seizures in epidemiologic studies in the population of Co- referral center for a population of -1,700,000 inhabitants. We lombia. We attempted to duplicate their results using a different analyzed 181 patients with complex partial seizures (CPS) se- social setting and comparing patients with epilepsy with patients lected from 660 epileptic patients treated in 1992. Age and mode with nonepileptic paroxysmal pathology in our outpatient head-

Epileppsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 25 ache clinic. The 20 questions were translated into Portuguese ters by general practitioners, 18.1% were reported by specialists, and asked of 93 patients of the headache outpatient clinic and of and 223 (2.9%) patients asked for a consultation with a specialist; 100 patients of the epilepsy outpatient clinic of our hospital. 34.6% were observed GI year after seizure onset, whereas Diagnoses were confirmed by evaluation of the patients and/or 45.7% were observed after a long-lasting epilepsy history (>5 their chart. The questionnaire, after validation by Placencia et years). The data analysis demonstrates that, except for some al., was restricted to nine questions, which were also applied and special categories, International League Against Epilepsy clas- evaluated in our population. sification criteria generally are suitable in defining groups with The restricted questionnaire (nine questions after validation) regard to both clinical diagnosis and prognosis. gave a better result of 100% for sensitivity and of 47.31% for specificity as compared with 98 and 92%, respectively, in the original study of Placencia et al. Negative predictive value was loo%, and positive predictive value was 62%. These results Computerized Record for Epileptic Patients: Diagnostic Classifica- show the possibility of transcultural use of this questionnaire in tion and Drug Treatment. Simona Binelli for the Network of an even more difficult setting of a population with paroxysmal Epilepsy Centers of the Lombardia Region (Milano, Bergamo, pathologic events. Brescia, Cremona, Gallarate, Lecco, Mantova, Monza, Pavia, and Sondrio, Italy)-3048.

Of 7,834 epileptic patients referred to Centre Network, 5,484 Computerized Record for Epileptic Patients: Influence of Prospec- (70.0%) showed electroclinical features that fit well with a spe- tive Surveillance on Diagnosis and Treatment. Ettore Beghi for the cific epileptic syndrome according to the International League Network of Epilepsy Centers of the Lombardia Region (Milano, Against Epilepsy classification. Recognized diagnoses were id- Bergamo, Brescia, Cremona, Gallarate, Lecco, Mantova, iopathic age-related generalized epilepsies (922 cases, 11 .S%), Monza, Pavia, and Sondrio, ItaIy)-3046. idiopathic age-related focal epilepsies (397 cases, 5.l%), symptomatic or cryptogenic focal epilepsies (3,850 cases, 49.1%), age- The activities of the epilepsy centers of the Lombardia region dependent symptomatic or cryptogenic generalized epilepsies included monthly medical staff meetings aimed at developing (293 cases, 3.7%), and other age-related specific syndromes (22 common strategies for a proper diagnostic assessment and effec- cases, 0.3%). The remaining cases were classified as having non- tive therapeutic approach to the epilepsies. An auditing of these specifically defined generalized epilepsies, idiopathic in 437 activities was undertaken by comparing diagnoses and treatment cases (5.6%) and symptomatic in 284 cases (3.6%); 455 patients in a sample of 3,649 cases (of 9,208 patients referred to the cen- had epilepsy without unequivocal generalized or focal features ters) before and after a 3-year follow-up. During follow-up, di- (i.e., tonic-clonic seizures during sleep); 185 cases had seizures agnoses (according to the International League Against Epilepsy provoked by acute toxic or metabolic known factors. Of the 989 classification) were modified as follows. Idiopathic or symptom- remaining cases, 194 (2.5%) were not classifiable; 795 (10.1%) atic well-defined syndromes increased from 59.0 to 64.6%, non- showed atypical expressions of specific epileptic syndromes. specifically-defined generalized epilepsies and tonic-clonic sei- Clinical features, diagnostic procedures, and etiologic factors zures decreased from 21.5 to 16.9%, specific epileptic syndromes were analyzed. with atypical features decreased from 9.3 to 8.0%, and unclassi- Drug treatment was monotherapy in 4,686 patients (59.8%), fiable epilepsy increased from 0.9 to 1.3%. and polytherapy in 2,173 (27.7%); 975 patients receive no drug The most significant changes concerned the number of pa- (12.4%). Pharmacoresistance was assessed in 12.5% of the entire tients in whom therapy was discontinued (9.1 vs. 15.7%, p < population; occurrence was significantly greater in patients with 0.0001). Prescription of phenobarbital decreased during follow- symptomatic focal epilepsy (20.8%) and symptomatic general- up from 34. I to 29.4%; use of drugs recently introduced in clin- ized syndromes (53.6%). ical use (i.e., y-vinyl-GABA) increased from 2.5 to 5.5%). The percentage of seizure-free patients increased significantly (45.2% at the first check vs. 52.1% after three years, p < 0.0001); no significant change occurred in percentage of pharmacoresistant Long-Term Consequences of Head Trauma: Posttraumatic Epi- patients. lepsy and EEG Evolution. *?$A. Martins da Silva, *J. Lopes, *J. Ramalheira, tPR. MagalhPes, and T§D. MendonCa (*ServiGo de Neurofisiologia, Hospital Santo Antcinio, and tLaborat6rio Bi- ometria and $Unidade de Fisiologia Humana, Instituto de Cih- Computerized Record for Epileptic Patients: Data Collection and cias BiomCdicas Abel Salazar, and Unidade de Neurofisiologia, Sample Characteristic. Ferruccio Panzica for the Network of Ep- and PPsicofisiologia do IBMC, Universidade do Porto, Portu- ilepsy Centers of the Lombardia Region (Milano, Bergamo, ga1)-3049. Brescia, Cremona, Gallarate, Lecco, Mantova, Monza, Pavia, and Sondrio, Italy)-3047. Neurologic deficits, among them posttraumatic epilepsy or other cerebral dysfunction, as assessed by EEG recording, are We report data concerning 9,208 patients (4,680 males and frequent consequences of head trauma. A prospective study was 4,528 females) registered between June 1990 and December 1993 made of 152 patients with head trauma (contusion, haematoma, by the network of epilepsy centers of the Lombardia region. or penetrating head injury) by neurologic and EEG assessment. Coded information for each patient, including anamnestic data, Five years later, we studied long-term neurologic posttraumatic family history, neurologic signs, EEG features, neuroradiologic consequences in this population. Five patients died in the inpa- findings, and drug treatment was collected on a simple form and tient admission period, after the first clinical and EEG assess- entered into a database developed in dBase IV, implemented on ment; 25 patients are now regularly followed at the outpatient a personal computer. The consistency of the criteria for collect- clinic, and their neurologic and EEG status is known. The pop- ing and coding clinical information among the different centers ulation discharged and not regularly followed in our hospital out- was verified in regular monthly meetings. patient clinic (n = 122) was queried regarding different medical, Of 9,208 referred cases, 7,834 were affected by various epi- social, and professional aspects. Each patient was asked to an- leptic syndromes, 427 had febrile convulsions, 66 had neonatal swer a questionnaire in which they evaluated their present oc- seizures, 5 had benign neonatal convulsions, 287 had a single cupation and general medical complaints [i.e., relevant neuro- unprovoked seizure, and 589 cases had had nonepileptic ictal logic deficits, including behavior or general motor incapacity and events. Of the 7,834 epileptic patients, 25.9% were aged <15 seizures (type, frequency)]. Medical treatment(s) and EEG con- years. Age of seizure onset was <5 years in 3 I. 1% and > 15 years trols if performed were also determined. Those who answered in 35.1% of cases. the questionnaire were asked to undergo clinical and EEG eval- Forty-two percent of patients were referred to epileptic cen- uation to assess their current neurologic status.

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS

Occurrence of posttraumatic epilepsy was analyzed. In pa- Integration of Brain Mapping, Magnetic Resonance Imaging and tients who reported seizures, time of onset, type(s) of seizures, Positron Emission Tomography. Alexander C. van Huffelen (De- their eventual change, EEG characteristics, and evolution were partment of Clinical Neurophysiology, University Hospital determined and related to trauma and patient characteristics. Utrecht, Utrecht, The Netherlands)-4000c.

For successful strategy in epilepsy surgery, integration of functional (EEG, metabolic, receptor-binding) and structural [computed tomography (CT), magnetic resonance imaging Topic IV: Neurophysiology and Imaging (MRI)] data is essential. Multimodality matching aims at precise three-dimensional localization of these data: the epileptogenic zone with brain mapping and dipole modeling, the functional Main Session (4000a4000d) deficit zone with MR spectroscopy and positron emission tomography, and the epileptogenic lesion with CT and MRI. Concern- ing spatial resolution, these techniques diverge widely. The functional and structural data studied may range from strictly local- Magnetoencephalographic Integration with Other Imaging Tech- ized (epileptogenic lesion) to widespread (functional deficit niques: Methodologic Problems. Gian Luca Romani, Cosimo Del zone). In some patients, the findings of different techniques will Gratta, and Marco Peresson (ITAB-Universita “G. D’Annun- converge, in others, the abnormalities found (epileptogenic le- zio,” Chieti, Italy)4000a. sion, epileptogenic zone) may be adjacent but separate. For these reasons, no simple superimposition of abnormalities will The state of the art of neuromagnetic instrumentation consists result from multimodality matching. Several methods for match- of helmetlike systems covering the entire scalp. Consequently, it ing are available: extrinsic marker-based matching (frame, mark- is becoming possible to study cerebral events, such as those ers) and intrinsic feature-based registration. The former method related to normal and pathologic spontaneous activity, that pre- is highly reliable but inconvenient. The latter is presently pur- viously could be investigated only by sequential repositioning of sued, aiming at integration of noninvasive methods of three- systems with limited scalp coverage. Therefore, accuracy in neu- dimensional localization. Such an integrative noninvasive ap- romagnetic functional localization is strongly dependent on the proach will diminish the need for intracranial electrode implan- quality of integration with anatomic features. Multimodal inte- tation and, when interactively used, may assist neurosurgeons in gration is now becoming a fundamental issue, since association performing a patient-tailored operation. with anatomic images can be determined not only by using magnetoencephalography (MEG) data, but also EEG data and information from positron emission tomography (PET) and functional magnetic resonance imaging (MRI). The problem of proper integration of functional data with computed tomography and/or Image(s) of the Epileptogenic Zones. Patrick Chauvel and Jean- standard MRI is common to all these techniques. MEG specifi- Marie Scarabin (University Clinics of Neurology and Neurosur- cally concerns four basic steps: (a) monitoring of the relative gery, Hospital Pontchaillou, Rennes, France)--4000d. patient-sensors positioning during the recording session by markers attached to specific anatomic landmarks, (b) localiza- Development of powerful imaging techniques has significantly tion of cerebral sources with respect to the array of sensors, (c) improved the accuracy of topographic diagnosis in partial epi- fitting of the identified sources in the patient’s head, and (d) lepsies during the last decade. Magnetic resonance imaging integration of the results with anatomic images where the same (MRI) has detected lesions and structural abnormalities hitherto landmarks are appropriately identified. invisible and assigned to them a definite anatomic localization. Functional imaging techniques [positron emission tomography, single photon emission computed tomography (SPECT), and MRI] during interictal periods have demonstrated altered re- Magnetic Resonance Imaging and Magnetoencephalography : Syn- gional metabolism, correlated with the epileptogenic area. A de- thesis of Function and Anatomy. H. Stefan, c. Hummel, P. tailed analysis of seizure symptomatology, in conditions of strict Schiiler, M. Deimling, and M. Buchfelder (Department of Neu- time correspondence with multichannel surface and/or depth rology, University Erlangen-Niirnberg, Erlangen, Germany)- EEG activities, provided by more general use of videotelemetry, 4000b. has promoted the concept of “localization-related epilepsies” in the last International Classification of the epilepsies. A better A particular advantage of localizing epileptic foci from mag- spatial resolution of SPECT technology, allied with the possibil- netoencephalography (MEG) as performed in the present study ity of injecting HMPAO during the course of partial seizures, has is merging anatomic data from magnetic resonance imaging offered a new tool for obtaining a representation of the epilep- (MRI) and functional information from MEG. Analyses of data togenic area. At last, the search for clinical applications of mag- from 37 channels were based on the equivalent current dipole netoencephalography (MEG) has led to design of new multichan- model in a homogeneously conducting sphere. nel magnetometers and has caused the EEG community to think To date, 107 epileptic patients have been investigated with in terms of source localization rather than in terms of grapho- MEG. In >90% of the evaluated cases with temporal lobe epi- elements. Thus, combined use of MEG and EEG brings new leptic (TLE) foci (46 of 50), specific epileptic signals were iden- refinements to anatomic identification of interictal discharge or- tified in MEG, the majority of which (82%) yielded localizations igin. However, the abundance of data produced by research and in the temporal lobe. MEG data of 36 patients with pharmacore- clinical teams, each specialized in one or the other of these meth- sistant TLE who underwent neurosurgical treatment were avail- ods, has also given rise to confusion about the parameter of the able; 29 patients were significantly improved postoperatively. epileptogenic organization that was actually measured. In par- Focus localization from MEG in 24 of these successfully oper- ticular, the separation between lesional, hypometabolic, and ep- ated patients was correct as to lobar assignment, and in 11 of 14 ileptogenic zones is far from being always clear. The “real time” cases closely corresponded with epileptogenic mass lesions. (physiologic and clinical) markers of epileptogenic activity on the To determine the relation between epileptic foci and function- one hand (dynamic markers) and the volume parameters of le- ally important areas, the sources of somatosensory evoked mag- sional and functional deficit areas on the other hand (static mark- netic fields were investigated in patients whose foci lay in central ers) should be considered and managed as having a distinct na- regions. Functional MRI was successfully tested as another tool ture, but physically fusioned into a common (stereotaxic) refer- to assess imaging of primary motor, supplementary motor, and ence representation. The present image analysis methods have sensory cortex. now made this hope accessible.

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 27

Platform Presentation 1 (4001-4006) in consecutive bipolar derivations or analysis of amplitude and duration variations in monopolar montages. Most computerized detectors emulate such classic methods and can extract some Neurophysiologic Approach to Children with Epilepsy. Perrine more information from the paroxysms present in the EEG. We Plouin (HBpital Saint Vincent de Paul, Paris, France)--4001. have been using such techniques with encouraging results, but in many cases, EEG monitoring of epileptic patients is still incon- The definition of epilepsy syndromes in infancy and childhood clusive. Sometimes no ictal events occur; in some cases, interic- includes the interictal and ictal EEG patterns of each. These tal events are too few, or, even if ictal or interictal events occur, EEG patterns may be univocal as in childhood absence epilepsy they lead to noncoherent locations (e.g., when synchronous or may exhibit different aspects as in infantile spasms. Use of spikes are present and suspicion of partial beginning seizures of polygraphic recordings, video EEG monitoring, and 24-h ambu- foci localization remains). In such cases, we must extract more latory EEG monitoring has allowed us to recognize isolated information to obtain a coherent result. spasms and clusters, to differentiate different types of spasms, That only an average of 30% of EEG tracings of our patients and to recognize other types of seizures associated with spasms. were considered paroxysmal, raises a first question: Why do we Partial seizures may occur independent of spasms, but may also generally use only paroxysmal activity to determine foci loca- precede them, be intermixed, or follow them. Generalized sei- tion? Thus, the central question is: Do changes in background zures, clonic or tonic, may also be present, as may even axkl EEG activity provide any information about foci localization? and erratic myoclonia. Association of different types of seizures We are studying a group of epileptic patients and a control is noted only in cryptogenic and symptomatic cases with poor group of normal subjects (as of now, there are 20 subjects in each outcome with regard to epilepsy. The interictal EEG pattern may group) using several linear and nonlinear interchannel correla- also be different according to various etiologies: typical or atyp- tion measures. The results obtained so Far appear to answer the ical hypsarthythmia, asymmetrical tracing, presence of focal or central question affirmatively. multifocal abnormalities, and presence of more specific patterns as in lissencephaly or laminar heterotopia. Asymmetry of the tracing can be delineated by intravenous injection of diazepam. Ictal Events During Sleep. Teresa Paiva (C. E. E. M., Hospital de The type of ictal and interictal EEG patterns aids in assessing Santa Maria, Lisbon, Portuga1)4004. diagnosis of infantile spasms, in guiding etiologic work-up, and in evaluating outcome. Sleep and sleep deprivation are important triggers of paroxysmal activity. Many epileptic patients (30-50% with generalized epilepsies and 40% with secondarily generalized epilepsies) ex- “Epileptiform’? and “Nonepileptiform” Ictal EEG Patterns in Ep- perience crisis only during sleep (Janz, 1962; Billiard, 1982). A ilepsy. W. van Emde Boas, G. J. F. Brekelmans, and D. N. Ve- nocturnal “crisis” requires specific investigation. First, one lis (Department of Clinical Neurophysiology, Instituut voor Ep- must distinguish between epilepsy and a nonepileptic disorder. ilepsiebestrijding, Meer en Boschide Cruquiushoeve, Heem- Second, possible relations with sleep stages, arousal stimuli, and stede, The Netherlands)-4002. the awakening period must be identified. Among nonepileptic disorders, several parasomnias should be considered, such as Ictal EEG studies are performed for diagnosis and classifica- somnambulism and sleep terrors. Somnambulism episodes are tion of seizures and seizure disorders, for quantification of sei- associated with bursts of slow-wave activity, but in most cases zures, for evaluation of treatment and, notably, for localization the differential diagnosis is straightforward. However, some pa- of the epileptogenic zone for possible surgical treatment. tients may have an association of the two disorders, somnambu- Whereas most types of generalized seizures are associated with lism and epilepsy, and others may have a truly epileptic disorder well-defined and “typical epileptiform” EEG patterns, during with nocturnal paroxysmal wanderings associated with focal partial seizures the EEG may show a wide variety of patterns or spikes. Nocturnal paroxysmal dystonia may also present com- even no change, depending on type of seizure, site of origin, and plex diagnostic problems owing to the overlap and association extent of seizure propagation, In scalp recordings, EEG changes with epilepsy; however, a normal critical EEG favors the ex- may coincide with or even precede clinical onset of the seizure, trapyramidal etiology. but in partial seizures usually have “delayed” onset patterns, lctal EEG patterns in epileptic disorders are generally similar which nevertheless may have definite localizing value. to those observed during the awake state. Differences are related Ictal patterns can be localized, lateralized, diffuse, or gener- to some specificities, as in Lennox-Gastaut syndrome, with tonic alized, and may consist of rhythmical typical epileptiform tran- events occurring during sleep concurrent with runs of rapid sients such as spikes or spike and waves, but can also consist of spikes; hypsarrhythmia showing enhanced stretches with de- rhythmic or irregular activity ranging from subdelta to Fast beta creased voltage, and electrical status epilepticus during sleep activity of varying amplitude and duration. Moreover, ictal pat- (ESES), with continuous spike and wave activity not associated terns may change during seizure evolution and may vary from with clinical manifestations. The specific influence of sleep seizure to seizure, even in an individual patient. Disappearance stages and arousal mechanisms on ictal and interictal events pre- of interictal paroxysmal activity or local or diffuse attenuation of sents different patterns for the epileptic entities. A deviant ongoing activity, although not an ictal pattern as such, should not arousal mechanism has therefore been proposed for generalized be disregarded. For preoperative evaluation, additional elec- epilepsies (Niedermeyer, 1984). trodes and modified montages may be required. To optimize diagnostic value and to assist in differentiation with artifacts, ictal EEG patterns should always be interpreted together with clinical signs and symptoms. Combined EEGklosed-circuit TV Effect of Epilepsy, Seizures, and Epileptic EEG Activity on Intel- is usually mandatory. ligence and Cognitive Function. A. P. Aldenkamp, Th. Gutter, L. Diepman, A. M. Beun, 0. G.Mulder, and J. Overweg (Instituut voor Epilepsiebestrijding, Meer en Bosch, Heemstede, The Do Changes in Background EEG Activity of Epileptic Patients Netherlands)4005. Provide Any Information on Foci Localization? *TJotio P. Silva Cunha, *Pedro Guedes de Oliveira, and tAnt6nio Martins da Impairment of intelligence and cognitive function in patients Silva (*INESC, Norte, and tDepartment of Neurophysiology, with epilepsy has been documented in several studies. Although St. Ant6nio Hospital, Porto, Portugal)4003. often associated with the pathologic sequela of seizures, the relative contribution of ictal and interictal effects of epilepsy is still Location of the sources of epileptogenic events is performed unclear. In a prospective nonrandomized controlled parallel visually using the classic methods of determining phase reversals group study, we examined five groups of patients to differentiate

Epilepsia, Vol. 35, Suppl. 7, 1994 28 EUROPEAN CONGRESS PROCEEDINGS

the interictal effects of epilepsy from the direct effects of sei- Phosphorous MRS may be used to measure pH, inorganic zures and epileptiform EEG activity. The first group of patients phosphorous, phosphocreatine, and ATP. Increased alkalinity (n = 25) had regular tonic-clonic or complex partial seizures and reduced inorganic phosphorous has been found in associa- (TCS, CPS). None of these patients had a seizure in the 24 h tion with epileptic foci. Proton MRS may identify N-acetyl as- preceding the testing day. A second group of patients (n = 25) partate, choline, and creatine in vivo. In patients with temporal had a TCS or CPS during the testing day, immediately after the lobe epilepsy owing to HS, the NAA/creatine plus choline ratio testing procedure. A third group of patients (n = 25) had seizures is reduced, suggesting neuronal loss and/or dysfunction in the with subtle symptomatology, observed during the testing day. region of the focus; 40% of patients also show a contralateral The symptoms were mostly facial movements, often hidden in reduction. the normal behavior pattern of the patients. A fourth group of patients (n = 25) exhibited frequent epileptiform activity in the EEG, but without manifest clinical symptoms. A control group of subjects (n = 25) did not have epilepsy. All subjects were assessed with the Wechsler intelligence test Hippocampal Asymmetry in Temporal Lobe Epilepsy: An Update. and a set of cognitive tests performed simultaneously with 21- Leyla de Toledo-Morrell, Frank Morrell, Michael P. Sullivan, channel EEG recording and continuous (two-camera) video Donna C. Bergen, Andres M. Kanner, Serge J. C. Pierre-Louis, monitoring. Our results demonstrate the detrimental effects of Ruzica Ristanovic, Michael C. Smith, and Walter W. Whisler seizures relative to other epileptic conditions, on cognitive func- (Departments of Neurological Sciences, Psychology and Neuro- tion. Global impairment (as indicated by lower intelligence surgery, Rush-Presbyterian-St. Luke’s Medical Center, Chi- scores) of the group of patients with “subtle seizures” was par- cago, IL, U.S.A.)--4008. ticularly apparent. Volumetric measurement of magnetic resonance images was used to estimate hippocampal atrophy to determine (a) if a significant asymmetry in hippocampal volume (HV) correctly lat- Relationship Between the Extent and Morphology of Hippocampal eralized the seizure focus, and (b) if the volume asymmetry cor- Sclerosis and Neuropsychological Function. Sallie A. Baxendale, related with electrocorticographic (ECoC) indexes of epilepto- Mark Cook, Pamela J. Thompson, Simon D. Shorvon, and Eliz- genicity. HV was computed from gapless 5-mm coronal slices abeth K. Warrington (Epilepsy Research Group, Institute of taken perpendicular to the long axis of the hippocampal forma- Neurology, Queen Square, London, and Chalfont Centre for Ep- tion. The mean normal (n = 21) difference ? 2 SD defined the ilepsy, Chalfont St. Peter, Bucks, England)4006. threshold for asymmetry. ECoG were derived from strip electrodes inserted in the temporal horn of the lateral ventricle dur- We examined the relation between preoperative magnetic res- ing operation. onance imaging (MRI) hippocampal morphology and neuropsy- Significant HV asymmetry was observed in 18 of 31 cases chological test performance. Thirty-two patients with temporal (58%). In 17 of 18 asymmetrical cases, the side of the smaller lobe epilepsy and hippocampal sclerosis [I6 left (LHS), 16 right hippocampus correctly identified the focus; in 1, it was mislat- (RHS)] underwent a neuropsychological assessment. Laterality eralizing. ECoG recordings directly from hippocampus were ob- effects were observed on two of the memory tasks. Patients with tained in 26 of 31 cases; 15 of 26 exhibited HV diminution, but in RHS made more intrusion errors on a list-learning task and had 3 of these the hippocampus was free of epileptic abnormality and poorer percentages of retained scores on a story-recall task than was judged by other functional measures (including amobarbital did those in the LHS group. In the RHS group, patients with test) to be functioning normally. Of the 11 cases without HV anterior volume loss were significantly more impaired than pa- asymmetry, 5 showed hippocampal spiking and functional defi- tients with diffuse volume loss on a design-learning task. In the cit. LHS group, patients with diffuse volume loss were significantly Thus, although hippocampal atrophy is helpful in lateralizing more impaired than patients with atrophy limited to the anterior the focus, it does not reliably predict epileptogenicity or func- portion of the hippocampal formation on the Graded Naming tional compromise. Moreover, lack of HV asymmetry does not Test. The findings were assessed in relation to previous research exclude an epileptogenic hippocampus. documenting memory-specific impairments in patients with hippocampal neuron loss.

Three-Dimensional Images and Robotics for Planning of Epilepsy Surgery. Isabelle M. Germano, AndrC Olivier, Arthur Cukiert, and Terry Peters (Department of Neurosurgery, Mount Sinai Platform Presentation 2 (40074012) School of Medicine, New York, NY, U.S.A.; and Department of Neurosurgery, Montreal Neurological Institute, Montreal, Can- ada)--4009.

Qualitative and Quantitative Magnetic Resonance Imaging and Use of three-dimensional (3D) magnetic resonance imaging Spectroscopy in Evaluation of Epilepsy. John S. Duncan (Institute (MRI) and computed tomography scans offers great advantages of Neurology: National Hospital for Neurology and Neurosur- for accurate planning and performance of neurosurgical proce- gery, National Society for Epilepsy, Chalfont St. Peter, Bucks, dures for medically refractory epilepsy. We used a computer- England)--4007. and robot-assisted system to plan and perform 31 operations for epilepsy, including selective amygdalohippocampectomy, “le- Considerable advances have been made in imaging of epilepsy sionectomy ,” callosotomy , temporal reoperation, neocortical re- the last 5 years using magnetic resonance imaging (MRI) and section, and placement of depth electrodes. This system consists magnetic resonance spectroscopy (MKS). Hippocampal sclero- of an image-processing computer that creates 3D and triplanar sis (HS) can be reliably identified using optimal MRI, and the images, a mobile computer to display the reformatted images, cardinal MRI features of HS have been determined. Quantitation and a robotic arm. Preoperative planning is done on the 3D im- of hippocampal volume and shape and measurement of T, relax- ages, allowing optimization of the surgical approach. At the be- ation time adds precision and sensitivity to visual assessment. ginning of the operation, the patient’s facial features are identi- MRI is Significantly superior to x-ray computed tomography for fied with the robotic arm and correlated with the 3D images. The identification of lesions that give rise to partial seizures, such as arm can then be used intraoperatively to guide the surgeon. indolent gliomas. dysembryoplastic neuroepitheliomas, caverno- Advantages of this system include the design of smaller cran- mas, and areas of cortical dysplasia. iotomies and easier intraoperative localization of the lesions or

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 29 structures to be removed. Postoperative MRI showed that this planes. Decrease in FLU binding was spatially more restricted technique was accurate within 3 mm in measuring the anteropos- than GH and could therefore have a closer relation with the terior resection of the hippocampus and corpus callosum. In our epileptic focus than GH. in these patients suspected of having experience, use of this system is most helpful in planning and mesiotemporal epilepsy (and sclerosis), FLU is probably a very performing most surgical procedures for the epilepsies. sensitive marker of neuronal loss. Loss of benzodiazepine receptors paralleled neuronal loss in surgical specimens of TLE patients. To test the hypothesis that FLU is a neuronal marker, we also Imaging and Pathologic Studies in Temporal Lobe Epilepsy. J. studied 2 patients with partial epilepsy and neuronal migration Zentner, $H. K. Wolf, tB. Ostertun, A. Hufnagel, J. Schramm, disorders. In both, the neurons abnormally located were labeled *C. E. Elger, and *O. D. Wiestler (Departments of Neurosur- with FLU and FDG; delineation of these neurons cerebral white gery, *Epileptology, tNeuroradiology, and $Institute of Neuro- matter was sharper with FLU than with MRI of FDG scans. pathology, University of Bonn, Bonn, Germany)4010. FLU is a particularly useful neuronal marker in evaluation of partial epilepsy. The relationship between structural abnormalities and seizures is a matter of increased interest. We report the correlation of preoperative magnetic resonance imaging (MRI) studies, histopathological findings, and postoperative seizure control in 216 Combination of Information in Epilepsy: Integration of Magnetic consecutive patients with chronic medically intractable temporal Resonance Imaging, Single Photon Emission Computed Tomogra- lobe epilepsy who were operated on between November 1987 phy, Electrocorticography, and Magnetoencephalography. * tG. and January 1993. Hellmann, tM. Spreng, and *H. Stefan (*Departments of Neu- Histopathologically, 75.9% of surgical specimens showed dis- rology and ?Physiology and Biocybernetics, University Erlan- tinct structural abnormalities. Signal abnormalities on MRI were gen-Niirnberg, Erlangen, Germany)--4012. evident in 98.6% of all patients with neoplastic lesions (n = 79, 75% of patients with nonneoplastic focal lesions (n = 51), and Epilepsy diagnostics is based on results of various consulting 68.4% of patients with Ammon's horn sclerosis (n = 38). Over- methods. The aim of all investigations is localization and defini- all, structural abnormalities were detected by MRI in 78.7% of tion of size of the epileptogenic area. The necessary precise an- patients. Mean postoperative follow-up period was 2.75 years. atomic correlation of all information can be achieved by mag- During this time, 118 patients (57.3%) were seizure-free, 32 netic resonance imaging (MRi). To calculate slices of the shape (15.5%) had two or fewer seizures a year, 35 (17%) showed a of the patient's individual brain, the implanted electrodes are reduction in seizure frequency of at least 75%, and 21 patients positioned semi-automatically or according to radiographic im- (10.2%) had no worthwhile improvement. in particular, 68.1% of ages. Similarly, magnetoencephalography data, and ictal and inpatients with neoplastic lesions and 68.4% with Ammon's horn terictal single photon emission computed tomography (SPECT) sclerosis were seizure-free as compared with 51. I% of patients images are combined on the same system, by markers or contour with nonneoplastic lesions and 3 1.2% of those with no specific lines. Thus, the quantitative results of MRI, SPECT, spike den- histopathological abnormalities. sity, propagation of spike events, leading information, and dipole The presence of focal lesions or Ammon's horn sclerosis is localization are visualized. We used this method in a case of associated with improved postoperative seizure control as com- temporal lobe epilepsy. A multimethod localization and integra- pared with that of patients with no specific pathological findings. tive approach for improvement of the definition of resection area MRI is very sensitive in detecting neoplasms, but its sensitivity is now possible, allowing all information about the patient to be and specificity is limited with respect to nonneoplastic focal le- easily documented. sions and Ammon's horn sclerosis. Improvement of imaging techniques may provide more precise definition of structural lesions in such cases and facilitate limited surgical resections of the epileptogenic area rather than standardized anatomic resections. Poster Session (4013-4087)

["C]Flumazenil Positron Emission Tomography: An In Vivo Marker of Neuronal Loss in Temporal Lobe Epilepsy. B. Sadzot, *R. M. Debets, G. Delfiore, *C. W. Van Huffelen, *A. C. van Quantitative Intraoperative Electrocorticographical Monitoring Veelen, C. Degueldre, G. Moonen, and G. Franck (Heemstede, Using a High-speed Computer System. *tG. Hellmann, tM. The Netherlands; and *Department of Neurology CHUB35, Spreng, and *H. Stefan (*Departments of Neurology and tPhys- Likge, Belgium)-4011. iology and Biocybernetics, University of Erlangen-Niirnberg, Erlangen, Gerrnany)4013. We evaluated and compared the regional changes in benzodiazepine receptors and in glucose metabolism in patients with During epilepsy surgery, electrocorticographic (ECoG) re- temporal lobe epilepsy (TLE) included in a presurgical protocol: cordings are made before and after resection of epileptogenic 20 patients with TLE underwent magnetic resonance imaging areas and must be evaluated in a limited time, e.g., before re- (MRI), scalp EEG with video monitoring, and sequential posi- section is completed. Beside monitoring functions, a new ana- tron emission tomography studies with 20 mCi high SA ["Clflu- lytical system for spike recognition also makes possible use of mazenil (FLU) and 10 mCi 18FDG (FDG). FDG scan was per- detailed spike search analysis and representation of absolute and formed 105 min after FLU injection. Parametric images of glu- temporal distribution of spikes. In addition, the results are also cose consumption and summed images of FLU uptake were visualized in an anatomic scheme. Furthermore, spike-leading obtained. For each tracer, a transverse and a coronal plane pass- information, which is referred to channels, and direction of spike ing through the hippocampus (HP) and the temporal cortex propagation are computed. Thus, the size of the epileptogenic (TpCx) were selected and percentage of asymmetry between left area is proved quantitatively for tailored resection. The basis of and right regions was calculated. No patient had gross anatomic this system is a program able to distribute failsafe orders to sev- lesion on MRI, hut 10 demonstrated changes in signal intensity in eral computer systems and process them in parallel simply using the mesiotemporal region. FDG and FLU scans were always the master-slave principle. With increasing recording condi- abnormal in the temporal lobe suspected of including the epilep- tions, one can keep up with the recording through additional tic focus. Degree of glucose hypometabolism (GH) was similar in connected computer systems. We demonstrated results of com- HP and TpCx (+-20%),whereas the decrease in FLU binding was puterized analyses for intraoperative ECoG monitoring in tem- predominant in or limited to HP and best appreciated on coronal poral lobe epilepsy. 30 EUROPEAN CONGRESS PROCEEDINGS

Magnetic Resonance Imaging Detection of Hippocampal Pathology the largest circle (T, circle) that could be placed in the hippo- in Temporal Lobe Epilepsy: Role of Hippocampal T, Relaxometry campus while still avoiding CSF boundaries. We also outlined in Childhood Epilepsy. Graeme D. Jackson, J. Helen Cross, Alan the hippocampal formation on the T, map and measured the area Connelly, Brian G. R. Neville, and David G. Gadian (Institute of and T, values (T, outline) in the same outline. Mean difference Child Health, Hospital for Sick Children, London, England)- between T, circle and T, outline was 2.5 ms (SD 4.5 ms). T, 4014. circle was > 115 rns in 32 of 36 patients (89%) with hippocampal sclerosis (HS); T, outline was >115 ms in 24 of 36 patients with Quantitative magnetic resonance imaging (MRI) T, relaxome- HS (67%). However, all 31 patients with T, outline >108 ms and try provides an objective means of assessing signal abnormality hippocampal area ratio <0.71 (ipsilateral small hippocampus) in the hippocampus. We applied this technique to children with had HS. In addition, 3 patients with area ratio >0.71 had a T, intractable temporal lobe epilepsy (TLE). outline >I15 ms, consistent with HS. The outline therefore cor- Fourteen children (mean age 11 years 5 months) with intrac- rectly identified 34 of 36 patients (94%) with HS and also iden- table TLE were investigated. Structural imaging was performed tified a patient with a small hippocampal area and high T2on the in the tilted axial and coronal planes. T2 maps throughout the opposite side. Hippocampal outline on a T, map gives lower T, hippocampal body were calculated from 16 images obtained at values than a circle, but provides additional information on hip- echo times of 22-262 ms using a Carr-Purcell-Meiboom-Gill se- pocampal area ratio, making it an attractive screening test in quence. Previous adult control data has suggested a normal patients with intractable TLE. range of 106106 ms. All but 1 child had T, relaxation time greater on the side ipsilateral to the seizure focus. In 9 children, this time was > 116 ms (range 117-140 ms); 8 of these children had diagnostic features of Combination of T, Relaxometry and Volumetrics of the Hippocam- hippocampal sclerosis on MRI, and 1 had hippocampal atrophy pus Identifies Clinically Useful Subgroups of Patients with Intrac- (Rasmussen's encephalitis on pathology). Four children had an table Temporal Lobe Epilepsy. W. Van Paesschen, *S. Sisodiya, ipsilateral T, in the range of 108-113 ms (2 tumors, 1 dysplasia, *A. A. Raymond, *R. A. Griinewald, *tJ. S. Duncan, $A. Con- nelly, $G. D. Jackson, *tS. Shorvon, *tD. R. Fish, and and 1 normal). In 1 child, T2 was bilaterally normal. Of the con- D. tralateral hippocampi, 4 showed definite abnormality (1 16115 tJ. M. Stevens (*Institute of Neurology, Epilepsy Research ms), 5 showed borderline abnormality (107-110 ms), and 5 were Group; ?National Hospital for Neurology and Neurosurgery; normal. Hippocampal T, relaxation time measurement is a sen- and $Institute of Child Health, Queen Square, London, En- sitive and useful measure of hippocampal pathology and bilateral gland)-40 17. abnormalities are visualized in at least 30% of these children with intractable TLE. We studied 38 patients with T2 relaxometry and volumetrics of hippocampus in preoperative evaluation of intractable temporal lobe epilepsy (TLE). We divided patients into groups according to results of hippocampal T, ipsilateral to seizure focus and hip- Metabolite Abnormalities in the Temporal Lobes of Children with pocampal volume ratio (ipsilateral/contralateral). Twenty-nine Intractable Epilepsy Demonstrated by Proton Magnetic Resonance patients had a T, value >lo6 ms in combination with volume Spectroscopy. J. Helen Cross, Alan Connelly, Graeme D. Jack- ratio <0.95. Twenty-eight of these 29 patients (97%) had mag- son, Brian G. R. Neville, and David G. Gadian (Institute of Child netic resonance imaging evidence of hippocampal sclerosis (HS), HealthiHospital for Sick Children, London, England)4015. confirmed pathologically in 24. One patient had a glioma. A second group of 4 patients had normal T, and a volume ratio <0.95: Noninvasive localization of the seizure focus is an essential 1 patient had a DNT, another had gliosis of hippocampus, and 2 step in preoperative evaluation of children. Magnetic resonance require depth EEG. Two patients had normal T, and volumet- imaging spectroscopy (['HIMRS) can detect neuronal loss or rics: 1 had a DNT; the other had a high T, signal in the ipsilateral damage and possibly astrocytosis by detecting the metabolites amygdala. Two patients had high T, but normal volumes: 1 had N-acetylaspartate (NAA), choline-containing compounds (Cho), a cavernous hemangioma; the other had unspecified temporal and creatine plus phosphocreatine (Cr). lobe gliosis. One patient with high T2 and contralateral atrophy Twenty-one children aged 5-17 years (mean 11 years) with had two seizure foci. intractable temporal lobe epilepsy (TLE, 14 left, 7 right) were High T, with hippocampal atrophy reliably identified HS. Dis- investigated. Magnetic resonance was performed with a 1.5-T cordance of T, and volumetrics might be indicative of other Siemens whole body system. Structural imaging was performed cause or a combination of causes of intractable TLE. in the tilted axial and coronal planes. ['HIMR spectra were obtained from 2 X 2 X 2-cm cubes in the mesiotemporal region. Results were expressed as the signal intensity ratio NAA/Cho + Cr. MRI demonstrated unilateral abnormality of one temporal Demonstration of Unsuspected Gyral Abnormalities by Three- lobe in 14 children and bilateral abnormality in two. Five had Dimensional Reconstruction of Magnetic Resonance Images. s. M. normal imaging. ['HIMRS was abnormal in 17 of 21 patients, Sisodiya, A. A. Raymond, J. Stevens, D. R. Fish, and S. D. with unilateral abnormalities in 11 children (consistent with the Shorvon (Epilepsy Research Group, Institute of Neurology, clinical focus in 10) and bilateral abnormalities in 6 (lower on the London, England)4018. ipsilateral side in 5). In the remaining 4 children, ratios were bilaterally normal but lower on the ipsilateral side. Therefore, Magnetic resonance imaging (MRI) has detected cerebral ['HIMRS may aid in lateralization of the seizure focus and can structural abnormalities in many patients with partial epilepsy. detect bilateral pathology in children with intractable TLE. Occasionally, however, where even focal EEG abnormalities direct the attention of neuroradiologists to a given area, abnormalities are not always apparent on multiple sequences and volumetric acquisitions displayed in two dimensions. Even multipla- T, Mapping Can Provide Quantitative Information on Both T, nar reformatting may not show lesions. Signal Change and Atrophy in the Hippocampus of Patients with Using a dedicated computer system, we reconstructed volume Intractable Temporal Lobe Epilepsy. W. Van Paesschen, *G. D. acquisition scans into three-dimensional objects representing ei- Jackson, R. Griinewald, *A. Connelly, and J. S. Duncan (Insti- ther the cortical surface or the surface of the white matter, which tute of Neurology, Epilepsy Research Group, Queen Square; also constitutes an MRI gray-white interface. In 10 subjects, this and *Institute of Child Health, London, England)4016. technique disclosed gyral abnormalities that had not been detected in two-dimensional analysis initially. In 3 cases, the posi- We studied 51 patients with intractable temporal lobe epilepsy tion of the abnormalities, exposed by the greater information (TLE) with T, relaxometry of hippocampus. T, was measured in content of three-dimensional pictures, was consistent with ob- EUROPEAN CONGRESS PROCEEDINGS 31 served semiology and focal EEG changes. Structural changes Paola Salvadori, SPietro Pietrini, and Daniela Brizzolara (INPE- were disclosed for the first time in a case of familial frontal lobe IRCCS Stella Maris; *Istituto Clinica, Psichiatrica; and tlstituto epilepsy and in the ipsilateral frontal lobe of a patient who had di Fisiologia Clinica, CNR Univerita Pisa, Italy; and $National previously undergone temporal lobectomy in an unsuccessful at- Institutes of Health, Bethesda, MD, U.S.A.)4021. tempt to control his seizures. Therefore, although currently labor-intensive and time-consuming, such reconstruction is of Of 90 consecutive patients with epilepsy or prolonged febrile value in detecting abnormalities and guiding clinical manage- seizures as initial symptom who underwent cerebral magnetic ment. resonance imaging (MRI), 10 showed hippocampal atrophy and sclerosis, with or without amygdalar involvement. Nine had prolonged febrile convulsions (PFC) (>30 min) in infancy and 8 had epilepsy, characterized in 7 by temporal lobe complex partial Magnetization-Prepared Rapid Gradient Echo Magnetic Reso- seizures, well controlled in most. In only 1 patient, interictal nance Study of Neuronal Migration Anomalies. R. De Blasi, *R. EEG abnormalities were homolateral to the lesion; 8 had bilat- Bellomo, *L. M. Specchio, C. Andreula, and A. Carella (Neu- eral and 1 had contralateral abnormalities. Memory function as- roradiology and Neurophysiopathology, Neuroradiology Poli- sessment in 5 of 8 patients showed material specific impairment clinico, Bari, Italy)-4019. not found in controls or in children with frontal lobe seizures and temporal lobe seizures without demonstrable lesions. We examined 15 patients, all with neuronal migration disor- Five of the 8 patients studied neuropsychologically underwent ders (NMD) for epileptic syndromes, with a three-dimensional, positron emission tomography with '*FDG to evaluate regional TI-weighted gradient-echo sequence termed MP RAGE (magne- cerebral glucose metabolism (rCMRglc). All showed asymmetric tization prepared rapid gradient-echo) to define accurately the rCMRglc with hypometabolism on the lesion side with lowest nature of the lesion and its extent for eventual surgical treatment, values in the mesiotemporal region, consistent with neuropsy- even for the most drug-resistant forms. chological data and with ictal EEGs recorded in 2 patients. Accurate differentiation between pachygyria and micropo- Structural mesiotemporal abnormalities observed on MRI in lygyria is necessary for determination of their different etio- children can be correlated with a specific memory dysfunction pathogenesis, the first being more linked to genetic disorders, the and with interictal hypometabolism, even when seizures are in- last to acquired factors, above all infective, and expressed as frequent. Surface interictal EEG is not reliable in lateralizing the vascular damage. The MP RAGE sequence represents a useful epileptogenic area or lesion. diagnostic tool with all the advantages of three-dimensional technique: slice thickness of 1-2 mm, images heavily TI-weighted, and the possibility of multiplanar reconstruction along planes different from the acquisition plane. With this technique, the thickness of cortical gray matter is easily calculated and the pres- Value of Postoperative Imaging Studies in Epilepsy Surgery. Neil ence of subtle interdigitations between cortex and subcortical D. Kitchen, David R. Fish, and Simon D. Shorvon (Epilepsy white matter are better defined. We considered MP RAGE im- Research Group and the Institute of Neurology, Queen Square, ages superior to SE TI and T,, sequences, especially for detec- London, and the Chalfont Centre for Epilepsy, Chalfont St Pe- tion of small cortical dysplasias and differentiation between lo- ter, Bucks, England)4022. calized areas of mycropolygyria and pachygyria. Epilepsy surgery has become increasingly image guided, with advanced preoperative neuroradiologic imaging studies routinely used in many centers. Postoperative imaging, however, has not Functional Integrity of Cortical Dysplasia. M. P. Richardson, been widely reported, which represents a significant loss of po- M. J. Koepp, J. S. Duncan, M. C. Prevett, V. Cunningham, R. tentially useful scientific and clinical information. Ali, S. Free, D. Fish, and D. J. Brooks (MRC Cyclotron Unit, We used high-resolution, volumetric magnetic resonance im- Hammersmith Hospital, London, England)-4020. aging (MRI) in ,100 patients who had undergone various types of epilepsy surgery. Comparison with identical preoperative We wished to determine the extent of reduced benzodiazepine studies allows correlation between the imaging abnormality and receptor density in patients with focal cortical dysplasia, hypoth- site of operation both in cases of lesional epilepsy and in those esizing that the area of functional abnormality in cortical dyspla- caused by mesiotemporal sclerosis. Not only do such studies sia exceeds the structural abnormality apparent on magnetic res- provide feedback for surgeons in individual cases and for physi- onance imaging (MRI) scan. We studied 4 patients with gyral cians investigating surgical failures, but also provide the cru- abnormalities, performing ["C]flumazenil positron emission to- cially accurate baseline required for a more rational approach to mography (PET) scans to determine volume of distribution follow-up outcome studies, comparing different surgical tech- (["CIFMZ-V,). These scans were coregistered with high- niques. resolution MRI on a pixel-by-pixel basis. The extent of dyspkasia was defined on the MRI Scan and regions of interest (ROI) were placed on the abnormality and the overlying cortex, on the adjacent gray matter, and in corresponding areas in the opposite hemisphere. The same set of ROI was applied to the PET scans, Benzodiazepine Receptor Binding with [ "C]Flumazenil Positron and ["CIFMZ-Vd was determined. The results were compared Emission Tomography (PET) and [1231]Iomazenil Single Photon with those of 4 age-matched normal controls. Emission Computed Tomography, as Compared with '*FDG PET Preliminary analysis suggests that in 3 of 4 cases, the areas of in Temporal Epilepsy. R. M. Chr. Debets, *B. Sadzot, ?H. W. reduction in ["C]FMZ-Vd were larger than corresponding abnor- van Isselt, SC. W. M. van Veelen, $A. C. van Huffelen, and *G. malities on MRI scan. The finding of more widespread functional Franck (Instituut voor Epilepsiebestrijding, Heemstede, The as compared with structural abnormality may explain in part the Netherlands; *Department of Neurology, University of Liege, poor outcome of focal resections in patients with focal dysplasia. Belgium; and Departments of ?Nuclear Medicine, SNeurosur- gery, and $Clinical Neurophysiology, University Hospital Utrecht, Utrecht, The Netherlands)4023.

Magnetic Resonance Imaging-Demonstrated Atrophy and Sclerosis Seven of 10 candidates for temporal surgery showed conver- of Mesiotemporal Structures in Children: Good Correlation with gence of clinical semiology, ictal scalp EEG, and magnetic res- Positron Emission Tomography and Neuropsychological Data and onance imaging that warranted operation without DEEG. Com- Lack of Correlation with Interictal EEG. Renzo Guerrini, *Mario plete convergence with respect to lobe of seizure onset, was Guazzelli, ?Pier0 Salvadori, Paola Brovedani, Claudia Casalini, noted on "FDG positron emission tomography (PET) in 8 of 10,

Epilepsia, Vol. 35, Suppl. 7, 1994 32 EUROPEAN CONGRESS PROCEEDINGS in ["C]flumazenil PET in 9 of 10, and with ['231]iomazenil single combination of interictal and postictal SPECT, in some patients photon emission computed tomography (SPECT) in 3 of 10 pa- only the ictal SPECT confirmed the EEG focus. tients. Mesiotemporal localization was demonstrated on I8FDG PET in 1 of 10, on ["C]flumazenil PET in 8 of 10, and on [1231]i- omazenil SPECT in 0 of 10 patients. False lateralization and inconclusive bilateral abnormality occurred only with ['231]iom- Iomazenil Single Photon Emission Computed Tomography azenil SPECT, in 3 and 2 patients, respectively. The area of (SPECT) is Significantly More Sensitive Than HMPAO SPECT in decreased uptake in [' 'Clflumazenil binding is more restricted Preoperative Epilepsy Monitoring. H. B. Straub, *S. Venz, B. and has a closer spatial relation with the zone of ictal onset than Schmitz, *R. Siekmann, *M. Cordes, and H.-J. Meencke (De- with the area of glucose hypometabolism. partments of Neurology and *Radiology, Universitatsklinikum Rudolf Virchow, FU Berlin, Germany)--4026.

HMPAO single photon emission computed tomography and Iomazenil SPECT are used for functional neuroimaging in focal of Cerebral Blood Flow in Children with Intractable Focal Patterns epilepsies. We compared both methods with regard to localiza- Epilepsy Demonstrated During Ictal and Interictal Single Photon tion of the epileptogenic region and postoperative results, per- Emission Computed Tomography. J. Helen Cross, Isky Gordon, forming interictal SPECT studies with [1231]lomazenil(IMZ) and Andrew Todd Pokropek, Peter Anderson, Graeme D. Jackson, [""'Tc]HMPAO (HMP) in 25 patients with pharmacoresistant Stewart G. Boyd, Alison Harper, and Brian G. R. Neville (In- focal epilepsies who underwent preoperative epilepsy monitor- stitute of Child HealthiHospital for Sick Children, London, En- ing with closely spaced surface and sphenoidal electrodes. gland)-4024. After transverse, coronal, and temporal (parallel to longitudinal axes of temporal lobes) reconstruction, these studies were 99mTcHMPAO single photon emission computed tomography interpreted visually and quantitatively by a region of interest (SPECT) may provide a noninvasive means of seizure localiza- technique. Results were correlated with localization of the epi- tion in patients with intractable focal epilepsy. We investigated leptogenic region identified by EEG and postoperative outcome. 25 children with intractable complex partial seizures using this Eighteen of 25 (72%) IMZ studies were concordant with local- technique (age range 2 years 8 months to 17 years 10 months). ization on EEG; HMP correlated in only 12 of 25 (48%). This lctal scans were achieved in 17 (at a mean 50 s after seizure difference was highly significant (p = 0.003, chi square). Epi- onset, range 7-105 s; four injections were given during seizures lepsy surgery was performed in 10 patients (eight temporal and secondarily generalized). Immediate postictal scans were ob- two neocortical resections). All have been seizure-free for 3-16 tained in 8 children (a mean of 22 s after seizure cessation, range months (mean 8 months). In all cases in this group, IMZ pre- 943 s). Interictal scans were obtained in all children by injection dicted the resected area correctly. HMP showed concordance in 30 min to 72 h after the last seizure. only 7 of 10 cases. After ictal injection, 15 of 17 patients (88%) demonstrated a IMZ is significantly more sensitive than HMP in localizing the focal area hyperperfusion corresponding an of hypo- of to area epileptogenic region in focal epilepsies, possibly owing to com- perfusion on the interictal scan that was concordant with the bined effects of reduced cerebral blood flow and functional im- clinical focus as defined by consensus diagnosis based on clini- pairment of the benzodiazepine receptor complex in the epilep- cal, EEG, and magnetic resonance imaging data. This included 3 children injected during seizures secondarily generalized. Only 3 togenic region, which might be acting synergistically on IMZ distribution. IMZ is an important technique for preoperative ep- of 8 (38%) demonstrated these abnormalities after postictal injection. These studies suggest that timing of injection of 99mTc ilepsy monitoring. HMPAO relative to seizure onset, seizure cessation, and onset of seizures secondarily generalized is critical for later interpretation of scans. Place of Noninvasive and Invasive Evaluation in Mesiotemporal Lobe Epilepsy. M. Baulac, C. Adam, F. Semah, S. Samson, D. Dormont, and S. Clemenceau (Clinique Paul Castaigne, HBpital la Salpttritre, Paris, France)4027. Periictal Single Photon Emission Computed Tomography (SPECT): Comparison of Interictal, Ictal, and Postictal 99"T~HM- Twenty-six patients underwent preoperative evaluation lead- PA0 SPECT in Patients with Temporal Lobe Epilepsy. Maria ing to diagnosis of mesiotemporal lobe epilepsy. Clinical data Weis, Hermann Stefan, and *Herbert Feistel (Neurological and collection showed febrile convulsion history (69%), ictal symp- *Nuclearmedical Departments, University Erlangen-Numberg, tomatology including epigastric aura (73%), motionless stare Erlangen, Germany)4025. (19%), oroalimentary (45%), and gestural (73%) autornatisms, and unilateral dystonia (65%). In all but I case, hippocampal We evaluated use of interictal, ictal, and postictal single pho- sclerosis was detected on magnetic resonance imaging (MRl) by ton emission computed tomography (SPECT) in identical groups volume reduction and/or signal abnormalities. Interictal "FDG of patients with temporal lobe epilepsy (TLE). Interictal positron emission tomography (PET) showed a characteristic hy- y9m TcHMPAO-SPECT was performed during a seizure-free pe- pometabolic pattern involving temporal pole and mesial struc- riod in 15 patients with unilateral TLE. Ictal and postictal tures in 96%. Interictal and ictal EEG abnormalities were clearly SPECT scans were obtained during preoperative evaluation. The lateralized in 69 and 77% of cases, respectively. injection latency of ictal SPECTs was 40-79 s (@ 57 s) after Diagnosis and lateralization of mesiotemporal epilepsy were seizure onset; that of postictal SPECT scans was 1-6 min (@ 2% obtained noninvasively in 73% (10 left, 9 right). In 7 patients min) after seizure cessation. SPECT was visually analyzed by an (27%), discordant localizing and/or lateralizing data led to place- experienced nuclear medicine physician. ment of intracerebral electrodes by an MRI-compatible stereo- Ictal SPECTs showed focal hyperperfusion in 73% of patients. taxic procedure. The depth-recorded mesial focus was unilateral On interictal SPECT, only 60% of patients had patterns of focal (n = 3) or bitemporal but predominant on one side (n = 4). The hypoperfusion. Postictal SPECT showed focal changes of cere- active or most active side always corresponded to imaging data. bral perfusion in the region of the EEG focus in 67% of patients. Temporal pole and mesial structures were selectively re- Postictal SPECT with injection latency <2 min after seizure ces- sected. Two patients who failed the sodium amytal procedure sation showed preferentially focal hyperperfusion; with later in- had only partial resection of amygdalohippocampal structures. jection, patterns of focal hypoperfusion were apparent. Postictal Postoperative outcome (mean follow-up 13 months) showed 73% and ictal SPECT improves information yield, especially in pa- seizure-free and 15% with persistant auras. Three patients had tients with normal magnetic resonance imaging scans. Despite rare seizures; 2 of them were in the bitemporal group.

Epilepsiu, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 33

Single Photon Emission Computed Tomography Study of Cerebral secutive sessions: first during EEG recording in the resting state Blood Flow Reactivity in Patients with Focal Epilepsy. Anoop R. when no abnormal finding was present, and second during hy- Varma, John Moriarty, Michael R. Trimble, Durval C. Costa, perventilation 2 min after onset of 3-Hz spike and wave bursts. and Peter J. Ell (Institute of Neurology, Queen Square, London, An aged-matched control group with normal hyperventilation England)4028. response on EEG underwent similar procedures. SPECT data were reevaluated with particular reference to Patients with focal epilepsies were shown to have localized thalamus, basal ganglia, cerebral hemispheres, and different cor- cerebral hypoperfusion at the epileptic focus. HMPAO single tical regions; results were normalized according to cerebellum. photon emission computed tomography (SPECT) is used to lo- Nonparametric Wilcoxon test was used for correlations. Results calize the focus. The effect of agents that increase cerebral blood showed a significant overall increase in cerebral blood flow dur- flow, such as acetazolamide, on relative perfusion of the epilep- ing spike and wave discharges in all patients as compared with tic focus is of both theoretical and practical importance. Previous resting state SPECT data as well as with SPECT values during studies using acetazolamide yielded conflicting results. Prelimi- hyperventilation. No regional preponderance in blood flow rates nary communication from one center indicated that focus local- was evident. ization was improved by oral acetazolamide-activated HMPAO SPECT scans owing to increased local perfusion. Another group of investigators showed that intravenous acetazolamide as measured by '"Xe SPECT caused increased severity of relative cerebral hypoperfusion. Quantitative Evaluation of the Specific and Nonspecific Binding of We studied 10 patients with focal epilepsy, using a split-dose ['231]Iomazenil in Treated and Untreated Patients Using Single HMPAO SPECT technique. A resting scan was obtained after Photon Emission Computed Tomography (SPECT): Comparison injection of 270 MBq HMPAO. Fifteen minutes after injection of withW"TcHMPAOSPECT. S. Venz, B. Schmitz, W. Poewe, W. I g acetazolamide, 270 MBq HMPAO was again administered Richter, and M. Cordes (Department of Radiology and Neurol- and another scan was acquired. Conditions were otherwise iden- ogy, UK R. Virchow, FU Berlin, Germany)4031. tical for the two scans. A region of interest (ROI) method of analysis was used to determine both quantitative and qualitative We investigated differences in binding of ['Z31]iomazenil (IMZ) measures of perfusion before and after acetazolamide activation. in newly diagnosed patients who had never received anticonvulsant drugs and in treated patients with focal epilepsies. Focal epilepsies were confirmed by routine surface EEG in 20 patients (13 untreated and 7 treated with carbamazepine). All patients lctal and Interictal Single Photon Emission Computed Tomogra- underwent single photon emission computed tomography phy in Epilepsy Surgery. Gabriella Colicchio, Giuseppe De Rossi, (SPECT) examination 10 min after intravenous (i.v.) application and Giovanni Parronetti (Neurosurgery Institute, U.C.S.C., of 740 MBq 99mT~HMPAO. In addition, all patients were studied Rome, Italy)--4029. with SPECT 5 and 90 rnin after i.v. application of 111 MBq Iz3I IMZ. SPECT data were evaluated quantitatively by regions of Forty epileptic patients underwent interictal single photon interest (frontal, parietal, occipital, temporal, cerebellar, and emission computed tomography (SPECT) during preoperative white matter) drawn symmetrically on both hemispheres. Re- evaluation for drug-resistant seizures. Twenty-one patients also gional count density (RCD) was normalized to whole brain ac- underwent ictal SPECT after pharmacologically provoked sei- tivity and body surface, and the ratio for specific (SB) and non- zure (dimefline). The study was performed to obtain information specific (NB) binding of IMZ was calculated. Magnetic reso- on cerebral blood flow during interictal and ictal phases, to be nance imaging performed in all patients showed no pathologic evaluated for epilepsy surgical diagnosis. findings. The high incidence of multiple hypoperfusion areas showed by Normalized NB of IMZ in SPECT examinations acquired 5 interictal SPECT was also confirmed "monofocal" patients by and 90 min pi. was higher in the treated patients than in un- our results: 19 patients with multiple hypoperfusion areas, 18 treated patients (p < 0.003, t test). There was no statistical dif- patients with monoperfusion areas, and 3 negative examinations. ference between normalized SB and regional blood flow mea- For ictal SPECT, on the contrary, 14 patients aged >21 years sured with HMPAO SPECT in either group. The higher normal- showed a unique hyperperfusion area. Three were "multifocal," ized NB in treated patients may be caused by endogenous factors and four examinations failed to show changes in comparison with (severity of epilepsy) or exogenous factors (anticonvulsant interictal SPECT. We evaluated the data by interictal neurophys- drugs). iologic study and by ictal video EEG results. Patients treated by resective surgery, with at least 1-year follow-up were again submitted to interictal SPECT to compare surgical results with previous diagnostic information. In Vivo 'H Magnetic Resonance Spectroscopy of Temporal Lobe Epilepsy. Jose A. Ribeiro, *Raquel Soares, Georgina Sousa, Dina Pinto, Isabel Pires, and M. Luisa Guimaraes (Neurophys- iology Department, S. Joao Hospital; and *Institute PortuguCs Single Photon Emission Computed Tomography Imaging During de Oncologia, Porto, Portugal)--4032. 3-HZ Spike-Wave in EEG. Yeni Naz, Kabasakal Levent, Yal- Ginkaya Cengiz, Dervent Ayah, and Onsel Cetin (Neurology De- We performed in vivo 'H magnetic resonance spectroscopy partment, Cerrahpasa Medical Faculty, University of Istanbul, (['HIMRS) to study several regional metabolites [N-acetylaspar- Istanbul, Turkey)--4030. tate (NAA), glutamate, aspartate, creatine, cholines, y-aminobutyric acid, inositol, lipids] in brain of normal controls and in two Regional blood flow changes in cortical and subcortical brain temporal lobe epilepsy groups, one conventional drug-resistant regions concomitant with seizure discharges in epilepsies with group (n = 7) and another group with good seizure control (n = strictly generalized clinical and EEG features were investigated 7). In uncontrolled complex partial seizure patients (mean sei- for any possible contributory evidence for the established diag- zure frequency in the past 6 months >l/month), levels of NAA in nosis and/or for pathophysiology of discharge propagation. Four- a defined area of temporal lobe were lower than in well-con- teen children with absence seizures whose spike and wave dis- trolled patients. Both groups (especially the drug-resistant charges were easily provoked during hyperventilation, were se- group) had increased levels of glutamate, aspartate, and lipids. In lected for the study; all had normal background activity. vivo proton magnetic resonance spectroscopy may aid in diag- For single photon emission computed tomography (SPECT) nosing the extent of brain metabolic impairment in temporal lobe imaging, 99Tc HMPAO was injected in each patient at two con- epilepsy patients.

Epilepsiu, Vol. 35, Suppl. 7, 1994 34 EUROPEAN CONGRESS PROCEEDINGS

Volumetric Analysis of the Cerebellum of Epileptic Patients patients with phenylketonuria (PKU). The frequency and extent Treated with Either Phenytoin or Carbamazepine. Gerhard Luef, of MRI anomalies and their relation to dietary treatment remain Stephan Felber, Giinther Birbamer, Franz Aichner, and Gerhard unclear. Furthermore, there has been no consistent relation be- Bauer (Departments of Neurology and MRI, University of Inns- tween clinical signs or electrophysiologic changes and white mat- bruck, Innsbruck, Austria)-4033. ter anomalies on MRI. We report a case of atypical PKU with occipital encephalopathy and MRI anomalies in occipital cortex. Phenytoin, as an agent that acts reversibly on the specific A 6-year-old girl had received dietary and pharmacologic treatment since age 8 structure in a characteristically toxic fashion may produce irre- months. At first follow-up at age 5 years, she versible cerebellar dysfunction. We evaluate the relation be- had ataxospastic gait, poor vision, and some impairment in at- tween phenytoin (PHT) and carbamazepine (CBZ) and cerebellar tention. She had frequent and brief seizures with arrest of ongoing activity, eye deviation, sometimes with drop, not well con- atrophy in epileptic patients treated with these antiepileptic drugs for several years. Three-dimensional gradient-echo data trolled by therapy. The phenylalaninemia was 2%. EEG showed subcontinuous and independent paroxysms in both occipital sets from 10 patients treated with CBZ, 10 treated with PHT, and 10 healthy volunteers were used to evaluate cerebellar volume. regions with bilateral diffusion. MRI showed slight demyelina- tion of white matter, particularly posteriorly with involvement Magnetic resonance imaging scans were obtained on a 1.5-T Magnetom imaging system. A three-dimensional flash sequence of corpus callosum and two small discrete lesion (possibly glio- was used to obtain T,-weighted brain images. During each ex- sis) in occipital cortex. Better therapeutic control resulted in a direct rela- amination, 80-90 slices were acquired in a sagittal direction and improvement in attention and vision. We suggest transferred to an external image-processing system where cere- tion between cortical localization of lesions and electroclinical bellar volume was determined. data. Cerebellar volume was measured by an interactive segmentation procedure based on a combination of tracing and threshold- ing technique. Linear regression showed no correlation between seizure duration and cerebellar volume, but multiple regression Three-Dimensional Localization of Interictal Epileptic Activity by for daily dosage, duration of PHT treatment, and cerebellar vol- Neuromagnetic Method. Marco Peresson, Vittorio Pizzella, Gi- umes showed correlation of these parameters. anLuca Romani, and Paolo Curatolo (I.T.A.B., Universita “G. D’Annunzio” Chieti, Itdly)-4036.

Localization and quantification of the epileptic foci and epi- Magnetic Resonance Imaging in Partial Seizures. Cigdem Ozkara, leptogenic area is essential for surgical treatment of medically Betiil Yal~iner,*Alp Omeroglu, “Haydar Akbari, and Sevim intractable partial epilepsy. We studied 6 patients aged 13-18 Baybaz (Bakirkoy State Hospital for Psychiatric and Neurolog- years with refractory partial epilepsy. Etiology was tuberous ical Diseases; and “Ozemar MRI Center, Istanbul, Turkey)- sclerosis (4) and gliosis (2). Magnetoencephalographic (MEG) 4034. recordings were performed with a 28-channel system (in a mag- netically shielded room; CNR IESS) which was placed over four different scalp locations to obtain complete head covering. All Magnetic Resonance Imaging (MRI) is an important diagnostic subjects underwent magnetic resonance imaging (MRI) exami- tool in investigation of patients with partial seizures. Studies nation. Anatomic and functional information was integrated have demonstrated different abnormalities such as acquired ep- through appropriate reference markers placed on predefined an- ileptogenic lesions, including tumors and atrophic processes, or atomic landmarks (nasion and preauricular points). Epileptic congenital lesions, including glial hamartomas, vascular malfor- complexes were automatically identified based on preselected mations, developmental anomalies and migrational disorders template. Averaging the corresponding MEG complexes pro- and, mostly (50-70%), mesiotemporal sclerosis (MTS). vided the field distribution over the scalp to be used eventually We performed MRI in 21 patients (2 female, 9 male; mean age for source localization. In all patients, three-dimensional local- 24.1 years; range 1147 years) with partial epileptic seizures ac- ization of the epileptic focus was in agreement with the lesions as cording to a specific protocol that yields more accurate investi- identified by MRI. In some cases, we were able to follow the gation for MTS. Twelve of 21 patients (57.1%) had abnormal epileptic discharge inside the brain cortex, therefore identifying MRI. Four patients had MTS (1 cavernoma, 1 arachnoid cyst, 1 the epileptogenic area. This noninvasive method is expected to hemispheric atrophy, 1 occipitoparietal cortical lesion suggesting show further clinical applicability in preoperative investigation in a chronic infection). Three patients had diffuse small lesions hy- patients with refractory partial epilepsy. perintense in T,- and hypointense in T,-weighted images. Inves- tigation of these patients for multiple sclerosis was negative, and patients had no symptoms or signs of any disease other than seizures. Scalp EEG was abnormal in 14 patients. Five patients with pathologic MRI had normal EEG. Computed tomography Epileptic Seizures with Onset After Age 50 Years: Computed To- (CT) was negative except in 3 patients with posttraumatic lesions mography Findings. J. Ramalheira, E. LourenGo, M. R. Silva, R. in both MRI and CT. The importance of MRI is obvious in eval- Garcia, A. Lopes, A. Stocker, J. Pereira, H. J. Pereira, and uation of epileptic patients, but more knowledge is needed to J. M. Lopes Lima (Consulta de Epilepsia, Servico de Neurolo- explain some of the lesions. gia, H.G.S. Antonio, Porto, Portugal)--4037.

The incidence of epileptic seizures in the last years of life is increasing, mainly due to the symptomatic epilepsies. We evaluated all the computed tomography scans of patients aged >50 Atypical Phenylketonuria, Occipital Encephalopathy, and Mag- years treated in the emergency room from 1990 to 1991 for a first netic Resonance Imaging Anomalies in Occipital Cortex. V. Sgrb, seizure. We compared the findings with two other control groups *G.Biasucci, L. Minotti, *A. Maestroni, A. Saltarelli, L. Guido- (50 patients each) selected randomly and investigated in the same lin, A. Vignoli, M. P. Canevini, Riva, and R. Canger (Re- *E. period: the first group had headaches of recent onset and normal gional Epilepsy Centre; and *V Pediatric Clinic, Paolo S. Hos- clinical examination; the second had transient neurologic dys- pital, University of Milan, Milan, Italy)--4035. function lasting <24 h (transient ischemic attack, vertigo, syncope). Many reports have stressed neurologic impairment with white Among 290 patients evaluated, definite etiology was deter- matter abnormalities on magnetic resonance imaging (MRI) in mined in almost 60% of patients with seizures. The most impor-

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 35

tant findings were vascular abnormalities that occurred with in- Time Course of HMPAO Uptake During Intraarterial Amobarbital creasing frequency with age. A significant number of patients Application (WADA Test). H.-Joachim Meencke, R. Siegmann, also had generalized atrophy as compared with the two control S. Venz, H. B. Straub, M. Kordes, and W. Richter (Universi- groups. tatsklinikum Rudolf Virchow, Free University of Berlin, Berlin, Germany)--4040.

Hemispheric amobarbital (AB) anesthesia (Wada test) is Intraarterial/Venous Amobarbital Concentrations During the In- widely accepted for evaluation of speech and memory in preop- tracarotid Amytal Test. H. Silfvenius, *H. Jakobsson, M. Olive- erative evaluation of epilepsy surgery candidates. AB is injected crona, and J. Saisa, (Departments of Neurosurgery and *Clinical in the internal carotid artery, but the mesiotemporal structures Chemistry, University Hospital, UmeH, Sweden)A038. are also invariably perfused by anastomoses of the posterior artery. To obtain better knowledge of the brain area perfused by The intraarterial and intravenous (i.v.) concentrations of AB, we combined Wada testing with HMPAO single photon amobarbital, injected in conjunction with the intracarotid emission computed tomography to analyze HMPAO uptake dur- amobarbital test, were measured by high-performance liquid ing AB anesthesia. We injected 74 MBq (2 m ci) HMPAO 5 min chromatography technique in 14 candidates for epilepsy surgery before, immediately after (5 s), and 1, 3, 5, and 8 min after AB (I1 females aged 3244 years, mean 38 years; 3 males aged 23-47 injection. The time differences of the test of both sides (left and years, mean 33 years). Their corresponding body weights were right) was 60 min. Activity was measured with a rotating y-cam- 51-84 kg (mean 64 kg) and 77-100 kg (mean 85 kg). The controls era (APEX 409 ECT, Elscint) with LEAP Kollimator (APC 4, were taken 1 min before the injection in the internal carotid Elscint). We measured pixel counts in the region of interest in artery (ICA) of 12G.150 mg (mean 144 mg) 10% amobarbital four axial levels. The quotient of activity (QA) was calculated as: mixed with saline. Blood samples from the ICA and a cubital QA = activity intraarterial i.a. HMPAO after AB ipsilateral/ vein were taken 1, 3, 5, and 10 min after amobarbital injection. activity interarterial HMPAO before AB contralateral. The Not all samples were obtained in each patient (n = 17-23). ICA change in uptake was correlated with the EEG and neurologic mean baseline value was 0.23 pM; i.v. mean baseline value was status. 0.35 pM. First ICA values >lo0 pM (n = 5) were probably due Immediately after AB injection, HMPAO uptake is reduced, to incomplete flushing of the catheter. Mean I-, 3-, 5-, and 10- with slowing in EEG. After 3 min, there is maximal reduction of min ICA amobarbital concentrations were 36.1, 16.0, 13.8, and 77%, with maximal slowing in EEG and complete hemiparesis. 11.2 pM, respectively. Corresponding i.v. concentrations were After 5 min, there is only 29% reduction; after 8 min, uptake is 17.3, 10.2, 10.0, and 9.0 pM. Comparable 1CAh.v. mean quotas increased by 7%, with normalizing EEG and full power. The were 2.07, 1.57, 1.38, and I .24. Mean ICA concentrations related maximal reduction in uptake under AB is five times that of up- to body weight were 0.43, 0.20, 0.18, and 0.14; those of the i.v. take in the contralateral side. If this were related only to distur- means were 0.17,0.11,0.10, andO.lO. All concentrations, except bances of the perfusion, functional metabolism would be blocked those at 1 and 3 min, were probably subthreshold for functional completely, with persistent structural metabolism of only -20%. suppression of the contralateral hemisphere or of the ipsilateral This raises the question of whether specific blocking of uptake of region not perfused by the ICA. neurons occurs in AB anesthesia.

Speech Activation Positron Emission Tomography as Compared Relationship Between Magnetic Resonance Imaging Hippocampal with WADA Test. Gunter Pawlik, Gereon R. Fink, Thomas Morphology and the Intracarotid Sodium Amytal Test in Preoper- Treig, Detlef B. Linke, Hermann Stefan, and Wolf-Dieter Heiss ative Evaluation of Patients for Temporal Lobe Epilepsy. Sallie A. (Max-Planck Institut of Neurologic Research and University Baxendale, Mark Cook, Simon D. Shorvon, Pamela J. Thomp- Hospitals of Neurology, Cologne, Erlangen, and Bonn, Ger- son, and Elizabeth K. Warrington (Epilepsy Research Group, many)--4039. Institute of Neurology, Queen Square, London, and Chalfont Centre for Epilepsy, Chalfont St. Peter, Bucks, England)--4041. In candidates for epilepsy surgery, positron emission tomography (PET) of brain glucose metabolism during speech perfor- The increasing sophistication of magnetic resonance imaging mance efficiently discloses presumably epileptogenic dysfunc- (MRI) volumetric measurement has led to speculation that it may tional areas. Considering the obvious disadvantages of intraar- supersede the intracarotid sodium amytal test in preoperative terial amobarbital tests according to Wada, we investigated the screening for bilateral abnormalities in prospective temporal potential of activation PET studies to provide noninvasive com- lobectomy patients (Neurology 1993;43: 1800-5). We report 50 parable lateralizing information regarding language function. preoperative patients who underwent the intracarotid sodium Thirty patients (26 righthanded, 4 lefthanded; aged 19 to 52 amytal test and morphometric analysis of hippocampal sclerosis years; no gross anatomic abnormality on magnetic resonance identified by MRI scan. The predictive power of each technique imaging) with long-standing temporal lobe epilepsy (focus: 18 was compared and contrasted with respect to preoperative sei- right, 11 left, 1 bilateral) had paired PET studies (2[''F]FDG zure lateralization and postoperative seizure control and changes method, Scanditronix PC 384, 14 slices per session, resting con- in memory function. The combination of functional and struc- dition and continuous speech) and bilateral intracarotid amobar- tural measures provides valuable information in the preoperative bital tests for speaking sequences, verbal comprehension, verbal assessment of patients for temporal lobectomy. repetition, and memorization. Side-to-side differences of performance under amobarbital were related to individual changes in regional metabolic asymmetry, as shown by Freeman-Halton tests and Somer's D to measure concordance. Intracarotid Amytal Procedure in Patients with Medsiotemporal Because of the asymmetry of metabolic recruitment in Broca's Lobe Structural Lesions. P. Boon, E. Thiery, R. Novelly, E. area, contralateral cerebellum, premotor cortex, striatum, and Achten, L. Calliauw, and J. De Reuck (Departments of Neurol- thalamus, PET correctly (according to Wada test) classified 25 ogy, Neuropsychology, Neuroradiology and Neurosurgery, Uni- patients (24 left, 1 right dominant), achieving significant (p < versity Hospital, Gent, Belgium)--4042. 0.05) Ds between 0.86 (comprehension) and 0.95 (repetition). Wada testing failed to detect distinct language dominance in 4 Although the intracarotid amytal procedure (IAP) is consid- patients; PET failed in 1. We suggest that FDG-PET with speech ered a valid test of hemispheric language dominance, its ability to activation may largely substitute for amobarbital tests in assess- evaluate memory and predict focal pathology in medsiotemporal ment of language dominance. lobe (MTL) is criticized. Ten patients (mean age 27 years, range

Epilepsia, Vol. 35, Suppl. 7, 1994 36 EUROPEAN CONGRESS PROCEEDINGS

12-44 years) with intractable complex partial seizures (CPS) sec- speech-dominance was expected according to handedness and ondary to a structural lesion confined to the MTL (hippocampal Wada test. Activating tasks differed individually, however. formation) were studied. All patients are seizure-free after resective surgery with an average follow-up of 33 months (range 1248 months). All patients had typical temporal CPS and an interictal Electrical Stimulation of Hippocampus and Verbal Memory Per- and ictal EEG congruent with lesion location. Neuropsycholog- formance. J. Vermeulen, G. Brekelmans, D. Velis, W. C. J. AI- ical assessment localized congruently in 6 patients. Mean IQ pherts, C. van Veelen, and W. van Emde Boas (Instituut voor score (WAIS-FSIQ) was 103 (range 78-124). During IAP, both Epilepsiebestr, Meer en Bosch, Heemstede; University Hospi- sides were separately injected with 125-150 mg amobarbital; the tal, Utrecht, The Netherlands)4045. side of the lesion injected first. Nine patients were left language dominant; 1 patient had right-sided language. Memory testing In 14 neurosurgery candidates with temporal lobe epilepsy re- identified two types of patients. Five patients passed the memory quiring depth electrode placement to identify seizure onset ac- (verbal, visuospatial) testing on both sides with scores that did curately, we studied the contribution of left and right hippocam- not allow lateralization; 5 patients showed a memory deficit on pus to verbal memory function during unilateral hippocampal the side of the lesion. Results of the IAP in this selected patient electrical stimulation, assessing verbal memory with a Brown/ population challenge the validity of the procedure in testing Peterson distractor paradigm during left and right hippocampal memory. Patients with structural lesions confined to hippocam- stimulation and during no-stimulation baseline. A retention in- pal formation have an inconsistent memory deficit demonstrated terval of 20 s was used. Electrical stimulation was applied during by IAP. stimulus presentation and the retention interval. Strong effects on memory were observed with stimulation of left hippocampus in subjects with left hemisphere dominance for language according to the Wada test. In these subjects, right Functional Tests with Near-Infrared Spectroscopy. F. Eberhard, hippocampal stimulation did not interfere with verbal memory. H. Stefan, G. Hellmann, and J. Volmer (Neurologische Klinik These effects were unrelated to seizure focus lateralization. The der Universitat Erlangen-Nurnberg, Erlangen, Germany)4043. effect on memory with left but not right hippocampal stimulation was also strongly related to current intensity (r = 0.70). Near-infrared spectroscopy (NIRS) is a new method for non- Results suggest that in our subjects verbal memory impairment invasive in vivo measurement of concentration of oxyhemoglo- will always occur after left hippocampal stimulation, provided bin, deoxyhemoglobin, and cytochrome c-oxidase (Caa,) redox the current administered is high enough. In patients with left state in brain tissue. Caa, as the key enzyme of the respiratory temporal seizure onset, verbal memory is still mediated by left chain catalyses >90% of cellular oxygen utilization. As a direct hemisphere and is not transferred to the opposite side. parameter for’metabolic turnover of brain tissue, the redox state of Caa, provides information about functional brain performance. Two NIRS monitors were used to derive bilateral NIRS sig- Speech Arrest in Supplementary Motor Area Seizures in Two Pa- tients Who Became Seizure Free After Operation. Udo Wieshmann nals symmetrically from the frontoparietal brain area of an adult female patient with temporal lobe epilepsy. Speech activation and Hartmut Meierkord (Universitatsklinikum CharitC, Mediz- inische Fakultat der Humboldt Universitat Berlin, Neurolo- and additional acoustic and visual tests were performed simul- zu taneously. gische Klinik, Berlin, Germany)-4046. A bilateral increase in oxygen saturation followed by an increase in Caa, oxidation was observed at the beginning of several Epileptic seizures originating in supplementary motor area (SMA) may present with various ictal clinical features, including tests. A unilateral increase in Caa,, overproportionally and asyn- posturing, head turning, bizarre vocalization, and other phenom- chronously to the increase in oxygen saturation, was demonstrated on the left during speech activation and on the right while ena. Some features may occur in isolation, but detailed anatomic the patient Listened to music, proving metabolic activity. NIRS studies are lacking. Localization in this area is particularly prob- appears to be a good method for functional diagnosis of brain lematic since both clinical and EEG features may be misleading. In previous studies, computed tomography scanning showed the (Clin Perinatol 1991; 183 19-34). effect of antiepileptic medication on seizure control. We chose magnetic resonance imaging combined with the sterotaxic method described by Talairach to localize circumscribed lesions Speech Lateralization with Near-Infrared Spectroscopy: Comple- in the frontal lobe. We report two patients with structural lesions mentary Noninvasive Information in Preoperative Evaluation? H. in left SMA who became seizure-free after surgical removal of Stefan, F. Eberhard, G. Hellmann, and J. Volmer (Neurolo- the lesion. EEG was not helpful in determining seizure origin. gische Klinik der Universitat Erlangen-Nurnberg, Erlangen, Indeed, ictal discharges were observed constantly on the side Germany)--4044. opposite the lesion. The unusual clinical feature was speech arrest in 1 patient as an isolated phenomenon and speech arrest The invasive Wada test (J Neurosurg 1960;17:266-82) is the associated with some ipsilateral facial jerks in the other. current established investigation method for speech lateraliza- The cases suggest that speech arrest may have a localizing tion in preoperative epilepsy diagnosis. We used near-infrared value and emphasize the role of SMA in arrest phenomena. Iso- spectroscopy (NIRS) (Clin Perinatol 1991;18:519-34) to develop lated speech arrest has rarely been described in the literature and a noninvasive method for speech lateralization involving less may easily be overlooked in clinical praxis. stress and risk for patients. We examined whether local metabolic changes during speech activation, measured by NIRS, could provide hints regarding lateralization of the speech- Visual Agnosia in Two Patients with Epilepsy. Anne-Lise Rug- dominant hemisphere. land, Helge BjZrnzs, and Olaf Henriksen (The National Center Bilateral synchronous NIRS monitoring of cytochrome-c- for Epilepsy, Sandvika, Norway)4047. oxidase (Caa,) and oxygen saturation was performed above the frontal speech area in 2 adult controls and 2 patients with tem- Patients with visual agnosia do not respond appropriately to poral lobe epilepsy. Speech activation and additional acoustic visually presented material even though visual sensory percep- and visual tests were performed simultaneously. Wada-test re- tion, language, and general intellectual functions are preserved at sults for the epilepsy patients had been obtained previously. sufficiently high levels. Therefore, impairment in one or more of Typical changes in NIRS curves, closely related to the acti- these functions cannot account for the failure to recognize ob- vating tasks, were evident, indicating local brain activity. Lat- jects. Poor recognition is usually limited to the visual sphere, and eralized activity correlated well with the hemisphere where appropriate responses are obtained when the patient is allowed

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 37 to handle the object or hear it in use. We report test results of 2 video games, the possible risks for photosensitive patients with patients with epilepsy; I patient shows clear visual agnosia on epilepsy have repeatedly been discussed and various reports neuropsychological tests: the other shows similar but less pro- have been made of children experiencing tonic-clonic seizures nounced problems. In both, EEGs show epileptic discharges after playing video games on a television set. To determine the most pronounced over occipital, parietal, and temporal regions effect of these types of visual stimuli on photosensitive patients in right hemisphere. with epilepsy as well as in (possibly) nonepileptic subjects both- One of the patients (2-year follow-up) underwent surgical re- ered by these stimuli and to evaluate the intrinsic contribution of section of an area in the right parietooccipital region. Visual the visual material versus that of the machinery, we developed a agnosia disappeared, but he acquired a scotoma. The other pa- standardized investigation protocol as an extension of routine tient (S-year follow-up) has followed a habilitation program and EEG procedures for evaluation of photosensitivity. This stan- has learned to compensate for many of his problems although his dardized study consists of (a) determination of photosensitivity visual agnosia can still be recognized on neuropsychological ranges in the conditions (eye closure, eyes closed, and eyes tests. open); (b) determination of pattern sensitivity (horizontal and vertical orientation of black and white stripes); (c) 50-Hz TV stimulation at distances of 2, 1, and 0.5 m, at each distance Role of Television, Video Games, and Computers in Epileptic Pho- offering a video-clip with images flashing at 6 and 13 Hz, a news- tosensitive Patients: Preliminary Results. D. G. A. Kasteleijn- reader, and a “Mario world video game, the latter both viewed Nolst TrenitC, E. Dekker, S. Spekreijse, G. J. F. Brekelmans, passively and played actively; (d) 100-Hz TV stimulation at the *A. J. Wilkins, and W. van Emde Boas (EEG Department, In- same distances and with the same programs; and (e) stimulation stituut voor Epilepsiebestrijding, Heemstede, The Netherlands; by viewing a 17-inch 70-Hz noninterlaced SVGA color monitor, and *MRC Applied Psychology Unit, Cambridge, England)- the computer running a demonstration program including scroll- 4048. ing and flashing of various modes of text, images, blocks, stripes, or grids at various speeds and colors or computer game (active). Photosensitive patients may experience seizures evoked by The procedure is performed under normal background illumi- visual stimuli such as sunlight shining through trees, disco lights, nation, and patients are continuously monitored with synchro- television, and escalators. Usually these patients show epilepti- nized video and EEG, including additional polygraphic registra- form discharges in their EEG on intermittent photic stimulation tion of horizontal and vertical eye movements, eyelid move- (IPS), and -50% respond to pattern stimulation and/or SO-Hz ments (by use of an eyelid transducer), and cervicobrachial television. Some complain about computer screens, and seizures electromyography. A standard history focused on visual sensi- are reported to have been provoked by computer games. At tivity is taken with the aid of a questionnaire. The study is per- times, patients not (yet) known to have epilepsy report the same formed with 2 qualified EEG technologists present, 1 continu- problem. Various factors may be involved: hardware, viewing ously observing the patient; all clinical signs and symptoms dur- material (grids, flashes, color), cognition, interaction between ing the entire procedure are noted. The protocol is now applied hard and software (games!), and stress, fatigue, and intensity of in various laboratories in the context of a European Study. involvement of the patient. We studied 30 patients with a history of seizures or complaints when viewing television or computer screens, whether or not Transitional Response in Pure playing a video game, whether Photomyoclonic/Photoparoxysmal or not known to be epileptic but Photosensitive Epilepsy: The Effect of Piracetam. Pierre Thomas, to be photosensitive, and 50 patients not previously known *Georges Suisse, Philippe Soubielle, *Clause Dolisi, and Marcel known to be photosensitive after they underwent standardized Chatel (Services de Neurologie et *Explorations Fonctionnelles stimulation with IPS, pattern, SO- and 100-Hz TV, and standard du Systeme Nerveux, HBpital Pasteur, Nice, France)--4050. computer screens and viewing of various programs. In all patients, a detailed clinical history was taken, with special empha- A 42-year-old nonalcoholic female patient had pure photosen- sis on visually induced seizures and complaints. sitive epilepsy. She exhibited marked initial photomyoclonic re- Of the photosensitive patients, -50% proved to be TV- sponse (PMR), with eyelid myoclonias and sharp myogenic po- sensitive (all for 50-Hz TV but -2.5% for 100-Hz tubes as well); tentials occupying the anterior part of the scalp on surface EEG all TV-sensitive patients were also sensitive. A videoclip IPS when intermittent light stimulation (ILS) was performed between containing images flashing at 6 and 13 Hz proved to be the most 0.5 and 8 Hz. Photoparoxysmal response (PPR) with generalized provocative program regardless of the hardware used. Video paroxysmal spike-waves and massive myoclonus was superim- games (active or passive) were less provocative; the most neutral posed on PMR when ILS frequency was >8.S Hz. This unusual program (newsreader) evoked the smallest amount of epileptiform of photosensitivity was first described by Gastaut et al. form discharges in these subjects. Provocation by the computer (1951) and termed “transitional photosensitive response” (TPR). screen as such appeared to be minimal: paroxysmal activity Back-averaging of ictal activity confirmed that PMR preceded could be provoked in only 1 patient. Although the population at PPR. Antiepileptic drugs (valproate, phenobarbital, clobazam, risk appears to be limited, these results indicate that for some phenytoin, vigabatrin) were ineffective in blocking PPR, which subjects with epilepsy TV and/or video games indeed constitute was not abolished by monocular eye occlusion or dark sun- a possible risk factor; in comparison, computer screens appear glasses. Acute administration of piracetam, 8-12 g/day abolished relatively safe. These investigations are now being extended in the PMR. Under piracetam monotherapy, the PPR persisted, but the context of a joint European Study, involving EEG laborato- was elicited only when ILS frequency was >14-16 Hz. This ries in Belgium, England, France, Germany, Italy, the Nether- observation suggests that PPR in TPR may be triggered by an lands, Slovenia, and Spain, coordinated by Dr. D. G. A. initial PMR and that piracetam may be useful in this rare form of Kasteleijn and Nolst TrenitC. pure photosensitive epilepsy.

Evaluation of Effect of Visual Stimulation with Television, Video Games and Computers in Epileptic Photosensitive Patients: Tech- Pure Cortical Negative Action Myoclonus Showing Lafora Disease. nical Procedure. S. Spekreijse, E. Dekker, J. de Vries, G. J. F. Pierre Thomas, ?Catherine Meneguz, Hale1 Alchaar, *Georges Brekelmans, W. van Emde Boas, and D. G. A. Kasteleijn-Nolst Suisse, and Claude Desnuelle (Services de Neurologie and Trenite (EEG Department, Instituut voor Epilepsiebestrijding, *E.F.S.N. Hdpital Pasteur, Nice; and ?Service de PCdiatrie, Heemstede, The Netherlands)--4049. CHG, Grasse, France)4051.

Subsequent to the widespread introduction of computers in the Ten months before receiving medical attention, a 15-year-old office and at home and notably after the recent massive sales of Spanish girl developed bilateral myoclonias that first occurred

Epilepsiu, Vol. 35, Suppl. 7, 1994 38 EUROPEAN CONGRESS PROCEEDINGS

early in the morning. She was admitted for catatonic state con- (["CIDpn) binds to all opiate receptors in vivo and is displacable sistent with absence status epilepticus. Neurologic examination by endogenous opioids. showed serious cognitive disorders intermixed with severe mood Two patients with RE were studied with paired ["CIDpn pos- disturbances, cerebellar signs, and bilateral sudden atonias when itron emission tomography scans at rest and on a separate occa- she was asked to perform a voluntary movement. EEG showed sion with reading-induced seizures 15 and 60 min after injection a fundamental activity at 5-6 Hz and frequent discharges of fast of the tracer. Relative differences in ["CIDpn volume of distri- (4-6 Hz) generalized irregular spikes-waves, isolated or in brief bution (V,) were compared with that of 6 healthy normal volun- bursts. In addition, she showed a right posterior spike focus hut teers. no photosensitivity. Polygraphy showed that voluntary move- Magnetic resonance imaging (MRI) showed an old left tempo- ments elicited only negative bilateral arryhthmic myoclonus with ral infarction in 1 patient and was normal in the other. Coregis- a right predominance preceded on surface EEG by a burst of tration of ["CIDpn V, images and MRI data showed significant irregular spike-waves. At rest, there were no positive myoclonic decrease in V, in the thalamus and the right and left posterotem- jerks. Fundoscopy and somatosensory evoked potentials were poral and inferoparietal lobes after seizures. The decrease in normal. Negative myoclonus improved partially after antiepilep- ["CIDpn V, suggests release of endogenous opioids associated tic treatment with valproate, phenobarbital, and clobazam. Ad- with epileptiform activity at these sites. dition of piracetam 18 g/day produced further improvement. Ax- illary skin biopsy showed Lafora bodies in the cells of both exo- crine and eccrine sweat gland ducts. Auditory Event-Related Potentials in Epileptic Patients Treated with Valproate or Carbamazepine Monotherapy. G. Panagopou- los, G. Tagaris, Th. Thomaides, G. Lekkou, I. Rakopoulou, and Reading Epilepsy: Report of Two Cases. J. A. Mauri, E. Mosta- C. L. Karageorgiou (Neurology Department, General Hospital cero, E. MuAoz, J. M. Sanz, and F. Morales (Servicio de Neu- of Athens, Athens, Greece)4055. rologia, Hospital Clinico, Zaragoza, Spain)4052. Auditory event-related potentials were recorded in 20 epileptic Reading epilepsy (RE) is a benign idiopathic syndrome pref- patients receiving valproate (VPA), 20 epileptic patients receiv- erentially related to the temporoparietal region of the language- ing carbamazepine (CBZ), and 30 age- and sex-matched healthy dominant hemisphere but also to other regions functionally in- controls. All subjects performed a simple auditory discrimination volved in reading. We report 2 patients aged 24 and 26 years with test in which a target tone was presented in 20% of trials. abnormal sensations developing in full consciousness after a cer- Mean P3 latency of the VPA group was significantly prolonged tain amount of reading in the musculature involved in reading: in comparison with the CBZ group and the control group; 5 tongue, lips, and face. This symptomatology was followed by a patients receiving PA had abnormally prolonged P3 latencies; in generalized tonic-clonic seizure. In 1 patient, seizures were pre- 2 VPA patients, P3 was undetectable. This difference might be cipitated by calculation, board, and card games occurred. Rou- attributable to effects of VPA treatment. The possible influence tine EEG was negative. Reading EEG showed bilateral, sym- of GABAergic mechanism on P3 generation was investigated. metric paroxysms (very short spike and wave complexes). Sei- zures were controlled in both patients by valproate. Giant Somatosensory Evoked Potentials in Benign Epilepsies. Pas- quale De Marco and Stefan0 Calzolari (Pediatric Neurology Unit, "S.Chiara" Hospital, Trento, Italy)-4056. Functional Imaging in Reading Epilepsy: A Case Report. M. J. Koepp, M. L. Hansen, B. Guldin, R. M. Pressler, W. Scheuler, In recent years, midlatency extreme somatosensory evoked and S. Ried (MRC Cyclotron Unit, Hammersmith Hospital, Lon- potentials (ESEPs) (amplitude >25 pV) have been described and don, England, and Berlin, Germany)-4053. associated with the benign partial epilepsies. We performed a median nerve SEP study in 45 subjects aged 6-18 years. These We investigated the precipitating mechanism in a 34-year-old children were divided into three groups: group A, subjects with woman with reading epilepsy. Seizures were triggered by reading the phenomenon of the tactile-evoked spikes in EEG, with or and language-related activities such as writing and hearing. Com- without epilepsy; group B, subjects with various epileptic syn- prehension was not a necessary provoking factor. Reading Ger- dromes and EEG abnormalities but without tactile-evoked man nonsense words, a Yiddish text, and even Japanese Kana spikes; and group C, healthy subjects with normal EEG. produced EEG activity, indicating that decoding was not essen- About half of the children in group A, none in group B, and tial. Saccadic and pursuit eye movements atone did not provoke only 1 in group C had ESEPs. Group A had a significant higher discharges. Our case supports the theory that grapheme to pho- amplitude of N60 and N140 as compared with group B and C. neme transformation is one critical stimulus in reading epilepsy. Moreover, the N140 latency was increased in group A. Magnetic resonance imaging was normal, but 2 ["Cldiprenor- We showed that the presence of ESEPs is linked to the phe- phine positron emission tomography scans showed endogenous nomenon of tactile-evoked spikes on EEG rather than to an ep- opioid release during epileptic activity in thalamus and left and ileptic condition. On the other hand, the presence of tactile- right temporoparietal region. Brain mapping showed centers of evoked spikes can predispose to benign partial epilepsy. maximal epileptic activity in right temporal, frontocentral, and left frontal regions. To our knowledge, this is the first report of functional neuroimaging in a patient with reading epilepsy. Patterns of Visual Evoked Potentials Distribution in Normal Sub- jects and in Patients with Epilepsy. Melania Radionova, Dirnitar Chavdarov, and Petjo Kovachev (Department of Neurophysiol- Endogenous Opioid Release in Reading Epilepsy. M. J. Koepp, ogy, Alexsandrov University Hospital, Sofia, Bulgaria)-4057. M. P. Richardson, H. Watabe, M. C. Prevett, V. Cunningham, J. Ashburner, D. L. Stevens, J. S. Duncan, and D. J. Brooks In healthy persons and in patients with epilepsy (generalized (MRC Cyclotron Unit, Hammersmith Hospital, London, En- and partial forms), we studied the dynamic of potential field gland)4054. distribution of visual evoked potential (VEP) to checkerboard pattern reversal. The potential field evolution was studied as We wished to determine ictally related changes on opiate re- map series in three time intervals according to classic VEP com- ceptor binding in patients with reading epilepsy (RE), a recog- ponents. nized form of reflex seizure disorder. Functional imaging data In the first period (corresponding to N75), observed quick have not yet been reported on RE. ["CIDiprenorphine changes in the potential field with irregular patterns of distribu- EUROPEAN CONGRESS PROCEEDINGS 39

tion. The third period (N175) also showed irregular distribution Epileptic Psychosis and Cartography: A Preliminary Study. 0. J. but with slow changes. A regular pattern of potential field dis- Hernandez-Fustes, 0. J. Hernandez-Fustes, and 0. Hernandez- tribution was observed in the time interval corresponding to the Cossio (Institute of Neurology, Havana, Cuba)4060. PlOO component: occipital appearance and disappearance (with or without lateralization), and unchangeable localization of the The relation between epilepsy and psychosis has been of in- field maximum. terest for many years. Thanks to introduction of EEG we have That regular distribution of Pl00 was replaced by different been able to seek the pathogenesis of epilepsy. We used quan- patterns of distribution in the patients with epilepsy: movement titative EEG, to study 17 patients diagnosed with epileptical psy- of the potential field in longitudinal or transversal direction or in chosis to determine perceptible alterations from conventional complicated patterns, changeable localization of the field maxi- EEG, recording and analyzing interictal data with Cuban equip- mum, and appearance and disappearance in opposite sites. In ment, MEDICID-3M. Patients were aged 20-64 years; 89% some of the patients, we calculated equivalent dipole localization showed brain lesion and/or paroxysm. Of the 12 paroxysmal of P100, which also showed some characteristics different from records, 100% showed focal frontotemporal origin, mainly in left those of the healthy group. hemisphere. The most outstanding data of background activity were poor organization of fundamental rhythms, decreased in absolute power (AP) alpha, increased in absolute and relative power (RP) theta-delta, and decreased in total dominant fre- EEG and Visual Evoked Potentials Changes in Patients with Al- quency. We compared the results with those of a control group coholic Epilepsy. Stoyan Bojinov, Dimitar Chakarov, and Rossen of patients with epilepsy but without psychosis in whom we also Rousseff (Department of Neurology, Medical University, noted pattern of decrease in AP alpha and increase in AP-RP Pleven, Bulgaria)-4058. theta-delta; of coincidence was 50% between focal anomalies of EEG and localization of paroxysms in digital EEG. Twenty-five patients aged 25-50 years with chronic alcohol abuse and generalized epileptic seizures were studied. All patients had signs of cerebellar incoordination and slight upper motor neuron involvement, clinical symptoms and signs of poly- neuropathy were detected in 13 of the patients: EEG changes Clinical and Neurophysiological Correlations in Complex Partial usually included nonspecific diffuse abnormalities. Only 4 pa- Seizures. Dimitar Chavdarov, Maria Bratoeva, and Melania Ra- tients had well-formed foci of paroxysmal activity. dionova, (Department of Neurophysiology, Alexsandrov Uni- Visual evoked potentials (VEP) showed a delay in PlOO of 115 versity Hospital, Sofia, Bulgaria)--4061. ms in 13 of the patients and, much more frequently, changes in shape of the waves and of inter pick latencies of both early and To examine the correlation between clinical and neurophysi- late responses. Results of EEG and VEP performed in parallel in ologic findings in complex partial seizures (CPS), we compared patients with chronic alcoholism and symptomatic epilepsy are dominant symptomatology with EEG mapping data. The exis- indicative of extensive CNS lesions. tence of affective, psychosensory, and autonomic symptomatology correlated with abnormal findings in both temporal and pa- rietocortical projections; ideational symptoms or speech arrest involved both temporal and frontal areas; patients with visual EEG Quantitative Studies in Epileptic Persons. t§D. MendonCa, hallucinations had abnormalities in the occipital areas; and those 'IS. Abreu, "M. Oliveira e Silva, *"J. P. Cunha, 'IF. Vaz, *J. with psychomotor automatisms always showed bitemporal dis- Lopes, *R. Brito, and *$A. Martins da Silva (*ServiCo de Neu- charges or slow wave activity. Distribution of abnormal EEG rofisiologia, Hospital Santo Antbnio, Porto, tLaborat6rio de phenomena showed a different but specific spreading pattern for Biometria and tUnidade de Fisiologia Humana, Instituto de each patient. Ci6ncias Biomtdicas Abel Salazar; PUnidade de Neurofisiologia The results imply that CPS engage temporal lobe and different e Psicofisiologia do IBMC, Universidade do Porto, Porto; and areas in a complicated manner. CPS with obligatory qualitative "INESC, Universidade de Aveiro, Aveiro, Portugal)--4059. changes in consciousness involve spatiotemporally greater brain zones than the discrete cortical areas in focal bursts and more In recent years, the importance of analysis of brain functional restricted areas than in absence or generalized tonic-clonic sei- status assessed by EEG quantitative studies based on neuromet- zures. Therefore, CPS do not coincide precisely with the defini- ric approaches as an adjunct to clinical evaluation has been tion of focal discharges; they constitute a more restricted form widely stressed. Frequency, asymmetry, coherence, and abso- than generalized seizures. lute and relative power of brain potentials are calculated pro- jected on the scalp and represented in the spatial domain. By such methods, definition of abnormality/normality is a function of statistical evaluation relative to distribution of values of EEG features extracted from a normative database. The observed val- Effects of Vagus Stimulation on Epileptic Activity in Rats. Leonid ues are classified in or outside the normal range by multivariate Godlevsky, Alexei Shandra, and Andrey Mazarati (Department statistical analysis with corrections for age. of Normal Physiology, Medical Institute, Odessa, Ukraine)- The method is valid to analyze background EEG activity but is 4062. not useful if applied to epileptiform events. Our research ad- dressed data acquisition, segmentation and processing using The effects of electrical stimulation (ES) of right nervus vagus methods similar to those of John et al. (Handbook of electroen- (NV) on the behavior of penicillin foci created in brain cortex of cephalography and clinical neurophysiology . Elsevier, Amster- artificially ventilated anesthetized rats were studied. ES (100- dam: 1987;449-95; Electroencephalography: basic principles, 300 Hz) increased latency of foci occurrence and shortened du- clinical applications and related fields. Baltimore: Williams & ration of their lifespan. Frequency of epileptic discharges was Wilkins. 1993:989-1003) to quantify EEG background activity in also decreased by ES, but their magnitude was unchanged. Di- epileptic persons. Data of 60 healthy subjects analyzed on neu- rect ES of the vagal nucleus caused similar effects. rometrically were compared with values of background EEG of Lesioning of the NV nucleus by ibotenic acid resulted in sig- epileptic persons. Preliminary results in children showed de- nificant decrease in seizure threshold during systemic adminis- crease in relative power in alpha band and in posterior scalp tration of picrotoxin and bicuculline. Strychnine-induced sei- areas, and increase in relative power of low frequencies (theta zures were not sensitive to NV nucleus damage. Antiepileptic predominantly) in anterior regions on background EEG of epi- influence of NV ES is induced through activation of GABAergic leptic persons. mechanisms. 40 EUROPEAN CONGRESS PROCEEDINGS

Vagus Nerve Stimulation: Seizure Rate Evolution After Generator treatment. Eight RTMS trains were applied to left and right tem- End-of-Service and After Replacement of the Generator. Ruzica poral and frontal areas, using a stimulus intensity of 1.2*Tm (the K. Ristanovic, Donna Bergen, Michael Smith, *W. Brent motor threshold to a twitch in the right hand), stimulus duration Tarver, and *Joachim F. Wernicke (Rush Epilepsy Center, of 1 s, and stimulus frequency of 30 Hz; 50-Hz stimulations, with Rush-Presbyterian-St. Luke’s Hospital, Chicago, IL; and *Cy- stimulus duration of 1 s and stimulus intensity of 1.2*Tm, were beronics, Webster, TX, U.S.A.)--4063. applied to both anterotemporal regions, in all, 10 TMS and 340 RTMS pulses to each patient. The number of sharp wavedspikes Vagus nerve stimulation (VNS) has emerged as an effective and low-frequency potential were lower (p < 0.01) as compdred alternative treatment for intractable epilepsy. A controlled trial with prestimulus values and returned to prestimulation values was recently completed, with 115 patients exiting to an extension ~10min. Paroxysmal activity was provoked, and no seizures period. VNS was delivered through an implantable system con- developed. RTMS as used in this study is not effective as an sisting of a battery-driven stimulating generator and lead elec- activation procedure for paroxysmal activity. Because the risk of trodes. seizures may depend on stimulus parameters, further studies are We evaluated seizure frequency during an end-of-service needed to evaluate the safety of RTMS. (EOS) period and compared it with baseline, the stimulation period preceding the EOS period, and the stimulation period after battery replacement. Eight-four of 115 patients experienced battery depletion and generator EOS; 62 of 84 patients (73.8%) elected to replace the generators. Data from all four periods were Experience of 36 Patients with Vagus Nerve Stimulation at a Swed- available for 41 patients. ish Epilepsy Center. Elinor Ben-Menachem and Lars Erik Au- Twenty-two patients were responders to VNS (>SO% seizure gustinsson (Sahlgren Hospital, Goteborg, Sweden)-4066. reduction), and 19 were nonresponders (40% seizure reduction). The two groups were well matched for all demographic Vagus nerve stimulation (VNS) was evaluated in a multicenter variables. Responders demonstrated persistent seizure control double-blind study in 113 patients with refractory partial sei- for 2 weeks after detected EOS. Return to baseline seizure rate zures. We implanted 15 study patients who were followed indef- occurred gradually. Rechallenge by repeat stimulation restored initely (open extension). We have also implanted 20 refractory improved seizure control. The data suggest that VNS causes patients since commercialization of VNS and compared data of enduring suppression of susceptibility to seizures that outlasts study and commercial patients. Baseline characteristics for each the immediate effects. group were similar. Of the 12 study patients receiving 18-month stimulation, 5 had >50% seizure frequency reduction (SFR). Side effects were hoarseness (n = I), shortness of breath (n = l), and muscle pain (n = 1) during the 12- to 18-month period. One patient withdrew Relationship Between Antiepileptic Effect of Vagus Nerve Stimu- (throat pain), another has not reached 18 months of treatment, lation and Interictal Epileptiform Discharges. Ramon Manon- and another had seizure surgery. Seven of 16 commercial pa- Espaillat and Joe F. Wernicke (Thomas Jefferson University, tients had >50% seizure SFR, (mean stimulation 15 months). Philadelphia; and Cyberonics, Webster, TX, U.S.A.)--4064. Data were unavailable for 4 patients (stimulation <2 months). Side effects were comparable to those of study patients. We wished to determine the relationship between antiepileptic Comparison of percentage of responders (>50% SFR) in each activity of left vagus nerve stimulation (VNS) and site of interic- group, showed no statistical difference. With the groups com- tal epileptiform discharges (IED). Most vagal sensory afferents bined, 12 of 28 patients had >50% SFR (p = 0.00005), and 28 of synapse in ipsilateral nucleus tractus solitarius, with further pro- 31 of patients have continued therapy 6 jections to ipsilateral thalamus and cortex. Left VNS is effective months after implant. Results of VNS for refractory partial seizures in study patients in treatment of partial onset seizures, but the relation between and in commercial patients were the same. efficacy and site of seizure foci has not been determined. Location of IEDs was correlated to efficacy in patients treated with left VNS after 1 year of therapy. Enough temporal and frontal IEDs were recorded to allow us to draw tentative conclusions regarding lobe or origin. Discharges from all lobes were Eighteen-Month Follow-up of 70 Partial Seizure Patients Receiving considered in analysis of laterality. Patients with only a temporal Vagus Nerve Stimulation. M. Basim, B. Uthman, Joe Wilder, *R. focus had a meadmedian seizure frequency reduction of 30.9/ Eugene Ramsay, and ?Richard E. George (V. A. Medical Cen- 34.6% and those with only a frontal focus had a reduction of ter, Gainesville, FL; *University of Miami, Miami, FL; and 5.9/17.4% (p = 0.244/0.269). Those with only left foci in any lobe ?Texas Tech University, Lubbock, TX, U.S.A.)4067. had a meadmedian reduction of 39.2/27.1% and those with only right foci had meadmedian reduction of 24.1/46.0% (p = 0.407/ 0.835). VNS appears to be effective, regardless of IED focus. We analyzed long-term effectiveness of vagus nerve stimulation (VNS) in reducing seizure frequency in epilepsy patients with refractory partial seizures, studying 114 patients at 17 centers in a double-blind, randomized trial. A VN stimulator was surgically implanted, delivering chronic intermittent stimulation EEG Changes After Repetitive Transcranial Magnetic Stimulations for 30 s every 5 min, 24 h/day. Mean seizure frequency (MSF) in Patients with Epilepsy. Poul Jennum, Anders Fuglsang- after 3,6, 12, and 18 months of VNS was compared with baseline Frederiksen, and Mogens Dam (Department of Clinical Neuro- for the first 70 patients to receive 18 months of stimulation. physiology, Hvidovre Hospital, Hvidovre, Denmark)4065. MSF decreased in the 18-month period. After 3 months, MSF was reduced by 21%. After 6, 12, and 18 months, reductions Transcranial magnetic stimulation (TMS) has been proposed were of 27, 35, and 39%, respectively (p < 0.0001, t test for all as an epileptogenic-activating procedure in evaluation of patients periods). At 18 months, 31 patients (44%) had 250% reduction in with partial epilepsy. With introduction of repetitive (rapid rate) seizure frequency, including 15 patients (21%) with 275% reduc- transcranial magnetic stimulators (RTMS), cortical stimuli can tion. Side effects included hoarseness, coughing, and throat pain be applied at a stimulus of 40Hz. We evaluated the epilepto- and occurred primarily during stimulation phases; 82% of pa- genic effect of RTMS. Ten patients with medically intractable tients were continuing therapy at 18 months. Efficacy of VNS for temporal lobe epilepsy were included. As part of preoperative treatment of refractory partial seizures is sustained for 18 months evaluation, all patients were studied with ictal video-EEG scalp and appears to improve with time in some patients. VNS is well recordings during a period of discontinuation of antiepileptic tolerated.

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 41

Surgical Outcomes Associated with Implanting a Vagus Nerve stimulation (1 mA, 30 Hz for one min every 5 min was started in Stimulator. Richard E. George and *Steven Reid (Texas Tech January 1992 and increased 6 months later to 1.25 mA, 35 Hz University, Lubbock, TX; and *University of Florida, Gaines- until January 1993. During this time, monthly digital EEG re- ville, FL, U.S.A.)--1068. cordings were made. In the first 5 months, no clinical changes were noted. With a new system for “paperless” EEG (Walther Vagal nerve stimulation (VNS) has proven an effective anti- Graphtek) offering the possibilities of rematting, filtering, and convulsant for some patients with refractory partial epilepsy. We zooming, focal spikes-sharp waves frontally to the right and tem- wished to determine the complications associated with the im- porocentrally to the left were evident on EEG, otherwise dom- plant procedure. A double-blinded, randomized trial of VNS was inated by rhythmic delta with high amplitude with maximum undertaken at 17 centers implanting 113 patients. General anes- frontally and bilaterally. No background activity was noted in thesia was usually used during the I-h procedure. A subcutane- the alpha band. In spectral analysis aimed at grading changes in ous pocket over the left chest was created for the generator. theta-delta activity. Ten 3-s artefact-free 19-channel EEG seg- After a second incision in the neck, the electrodes were placed ments were chosen from which a mean value of each frequency around the left vagal nerve. The other end of the lead was tun- band and relative alpha-delta power could be calculated. With neled into the chest and attached to the generator. Patients were few exceptions, the relative delta amount followed seizure fre- usually discharged the following morning. quency. Correlation was good (r = 0.65, p = 0.031). In the first Four patients developed superficial wound infections, suc- 5 months, seizure frequency was reduced despite in medication cessfully treated with antibiotics without generator removal. In 1 reduction. patient transient hoarseness developed after placement of an Vagus stimulation alone could not control the seizures, but a electrode around an unusually large vagal nerve but subsided new drug, lamotrigine, reduced seizure frequency. Significant (r spontaneously without further intervention. One patient experi- = 0.74, p = 0.01) seizure reduction was noted during 18-month enced temporary hyperthesia of the left neck and face, and an- follow-up, not including the drug-free period. Use of quantitative other patient had facial nerve palsy; both spontaneously re- digital EEG facilitated evaluation of degree of changes in EEG solved. There were no cardiac, pulmonary, or gastrointestinal during additional treatment with vagus stimulation of a 10-year- complications. No generator required removal as a result of sur- old child with chronic drug-resistant epilepsy. gical complications. The complication rate from implantation of the vagus nerve stimulator is very low. Long-Term Adverse Events Associated with Vagus Nerve Stimula- tion. R. Eugene Ramsay, *B. Joe Wilder, and Jeremy Slater Experience with Vagal Nerve Stimulation in Children with Intrac- (University of Miami, Miami, FL; and *V. A. Medical Center, table Epilepsies. Jerome V. Murphy, Gregory Hornig, Gloria Gainesville, FL, U .S. A.)--407 1. Schallert, and Melissa Baldus (Departments of Neurology and Neurosurgery, The Children’s Mercy Hospital, Kansas City, We describe the adverse events (AE) associated with vagus MO, U.S.A.)-4069. nerve stimulation (VNS) for 113 refractory partial seizure patients implanted in a double-blind, parallel study comparing two Ten children aged 5-16 years with medically and surgically stimulation patterns. After 12 weeks, all patients received ther- intractable seizures were treated with implanted vagal nerve apy in an open extension phase. stimulators (VNS) for 1-11 months. Epilepsy had been symp- During the 12-week study, side effects reported by >5% of tomatic for 4-12 years. Nine children failed previous research patients in the therapeutic arm (n = 56) were hoarseness protocols and 4 failed corpus callostomies. Etiologies were un- (37.5%), throat pain (12.5%), coughing (8.9%), paresthesia known in 8, radiation and medulloblastoma in 1, and pachygyria (5.4%), and shortness of breath (5.4%). Hoarseness, throat pain, in I. Seizures were generalized in 7 and partial in 3. At the time and coughing were statistically significant (p < 0.05) as com- of implantation, this group was receiving from 1 to 4 anticonvul- pared with baseline. Serious AE included 1 patient with a para- sant drugs (ACDs), mean 2.4. lyzed vocal cord caused by a malfunctioning generator. Seventy All improvements occurred in the first week of VNS activa- of a possible 85 patients reached 18 months (15 withdrawals due tion, and there were no relapses for the time of observation. Five to inefficacy). Side effects reported by >5% during the 16-18- (50%) patients had >90% reduction in number of seizures and month period included hoarseness (7.1%); statistically signifi- marked improvement in quality of life. Of these 5,3 were able to cant). There were no serious AE. eliminate at least one ACD. One patient was able to shorten Short-term side effects included hoarseness, throat pain, and seizures using prn magnet activation, eliminating prolonged post- coughing and occurred primarily during the stimulation pulse (on ictal lethargy. The most remarkable patient went from aphasia, for 30 s every 5 min). Long-term side effects include hoarseness. nonambulation, and gastrostomy feeding to speech, ambulation, VNS was well tolerated, with only 1 of 113 patients not com- and self-feeding. Information on at least 4 additional patients will pleting the 12-week study and no patients dropping out because soon be available. Our results are far superior to what has been of side effects. reported in adult patients.

Neurohumoral Changes with Vagus Nerve Stimulation for the Digital EEG Monitoring of a Child with Chronic Drug Resistant Treatment of Epilepsy. Elinor Ben-Menachem, Tomas Hedner, Epilepsy During Vagus Stimulation: An 18-Month Follow-Up. P. Anders Hamberger, *B. Joe Wilder, and tR. Eugene Ramsay Andlin-Sobocki and P. Leissner (Department of Clinical Neuro- (University of Goteborg, Goteborg, Sweden; *V. A. Medical physiology, Orebro Medical Center Hospital, (irebro, Swe- Center, Gainesville, FL; and ?University of Miami, Miami, FL, den)--4070. U .S.A.)-4072.

Additional treatment with vagus stimulation of a 10-year old Vagus nerve stimulation (VNS) has demonstrated anticonvul- girl with chronic drug-resistant epilepsy was monitored with dig- sant properties in clinical study patients with refractory partial ital EEG. Since onset of epilepsy at age 8 months, the girl had seizures. The anticonvulsant effect improves with time in some had 1-4 generalized tonic-clonic and at least 2 myoclonic sei- patients, although the mechanism of action is unclear. We ana- zures a day. Computed tomography (CT), magnetic resonance lyzed cerebrospinal fluid (CSF) concentrations of neurotransmit- imaging, Ceretec-single photon emission CT, positron emission ters and their metabolites, amino acids, and neuropeptides be- tomography, and magnetoencepalography had shown no patho- fore and after VNS, comparing CSF samples from 16 patients logic signs. Because previous pharmacologic treatment had not from study baseline and after 3 months of VNS. been successful enough, additional treatment with chronic vagus Four of the 16 patients had >25% seizure frequency reduction

Epilepsia, Vol. 35, Suppl. 7, 1994 42 EUROPEAN CONGRESS PROCEEDINGS after 3-month VNS. Mean and median concentrations of phos- sharp waves were averaged, and dipole reconstructions of the phoethanolamine were increased in responders and decreased in extracranial signals were performed with BESA program. nonresponders. These differences were statistically significant. Subtemporal spikes in most cases showed strong extracranial Similar patterns were noted for asparagine, phenylalanine, ala- fields, and the dipole analysis program differentiated quite well nine, and tryptophan (no statistical significance). Free GABA between medial and lateral subtemporal spike locations. In some tended to be increased in both groups, but more so in nonre- cases, however, high-amplitude subtemporal spikes were com- sponders. pletely invisible on the surface. Laterotemporal intracranial Comparison of all patients, regardless of response, showed spikes generally showed weaker extracranial fields than did sub- that total and free GABA were significantly increased, as was temporal spikes, but in these cases as well dipole analysis ethanolamine. A decrease in aspartate was marginally signifi- yielded reasonably accurate dipole locations, well distinguish- cant, and a tendency to decrease in glutamate and increase in able from those obtained with subtemporally generated spikes. 5-HIAA was noted. VNS appears to affect CSF composition. These preliminary results indicate great interpatient variability in extracranial expression of intracranial spikes of similar appearance; the dipole analysis program separates events in different parts of the temporal lobe quite well. Epilepsy Monitoring Revisited 10 Years Later. *M. R. Brito, *P. M. Ribeiro. *R. Pinto. *O. Leite. *M. G. Maia. *I. Paiva. tD. Mendonqa,’and *$A. Martins da Silva (*Serviso be Neurofi: siologia, ~~~~i~~lSanto Antbnio; and tLaborat6rio Biometria Localizing Value of ScalplSphenoidal EEG Interictal Epileptiform and $Unidade l+iologia H~~~~~,Institute ciencias BiomCdicas Paroxysm Amplitude and Distribution Ranking. D. N. Velis, *A. Abel Salazar, Universidade Porto, Porto, Portugal)-4073. Kohli, G. J. F. Brekelmans, and W. van Emde Boas, (EEG De- partment, Instituut voor Epilepsiebestrijding, Meer en Boschl Guidelines for long-term monitoring (LTM) for epilepsy were DeCruquiushoeve, Heemstede, The Netherlands; and *Depart- ment of Neurology, Lucknow, Uttar Pradesh, India)--4075. recently published (Electroencephalonr Clin Neurophvsiol 1993; 87:437158), emphasizing the needs of standards and qualified Interictal EEG records 13 adult patients with refractory experience to improve their utility, i.e., in “difficult cases” of of symptomatic localization-related epilepsy of either frontal epilepsy. Our experience is based on 521 records representing 10 or years of epilepsy monitoring. LTM was performed with an EEG temporal lobe origin who underwent preoperative evaluation seizure monitoring were reviewed retrospectively. Evaluation con- cable telemetry system combined with video monitoring of behavior and blood drug level monitoring to assess 384 patients sisted of epileptiform paroxysm amplitude ranking based on 16 (repetition records 137). Data from monitoring sessions (sei- symmetrically and anteriorly placed electrodes, including inter- zures, EEG, behavior, drug level parameters) were analyzed in ofrontal (Maudsley system), true temporal, and sphenoidal elec- different ways: “daytime registrations”4-h periods of EEG trodes. Results with respect to lateralization and localization of the recording including a sleep nap, and full night (8-10 h) or longer trigger zone were compared with ictal records. Correct lateral- (s24 h) registrations. The relevance of monitoring was defined ization was obtained in all cases. Amplitude ranking and coinci- according to influence on better EEG characterization (focal, dence-of-occurrence analysis (COA) showed three different nonfocal, status, normal) and their relevance to seizurelepilepsy patterns of paroxysmal distribution. Sphenoidal/Maudsley classification; relation between EEG and behavior (ictal and or nonictal events: seizures and psychogenic seizures); quantifica- Maudsley/sphenoidal maxima followed by true temporal, tion of seizures and of epileptiform EEG activity by automatic midtemporal, and laterofrontal/frontopolar COA always corre- detection and assessment of spread of epileptiform events and lated with antero/mesiotemporal seizure onsets. Low frontal their relevance to seizures and epilepsy classification; relevance maxima followed by Maudsley, high frontal, and frontopolar of drug monitoring on definition of therapeutic strategies; and COA correlated with lateral/dorsal frontal more often than with identification of stimuli including seizures and/or epileptiform temporal neocortical seizure onsets. Frontopolar/sphenoidal or discharges. Finally, the reasons for repetition of monitoring were sphenoidaYfrontopolar maxima, regardless of further ranking, studied. were never associated with antero/mesiotemporal seizure on- Although epilepsy monitoring is a relevant technique for epi- sets. Ranking of amplitude and COA of interictal epileptiform paroxysms recorded by nonstandard electrodes is very helpful in lepsy diagnosis, seizures, and EEG classificationlquantification, its usefulness must be assessed by strict criteria. One of the main localizing the ictal trigger zone in preoperative evaluation of tem- reasons for success or lack of success or utility versus inneficacy poral or frontal lobe epilepsy but does not obviate the need for of epilepsy monitoring is correct assessment of the necessity for seizure monitoring. monitoring, which when requested, considerably decreases the relatively high costs of this procedure.

Contribution of Ambulatory EEG to Diagnosis of Epilepsy at the Hospital Militar Principal, in Lisbon. Luiza Rosado and Carlos Sebrosa (Hospital Militar Principal, Lisbon, Portugal)4076. Simultaneous lntra- and Extracranial Recording of Epileptic Dis- charges in Patients with Therapy-ResistantPartial Epilepsy. Goran Each year in Portugal, -25,000 young men (aged 18-28 years) Lantz, Ingmar RosCn, and Mikael Holub (Department of Clinical are evaluated for mandatory military service. Because epilepsy Neurophysiology, University Hospital, Lund, Sweden)-4074. prevalence is 0.4%, -100 epileptic subjects are expected to be detected. According to the present rules in our country, epilepsy lntracranial investigations may prove the results of extracra- excludes one from military service. Therefore, among truly ep- nial investigations to be misleading. Extracranially recorded ileptics, some persons are expected to feign ill-defined loss of spikes may represent only a fraction of intracranially recorded consciousness (epilepsy) to avoid such service. interictal epileptiform activity, and methods for directly compar- We studied a group of patients with complaints related to ep- ing extra- and intracranially recorded epileptiform activity are of ilepsy (loss of consciousness, syncope, seizures) who were sub- interest. mitted to routine EEG testing in the laboratory of the principal Eight patients with partial complex epilepsy of temporal lobe military hospital in Lisbon. When the EEG was negative or in- origin undergoing invasive video/EEG monitoring were recorded conclusive, patients were submitted to a 24-h eight-channel am- with a combination of 10 intracranial spike-producing electrode bulatory EEG. We report results of -300 such ambulatory contacts and 22 extracranial recording sites. Several intracranial EEGs. EUROPEAN CONGRESS PROCEEDINGS 43

Epilepsy with Occipital EEG Focus and Refraction Abnormalities. Partial Complex Seizures with Pseudoperiodic Motor Events. B. Stoyan Bojinov, Dimitar Chakarov, and Rossen Rousseff (De- Dalla Bernardina, F. Darra, A. Franco, F. Piardi, E. Santorum, partment of Neurology, Medical University, Pleven, Bulgaria)- A. Montagnini, and R. Grimau-Morino (Neuropsichiatria Infan- 4077. tile, Universita, Verona, Italy)--4080.

Fifty patients aged 4-16 years with various types of epileptic The peculiar ictal electroclinical pattern of spasms in series seizures (tonic-clonic in 72%, absence in 6%, tonic-clonic and related with a pseudoperiodic slow wave triggered by partial absence in 12%, focal seizures in 8%. other forms in 2%) and discharges with motor or subclinical expression is well known established occipital EEG focus, as well as developed secondary and documented. On the contrary, partial complex seizures with foci in some, were followed for 12 years. All patients had refrac- pseudoperiodic events are rarely described. We report the elec- tion abnormalities detected at first EEC examination (hyper- troclinical study of 8 children (5 females and 3 males aged 18 metropia in 6670, astigmatism in 28%, myopia in 4%, and em- months to 4 years) with partial epilepsy with long-lasting and etropia in 2%). All patients received anticonvulsant treatment frequent seizures characterized by repetitive “motor events” and correction of refraction abnormalities. Clinical and EEC fol- evolving to partial status with affective symptomatology. In all low-up showed significant reduction in both seizure frequency but 1, seizures appeared during infancy. The ictal repetitive mo- and EEG paroxysmal activity in 72% of patients, with lesser tor event constituted a “dystonic movement” often evoking an reduction in 28% of patients, most with astigmatism. Visual automatic act. Frequently, blinking with eye deviation is ob- evoked potentials showed a tendency for delay and higher am- served concomitantly. The sequence can persist for several min- plitude in 50% of these patients. We suspect that astigmatism utes or hours, accompanied by severe behavioral disturbance. contributes to more prolonged paroxysmal activity in patients Because of the very poor ictal EEG pattern, nonspecific in- with epilepsy and occipital lobe EEG focus. terictal abnormalities and unusual clinical manifestation, the epileptic nature of this status is often misunderstood. We discuss the nosologic classification of this peculiar ictal electroclinical pattern and stress the importance of early recognition of this epileptic status, which can lead to severe psychic disturbance. Seizure Abatement After Continuous Spike and Wave During Slow Waves in Localized Cortical Dysplasia. Renzo Guerrini, *Antonia Parmeggiani, ?Michelle Bureau, $Xavier Salas-Puig, ?Pierre Genton, and *Margherita Santucci (INPE-IRCCS Stella Maris, All-Night Sleep Polygraphic Studies in Rett Syndrome. M. A. Col- Pisa; and *Clinic of Neurology, University of Bologna; Italy; lado, A. Gonzalez, L. Cordero, B. G. Ramos, B. Reyes, and M. ?Centre St. Paul, Marseilles, France; and $Hopitdl Asturias, Shkurovich (Instituto Nacional de Pediatria and ABC Hospital, Oviedo, Spain)4078. Mexico City, Mexico)-4081. Among 34 patients with localized cortical dysplasia shown by Six female patients aged 34years with progressive encepha- magnetic resonance imaging, EEG showed continuous general- lopathy, motor deterioration, stereotyped hand movements, loss ized spikes and waves (CSWS) during slow phases in 6 children of language, autistic behavior, and seizures, fulfilling the diag- with perisylvian dysplasia (unilateral in 5 and bilateral in 1). All nostic criteria of Rett syndrome (RS), were submitted to all-night 6 had mental retardation (mild to moderate), as well as intracta- polygraphic sleep recordings (PSG) to assess the relation be- ble atypical absences and atonic drop attacks. tween sleep stages and paroxysmal activity in EEG and respira- Epilepsy had onset between the ages of 2 and 4 years, with tory and heart rate patterns. infrequent unilateral seizures. CSWS onset (between the ages of All 6 patients had paroxysmal activity during wakefulness and 2 and 5 years) paralleled the appearance of disabling atonic sei- respiratory abnormalities, superimposed on slow EEG back- zures and atypical absences. CSWS lasted 1-10 years and was ground. Sleep was staged as slow wave sleep (SWS) and REM not modified by callosotomy (two-thirds anterior) performed in I sleep. During SWS, spindles and K complexes were difficult to patient aged 6 years. In 5 children, CSWS, atypical absences and evaluate, during REM, EEG voltage was decreased, and muscle drop attacks ceased simultaneously. These patients are now aged atonia and REM were evident. Paroxysmal activity was present 10-14 years and are seizure-free or have infrequent unilateral during wakefulness and in all sleep stages including REM, with seizures during sleep. central alternating spikes and slow wave bursts without seizures Patients with localized gyral disorders and intractable seizures and spikes over slow wave paroxysmal discharges. Another con- can benefit from epilepsy surgery. Either resective surgery or stant finding was burst-suppression pseudoperiodic paroxysmal callosotomy can be performed, depending on seizure type, loca- discharge during SWS. 1 patient, EEG power spectra showed tion, and extent of lesions. Some centers recommend early in- In asymmetry in EEG background not correlated with structural tervention, but the good prognosis for epilepsy should discour- abnormalities on magnetic resonance imaging. This patient age a surgical approach to patients with CSWS. Sleep EEG showed no respiratory abnormalities during sleep. should be performed routinely in patients with localized cortical dysplasia, especially at the age when CSWS occur.

Unusual Partial Complex Status with Autisticlike Behavior in In- fancy. B. Dalla Bernardina, E. Fontana, E. Zullini, E. Avesani, Epilepsy During Sleep.I.Sleep Polygraphic Recording During a L. Zoccante, A. Perez Jimenez, and L. Giardina (Neuropsichi- Nap Period. J. A. Mauri, E. Mostacero, E. Mu~ioz,J. M. Sanz, atria Infantile, Universita Verona, Italy)--4082. P. LarrodC, and F. Morales (Servicio de Neurologia, Hospital Clinico, Zaragoza, Spain)4079. Epileptic status characterized by a behavioral disturbance in early life has rarely been reported. We report electroclinical We studied 20 epileptic patients (10 males and 10 females, study of 6 children (3 males and 3 females aged 18 months to 4 mean age 34 years) with the following criteria: age >I6 years, years) with partial epilepsy with onset during the first year of life seizures occurring only during sleep, and follow-up >3 years. in 5. Taking into account clinical data, waking EEG, sleep poly- The ictal symptomatology consists of several daily long-lasting graphic recordings during a nap period, computed tomography periods of unexplained behavioral disturbance associated with scan and/or magnetic resonance imaging data, we distinguished pseudoperiodic spasms in 3, repetitive automatic acts in 1, and well-defined epileptic syndromes among these patients: 13 focal brief staring or eye deviation in 3. In most cases, these motor cryptogenic epilepsies (6 temporal, 5 frontal, 2 occipital), 2 focal phenomena are very brief and unusual, and are masked by psy- symptomatic epilepsies, and 5 undetermined epilepsies. chomotor excitement, making them impossible to recognize

Epilepsia, Vol. 35, Suppl. 7, 1994 44 EUROPEAN CONGRESS PROCEEDINGS without video polygraphic records. In 5, this status was the only Electromistagmographicand EEG Patterns in the Cycle “Waking- paroxysmal manifestation since onset; the ictal EEG pattern Sleep-Arousal” in Epileptic Patients. Tsotne Chkhikvishyili and characterized by brief “depression” was also very difficult to Ramaz Abelashvili (Department of Nervous Diseases, Tbilisi recognize. Medical Academy, Tbilisi, Georgia)-4085. Because of such unusual electroclinical expression, the epileptic nature of this status was not known for several months in Electromistagmographic and EEG study of the cycle “wak- most of the patients. All of the children appear autistic during the ing-drug induced-sleeparousal” was performed in patients with status. In I, status has been completely controlled by treatment, focal temporal, focal, nontemporal seizures and primary gener- with no residual deficit. in the other 5, status was controlled only alized epilepsy. in those with focal temporal seizures, SHN pat- partially by treatment and the children show varying severity of terns of arousal were enhanced as compared to waking, whereas cognitive and psychic disturbance. We stress the need for cor- EEG convulsive activity at arousal as compared with waking rect recognition of this peculiar epileptic status, which is often patterns was depressed. Those with nontemporal focal seizures misdiagnosed. showed inverse enhancement of SHN patterns at arousal, whereas EEG activity in this stage did not change. In patients with primary generalized epilepsy, activity of both SHN and EEG patterns at arousal stage was enhanced. Anticonvulsant therapy in all was mostly effective when EEG Epilepsy and EEG Evolution in Disorders of Neuronal Migration. and ENG showed normalization of or decrease in both patterns Manuela Santos and Dilio Alves (Serviso de Neuropediatria, at arousal stage. Study of SHN and EEG patterns is of great Hospital de Criansas Maria Pia, Porto, Portugal)-4083. interest, because their changes tend to be reliable criteria for differential diagnostics and highly authentic for choosing ade- From our records, we selected cases with neuronal migration quate and effective therapy. disorders (NMD), who were classified according to neuroimaging findings and reviewed according to age, development, neurologic examination, presence of epilepsy, and EEG recordings. Those with epilepsy were evaluated according to age of seizure Evaluation of Autonomic System Function in Epileptic Patients. F. onset, type of epilepsy, and prognosis. Pinto, M. Correia, D. Ferreira, A. Longo, J. Pimentel, Twenty-one patients had agyria-pachygyria. Sixteen had epi- J. A. L. B. Sa, P. Mota, J. L. Tuna, and C. Ribeiro (Consults Neu- lepsy and, in most cases (9 of 16), epilepsy had onset in the first rologia, UTIC Arsenio Cordeiro, Hospital Santa Maria, Lisbon, year of life. Very high-amplitude rhythmic activity with promi- Portugal)--4086. nent fast activity was apparent in 18 and paroxysmal activity in 3 EEG recordings. These last 3 had calcifications and hypoden- Knowing the occurrence of sudden unexplained death in epi- sities of white matter associated with agyria-pachygyria. leptic patients and assuming possible association of autonomic Seven patients had schizencephalia, 2 of them with epilepsy. dysfunction in such cases, we evaluated several parameters of Five underwent EEG; 4 were normal and I had paroxysmal re- heart rate variability (HRV), reflecting autonomic function, in an cordings. One of the patients had hemimegalencephaly. He had epileptic population. We studied 26 epileptic patients [mean age epilepsy with fast activity with high amplitude over the hemi- 35.9 -+ 13 years (range 11-62 years), 12 males and 14 females] sphere shown to be affected on EEG. Two patients had focal treated with antiepileptic medication, who were in an interictal heterotopia, both with epilepsy and paroxysmal recordings, 1 phase and without organic heart disease. Patients were classified patient had periventricular heterotopia with epilepsy and normal (ILAE-89) as group A (partial epilepsy, n = 12) and group B EEG, and one patient had double cortex with epilepsy and par- (generalized epilepsy, n = 14). oxysmal EEG. HRV was analyzed on a long-term ECG (24-h Holter) and on EEG recordings showed the same pattern (fast activity with short-term ECG (256 beats series), with Holter parameters on high amplitude) in all cases of agyria-pachgyria except for those time domain analysis: SD of the mean of R-R normal intervals with other associated findings in neuroimaging. The patient with (SDNN), and short-term ECG parameters on frequency domain hemimengalencephaly showed the same unilateral fast activity analysis [low-frequency power (LF), high-frequency power with high amplitude. In all other cases, we noted no correlation (HF), total power (total) and LFlHF ratio. between EEG and neuroimaging. No significant differences were noted in the parameters between group A and B. Neither those reflecting total variance of HRV (SDNN, total) nor those reflecting sympathetic modulation of HRV (LF) or parasympathetic (HF) and their balance (LFI Cardiac Arrhythmias in Complex Partial Epilepsy. Sanja HajnSek HF) were different. Great dispersion of values was noted. Fol- and Zdravka PoljakoviC (Clinical Hospital Center “Rebro,” Za- low-up will show if these findings have any relevant prognostic greb, Croatia)-4084. value.

Known areas in the brain, when stimulated, can cause cardiac arrhythmias, especially the limbic system and hypothalamus, where epileptic activity can result in many different types of EEG Dipole Localization with Spherical and Realistic Models in cardiac rhythm disturbances. We report 15 patients with various Epileptic Patients. *C. Silva, J. P. Foreid, T. Pimentel, A. Al- types of cardiac arrhythmias and an abnormal EEG recording; 12 meida, M. M. Botelho, *A. L. Ferreira, tT. Oostendorp, and patients also had clinically different types of epileptic seizures. *E. Ducla-Soares (Instituto Portugues de Oncologia; and Cardiac evaluation showed no specific cardiac disease. In all *I.B.E.B. da F. Citncias, Lx, Lisbon, Portugal; and tlabora- patients, however, EEG recording showed either diffuse parox- tory of Biophysics, Nijmegen, The Netherlands)--4087. ysmal dysrhythmic changes or epileptic discharges in temporal lobes (uni- or bilateral), and in 1 patient spike-wave complexes We report results obtained from EEG data and use of both also were registered. Furthermore, videopolygraphic recordings spherical and realistic head models on localization of neural of our patients registered epileptogenic discharges concurrent sources in patients with focal epilepsy. For the spherical model, with premature ventricular contractions and sinus tachycardia in the head is approximated by a set of four concentric spheres, ECG. in patients who were examined first by the cardiologist, with different conductivities, that represent brain, cerebrospinal cardiologic therapy only did not prevent symptoms, but in all fluid, skull, and scalp. For the realistic head model, we digitize patients antiepileptic therapy with or without @-blockers im- the brain, skull, and scalp surfaces from magnetic resonance proved clinical symptoms as well as electrocardiographic and imaging (MRI) scans and generate a set of 1,200 triangles to EEG parameters. simulate each surface. In both cases, the neural source is ap-

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 45 proximated by a single current dipole, as is usual for focal epi- hand, drug-induced psychiatric complications of epilepsy such as lepsy discharges. toxic psychosis and paradoxic normalization may negatively in- Our initial trial simulations indicate that for positions of the fluence psychiatric prognosis and have even been described with source near the clinical sources we studied the spherical approx- most recent antiepileptic drugs (AEDs). imation easily introduce errors of 1-2 cm. For the realistic head A retrospective analysis of the influence of epilepsy surgery on models, the accuracy is strongly dependent on the number of long-term prognosis (Epilepsia (1991; 32:375-88a, 477-86) triangles in each layer: -2-3 mm for 1,000 triangles per surface. showed less difference than expected between AED-treated pa- These models were applied to localization of clinical data from tients and medically treated patients. Like successful drug ther- epileptic patients. When a lesion was visible on MRI or com- apy, successful surgery decreases secondary morbidity, includ- puted tomography scans, our localization could be validated and ing psychiatric morbidity. Most descriptions of postoperative de results are compatible with those obtained from simulation and novo psychoses are deplorably imprecise and provide little evi- other clinical patient data. Our results appear promising for lo- dence of the far-reaching hypotheses about their pathogenesis calization of clinically interesting neural sources, especially they have provoked. The literature on the influence of epilepsy those achieved with the realistic head model. This approach surgery on depression is conflicting. In view of the scarcity of should be applied to other neural sources to validate this tech- reliable data, a comparative prospective study of the psychiatric nique fully. prognosis of patients receiving different treatments for epilepsy is highly desirable.

Topic V: Quality of Life and Psychological and Perceptions of Control in Patients with Epilepsy. Sarah Gehlert Psychiatric Aspects (The University of Chicago, Chicago, IL, U.S.A.)-5000c. External perceptions of control secondary to repeated epi- Main Session (5OOOa-5000~) sodes of seizure activity that generalize to the social sphere have been implicated as causes of psychosocial problems in epilepsy. The hypothesis that individuals who continue to experience seizures become more and more external in perceptions of control was tested by a survey mailed to a sample of persons with epi- Definitions and Measurement in Quality of Life in Persons with lepsy in St. Louis, MO, U.S.A. Dependent variables were scores Epilepsy. Rupprecht Thorbecke (Klinik Mara I, Bielefeld, Ger- on instruments measuring locus of control and attributional many)-5000a. style. The independent variable was a measure of seizure control based on present age, age at disease onset, and length of time The concept of quality of life (QOL) is still controversial with since last seizure. The hypothesis was confirmed by multiple ongoing philosophic and ethical objections and discussions as to regression techniques when perceptions of control was concep- how the concept may be differentiated from psychosocial assess- tualized as learned helplessness for bad, but not for good, ment. events. It was not confirmed when perceptions of control was Although specific instruments now exist to measure QOL in conceptualized as locus of control. persons with epilepsy, questions remain regarding measurement The implications of this study will be integrated with earlier of different perspectives of QOL (patient, relatives, profession- theoretical and empiric work on locus of control and learned als), measurement of the impact of social stigma on QOL, dif- helplessness in epilepsy. An interventive approach based on our ferentiated measurement of QOL in the fields of leisure, work, current knowledge of the etiology of psychosocial problems in social contacts, significant other, and usefulness of instruments epilepsy will be reviewed. for measuring long-term outcome and in mentally retarded persons. We report data from 153 consecutive patients on our preoperative monitoring unit. Data on social functioning (mobility, sports, employment, significant other) and on QOL assessment of the patients were contrasted with each other. The influence of Platform Presentation 1 (5001-5006) social stigma and of seizure severity was evident. Fifty-three patients were asked to rate current QOL and expected QOL, presupposing being seizure-free postoperatively. We report definitions, methods, and our results with regard to Dysfunctional Face Processing Capacity in Patients with Unilateral two questions. First, can QOL instruments improve clinical Temporal Lobe Epilepsy. *?Elizabeth Anderson and tAndrew W. practice and in which areas (what are the preconditions-e.g., Ellis (*York Neurology Unit and Special Centre for Epilepsy; personnel for counseling, additional psychosocial data)? Second, and tPsychology Department, University of York, York, En- can QOL instruments widen our insight into what it means to gIand)-5001 . have epilepsy and what kind of studies do we need? The status of face processing in relation to unilateral temporal lobe epilepsy has not been investigated extensively and the literature contains few references to this aspect of cognitive pro- Influences of Pharmacotherapy and of Epilepsy Surgery on the cessing. Yet findings from many animal studies have demon- Psychiatric Prognosis of Patients with Epilepsy. Peter Wolf, *Bet- strated that primate temporal cortex has a central role in many tina Schmitz, and Steffi Koch-Stocker (Klinik Mara I, Epilepsie- different aspects of face processing. Zentrum Bethel, Bielefeld; and *Krankenhaus am Urban, We compared 24 patients with either right or left temporal lobe Abteilung Psychiatrie, Berlin, Germany)-5000b. epilepsy with a matched control group (n = 12) on a range of face processing tests, including recognition of famous people, ability The influences of therapeutic interventions on all aspects of to learn new faces, and processing of emotional expressions. epilepsy prognosis are difficult to assess owing to manifold meth- Results largely reflected orthodox laterality theory of cognitive odologic problems. Development of increasingly effective drug functioning; i.e., patients with right temporal lobe epilepsy were therapy during this century has resulted in improved life quality, disadvantaged. However, patients with left temporal lobe epi- increased life expectancy, and decreased seizure-induced mor- lepsy did not reach the performance level of the control group bidity, including postictal psychiatric morbidity. On the other obtaining an intermediate level instead. Thus a distribution effect

Epilepsia, Vol. 35, Suppl. 7, 1994 46 EUROPEAN CONGRESS PROCEEDINGS of cognitive dysfunction for processing of faces may exist and Emotional problems, psychosocial dysfunctions, and low should have implications for preoperative neuropsychological quality of life (QOL) are common in epileptic patients with sei- work. zures resistant to drug therapy. Current studies show that complete relief from seizures after temporal lobectomy leads to improvement in psychosocial well-being. Change in QOL and psychosocial functioning after selective amygdalohippocampectomy (AHE) has not yet been clearly determined. We studied psycho- Psychiatric Outcome After Neurosurgical Arrest of Temporolimbic social consequences of postoperative seizure relief in 26 pa- Seizures. Shirley M. Ferguson, *Mark Rayport, and Carolyn A. tients, using self-report measures, psychiatric rating scales, in- Schell (Comprehensive Epilepsy Center and Departments of terview techniques, and neuropsychological tests. Successfully Psychiatry and *Neurological Surgery, Medical College of Ohio, operated patients experienced improved QOL, including better Toledo, OH, U.S.A.)-5002. and more stable vocational adjustment, self-assertiveness, and higher social competence. Cognitive functions were only slightly Aggression and psychosis are known problem behaviors (PB) altered. In no case did the changes in cognitive functions require associated with temporolimbic epilepsy (TLmE). Amelioration a rehabilitative training procedure. We noted transient depres- of aggression after temporal lobectomy (TLX) has been de- sive and other neurotic symptoms in 25% of patients seizure-free scribed. In studies of outcome groups combining seizure-free after AHE, while they were adapting to the new situation with- and “improved,” outcome of psychosis was uncertain. Among out seizures. This is highlighted by the fact that almost 20% of 39 consecutive TLmE cases studied by our multidisciplinary patients need psychotherapeutic help after successful AHE. No team before and after TLX, seizure focus localization required appreciable improvements in psychosocial functioning occurred stereoEEG in 21 (54%). Age at operation was 8-54 years and in patients who did not obtain complete relief from seizures. postoperative follow-up was 2.2-21.3 years (mean 9.9 years). Thirty-three (84.6%) patients who remained seizure-free for >2 years were used to determine the effects of brain ablation and seizure cessation on target behaviors. Prehabilitation for Epilepsy Surgery Patients. Susan Lannon and Aggression variously related to the ictus in 4 patients was Cari Bennett (University of Cincinnati Medical CenterEood Sa- absent after TLX. When seizures recurred after 2.3 years in 1 maritan Hospital, Cincinnati, OH, and Portland, OR, U.S.A.)- patient, aggressive behavior resumed, requiring reinstitutional- 5005. ization. Episodic epileptic psychosis occurred preoperatively, with intensification of seizure activity, in 3 patients, indicating a Surgery for removal of an epileptogenic focus can greatly en- psychotogenic risk,of complex partial seizures (CPS) (Ferguson hance a person’s quality of life (QOL), but persons with epilepsy and Rayport, 1988; Ferguson et al., 1993). Psychodynamic may have other psychosocial or behavioral problems that com- themes were incorporated into the psychotic mental content in plicate their ability to benefit from a surgical intervention. Cha- some cases. In the absence of CPS after TLX, psychotic symp- otic or dysfunctional family situations, lack of permanent hous- toms did not recur. Classification of mechanisms of preoperative ing, involvement with the legal system, and substance abuse are PB permitted prediction of postoperative behavioral outcome. example of factors that, although not directly related to the diagnosis of epilepsy, have great impact on a person’s ability to cope effectively with life problems. At some epilepsy centers, these problems may restrict the person’s access to operation. Psychiatric Morbidity After Temporal Lobe Resection. John Mori- Prehabilitation is a concept of intervention that can be used to arty, Howard A. Ring, and Michael R. Trimble (Institute of Neu- address such factors before operation and thus allow even “high- rology, Queen Square, London, England)-5003. risk” patients a chance to become seizure-free and improve their QOL. We report two case studies of patients who participated in a prehabilitation program coordinated by a multidisciplinary Psychiatric disability is common in patients with intractable team at a comprehensive epilepsy center. We identify patient localization-related epilepsies being considered for surgical re- problems, describe interventions, use of community resources, section. As part of the epilepsy surgery program at the National team member roles, and evaluate patientlS.0. response and out- Hospital, Queen Square, patients receive a standardized clinical comes. psychiatric assessment. They are also asked to complete rating scales as a measure of mood and personality variables. The Bear- Fedio, Beck Depression Inventory, and Leyton Obsessional In- ventories are used. We report the results of a prospective study of our first 50 Quality of Life in Medical Care and Rehabilitation of Young Pa- patients. Early psychiatric morbidity is common, usually is not tients with Epilepsy in Germany. Peter Wolf, Paul Wolters, Nor- sustained, and may be a nonspecific effect of operation. Later bert van Kampen, and Dorothea Wiemann (School of Public morbidity, particularly mood disorders, may relate more to pre- Health, University of Bielefeld, Bielefeld, Germany)-5006. operative psychopathology. Psychosis is rare. At 3 months, there were nonsignificant decreases in scores of obsessionality. In two large German cities (Bielefeld and Dortmund) with Decreases in measures of depression were significant. comparable social structure, 150 persons with epilepsy were in- A good outcome in terms of seizure control is associated with terviewed by questionnaire. The Bethel Epilepsy Centre is lo- good psychiatric prognosis. Patients who have poor psychiatric cated in Bielefeld; Dortmund has no similar institution. outcome will be examined to determine if such outcome could We wished to investigate quality of life (QOL) of persons with have been predicted from preoperative assessment. Poor psy- epilepsy. W. Zapf (1984) defined QOL as “good living conditions chological outcome despite good seizure control can often be that go together with a positive personal well-being.” understood in terms of patients’ unrealistic expectations. We report an instrument that measures QOL in its two dimensions: living conditions and well-being. In preliminary results, we compared QOL of patients from an outpatient clinic with QOL of patients treated mainly by neurologist practitioners. We will contrast our results with those of qualitative inter- Quality of Life After Selective Amygadalohippocampectomy.Josef views conducted with experts in both cities who in their profes- Saar, Rainer Wohlfarth, and Gerhard Reinshagen (Epilepseizen- sional or honorary work are involved in counseling, medical trum Kork, Klinik fur Erwachsene, Kehl-Kork, Germany)- care, medical, vocational, and social rehabilitation or self-help 5004. groups of persons with epilepsy.

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 47

Platform Presentation 2 (5007-5012) versity of Liverpool; and SPrudhoe Hospital, Northumberland, England)-5009.

Quality of life (QOL) is recognized as an important outcome Impact of Epilepsy on Health-Related Quality of Life. §11J. L. measure in clinical trials, and its assessment may be particularly Ribeiro, t$D. MendonGa, 111. Gomes, JIL. GonCalves, and *$§A. relevant for children with severe seizure disorders, in whom, Martins da Silva (*ServiGo de Neurofisiologia, Hospital de Santo owing to the nature and frequency of seizures, seizure counts are Ant6nio; tLaborat6rio de Biometria, tUnidade de Fisiologia Hu- not always helpful. We developed a brief QOL questionnaire mana, Instituto de CiCncias BiomCdicas Abel Salazar; OUnidade intended for completion by the parents of children with severe Neurofisiologia e Psicofisiologia do IBMC, Universidade do epilepsy and based on in-depth interviews with parents and dis- Porto; and IlFaculdade de Psicologia, e Ciencias da EducaCio da cussion with expert clinicians. The questionnaire consists of Universidade do Porto, Porto, Portugal)-5007. novel scales to measure parents’ perceptions of seizure severity, adverse drug effects, child’s mood and behavior, and single Quality of Life (QOL) is a broad concept that can be defined as items relating to injuries associated with seizures, overall health, individuals’ overall satisfaction with life and their sense of per- and overall QOL. sonal well-being. Health is the most important domain in QOL, The psychometric properties of the scales and items were ex- and in clinical settings health related QOL (HRQOL) is a domain amined in a pilot study of 50 children with a severe seizure dis- studied in itself. HRQOL (a) is based on personal perception of order, all of whom had accompanying mental handicap. They the patient and not on the perception of relatives or peers or on had good face and construct validity and good reliability, as as- the opinion of medical staff; (b) includes psychological, social, sessed by their internal consistency (alpha range 0.714.84) and and physical aspects; and (c) involves either objective and subtest-retest correlation (r 0.674.84). The questionnaire is cur- jective aspects. In an exploratory study, we wished to determine rently being used in a European clinical trial of the efficacy of HRQOL in epileptic patients, how HRQOL is affected by epi- lamotrigine in treatment of Lennox-Gastaut syndrome and other lepsy characteristics, and how HRQOL is affected by personal severe epileptic disorders of childhood. characteristics of epileptic patients. Our research was started in 1993 in patients followed up at the epileptic outpatient clinic of Hospital Santo Antonio (Porto). The analysis is based on data New Method for Measuring Quality of Life Based on Repertory collected from a sample of 90 patients, men and women aged Grid Technique. C. E. Selai, A. Kendrick, and M. R. Trimble 15-65 years, who had completed basic education level, and had (Institute of Neurology, The National Hospital, Queen Square, seizures of various severity levels and types (simple partial, com- London, EngIand)-SOlO. plex partial, myoclonic seizures, generalized tonic-clonic, seizure-free). Data were collected by trained psychologists when We report a novel technique for quality of life (QOL) mea- patients came to the hospital to undergo routine EEG. The ques- surement based on repertory grid technique. The key feature is tionnaire was an adaptation of the Medical Outcomes Study that individuals can define the areas they consider relevant to Short-Form General Health Survey (MOS-20) and the Epilepsy their own QOL. Subjects choose two constructs (items) in the Surgery Inventory (ESI-55). It includes 33 items, Likert-type five domains commonly accepted as being relevant to a compre- response distributed across nine subscales (emotional well- hensive assessment of QOL, i.e., Physical, psychological, so- being, role limitations due to disease, pain, physical functioning, cial, work/economic, and cognitive. health perceptions, cognitive functioning, overall QOL, changes Within this framework, subjects design their own QOL sched- in health). ule and rate the items on a 5-point rating scale according to how much a problem each item is for them at the moment. In addition, they are asked to rate other situations and persons in their Self-control in Epilepsy and Quality of Life. Christiane Schmid- lives. In this way, a picture is constructed (repertory grid) of Schonbein (Freie Universitat Berlin, UKRV, Children’s Hospi- their view of their current situation in relation to their past, their tal, Berlin, Germany)-5008. expectations for the future, and other persons. The method measures the subjects’ view of their current life Matthews et al. (1982) characterized the so-called “epileptic situation (NOW) in relation to how far they must progress to condition” by three aspects: unpredictability of seizures, overt achieve their desired state (LIKE). It is suggested that the manifestation of the symptom, and seizure-related loss of con- shorter this distance (NOW-LIKE), the greater the QOL of the trol. In particular, the feeling of lack of control over seizure individual. QOL data can be provided at two levels: global level activity represents a serious reduction in quality of life (QOL), as (composite score) and individual level (profile). Preliminary data were obtained in a sample of patients with loss of control over seizures often is generalized to other aspects epilepsy who have elected to undergo temporal lobectomy or of life. Thus, the feeling of awareness of being in control of seizures must be considered a central aspect of QOL for patients other surgical procedures to relieve their symptoms. QOL will be appraised preoperatively and at 3-month follow-up. with epilepsy. But what applies to patients with refractory epileptic seizures‘? A study in which 20 patients with refractory seizures were trained in self-control (behavioral control of seizures) showed Psychosocial Situation of Children and Adolescents with Epilepsy that all patients could improve their “sense of control” during in Parent’s Estimation. Margarete Pfafflin, Joachim Sander, training to a considerable degree; three components of the pa- Hans-Erich Boenigk, and *Hans-Helmut Richardt (Epilepsie- tients’ concept of sense of control could be differentiated. The Zentrum Bethel and *Kinderklinik Konigsborn, Bielefeld, Ger- relations between this seizure-related concept of sense of control many)-5011. and the general concept of perceived internal control/mastery and other psychological variables included in the complex model In three outpatient epilepsy clinics, a parent questionnaire was of health-related QOL by Baker et al. (1993) were assessed. distributed to collect data about variables such as illness-induced stress, knowledgeability of education staff, social integration, and treatment status. In a primary survey, parents of 103 children were questionated (children aged 0-19 years). Results show Development of an Instrument to Assess Quality of Life in Children that parents usually overestimate the success of treatment and with Epilepsy and Learning Disability. Gus Baker, ?Ann Jacoby, underestimate illness-related familiar stress. Results were as- $Tom Berney, $Mike Dewey, *Gwilym Hosking, *Elaine Forret, sessed in terms of strategies used by parents to cope with chil- and David W. Chadwick (Walton Hospital, Liverpool; *The dren’s illness, and conclusions were drawn for use in information Wellcome Foundation, Kent; ?University of Newcastle; $Uni- to be disseminated in outpatient clinics.

Epilepsin, Vol. 35, Suppl. 7, 1994 48 EUROPEAN CONGRESS PROCEEDlNGS

Dependency Needs in Children and Adolescents with Epilepsy. To determine a possible dissociation of language dominance Dragana MarinkoviC, NebojSa JoviC, and Aarko MartinoviC and size of temporal lobe volume in a sample of candidates for (Medical Faculty of Belgrade University, Belgrade, Yugosla- epilepsy surgery (two-thirds anterotemporal lobe resection), we via)-50 12. evaluated speech laterality by successive bilateral Wada test, size of planum temporale (MRT), verbal and nonverbal memory Clinical experience shows that certain parent’s attitudes and functions, and size of feet. actions can negatively influence children’s achievement. Identi- Some patients cases with smaller left temporal lobe had asso- fication of factors that define higher dependency level in children ciated left-sided dominance for language. Nonverbal memory with epilepsy is important in a holistic approach to epilepsy. functions were reduced. We interpreted the pattern of deficits as We studied 246 children and adolescents: group I, 116 patients involvement of the right temporal lobe in verbal memory. This with epilepsy; group 11, 59 patients with migraine; and a control compensation interferes with nonverbal memory performance. group of 71 healthy school children of the same age; all were randomized and stratified into subgroups depending on age. The Berg’s Self-Administered Dependency Questionnaire was used. Questions were divided according to similarity into four sub- Preoperative Prediction of Laterality Using the Burden Maze Test. scales: affection, communication, assistance, and independent Nigel H. Walton, Hutch S. Curry, Catherine Goodsman, and traveling. Jonathan M. Bird (The Burden Neurological Hospital and Insti- Parent dependency level was significantly higher in the group tute, Bristol, England)-50 15. with epilepsy. There was no significant difference between patients with migraine and the control group. Boys with epilepsy, Rapid growth in surgical treatment of temporal lobe epilepsy as well as healthy boys, showed higher dependency level as com- has resulted in increased demand for preoperative neuropsycho- pared with girls of the same age. Factors that can influence de- logical assessment to provide information regarding laterality of pendency level were analyzed in the epilepsy group (duration of the epileptogenic focus. Although considerable effort has been illness, type and frequency of attacks, antiepileptic therapy). expended in measuring verbally mediated sequelae of left-sided Test-retest reliability was satisfactory. pathology, concomitant nonverbal sequelae of right-sided pa- The high dependency level of the epilepsy, confirmed by ques- thology and eventual operation is less well understood. We stud- tionnaire, demands therapeutic intervention in both children and ied 15 patients being evaluated for epilepsy surgery on the Bur- parents. With modification of parents’ attitude, children with den Maze test, a computerized measure of spatial memory and epilepsy in this age group (7-17 years), can achieve complete learning, predicting that the right-sided group (n = 7) would development and greater success in education and social func- perform less well than the left-sided group (n = 8). Despite the tioning. relatively small population, we noted a significant difference between the groups in the expected direction at preoperative assessment. Spatial maze learning promises to provide valuable lateralizing information and should be included in a comprehensive neuropsychological assessment of surgical candidates. Poster Session (5013-5079)

Neuropsychological Test Performance in Frontal Lobe Epilepsy. Undiagnosed Language Impairment in Children with Complex Ep- Dominic Upton and Pamela J. Thompson (Epilepsy Research ilepsy: A Survey. G. M. Parkinson and S. P. Whitfield (The Group, Chalfont Centre for Epilepsy, Chalfont St. Peter, Bucks, David Lewis Centre for Epilepsy, Cheshire, England)-5013. and Institute of Neurology, Queen Square, London, England)- 5079. We conducted a 4-year survey of children admitted to a national residential children’s assessment unit to ascertain the per- We compared the neuropsychological test performance of 100 centage of undiagnosed language impairment on entry. The 76 persons with frontal and 50 with temporal lobe epilepsy (FLE, patients were aged 5-17 years (32 females and 44 males). TLE) on a series of neuropsychological measures. Individually, Admission case histories, correspondence relating to admis- most tests showed no consistent deficits in the FLE group; nei- sion, accounts by parents and teachers, psychological assess- ther did they distinguish between the groups. A logistic regres- ments, and evidence of any previous contact with a speech and sion equation devised on the basis of the results obtained from language pathologist were used as sources of possible informa- the two groups proved to have more discriminatory power than tion indicating a history of language impairment before admis- any individual test; indeed, it correctly classified >90% of the sion. Twelve-week assessment of the subjects with regard to sample. The power of such an approach is emphasized; with language and communication abilities showed that many of these future refinements, this approach should prove an appropriate patients had gone undetected. This has implications regarding preoperative measure of frontal dysfunction. educational placement and other management issues in planning for a child’s future needs. Relevance of Epileptic Focus and Magnetic Resonance Imaging Findings for Memory Performance in Patients with Temporal Lobe Laterality of Speech and Trophic Brain and Body Features in Tem- Epilepsy. Herbert F. Durwen (Neurologische Uniklinik, Knapp- poral Lobe Epilepsy. H. A. Hattig, F. Wormann, H. Straub, and schaftskrankenhaus, Bochum, Germany)-50 16. H.-J. Meencke (UKRV, Department of Neurology, Presurgical Epilepsy Unit, Berlin, Germany)-5014. Quality of life in patients with temporal lobe epilepsy (TLE) is frequently affected by memory problems. Whether the neuro- Patients with epilepsies of the temporal lobe often exhibit a psychological impairment is determined by epileptogenic alter- pattern of peculiarities in speech laterality , and memory capac- ation in neuronal tissue or by underlying morphologic substrates ity, as well as asymmetries in size of temporal lobe and feet. In demonstrated on magnetic resonance imaging (MRI) is not clear. particular, an association with a smaller temporal lobe volume on Therefore, we investigated 43 patients with left-sided TLE for the side of origin of epileptic activity has been reported even verbal memory performance, using a German version of the when patients with signs of atrophy were excluded (Meencke et AVLT (Auditory Verbal Learning Test). Patients with tem- al., 1985). Ln normal samples, a greater left temporal lobe in poromesial or neotemporal localization of the epileptic focus as association with assumed left-sided dominance for language well as MRI findings in the same locations but with different functions has been described. distribution were compared by analysis of variance.

Epilepsia, Vol. 35, S~ppl.7, 1994 EUROPEAN CONGRESS PROCEEDINGS 49

Particular steps in memory processing were significantly influ- seizures were without EEG changes, and seizures played a sig- enced by localization of the epileptic focus (p < 0.05), whereas nificant role in the patient’s social and emotional interplay with localization of the lesions as shown by MRI had no such effect. the family. The children were aged 18 months to 16 years (10 Patients with a temporomesial epileptic focus showed significant males and 16 females), and had been treated with antiepileptic impairment. The epileptogenic alteration of the neuronal net- drugs (AEDs) from age 1 week to 6 years 6 months (mean 23 work in a particular region of the temporal lobe appears to be months). The number of AEDs varied from 1 to 5 (mean 2.4). most relevant with regard to memory problems in patients with Computed tomography scan had been performed in 22; 8 had an TLE. abnormal interictal EEG; 18 were intellectually normal, 6 were slightly retarded or had learning difficulties, and 2 were mentally deficient. The children and their families were treated psycho- logically. Follow-up period was 6 months to 4 years 6 months. At Carotid Amobarbital Memory Test in a Patient with Bilateral Hip- the latest control, 20 (76.9%) children had no pseudoepileptic pocampal Sclerosis. *W. Van Paesschen, tS. Baxendale, tP. J. seizures, 1 still had seizures, and 5 were lost to follow-up. The Thompson, and *tJ. S. Duncan (*Institute of Neurology, Epi- results indicate good prognosis. lepsy Research Group; tNational Hospital for Neurology and Neurosurgery, Queen Square, London, England)-5017.

Bilateral hippocampal lesions are a cause of amnesic syn- Psychogenic Seizures in Refractory Epilepsy. Otto J. Hernandez- drome. The carotid amobarbital memory test generally has been Fustes, Otto Hernandez Cossi, Gabriel Martinez, Guido Diaz, assumed to cause a transient amnesic syndrome with hippocam- and Olga J. HernBndez-Fustes (Instituto de Neurologia, Havana, pal damage contralateral to the injected side. We report results of Cuba)-5020. a carotid amobarbital memory test in a patient with bilateral hippocampal sclerosis, a 30-year-old righthanded woman with To diagnose psychogenic seizures in patients with “refractory intractable temporal lobe epilepsy and no evidence of an amnesic epilepsy” and assess the utility of the induction test in evaluation syndrome. Interictal EEG showed bilateral independent tempo- of psychogenic seizures, we studied 100 refractory inpatients (4 ral spikes. Ictal EEG suggested left temporal onset. Magnetic years) of the Epilepsy Clinic, National Institute of Neurology, resonance imaging showed bilateral small hippocampi. Right hip- Havana, Cuba. Patients with atypical seizures, psychiatric prob- pocampal T, was 142 ms (N < 107 ms) and left hippocampal T2 lems, and/or primary or secondary gain were evaluated by lab- was 118 ms, consistent with bilateral severe hippocampal scle- oratory, EEG, imaging, psychologic, and induction tests. The rosis. The patient underwent a carotid amobarbital test as part of induction test consists of administration of 5 ml normal saline preoperative evaluation. After amobarbital injection into the and suggestion to the patient that this procedure induces sei- right hemisphere, she had perceptual difficulties and poor recall zures. EEG monitoring was performed during the test. of visual but not verbal material. After its injection into the left Sixty patients were women (average age 23 years); 73 patients hemisphere, she had weak recall of verbal but not visual mate- had psychogenic seizures (in 52 only psychogenic seizures, and rial. The carotid amobarbital test thus predicted material-specific in 21 psychogenic seizures associated with epilepsy). In 27 pa- memory deficits after temporal lobectomy but not an amnesic tients, a psychogenic response was not obtained. The induction syndrome. Bilateral hippocampal lesions do not necessarily pro- test is useful and easy to perform in diagnosis of psychogenic duce an amnesic syndrome, as was confirmed by the carotid seizures. amobarbital test.

Nonepileptic Seizures in Children: An Overview of Cases Treated Seizures Triggering Factors, According to Patients. Carlos Garcia, at a Specialist Children’s Epilepsy Assessment Unit. S. P. Whit- Francisco Pinto, Jose Pimentel, Jost Ferro, Antdnio Atalaia, and field, E. R. Newton, and G. Parkinson (The David Lewis Cen- Ant6nio Martins (Instituto de Neurologia, Hospital de Santa tre, Manchester, England)-5018. Maria, Lisbon, Portugal)-5021.

During a 3-month in-patient admission period for each patient, In the last 6 months, we administered a questionnaire to every the David Lewis Centre Children’s Epilepsy Assessment Unit patient attending the outpatient epilepsy clinic of our hospital. has assessed and treated 76 children since its inception in 1989. Our main purpose was to gather information regarding the pa- During this time, 8 patients have been referred for clarification of tients’ knowledge of what might have triggered their last seizure. whether they have nonepileptic seizures (NES). Of these, 4 chil- We wished on determine the psychological reality of the patients dren were shown to have psychogenic nonepileptic seizures independent of any scientific basis. We believe that the answers (PNES). Although much information is now available on the to our questionnaire may provide doctors with better knowledge prevalence and nature of PNES in adults, little is known in re- of what patients think about epilepsy. gard to children. We examined the reasons for referral, the assessment process, the differential diagnosis of PNES, treatment (medical and psychological), and long-term outcome at follow-up of each patient through individual case synopses, and compared Group Psychological Intervention for Adults with Epilepsy. Shiri our findings with those of a similar study by Sahlholdt and Alving Spector, *Alexis Foots, and Laura H. Goldstein (Psychology in Denmark. (Pseudo-epileptic Seizures Petersfield, U.K.; Department, Institute of Psychiatry; and *O. T. Department, Wrightston Biomedical, 1993). Maudsley Hospital, London, England)-5022. Growing evidence shows that environmental and emotional factors can trigger epileptic seizures and that psychological in- Pseudoepileptic Seizures in Childhood: Outcome. Birgitte Bang, tervention may be effective for improving seizure control, but Lene Sahlholdt, Peter Uldall, and JZrgen Alving (Dianalund Ep- only one controlled clinical study has examined such an inter- ilepsy Hospital, Dianalund, Denmark)-5019. vention in a group setting, suggesting that an important factor for successful outcome may be patients’ rating on self-control From January 1989 to July 1993,486 children were admitted to scales. Therefore, we investigated the potential effectiveness of the children’s department of Dianalund Epilepsy Hospital. group-based therapy in reducing psychosocial problems and sei- Twenty-six were diagnosed as having only pseudoepileptic seizure frequency in adults with epilepsy and whether patients who zures. All 26 fulfilled the following three criteria for the diagno- rate higher on self-control measures will benefit more from the sis: seizures were regarded and treated as epileptic seizures, intervention.

Epilepsia, Vol. 35, Suppl. 7, 1994 50 EUROPEAN CONGRESS PROCEEDINGS

Twenty adult outpatients with epilepsy were randomly as- studies. Sixty subjects participated in the present study: 20 chil- signed to either the therapy group or a control waiting list. Pa- dren (10 who had undergone unilateral temporal lobectomy for tients were rated as highflow “controllers” through an interview relief of intractable seizures and 10 potential surgery candidates) and the Health Locus of Control Scale. Patients participated in and 40 adults (20 who had undergone unilateral temporal lobec- eight 2-h weekly sessions, which included general support, rec- tomy for relief of intractable seizures, 10 potential surgery can- ognizing auras and triggers, recording daily stresses and practic- didates, and 10 normal control subjects). Standard locus of con- ing coping techniques, training in self-observation and relax- trol scales were administered to children and adults. ation, and facilitating social skills. Seizure frequency and various There was no significant difference between scores of the pe- psychological questionnaires were used to evaluate outcome. diatric groups and no significant difference between scores of the adult groups for locus of control. All groups of children and adults displayed an internal locus of control as compared with normative data. The findings were independent of surgery, sei- Working Psychodynamically with Clients with Epilepsy. Kate zure status, sex, age, and of side of operation and age of onset in Fuggle (The David Lewis Centre for Epilepsy, Cheshire, En- adults. gland)-5023. Although the number of subjects in this Irish study is small, present findings are not in agreement with those of previous The psychodynamic theory of human development attaches research. This discrepancy probably cannot be fully explained considerable importance to the way in which past events influ- by cultural differences, but construct validity, the validity of the ence present circumstances. Responses to other persons in adult measures, and good psychological adjustment and resilience in life are influenced by reaction experienced by infants and chil- the face of adversity may be contributing factors. dren to time and space boundaries, such as periods of waiting for mother and father to arrive when the child needs attention. Therefore, psychodynamic therapists establish contracts with new clients with respect to time and place. The client’s use of and response to these boundaries is of major significance to the Effects of Quality of Life for Children and Families of Admission to psychodynamic therapist. We investigated the influence of the a Specialist Children’s Epilepsy Assessment Unit. S. P. Whitfield, medical condition on the work of a music therapist working E. R. Newton, G. Parkinson, and K. L. Plincke (The David solely with clients with epilepsy. We considered the effect on the Lewis Centre, Manchester, England)-5026. therapeutic process of clients who experience sudden loss of consciousness and whose mood may be influenced both by med- During a 3-month inpatient admission period for each patient, ication and pre and postictal changes. We report 2 cases studies The David Lewis Centre Children’s Epilepsy Assessment Unit of recent clients, 1 with prolonged postictal phase and 1 with has assessed and treated 76 children since its inception in 1989. prolonged frequent partial seizures. We also describe another Although short-term outcome data was available on improve- client who frequently has seizures during a session. ments in seizure control, medium- and long-term evaluation of changes in quality of life (QOL) after discharge had not previously been investigated. Duncan (The quality of life and the quality of care in epilepsy London: Royal Society of Medicine, 1990) has indicated the need Behavior Therapy, Self-Management and Quality of Life. Rainer to evaluate QOL in four dimensions: neurologic, psychological, Wohlfarth, Josef Saar, and Gerhard Reinshagen (Epilepseizen- social, and educational or occupational. We used these dimen- trum Kork, Klinik fur Erwachsene, Kehl-Kork, Germany)- sions to identify medium- to long-term positive and negative out- 5024. comes of admission to the unit, subsequently translating them into a questionnaire sent not only to patients and their families As a heavily stigmatized disorder, epilepsy often results in but also to psychologists, social workers, and teachers working poor interpersonal, emotional, and vocational adjustment, which directly with patients in their home environment. We report leads to low life satisfaction. A high degree of psychosocial func- changes in seizure control, general health, parental coping, in- tioning depends on the patient’s ability to cope with the impact of tellectual functioning, and behavior in patients at S3-year fol- seizures as well as with handicaps and disabilities evoked by the low-up. illness “epilepsy.” Until now, behavior therapy in epilepsy focused mainly on seizure-control techniques, but this approach is limited. To improve psychosocial adjustment and quality of life, we must focus not only on strategies for seizure control, but also on improving patients’ ability to cope with epilepsy and its con- Quality of Life as Self-Image, Defense Methods, Expectations, and sequences in daily life. We propose a “broader,” non-seizure- Difficulties in an Adolescent Group with Epilepsy: Proposal for Use focused psychotherapeutic approach of behavioral and cognitive of a Self-Evaluation Questionnaire. Alida Labella, Marina Buon- techniques (health education, self-monitoring, self-control tech- giovanni, Daniela Cantone, t Antonio De Rosa, and *Maria niques; communication skills and assertiveness training, stress Rossana Tata (Universita Napoli; and *Neurofisiopatologia 1, management training; cognitive therapy for depression and anx- Polyclinico P. Miraglia, Naples, ltaly)-5027. iety; training for coping with the illness; problem-solving training). These techniques are integrated in a self-management ap- Epilepsy is a disease that can be explained by different pat- proach. Independent of seizure relief, this technique may help terns. We investigated psychodynamic features of epilepsy by improve psychosocial functioning by qualifying patients to ex- administering a self-evaluation questionnaire to 50 epileptic ad- tend their personal independence and by minimizing social olescents. This questionnaire has been already tested in 1,000 stigma. We report several single case studies. healthy adolescents. The aim of the questionnaire is to explore “adolescent persons’’ and problematic aspects related to their position in time and space, their communication with the group and with author- Locus of Control in Children and Adults in an Irish Epilepsy Sur- ity and, above all, their attitude to change. With regard to sei- gery Context. Eleanor Maguire, Simone Carton, Teresa Burke, zures, psychological problems identified in epileptic adolescents Hugh Staunton, and Jack Phillips (Departments of Neurology related to self-image, defense methods, expectations, and atti- and Neurosurgery, Beaumont Hospital, Dublin, Ireland)-5025. tude to change. Further analysis of our data may provide an incentive to wide use of the questionnaire. Indeed, it appears to Perception of control as being external to oneself has been offer a starting point for psychological assessment of adolescents demonstrated in children and adults with epilepsy in several with epilepsy.

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 51

Quality of Life in Patients with Epilepsy. Carlos Cardoso, *Inks MOS SF-36 Health Survey; additional mental health items, mea- Cunha, tMargarida Silva Dias, Rui Durval, *Ana Grilo, Maria sures of cognition, epilepsy-specific perception of control, be- Joao Heitor, Alice Nobre, tVitorina Passgo, and tAna Sacra- havior problems, distress, worries and experiences, and the Liv- mento (Psiquiatra do H. Miguel Bombarda, *Psiquiatra do H. erpool Epilepsy Impact and Seizure Severity Scales. Reliability, Jhlio de Matos, TNeurologista do Hospital de St. Antonio dos validity, and patient acceptance were evaluated in a cross- Capuchos, Lisbon, Portugal)-5028. sectional, multicenter study of 136 patients treated with AEDs in the United Kingdom. Mean HRQOL scale scores significantly Epilepsy and its symptoms tend to be chronic and potentially discriminated among groups of patients differing in seizure con- incapacitating and may lead to physical, psychological, and so- trol, consistent with hypotheses. Regardless of seizure control, cial deficits that determine impairment of the patient’s quality of mean HRQOL scale scores were also significantly lower for pa- life (QOL). We studied a population of 56 ambulatory patients, tients reporting systemic and neurologic symptoms. For further 21 males (aged 15-72 years, median 29) and 35 women (ages study, we developed a shorter 100-item questionnaire to con- 1&59 years, median 39), using a semistructured interview, to struct 22 scales, and a 16-item symptom checklist. Use of a re- assess place of residence, financial situation, general health, liable and “clinically” valid HRQOL questionnaire will make it family, friends, work, self-confidence, what others think of the possible to estimate the burden of epilepsy and the HRQOL person, life, medication, seizures, symptoms, sexuality, and so- benefits of AEDs. (Supported by Schering-Plough International.) cial anxiety. We noted good QOL in 34% of patients, medium QOL in 55% and poor QOL in 11%. We analyzed the relevance of the selected areas, interview results, and their relation to other variables such as age and sex, Novel Scale to Measure the Impact of Epilepsy on Quality of Life. marital status, profession, duration of illness, type of epilepsy, Ann Jacoby, *GUSBaker, and *David W. Chadwick (Centre for pharmacologic treatment, and psychopathology. More specific Health Services Research, University of Newcastle, Newcastle and accurate instruments to evaluate QOL of epileptic patients upon Tyne; and *Department of Neurosciences, Walton Hospi- must be designed, considering implications at different levels of tal, Liverpool, England)-503 1. prevention. The impact of chronic illness on an individual’s quality of life (QOL) is experienced not only through physical symptoms, but also as a result of its effect on psychosocial functioning. We Domains of Quality of Life and Epilepsy. OlIJ. L. Ribeiro, TsD. devised a novel scale to measure patients’ perceptions of the Mendonca, 111. Gomes, IIL. Concalves, and *$$A. Martins da impact of their epilepsy and its treatment on various aspects of Silva (*ServiGo de Neurofisiologia, Hospital de Santo Antonio daily functioning. The scale is brief, comprising 10 items, se- (Porto); Laboratorio.de Biometria and, 4Unidade de Fisiologia lected on the basis of interviews with patients and previous re- Humana, lnstituto de Ciencias BiomCdicas Abel Salazar, search. Patients are asked the extent to which epilepsy affects BUnidade de Neurofisiologia e Psicofisiologia do IBMC, Univer- particular aspects of their daily life; a simple 4-point Likert scor- sidade do Porto, and IIFaculdade de Psicologia e CiCncias de ing system is used, with responses ranging from “a lot” to “not Educacao da Universidade do Porto, Porto, Portugal)-5029. at all.” The psychometric properties of the scale have been demon- Overall satisfaction of healthy individuals expressed as quality strated in two recent studies, one a pilot study of 136 epilepsy of life (QOL) is influenced by several different domains ranging patients drawn from two epilepsy clinics and a single general from physical personal well-being to cultural and social interre- practice in the United Kingdom, the other a community study of lations. The domains affecting this “broad concept” were pre- 700 people with active epilepsy, undertaken in one U.K. health viously identified by other researchers. To study QOL domains region. In both studies, the scale showed good validity and high in epileptic persons, we constructed a 16-item Likert-type ques- reliability (alpha = 0.89). The scale represents a potentially valu- tionnaire. In an exploratory study, we wished to determine (a) able, simple measure for clinical trials of de novo antiepileptic the importance of QOL domains in epileptic patients, (b) how persons and a useful tool for identification of areas of need for domains of QOL are affected by epilepsy characteristics, and (c) counseling among persons with epilepsy. how domains of QOL are affected by personal characteristics of epileptic patients. Research began early in 1993, with patients followed up at the epileptic outpatient clinic of Hospital Geral de Santo Antonio at Porto, and was based on analysis of data col- Quality of Life in Patients with Epilepsy: Psychology, Neuropsy- lected from a sample of 90 men and women, aged 15-65 years, chology, and Medical Aspects. *?Nicole von Steinbuchel, *We- who had completed the basic education level and had seizures of fanie Krauth, *tInge Kirchberger, *Monika Bullinger, $Beat various severity and type (simple partial, complex partial, myo- Hiltbrunner, *t§Ernst Poppel, tKarl Zander, //Stefan Stodieck, clonic, generalized tonic-clonic, seizure-free). Patients were in- TGerhard Bauer, TDiana Soucek, #Peter Hiedl, and tUlrich terviewed by trained psychologists for 20 min. From patients’ Scheidereiter (*Institut fur Medizinische Psychologie; tSciencia answers, we defined the domains of QOL affecting epileptic pa- Gesellschaft fur Forschung im Gesundheitswesen, Munchen, tients’ overall satisfaction and well-being. Germany; Kiba-Geigy Limited, Basel, Switzerland; Worschung- szentrum Julich GmbII; IIZentralklinik, Munster, Germany; Wniversitatsklinik fur Neurologie, Innsbruck, Austria; and #Neurologische Praxis, Freising, Germany)-5032. Development and Validation of a Health-Related Quality of Life Questionnaire for Persons with Epilepsy. Anita K. Wagner, Mark Assessment of quality of life (QOL) in patients with epilepsy is Kosinski, San Keller, *Gus Baker, tAnn Jacoby, $Ming-Ann a relatively new issue in epileptology. We report results of a Hsu, *David Chadwick, and John E. Ware (New England Med- study of 202 patients with epilepsy, 102 treated with carbam- ical Center, Boston, MA, U.S.A.; *The Walton Hospital, Liv- azepine (CBZ) and 100 treated with phenytoin (PHT). Study erpool; ?University of Newcastle upon Tyne, Newcastle upon aims were (a) translation and psychometric analysis of 10 generic Tyne, England; and Wchering-Plough Corporation)-5030. and disease-specific QOL instruments and four predictors; (b) identification of prerequisites for development of a new compre- Epilepsy and antiepileptic drug (AED) therapy have impact on hensive disease-specific German QOL instrument, and (c) com- patients’ quality of life (QOL). To measure this impact in clinical parison of the QOL status of the two patient groups. Elementary trials of AED, we evaluated a 172-item patient-completed ques- and complex neuropsychological functions (NPSY) were also tionnaire containing previously validated and newly developed assessed, as were medical data, with focus on comparison of measures of general and epilepsy-specific health-related QOL self- and observer-ratings concerning QOL-related medical as- (HRQOL), along with a symptom checklist. Included are the pects.

Epilepsia, Vul. 35, Suppl. 7, 1994 52 EUROPEAN CONGRESS PROCEEDINGS

Psychometric properties of the QOL instruments ranged from a role in daily functioning of epileptic persons. The Holmfrid sufficient to very good. Meta-level analysis of the instruments study suggests that this effect is epilepsy bound and not due to (scales treated as items) showed a highly significant difference use of antiepileptic drugs. between the two groups in favor of CBZ. In NPSY assessment, PHT patients performed less well than CBZ patients or healthy controls, e.g., in time-critical tests such as reaction time, tapping, or sensorimotor synchronization. Analysis of self-rating Mental Deterioration at Epilepsy Onset: A Hypothesis. L. G. J. and medical assessment of physical symptoms showed that CBZ Neyens, A. P. Aldenkamp, H. Meinardi, and *A. Martins da patients to have fewer symptoms than PHT patients. Doctors’ Silva (Instituut Voor Epilepsiebestrijding, Meer en Bosch, rating of patients’ QOL was much higher than patients’ self- Haemstede, and Radboudziekenhuis, Nijmegen, The Nether- rating (93 vs. 65% of theoretical optimum). lands; and *Hospital Geral de Santo Antonio, Porto, Portugal)- 5035.

Although patients with epilepsy show an overall trend to a low A-B Neurotoxicity Scale: Validity of a Patient-Based Scale Assess- intelligence level, studies could not prove the hypothesized cog- ing Neurotoxicity. A. P. Aldenkamp, G. Baker, M. S. M. Piet- nitive decrease. We believe that the length of the interval be- ers, H. C. Schoenmaker, A. F. Cohen, and S. Schwabe (Insti- tween age of onset and first cognitive assessment was the inter- tuut voor Epilepsiebestrijding, Meer en Bosch, The Nether- fering factor. Epilepsy onset entails a reset of brain functioning lands)-5033. in a relatively short time (2-3 years), after which it stabilizes at a subnormal functioning level. Most assessments were per- The clinical sensitivity of a patient-based scale (A-B Neuro- formed after this critical period. Results of several studies indi- toxicity Scale) measuring neurotoxicity was examined in a nor- cate this hypothesis. To test the hypothesis, however, longitu- mal volunteer study. Thirty subjects were randomly assigned to dinal follow-up of cognitive functioning in patients with epilepsy, placebo or two doses of a benzodiazepine: temazepam (10 and 20 initiated before epilepsy onset, is necessary. Because patients mg) in a double-blind placebo-controlled parallel-group design. may have unrecognized seizures before diagnosis is made, ap- Plasma samples were taken before the scale was completed and plication of a posttraumatic epilepsy model appears useful. In- for 8 h postdose. After administration of medication, subjects cidence of epilepsy is 5-20 times higher in patients with mild/ were asked to maintain their normal daily routine as much as moderate head injuries, whereas fast and complete recovery of possible. The inventory was administered twice, at 1 and 2 h cognitive aftermath allows a reliable baseline measurement of postdose (peak level). Results showed differences between the cognitive functions, performed with the same battery of tests three groups on the overall score (A-B endscore) only for the used before epilepsy onset. To obtain 10CL200 patients with ep- second assessment, 2 h post-dose (analysis of variance p < 0.02). ilepsy, >2,000 head-injured patients must be assessed. We there- Multiple t testing between the three groups showed statistically fore aim at international collaboration on this matter. significant differences between the placebo and the 10-mg temazepam group (p = 0.02) and between placebo and the 20-mg temazepam group (p = 0.006). Analysis of the separate questions showed least sensitivity for questions related to “hyperex- Verbal Memory in Newly Diagnosed Epilepsy. Maria Aikia, Reetta citability” and most sensitivity for “fatigue and slowing.” Kalviainen, and Paavo J. Riekkinen (Department of Neurology, In accord with our assumptions, the overall score (A-B end- University of Kuopio, Kuopio, Finland)-5036. score) appeared to be the most sensitive outcome variable. Al- though clearly the questions that pertain to fatigue and slowing Patients with epilepsy are reported to have interictal memory have greater impact on endscore, the scores on the scale cannot problems. Heterogeneous brain pathology, recurrent seizures, be used to draw conclusions about impairment in specific do- and antiepileptic drug (AED) use have been suggested as etiol- mains. Moreover, the overall score appeared to be already sen- ogy of memory dysfunction. sitive for the lower toxicity range, suggesting an “all or nothing We studied the verbal memory of 61 newly diagnosed, un- effect.” The subjective reports with this scale therefore allow treated adult epilepsy patients was compared with memory per- detection of gross overall changes in cognitive functioning. formance of an age-, sex-, and education-matched control group of 44 normal subjects. Only patients with no known etiologic factor for epilepsy (i.e., cryptogenic seizures), based on clinical and computed tomography scan data were included. As part of a Results of Reaction Time Measurement in Patients with Epilepsy. neuropsychological test battery, verbal memory was assessed by Willem C. J. Alpherts and Albert P. Aldenkamp (Department of Logical Memory paragraph recall and the List Learning task. Neuropsychology, Meer en Bosch, The Netherlands)-5034. Immediate and delayed paragraph recall and total learning of word list did not differ between patients and controls. Control Human information processing takes time. The faster mes- subjects performed better (p <0.01) in delayed recall of word list. sages from different information channels can be processed, the The control group had better score for long-term retention of better the system is prepared for new input. Epileptiform activity words. Certain aspects of memory function in patients with ep- in brain is believed to slow higher cognitive (mental) processes. ilepsy but without other known major brain pathology may al- Computerized assessment offers a sensitive way to measure re- ready be compromised at time of diagnosis and before treatment action time and can thus provide insight into differences in in- with AEDs. formation processing speed between persons with epilepsy and “normal” controls and also into differences between different levels of complexity. The subtest “Binary Choice” from our computerized neuropsychological battery “Fepsy” is a reaction- Verbal Comprehension and Imitation in Children with Complex time test with built-in two-choice decision component. The data Epilepsy. G. M. Parkinson (The David Lewis Centre for Epi- from 800 persons with epilepsy have been gathered in the last 5 lepsy, Cheshire, England)-5037. years and compared with those of 150 controls. No difference was noted between simple reaction time (auditory and visual), We compared two groups of nonrepresentative subjects, a but the more complex (binary) reaction time was slower in the group with complex epilepsy, and a seizure free group. We epilepsy group, Furthermore, persons with epilepsy tended to wished to compare the groups’ abilities regarding verbal com- make more errors. A slight speed/accuracy tradeoff was noted prehension skills and a possible correlation with verbal imitation between speed of reaction and errors, but this tradeoff did not abilities, presented with varying degree of semantic and syntac- play a role in the difference between the groups. The phenome- tic support (i.e., degree of contextual cueing in terms of grammar non of basically slowed information processing speed must play or meaning).

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 53

Results indicated a significant relation between level of verbal Neuropsychological, Cognitive and Psychological Studies of Chil- comprehension and the groups’ ability to recall verbal material. dren with Previous Infantile Spasms. Bjorg Blom (Children’s Subjects with complex epilepsy relied on contextual cues in the Clinic, Hankeland Hospital, Bergen, Norway)-5041. form of predictable word order and word meanings to a significant degree as compared with the seizure-free group with similar A population-based follow-up study of 34 children with previ- verbal comprehension age. ous infantile spasms was performed in Hordaland, a county in Western Norway. When possible, we studied cognitive and neuropsychological function (WISC-R and parts of the Halstad- Intellectual Performance and Epilepsy. Carlos Arteaga, Arturo Reitan test battery). Personality (PIC) and family variables Caro, Luis Rodriguez, Otto J. Hernandez, Marta Goizueta, and (Greenberg: Inventory of parent experiences (WE) were in- Alberto Garcia (Grupo de Epilepsia, Hospital Dr. Finlay, Ha- cluded for all children participating. Coping patterns were also bana, Cuba)-5038. included both for the children (McCubbin; Coping Health Inven- tory for children, CHIC) and the family (F-Cope, Family Crises We compared 60 epileptic patients with 60 supposedly normal Oriented Personality Evaluation Scale). Socioeconomic vari- persons as a control group to analyze intellectual performance ables are included. We compared our findings with results of a and possible causal factors. In both groups, general data, school neurologic examination and medical history. performance, and the psychometric test of WAIS were applied. In the epileptic group, clinical aspects were also analyzed. Data were analyzed by the chi-square test. Mental Disorders in Epileptic Children. Daniela Bohn, Klaus WAIS showed the epileptic group to have a lower intellectual Lenz, Michael Elpers, and Alexander Naumann (Department of level than the control group. The relation between intelligence Child and Adolescent Psychiatry, Free University Berlin, coefficient and type, age of onset, evolution time, frequency, and UKRV, Berlin, Germany)-5042. treatment of epileptic seizures was not statistically significant. Forty children treated at the outpatient clinic for epileptic children in the Department of Child and Adolescent Psychiatry, Free Epilepsy and Mental Retardation. Marc Derouaux and Christiane University of Berlin, were examined by 2 experienced clinicians. de Decker (Institut MCdico PCdagogique, Andrimont, Bel- Although most of the patients had behavioral problems, only a gium)-5039. few met the diagnostic criteria for mental disorders according to ICD-10. Five-year follow-up of 268 mentally handicapped institution- Psychopathologic items (ratings based on the AMDP system) alized adults (63 severely and 205 profoundly handicapped) were statistically analyzed in an attempt to specify possible cor- showed 159 to be epileptic: 91 are seizure-free, and 68 have relations between behavioral disorders and different types of ep- active seizures. Mean frequency of seizures per month varied ilepsy (focal, generalized) or localization of epileptiform dis- from 1 to 12 for 51 subjects and from 13 to 52 for 17 patients. charges in the EEG of the children. We hypothesize that epilep- Seizure prevalence was inversely correlated to IQ in 12% of tic children might have specific psychopathologic patterns severely and 30% of profoundly handicapped persons. Type of usually not covered by the diagnostic categories in the ICD-10. seizures, according to the classification of the International League Against Epilepsy showed a high incidence of complex partial seizures (72%). Phenobarbital, carbamazepine, valproate, and phenytoin were Psychiatric and Developmental Disorders in Epileptic Children At- commonly used, with serum concentrations in the therapeutic tending Psychiatric Outpatient Care Unit. Michael Elpers, Klaus range. Most patients received monotherapy. New antiepileptic Lenz, Alexander Naumann, and Daniela Bohn (Department of drugs, such as vigabatrin and lamotrigine, did not decrease sei- Child and Adolescent Psychiatry, Free University Berlin, zure frequency significantly but improved quality of life. UKRV, Berlin, Germany)-5043.

We evaluated children and adolescents with epilepsy (n = 40) Psychopathological Risk in Children with Early-Onset Partial Ep- attending the outpatient care unit in the Department of Child and ilepsy as Presenting Manifestation. Stefania BargBgna, Renzo Adolescent Psychiatry, Free University of Berlin, from 1992 to Guerrini, and Elisabetta Romolini (INPE, Universita di Pisa, 1993. Data were gathered from clinical documentation based on IRCCS Stella Maris, Pisa, Italy)-5040. World Health Organization recommendation, and psychiatric and neurologic diagnoses were based on ICD 10 criteria. The Nonidiopathic epilepsy is a definite risk factor for psycho- patients were compared with a matched control group of children pathologic disorders. We compared the psychopathologic pecu- attending the clinic in the same time period who had no neuro- liarities of children with epilepsy with those of children with logic or other chronic organic disease. chronic illness requiring continuous drug treatment and with at- In our sample, most of the epileptic children showed develop- tacks (diabetes) and/or risk of mental retardation (congenital hy- mental delays in early childhood. In kindergarten and elementary pothyroidism) (CH). Sixteen children aged 2-9 years (10 males, school, they showed social and learning problems. The control 6 females) with symptomatic or cryptogenic partial epilepsy and group and the sample of epileptic children differed on axis I-V of a discrete brain lesion or epileptogenic focus (group A) were the multiaxial classification system. On axis V (associated ab- compared with 15 children with type I diabetes mellitus (group normal psychosocial situations) epileptic children showed fewer B) and 15 children with early-treated CH (group C) of the same disturbances. We assessed the relation between our findings and age. Methods for psychological evaluation included Rutter scales psychiatric diagnoses. for parents and teachers; questionnaire on maternal attitude toward epilepsy, modified for diabetes and CH; interviews with epilepsy patients; and individual psychodynamic observations. Acute Psychological Disorders in Patients with Epilepsy: A Nation- Preliminary results indicated that (a) psychopathologic risk was wide Survey. Oliver C. Cockerell, John Moriarty, Michael Trim- higher in children with epilepsy, (b) ictal episodes were the most ble, Josemir W. Sander, and Simon D. Shorvon (Epilepsy Re- striking factor affecting quality of life in children with epilepsy or search Group and the Institute of Neurology, Queen Square, diabetes; (c) children with epilepsy or CH showed considerable London; and the Chalfont Centre for Epilepsy, Chalfont St. Pe- anxiety about cognitive and behavioral disturbances; and (d) peter, Bucks, England)-5044. culiar to epilepsy, families were worried about the causative role that ictal episodes could play in cognitive impairment and be- Acute psychological disturbance (APD) is said to be more havioral disorders. common in patients with epilepsy than in the general population,

Epilepsiu. Vol. 35, Suppl. 7, 1994 54 EUROPEAN CONGRESS PROCEEDINGS with estimates varying from 2 to 16% depending on the popula- Relief of Depression After Successful Temporal Lobectomy. G. tion sampled and the diagnostic classification of the APD. APD Elger, C. E. Elger, W. Burr, A. Hufnagel, *J. Zentner, and *J. may be related to ictal activity or the underlying cause of the Schramm (Departments of Epileptology, and *Neurosurgery, epilepsy itself or may be a consequence of psychosocial factors. University of Bonn, Bonn, Germany)-5047. There has also been concern that the frequency of this complication may be increased as a consequence of use of antiepileptic Because the primary aim of epilepsy surgery is to increase the drugs, such as vigabatrin. To determine the frequency and nature quality of life (QOL) of patients, outcome measurements should of APD, we used a system of prospective active surveillance of include changes in psychiatric performance as well as postoper- all neurologists and associated specialists in the United Kingdom ative seizure frequency. Therefore, we studied patients with in- (n = 400) for I year. Case definition was any patient with epi- tractable complex partial and tonic-clonic seizures of temporal lepsy who developed an acute psychological disorder, such as origin undergoing epilepsy surgery, using standardized psychiat- psychosis or depression, whatever the cause; of 144 cases ascer- ric battery consisting of semistructured questionnaires and phy- tained, 69 fulfilled our case definition. Only a few cases were sician-rated and self-reported inventories before and after tem- associated with vigabatrin. The APD will be fully characterized poral lobectomy. We rated 43 female and 36 male patients aged by standard psychiatric instruments, and 6-month prognosis will 15-57 years: 38 underwent left and 41 right temporal resection. be reported. Postoperatively, 38 patients were seizure-free, 16 still had seizures, and 25 rarely had auras or tonic-clonic seizures after the intervention (follow-up is 1-5 years). Postoperatively seizure- free patients had a decrease in depression level, and patients who underwent right temporal lobectomy had a higher depression De Novo Psychosis After Temporal Lobectomy. G. Elger, C. E. level than those who underwent left temporal surgery. Success- Elger , A. Hufnagel , * J . Zentner, and * J . Schramm (Departments fully performed epilepsy surgery of temporal lobe influences psy- of Epileptology and *Neurosurgery, University of Bonn, Bonn, chiatric prognosis of depression in a positive way: seizure free- Germany)-5045. dom leads to relief of depression,

De novo psychosis after temporal lobectomy constitute a severe additional handicap for patients. The postoperative risk of such psychosis is reported to be 3-14%. We investigated the Outcome After Preoperative Evaluation With or Without Surgery incidence and possible predictors of de novo psychosis after for Intractable Epilepsy. Boel Jonsson, Helen Holmgren, Niels temporal lobectomy in 252 patients undergoing temporal lobe Dige, Helene Samuelsson, and Birgitta Soderfeldt (Departments surgery in Bonn since 1987: 135 underwent right and 117 under- of Neurology and Neurophysiology, University Hospital, Linko- went left temporal resection. In 4, we diagnosed a transient de ping, Sweden)-5048. novo postoperative psychotic episode, in 1 occurring immediately after operation and, in 3 in the first 2 postoperative years. Three of 4 were treated with neuroleptic medication for 6 months The University Hospital in Linkoping has had a program for (3 of 4 with a right and I with left temporal lobectomy). One is epilepsy surgery for 3 years. We evaluated the outcome for the seizure-free and 2 still have auras (1 of the 2 rarely has seizures), 33 patients in the program who had undergone a more extensive and 1 is unchanged. Apart from the patients with transient psy- evaluation: Group 1 had had resective surgery (11 patients); chotic episodes, 2 patients developed chronic psychosis. Neither group 2 was evaluated with intracranial electrodes (9 patients); is seizure free (1 with right and 1 with left temporoparietal re- and in group 3, evaluation was completed after single photon section). The risk of de novo psychosis in our group was 3%, emission computed tomography (13 patients). with no predictors. The patients in the study were sent a questionnaire regarding their social situation and changes in seimre frequency after the operation/evaluation. The questionnaire was completed with data from case records. After resective surgery, 73% reported being completely seizure-free and 10 of 11 experienced improvement. The second Emotional Changes After Temporal Lobe Epilepsy. E. Pad, J. group showed a subjective and actual improvement in seizure Volmer, CH. Lang, S. Fitzek, and H. Stefan (Department of condition although they did not undergo operation; 82% group 3 Neurology, University Erlangen-Nuremberg, Erlangen, Ger- showed a subjective improvement, but objective seizure condi- many)-5046. tion was the same or worse in 75%. As shown in other studies, surgical treatment of intractable Changes in the dynamics of emotional behavior after temporal epilepsy successfully produced seizure reduction. However, lobe epilepsy (TLE) surgery are important for the future life of many patients indicated improvement even though they did not the patient and may restrict the advantage of being seizure-free. undergo operation, an improvement not related to seizure con- The State Trait Anxiety Inventory was used to study the anxiety dition but to quality of life, Further extended care for severe levels in 36 patients with pharmacoresistant TLE before and intractable epilepsy is of great importance and should prove ben- after TLE surgery. This questionnaire measures anxiety with eficial both for patients and society. respect to well-being and self-confidence. In addition, we took into account site of the epileptic focus, type of resection, etiology, age at seizure onset, seizure outcome, and pre- as well as postoperative memory test results from the Wechsler Memory Scale. Good Outcome for Epilepsy Surgery After Repeated Episodes of We noted no difference in preoperative anxiety scores be- Psychosis. E. R. Newton and S. P. Whitfield (The David Lewis tween patients with right- and left-sided foci. Both groups Centre for Epilepsy, Cheshire, England)-S049. showed increased anxiety scores as compared with normal data. (right focus 41.1, left focus 42.4; mean, normal reference 36.7). A Magnetic resonance imaging scan showed the presence of a clear and statistically significant postoperative difference was small superficial lesion in the right frontal lobe of a child of noted between the groups. Patients with resections of left tem- average intelligence developed epilepsy at age 1I years. EEGs poral tissue showed no gain with respect to their anxiety level. In appeared to indicate multifocal and bilateral abnormalities. We contrast, patients with resection of the right temporal lobe had report the diagnostic and treatment difficulties presented by this significantly lower anxiety scores (F = 8.11, p = 0.008). Anal- child, the demonstration of forced normalization in his EEG dur- ysis of variance showed no effect of any other variable. ing his psychotic periods, the psychosocial consequences of sub-

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 55

sequent delays before operation was offered, and the favorable Study of Family Functioning in an Epilepsy Group. R. Curral, F. medical outcome of surgical treatment of the epilepsy. Dourado, R. Torres, A. Palha, and H. Barros (Consultation Li- aision Psychiatry of the Psychiatry Department, University Medical School, Oporto, Portugal)-5053.

Pre- and Postoperative Behavioral Disturbances in Children with We evaluated family cohesion and adaptability in an epilepsy Medically Intractable Temporal Lobe Epilepsy. Andreas Kowalik, group. These family dimensions were self-reported through Fam- Christian E. Elger, *Josef Zentner, and *Johannes Schramm ily Adaptability and Cohesion Evaluation Scale-Faces 111 (01- (Kliniks fur Epileptologie and *Neurochirurgie, Universitat son et al., 1985). We compared the epileptic group with a group Bonn, Bonn, Germany)-5050. of multiple sclerosis patients and another group randomly obtained from the general population. All groups were also strati- We analyzed retrospectively the histories of 33 children with fied for social classes. Social status appears to be more important medically intractable temporal lobe epilepsy who underwent pre- in determining vulnerability to family dysfunction than are some operative evaluation for temporal lobe resection with regard to clinical variables. In the epileptic patient group, those in lower behavioral disturbances such as rage, aggression, and hyperac- social classes evidenced a tendency to family dysfunction. tivity. Mean age at first seizure was lower in children with behavioral disturbances (group A, 44 months) than in children without psychiatric symptoms (group B, 84 months). Mean seizure frequency was three times higher in group A. EEG electrocorti- Employment and Psychosocial Adjustment in Epilepsy. R. Curral, cography recordings from children of group A more often dem- I. Mota, A. Gomes, A. Palha, and F. Peixoto (Psychiatry De- onstrated a highly active interictal spike-focus. Magnetic reso- partment, Hospital S. JoBo, University Medical School, Oporto, nance imaging (MRI) scans in 10 of 11 (91%) children in group A Portugal)-5054. showed a temporal low-grade tumor or a nonneoplastic lesion; only 12 of 22 (55%) in group B showed such findings. About 50% We report the preliminary results of psychosocial adjustment of the children in group A demonstrated right temporal seizure in a group of epileptic patients identified among a working pop- onset in combination with MRI lesion. Postoperatively, 9 of 11 ulation in the Oporto metropolitan area. Psychosocial adjust- (82%) of children in group A are seizure-free for at least 6 ment was assessed by Washington Psychosocial Adjustment In- months, and 5 of 11 (45%) show marked improvement in behav- ventory (WPSI), a paper test of 132 items on which patients ior. An epileptogenic focus combined with a specific lesion in the self-report their emotional and social problems. It provides an right temporal lobe (including the limbic structures) in children is indication of psychosocial adjustment on eight clinical scales: often associated with behavioral disturbances. family background, emotional adjustment, interpersonal adjustment, vocational adjustment, financial status, adjustment to seizures, medicine and medical management, and overall psychosocial functioning. Unrealistic Expectations of Epilepsy Surgical Candidates and Their Family cohesion and adaptability was assessed by Family Families. Sallie A. Baxendale and Pamela J. Thompson (Epilepsy Adaptability and Adaptability Evaluation Scale (FACES 111). Research Group, Institute of Neurology, Queen Square, Lon- We compared results with those obtained from unemployed ep- don, and Chalfont Centre for Epilepsy, Chalfont St. Peter, ileptic patients. Bucks, England)-5051.

We describe application of a questionnaire to assess the expectations of patients undergoing preoperative assessment for Quality of Life and Employment in Epileptic Patients. Olga Judith temporal lobectomy. Patients were asked to rate themselves on Hernandez-Fustes, Otto Hernandez-Cossio, Maria de la C. Gar- 20 descriptive scales of personality, memory, and emotional di- cia Roca, and Otto Jesus Hernandez-Fustes (Institute of Neu- mensions. They were also asked to rate how they believed they rology, Havana, Cuba)-5055. would be if the epilepsy surgery was successful and their seizures were controlled. A close relative or friend also rated the From 1989 to 1992, 325 epileptic patients aged 18-78 years patient’s present self and noted the dimensions in which they were hospitalized for classification in the epilepsy service of the believed the patient might change if the operation were success- Institute of Neurology, Havana, Cuba. Results of the surveys ful. An analysis of the results showed that both patients and their related to employment were analyzed. The sample was evenly relative were expected major positive postoperative changes in distributed with regard to sex and age. A relation was noted personality and emotional functioning. These expectations do between epileptic seizures, epilepsy and job accidents, the con- not compare with changes associated with temporal lobectomy sideration of limiting illness, and educational level. in the literature. Use of the questionnaire as a basis for preop- In general, patients with partial crisis considered their illness a erative counseling and psychological intervention may be bene- limiting factor. Those with secondarily generalized crisis did not. ficial. The 46% of patients with high educational level (preuniversity or high school) generally were well accepted by employers and co- workers. Only 12% were physically and/or mentally limited. The unemployment rate is 2%. Thirty-seven patients have a Quality of Life of Children with Epilepsy. Peter Hoare (Depart- driving license. In general, patients experienced no economic ment of Child Psychiatry, Edinburgh, Scotland)-5052. difficulties after treatment and no important decrease in income due to illness, although most patients have low income. We investigated quality of life (QOL) of 108 school children with chronic epilepsy attending the epilepsy clinic at a children’s hospital. QOL measurement was assessed by two questionnaires completed by parents. The results showed clearly that epilepsy Psychosocial Adjustment in Epilepsy: A Community Study. R. had the greatest impact among children who not only had intrac- Curral, A. Palha, J. Barbosa, and R. Cruz (Psychiatry Depart- table epilepsy but also had additional disabilities. The adverse ment, Hospital S. JoBo, University Medical School, Oporto, Por- impact was evident in three main areas: the management of ep- tugal)-5056. ilepsy, including the side effects of antiepileptic drugs; the del- eterious effects on the child’s adjustment and development; and Psychologic and social aspects of epilepsy were assessed in the restrictions on family life and activities. Concentrating scarce Portugal with the Washington Psychosocial Seizure Inventory professional resources on this group of children and their fami- (WPSI), a paper-test of 132 items, on which patients self-report lies appears sensible. their emotional and social problems. It provides an indication of 56 EUROPEAN CONGRESS PROCEEDINGS psychosocial adjustment on eight clinical scales: family back- any possible cognitive or memory deficits is necessary so that an ground, emotional adjustment, interpersonal adjustment, voca- appropriate program can be provided and prove useful and tional adjustment, financial status, adjustment to seizures, med- meaningful to the patient. icine and medical management, and overall psychosocial func- With reference to drug treatment and medication compliance, tioning. We report data collected in two epileptic groups, one we report examples of an education program with modifications attending outpatient epileptic clinic and the other under the care to address these specific learning needs that encompasses tech- of a family doctor (community sample). niques for assessing patient knowledge, learning readiness, neu- ropsychometric testing for evaluation of cognitive and memory impairments, program content, and use of supports such as leaf- Relation Between Medical Condition, Psychosocial Situation, and lets and audiolvisual materials. Treatment. K. Fuggle (The David Lewis Centre for Epilepsy, Cheshire, England)-5057. Review of an Information Pack About Epilepsy. Catherine Bugler, We describe the relation between the medical condition, the Linda Hall, and Jane Wellman (National Society for Epilepsy psychosocial situation, and the treatment offered to 16 (11 fe- (U.K.), London, England)-5060. male, 5 male) patients admitted to the Assessment Unit of the David Lewis Centre in a 12-month period. The patients were The knowledge persons with epilepsy have about their illness referred to the unit for assessment of their medical condition, is crucial in helping them cope successfully with it. The need for evaluation for neurosurgery, rationalization of medication, psy- knowledge and understanding is particularly great at the time of chosocial difficulties, and the possibility of nonepileptic sei- initial diagnosis. zures. After a detailed review was made of enquiries to the Informa- Patients with adult-onset of epilepsy had a primary or addition and Education Department of the National Society for Ep- tional diagnosis of nonepileptic seizures on discharge. All 5 such ilepsy (NSE) U.K. in 1990, an information pack particularly patients were female, and all had received a mainstream educa- aimed at persons who have just been diagnosed with epilepsy, tion. Twelve had been educated in mainstream schools and 3 had their families, and friends was developed in 1991 and launched in received further education; all had been in employment but at January 1992. The pack, entitled Putting You in the Picture: An time of admission had been unemployed for some time. We Information Pack About Epilepsy comprises a video presented noted no clear correlation between length of stay on the unit and by Rolf Harris, artist and celebrity, plus an accompanying book- marital status or with dependent family members, but individual let. psychosocial situations did appear to be important. Two years later, 1,229 copies of the pack have been sold, the greatest number of individuals with epilepsy and their families, but also to schools, colleges, health centers, and voluntary or- Studies, Work Situation and Way of Life After Leaving a School ganizations. Questionnaires were sent to 10% of purchasers, ran- Specialized in Educating Children with Epilepsy. Cees v.d. Lin- domly selected, to elucidate how they heard about the pack, den and Henny Bastiaansen (Epilepsy Centre Kempenhaeghe, whether it fulfilled their information needs, and any ideas they Heeze, The Netherlands)-5058. had for further resources, information, or services. The review has provided vital guidance for development of future resources De Berkenschutse is a school community for special and sec- and marketing strategies. ondary special education and part of the Kempenhaeghe Corpo- ration (Heeze, the Netherlands). In 1991, De Berkenschutse began a study of previous pupils to gain more knowledge regarding Living with Epilepsy: An Interactive Multimedia Computer-Based the social situation of persons educated for a shorter or longer Training Program for Persons with Epilepsy. Tim Betts, Kate period of time at a school specializing in educating children with Smith, and *David Smith (Birmingham University Seizure epilepsy. Clinic, Department of Psychiatry, Queen Elizabeth Psychiatric Despite their handicap most of ex-pupils were employed: 43% Hospital, and *AVC Multimedia, Birmingham, England)-5061. attend school and 52.0% are employed (full time or parttime); their unemployment rate is lower than the national average. With A young person with epilepsy, while coming to terms with the regard to level of education, however, most ex-pupils receive condition, needs to assimilate much information about it: videos (have received) slightly less qualified training and have employ- provide some information but are difficult to interact with, and it ment of lesser grade. is also difficult to find information in books when it is needed. Because results show that children who must be educated in Most young persons are computer literate and might find an special schools are a vulnerable group, we wished to know what interactive user-friendly computer program more acceptable. ex-pupils considered strong and weak points in their education. We present an interactive multimedia computer program con- They responded that special attention must be paid to social taining the basic information about epilepsy needed by persons skills, applications, and leisure activities. This information has with the disease. In text and pictures, the medical process is permitted De Berkenschutse to optimize the pedagogic and di- explained, and issues of self-control and self-empowerment are dactic level, providing even more optimal preparation for future discussed. The program can be presented on an appropriate study, work situation, and life style for persons with epilepsy. IBM-compatible PC and is suitable both for clinic and home use. It is written in English and applies to U.K. practice but could easily be adapted to other European languages and practice. Needs-Specific Patient Education. Susan Lannon and Diana Ri- grish (University of Cincinnati Medical Center, Cincinnati, OH, U .S.A.)-5059. Focus on Epilepsy: An Interactive Multimedia Computer-Based Training Program for Nonmedical Health Professionals. Kate The ability to cope with the changes epilepsy causes in an Smith, Tim Betts, and *David Smith (Birmingham University individual’s life is improved by correct and current information Seizure Clinic, Department of Psychiatry, Queen Elizabeth Psy- provided at the time of diagnosis and throughout the lifespan. chiatric Hospital; and *AVC Multimedia, Birmingham, En- Education assists with acceptance of the diagnosis and compli- gland)-5062. ance with treatment. It dispels myths, promotes understanding, and empowers the patient to self-advocate for the best possible Nonmedical health professionals (hospital nurses, primary care. It is our responsibility to provide this education. However, care nurses, occupational therapists) are frequently consulted by an appreciation of the individual’s degree of literacy, age, and persons with epilepsy seeking advice and counseling. Most

Epilepsia, Vol. 35, Supyl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 57 health professionals (unless they work with epilepsy all the time) well as on issues of correct diagnosis and medical treatment. We have poor knowledge of epilepsy, particularly in regard to recent have constructed a systematized patient-flow model in accor- advances in management of the condition that have revolution- dance with the department’s fundamental policy of providing ized the outlook for so many persons with epilepsy. Because qualified treatment. Therapeutically, our methods differ signifi- most health professionals’ knowledge about epilepsy is so out- cantly from those of other Danish centers in that we have a dated, they may give patients inadequate or wrong advice. Yet multidisciplinary team whose primary task is to solve all issues no published material is written solely for nonmedical health of youngsters with intractable seizure problems. Total therapy professionals. and evaluation includes the following: medical knowledge, We report an easily interrogated, user-friendly, multimedia school teaching, testing work skills, evaluating occupational ca- computer program containing the essential current information pacity, coping with social demands, psychological treatment, about epilepsy in text and pictures. It is suitable for an appro- and social worker’s advice and assistance. Individual patient- priate IBM-compatible PC and can be used for education and as flows are continuously evaluated, ending with comprehensive a reference source on hospital wards, in clinics, or in primary evaluation on discharge, at which time all aspects of the patient’s care. It is complementary to a similar computer program for hospital stay are commented on by members of the multidisci- persons with epilepsy. The version is in English and applies to plinary team in accordance with, and understanding of, the U.K. practices but could be easily adapted to other European young person’s wishes and demands. A flow diagram showing languages and practice. movements of patients through the different steps and activities was established to demonstrate the systematized course.

Evaluation of Professional Conferences 1991-1993. Alice Hanscomb (National Society for Epilepsy (U.K.), London, En- Epilepsy Liaison Service: Improving Communication Between the gland)-5063. Specialist, the Patient, and the Primary Care Physician. Kate Smith and Tim Betts (Birmingham University Seizure Clinic, The Information and Education Department of the National Department of Psychiatry, Queen Elizabeth Psychiatric Hospi- Society for Epilepsy (NSE) provides a range of services, includ- tal, Birmingham, England)-5066. ing professional training in the form of multidisciplinary conferences. The conferences which are run every year are “Coping Although most persons in the United Kingdom are treated by with Epilepsy: The Special Needs of People with Learning Dis- a primary care physician most also visit a specialist at times. ability” and “Epilepsy in Children and Young People.” We re- Communication between specialists and primary care physicians viewed the way in which these conferences have been evaluated is often poor or nonexistent. In our experience, most persons in the last 3 years (1991-1993) by those who attended to establish with epilepsy, even if they have had the condition for a long time, which elements of the conferences participants have found most remain relatively ignorant about it condition and have no knowl- valuable and why and to compare and contrast the collated re- edge of the nature or results of tests or of their treatment plan. sponses from the six different conferences. Epilepsy is a condition that produces strong feelings of helpless- Identical evaluation forms were always used. Responses were ness and loss of control: Such feelings are reinforced if patients collated for each conference and then collated under conference believe they have no say or influence in their management. titles; finally, all 206 were grouped together to obtain an overall We present a model of working with persons with epilepsy in response to all six conferences. which communication between primary and secondary care is Most persons attended as a result of receiving mail from the fostered by persons with epilepsy becoming the holders of their NSE rather than in response to journal advertising. There was no own information (through a comprehensive cooperation card, great difference between responses to evaluation forms com- later to be linked to a computer disk) which is also shared by the pleted for the different conferences: the reasons for attending primary and secondary care physician. Patients become edu- and the points of value appeared to be common to participants in cated participants in the process rather than passive recipients of each conference. care. Computer links between clinic and primary care physicians also facilitate communication, particularly if the clinic is prepared to help primary care physicians audit their practice and Utility of Video Recording Without Simultaneous EEG for Inpa- educate patients about acceptable standards of care. tients. Helene Meinild, Berit Lindberg, and Peter Uldall (Di- analund Epilepsy Hospital, Dianalund, Denmark)-5064. Psychological Approach in Patients Treated in a Regional Epilepsy In our children’s ward, we have used video recordings without Center: Analysis of the Needs of 300 Patients. M. Bracco, M. P. simultaneous EEG since May 1992 to observe and register epi- Canevini, L. Guidolin, A. Saltarelli, A. Piazzini, V. Sgrb, and R. leptic seizures in patients to document our observations, and Canger (Centro Regionale per I’Epilessia, Ospedale “San Pa- communicate those observations objectively. The video record- 010,” Milan, Italy)-5067. ings also can be used as a psychological/educational tool to help the children and their families become informed about the sei- In a Regional Epilepsy Center, we analyzed the motivation for zures; ensure that all persons involved have the same reference referral, to the clinical psychological service of the center of 300 when discussing the seizures, and ensure that the seizures we patients in the first 5 years (1989-1994) of the service’s existence. observe are identical to the seizures that prompted hospital ad- The model of practice of the psychological service (counseling as mission. well as psychotherapy) established and carried on by the authors We describe a case in which the video recordings were used as results in a shared global approach of the epilepsy center; a a psychologicalieducationaltool to help a 14-year-old boy under- specialized approach, i.e., one based on the psychological prob- stand his seizures. In another case, the recordings supplemented lems referring to epilepsy and seizures; and an approach open to other existing examinations in providing conclusive diagnosis. National Health Services for the activities not specific to the service itself. The patients of the psychological service represent 20% of the population of the center (80% counseling and 20% Systematized Course of Hospitalization. Per Olesen, Nelly Mad- psychotherapy). The data analysis classifies the population from sen, and John P. A. Jensen (Dianalund Epilepsy Hospital, Di- the viewpoint of “motivation for referral” in the following analund, Denmark)-5065. classes: the seizure problem; epilepsy as related to psychosocial prejudice, family dynamics, pharmacologic management/ In our department for adolescent patients, significant empha- compliance, social adjustment, sexuality, pregnancy and moth- sis is placed on treating psychological and social problems as erhood, and functional seizures; neurosurgery; psychodiagnostic

Epilepsia, Vol. 35, Suppl. 7, 1994 58 EUROPEAN CONGRESS PROCEEDINGS evaluation; and possible referral to the competent and pertinent cally to undertake counseling and, if so, whether that person held services. For each factor, we underscore the correlation with recognized qualifications in counseling; whether, other than that clinical data (type of epilepsy, associated handicaps, seizures, person, any other persons in the clinics were expected to counsel therapy, epilepsy onset) and social data (invalidity, job place- clients; and whether the nurses believed counseling to be a part ment), and the psychological needs involved and the approach to of their role. I inquired as to the method of referral, the number those needs. of sessions provided, and the models of counseling used. All nurses questioned considered that their role included counseling their clients and the work to be a valued part of the care given to Evaluating Patient Satisfaction of a Specialist Epilepsy Assessment patients with epilepsy. Service. Dominic Upton and Pamela J. Thompson (Chalfont Cen- tre for Epilepsy, Chalfont St. Peter, Epilepsy Research Group, Bucks, and Institute of Neurology, Queen Square, London, En- Management of Psychosocial Problems in Epileptic Children and gland)-5068. Adolescents in Slovenia. Igor Mihael Ravnik (Department of Child Neurology, Centre for Epilepsy, Ljubljana, Slovenia)- We report a detailed study of patient satisfaction with the ser- 5071. vice provided in a specialized epilepsy assessment unit in the United Kingdom. Patients were interviewed to assess their per- Historical evolution of the work performed by the Centre for ceptions of the quality of the service and the benefits they had Epilepsies and the current level of care for epileptic children and derived from attending the unit. Close relatives were also con- adolescents in Slovenia was evaluated with special emphasis on tacted for their assessments. In all, 76 patients were interviewed. psychosocial disorders, emphasizing initial inquiries into the The results showed positive appraisal of treatment. The most psychosocial aspect of living with epilepsy in Slovenia; assessing frequent comment referred to the importance of a multidisci- adequacy of professional assistance; studying self-concept of ep- plinary approach. Almost 90% believed that their medical and ileptic children; creating a multidisciplinary team; promoting social situation had been improved by attendance at the unit. awareness about epilepsy in kindergartens and elementary Future research of patient satisfaction should be undertaken; the schools, using existing counseling networks, and promoting findings could form the basis for future developments in provi- awareness about epilepsy in primary and specialist health ser- sion of care. vices; organizing group work for adolescents and their parents; introducing a family approach; introducing training in social skills; initiating self-help groups; studying attitudes in special Appraisal of Patients’ and General Practitioners’ Views of Aspects target groups of the public; helping with employment; attempting of an Inpatient Neuropsychiatric/EpilepsyService. Laura H. Gold- to change driving legislation; and attempting to influence media. stein, Alice M. Parshall, and *Peter B. C. Fenwick (Psychology Department, Institute of Psychiatry; and *Neuropsychiatry/ Epilepsy Unit, Maudsley Hospital, London, England)-5069. ACE as a Unique Model of Epilepsy Rehabilitation Counseling Two cohorts of patients admitted to the Maudsley Hospital Service. Irit Shimshon and Judith Manelis (Advisory Centre for Neuropsychiatry/Epilepsy Unit (from April I, 1991 to March 31, Epilepsy, Neurology unit, Western Galilee Regional Hospital, 1992 and April 1, 1992 to March 31, 1993) for investigation of Haifa, Israel)-5072. paroxysmal behavior disorders were sent questionnaires regarding their perceptions of their hospital treatment. Response rates The Israeli League Against Epilepsy, together with the Israeli of 61 and 54.1% were obtained for the first and second cohorts, ministry of Welfare, established an Advisory Centre for Epilepsy respectively. Demographic characteristics (age, gender), mean (ACE). ACE is the only multiprofessional service in lsrael that length of hospital admission and time since discharge did not focuses on epilepsy and its implications for persons with epilepsy differ between cohorts. More than 53% of each indicated that the and for society. condition for which they were admitted to the unit had improved ACE is an independent trust, which permits low cost and high since discharge; 47% of each cohort rated their admission as very efficiency, and which consequently can be used as a unique and valuable. Slightly more in the second than in the first cohort accountable model both professionally and financially. The ACE considered their admission easy to manage. For the first cohort, team includes a rehabilitation social worker, a psychologist, a longer admissions were associated with less severe problems neurologist, and a secretary. The director is a League member. since discharge; for the second cohort, longer admissions were All activities are psychosocially oriented and are divided into easier to manage than short. General practitioner (GP) ratings of five domains: (a) psychosocial personal short-term intervention patients’ problem outcomes, obtained for the second cohort, cor- that also involves family interaction, employment problems, and related positively with patient’s self-ratings. Of the GPs respond- social activities; (b) self-help group meetings for youth and for ing, 91.9% would refer patients to our unit again. Findings sug- parents; (c) policy-making activation-ACE as a leading organi- gest that for different reasons patients will view longer rather zation fights for rights in areas concerning education, driving than shorter admissions positively, possibly as a consequence of license, insurance, army service, and employment; (d) re- their average age (thirties), and the chronicity, severity, and search-ACE took part and initiated five studies, all concerning complexity of their problems. quality of life of persons with epilepsy (presented in National and International meetings); and (e) publication of leaflets and book- lets about epilepsy on issues of interest to persons with epilepsy and their families. We consider ACE a model suitable for adap- Quality of Counseling in Epilepsy Clinics. Kate Fuggle (The David tation in other countries. Lewis Centre for Epilepsy, Cheshire, England)-5070.

Counseling is increasingly considered an important aspect of treatment of persons with epilepsy. To discover the characteris- Knowledge and Attitudes Toward Epilepsy Among German Re- tics of counseling available in epilepsy clinics in England and cruits. Christian Brandt (Bielefeld, Germany)-5073. Wales, I designed a questionnaire which was sent to all members of the Epilepsy Specialist Nurses Association. These nurses are Quality of life (QOL) for persons with epilepsy depends to a attached to the epilepsy outpatient clinics throughout England great extent on knowledge about and attitudes toward epilepsy of and Wales. There are 9 such nurses at present, and I received other persons. In several recent studies of these issues either replies from 8 of them. From the data collected, I wished to representative populations or special groups such as general determine whether anyone was employed in the clinics specifi- practitioners or teachers in different nations were surveyed.

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 59

In the present study, 250 recruits of the German navy were We studied 100 patients from the epilepsy ambulatory unit of asked to answer a few questions concerning their knowledge and the Dr. Carlos J. Finlay Hospital to analyze their sexual activity. familiarity with epilepsy, e.g., whether they had heard about We studied as a control group 100 patients with no epilepsy but epilepsy, whether they knew different seizure types, and wheth- with the same sex, occupation, and age variation as the epilepsy er they knew how to help someone having a seizure. They were group. The variables were: general data, clinical characteristic of queried about their attitude toward persons with epilepsy, e.g., the disease, and sexual history. To determine if sexual dysfunc- whether they would allow their children to play with a child with tion was functional or organic, we used penaldigital plethys- epilepsy, whether they would marry someone with epilepsy, and mography and determined penal-arm index and dosage of folli- how they would react if they learned that one of the friends had cle-stimulating hormone and testosterone. More epileptic pa- epilepsy. We evaluated the relation between knowledge, famil- tients had no sexual partner (2 < 1645) and fewer had a regular iarity, and attitudes and compared our results with those of other sexual partner. Comparison of the two groups did not show a studies. greater number of sexual dysfunctions, and the dysfunction had no relationship to type of seizures or treatment.

Epilepsy and the Media. Helen Coyle, Stephen Brown, Russell Sexual Behavior of Epileptic Patients. A. P. Palha, M. Viana, and Ciallis, and Nicholas Baker-Brian (The David Lewis Centre, I. Mota (ServiGo de Psiquiatria, Hospital S. Jogo, Porto, Portu- Cheshire, England)-5074. gal)-5077.

Mass communication media are commonly believed to exert We studied sexual behavior in a sample of epileptic outpatients powerful influence on what the general public thinks and be- (male and female) attending a psychiatric department of a general lieves. Consequently, we examined reports mentioning epilepsy: hospital. All patients were invited to answer scales 2 and 3 of the 1,013 reports identified by a clippings service were content- Sexuality Experience Scales (SES, Frenken and Vennix), which analyzed, and operational definitions were used to divide them are intended to measure sexual fantasies, libido, and sexual per- into nine categories: general announcements, self-help, letters, formance. We assessed our results in light of the influence of unpleasant, charity, deaths, general education, human interest, psychological, social, and organic variables in sexuality of the and general interest. The reports were analyzed in terms of type epileptic patients in this sample. of publication, space allotted, presence of a photograph, and terminology used, both in the title and general text. Although methodologic problems associated with content Epilepsy and Pregnancy: A Prospective Study of 25 Cases. Mar- analysis were realized, our results suggest that a substantial garida Silvestre, Ana Cristina David, Elsa Vasco, and Reis amount of media coverage continues to portray persons with Marques (Hospitais da Universidade de Coimbra, Psiquiatria, epilepsy as sufferers or helpless, tragic victims, with unaccept- Marcarida Silvestre/Reismarques, Coimbra, Portugal)-5078. able numbers of references to “epileptics” and “fits.” Because the media are commercial ventures whose policies and presen- We assessed the influence of epilepsy on pregnant women, tations are determined in part by their internal needs, they may studying evolution of epilepsy and development of pregnancy emphasize unpleasant, often irrelevant symptoms to make the with regard to psychological aspects of pregnancy and epilepsy, presentations more exciting and to enlarge their audience appeal. psychopathology during pregnancy, and evolution and outcome The potential impact of the media on public opinion on persons of pregnancy. The sample consisted of a group of 25 pregnant with epilepsy was assessed. and epileptic women examined in the outpatient epilepsy and obstetrics clinic of Coimbra University Hospital between No- vember 1992 and July 1994. A structured clinical interview used for assessment included a “Epileptic Personality” or Reaction to the Disease? Preliminary questionnaire about epilepsy and pregnancy, the “Inventory of Data From an Original Personality Inventory Administered to 50 Physical Self-Concept’’ (A. Vaz Serra, 1988), an SCL-90-E. Two Subjects with Epilepsy. A. De Rosa, D. Cirafici, *A. Iavarone, groups of control were used: pregnant women with no pathology tA. Labella, F. Voria, and $M. R. Tata (Servizio di Psicoterapia, and nonpregnant epileptic women. *Clinics Neurologica, tcattedra di Psicologia Medica, and $Cat- tedra di Neurofisiopatologia, Seconda Universita degli Studi, Napoli, Italy)-5075. *Abstract 5079 appears on page 48. The concept of “epileptic personality” has been considered in the neuropsychiatric literature as a cluster of interictal behavioral changes often associated with epilepsy. Many such behavioral Topic VI: Pharmacology and Pharmacotherapeutics changes are reported in patients with temporal lobe epilepsy (TLE). We attempted to verify the extent to which personality traits Main Session (6OOOa-6OOOc) described in patients with TLE could be found in patients with other forms of epilepsy or invalidating diseases other than epilepsy. Modification of Amino Acid Neurotransmission in Brain Slices by A personality inventory devised to assess 13 traits was admin- Antiepileptic Drugs. J. A. Davies (Department of Pharmacology istered to subjects with different forms of epilepsy. A group of and Therapeutics, University of Wales College of Medicine, patients with other invalidating disease was also studied. Prelim- Cardiff, Wales)--6000a. inary results led us to doubt the existence of an epileptic personality. Indeed, behavioral changes observed in epilepsy may be The role of amino acid transmitters is fundamental to the neu- better explained in the perspective of a psychological adjustment rochemistry underlying epilepsy. Although y-aminobutyric acid to the disease. has been recognized as being involved for many years, the role of glutamate has been investigated only relatively recently. Find- ings that antagonists of the N-methyl-D-aspartate (NMDA) sub- type of glutamate receptor show potent anticonvulsant proper- Sexual Dysfunction and Epilepsy. Carlos Arteaga, Sergio Santa- ties in animal models of epilepsy have been instrumental in ini- maria, Luis Rodriguez, Jorge Otero, Fermin Morera, and Otto J. tiating this research. Alternatively, compounds that reduce Hernandez (Grupo de Epilepsia, Hospital Dr. Finlay, Havana, release of excitatory amino acid neurotransmitters from the pre- Cuba)-5076. synaptic terminal could also prove to be effective anticonvul-

Epilepsiu, Vol. 35, Suppl. 7, 1994 60 EUROPEAN CONGRESS PROCEEDINGS sants. Use of in vitro techniques allows study of potential anti- A. Tiberti, 0. Bruni, A. Pelliccia, D. Buti, P. Tromboni, E. Del convulsant drugs on stimulated release of endogenous neuro- Giudice, G. Coppola, M. Deodato, F. Guzzetta, G. Tortorella, transmitters. Compounds acting at various sites on the NMDA R. Gaggero, M. De Negri, R. Guerrini, M. Loi, A. Parmeggiani, receptor complex, such as ketamine and remacemide, reduce E. Malaspina, M. Ruggieri, A. Tint, and P. Veggiotti.) (Depart- stimulated release of glutamate. The function of nitric oxide ment of Child Neurology, University La Sapienza, Rome, It- (NO) as a retrograde messenger in the CNS is another factor to aly)-6001. be considered in release mechanisms. Debate exists as to whether NO has facilitatory or inhibitory synaptic actions. NO has To study the localization dependent efficacy of vigabatrin been shown to increase both glutamate and aspartate release in a (VGB), we selected 51 children with tuberous sclerosis and re- variety of tissues and consequently is implicated in epilepsy, but fractory partial epilepsy retrospectively. Patients aged 6 months it has also been reported to be an antagonist at NMDA receptors. to 14 years (mean 5.6 years) were treated with VGB 30-100 mgikg daily as add-on to their existing therapy for 12-28 months (mean 19 months). Concomitant medications ranged from one to Release of Neurotransmitters in the Epileptic Brain. Matthew J. three other drugs (mean 2.2). After onset of VGB therapy, 37 During (Molecular Pharmacology and Neurogenetics Ldbora- (73%) showed reduction in seizure frequency 250% and 21 (41%) tory, Yale University School of Medicine, New Haven, CT, became seizure-free. Ten of 21 relapsed after 2-12 months. The U.S.A.)4000b. remaining 11 patients (22%) were seizure-free for 62years; 9 had partial seizures originating from parietooccipital or postotempo- Regulation of neurotransmitters in regional brain extracellular ral areas, unifocal EEG abnormalities, and no evidence of sei- fluid (ECF) in patients with complex partial epilepsy (CPE) with zures secondarily generalized. Only 2 of 24 with frontal lobe a primary focus on in vivo glutamatergic and y-aminobutyric acid epilepsy remained seizure-free. Overall experience suggests an (GABA)ergic neurotransmission was investigated. Depth elec- important role of VGB in partial seizures of posterior origin. trodes modified to include a microdialysis probe were implanted for 1&16 days in hippocampus of patients with intractable CPE to test several hypotheses: first that epileptogenic regions are characterized by increased basal and ictal release of glutamate Audit of Lamotrigine and Vigabatrin Chronic Therapy in Outpa- and a reduction in both basal and ictal levels of extracellular tients with Refractory Epilepsy. G. J. Schapel and D. W. Chad- GABA, and second that a potential homeostatic mechanism that wick (The Walton Centre for Neurology and Neurosurgery, Liv- acts to maintain basal extracellular concentrations of GABA may erpool, England)-6002. limit the inhibitory GABA response to excitation under conditions in which transporter reversal is a major mechanism of Lamotrigine (LTG) and vigabatrin (VGB) are chemically novel GABA release. A related hypothesis, that ECF glutamate is in- antiepileptic drugs (AEDs), recently introduced in clinical prac- creased in the epileptogenic region because of reduced uptake, tice in Europe. We audited the case notes of 356 patients attend- has also been studied. Further hypotheses relate to the mecha- ing the outpatient clinic of a tertiary referral epilepsy service nism of seizure arrest, specifically that generation of extracellu- with a population source of 4 million in Northwest Britain to lar lactate during seizures reflects acidification of the extracel- assess LTG and VGB treatment. Mar space with increased inhibition and that seizure activity is Two thirds of patients with localization-related epilepsy (LRE) arrested when a critical lactate concentration is reached. Fur- and one third with generalized epilepsy (GE) were treated with thermore, the neuromodulatory action of adenosine in inhibiting LTG for 1-56 months; i.e., patients were treated with VGB in a epileptiform activity was studied. The data provide evidence for ratio of 30 with LRE to 1 with GE for 1-56 months. LTG was still specific direct involvement of glutamate, GABA, lactate, and being taken by 70% of patients (12% monotherapy) and VGB by adenosine in onset and termination of seizure activity in humans. 50% (12% monotherapy); 47% of patients receiving LTG and 32% receiving VGB showed decrease in seizure frequency New Antiepileptic Drugs in Clinical Practice: The Present Position. 250%, and 8% of patients receiving LTG and 5% receiving VGB Alan Richens (Department of Pharmacology and Therapeutics, were seizure-free. University of Wales College of Medicine, Cardiff, Wales)- Adverse effects caused LTG discontinuation in 11% of pa- 6000c. tients (e.g., skin rash, nausea, ataxia, and visual disturbance) and VGB discontinuation in 16% (e.g., personality disturbance, In the last 5 years, six new antiepileptic drugs (AEDs) were drowsiness, and weight gain). LTG and VGB are clinically ef- developed and marketed in at least one country: felbamate fective safe drugs for long-term treatment of a wide range of (U.S.A. only); and gabapentin, lamotrigine, oxcarbazepine, vi- patients with refractory epilepsy. gabatrin, and zonisamide (Japan only). Never before have so many AEDs been developed in such a short time. Some have a known or partly known mode of action (e.g., vigabatrin inhibits y-aminobutyric acid (GABA)-transaminase), some have simple Gabapentin (Neurotin) Add-on Therapy in Patients with General- kinetics (e.g., vigabatrin and gabapentin are eliminated renally), ized Epilepsy. Elizabeth Garofalo, Deborah Leiderman, David and all have established efficacy. Whether they will replace ex- Chadwick, Wilhelm Sauermann, and Mark Pierce (Warner- isting drugs or be simply alternatives with defined indications Lambert/Parke-Davis, Ann Arbor, MI, U.S.A.; Walton Hospi- cannot yet be determined because comparative studies against tal, Liverpool, England; and DATAMAP, Freiburg, Germany)- old drugs or between the new drugs are only just beginning to 6003. emerge. Unfortunately, some of the traditional problems still exist (e.g., interactions with felbamate and lamotrigine) although We assessed the efficacy and safety of gabapentin as add-on some of the new agents generally may be better tolerated than therapy in patients with refractory generalized tonic-clonic sei- established drugs. Several other interesting drugs are in the pre- zures (GTC). After a 12-week baseline, patients received placebo marketing stages of clinical development. (n = 71) or gabapentin (1,200 mg/day, n = 58) for a 14-week double-blind treatment period. Primary efficacy variables were responder rate (percentage of patients with 250% reduction in Platform Presentation 1 (60014006) GTC frequency), and response ratio [(T - B)/(T + B)] where B and T are frequency of GTC during baseline and treatment, respectively, with values ranging from - 1 to + 1 and negative Vigabatrin in Refractory Epilepsy Associated with Tuberous Scle- numbers, indicating improvement from baseline. In the intent- rosis. Paolo Curatolo, on behalf of the Italian Collaborative to-treat analysis, response ratio was -0.155 for the gabapentin Study Group (G. Bartalini, S. Buoni, S. Battaglia, E. Menegatti, treatment group as compared with -0.057 for placebo. Re-

Epilepsia, Vol. 35, Suppl. 7. 1994 EUROPEAN CONGRESS PROCEEDINGS 61 sponder rate was 28% for gabapentin-treated patients and 18% ren, L. Nilsson, L. gstergaard, G. Alarcon, L. C. Lassen, and for placebo-treated patients. Differences between treatment K. Lyby). (Epilepsy Research Unit, Department of Medicine groups were not statistically significant. In a retrospective subset and Therapeutics, Gardiner Institute, Western Infirmary, Glas- analysis, neurologic histories and clinical data were reviewed in gow, Scotland)-6006. blinded fashion, and patients were classified by type of generalized epilepsy (primary or secondary). Results of the subset anal- Tkagabine (TGB), a unique y-aminobutyric acid uptake inhib- ysis showed that patients with primary generalized epilepsy had itor was shown in recent controlled studies to be safe and effi- a larger improvement in seizure control than those with second- cacious as add-on therapy in patients with partial-onset seizures. arily generalized epilepsy, suggesting that gabapentin may be Additional controlled trkals are now underway to establish the efficacious in some patients with primary generalized epilepsy. appropriate dose regimen. We report details the results of a randomized, double-blind, placebo-controlled, parallel-group, add- on study undertaken in I1 European centers of patients aged 1675 years with partial-onset seizures with unsatisfactory sei- Comparison of lamotrigine (Lamictal) and Phenytoin Monotherapy zure control. Each patient reported at least six partial-onset sei- in Newly Diagnosed Epilepsy. Tim J. Steiner, *Charmaine Sil- zures in the 8 weeks preceding study enrollment despite optimal veira, *Alan W. C. Yuen, and the North Thames Lamictal Study doses of one-three antiepileptic drugs approved by the regula- Group (Academic Unit of Neuroscience, Charing Cross Hospi- tory agency. A 12-week prospective baseline and a 6-week run-in tal, and Westminster Medical School, London; and *The Well- period preceded a 12-week assessment period: 156 patients were come Research Laboratories, Beckenham, Kent, England)- randomized in a ratio of 1:1 at each center to receive either 6004. placebo or TGB 30 mg/day in three divided daily doses, and 125 patients completed the study. Efficacy endpoints included me- In a multicenter, parallel-group, double-blind, 48-week study, dian percentage reduction in weekly seizure frequency, percent- 181 patients [86 lamotrigine (LTG), 95 phenytoin (PHT)] aged age of patients achieving at least 50% reduction in weekly seizure 14-75 years, who had experienced at least two seizures in the frequency, number of seizure-free days, and number of days previous 6 months were entered. The modal daily dose was 150 before occurrence of the sixth seizure in the assessment period. mg LTG and 300 mg PHT. There were no significant differences between LTG and PHT in time to withdrawal from study, time to first seizure, proportion of patients seizure-free in the last 24 and 40 weeks of the study, or percentage change from baseline in seizure counts for Platform Presentation 2 (6007-601 2) all seizure categories: partial, secondary, primary generalized tonic-clonic seizui-es (GTC), and total seizures. Overall, 43% of LTG and 36% of PHT patients were seizure-free and 44% of LTG and 34% of PHT patients with primary GTC were seizure- Remacemide Hydrochloride Safety, Tolerability, and Pharmaco- free for the last 24 study weeks. kinetics. D. W. Chadwick, D. Smith, G, Baker, *P. Crawford, Asthenia, somnolence, and ataxia were reported significantly *E. Anderson, TB. Harrison, and tV. Jamieson (Liverpool; more frequently in the PHT group. Adverse experiences led to *Bootham Park Hospital, York; and tFisons PLC, England)- withdrawal of 15% of LTG patients and 19% of PHT patients. 6007. Vital signs, neuropsychological tests, and laboratory safety measures showed no difference between groups other than the ex- Forty patients (33 males, 7 females) with refractory epilepsy pected laboratory changes due to the enzyme-inducing proper- were randomized to receive ascending weekly doses of remace- ties of PHT. mide hydrochloride tablets, in a twice (b.i.d.) or four times (qid.) daily regimen or placebo for 50%. In phenytoin. No adverse effects on seizure frequency were ob- 6 children, LTG was continued even though seizure reduction served. Neuropsychology tests showed no significant changes. was 40%.In 21 children, LTG was tapered, mainly because of Remacemide and the desglycine metabolite demonstrated dose rash (2) increased seizures (7), and lack of efficacy (12). Children proportional pharmacokinetics over the dose range tested. with generalized epilepsy showed best response. More than 50% of such children had excellent response, and all 5 who became seizure-free had generalized epilepsy. Survey of 260 Epileptic Patients Treated with Oxcarbazepine (Tri- leptal) on a Named-Patient Basis. Johan A. P. van Parijs, Harry Meinardi, and *Marc H. A. P. Broeren (Instituut voor Epilep- Randomized, Double-Blind, Placebo-Controlled, Parallel-Group siebestrijding, Heemstede; and *Ciba-Geigy B. V. Arnhem, The Study of Safety and Efficacy of Tiagabine administered Three NetherlandsL6008. Times Daily as Adjunctive Treatment for Partial Seizures. Martin Brodie and Lars Chr. Lassen, on behalf of The Northern Euro- We report the clinical findings of all 260 epileptic in- and out- pean Tiagabine Study Group. (P. Riekkinen, M. J. Brodie, J. patients of a Dutch epilepsy center treated with oxcarbazepine Duncan, D. Chadwick, A. Richens, G. Venables, E. Ben- on a named-patient basis before marketing approval was ob- Menachem, M. Sillanpaa, J. Morrow, M. Dam, R. Elwes, R. tained. We wished to provide further information on prolonged Kalviainen, J. P. Leach, M. O’Donaghue, G. Shaples, C. War- use of oxcarbazepine.

Epitepsin, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS

Total exposure to oxcarbazepine was 935 patient-years. Mean Plasma PHT concentration before death was 76 ? 28 pM duration of treatment was 43 months (range 0-119). All but 3 (mean 2 SD), whereas postmortem whole blood concentrations patients had previously been treated, in vain, with carbam- of PHT in the same patients were 17 -t- 14 pM (mean ? SD). azepine (CBZ). Of these, 164 patients were changed to oxcarba- Postmortem whole blood PHT levels were significantly lower zepine because of adverse effects of CBZ, 89 because CBZ had than preceding PHT plasma concentrations before death (p = been insufficiently efficacious, and 4 because of unknown rea- 0.02, Wilcoxon signed-rank test). Although limited, these data sons. provide further support to the hypothesis that low and decreas- At the end of the reference period, 161 patients were still ing plasma concentrations of AEDs may play a role in SUD in treated with oxcarbazepine: 4 successfully discontinued all treat- epilepsy. ment after being seizure-free for >3 years, 73 did not benefit sufficiently, 7 discontinued because they became worse instead of better, and 14 were lost to follow-up. In 1, the final diagnosis SafetyIEfficacy of Antidepressants in Epilepsy. Enrico Sasso and was pseudoseizures. Domenico Mancia (Istituto di Neurologia, Universita di Parma, Of the 253 patients for whom oxcarbazepine was substituted Parma, Italy)6011. for CBZ for either reason, 21 (8%) became seizure-free, 81 (32%) showed clear improvement in seizure control, and 142 (56%) Depressive disorders can occur in epileptic patients due either reported fewer side effects. The lesser amount of side effects and to implications of the basic process or to length of chronic ex- the apparent broader dose range enabled increase in dosages and posure to antiepileptic drugs (AEDs). Nevertheless, manage- reduction in polypharmacy . ment of antidepressive agents often can be hazardous owing to the risks of counteracting AED efficacy. The present controlled study compared the safety/efficacy outcomes of amitriptyline Multicenter Comparative Trial of Valproate and Phenytoin. Ray- and fluvoxamine, a selective serotonin reuptake inhibitor mond Tallis and “Derrick Easter (Department of Geriatric Med- (SSRI), in epileptic patients with depressive disorders; 22 out- icine, Manchester University, Manchester; and *Sanofi Win- patients were recruited in a double-blind comparison on the basis throp, Guildford, England)--6009. of Hamilton Score (HS) > 18. Patients were assessed after 1 and 3 months of sustained oral treatment with amitriptyline (75 mg/ In this study, 166 patients (72 males, 94 females) aged >60 day) or fluvoxamine (150 mg/day) by HS, Zung anxiety scale, years with newly diagnosed epilepsy randomized to valproate seizure evaluation, and performance tests. Baseline HS was sig- (VPA, Epilim) or phenytoin (PHT, Epanutin) were followed as nificantly ameliorated by both amitriptyline (p < 0.01) and flu- outpatients for 12 months at 37 participating centers. Initial drug voxamine (p < 0.03) after 1 month, whereas at 3 months only doses were low, with increase as required to achieve seizure fluvoxamine caused significant improvement (p < 0.03) owing to control. Tolerability was assessed from spontaneous reports and a relevant number of dropouts who had been treated with am- health questionnaires. In all, 149 patients (78 VPA, 71 PHT; 82 itriptyline (exacerbation of epilepsy and/or adverse events were with primary generalized seizures, 67 with partial seizures either the main reasons for discontinuation). Despite the high cost of secondarily generalized or not) were eligible for efficacy analy- SSRI as compared with that of tricyclic agents, our data appear sis, and 163 patients (84 VPA, 79 PHT) were eligible for safety to support use of SSRI, at least in for epileptic persons for whom evaluation. safety strategies are recommended. By 12 months, 10% VPA patients (poor control I%, adverse events 9%) and 18% PHT patients (poor control 4%, adverse events 14%) had failed randomized treatment. Actuarial analysis Prognosis in Newly Diagnosed Childhood Epilepsy. E. Hughes, M. of recorded seizure data regarding time taken to achieve 6-month de Silva, B. G. R. Neville, A. L. Johnson, and E. H. Reynolds remission showed that approximately half of patients (51% VPA, (The Centre for Epilepsy, The Maudsley Hospital and Paediatric 59% PHT) were seizure-free for the first 6 months of treatment. Neurology, Guy’s Hospital, London, and MRC Biostatistics By 12 months, 78% VPA patients and 76% PHT patients had Unit, Cambridge, England).dOl2. achieved at least 6-month remission. Patients with primary generalized seizures had higher 6-month remission rates (88%) than We conducted a prospective, comparative, monotherapy trial those with partial seizures either secondarily generalized or not of four antiepileptic drugs (AEDs: phenobarbital, phenytoin, car- (64%), but there was no significant difference between treat- bamazepine, and valproate) in 167 children aged 3-16 years with ments by seizure type. newly diagnosed epilepsy. At time of study entry, they had experienced either two or more tonic-clonic seizures or partial seizures that did or did not become secondarily generalized. At the Postmortem Blood Concentrations of Phenytoin in Sudden Unex- time of our initial report, these children had been followed for a pected Death. Torbjorn Tomson, Lena Nilsson, *Ingmar Tibblin, median of 44 months. We noted no difference in efficacy be- tVinod Diwan, and fGunnar Persson (Departments of Neurol- tween the four drugs. ogy, *Forensic Medicine, ?International Health Care Research, We have now analyzed the outcome for this group of patients and $Environmental Medicine, Karolinska Institute, Stockholm with median follow-up of 88 months (range 8-152) with regard to Sweden) ,6010. relative efficacy of the four drugs studied and factors other than drug therapy influencing seizure prognosis. The incidence of sudden unexpected death (SUD) has been estimated to 1 in 400-1 in 1,000 in the epileptic population. Low postmortem blood concentrations of antiepileptic drugs (AEDs) has been a frequent observation in previous studies, suggesting Poster Session (6013-6137) noncompliance as an important contributing factor in SUD. Pre- viously observed blood levels postmortem were compared with established therapeutic ranges in AED plasma concentrations however, and not with individual plasma levels before death. Vigabatrin in Treatment of Children with Pharmacoresistant Epi- In an ongoing study of epilepsy-related death in Stockholm, 7 lepsy: One-Year Follow-up. Michael c. Laub (Neuropediatric De- patients were identified who all had been continuously treated partment, Behandlungszentrum Vogtareuth, Vogtareuth, Ger- with phenytoin (PHT), who had died in SUD, who had under- many)--6013. gone autopsy including determination of PHT blood concentration, and who had been subjected to therapeutic monitoring of Vigabatrin (VGB) has been proven effective as an add-on an- PHT before death. tiepileptic drug (AED) in -50% of patients with resistant partial

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 63 epilepsy in adulthood. In children, experience with VGB is still dementia were discounted, and treatment with ESM was gradu- slight. ally discontinued. In an open trial with VGB as add-on AED in a group of 56 children with drug-resistant epilepsies, we followed patients prospectively for at least 1 year; 19 of 56 patients (34%) had reduc- Open-Label Trial with Vigabatrin in Children with Intractable Ep- tion of seizure frequency >50%. Five patients became seizure- ilepsy. Virginia Wong Chun-Nei (Department of Paediatrics, The free. In most responders, VGB was effective in 1-2 weeks. In 6 University of Hong Kong, Hong Kong)-6016. of the 19 responders (32%), treatment effect decreased 63 months; 41% of all patients had some unwanted side effect, all of Twenty-eight children (17 males, 11 females) aged 2-21 years which were reversible after dose reduction. In 8 of 56 patients with intractable epilepsy received vigabatrin (VGB) on an open- (including 3 nonresponders) VGB resulted in better cognitive label basis as add-on therapy to preexisting antiepileptic drugs functioning, and 25% of our patients with drug-resistant epilepsy (AEDs). Parents and caretakers regularly recorded children’s obtained persistent benefit from VGB as add on AED. seizure frequency and duration before the VGB trial was started. Seizure types were generalized epilepsy (lo), complex partial epilepsy (8), simple partial epilepsy (l), myoclonic epilepsy (7), and mixed type with complex partial seizure and generalized Preliminary Assessment of Vigabatrin (Sabril) in Treatment of Ep- seizure (2). The cause of epilepsy was idiopathic in 10 and symp- ilepsy in Children. Tomasz KmieC, Roman Ignatowicz, Lucja tomatic in 16. Seizure frequencies were monitored by parents at Ignatowicz, Roman Michalowicz, Barbara Karkowska, and Jo- home and by caretakers in nurseries and schools. The number of lanta Chmielik (Department of Child Neurology, Child Health AEDs received by the children was unchanged (two to four). All Centre, Warsaw, Poland)--hO14. children failed to respond to first- and second-line AEDs prescribed for the main seizure types. The current dosage regimen Sabril (vigabatrin), a product of Marion Morel1 Dow in 500-mg of AEDs was maintained during the trial period. VGB 20-80 tablets, is a promising new antiepileptic drug (AED), was spe- mg/kg/day was titrated according to the clinical response for 3-42 cifically designed to enhance y-aminobutyric acid (GABA) func- months. Results of treatment were categorized as responders tion in CNS. By increasing brain concentrations of the inhibitory and nonresponders and were analyzed according to seizure type, neurotransmitter, the drug apparently reduces seizure activity. etiology, associated mental deficiency, neurologic deficit, and We studied 29 children aged 3-15 years with primary general- computed tomography (CT) scan abnormalities. Only 1 child ized tonic-clonic seizures, complex partial seizures, myoclonic- achieved complete remission on day 2 of treatment despite hav- astatic seizures in Lennox-Gastaut syndrome, and myoclonic ing severe myoclonic epilepsy for 10 years. Eleven (39%) chil- seizures. Sabril ‘had been used as adjunct therapy in children dren had 50-75% reduction in seizure frequency. Fourteen (50%) treated previously with phenobarbital, carbamazepine, val- children had 40%reduction in seizure frequency, with minimal proate, and phenytoin for refractory seizure disorders (Sabril change in seizure severity. Three children had increase in seizure dosage 250-1,500 mg/24 h hours in two divided doses; observa- frequency or severity. Side effects were few, with sedative effect tion time was 3-6 months). The significant clinical benefit was noted in 2 children. VGB is useful in drug-resistant epilepsy in 50-100% decrease in seizure frequency in 70% of children. Im- children. The relation between responders and nonresponders provement was more effective against partial seizures and gen- with various seizure types, etiology, associated mental or neu- eralized tonic-clonic epileptic syndromes. Five children with Ko- rologic abnormality, or CT findings was analyzed. jewnikow’s and Lennox-Gastaut syndrome obtained no benefit from therapy. Some patients who became seizure-free after addition of sabril subsequently were able to reduce or eliminate Monotherapy with Vigabatrin in Childhood Partial Epilepsy. G. other AEDs. No adverse events occurred, and tolerance was Gobbi, G. Bertani, A. Pini, *R. Guerrini, tE. Tiberti, tM. Val- good in all children. seriati, tE. Menegatti, SD. Besana, SR. Rosmini, PO. Martinelli, I’P. Veggiotti, IIC. Resi, TD. Galeone, and #G. Capovilla (Reggio Emilia, *Pisa, tBrescia, SAlessandria, SLecco, IIPavia, TBari, and #Mantova, Italy)-6017. Ethosuximide-Induced Subacute Dementia. F. Sanmarti, J. Mon- talvo, and A. Sans (Hospital Saret Joan de Deu, Barcelona, Fifty children (30 males, mean age 8 years) with idiopathic Spain)dOlS. (17), cryptogenic (14), and symptomatic (19) partial epilepsy (IPE, CPE, SPE) were entered into open study with vigabatrin The side effects of ethosuximide (ESM) are very well known. (VGB) as monotherapy. Oral dose was 20-100 mg/kgldaily. Ef- Psychosis has been reported, although rarely and, very occasion- ficacy was not evaluable in 1 patient who withdrew early because ally, deterioration of the cognitive functions. We report a case of of increase in EEG epileptiform abnormalities. In the evaluation dementia closely related to use of ESM. phase (first 3 months), seizures disappeared in 34 (70%), de- A 13-year-old boy experienced partial motor crisis of the upper creased >50% in 8 (16%), and were unchanged in 7 (14%). left extremity which was difficult to control pharmacologically. Thirty patients (23 of 34 in whom seizures ceased and 7 of 8 in Family and personal background showed no antecedents. The whom seizures decreased >50% were included in long-term patient’s educational performance was adequate for his age. phase study (mean follow-up 16.6 months, range 10-33 months). Neurologic examination showed nothing. EEG showed fre- Nine IPE, 5 CPE, and 8 SPE cases continued to show complete quent bilateral paroxysms. Brain magnetic resonance imaging suppression of seizures. One IPE, 2 CPE, and 4 SPE cases con- (MRI) showed a right frontotemporal aracnoid cyst. Owing to tinued to have >50% reduction in seizure frequency. Seizures lack of a favorable response to the crisis and to the size of the recurred in 1 SPE case 6 months after initiation of treatment. cyst, a peritoneal-cyst valve was implanted. MRI then showed a VGB tolerability was excellent, with only 5 children reporting significant decrease in size of the cyst. Nevertheless, the sei- side effects, such as excitation, hyperkinesia, or weight gain. zures persisted daily. Results were compared with those of a homogeneous group of The patient was treated with phenobarbital 100 mg/24 h and patients receiving carbamazepine monotherapy . Statistical anal- ESM 1,500 mg/24 h, which led to complete disappearance of the ysis of data is currently being conducted. crisis. Two months after treatment with ESM, the patient showed lack of motivation, a negative attitude, and memory decrease to a degree that caused him to fall behind at school. Vigabatrin in Childhood Epilepsy: A 5-Year Follow-up Study. Pe- Neuropsychological evaluation showed diffuse and severe deter Uldall, Jergen Alving, Lennart Gram, and Hans Hegenhaven terioration of the higher cognitive functions. Other causes of the (Dianalund Epilepsy Hospital, Dianalund, Denmark)--60 18.

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS

In an open add-on dose-ranging study, 33 children with four or R. Canger (Regional Epilepsy Center, San Paolo Hospital, Uni- more seizures a month treated with conventional antiepileptic versity of Milan, Milan, Italy)-6021. drugs (AEDs) at maximal tolerable blood levels and with reliable seizure registration entered a prospective study 5 years ago. We retrospectively studied 233 patients with drug-resistant Three children were lost to follow-up in the first 6 months. Of the partial epilepsies (228) or cryptogenic/symptomatic generalized remaining 30 children, 27 had partial seizures. At 12-month fol- epilepsy (5) (mean age 36.8 years) treated with y-vinyl-GABA low-up, 12 children (40%) had remained on vigabatrin (VGB) (VGB; combined with other antiepileptic drugs, AEDs) as out- with seizure reduction of at least 50%. Of these, 3 were seizure- patients for the last 6 years. We evaluated a 12-month period (6 free. At latest follow-up, 10 of the 12 children had been contin- months before addition of VGB, 6 months after VGB titration uously treated with VGB for at least 5 years with stable seizure period). Six percent of patients (14) became seizure-free; 24.4% reduction 250% as compared with baseline. One patient was (57) experienced >50% reduction in seizure frequency. Among seizure-free. Attempts to reduce to VGB monotherapy were these, 29 (12.4%) experienced >75% reduction in seizure fre- rather unsuccessful. No signs of cognitive deterioration were quency. Seizure-free patients were subsequently followed for a noted. Evoked potentials (VEP, BAEP) were performed with period of 4 months to 4 years (mean 1.1 years); 5 relapsed after and without VGB and results were evaluated blindly. No signif- 6 months to 1 year. These data confirm the probable tolerance icant differences in latencies were observed. that develops to the effects of VGB previously reported. Thirty- seven percent of patients (87) experienced side effects. Four (1.7%) discontinued VGB treatment owing to side effects (in all, Monotherapy and Polytherapy in 98 Epileptic Patients Treated side effects were harmless and disappeared after discontinuation with Vigabatrin: Different Response to Treatment. Two-Year Fol- of VGB), and 3 (1.3%) discontinued owing to increase in seizure low-up. Maria Rossana Tata, Angelo Ammendola, Roberto Can- frequency. VGB is a valuable AED in a limited but significant tore, and Salvatore Iannaccone (UniversitB Napoli, Naples, It- number of patients with drug-resistant partial epilepsy. VGB aly)--60 19. should always be tried in association with first-choice AEDs before a patient is classified as drug resistant. We report follow-up of 98 epileptic patients with different forms of epilepsy treated with vigabatrin (VGB) for 2 years (85 received polytherapy and I3 received monotherapy). The two groups responded differently to treatment. Patients treated with Efficacy and Safety of Vigabatrin in Drug-Resistant Epilepsy: A polytherapy showed significant improvement 5-6 months after Follow-up Study. Georgina Sousa, Dina Pinto, Jose August0 first introduction of VGB (in 1 after 9 months). A more preco- Ribeiro, Isabel Pires, F. Silveira, and Maria Luisa Guimarges. cious and long-lasting improvement (in the first month of ther- (Neurophysiology Department, Hospital S. Jogo, Porto, Portu- apy), when it occurred, was noted in patients receiving mono- gal)-6022. therapy. Five patients with complex partial epilepsy (CPE) treated with We participated in a 6-month multicenter study of the efficacy polytherapy experienced tonic-clonic seizures. Patients with and safety of vigabatrin (VGB) (Sabril, Marion Merrell, Dow), CPE treated with monotherapy with 2-year follow-up did not. with follow-up (18 months) of 15 of the original 18 patients with We consider that VGB may be more effective in monotherapy partial seizures refractory to conventional drugs. than in polytherapy. Each patient underwent full examination to determine seizure frequency, general and neurologic examinations, EEG, routine chemistry analysis, examination for adverse events, ophthalmo- Vigabatrin Versus Carbamazepine in Newly Diagnosed Epileptic logic, visual, and (VEP, SEP), and psychometric and psycholog- Patients: A Randomized Response Conditional Cross-Over Study. ical studies, and somatosensory evoked potentials. Paolo Tanganelli and Giovanni Regesta (Department of Neurol- With VGB, 11 patients (73.3%) had 250% reduction in mean ogy, Epilepsy Center, San Martino Hospital, Genoa, Italy)- seizure frequency; thus, maintenance of efficacy was demon- 6020. strated. Clinical and biological tolerability was excellent. Psychological, psychometric, ophthalmologic, and VEP and Clinical efficacy and safety of vigabatrin (VGB) as add-on SEP evaluation showed no abnormal effects of long-term ther- therapy in pharmaco-resistant focal epilepsies is well estab- apy. lished, but objective evaluation may be determined only through use of PVG in monotherapy in newly diagnosed subjects. We compared VGB in a randomized response, conditional cross- over study with carbamazepine (CBZ), the more frequently pre- Retrospective Study of Vigabatrin Therapy in 141 Epilepsy Pa- scribed drug in focal epilepsies. tients. G. Paglia, *R. Guerrini, *A. R. Ferrari, *P. Salvadori, *A. Thirty-nine patients with complex partial seizures (CPS) were Battaglia, P. Genton, E. Mesdjian, and C. Dravet (Centre Saint- randomly assigned to the VGB or CBZ group and evaluated after Paul, Marseille, France; and *Institute of Child Neurology and an initial 4-month period. Patients were then crossed over to the Psychiatry, Pisa, Italy)-6023. alternative drug for an analogous period, except for those with persisting seizures or intolerable side effects. In noncontrolled Among resistant epilepsy cases followed in Marseille and Pisa, cases, the two drugs were subsequently associated. No signifi- 141 patients received vigabatrin (VGB) for at least 3 months. We cant difference in efficacy was between VGB and CBZ during analyzed age at onset of treatment, epilepsy duration, type and subsequent follow-up (mean 45.8 + 6.6 and 48. I + 6.9 weeks, etiology, seizure type, associated antiepileptic drugs (AEDs), respectively); side effects were slightly more frequent and severe efficacy on seizures, side effects, and EEG changes. Patients with CBZ. Combined treatment with the two drugs reduced or were aged 1-15 (65), 16-20 (24), and 21-48 years (54); 78 had suppressed seizures in some resistant cases. Results suggest that symptomatic focal epilepsy, 21 had cryptogenic focal epilepsy, VGB may be considered a first-choice drug in focal epilepsies 18 had epilepsy undetermined as to whether it was focal or gen- with CPS and a valid alternative when other monotherapies are eralized (including 12 with severe myoclonic epilepsy), and 24 ineffective or poorly tolerated. had symptomatic generalized epilepsy (including 9 with Lennox- Gastaut syndrome). VGB was added to a single AED in 38, to two AEDs in 59, and to more than two AEDs in 45. Follow-up Vigabatrin in Drug-Resistant Epilepsies: A Retrospective Study of ranged from 3 months to 5 years. Ten patients had complete Efficacy and Tolerability in 233 Patients. M. P. Canevini, M. Fedi, seizure control, 34 had reduction >75% (lasting in 21), and 23 V. Sgro, L. Minotti, A. Saltarelli, A. Vignoli, L. Guidolin, and had reduction of 50-75% (lasting in 13); 21 showed behavioral

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 65

improvement with increased vigilance and social adjustment. GABA, the main inhibitory neurotransmitter in brain, is syn- Undesirable side effects consisted of weight gain >3 kg in I year thesized from glutamate by the action of the enzyme glutamic (42), hyperexcitability (7), apathy (2), drowsiness (9,and insom- acid decarboxylase. GABA is then released into the synaptic nia (4). Two patients had to discontinue VGB because of serious cleft, where it acts on the GABA receptor on postsynaptic neu- psychic adverse events. About half of our patients with particu- rons and the presynaptic nerve terminal. larly severe epilepsies clearly benefited from addition of VGB; 6 Vigabatrin (VGB, Sabril) is a suicide inhibitor of GABA- were tapered to VGB monotherapy. transaminase. Because Sabril is structurally very similar to GABA, it fits into the active site of the enzyme in the same way. When the enzyme tries to inactivate it, the Sabril-enzyme com- Vigabatrin in Unsatisfactorily Controlled Epilepsy. Swiss Vigaba- plex is irreversibly destroyed. The resulting loss of GABA- trin Study Group, Wolfgang Russ, and *P. A. Despland (Marion transaminase activity allows GABA levels to increase and so Merrell Dow, Thalwil; and *Service de Neurologie, CHUV, prevent seizures. Lausanne, Switzerland)d024. Our study included 16 patients with focal motor crises Bravis Jackson. Six patients with recent onset of crises, without other Before marketing authorization was in Switzerland, vigabatrin treatment, received VGB 3 g, 10 patients during concomitant (VGB) was provided for individual patients for whom effective treatment with carbamazepine and valproate also received VGB alternative treatment was not available. Data were prospectively 3 g (the drugs were administered double-blind and randomized). recorded with a standardized case record form: 127 patients (52 Sabril is a promising drug for treatment of focal motor seizures females, 75 males) were treated with VGB for a total exposure of and is more effective in patients treated from onset with this 1,124 patient-months and mean follow-up of 10 months (range medication. Patients with concomitant medication experienced 0.149). Mean duration of epilepsy before treatment with GVG adverse events such as ataxia, sleep disorders, and nausea; most was 17 years and, on the average, each patient treated with two of these occurred early in treatment. other antiepileptic drugs (AEDs). Mean daily dose of VGB was 2.3 g. Safety was analyzed for all; patients with <3-month treatment were excluded from efficacy evaluation. Eighteen of 24 patients with primarily generalized seizures were available for efficacy Interactions Between Vigabatrin and Standard Antiepileptic analysis [seizure free (I), >50% reduction (2), 2549% reduction Drugs. Souad Sennoune, Joelle Bonneton, Pierre Genton, Char- (3), no significant change (9), worse (3)]. Ninety-three of 103 with lotte Dravet, Joseph Roger, and Edouard Mesdjian (Inserm, focal seizures were available for efficacy analysis: 41 (44%) were Centre Saint-Paul, Marseille, France)d027. responders with a >50% reduction (8 seizure free), 13 had reduction of 2549%, 30 were unchanged, and 9 were worse. Ap- Vigabatrin (VGB), a specific irreversible inhibitor of GABA athy, drowsiness, fatigue, and somnolence accounted for 17 of 58 transaminase, is now widely used in treatment of refractory focal adverse events observed in 36 (28%) patients; adverse events epilepsy. It is neither bound to plasma proteins nor metabolized were primarily CNS related and reversible. Two patients were by liver, and interactions with concomitantly prescribed antiep- withdrawn because of somnolence and 8 were with withdrawn ileptic drugs (AEDs) concomitantly thus are unlikely. However, because of behavioral disturbances. Reducing concomitant slight decreases in phenytoin, phenobarbital, and primidone pre- AEDs was difficult in this population with severe epilepsy. scribed concomitantly have been reported. We studied the changes in plasma levels (PL) in 40 patients treated with a stable Efficacy of Vigabatrin as Add-on Therapy in Relation to Type of regimen of standard AEDs after introduction of VGB using the Epilepsy or Epileptic Syndrome: Retrospective Study of 120 Pa- nonparametric Wilcoxon test. Before addition of VGB, 9 patients. Renzo Guerrini, *Gabriella Paglia, ?Charlotte Dravet, tients were receiving monotherapy and 12, 14, and 5 were re- Anna Rita Ferrari, Agatino Battaglia, *Pierre Genton, Paola Sal- ceiving 2, 3, and 4 AEDs, respectively. Our results show that vadori, and Paolo Bonanni (INPE-IRCCS Stella Maris, Pisa, It- VGB does not change PL of carbamazepine and its epoxide (n = aly; *Centre St. Paul, Marseille, France; and tClinica Neurolog- 33), clonazepam (n = 4), or primidone (n = 3); significantly ica, University of Torino, Turin, Italy)d025. decreases phenobarbital PL (- 15%) (n = 23); nonsignificantly decreases phenytoin PL (- 15%) (n = 8); nonsignificantly de- We studied the efficacy of vigabatrin (VGB) as add-on therapy creases valproate PL (- 12%) (n = 10); and significantly in- in 120 patients with classifiable drug-resistant epilepsies treated creases clobazam PL (+37%) without causing changes of its for 3 months to 5 years (mean 1 year 6 months) with 15-100 major metabolite (norclobazam) (n = 12). Further studies of mg/kg/day (mean 50 mg/kg/day). Effectiveness was determined absorption, tissue distribution, and excretion of associated by evaluating percentage of seizure reduction. Patients with sta- AEDs may provide an explanation for these unexpected interac- ble reduction >30% were considered responders. tions. Of 10 patients with Lennox-Gastaut syndrome (mean age 12 years), 4 (40%) responded, with an average seizure reduction of 80% (maximum 100%). Of 12 patients with severe myoclonic epilepsy (mean age 1I years), 8 (66%) responded, with an aver- Daytime Sleepiness in Epileptic Patients Treated with Carba- age seimre reduction of 57% (maximum 75%). Of 78 patients mazepine Monotherapy and Receiving Vigabatrin Add-on Treat- with symptomatic partial epilepsy (mean age 20 years), 39 (50%) ment. Roberto Massetani, Renato Galli, Enrica Bonanni, Carlo responded. In 3, VGB was discontinued because of weight gain; Gneri, Maurizio Petri, *Silvano Milani, Alfonso Iudice, and in the remaining 36 (46%), average seizure reduction was 56% Luigi Murri (Department of Clinical Neurophysiology, Institute (maximum 100%). Of 21 patients with cryptogenic partial epi- of Neurology, and *Medical Statistics and Biometry, University lepsy (mean age 23 years), 16 (76%) responded. In 3, VGB was of Pisa, Pisa, Italy)-6028. discontinued because of weight gain; in the remaining 13 (62%), average seizure reduction was 56% (maximum 100%). Although the highest percentage of responders was observed among epi- The clinical relevance of daytime sleepiness associated with lepsies without demonstrable brain lesions, total seizure control chronic dosing of carbamazepine (CBZ) monotherapy and add- was attained only in some patients with symptomatic forms. on vigabatrin (VGB) for better seizure control was assessed objectively by the Multiple Sleep Latency Test (MSLT). Fourteen patients with partial epilepsy aged 2044 years (average 35) y-Vinyl Gaba (Vigabatrin) in Treatment of Motor Crises Bravis- treated with CBZ monotherapy (600-1600 mg/day for 2-6 Jackson. Buraga Ioan and Cheroiu Antoniu Ioana (Bucharest, months) took part in the study. Their seizure frequency was RomaniaL-6026. unsatisfactorily controlled by CBZ despite highest tolerated in-

Epilepsia, Vol. 35, Suppl. 7, 1994 66 EUROPEAN CONGRESS PROCEEDINGS dividual doses; therefore add-on treatment with VGB 2-3 g/day sured by Beck Depression Inventory; the Irritability, Depression was initiated. Daytime sleepiness was reported by 7 patients and Anxiety Scale; and the Mood Adjective Check List. We both during initial CBZ therapy and subsequent VGB add-on assessed the cognitive profile of VGB in relation to those of other treatment. Two patients experienced drowsiness only when anticonvulsant compounds. VGB was combined with preexisting CBZ treatment. MSLT and visual reaction times were assessed twice, i.e., during CBZ treatment and 1 month after GVG treatment. In addition, drowsiness was self-rated by each patient by the Stanford Sleepiness Scale Vigabatrin, Psychosis, Depression: A Retrospective Survey. Laura (SSS). Thomas, Michael Trimble, and Howard Ring (The National Hos- CBZ therapy was associated with statistically significant pital, Queen Square, London, England)-6031. shorter daytime sleep latencies and longer reaction times, as compared with those of control healthy subjects, which re- Vigabatrin (VGB) is an antiepileptic drug (AED) with a rela- mained unchanged during VGB add-on treatment. Sleep latency tively favorable side effect profile. In clinical trials, however, showed no significant correlations with CBZ plasma levels, ther- behavior disorders have been reported, including agitation, de- apy duration, disease duration, seizure frequency, or sleep pat- pression, and psychoses. tern on the night preceding the tests, but was inversely related to We studied 136 cases of behavioral problems that had been SSS drowsiness score. The results appear to confirm that CBZ reported to us or to Marion-Merrell-Dow, Satisfactory clinical chronic administration is prone to cause daytime sleepiness, information could be obtained for only 81 patients. Of these, only which can be objectively measured by MSLT. Add-on therapy 50 cases met the criteria for either a psychosis (n = 28) or de- with VGB does not further exacerbate daytime sleepiness. pression (n = 22). These 50 were compared with a group of Queen Square patients with epilepsy and psychosis who had never been prescribed VGB (n = 21) and another group who received VGB without experiencing any behavioral problems. Effects of Vigabatrin on Cognitive Functions. A. Piazzini, A. Vi- Psychosis as a treatment-emergent effect of VGB appeared gnoli, V. Sgro, M. P. Canevini, and R. Canger (Centro Regionale with associated prescriptions of barbiturate-related AEDs, right- per I’Epilessia, Ospedale S. Paolo, Milan, Italy)-6029. sided EEG focus, and suppression of seizures (64% became seizure-free). Depression as a treatment emergent-effect of VGB We investigated the possible influence of vigabatrin (VGB), as was associated with a past history of depressive illness, fewer add-on therapy, on cognitive performance of patients with tonic-clonic seizures, and fewer bilateral EEG abnormalities. chronic refractory epilepsies. Twelve patients aged 20-45 years There was little or no change in seizure frequency in this group. with drug-resistant partial epilepsies, normal IQ, and with no Clinical usage of VGB was assessed in relation to profiles of history of psychiatric disorder were administered a battery of patients vulnerable for psychopathology. neuropsychological tests measuring central cognitive processing (Raven Test), attention (Test of Attentional Matrix), visual memory (Rey Test), long-term memory (List of Words Test), motor speed (Tapping Board), perceptuomotor performances (Pordue Psychosis Associated with Vigabatrin. L. Guidolin, L. Minotti, *J. Pegboard Test), along with standardized mood assessments Galletta, ‘P. Mita, M. Bracco, M. P. Canevini, V. Sgrb, A. (Hamilton Depression and Anxiety Questionnaires). At the same Saltarelli, and R. Canger (Regional Epilepsy Centre, S. Paolo time, all patients underwent EEG recording to verify possible Hospital, University of Milan, Italy; and *Psychiatry Service, EEG modifications before, during, and after the test application. Magenta Hospital, Magenta, Italy)4032. After 6 weeks, when patients received VGB as add-on therapy (50 mg/kg), the entire evaluation was repeated. Use of y-vinyl GABA (VGB) in treatment of drug-resistant Final data confirm improvement (though not statistically sig- epilepsy has been associated with development of psychotic nificant) in cognitive, function, especially in mental general ca- states in patients with previous family or personal history of pacity (Student’s f = 2.13, with two-tailed p = 0.06), in memory psychosis. We report a case of psychosis in a 23-year-old girl (Student’s f = 1.50, with two-tailed p = 0.168), as well as re- with epilepsy with no previous history of psychiatric disorders duction in anxiety level (Student’s f = 0.57, with two tailed = who became seizure-free and developed schizophreniclike psy- 0.058). chosis while receiving VGB treatment as monotherapy. VGB dose at onset of psychosis was 40 mglkglday, and psychosis occurred 5 days after the end of the titration period. Hos- pitalization was required, and VGB was immediately discontin- Effects of Vigabatrin on Cognitive Function and Mood in Healthy ued. Volunteers. Laura Thomas and Michael Trimble (The National Psychotic symptoms lasted 10 days; high doses of neuroleptic Hospital, Queen Square, London, England)-6030. drugs were administered to obtain normalization of mental status. With introduction of carbamazepine, the patient became sei- Vigabatrin (VGB) has been tested in several clinical studies zure-free without subsequent recurrence of psychosis. Psychotic and to date appears to have no demonstrable effects on cognitive reaction cannot be linked to a sudden cessation of seizures as in function, despite its powerful anticonvulsant effect. A difficulty “forced normalization.” in interpretation is the number of variables that may influence cognition, such as polytherapy and seizure frequency, which these studies have not been able to control for. We examined healthy volunteers for the effect of VGB on cognitive function Biochemical and Hematologic Profile in Patients Treated With Vi- and mood to assess the effect of the drug in the absence of such gabatrin Long Term. Leonard0 Cocito, Claudio Albano, Maura contaminating factors. Maffini, and Vitantonio Rubino (Clinica Neurologica dell’Uni- Ten adult volunteers were recruited and included in the study versitk di Genova, Genova, Italy)4033. if they were free of psychiatric or neurologic disease and not taking any CNS drug. In this double-blind, placebo-controlled, Fifteen patients with severe epilepsy receiving long-term viga- cross-over design, subjects were tested on four occasions, i.e., batrin (VGB) as part of their antiepileptic drug (AED) regimen before and after the first and second treatment phases. There were screened for a complete biochemical and hematologic pro- was a minimum washout period of 1 week between treatments. file. Duration of VGB treatment was 4-8 years and daily dose VGB dosage was 2 g at testing. was 1.54 g. In all patients, VGB had been added to preexisting Subjects were given a battery of motor-free cognitive tasks, treatment that included carbamazepine in most cases; a few pa- including Critical Fusion Flicker, Paced Auditory Serial Addi- tients were receiving phenobarbital or valproate. Clinical chem- tion Task, the Stroop, and the Sternberg tests. Mood was mea- istry included serum glucose, creatinine, uric acid, bilirubin, al- EUROPEAN CONGRESS PROCEEDINGS 67 kaline phosphatase, AST, ALT, .I-GT, CK, lactate dehydroge- with renal insufficiency and hemodialysis. We recommend ad- nase, cholinesterase, sodium, potassium, chloride, calcium, ministration of 100-200 mg (1.5-3.0 mg/kg) GBP as a mainte- phosphate, protein electrophoresis, cholesterol, triglycerides, nance dose after each dialysis treatment. VGB should be re- B,-, and folate levels, coagulation tests, and urinalysis. Hemato- duced to a daily dose of 750 mg (10 mg/kg). GBP and VGB can logic examination included white and red blood cell counts, he- be easily eliminated through dialysis. moglobin level, mean corpuscular volume, and platelet count. Values were recorded at yearly visits and compared with pretreatment baseline. Minor deviations from normal range were occasionally observed for liver enzymes, serum lipids, and he- Actions of Anticonvulsant Drugs on GABA-Dependent CI- Chan- matologic parameters both before and during VGB treatment. nels in Primary Neuronal Cultures. Anna PomCs, *Eduardo Ro- These findings are likely to represent an aspecific feature of pa- driguez-FarrC, and Cristina Sudol (Departments of Neurochem- tients receiving antiepileptic drugs for many years, whereas no istry and *Pharmacology and Toxicology, CID, CSIC, Barce- major or systematic changes occurred during VGB long-term lona, Spain)-6036. treatment. VGB treatment is not associated with any significant derangement of biochemical or hematologic parameters even Primary neuronal cultures from cerebellum or neocortex are in during very protracted treatment periods. vitro neuronal systems that express the GABA, receptor, a ligand-gated CI- channel receptor that has separate but alloste- rically interacting binding sites for GABA, benzodiazepines (BZD), and the convulsant drug picrotoxin (PTX). Effect of Initial Vigabatrin Treatment to Prognosis of Epilepsy. We studied the effect of BZDs, phenobarbital, (PB), and the Reetta Kalviainen, Marja Aikia, Esa Mervaala, Anna Maija new antiepileptic drug gabapentin (GBP) on GABA-dependent Saukkonen, and Paavo J. Riekkinen, Sr. (Department of Neu- CI- channels in primary neuronal cultures. [3SS]TBPSwas used rology, University of Kuopio, Kuopio, Finland)-6034. as a radioligand to label the PTX recognition site at the chloride channel of the GABA, receptor and 36Cl- uptake was deter- Early predictors of epilepsy and influence of treatment on mined to assess GABA-induced CI- flux. BZDs diazepam (1 prognosis are largely unknown. We wished to determine new p1M) and flunitrazepam (1 pM) and the barbiturate PB (1 mM) interictal predictors of prognosis of epilepsy and to compare ini- significantly increased GABA-induced CI- flux; GBP (1 pM-1 tial vigabatrin (VGB) monotherapy with standard initial carba- mM) had no effect. Moreover, exposure of cultures to GBP (10-1 mazepine (CBZ) monotherapy in 100 newly diagnosed adult mM) for 3 days did not modify GABA-induced "CI- uptake. patients. PTX blocked GABA-induced 36Cc1- uptake completely. PB re- Patient retention rate and side effects were evaluated. Cogni- verted this blockade, whereas BZDs only partially reversed it tive assessments and electrophysiology were used as prognostic and GBP had no effect. Flunitrazepam increased binding of and safety measures at baseline and after 1, 2, and 5 years of ["SITBPS to primary cultures of neocortical neurons; gabapen- treatment. In addition to classic predictive factors, longer visual tin had no effect, These results indicate that BZD and barbitu- evoked potential (VEP) P2 peak latencies, abnormalities in EEG rates facilitate GABA neurotransmission. They also indicate that background activity, and attentional difficulties proved signifi- the antiepileptic properties of GBP are not mediated by enhance- cant predictors of outcome. During mean follow-up of 3.5 years, ment of GABA-induced CI- flux. (Supported by Projects No. 52% of patients in both drug groups were treated successfully. 93/0899E (FIS) and SAL91-0707 (CICYT), and by Parke-Davis CBZ was discontinuated mainly due to side effects, VGB only Laboratories.) due to lack of efficacy. In successfully treated VGB patients, memory retrieval and flexibility of mental processing improved significantly as compared with that of CBZ patients. VEP P2 peak latencies normalized only during VGB treatment. Neurontin Monotherapy in a Patient with Refractory Complex Par- New predictive factors of epilepsy can be detected by exam- tial Seizures. Ronald Benjamin, Elizabeth Garofalo, Deborah ining interictal cerebral functioning. Initial VGB monotherapy Leiderman, and Beth Baron (Parke-Davis Pharmaceutical Re- ~6 years and may im- remains effective and safe for periods of search, Warner-Lambert, Ann Arbor, MI U.S.A.)-6037. prove prognosis of epilepsy as measured by cognitive performance. We report a 13-year-old boy with refractory complex partial seizures (CPS) who attained gabapentin (GBP Neurontin) monotherapy (MT) in an open-label safety study. At study entry, the Gabapentin and Vigabatrin in Renal Insufficiency Requiring He- patient was receiving carbamazepine (CBZ) 1,500 mg/day and modialysis. Annette Fiaux, Walter Froscher, *Thomas Feuer- continued this treatment during the 8-week baseline. Neurontin stein, and tWolfgang Brech (Department of Neurology, Psychi- (GBP) was then added; dosage was adjusted to 2,100 mg/day on atrische Krankenhaus Weissenau, Abteilung Psychiatrie, I, Uni- day 56 and remained stable thereafter. At day 160, CBZ was versity, *Parke Davis Freiburg: Freiburg; and TDialyse Institut discontinued and the patient remained on Neurontin monother- Friedrichshafen, Friedrichshafen, Germany)--6035. apy for 394 days, after which he refused to come back and was lost to follow-up. We conducted a therapeutic trial using the new antiepileptic CPS frequency was highest during baseline (4 seizures in 28 drugs (AEDs) gabapentin (GBP) and vigabatrin (VGB) to treat a days) as compared with 3.3 seizures in 28 days during Neurontin 26-year-old male patient with chronic renal failure requiring he- monotherapy and 2.27 seizures in 28 days during combination modialysis and pharmacoresistant complex partial seizures. Be- therapy (CBZ + GBP). Seizure frequency during combination cause the major elimination pathway for both drugs is renal ex- therapy (CBZ + GBP) was slightly lower than that during Neu- cretion, we considered it important to determine their pharma- rontin monotherapy, but four adverse events (sleepiness, diplo- cokinetics. pia, nystagmus, and lethargy) were experienced during combi- After a single oral dose, absorption and maximum concentra- nation therapy and resolved on Neurontin monotherapy . Neu- tion of GBP (400 mg) and VGB (1,500 mg) were the equivalent of rontin monotherapy diminished CPS and was well tolerated for those of healthy subjects. Elimination of GBP was extremely >I year in this patient with refractory partial epilepsy. delayed [half-life (t%) = 381 h; healthy subjects t% = 5-7 h]. Owing to dialysis, plasma level decreased on the average by 7040%. Elimination of VGB was considerably delayed (tlh = 18 h; healthy subjects t% = 5.3-7.4 h). Owing, to dialysis, plasma Gabapentin (Neurontin) Polytherapy for Patients With Refractory level decreased on the average by 40%. To avoid cerebral side Mixed Generalized Seizure Disorders: Two Case Studies. Roy G. effects, dosage of GBP and VGB must be adjusted for patients Beran (Chatswood, Australia)4038. 68 EUROPEAN CONGRESS PROCEEDINGS

Seizure frequency (number/28 days) improved dramatically in completion of the titration period, patients continue in a 24-week 2 patients in a long-term, open-label, add-on study of gabapentin evaluation period. Responders successfully complete this evalu- (GBP). Patient A, a 30-year-old woman with a 23-year history of ation period with less than three partial seizure and no general- refractory absence and atypical absence seizures and well- ized seizures. Patients withdrawn from the study may enter an controlled primary generalized tonic-clonic seizures (GTC) com- open-label monotherapy extension study with free-dose adjust- pleted 1,436 days. Concurrent antiepileptic drugs (AEDs) were ment (GBP to 2,400 mg/day or CBZ at the discretion of the carbamazepine (600 mg/day) and valproate (I ,500-2,500 mg/ investigator). To date, 55 patients have entered; 46 were ran- day). GBP was adjusted from 600 to 1,200 mg/day by day 69; domized to GBP (dose-blinded) and 9 to CBZ. Ten patients have absence seizures decreased from 289 (baseline) to 110 (day 84). received 18 weeks of treatment, (9 GBP and 1 CBZ). Ten pa- GBP was increased to 1,800 mg/day (days 566-707); 20-40 ab- tients receiving GBP were withdrawn, 9 for lack of efficacy and sence seizures occurred during this period. The patient became 1 for adverse events. One patient receiving CBZ was withdrawn seizure-free (day 971) and remains so. Patient 9, a 20-year-old because of adverse events. Eight patients have entered the long- man with a 14-year history of refractory atypical absence and term extension study (7 receiving GBP). myoclonic seizures and GTC, completed 1,434 days. Concurrent AEDs were clobazam (reducing dosage), valproate (3,00&7,000 mg/day), and primidone (750-1,500 mg/day). GBP stabilized at 1,200 mg/day (day 337); GTC decreased from 14 (baseline) to 9; atypical absence seizures decreased from 136 to less than 1, and Double-Blind, Multicenter Study of Gabapentin (Neurontin) Mono- myoclonic seizures decreased from 795 to 297. GBP was in- therapy in Hospitalized, Refractory Patients with Epilepsy. Debo- creased from 1,200 to 1,600 mg/day (days 561645); 10-20 GTC rah B. Leiderman and Jerry G. Crockatt (Parke-Davis Pharma- and 30&350 myoclonic seizures occurred. No absence seizures ceutical Research, Warner-Lambert, Ann Arbor, MI, U.S.A.)- occurred during this period. GBP was well tolerated and effec- 6041. tive in both patients and may have a significant therapeutic role in some patients with difficult-to-treat generalized epilepsies. Gabapentin (GBP) high-dose monotherapy is being evaluated in a multicenter, double-blind, parallel-group trial in hospitalized medically refractory patients with complex partial seizures (CPS) or secondarily generalized tonic-clonic seizures (GTC). Gabapentin (Neurontin) Add-on Therapy in Patients with Refrac- Gabapentin (GBP, Neurontin, FDA approval December 1993) tory Partial Seizures: A 12-Week Open-Label Extension Study. provides effective and safe antiepileptic add-on therapy with low Deborah Leiderman, Elizabeth Garofalo, and Mark Pierce toxicity and lack of interactions. Patients whose standard anti- (Warner-Lambert/Parke-Davis, Ann Arbor, MI, U .S.A.)-6039. epileptic drugs (AEDs) are discontinued during hospitalization for clinical seizure monitoring enter an &day, dose-controlled In a 12-week open-label (OL) extension of a 12-week, double- study receiving blinded GBP 300 or 3,600 mg/day, with titration blind (DB), placebo-controlled study of gabapentin (GBP) in pa- for 24 h. Patients terminate from the study after completing 8 tients with refractory partial seizures, 295 patients received add- study days or meeting one or more exit criteria: total of four CPS on GBP (600-2,400 mglday). The placebo/GBP treatment group or GTC, one GTC if no history of GTC, status epilepticus, pro- comprised 96 (98%) of the 98 patients who had received placebo longation and/or clinically significant intensification of seizures, in DB; the GBP/GBP treatment group comprised 199 (96%) of or continued intolerance after one dose reduction. The primary the 208 patients who had received GBP in DB. Efficacy in OL efficacy parameter is time to exit. Patients meeting exit criteria was assessed based on change in frequency of partial seizures may continue GBP in an open-label follow-on monotherapy trial from the 12-week baseline period preceding DB. Efficacy param- at doses of <4,800 mglday. eters were responder rate (frequency of patients experiencing 250% reduction in partial seizure frequency) and response ratio @Ratio), defined as (T - B)/(T + B), where B and T are partial seizure frequency during baseline and treatment, respectively. Safety and Effectiveness of Gabapentin Monotherapy in Patients RRatio ranges from 1 to - 1, with negative numbers indicating improvement from baseline. For patients in the GBP/GBP treat- with Medically Refractory Partial Seizures: An Ongoing Open- ment group, efficacy was maintained from DB through OL Label Multicenter Study. Aileen Hayes, Deborah Leiderman, Elizabeth Garofalo, M. Pierce, Christine Greeley, Mary Kay (DB,OL): mean RRatio = (-0.139, -0.136); responder rate = (l9%, 20%), seizure control improved for patients in the placebo/ Hes, Mark Mann, and Pamela Spring (Parke-Davis Pharmaceu- tical Research, Warner-Lambert, Ann Arbor, MI, U3.A.)- GBP treatment group from DB to OL: mean RRatio = (-0.024, 6042. -0.191); responder rate = (8%, 26%). Adverse events were generally mild to moderate and were similar to those noted in DB. The efficacy and tolerability of GBP were maintained for 24 The safety and effectiveness of gabapentin (GBP) monother- weeks of therapy in DB and OL. apy is being evaluated in an on-going, open-label, multicenter trial. Patients with medically refractory complex partial seizures (CPS) or secondarily generalized seizures who were receiving one or two marketed antiepileptic drugs (AEDs) entered a dou- Gabapentin (Neurontin) Monotherapy: A Fixed-Dose Comparison ble-blind, lead-in study. GBP (600, 1,200, or 2,400 mg/day) was in Newly Diagnosed Patients with Partial Epilepsy. Henning An- added, and concurrent AEDs were tapered to achieve GBP hut, *Martha Greiner, Volker Mockel, Guta Murray, and the monotherapy. Patients who successfully completed the double- International Gabapentin Monotherapy Study Group (945-77) blind monotherapy protocol or who prematurely terminated the (Parke-Davis, European Clinical Development, Freiburg, Ger- study were eligible to enter the open-label GBP study with the many; and *Parke-Davis, Clinical Research, Ann Arbor, MI, objective of maintaining or achieving GBP monotherapy at dos- U .S .A .)-6040. ages of <3,600 mg/day. To date, 74 patients have entered the open-label study, 21 of whom were receiving GBP monotherapy; A multicenter fixed-dose study was initiated to evaluate the 45 were receiving one concurrent AED, and 8 were receiving two safety and efficacy of gabapentin (GBP) as monotherapy. In a concurrent AEDs. Fifty-nine patients are continuing open-label parallel-group study, three doses of GBP (300, 900, and 1,800 treatment, 23 receiving GBP monotherapy and 36 converting to mg/day double-blinded) are compared with open-label carba- GBP monotherapy. Fifteen patients have withdrawn, 4 because mazepine (CBZ 600 mg/day). Eligible patients have a minimum of nonserious adverse events, 8 because of lack of efficacy, and of two partial seizures during a 6-month historical baseline pe- 3 for noncompliance. GBP is safe and well tolerated at dosages of riod and are either previously untreated or treatment is at- <3,600 mgiday. Patients can achieve and maintain GBP mono- tempted for no longer than 2 weeks. After randomization and therapy.

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 69

Response Ratio for Analysis of the Efficacy of Anticonvulsants: - 0.172, respectively. Females showed greater improvement, Examples From the Gabapentin (Neurontin) Program. Mandyam with RRatios of -0.031, -0.192, -0.158, -0.184, and -0.341, Srirama, Elizabeth Garofalo, and *Willi Sauermann (Parke- respectively. As for daily dose, linear regression of dose on RRa- Davis Pharmaceutical Research, Warner Lambert, Ann Arbor, tio gave a negative slope (p = 0.0001, r2 = 0.047), indicating MI, U.S.A.; and *DATAMAP GmbH, Freiburg, Germany)- greater efficacy with higher dosages. 6043. GBP as add-on therapy improves RRatio in both males and females. Females showed a greater improvement than males at We compared two statistical methods, the response ratio all doses studied. Efficacy of GBP was dose-related over the (RRatio) and percentage of change in seizures (PCH) to analysis range of 600-1800-mg/day. the efficacy of anticonvulsants. In epilepsy trials, seizure counts vary widely during baseline and treatment phases. Clearly, seizure frequency can only decrease by 100% (bounded), yet it can increase by infinity (unbounded). Thus, a few patients with Effects of Lamotrigine on Behavior in Children. Maria Fowler, marked increases in seizure frequency can skew the interpreta- Frank Besag, and Felicity Pool (St. Piers Lingfield, Lingfield, tion of the data. England)-6046. RRatio is defined by the formula RRatio = (T - B)/(T + B) and PCH = lOO(T - B)/B. We compared data from a trial of Forty-seven children and adolescents with epilepsy at St. Piers gabapentin in primary generalized tonic-clonic seizures. RRatio Lingfield were studied for possible behavior changes after treat- and PCH were compared by probability plots to determine if data ment with lamotrigine (LTG). The behavior of each subject was were normally distributed. rated on Rutter Behavior Scale A for parents, completed by their The RRatio was more normally distributed (linear probability healthcare workers and on Rutter Behavior Scale B for teachers, plot) than PCH (data displayed). Unlike PCH, RRatio allows completed by their teacher, before introduction of LTG and analysis of patients with no seizures during baseline phase. The again after an average treatment time of 19.6 weeks (range 8-36 RRatio offers distinct advantages over PCH in analysis of seizure weeks). Results indicated a slight but significant (p < 0.05) im- data, most important of which is transformation of the data to a provement in behavior reported by healthcare workers. The more normal distribution, allowing use of parametric statistics. teachers’ scales, however, showed a very slight deterioration in behavior, not statistically significant. The differences may be explained in terms of the patients’ increased awareness in different contexts. Caregivers and teachers may have different ex- Effect of Gabapentin (Neurontin) on Seizure Days and Seizure-Free pectations: Some types of liveliness in children may be viewed as Intervals. Amy Roberts, Maira Rieger, *Linda LaMoreaux, and a positive attribute at home but not in school. The overall effect *Mark W. Pierce (Morris Plains, N.J.; and *Warner-Larnbert of the drug on behavior was beneficial, with a slight deterioration Pharmaceutical Research Ann Arbor, MI, U.S.A.)4044. in children’s behavior at school (not significant) and improvement reported by healthcare workers (significant). We evaluated the effects of gabapentin (GBP) as add-on therapy on seizure days and seizure-free intervals for the duration of patient treatment. GBP was administered an add-on therapy (600-2,400 mg/day) to 919 patients who participated in either Lamotrigine (Lamictal) Versus Carbamazepine as Monotherapy in open extensions of double-blind trials or long-term safety stud- Patients with Epilepsy. Alan Chapman, Alan W. C. Yuen, and ies. Maximum treatment duration was 120 weeks. 106 Investigators (The Wellcome Research Laboratories, Beck- A seizure day was defined as a day with at least one seizure of enham, Kent, England)-6047. any type, and a seizure-free interval was an interval of at least 1 day during which no seizure occurred. The parameters were The efficacy and safety of lamotrigine (Lamictal, LTG) versus evaluated by calculating the median number of seizure days and carbamazepine (CBZ) as monotherapy was assessed in an open, maximum duration of seizure-free interval in days and the per- randomized trial in 343 patients with newly diagnosed or recur- centage of change from baseline. rent partial or generalized tonic-clonic seizures. Patients were Maximum duration of seizure-free intervals increased during randomized to one of three treatment arms either (a) LTG 100 the total treatment period, with the percentage of change from mg, (b) LTG 200 mg, or (c) CBZ 600 mg, and were treated for 6 baseline ranging from 33 to 100%. Median number of seizure months. The proportion of patients remaining seizure-free (a = days decreased by 1-2 days from 8-6 days during a 28-day in- 51%, b = 60%, and c = 55%) and time to first seizure were not terval. GBP as add-on therapy increases duration of seizure-free statistically different between treatment groups. Overall, data intervals in long-term treatment. suggest that LTG has efficacy similar to that of CBZ, although the LTG 200-mg dose may be more effective than LTG 100 mg. Patients tolerated LTG better than CBZ. A greater proportion of patients treated with CBZ reported asthenia, dizziness, and Effectiveness of Gabapentin (Neurontin) Stratified By Gender. somnolence. The difference was significant for somnolence. David Eardley, *Edwina Koto, *Linda LaMoreaux, and *Eliza- More patients reported headache and insomnia while receiving beth Garofalo (Morris Plains, N.J., and *Warner-Lambert Phar- LTG. The most common adverse event leading to withdrawal maceutical Research, Ann Arbor, MI, U.S.A.)4045. was rash (a = 1.7%, b = 2.7%, c = 5.1%). Laboratory measures showed changes due to enzyme induction properties of CBZ. No We evaluated the effectiveness of gabapentin (GBP) as add-on changes in vital signs were observed between treatment groups. therapy by gender in patients with refractory partial seizures: 792 patients were randomized in five placebo-controlled studies to receive placebo or GBP as add-on therapy at dosages of 600- 1,800 mg/day for 12 weeks after a 12-week baseline period. Re- Open Multicenter Trial of Lamictal (lamotrigine) in Patients with sponse ratio (RRatio) was used to assess partial seizure reduc- Treatment-Resistant Epilepsy Withdrawing From Add-on to tions induced from treatment relative to baseline. Lamictal Monotherapy. Martin J. Brodie, *Jo S. Clifford, *Alan RRatio, defined as (T - B)/(T + B), compares baseline sei- W. C. Yuen, and the Lamictal Study Group (Epilepsy Research zure frequency (B) with treatment (T). Values range from - 1 to Unit, Western Infirmary, Glasgow, Scotland; and *The Well- + 1, with negative values indicating improvement. An RRatio of come Research Laboratories, Beckenham, Kent, England)- -0.33 equals a 50% reduction in partial seizure frequency. RRa- 6048. tio was analyzed by combined data stratified by sex. For males treated with placebo 600, 900, 1,200 and 1,800 mg/ Final results of an open multicenter study of lamotrigine day, mean RRatio was -0.041, -0.090, -0.114, -0.153, and (Lamictal, LTG) in patients with treatment-resistant epilepsy

Epilepsiu, Vol. 35, Suppl. 7, 1994 70 EUROPEAN CONGRESS PROCEEDINGS treated with one antiepileptic drug (AED) are reported. Patients firming the expected benefits of lower dose escalation used in receiving carbamazepine (CBZ, 129), phenytoin (PHT, 92) or combination with valproate treatment and shows that LTG is a valproate (VPA, 117) entered the trial consisting of 16-weeks well-tolerated drug that can reduce seizures by >50% in -48% of LTG add-on phase, 12-week AED discontinuation phase and refractory patients. 12-week LTG monotherapy phase. Of patients completing the add-on phase, 46% had seizure reduction of at least 50% (40% CBZ, 40% PHT, 60% VPA). Of patients attempting AED discontinuation, 56% were successful and 75% of patients entering Effect of Lamotrigine in Treatment of Postoperative Epilepsy Pa- the monotherapy phase completed it. For patients completing tients Not Seizure-Free. A. Flierl, H. Stefan, and S. Fitzek (Neu- the monotherapy phase, median weekly seizure count reduced rologische Klinik der Universitat Erlangen-Nuremberg, Erlan- from 7 during baseline to 2 during LTG monotherapy. gen, Germany)-605 1. The most commonly reported adverse events (AE) were dizziness in the CBZ group, asthenia in the PHT group, and rash in Postoperative epilepsy patients who still have seizures were the VPA group. Overall, 16% patients discontinued owing to AE, treated in a pilot trial with lamotrigine (LTG). Ten patients aged most during the add-on phase. Slower dose escalation of LTG 18-32 years (2 female, 8 male) had focal epilepsy secondarily resulted in a reduction in the proportion of patients discontinuing generalized. Etiology was cryptogenetic (4), residual (4), and due to rash, particularly in patients treated with VPA. LTG had symptomatic (2). Average LTG dose was 200 mg, and average no effect on vital signs, laboratory parameters, or plasma con- treatment period was 6 months. centrations of concomitant AEDs. One patient was seizure-free, 1 had no more tonic-clonic seizures, 2 had 50% reduction in complex partial seizures (CPS), 1 had increase in CPS, and 1 had 75% reduction in simple partial seizures and described a change in seizure quality. In 4 patients, Efficacy and Safety of Lamotrigine in Partial Epilepsy. Sauro seizures were unchanged. Severi, Amedeo Bianchi, *Gian Carlo Muscas, and Paolo Zolo Seizure reduction in patients who postoperatively are not sei- (U.O. Neurologia, Ospedale USL 23, Arezzo; and *Clinics Neu- zure-free can be achieved with LTG treatment. More cases rologica 11, Universita di Firenze, Firenze, Italy)--6049. should be examined in a standardized comparative trial. Lamotrigine (LTG) is a new antiepileptic drug (AED) chemically unrelated to currently used AEDs. It has proved efficacious in treating patients with partial seizures and generalized tonic- Open Add-on Trial with Lamotrigine in Refractory Partial Sei- clonic seizures (GTC) not satisfactorily controlled by other zures: A Brazilian Experience. Otto J. Hernandez-Fustes and AEDs. Paulo RogCrio M. de Bittencourt (Unidade de Neurologia, Cu- We report the data of a randomized, open trial comparing LTG ritiba, Brazil)dO52. and carbamazepine (CBZ) in patients with partial or seizures or GTC. Patients were randomized to receive either LTG 100 mg/ The efficacy of lamotrigine (LTG) was evaluated in 20 patients day, LTG 200 ml/day, or CBZ 600 mg/day. Twenty-seven pa- (9 females and 1 I males aged 282 years, mean +- SD) with partial tients were entered (17 males and 10 females, age 17-58 years, epilepsy refractory to previous treatments. Epilepsy was local- mean 39.7 years): LTG 100 mg (9), LTG 200 mg (9), and CBZ 600 ization-related (18 temporal, 1 frontal, I parietal). Duration of mg (9). Patients were treated for 72 weeks (range 2-1 12 weeks). epilepsy was 20 f 9 years. Age at onset of epilepsy was 8 f 8 Clinical data suggest that LTG has antiepileptic efficacy al- years. Computed tomography showed static lesions in 10 of 16 most similar to that of CBZ. There were significantly fewer sei- cases. EEGs showed localized abnormalities in all cases. At time zures both in the LTG and CBZ treatment groups as compared of study, antiepileptic drug (AED) therapy was carbamazepine with the baseline month. All LTG and CBZ patients achieved at (17 cases), valproate (6), phenobarbital, (2), and phenytoin (2). In least 75% reduction in total seizures. the 3 months before the trial, patients treated with these three Safety data show that LTG is associated with a low incidence AEDs had 24 2 30, 26 2 31, and 23 2 29 seizures a month, of adverse events (AE) especially CNS-associated side effects. respectively. In the 3 months of the trial, on progressive doses of LTG appears clinically safer than CBZ. The incidence of AE LTG 50400 mg daily, seizure frequencies were 6 f 9,5 f 8, and with LTG (27%) was lower than that with CBZ (67%). In LTG 3 2 5, respectively. These results indicate improvement 75% as treatment group 3, AE reported were somnolence, maculopapu- compared with baseline average (p < 0.05). Serum AED concen- lar rash, and weight loss. Only 1 patient with LTG had AE lead- trations and biochemical and hematologic measurements were ing to discontinuation. unchanged. Side effects of AEDs were dizziness, asthenia, diplopia, insomnia, and somnolence. Insomnia appeared to be related to LTG treatment; the other symptoms appeared to be caused by carbamazepine or its epoxide. These favorable obser- Multicenter, Open Add-on Trial with Lamotrigine in Refractory vations of efficacy of LTG in refractory partial epilepsy, ob- Epilepsy. Belgian Collaborative Lamotrigine Study Group and L. tained in open trial, may reflect our selection of outpatients with Devos and J. M. Steens (Wellcome N.V., Erembodegem, Bel- little neurologic impairment and to the rational approach to poly- gium)4050. therapy. The safety and efficacy of lamotrigine (LTG) was evaluated in a slower dose escalation regimen in an open, add-on study in patients with poorly controlled epilepsy. Seizure counts and Lamotrigine in Patients with Refractory Partial Epilepsy. J. A. safety data were measured at intervals during the study. In- Mauri, E. Mostacero, J. M. Sanz, E. Mudoz, C. Iniguez, and F. cluded were 120 patients (60 males and 60 females, mean age 30 Morales (Servicio de Neurologia. Hospital Clinico. Zaragoza, f 13.2 years). After 12-week treatment, 48% (57/120) had at least Spain)--6053. 50% reduction in total seizures as compared with the retrospective 3-month baseline. Twelve (10%) patients were seizure-free. Lamotrigine (LTG) is a novel triazine antiepileptic drug (AED) Mean seizure reduction was 40%. The most commonly reported whose efficacy in refractory epilepsy has been confirmed in adverse events (AE) during a period equivalent to 53 treatment- many studies. Twenty-five patients with refractory partial epi- years were somnolence (9%) and dizziness (5.8%). Treatment of lepsy received LTG openly as add-on therapy. LTG was admin- four (3.3%) patients was discontinued because of AE (rash 1, istered twice daily at a dosage increasing to 100400 mg/day. fever 1, dizziness I, and somnolence l), and 17 (14%) patients LTG was withdrawn for side effects in 1 (vomiting) and for un- discontinued treatment of lack of efficacy. changed seizures frequency in 2. Rash was less frequent (2 of 120) than in earlier studies, con- Some seizure decrease was noted in 80% of patients during

Epilepsia, Vol. 35, Suppi. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 71

LTG treatment, 20% had 100% decrease, 24% had 90% decrease, our use of LTG both pre and postmarketing (postmarketing pa- 24% had SO% decrease, and 12% had 225% decrease. Patients tients have been followed up for at least 1 year after initial drug received one to three concurrent AEDs. Despite the polyphar- prescription). We then compared experience and use of LTG pre macy created by this add-on study, addition of LTG was well and postmarketing to determine what lessons we had learned tolerated. There was no evidence that LTG affected vital signs or about its use. clinical, laboratory, or ECG parameters. LTG is a safe and ef- LTG appears to be a broad spectrum drug worth trying in any fective agent in treatment of refractory partial seizures. patient with intractable epilepsy. As our experience has grown, we use LTG increasingly often in patients with primary generalized epilepsy and nontemporal partial seizures. Postmarketing, Lamotrigine in Clinical Practice. N. Buchanan (Westmead Hos- more patients appear to have benefited from the drug (less in- pital, Sydney, Australia)4054. tractable epilepsy?), and withdrawals owing to side effects have been much fewer owing to better knowledge of ways to prevent Ninety-three patients (children and adults) received lamotrig- them: “low, slow” induction and recognition of pharmacody- ine (LTG) mainly as add-on therapy. Those who discontinued namic interaction with carbamazepine. Because it has positive LTG (D), who continued LTG (C), who were evaluable (E), and psychotropic properties and does not cause cognitive impair- who were seizure-free (SF, percentage evaluable) had the fol- ment LTG is a particularly valuable drug in a mentally impaired population. lowing conditions: generalized secondary to brain damage-D = 4, C = 38, E = 23, SF = 39%; complex partial seizures (CPS)-D = 7, C = 11, E = 17, SF = 29%; CPS with generalized tonic-clonic seizures (GTC)-D = 7, C = 18, E = 17, SF = 0%; generalized Cjuvenile myoclonic epilepsy (JME)J-D = 1, Clinical Use of Lamotrigine Under the Special Access Scheme. Roy C = 10, E = 6, SF = 67%; generalized absences + GTC-D = G. Beran and Kelly Sheehan (Epilepsy Research and Services, 0, C = 10, E = 8, SF = 50%; generalized GTC-D = 3, C = 2, Chatswood, Australia)dOS7. E = 3, SF = 0%; generalized reading epilepsy-D = 0, C = 1, E = 1, SF = 0%; tonic seizures-D = 2, C = 4, E = 6, SF = Lamotrigine (LTG), a new-generation antiepileptic drug, was 0%; Lennox-Gastaut syndrome (LGS)-D = 4,C = 7, E = 9, demonstrated in clinical trials to be efficacious in focal epilepsy, SF = 22%; simple partial seizures-D = 1, C = I, E = 1, SF = but only anecdotal reports suggest efficacy in generalized epi- 0%; and Landau-Kleffner-D = 0, C = 1, E = 1, SF = 0%. lepsies. We analyzed 30 patients with refractory mixed seizure Totals were D = 29, C = 103, E 93, and SF = 25.8% types treated with open-label LTG provided under the individual The results confirm that LTG is useful in CPS, JME, intrac- patient use or special access scheme (SAS) in Australia. The trial table epilepsy, and LGS, especially in individuals with brain demonstrated a wide range of efficacy, with higher global scores damage and subsequent seizures. In this latter group and in LGS, indicating greater improvement for generalized epilepsies than alertness and quality of life often are markedly improved. Of the for focal epilepsies. Only patients with generalized epilepsies 29 patients who discontinued LTG, 13 did so because of lack of were rendered seizure-free for 26months after addition of LTG, effect and 9 did so because of side effects, which included inter- which is further evidence of its efficacy in generalized epilepsies. action with carbamazepine (9), rash (6), therapeutic LTG over- Blood levels of LTG were routinely measured by high- dosage (6), and increased seizure frequency (3). performance liquid chromatography, but no consistent therapeutic range was defined. Levels in different seizure-free patients ranged were 10 to >60 pM. Very few side effects were reported; Using Lamotrigine to Full Advantage. Frank M. C. Besag (St. rash was the most common side effect, but no patients discon- Piers Lingfield, Lingfield, Eng1and)dOSS. tinued LTG treatment because of adverse events. Our data emphasize the need for use of LTG to be based on clinical obser- Treatment of >150 young people with lamotrigine (LTG) in- vations rather than laboratory determinations. Rigorous clinical dicated that appropriate management can avoid the potential dif- trials are needed to confirm the efficacy of LTG in generalized ficulties of pharmacodynamic interaction with carbamazepine epilepsies. (CBZ), pharmacokinetic interaction with valproate (VPA), rash, inadequate dose, and inadequate period of treatment before withdrawal. Fifty-two subjects treated with both LTG and CBZ showed no significant increase in levels of either CBZ or CBZ- Lamotrigine Add-on Therapy in 76 Adult Patients with Refractory epoxide (CBZ-E) when LTG was added. Diplopia and dizziness Generalized Epilepsies. Heinrich Vogt, Gordana Lazarevic, Jean appeared to be more likely in those with initial high CBZ level. Pierre Scalabrin, Viasta Zweifel, and Giinter Kramer (Swiss Ep- Allowance must be made for increasing LTG levels when VPA ilepsy Center, Zurich, Switzerland)-6058. is added and decreasing levels when VPA is discontinued, if toxicity and loss of efficacy, respectively, are to be avoided. Lamotrigine (LTG) is a new antiepileptic drug (AED) licensed Seven subjects developed a rash; In 6, VPA could be reintro- for add-on therapy of focal seizures; recent clinical observations duced if a very slow escalation regimen was used. Some children showed equal effectiveness in generalized epilepsies. We used with severe epilepsy responded to higher doses of LTG even if open add-on LTG treatment in 76 adult patients with refractory the blood level was already increased. The maximum dose and generalized epilepsies and a mean seizure frequency of 29 a blood levels have yet to be determined. month (50 patients with symptomatic and 26 with primarily gen- Dramatic beneficial response was sometimes delayed for sev- eralized epilepsy). Except for generalized tonic-clonic seizures, eral weeks. Two subjects with severe epilepsy became seizure- almost all seizures were documented by routine EEG or long- free after 6 weeks, during which time dose was unchanged. term monitoring. LTG dosage was ~200mg, with an average Knowledge of these practical issues enables clinicians to use serum concentration of 14.4 pM. The first 3 months after LTG LTG safely and with maximum benefit. add-on were compared with the 3 preceding months (baseline). A significant seizure reduction (>50%) was observed in 38 patients; 3 were seizure-free. Only 3 patients worsened; in 4 Audit of Lamotrigine Use in an Epilepsy Clinic. Tim Betts and others, LTG had to be discontinued owing to side effects, in- Kate Smith (Birmingham University Seizure Clinic, Birming- cluding rash, lymphadenopathy, and aggressiveness. The best ham, England)-6056. results were observed in atypical absences (14), myoclonic seizures (13), and tonic seizures (39, with significant improvement Lamotrighe (LTG) has been in use in the United Kingdom for of 57, 54, and 51%, respectively. Comparable effectiveness in 10 years, with >2 years’ postmarketing experience. We audited typical absences (32) and generalized tonic-clonic seizures (18)

Epilepsia. Vol. 35, Suppl. 7, 1994 72 EUROPEAN CONGRESS PROCEEDINGS was 50 and 44%, respectively. LTG appears to be an effective mg daily. Two weeks later, she developed papular rash. LTG add-on medication in generalized seizures. was discontinued. Eight months later, she was successfully gradually rechallenged to 200 mg daily. Seizures were reduced to two a week. Our results suggest that patients experiencing a rash may be considered for rechallenge with LTG. Behavioral Effects of Lamotrigine. Rainer Wohlfarth, Josef Saar, and Gerhard Reinshagen (Epilepsiezentrum Kork, Klinik fur Er- wachsene, Kehl-Kork, Germany)dO59. Cerebrospinal Fluid Investigations in Children with Intractable Lamotrigine (LTG) has been in official clinical use in Germany Epilepsy Treated with Lamotrigine. Ann-Sofie Eriksson, Arne since July 1993. We have treated 26 patients with seizures resis- Nerglrdh, and Olof Beck (Departments of Pediatrics and Phar- tant to conventional drugs with add-on LTG, exploring its effects macology, Karolinska Hospital, Stockholm, Sweden)4062. especially in respect to its behavioral effects by interview, self- ratings, and neuropsychological tests. In our population, 7.6% of Twenty-three children with generalized intractable epilepsy the patients were seizure-free, and 23% experienced marked re- were investigated with lumbar punctures before and during lief of seizures (>50%). Side effects were frequent but mainly steady-state lamotrigine (LTG) add-on treatment. We analyzed weak. Almost 50% of the patients reported side effects: rash, different antiepileptic drugs in cerebrospinal fluid (CSF) and de- diplopia, and vomiting episodes. The main behavioral effect of termined changes in exitatory and inhibitory amino acids after LTG treatment was nonspecific behavioral activation, which is LTG was introduced in both responders and nonresponders. A beneficial for patients (43%) with low activation levels, low mo- high-performance liquid chromatography method was used in tivation, and depressed mood. For more activated or agitated analysis of LTG and amino acids. Results of therapy with LTG patients (23%), increased activation led to behavioral distur- and changes in composition of CSF were correlated. bances such as hostility, aggressiveness, or loss of impulse control, especially in 2 patients (7.6%) who experienced paranoid episodes. We propose an inverted U-function of behavioral effects of LTG, which may lead to a differential indication for LTG Lamotrigine Treatment of 92 Patients with Therapy-Resistant Ep- in patients with low and high arousal. ilepsy. Merete Karlsborg, Lennart Gram, and Mogens Dam (De- partment of Neurology, Hvidovre Hospital, Hvidovre, Den- mark)-6 137. Cutaneous Rash with Lamotrigine and Concomitant Valproate Therapy. M. Russo, L. M. Li, M. F. O’Donoghue, J. W. A. S. The efficacy of treatment with lamotrigine (LTG) was evalu- Sander, and J. S. Duncan (The Epilepsy Research Group, Insti- ated in 92 patients with refractory epileptic seizures (46 women tute of Neurology, London, England)-6060. and 46 men aged 14-80 years, median 32 years). Seventy-one patients had partial epilepsy and 21 had primary generalized ep- Cutaneous rash is one of the most common adverse events ilepsy. associated with lamotrigine (LTG). In a population of 102 adult Patients were treated with 0-4 (most frequently 2) other anti- patients with intractable epilepsy who had LTG added to their epileptic drugs (AEDs). Maintenance dose of LTG was 50-800 therapy, we assessed whether risk of such rash is increased in mg daily (median 300 mg). Fifteen% of patients became seizure- patients receiving concomitant valproate (VPA) therapy. Of 32 free (13% of patients with partial epilepsy/24% with primary gen- patients treated with VPA, 9 (28%) developed a rash, whereas of eralized epilepsy). Thirty-eight% of patients experienced at least only 4 of the 70 (6%) not treated with VPA developed rash. This 50% reduction in seizure frequency; 22% of patients had in- suggests that the risk of cutaneous rash is significantly greater creased seizure frequency (24% of patients with partial epilepsy/ when LTG treatment is initiated in patients already receiving 14% with primary generalized epilepsy). VPA (p < 0.02, Fisher’s exact test). Possible mechanisms in- Adverse events were recorded in 61% of patients, but most clude higher LTG levels, owing to inhibition of metabolism, in symptoms disappeared after dose reductions in concomitant patients receiving concomitant VPA. AED. LTG was discontinued in 22% of patients, either because of adverse events or lack of effect. LTG is effective in reducing seizure frequency in patients with therapy-resistant primary generalized epilepsy or partial epilepsy. Toxicity appears to be lim- Rechallenge with Lamotrigine After Initial Rash. S. J. Tavernor, ited. E. R. Newton, and S. W. Brown (The David Lewis Centre for Epilepsy, Cheshire, England)4061.

Lamotrigine (LTG) is associated with rashes in 2% of patients; Case of Severe Acute Intoxication with Oxcarbazepine Combined rechallenge currently is contraindicated (Lamotrigine Data with Lamotrigine. JZrgen Alving (Dianalund Epilepsy Hospital, Sheet, Wellcome Foundation, October 1993). We report 3 pa- Dianalund, Denmark)--6063. tients rechallenged without rash recurrence. In a 28-year-old man with uncontrolled generalized epilepsy for 17 years treated Lamotrigine (LTG) can augment the clinical toxicity of car- with valproate 2,000 mg and clobazam 40 mg daily, LTG was bamazepine (CBZ); the mechanism of action has been debated, introduced over 4 days to 100 mg daily). He became seizure free. but some studies have shown a significant increase in the active On day 11, he developed truncal papular rash. LTG was discon- metabolite CBZ-10,l I-epoxide after supplementation with LTG. tinued. Eighteen months later, successful gradual rechallenge to A 40-year-old woman with intractable partial seizures since age 75 mg daily induced seizure freedom from day 1. In a 14-year-old 12 years had previously had several slight toxicity episodes on girl with localization-related epilepsy for 13 years who had six oxcarbazepine (OCBZ), especially after addition of LTG. Sub- seizures weekly while treated with carbamazepine 600 mg daily, sequent addition of valproate (VPA) caused an increase in serum LTG was introduced over 2 weeks to 200 mg daily. Facial rash LTG from 24 to 42 pM and severe acute intoxication, with ver- developed 11 days later, but resolved when LTG was discontin- tigo, diplopia, and vomiting, but unchanged serum level of ued. Twenty months later, she was successfully gradually rechal- OCBZ (70 pM); symptoms largely subsided after LTG was re- lenged to 150 mg daily for 4 months. LTG was then discontinued duced. Because we did not measure monohydroxy-CBZ, we (therapeutically ineffective). In a 17-year-old girl with Lennox- could not evaluate the possible r81e of metabolic changes, but Gastaut syndrome for 15 years who had 6 seizures weekly while since OCBZ is not metabolized through epoxides, the explana- treated with carbamazepine 1,000 mg, vigabatrin 3,500 mg, and tion for acute toxicity on CBZ/LTG combination treatment can- clobazam 40 mg daily, LTG was introduced over 6 weeks to 100 not be explained solely as an increase in epoxide level.

Epikpsia, Vul. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 73

Carbamazepine Toxicity with Lamotrigine: A Pharmacokinetic or glycine/NMDA receptor, increased ED,, values of FBM for sup- Pharmacodynamic Interaction? Frank M. C. Besag, Barry Subel, pression of tonic seizures 3.4-fold. Likewise, in GEPR, glycine Felicity Pool, *David Berry, and ?John E. Newbery (St. Piers itself increased ED,, 4.1-fold. FBM is a potent AED in both Lingfield, Lingfield; *Guy’s Hospital, London; and ?University models of reflex epilepsy. FBM may act through interaction with of Greenwich, London, England)-6064. glycine/NMDA and AMPA/kainate receptors. Lamotrigine (LTG) was added to the antiepileptic medication of 47 patients already taking CBZ. CBZ and CBZ-epoxide levels were analyzed before and after introduction of LTG. There were Effects of Felbamate on Sleepwaking Pattern in Rats. Rosalia no significant increases in either CBZ or CBZ-epoxide levels. Bertorelli, Nives Ferri, and Ennio Ongini (Schering-Plough SPA, Nine cases of diplopia or dizziness were recorded. Patients Comazzo, Milan, Italy)--6067. whose CBZ levels were already high before LTG was introduced showed a strong tendency toward these symptoms. Seven cases Because sedation is a common side effect of antiepileptic drug of diplopia or dizziness occurred in the group of 25 patients (AED) therapy, we designed to assess the effects of new drugs whose initial CBZ levels were 38 mg/L as compared with 2 cases on the sleepwake cycle in rats. The effects of felbamate (FBM), of diplopia or dizziness in the 22 patients with initial CBZ levels lamotrigine (LTG), carbamazepine (CBZ), and phenobarbital <8 mg/L. Results suggest that the symptoms of CBZ toxicity, (PB) were studied in two series of experiments with both con- which sometimes appear when LTG is added, are a pharmaco- ventional and reverse light/dark cycle. In the conventional cycle, dynamic rather than a pharmacokinetic effect. Patients with a FBM (30-300 mg/kg, orally, P.o.), LTG (3-30 mg/kg p.0.1, and high initial CBZ level mg/L should be warned not only of the 28 CBZ (10-100 mg/kg p.0.) had no sedative effects; neither did possibility of diplopia or dizziness, but also that decreasing the they alter overall sleep-wake architecture. Conversely, PB (100 CBZ dose slightly should eliminate this adverse effect. mg/kg p.0.) markedly suppressed rapid eye movement (REM) sleep. In the reverse cycle, FBM, at a high dose of 300 mg/kg P.o., did not influence the amount of total sleep and slightly Neuroprotective Effects of Felhamate on Ischemia in Gerbils. Ma- decreased REM. Similar results were obtained with CBZ (100 rina Adami, Rosalia Bertorelli, *Francesca de Rho, *Sandro mg/kg, p.0.) and LTG (30 mg/kg, p.0.). PB 100 mg/kg p.0. mark- Iannaccone, and Ennio Ongini (Schering-Plough SPA, Comazzo; edly increased the amount of total sleep and considerably re- and *Department of Neurology, S. Raffaele Hospital, Milan, It- duced REM. FBM at doses far above pharmacologically effec- aly)-6065. tive doses has little or no effect on sleep and waking states.

Felbamate (FBM) is a new antiepileptic drug that has proved to be safe in animals and humans and is currently used in treatment of some forms of epilepsy. In addition to having anticon- Felbamate in Patients with Intractable Childhood Onset Epilepsy. vulsant activity, FBM was neuroprotective against hypoxic and Stella Maris Ferraro, Celia Daraio, Andrea Murano, and Julio ischemic damage in both in vitro (Wallis et al., Stroke 1992; Castano (Hospital Italian0 Buenos Aires, Argentina)-6068. 23547-51) and in vivo studies (Wasterlain et al., Neurology, 1993; 43:2303-10). We examined the effects of FBM on ischemia- Twenty-five patients aged 8 months to 17 years (mean 8.5 induced hippocampal degeneration in Mongolian gerbils sub- years) with extremely resistant symptomatic partial and gener- jected to transient forebrain ischemia by 10-min occlusion of alized epilepsies of childhood onset (onset at 1 month to 7 years, both common carotid arteries. Dizocilpine (MK 801), a selective mean 6.3 months) were treated with felbamate (FBM), a dicar- noncompetitive N-methyl-D-aspartate (NMDA) antagonist, was bamate with anticonvulsant and possible neuroprotectant activ- used for comparison. FBM administered intraperitoneally (i.p.) ities, as add-on therapy. Patients were categorized as having 300 mg/kg 10 min after the carotid occlusion period increased the partial epilepsy with or without generalization (16), Lennox- number of surviving CA1 hippocampal neurons as compared Gastaut syndrome (9,and multifocal epilepsy (4). with the control ischemic group. Similar results were obtained Clinical effects and seizure frequency were quantified by ob- with dizocilpine (3 mg/kg i.p.). These findings further demon- servation of seizures at home before and during treatment. In the strate that FBM posttreatment exerts neuroprotective effects in first months of FBM treatment, results showed >SO% reduction a model of severe ischemia. in frequency and severity of seizures in 17, (68%, 2 seizure-free); 40%reduction (4, 16%); and no change in seizure frequency in (4, 16%). FBM was well tolerated when added to concomitant antiepileptic drugs (AEDs): patients demonstrated marked in- Effects of Felbamate on Two Genetic Models of Epilepsy. G. B. De 19 creases in alertness and awareness and/or improvement in func- Sarro, *D. Ammendola, *F. Nava, tR. Bertorelli, *A. De Sarro, tional abilities. Side effects were minimal and transitory: insom- and tE. Ongini (School of Medicine, University of Reggio Cala- nia (4), anorexia (4), and sleepiness (I). FBM appears to be an bria, Catanzaro; *Institute of Pharmacologia, University of effective and safe AED for patients with intractable epilepsy. Messina, Messina; and tSchering-Plough SPA, Research Labo- ratories, Comazzo, Milan, Italy)4066.

Animals with a genetic predisposition to seizures provide a useful model for insight into the action of new antiepileptic drugs Felhamate in Refractory Epilepsy: An Open-Label Study. L. (AED) on biologic mechanisms underlying epilepsy. Felbamate Nashef, J. W. A. S. Sander, D. Fish, J. S. Duncan, and S. D. (FBM) was shown to possess anticonvulsant activities in various Shorvon (The Epilepsy Research Group, Institute of Neurology, epileptic animal models. In DBA/2 mice and in genetically epi- London, and Chalfont Centre for Epilepsy, Chalfont St Peter, lepsy-prone rats (GEPR), FBM displayed ED,, values of 23 and England)-6069. 25 mg/kg intraperitoneally (i.p.) for tonus, respectively. To determine whether excitatory amino acid neurotransmission is in- Felbamate (FBM) is a new antiepileptic drug (AED) whose volved in FBM’s mode of action, we investigated its activity mode of action is still unclear. It is licensed in the United States against seizures induced by N-methyl-D-aspartate(NMDA) or both as mono- and add-on therapy in epilepsy. Its main limitation u-amino-3-hydroxy-5-methyl-4-isoxazolepropionic(AMPA), is its interaction with other AEDs. Phenytoin, valproate, and which stimulate either glycine/NMDA or AMPA/kainate recep- carbamazepine 10-1 I epoxide levels increase while carbam- tors. In DBA/2 mice, the ED,, value was 12.1 mglkg for tonic azepine levels decrease. extension induced by NMDA and 11.8 mg/kg i.p. for tonic ex- We are conducting an open-label add-on assessment of toler- tension induced by AMPA. Moreover, D-serine, an agonist at the ability and efficacy of FBM in adult patients with intractable

Epilepsia, Vol. 35, Suppl. 7, 1994 74 EUROPEAN CONGRESS PROCEEDINGS epilepsy: 48 patients (22 females, 26 males) have been entered, Tiagabine: Evaluation of Risk of Interaction with Cimetidine in 71% with localization-related epilepsy, 15% with idiopathic gen- Healthy Male Volunteers. S. Snel, *J. H. G. Jonkman, *P. N. M. eralized, 10% with other generalized, and 4% with undetermined van Heiningen, J. A. Jansen, and H. B. Mengel (Novo Nordisk epilepsy. Other AEDs at initiation of FBM therapy ranged from A/S, Bagsvaerd, Denmark; and *Pharma Bio-Research, Zuid- 1 to 4 (mean 2) and were often reduced. laren, The Netherlands)-6072. FBM has been withdrawn in 25% because of side effects (rash, persistent nausea, headaches, feelings of aggression, nonspecific Tiagabine (TGB) is a new antiepileptic drug that acts by inhib- aches, excess sedation), and apparent increase in seizure fre- iting y-aminobutyric acid uptake by glial and neuronal tissue. quency, and lack of efficacy. In 25% of cases, an early improve- After radiolabeled TGB was administered orally to healthy vol- ment appears to be sustained. FBM is a promising addition to the unteers, it was oxidatively metabolized in liver and <2% was available AED armory, but adjustments in doses of concomitant excreted unchanged in urine. Cimetidine inhibits metabolism of AEDs is often necessary and requires careful titration. several drugs through its inhibiting effect on the cytochrome P450 system. We report results of a single-center, open-label, cross-over trial evaluating the pharmacokinetic properties of TGB at steady state, with and without concurrent administration of cimetidine. TGB was administered to 12 healthy volunteers as Long-Term Safety and Efficacy Evaluation of Patients with Partial 4 mg twice daily for 4 days and as a 4-mg single dose on day 5 Seizures Treated with Tiagabine in Two Open Extension Studies. J. during two treatment periods. Cimetidine was administered as Duncan, J. W. Sander, and *K. Lyby on behalf of the study 400 mg twice daily for 5 days and as a 400-mg single dose on day group (P. Riekkinen, J. Duncan, A. Richens, M. Brodie, D. G. 6 in one of the treatment periods. The two treatment periods A. Kdsteleijn-Nolst TrinitC, E. Ben-Menachem, S. Brown, G. were separated by an interval of at least 9 days. Each subject was Venables, D. Chddwick, M. Dam, P. Crawford, J. Morrow, M. randomly assigned to one of the possible treatment sequences (6 Sillanpaa, T. Rentmeester, R. Elwes, B. Pedersen, R. Kalvi- subjects per sequence). ainen, M. O’Dondghue, J. P. Leach, M. Engelsman, M. Rade- maker, and M. Jongsma) (Chalfont Epilepsy Centre, Bucking- hamshire, England; and *NOVONovdisk, Krogshoejvej Bags- vaerd, Denmark)4070. Study Investigating Whether Tiagabine Potentiates Effects of Eth- anol on Cognitive Function. Helle Kastberg, *Graham Cole, Tiagabine (TGB) is a potential new antiepileptic drug (AED) +Keith Wesnes, and Helle B. Mengel (Novo Nordisk A/S, Bags- that inhibits y-amino-butyric acid uptake. In double-blind, pla- vmd, Denmark; *Besselaar Clinical Research Unit, United cebo-controlled, short-term studies, TGB was shown to be safe, Kingdom; and ?Cognitive Drug Research, United Kingdom)- well tolerated, and efficacious as adjunctive treatment of patients 6073. with partial-onset seizures. The objective of the extension studies was to determine safety and efficacy of TGB during long-term Tiagabine (TGB) is a new antiepileptic drug that inhibits the treatment. More than 75% of patients eligible for the double- y-aminobutyric acid reuptake into glial and neuronal tissue. We blind, short-term studies in Europe entered the extension studies report results of a double-blind, placebo-controlled, randomized, (189 patients at 16 centers). By January 1994, 48 patients had two-period, cross-over study. Ten healthy male and 10 healthy been treated for >I year and, as of now, 18 patients have been female volunteers aged 1840 years received study drug (TGB or treated >2 years. The patients received daily doses of TGB 12- placebo) in two 9-day treatment periods, each period separated 80 mg. Safety was evaluated by monitoring adverse events and by 6 days. In both treatment periods, study drug was adminis- laboratory data and by physical and neurologic examinations. tered orally at twice-daily dosing frequencies on days 1-8 and Efficacy was evaluated by recording seizures according to sei- once in the morning on day 9. TGB dose was gradually increased zure types. in 5 days in a blinded manner from TGB HCI 8 mg/day to TGB HC1 12 mg/day. Ethanol 0.7 g/kg (males) or 0.6 g/kg (females) was administered on day 9 30 min after study drug administration. Cognitive function tests were performed on days 8 and on Cognitive Effects of Tiagabine. Reetta Kalviginen, Maja Aikia, 9 30 min before and at 1, 2, 3, 4.5, and 6.5 h after morning Anna Maija Saukkonen, Asla Pitkanen, and Paavo Riekkinen Sr. administration of study drug. At each test time, the following (Department of Neurology, University of Kuopio, Kuopio, Fin- cognitive function tests were performed: digit vigilance, choice land)-6071. reaction time, immediate and delayed word recall, delayed word recognition, visual tracking, body sway, and visual analogue Tiagabine (TGB) is an effective new antiepileptic drug (AED) scales on alertness, calmness, and contentment. that acts as a y-aminobutyric acid (GABA) uptake inhibitor. Be- cause no data are available regarding the cognitive effects of TGB in humans, we studied such effects of TGB as add-on therapy in drug-resistant partial epilepsy. A randomized, double- Effect of FPL 12495 on Electrical Activity in Cortical Wedges. Ruo blind, placebo-controlled, parallel-group, add-on study design Qi Hu and John A. Davies (Department Pharmacology and Ther- was used. After the double-blind phase, all patients had the op- apeutics, University of Wales College of Medicine, South Glam- portunity of being treated with TGB on an open-label long-term organ, Cardiff, Wales)4074. basis. Neuropsychological assessments were performed at baseline, after a 12-week fixed-dose period with either 30 mg TGB/ Remacemide hydrochloride is a novel antiepileptic drug un- day or placebo, and after 6-8 months of open TGB treatment dergoing clinical trials for patients with generalized tonic-clonic with individually adjusted daily dose (12-80 mg). Neuropsycho- and complex partial epilepsy. FPL 12495 is the desglycinated, logical assessment consisted of evaluation of general intelli- active metabolite of remacemide hydrochloride that exhibits ef- gence, learning and memory, sustained attention, and flexible ficacy against N-methyl-D-aspartate (NMDA)-induced convul- mental processing. Forty-six patients entered the study; 37 pa- sions in experimental models of epilepsy. However, the mecha- tients concluded the 12-week fixed-dose period (age 20-69 years, nism underlying the anticonvulsant action of FPL 12495 remains mean 39; 1Q 41-119, mean 87). Preliminary analysis showed no unclear. We investigated the pharmacologic action of FPL 12495 significant change in any measure of neuropsychological func- on both NMDA-induced and spontaneous depolarizations in cor- tion. Detailed covariance analysis was made of the data, taking tical wedges prepared from genetically epilepsy-prone DBAR into account seizure frequency, age, and education. Short-term mice. TGB treatment had no adverse effect on cognitive measures as FPL 12495 caused significant reductions in frequency of spon- compared with placebo. taneous depolarizations and associated afterpotentials in a con-

Epilepsiu, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 75 centration-dependent manner (12.5-200 pM), and amplitude of Remacemide Hydrochloride: Open Assessment. P. M. Crawford, NMDA-induced depolarizations was also decreased. NMDA *P. K. Newman, and tI. Soryal (Bootham Park Hospital, York; dose-response curves were shifted to the right; and this antago- *Middlesbrough, and TCannock, England)dO77. nism was noncompetitive. FPL 12495 had no effect on a-amino- 3-hydroxy-5-methyl-4-isoxazolepropionic(AMPA)-induced de- Patients with refractory epilepsy who have participated in pre- polarizations. vious studies with remacemide hydrochloride have the opportu- Evidence shows that the NMDA receptor participates in ini- nity to receive the drug in an open long-term protocol. Patients tiation and/or propagation of epileptiform discharges; in wedge receive remacemide hydrochloride 400-800 mg/day in a flexible preparation, NMDA receptor antagonists block spontaneous de- dosage regimen (two, three, or four times daily). Patients attend polarizations. Our results suggest that the anticonvulsant action the clinic at monthly intervals for the first 3 study months and at of FPL 12495 involves a noncompetitive inhibitory effect at the 3-month intervals thereafter. Patients’ continuation in the trial is NMDA receptor complex. dependent on demonstration of continued clinical benefit as defined by maintained reduction in seizure frequency or maintained improvement in general condition. Current status of patients is 26 entered, 8 treated for 1 year with continued clinical benefit, 17 FPL 12495 Inhibits Glutamate Release From Cortical Slices. Ja- ongoing, 5 withdrawn owing to inadequate efficacy, and 4 with- yashri Srinivasan, Alan Richens, and John A. Davies (Depart- drawn owing to adverse events. No adverse safety findings have ment of Pharmacology and Therapeutics, University of Wales yet emerged during long-term treatment with remacemide hydro- College of Medicine, South Glamorgan, Cardiff, Wales)4075. chloride.

FPL 12495, the pharmacologically active desglycine metabolite of remacemide hydrochloride, is more potent than the parent compound against maximal electroshock and N-methyl-D- Efficacy and Safety of Oxcarbazepine: Two-Year Follow-up of 90 aspartate (NMDA)-induced convulsions in rodents. We investi- Patients. Olga San Martino, Pere Redo, and Carles Fina (Ciba- gated the effect of FPL 12495 on glutamate release from mouse Geigy S. A. Medical Department, Clinical R&D, Barcelona, cortical slices. Spain)4078. Glutamate release was elicited with two pulses of potassium or veratridine, and basal release was 2-5 pmol/mg tissue/2 min. The Oxcarbazepine (OCBZ), a keto-analogue of carbamazepine, is second pulse of potassium and veratridine resulted in an average a potent antiepileptic drug (AED) that has demonstrated antiep- release of 88 +- 6 and 68 2 6%, respectively, of the first pulse. ileptic efficacy comparable to that of first-line AEDs. We report Potassium-stimulated release was significantly reduced by FPL results of 90 patients treated with OCBZ for at least 2 years in 12495 at concentrations of 100 and 200 pM. Veratridine- Spain; 90% of patients were epileptic with partial seizures, and stimulated release of glutamate was also significantly reduced at 10% had other diagnoses (trigeminal neuralgia, tonic-clonic sei- concentrations of 25, 50, and 100 pM. zures). Radioligand binding studies indicated that remacemide has low Patients were treated with OCBZ treatment because previous affinity for both the glycine and ion channel sites on the NMDA treatment with conventional AEDs was not satisfactory (incom- receptor complex, but FPL 12495 is far more potent in displacing plete seizure control or undesirable side effects); 90% received dizocilpine binding than is remacemide. Such an effect could OCBZ as add-on therapy. Efficacy (decrease in seizure fre- account for its therapeutic action, but such action could also be quency) and tolerability (number of adverse events) were very due in part to the inhibitory action of the desglycine metabolite good, with substantial difference from previous treatment. Hy- on glutamate release. ponatremia incidence was low. OCBZ is an useful AED for treatment of epileptic patients in both monotherapy and polytherapy.

Interactions Between Remacemide and the Established Antiepilep- tic Drugs. J. P. Leach, J. Blacklaw, M. Stewart, V. Jamieson, R. Oxley, A. Richens, and M. J. Brodie (Epilepsy Research Unit, Levetiracetam (UCB L059): Anticonvulsant Effects are Mediated Western Infirmary, University of Glasgow, Scotland; University by the Parent Compound. Alma J. Gower and Alain Matagne, of Wales College of Medicine, Cardiff, Wales; and Fisons Phar- (UCB Pharma Sector, Braine L’Alleud, Belgium)-6079. maceuticals, England)-6076. The novel antiepileptic drug (AED) levetiracetam (UCB Remacemide hydrochloride has noncompetitive N-methyl-~- LO59) shows a broad spectrum of anticonvulsant effects in mice aspartate antagonist properties and was shown to be anticonvul- and rats after parenteral administration (Gower et al., Eur J sant in animal seizure models. The effect of remacemide hydro- Pharmacol 1992; 222;193-203). To determine whether the active chloride coadministration on levels of baseline antiepileptic component of levetiracetam is the parent compound, we inves- drugs (AEDs) has never been documented in humans. tigated its anticonvulsant effects after injecting it directly into Three groups of 10 epileptic patients treated with carbam- brain. Under ether anesthesia, audiogenic seizure-prone mice azepine, phenytoin, or valproate (VPA) monotherapy completed were injected intracerebroventricularly (i.c.v.) with levetirace- a double-blind, cross-over study of additional remacemide hy- tam or its enantiomer UCB LO60 and subjected 30 min later to a drochloride and matched placebo. After a screening visit, pa- sound stimulus that elicited wild running and clonic and tonic tients received a single dose of 300 mg and their plasma levels of seizures. Levetiracetam protected against all three indexes, with remacemide and baseline AED were monitored for the next 24 h. respective ED,, values of 16.2 and 30.7 pg per mouse for tonic One week later, each patient began 2-week treatment with rem- and clonic seizures and an estimated 54.8 pg per mouse for wild acemide hydrochloride or placebo in random order. Then, after running, whereas UCB LO60 was completely inactive at 50 pg a 1-week washout phase, patients were transferred to the alter- per mouse. In rats, the effects of levetiracetam injected i.c.v. native arm. The remacemide dose for those treated with an en- through implanted cannulas were tested against convulsant ac- zyme-inducer was 300 mg twice daily as compared with 150 mg tivity induced by bicuculline 0.6 mg/kg infused intravenously 30 twice daily for patients treated with VPA. Trough levels of rem- min later. Levetiracetam 10-100 pg i.c.v. per rat significantly acemide and baseline AEDs were measured throughout each increased the threshold bicuculline doses eliciting convulsions. treatment period, at the end of which further 24-h profiles were Results show that levetiracetam injected directly into brain in- obtained. Evidence for a slight inhibitory effect of remacemide hibits convulsant activity in both mice and rats and indicate that on phenytoin and carbamazepine metabolism was detected. Sim- the parent compound is responsible for this protective effect, ilar interaction with VPA was not noted. consistent with a lack of effect of metabolites.

Epilepsia, Vol. 35, Suppl. 7, 1994 76 EUROPEAN CONGRESS PROCEEDINGS

Cognitive Side Effects of Levetiracetam (UCB LO59) in Epilepsy. Losigamone-Lamotrigine Placebo-Controlled Drug Interaction Lidwien G. J. Neyens, Willem C. J. Alpherts, and Albert P. Study in Volunteers. Gunter Kramer, Nils Wad, *Anneli Bredel- Aldenkamp (Instituut voor epilepsiebestrijding, Meer en Bosch, GeiRler, and tAngelika Dienel (Swiss Epilepsy Center, Zurich, Heemstede, The Netherlands)-6080. Switzerland; *Department of Neurology, University Hospital, Mainz; and ?Department Clinical Research, Dr. Willmar In a single-blind add-on increasing-dose study, a new pyrroli- Schwabe, Karlsruhe, Germany)-6083. dine derivative (Levetiracetam, UCB L059) was given concomitantly as an antiepileptic drug to 10 adult patients with chronic Losigamone (AO-33 or AD-137022) is a new antiepileptic drug epilepsy receiving stable carbamazepine (CBZ), or phenytoin, or (AED) with a broad spectrum in animal models. Uncontrolled valproate plus CBZ treatment. To investigate cognitive side ef- observations showed promising effects in drug-resistant focal ep- fects, we had all patients perform a computerized neuropsycho- ilepsy (Runge et al., Epilepsia 1993;34(suppl 2):6) and placebo- logical test battery that measured broadly the domains of psy- controlled add-on studies have been initiated. There has been no chomotor functioning, memory, and information processing dur- positive evidence of interactions with AEDs such as carbam- ing baseline, after 1 week of 500-mg drug administration, and azepine or phenytoin, but detailed studies are lacking and no again after I-week of administration of 1,000-1,500-mg. Results data regarding new AEDs such as lamotrigine are available. did not show statistically significant drug-induced changes in We performed a placebo-controlled randomized study in 12 cognitive performance. Although the pharmacologic profile of healthy male volunteers (age 22-39 years, weight 55-80 kg). Sin- UCB LO09 is similar to the nootropic compound Piracetam, no gle-dose pharmacokinetics for losigamone (500 mg) and lamot- psychotropic effects were noted. The study disclosed target ar- rigine (LTG 25 mg) were studied on days 1 and 2, respectively. eas that may be investigated more thoroughly in a more sensitive On day 3, volunteers received 25 mg LTG twice daily (bid.); design with prolonged drug treatment. from days 4 to 42, LTG dosage was 25 mg three times daily. Repeated single-dose kinetics for losigamone as well as steady- state kinetics for LTG were investigated on day 28. From days 29 to 42, volunteers received 500 mg losigamone b.i.d. (n = 9) or Early Experience with UCB LO59 in Refractory Epilepsy. Mat- placebo (n = 3) as add-on medication double-blinded. At day 42, thew C. Walker, *Mohammed K. Sharief, *Josemir W. A. S. steady-state kinetics for losigamone and LTG were evaluated. Sander, *Philip N. Patsalos, and *Simon D. Shorvon (Depart- We compared standard parameters for single and steady-state ment of Clinical Neurology, and *Epilepsy Research Group, In- pharmacokinetics (C,,,, t,,,, area under the curve, volume of stitute of Neurology, London, England)-6081. distribution, half-life, mean residence time, and clearance). UCB LO59 is an ethyl analogue of piracetam with potent antiepileptic activity in a wide range of animal models. We reviewed 28 patients with refractory epilepsy treated with UCB Anticonvulsive Profile of AWD 140-190, a Derivate of a Series of LO59 as add-on treatment in two trials: a single-blind placebo- 3-Aminopyrroles. Angelika Rostock, Christine Tober, Reni controlled trial and a phenytoin (PHT) interaction study. Bartsch, *Chris Rundfeldt, *Dagmar Honack, and *Wolfgang Efficacy was evaluated after 20 weeks of treatment; 6 patients Loscher (AWD CmbH, Dresden; and *Institute of Pharmacology discontinued treatment before 20 weeks, 3 owing to adverse Tierarztl Hochsch, Hannover, Germany)-6084. events (agitation, diplopia, unsteadiness) and 3 owing to perceived lack of efficacy. Eleven patients experienced >50% re- AWD 140-190 is one of the most potent anticonvulsants in a duction in seizure frequency; of these, 3 patients became sei- series of 150 3-aminopyrroles. In the search for new antiepileptic zure-free. One of these patients has now been seizure-free for >2 drugs (AEDs), we elucidated its anticonvulsant profile in animal years and has been successfully converted to UCB LO59 mono- models. Models used were the maximal electroshock seizures therapy. (MES) in mice and rats, the subcutaneous metrazol test (s.c. Side effects in both studies were mild consisting of drowsi- MET) in mice, timed intravenous metrazol infusion (i.v. MET) in ness, depression, memory impairment, and unsteadiness. This mice, electrically corneally kindled test in rats, amygdala- last was associated with a concomitant increase in plasma PHT kindling test in rats, topical application of cobalt in rats, and concentrations and resolved with reduction in phenytoin dosage. DBA/2 mice. Neurotoxicity was determined in mice and rats. UCB LO59 appears to be an effective and safe add-on treatment AWD 140-190 is effective against electrically induced seizures, in refractory epilepsy. Controlled trials are needed. in kindling models against focal seizures, and against cobalt- induced paroxysmal discharges. Seizure severity in the DBA/2 mice is markedly suppressed. Maximal effect is obtained 2-4 h after oral administration. AWD 140-190 shows very good safety. Mechanism of Interaction Between UCB LO59 and Phenytoin. P. The protective indexes vary between 14 and 500 depending on N. Patsalos, M. C. Walker, N. Ratnaraj, J. M. Sharief, J. W. species and test used. Sander, and S. D. Shorvon (Institute of Neurology, Department Data available for AWD 140-190 show that the overall anti- of Clinical Neurology, London, and Chalfont Centre for Epi- convulsant profile is narrower than that of valproate and similar lepsy, Chalfont St. Peter, England)-6082. to that of carbamazepine and phenytoin. According to the anticonvulsant profile, potency, and tolerability, AWD 140-190 is a UCB LO59, a potential new antiepileptic drug currently un- promising anticonvulsant substance for further development. dergoing clinical evaluation, apparently is well tolerated and is efficacious in partial seizures. During a pilot single-blind, placebo-controlled increasing-dose, efficacy, and tolerability study in 17 patients, all 6 patients receiving phenytoin (PHT) comedi- Novel Fluorobenzoylamino Benzopyrans as Potential Anticonvul- cation exhibited some increase in PHT plasma concentrations. sant Agents. Neil Upton, John M. Evans, Mervyn Thompson, The extent of the interaction was variable; PHT dose was re- and Thomas P. Blackburn (SmithKline Beecham, United King- duced in 1 patient, and UCB LO59 dose was reduced in another. dom)--6085. To characterize the mechanism of this interaction, evaluated 13 patients in an open 9-week increasing UCB LO59 dose study Several studies have demonstrated that the antihypertensive (1,000, 2,000 and 3,000 mg/day). potassium channel activator cromakalim can inhibit overt sei- Plasma PHT profiles and 24-h urinary 5-(p-hydroxyphenyl)-5- zure activity in vivo when administered intracerebroventricu- phenylhydantoin/PHT ratios were used to ascertain any meta- lady directly into rodent brain route. Cromakalim was inactive in bolic mechanism, and ultracentrifugation and free (non-protein- a mouse maximal electroshock seizure threshold (MEST) test bound) PHT plasma concentration analysis were used to deter- (Loscher and Schmidt, Epilepsy Res 1988;2: 145-81) after sys- mine any plasma protein binding displacement effect. temic administration (10 mg/kg intraperitoneally), possibly re-

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 77 flecting the relatively poor CNS permeability of the compound. Pharmacokinetic Profile of a New Controlled-Release Valproate Replacement of the pyrrolidinone group of cromakalim to yield Formulation. David Roberts, Derrick Easter, and Gillies fluorobenzoylamino benzopyrans (FBB) led to identification of a O’Bryan-Tear (Sanofi Winthrop, Guildford, Surrey, England)- novel series of orally active analogues that effectively increased 6088. the shock level required to induce tonic hindlimb extensor seizures in mice at doses devoid of behavioral depressant actions A new formulation of valproate (VPA, Epilim Chrono con- (e.g., muscle relaxation). trolled release) has been developed to reduce the peak-trough The oral potency of lead compounds from the FBB series variation in plasma VPA levels that occurs with more conven- [minimum effective dose (MED) < 10 mg/kg] compared favor- tional formulations. In a three-period repeat-dose randomized, ably with that of clinically effective antiepileptic drugs such as cross-over study, we compared 1,000 mg VPA daily either as carbamazepine (MED 10 mg/kg) in the MEST model. Further- twice-daily enteric-coated tablets (Epilim EC), twice-daily Ep- more, in this new series, we could clearly differentiate the struc- ilim Chrono, or once-daily Epilim Chrono in 18 male volunteers. tural requirements for anticonvulsant and cardiovascular effects Epilim Chrono, whether given once daily (1,000 mg, a.m.) or in rodents. FBB are not structurally similar to other anticonvul- twice daily (b.i.d., 500 mg) was fully bioequivalent to the enteric- sant agents and may represent a novel approach to epilepsy coated tablets (500 mg bd). Chrono bid., showed reduced peak treatment. plasma VPA levels considerably and increased trough levels more than did the EC tablets, confirming the controlled-release characteristics of the formulation. Volunteers receiving Chrono once daily (a.m.) showed reduced post dose peak VPA levels but Anticonvulsant Effect of Fluoxetine in Humans. Claudio Albano, trough levels similar to those of the EC b.i.d. regimen. Vitantonio Rubino, Gabriella Besio, Gianluigi Lunardi, and Le- The reduced peak-trough variation in plasma VPA levels now onardo Cocito (University Department of Neurology and CNR possible with b.i.d. controlled-release formulation may further Neurophysiology Centre, Genova, Italy)--6086. reduce the low incidence of concentration-related side effects as well as risk of drug interactions; it will also permit more reliable Fluoxetine, a selective 5-hydroxytryptamine inhibitor exerted serum level monitoring for dose titration, tolerability, and com- anticonvulsant effect in animal models of epilepsy. On this basis, pliance. This new formulation also has the potential for once- 17 outpatients with poorly controlled epilepsy (9 men, 8 women, daily administration, with considerable benefits both in conve- mean age 37.9 years -t 19 SD, range 18-56) entered a pilot trial nience and in better patient compliance. of additional fluoxetine (20 mg/day) for a mean duration of 8 months 2 1.9 SD. All patients had complex partial seizures, often secondarily generalized, with a frequency of at least one Our Experience with Orfiril (Valproate) in Therapy for Epileptic seizure a day despite conventional antiepileptic drug (AED) Syndromes in Children R. Slapal, H. MiSurcovB, A. Zouhar, and treatment. Duration of epilepsy was 12-38 years (mean 20.1 * S. MareSovB (Department of Children’s Neurology, Masaryk 8.1 SD). Etiology was early brain damage in 12, Down syndrome University, Brno, Czech Republic)4089. in 1, and unknown in 4. Concomitant treatment was carbamazepine (CBZ) in 11, CBZ + phenobarbital (PB) in 5, and val- We assessed the effects of various forms of Orfiril (valproate, proate (VPA) + PB in 1. Six patients (35%) became seizure-free VPA) in 31 children (16 girls, 15 boys) aged 0.5-16.5 years (av- for the entire treatment duration; the other 11 patients had a erage 5 years). DRG Retard was administered to 16 children in a sustained decrease in seizure frequency, with an average de- single dose (to 8 in the afternoon, to 7 in the evening, and to 1 in crease of 30% as compared with pretreatment baseline. Two the morning) and twice a day in 2; DRG was administered to 9 patients also showed marked reduction in EEG abnormalities. children, and SAFT to 4 children twice a day. In most cases it No adverse events were reported; VPA serum concentrations of was monotherapy (12-50 mglkglday , the average 32 mg/kg/day). CBZ, PB, and VPA did not change significantly during treatment VPA was used for 1 month to 1.5 years (average 0.5 year); with fluoxetine. Because none of the patients ever obtained sig- 64.5% of patients had partial and secondarily generalized epilep- nificant benefit from any of the AEDs used, fluoxetine may rep- tic seizures, 32.3% from various age-dependent epileptic syn- resent a beneficial treatment of drug-resistant epilepsy. dromes, including encephalopathies. Regardless of drug form used and type of epileptic syndrome, we noted recorded excellent clinical effects (78.6%) even in EEG (73.1%). Side effects were observed in only 2 children (6.5%). Pharmacokinetics of Total and Free Valproate During Monother- The most stable VPA plasma level was noted during two-phase apy in Epileptic Children and Adolescents. Barbara Steinborn and application of DRG, the least stable level was noted during Bozena Galas-Zgorzalewicz (Department of Developmental twice-daily administration of DRG Retard (the highest level was Neurology, Poznan, Poland)d087. usually recorded 12-18 h after single application). More striking exceeding of the upper therapeutic limit (range 50-100 pg/ml) Because valproate (VPA) is a drug with high, concentration- was noted in 2 patients only, but explicit correlations between dependent binding in plasma, moderate changes in free drug lev- Orfiril dose and VPA plasma level, or between the degree of els may have considerable kinetic consequences. The pharma- increase in level and therapeutic or side effects cannot be con- cokinetics of free and total VPA in plasma after oral administra- firmed. tion during steady state was investigated in children and adolescents receiving monotherapy. Total and free VPA concentrations in serum were measured by TDX Analyzer (Abbott Di- agnostic Division, U.S.A.). Free fraction was selected by Ami- Depakine Chrono (Sanofi) in Epileptic Seizures in Children. Ro- con ultrafiltration method. VPA binding varied considerably. man Ignatowicz, Lucja Ignatowicz, Tomasz KmieC, Roman The percentage of free VPA in plasma increased with increasing Michaiowicz, and Jerzy PodleSny (Department of Child Neurol- total VPA concentrations. Diurnal fluctuation in total VPA (as a ogy, Child Health Centre, Warsaw, Poland)d090. fluctuation index) was higher than the same values of free VPA. Other pharmacokinetic parameters of total VPA also were Antiepileptic drugs with slow-release action appear to be more higher, e.g., mean half-life. Mean clearance (CI) calculated based valuable in disease management than in conventional therapy. on total VPA concentrations was significantly lower than mean Especially in children, it is important to reduce 3 or 4 daily doses C1 value based on free VPA levels. All pharmacokinetic param- to only 1 or 2 during long-term treatment with more than 1 drug. eters were compared with total daily dose of VPA and age of Frequently, this is a psychological issue for children. We treated subjects. Results indicate the great usability of pharmacokinetics 50 children aged 10-16 years with generalized tonic-clonic sei- research on free and total fraction in individualization therapy. zures, absence, myoclonic (Lennox-Gastaut syndrome), and

Epilepsia, Vol. 35, Suppl. 7, 1994 78 EUROPEAN CONGRESS PROCEEDINGS

partial complex seizures with Depakine Chrono (Sanofi) in 300- During this period, any comedication was left unchanged. After and 600-mg tablets with slow-release action. Two thirds of pa- 3 weeks, we repeated the protocol at about the same time. tients had psychotic and behavioral symptoms. All patients had Results showed a decrease in P300 latency in 19 of the 21 been treated with Depakine Chrono at daily doses of 30MOO mg patients (90.4%), with a mean of 15 ms. Changes in NlOO latency (25-30 mg/kg/day). During 6-12 months of treatment, we as- were more variable, with slight increase or decrease in -50% of sessed the effects of therapy; adverse events were assessed with cases. Despite the relatively low reports of side effects, sus- EEG tracings, laboratory tests, and serum level concentration. tained-release formulation was better tolerated and serum levels Mean therapeutic level of drug in serum was quite stable for 24 were usually lower. P300 could detect subtle changes in cogni- h (50 & 10 mg/L. Forty children had seizure frequency reduction tion even when no major side effects occurred. Our results indi- >50%, and 4 had slight gastrointestinal disturbance; liver labo- cate that quality of life is improved by use of the sustdined- ratory tests soon showed abnormality with no clinical signs in I. released VPA. Twenty-seven children received combination therapy: phenobarbital, carbamazepine, and phenytoin (rarely benzodiazepines). No child experienced an adverse event during Depakine Chrono treatment monotherapy or during treatment with Depakine Elimination Half-Life of Ethosuximide in Children. Ritva Anneli Chrono combined with other drugs. Salke-Kellermann, The0 May, Hansz-Erich Boenigk, and Peter Wolf (Epilepsy Center Bethel, Bielefeld, Germany)--6093.

Ethosuximide (ESM) is an effective drug in treatment of absence seizures. Its clinical pharmacology is not yet been com- Cognitive Function Impairments in Patients with Epilepsy Treated pletely understood. Its long half-life (tlh) was estimated to be with Valproate (Depakine Chrono, Sanofi). Piotr Czapidski and nearly 60 h by Dill et al. (1965) in adults. Later, the t% studied in Ewa Czapinska (Department of Neurology, Polish American clinical conditions by Salke-Kellermann (1993), appeared to be Children Hospital, Collegium Medicum, Jagiellonian University, shorter than in healthy persons (mean 32.0 h). Krakbw, Poland)-6091. Metabolism of ESM could be accelerated in children as compared with adults. We wished to determine whether the t% of Many factors can affect cognitive functions in epilepsy, including seizure type, duration, severity and etiology, age at seizure ESM could be accelerated in children as compared with adults. We wished to determine whether the t% of ESM in chronically onset, cerebral substrate, hereditary and psychosocial factors, treated children with comedication would be shorter than that and antiepileptic drugs. In 26 patients aged 15-18 years treated commonly reported in the literature (mean 29,7 h, Buchanan et with valproate (KPA) (Depakine Chrono) for epilepsy, we per- al. 1976 Clin Pharrnacol Ther 1976;19:143-7, and 35.5-39.2 h) formed repeated neuropsychological studies, including tests of Browne et al. (Neurology 1975;25:515-24). perception accuracy and speed, attention concentration and di- We followed ESM elimination prospectively in 8 children visibility, learning ability, visual and auditory memory span, vi- (mean age 8.6 years) in whom ESM had been discontinued. One sual-motor coordination, and intelligence level. Patients were patient had no comedication; the remaining patients was treated divided into three groups: (a) monotherapy with VPA (n = lo), with other nonenzyme-inducing antiepileptic drug (VPA, 6; bro- (b) patients in whom VPA was discontinued after 3-year treat- mide, 1). ment = (n 6), and (c) patients in whom VPA was substituted for The measured t% of ESM (range 34.8-78.1 h, mean 45.5 h) was = Group 1 showed impairment in carbamazepine (CBZ) (n 10). longer than expected, which may have clinical consequences. focal attention, digit symbol substitution, and complex reactions Abrupt discontinuation of ESM was not combined with symp- to visual-auditory stimuli. Three months after cessation of ther- toms of discontinuation or with greater seizure frequency. apy, group 2 demonstrated improvement in attention in visuomotor functions, spatial organization and conceptual-verbal functions. Three months after CBZ withdrawal, group 3 showed improvement in attention in visuomotor functions, learning abil- Efficacy of Carbamazepine Therapy Related to Laterality of Epi- ity, and immediate memory span. Results indicate slight and leptiform EEG Focus in Children and Adolescents. NebojSa JoviC, selective impairment of cognitive functions during VPA therapy, Aarko MartinoviC, and Dragana MarinkoviC (Medical Faculty of but impairment less than that observed with CBZ. Belgrade University, Belgrade, Yugoslavia)-6094.

We reviewed the clinical and EEG records of 142 patients, aged 5-16 years (mean 12.8 years) treated for partial seizures Sustained-Release Valproate Versus Conventional Formulation of (PS). Carbamazepine (CBZ) monotherapy, the drug of first Valproate Using P300 as an Index of Cognitive Function. J. P. choice, was administered for at least 2 years and monitored with Foreid, T. Pimentel, *G. Silva, and M. Moniz Botelho (Labora- serum levels. Subjects who remained seizure-free were consid- tory Neurofisiologia, Instituto Portugu&s Oncologia; and *S. ered completely controlled. Evaluation of efficacy of CBZ ther- Psiquiatria, H. J. M., Lisbon, Portugal)--6092. apy was based on number of seizures and time needed to achieve seizure control. Epilepsy is associated with cognitive disfunction. Much evi- Patients with left-sided (n = 77) and right-sided (n = 65) EEG dence shows that antiepileptic drugs (AEDs) also affect perfor- foci were compared. Complete control was obtained with CBZ in mance. Valproate (VPA) is considered to have little effect on 64(83.1%) patients with left and in 38(58.4%) with right EEG cognitive impairment, but side effects, including neurologic dis- abnormalities. Patients with PS alone responded better to CBZ function, may be related to the degree of serum fluctuations and (81.2%) than did those with seizures secondarily generalized peak levels. We compared sustained-release VPA with conven- (PSSG, 49.6%). tional formulation VPA, using P300 as an index of cognitive func- Efficacy of CBZ was not related to the site of the active epi- tion. leptogenic focus in patients with benign PS and other PS with Twenty-one patients were treated with VPA: 19 receiving elementary symptomatology. Patients with left EEG focus re- monotherapy, and 2 receiving combination VPA and CBZ. Pa- sponded better to CBZ, either having PS alone (84.2%) or PSSG tients had treated with VPA for at least 4 weeks. A series of (73.3%). In the group of incompletely controlled patients, 56.2% event-related potentials to auditory oddball paradigm was per- patients with PS alone and 80.9% with PSSG had right-sided formed -2 h after the first daily administration of VPA. Com- epileptiform EEG foci. puterized EEG was also registered to ensure vigilance. Serum Active EEG focus in the dominant hemisphere was related to concentrations were determined shortly after conventional VPA complete seizure control in 71.6% patients. Thus, there was high was replaced with an equal dose of sustained-release VPA (LA correlation between laterality of EEG abnormality and therapeu- 40220, Depakine Chrono) administered once daily, at supper. tic response to CBZ in children and adolescents with PS. EUROPEAN CONGRESS PROCEEDINGS 79

Nonepileptic Myoclonias Induced by Carbamazepine in a Child treatment of newly diagnosed patients, CBZ causes no cognitive with Benign Partial Epilepsy with Rolandic Spikes. V. Sgrb, A. impairment. How severe cognitive impairment might be with Saltarelli, L. Minotti, L. Guidolin, A. Vignoli, M. P. Canevini, faster titration, higher dosages, or combination therapies must be and R. Canger (Regional Epilepsy Centre, S. Paolo Hospital, demonstrated by further studies. University of Milan, Milan, Italy)-6095.

Carbamazepine (CBZ)-induced myoclonias and atypical seizures have often been reported. We observed myoclonic jerks Cognitive Side Effects of Phenytoin as Compared with Carbam- involving the left upper extremity in a 12-year-old boy with be- azepine in Patients with Localization-Related Epilepsy. A. P. Al- nign partial epilepsy (BPE) with rolandic spikes, both spontane- denkamp, W. C. J. Alpherts, L. Diepman, B. van-t Slot, J. Over- ous and those evoked by tapping, 1 month after initiation of CBZ weg, and J. Vermeulen (Instituut voor Epilepsiebestrijding, therapy (800 mg/day; plasma levels 9 pg/ml). The myoclonias Meer en Bosch, Heemstede, The Netherlands)d098. were very frequent during the day. EEG polygraph recording showed several myoclonias involving the distal muscles of the The adverse effects of carbamazepine (CBZ), as compared left upper extremity correlated to EEG paroxysms, topographi- with phenytoin (PHT), on cognitive function were investigated in cally and morphologically similar to the spontaneous myoclonias an open, parallel-group, nonrandomized clinical investigation: a and those evoked by tapping. group of 25 patients receiving CBZ monotherapy versus a group Hypothesizing a reflex origin of the myoclonic jerks, we ini- of similar size receiving PHT monotherapy. The two groups tially increased CBZ. Because myoclonias worsened, we substi- were carefully matched and showed no significant differences on tuted VPA for CBZ. Myoclonias ceased several days after dis- variables that could confound comparison of drug-specific ad- continuation of CBZ. We suggest that these involuntary move- verse effects: age, gender, intelligence, type of epilepsy, seizure ments, induced by CBZ, may be considered a trigger for related type, seizure frequency, EEG focus, and age at epilepsy onset. EEG paroxysms such as the tapping phenomenon. All patients had localization-related epilepsy, and serum levels were within therapeutic range. CBZ treatment did not immediately precede PHT treatment and vice versa. All patients were investigated with a comprehensive neuropsy- Influence of Carbamazepine on Serum Uric Acid Concentration in chological test battery assessing the cognitive domains of Epileptic Patients. H. Fichsel, G. Fichsel-Wigand, and N. Liap- “speed-factors” memory, and attention. Results showed poorer pis (University Children’s Hospital, Neuropediatrics, Bonn, performance by the PHT group as compared with the CBZ group Germany)d096. on all tests measuring motor speed. PHT can also affect speed of central “higher cortical” processing systems: Our results also Recent studies of serum uric acid concentration during anti- showed slower performance in tasks that measure speed of in- epileptic drug (AED) treatment demonstrated influences of the formation processing (“mental speed”). The other areas inves- various AEDs on this concentration. In a group of epileptic chil- tigated, i.e., short-term memory, long-term (verbal and nonver- dren and adolescents treated with carbamazepine (CBZ) mono- bal) memory, and selective attention showed no statistically sig- therapy and in a group of patients receiving CBZ therapy com- nificant differences between the groups. Our results reconfirm bined with other AEDs, we studied the influence of CBZ on that patients treated with PHT may have cognitive side effects serum uric acid concentration. Healthy children and adolescents even when the medication is sufficiently controlled and admin- of the same age were used as controls. istered within the assumed therapeutic range. CBZ monotherapy caused a statistically significant decrease in uric acid concentration. A similar effect was noted in patients receiving combined treatment with CBZ. In comparison with that of controls, the decrease in patients’ uric acid was -0.8 Changes in Attention and Concentration. L. J. A. E. Beech (The mg/dl, i.e., >15% of normal uric acid contrations. The underly- David Lewis Centre, Manchester, England)-6099. ing mechanism is not yet clear. The enzyme-inducing properties of CBZ may be one factors. Certain reductions in antiepileptic medication have been suggested to lead to significant improvement in attention and concentration of persons with epilepsy. As part of a detailed inquiry, we made three single case studies measuring attention and con- No Cognitive Impairment with Low to Medium Dosage of Carbam- centration on both FePsy Computerised Neuropsychological azepine in Newly Diagnosed Epilepsies. Birgit Zahner, Elisabeth Testing Battery and some of the psychometric tests used in Pauli, Jan Sommer, and Hermann Stefan (Psychiatry Depart- neuropsychological assessment (e.g., Wechsler Logical Mem- ment of the University of Erlangen, Erlangen, Germany)-6097. ory). Similar measurements were also obtained when no medication changes had been made. Our results show an appreciable The side effects of carbamazepine (CBZ) are still controver- difference in attention and concentration as measured by FePsy, sial. Many previous studies did not assess intraindividual perfor- but do not show similar changes on psychometric measurements. mance of patients before and during treatment. Ten patients received CBZ 450-750 mg/day for treatment of newly diagnosed epilepsies. The titration period lasted at least 2 weeks. Patients were asked for complaints and were evaluated neuropsycholog- Therapy for Epileptic Syndromes by Timonil Retard (Carbam- ically before treatment and after planned dosage was reached. azepine) in Childhood: Own Experience. R. Slapal, H. MiSurcovB, Ten subtests were performed at least twice in every patient. We A. Zouhar, and S. MareSova (Department of Children’s Neurol- used a rating scale of subjective alertness, multiple-choice vo- ogy, Masaryk University, Brno, Czech Repub1ic)dlOO. cabulatory test, Raven’s Progressive Matrices, general well- being scale, reproduction of a word list, continuous attention We administered Timonil Retard (carbamazepine, CBZ) to 30 test, Beck Depression Inventory, second reproduction of the children (16 boys, 14 girls) aged 1.5-16.5 years (average 8 years). word list, vigilance test (“Quatember Maly”), and Digit Span The most frequent indication for treatment was partial epileptic forward and backward. seizures, mainly with complex symptomatology and secondarily Ninety percent of patients became seizure-free. Plasma levels generalized seizures. Generally, all children received monother- were 4.7-9.3 pg/ml. There was no statistically significant dete- apy as single dose (16 children in the afternoon, 12 in the eve- rioration in any subtest correlated to dosage and plasma levels ning, 2 in the morning; 11-24 mg/kg/day, average 17.5 mg/kg/ and no truly statistically significant deterioration in any patient. day). Duration of antiepileptic drug treatment was 1 month to 1.5 Neither did subjective wellness change. year (average 0.5 year). At least at lower dosages and with slow titration as is used for We obtained excellent clinical effects (74.1%), which were less

Epilepsia, Vol. 35, Suppl. 7, 1994 80 EUROPEAN CONGRESS PROCEEDINGS evident on EEG (34.6%). Side effects were observed in only 2 GI and SBI indexes were higher in epileptic persons than in patients (6.7%). CBZ plasma level was relatively stable; noted; controls. Only the PI1 was similar in both groups. The gingival values were rarely greater than the required therapeutic range enlargement detected two thirds of epileptic patients was most (4-10 pg/ml), usually not significant. The highest level was usu- prominent in the mandibular incisors. There was no definite ally recorded 612 h after Timonil Retard administration, but, dose- or plasma and saliva concentration-dependent increase in more substantial differences in stability of therapeutic level, de- incidence of gingival overgrowth. A trend toward higher plasma pending on time of administration, were not observed. We noted PHT levels was associated with greater gum hyperplasia. no explicit correlations between dose and CBZ plasma level or between plasma level and therapeutic or side effects. Initial Development, Reliability, and Validity of a Patient-Based Adverse Drug Event Scale. G. A. Baker, P. Frances, E. Middle- Rectal Use of Carbamazepine in Postoperative Period. Olga Eisler, ton, A. Jacoby, G. J. Schapel, 9. Defalla, C. Young, D. F. Anna Gal, and Katalin T6th (National Institute of Neurosurgery, Smith, and D. W. Chadwick (Department of Neuroscience, The Budapest, Hungary)--* 101. Walton Centre, Liverpool, Englandf-6104.

Postoperative seizures are common and feared complications As part of the further refinement of a health-related quality of of operation in patients with tumor and epilepsy. One of the main life measure for persons with epilepsy, we developed a patient- cause of postoperative seizures is the decrease in serum level of based adverse drug event scale. In initial development of the antiepileptic drugs caused by difficulties in oral supplementation. scale, 250 patients were asked to describe common side effects Lacking the parenteral formulation, we administered 300-mg associated with early treatment. A 19-item Likert-type response carbamazepine (CBZ) suppositories two or three times daily dur- scale was constructed and further assessed in 90 patients with ing the postoperative days to prevent this complication in CBZ matched controls for evidence of reliability (alpha = 0.89) and therapy. Fifteen patients were studied. Blood samples were construct and content validity. taken every 4 h and the CBZ level was estimated by high- The scale was recently applied to a community study of performance liquid chromatography. The values remained within >I ,300 patients with epilepsy and comparisons of results from the therapeutic range in all investigated patients, and protection the adverse drug event scale were made with monotherapy, poly- from seizures was maintained. Our experience shows that risk of therapy, and individual antiepileptic drugs (AEDs). Although pa- postoperative seizures can easily be diminished by use of the tients reported no difference on a comparison of monotherapy rectal formulation of CBZ. and polytherapy, there were clear differences in the mean scores for the different AEDs. Further analysis will examine individual items and their ability to discriminate between different AEDs. We believe that the patient-based adverse drug event scale is a Carbamazepine (CBZ) Versus CBZ-Controlled Release: Long- useful contribution to assessing patients’ perceptions of the im- Term Study. Gianluigi Lunardi, Vitantonio Rubino, Paolo Main- pact of their treatment. ardi, Gabriella Besio, and Claudio Albano (Department of Clin- ical Neurology of University and Neurophysiology Center of C.N.R., Genoa, Italy)-6102. Epilepsy in Children: How Optimistic Should We Be About Treat- We studied 247 patients treated with conventional carbam- ment? Eulalia Calado and Karin Dias (Unidade de Neurologia azepine (CBZ-CO) and 59 treated with controlled-release car- Pediatrica, H. D. Estefgnia, Lisbon, Portugal)4105. bamazepine (CBZ-CR) for at least 6 months. The percentage of difference between evaluation of two plasma levels, one before With the advent of new antiepileptic drugs (AEDs) in the last first daily intake and the other 5 h later (delta level), was con- few years, doctors, patients, and families developed great expec- sidered an index of drug plasma level variations. A significantly tations of better control of resistant epilepsies. In our busy ref- lower delta level was noted in patients receiving CBZ-CR, espe- erence clinic for pediatric epilepsy, we reviewed all patients re- cially if the patients were treated with bitherapy with CBZ and ceiving AED treatment for at least 1 year to analyze the impact phenobarbital. Thirty-one other patients in whom CBZ-CR was of vigabatrin (VGB) on their daily life. We identified a population substituted for CBZ-CO had better clinical results. of 332 children and adolescents aged 1-19 years: 135 primary epilepsies, 187 secondary epilepsies, and 10 of doubtful etiology; 194 patients receive monotherapy (58%), with carbamazepine (CBZ) the most used drug (133 patients), followed by valproate Effect of Chronic Treatment with Phenytoin, Carbamazepine, and (61). At present, 63 children receive GVG (19%), with good or Valproate on Periodontal Condition of Epileptic Children and Ad- reasonable control in 20. All but 2 patients receive VGB in poly- olescents. Boiena Galas-Zgorzalewicz, *Maria Borysewicz- therapy; CBZ is the most commonly associated AED. Lewicka, *Eleibieta Borowicz-Andrzejewska, Malgorzata Ninety children (27%) have deficient or poor control of their Zgorzdewicz, and Barbara Steinborn (Departments of Develop- epilepsy (13 primary, 72 secondary, and 5 of doubtful etiology). mental Neurology and *Paediatric Dentistry, University of Med- All but 3 were treated with GVG without success. Next, we will ical Scences, Poznari, Poland)-6103. attempt use of lamotrigine and felbamate, but our experience indicates that even by the year 2000 too many children will still Periodontal condition was studied in 100 epileptic patients be treated with polytherapy yet will continue to have uncon- aged 8-18 years who had been assigned to antiepileptic drug trolled epilepsies. (AED) treatment for a period of at least 12 months. They were diagnosed as having partial seizures (simple or complex) or generalized tonic-clonic seizures and were treated with therapeutic oral doses of phenytoin (PHT), carbamazepine (CBZ), or val- Sales of Antiepileptic Drugs in Portugal from 1980 to 1992 I. Pre- proate (VPA) in mono- or polytherapy. All received drug dos- scription Tendency. J. Ramalheira, M. R. Silva, J. Lopes, A. P. ages that provided adequate plasma concentration and satisfac- Correia, J. Pinheiro, M. Correia, H. J. Pereira, and J. M. Lopes tory seizure control. AED saliva and plasma concentrations Lima (Consulta de Epilepsia, ServiCo de Neurologia, H. G. S. were measured by fluorescence polarization immunoassay Antonio, Porto, Portugal)dl06. method with the TDx Analyzer (Abbott, Diagnostic). Gingival index(GI), sulcus bleeding index (SBI), and plaque index (PII) We studied the evolution of sales of different antiepileptic were scored individually. The control group contained 30 healthy drugs (AEDs) in Portugal from 1980 to 1992. Data were obtained children and adolescents of matched age. from the different pharmaceutical companies operating in the

Epilepsiu, Voi. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 81

Portuguese market. The number of AEDs prescribed is increas- must feel they have infinite license to discuss alternative treating. Carbamazepine is the AED used most often, but the differ- ment. A rational approach is not sufficient; a supportive nonpa- ent formulations of valproate and even of phenytoin are also in ternalistic attitude is best. Consequently, we must evaluate the wide use. Phenobarbital has been in stable use in the same time course of an individual’s alternative experiment and hope that period and, in the last 3 years, the number of new medications future controlled studies will provide the needed answers about and/or formulations has increased. Our analysis showed positive the effects of alternative medication. evolution in epilepsy treatment, but also that some obsolete attitudes still exist. U.K. Survey of Treatment of Drug-Resistant Convulsive Status Epilepticus. Matthew C. Walker, Shelagh J. M. Smith, and Si- Sales of Antiepileptic Drugs in Portugal from 1980 to 1992: 11. mon D. Shorvon (Epilepsy Research Group, Institute of Neurol- Evaluation of Costs. J. Ramalheira, M. R. Silva, J. Lopes, A. P. ogy, London, Eng1and)dllO. Correia, J. Pinheiro, M. Correia, H. J. Pereira, and J. M. Lopes Lima (Consulta de Epilepsia, ServiGo Neurologia, Hospital G. S. Convulsive status epilepticus (SE) unresponsive to first-line Antonio, Porto, Portugal)--6 107. therapy is associated with significant morbidity and mortality, and the best treatment strategy is still debatable. Therefore, we Costlbenefit assessments of treatment of different diseases are wished to determine and evaluate critically the therapeutic and being made more often in modern societies. We evaluated the monitoring strategies used by those involved in management of costs of pharmacologic treatment of the epilepsies. SE resistant to initial therapy with intravenous (i.v.) diazepam Our data were supplied by Ciba-Geigy. We analyzed the evo- (DZP) and phenytoin (PHT) on intensive care units (ICUs) in the lution of cost in millions of Portuguese escudos (PTE) of the United Kingdom. Postal questionnaires were sent to 694 mem- main pharmacologic groups [carbamazepine (CBZ), valproate, bers of the Intensive Care Society working in the United King- phenytoin, and phenobarbital]. dom; 434 (62.5%) were returned. CBZ accounts for half of the money expended. The total Our survey showed that in U.K. ICUs, after failure of initial amount spent was five times greater by the end of the time period management with i.v. PHT and DZP benzodiazepine infusion studied as compared with 1980. The more recent medications, (35%) is the most popular second-line treatment. General anes- although in very restricted use, already account for considerable thesia would be induced s60 min after the start of SE by 57%; cost. This type of analysis is very important for evaluation of the the majority (82%) would use thiopental as the anesthetic agent, impact of a disease on society and also as an epidemiologic in- and patients would be monitored by most (45%) using clinical dicator. assessment only. Only 12% of the respondents had a protocol for SE on their ICU. Our study emphasizes the urgent need for multicenter comparative trials of treatment of SE. Pharmaco-Economic Study To Appraise Cost-Effectiveness of Four Antiepileptic Drugs. A. O’Neill, M. R. Trimble, and C. E. Selai (Institute of Neurology, London, England)dl08. Prognosis in Newly Diagnosed Adult Epilepsy. J. Stewart, A. Heller, A. L. Johnson, and E. H. Reynolds (The Centre for A model of treatment consequences for adjunctive therapy in Epilepsy, The Maudsley Hospital, London, SE and MRC Bio- epilepsy was developed to estimate the expected cost per patient statistics Unit, Cambridge, England)dll 1. of treatment and the proportion of successfully treated patients for each of three alternatives [initiating treatment of patients with We previously reported a multicenter prospective comparative either clobazam (CLB), vigabatrin (VGB), or lamotrigine monotherapy trial of four antiepileptic drugs (phenobarbital, (LTG)]. A 1-year treatment period was assessed; clinical and phenytoin, carbamazepine, and valproate) in 241 adults (aged cost data were obtained from review of the literature and clinical >I6 years) followed for a median of 30 months who had newly experience. Seizure control was defined as having at least 50% diagnosed previously untreated epilepsy, i.e., a minimum of two reduction in seizure frequency; at any time when a patient was or more tonic clonic seizures or partial seizures with or without not controlled, treatment was switched to another therapy, as becoming secondarily generalized. We noted no difference in would occur in normal clinical practice. In cases in which CLB, efficacy between the four drugs. At 36 months, 75% of the pa- LTG, and VGB were all unsuccessful, a fourth new adjunctive tients had achieved a l-year remission. therapy, gabapentin was administered. A theoretical “decision- We have now extended follow-up of the 127 patients who were tree” was drawn up and costed. Despite development of toler- recruited in the London area to the end of 1992, i.e., by 45 ance in some initial responders to CLB, it is nonetheless -40% months. In this group, we examined multiple factors that influ- more cost-effective than either VGB or LTG as first-choice ad- ence prognosis for prolonged remission. junctive drug in intractable epilepsy.

Epilepsy, Occipital Calcifications, and Celiac Disease: Anato- Antiepileptic Drugs and Alternative Medication. Gerard J. van der mopathologic Findings and Response to a Gluten-Free Diet. Linden (Instituut voor Epilepsiebestrijding, Meer en Bosch, Giuseppe Plazzi, Paolo Tinuper, Federica Provini, Angelina Cer- Heemstede, The Netherlands)4109. ullo, Carla Marini, *Danielle Gambardelli, and *Jean-Francois Pellissier (Neurological Institute, Bologna University, Bologna, In The Netherlands, insurers yearly pay -65 million guilders Italy; and *Department of Neuropathology, University of Aix- for alternative medication. Patients with resistent epilepsy or Marseille, Marseille, France)4112. with side effects from antiepileptic drugs (AEDs) also are responsible for such expenses, even though the effects of alterna- A 28-year-old epileptic woman had symptoms of celiac disease tive treatment of epilepsy have never been proven through con- (CD) from age 8 months to 15 years. At age 9, she had onset of trolled studies. Therefore, no rational reason exists for alterna- visual seizures. From age 12, she had complex partial seizures tive medication. Yet in epileptologic practice, use of alternative suggesting temporal lobe involvement. At age 17, computed to- medicine is not at all exceptional. Prescriptions from alternative mography scan showed a right occipital cortical calcification. medicine physicians may lead to dose reduction in AEDs and Lesionectomy was performed. Anatomopathology showed a cal- dysregulation of the epilepsy. To prevent such malpractice, ep- cified vascular malformation with pial angiomatosis, fibrosed ileptologists must create a confidential relation with patients who veins, and cortical microcalcifications. Seizures became increas- choose to use alternative medicine. To avoid excess, patients ingly frequent (daily) and drug resistant. At age 25, EEG showed

Epilepsia, Voi. 35, Suppl. 7. 1994 82 EUROPEAN CONGRESS PROCEEDINGS right temporoparietooccipital epileptic activity. Surface video- outcome, yet, 12 of the 24 patients became seizure-free or had EEG recording suggested right temporal ictal onset. Antigliadine only infrequent non-IS seizures. Complications (arterial hyper- antibodies were increased. A small-bowel biopsy showed find- tension, cerebral ventricle dilatation, cardiac hypertrophy, and ings typical of CD. After she starting a gluten-free diet, seizure prolonged adrenocortical hyporesponsiveness) were related to frequency diminished by >90%. A patient described by Bye et the dose. Such an individualized stepwise ACTH treatment reg- al. (Ann Neurol 1993;34:399403) had bilateral occipital calcifi- imen appears to offer patients all the benefits with minimal side cations and similar pathologic findings, but became seizure-free effects and cost. after extensive occipital resection. In our patient, surgical removal of the circumscribed lesion was ineffective and epilepsy worsened until a gluten-free diet was started. The poor surgical outcome may have been due to residual epileptogenic tissue left Prednisolone as an Effective Agent in Refractory Seizures Caused by Encephalitis: Five Case Reports. S. Jalal Ziaie (Medical Sci- to preserve the visual field or to an uninvestigated secondary epileptic temporal foci. Our observation confirms that a gluten- ence University of Isfahan, Isfahan, Iran)4ll5. free diet is mandatory in epileptic patients with suspected CD. During the 8 past years, we treated many epileptic persons aged 8-15 years) recovering from viral encephalitis who were receiving antiepileptic drugs (AEDs). However, in some, AEDs New Medicinal Extension of Thyroliberin in Children’s Neuropa- were not effective and even combination of three or four AEDs thology and Epilepsy. Igor P. Ashmarin, Ludmila M. Aslanova, had no desirable effect. Seven patients had prednisolone added Nina E. Chepurnova, Marina Ur. Nikanorova, Piotr A. Tyomin, to their AED therapy. Five with refractory seizures became sei- Serguey L. Yatzuk, and Serguey A. Chepurnov (Moscow State zure-free. University, Biology Faculty, Serbsky Center for Social and Fo- We suggest prednisolone as an effective agent in refractory rensic Psychiatry, and Institute of Pediatry and Child’s Surgery, epileptic seizures. We use a dose of prednisolone 4&50 mglday Moscow, and Polenov Neurosurgery Institute. Saint Petersburg, initially, gradually decreasing it to 10-20 mg daily. This should be Russia)--6113. continued for 2-3 years, and in some cases longer, even for life.

Thyroliberin (TRH) promoting endogenous antidepressive effect and activation of the nervous system is the most general Hormonal Treatment of Catamenial Epilepsy. Pawl Temin, Kon- regulator of central mechanisms and visceral functions. In cases stantin Muchin, and Pave1 Semenov (Institute of Pediatrics, Rus- of nervous disease or degenerative pathology, TRH included in sian Medical University, Moscow, Russia)dl16. restorative processes prevents degeneration of CNS and promotes fastest rehabilitation. We studied several prospective me- Catamenial epilepsy (CE) is often resistant to traditional anti- dicinal applications of TRH: stimulation of respiration, espe- epileptic drugs (AEDs). We treated 22 women with CE resistant cially for resuscitation; stimulation of lymphatic flow; and nor- to AEDs, using hormonal treatment in addition to AEDs. Ox- malization of cerebral blood flow in premature infants, especially yprogesterone capronatis (OPC) 12.5% solution 1 ml (125 mg) after asphyxia (Ashmarin et al., Vestnik Russian Acad Med Sci was injected intramuscularly from day 20 to day 22 of the men- 1992;6:40-4). TRH is beneficial in treatment of spinal diseases strual cycle once a month. Duration of treatment was 1-6 connected with degenerative processes of the descending brain months. pathways. We studied a novel neuropathologic application of A decrease in seizure frequency was observed in 63.6% of TRH in suppressing or decreasing the severity of epileptic sei- patients; 27.3% were seizure-free; 34.4% had reduction in seizures in an experimental rat model. Our new experimental and zure frequency >50%, and 1 patient had slight effect. The best clinical observations, using TRH in ultralow doses, indicate that therapeutic effect was achieved in “pure” CE. In “mixed” CE, use of TRH could be expanded. The main treatment route of for OPC transformed CE to non-CE with rare seizures. The effect of administration in low and ultralow doses is the intranasal path- OPC persisted for 1-3 months after the last injection and was way, since 10~9-10-’2Mis the level of TRH in cerebral spinal most significant in pure CE. fluid of human patients and animal brain after experimental epileptic seizures. A positive effect was shown in correlation between severity of clinical symptoms and EEG control of seizure frequency. Encouraging results were observed in children with Reflex Epilepsy: Clinical and Treatment Symptoms. G. Panago- attention deficit syndrome treated with TRH (before age 12). poulos, C. Derdelakou, Th. Thomaides, S. Tsiara, and C. L. Karageorgiou (Neurology Department, General Hospital of Ath- ens, Athens, Greece)dll7.

Individualized ACTH Therapy of Infantile Spasms. Hannu We describe the clinical picture and treatment of 8 patients Heiskala, Raili Riikonen, Pirkko Santavuori, *011i Shell, ?EEila with reflex epilepsy of recent onset with partial seizures second- Airaksinen, SAuli Nuutila, and Jaakko Perheentupa (Children’s arily generalized after exogenous stimuli. We report features of Hospital and Department of Child Neurology, University of Hel- the clinical symptoms and the different methods of treatment sinki, Helsinki; *Department of Pediatrics, University of Turku, used; follow-up is now 2 years. Turku; ?Department of Pediatrics, University of Kuopio, Kuo- pio; and tPediatxic Unit, Central Hospital Seinajoki, Seinajoki, Finland)--6 1 14. Therapy of Startle-Induced Seizures. Thomas Mayer and Ulrich ACTH treatment of infantile spasms (IS) was assessed in a Specht (Epilepsy Center Bethel, Bielefeld, Germany)dl18. prospective multicenter study. Each patient’s dosage was adjusted stepwise based on etiology of the spasms and response to Startle-induced phenomena are rare. Semiology, etiology, and ACTH. Six patients with cryptogenic and 24 with symptomatic pathophysiology vary considerably, and not all of them are of spasms participated. Total ACTH dose ranged from 58 to 373 epileptic nature; e.g., they appear in hyperekplexia, in some tic IUlkg. All but 1 patient with cryptogenic etiology responded to disorders (“jumping”) and in benzodiazepine withdrawal. Star- the lowest dosage (I had already responded to the pre-ACTH tle epilepsy most often occurs in patients with severe brain dam- pyridoxine) with cessation of spasms and good outcome (follow- age and neurops ychiatric handicap. This condition is character- up 1-4 years); the sixth patient, who required the highest dose, ized by epileptic seizures of predominantly tonic symptomatol- became developmentally retarded, but his seizures ceased. In ogy precipitated by sudden unexpected stimuli. Frequency of the symptomatic group, 21 of the 24 patients required a higher seizures is high, and drops are common. Additional spontaneous dosage. Problems due to the basic disease limited their long-term seizures occur in -70% of patients. Therapy is quite difficult.

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 83

Some effect had been reported with clobazam (CLB) and car- In a prospective study, we investigated 97 children with epi- bamazepine (CBZ). lepsy who had been seizure-free for 2 years with single-drug We investigated 31 patients in the Epilepsy-Center Bethel with therapy. Excluded from study were patients with simple febrile startle-induced seizures since 1980. In analyzing these patients, seizures and neonatal seizures. Children were divided into two we developed a classification of startle epilepsy, depending on groups. In the first group, medication was discontinued in 6 coexisting spontaneous seizures: simple startle epilepsy (no weeks (n = 49); in the other, medication was discontinued in 6 spontaneous seizures), twin type (startle-induced and spontane- months (n = 48). Patients were examined for possible associa- ous seizures with identical semiology), and polysymptomatic tion of relapse with duration of discontinuation period, type of type (spontaneous seizures with a semiology different from the seizure, mean duration of seizures, duration of seizure-free pe- startle-induced seizures). riod, the antiepileptic used to control seizures, EEG character- Twelve patients were treated with CLB and 20 were treated istics, behavioral function, and neurologic dysfunction. with CBZ. As a new approach derived from experimental stud- Of the 97 children in the study, 78 (80.4%) remained seizure- ies, we used propranolol (PPL) in 11 patients. PPL achieved free after drug discontinuation. Mean duration of follow-up in results comparable those achieved with CLB and CBZ. Present patients remaining seizure-free was 35.7 months (range 24-78). results and those of previous studies indicate that simple startle We concluded that in most children with epilepsy who have been epilepsy has the best prognosis. seizure-free for 32years, antiepileptic medications can safely be discontinued; risk of recurrence (relapse rate) was significantly different between the group with medication discontinuation in 6 months (12.5%, n = 6) and that of the group with medication Epilepsy During Sleep: 11. Outcome, Prognosis, and Treatment. J. discontinued in 6 weeks (26.5%, n = 13). A. Mauri, J. M. Sanz, C. Sanz, L. F. Pascual, E. Mufioz, and F. Morales (Servicio de Neurologia, Hospital Clinico, Zaragoza, Spain)4119. EEG Prognostic Value in Discontinuation of Antiepileptic Drugs: A We studied 20 epileptic patients (10 males and 10 females with Prospective Study in Partial Epilepsies. Paolo Tinuper, Federica mean age of 34 years and mean duration of seizures of I I .35 Provini, Patrizia Avoni, Roberto Riva, Carla Marini, Elio years) with the following criteria: Age >I6 years, seizures oc- Lugaresi, and Agostino Baruzzi (Neurological Institute, Univer- curring only during sleep, and follow-up >3 years. Epileptic syn- sity of Bologna, Bologna, Italy)-6122. dromes were 13 focal crytogenic, 2 focal symptomatic, and 5 undetermined. There is no consensus in the literature on the prognostic value After 3-year follow-up, 15 patients (75%) were seizure-free and of EEG before and during discontinuation of antiepileptic drugs 5 patients had seizure frequency of 3 seizures a day (1 patient) (AED). Most investigators consider changes in and prognostic and 1-4 seizures a year (4 patients). Antiepileptic drugs ranged significance of EEG in all epilepsies without distinguishing the from one (15 patients) to three drugs (2 patients). Epilepsy during different syndromes or different types of seizures that have dif- sleep has good prognosis, and most patients become seizure-free ferent clinical prognosis. with treatment. We studied 106 partial epilepsy patients: 44 complex partial (CPS), 22 simple partial (SPS), and 40 only focal generalized motor seizures (FGM), seizure-free for almost 2 years before AED discontinuation. Only epileptiform EEG features were con- Therapy with Psychotropic Drugs and Situation-Related Seizures. sidered. Eighty patients (75%) relapsed. R. Spatz, R. Grohmann, and *L. G. Schmid (Psychiatry Depart- In our general population, abnormal EEG at the start of AED ment, University of Munich; and *Psychiatry Department, Free reduction did not increase relapse probability: 27 (67%) patients University of Berlin, Berlin, Gerrnany)-dlZO. with abnormal EEG and 53 (80%) patients with normal EEG relapsed. In the different epilepsy types, epileptiform EEG ab- In 1989, a 10-year-multicenter-Drug Surveillence Study in psy- normalities increased relapse probability only in patients with chiatric inpatients, supported by the Federal Agency in Berlin FGM (p = 0.03); SPS were not included because all patients (BGA) that registered epileptic seizures caused by psychotropic relapsed. drug treatment was completed: 15,264 inpatients, treated with EEG changes during AED reduction and in the 3 years after antidepressive drugs, neuroleptics, and lithium salts were en- withdrawal were negative prognostic factors (p < 0.001). If EEG tered in the study. (normal or pathologic) worsened, relapse probability was very Twenty-one inpatients had generalized epileptic seizures for high: 97% in our general population, 100% in FGM patients, and the first time (I .4 in 1,000). The seizures were caused, partly in 90% in CPS patients. combination, by the following psychotropic drugs: maprotyline (4), amitriptyline (4), levomepromazine (3), haloperidol (3), cloz- apine (3), piperidene (3), lithium salts (3), dipenzepine (2), per- azine (2), fluphenazine (2), clomipramine (l), doxepine (l), and Effect of Valproate on Central Benzodiazepine Receptors in Pa- tranylcypromine (1). tients with Idiopathic Generalized Epilepsies. M. J. Koepp, M. C. The results are comparable to those of the Boston Collabo- Prevett, D. J. Brooks, M. P. Richardson, V. Cunningham, D. R. rated Surveillance Program of H. Jick and J. Porter (1970-1977). Fish, and J. S. Duncan (MRC Cyclotron Unit, Hammersmith In this study of 32,812 inpatients in medical clinics, 24 patients Hospital, London, England)4123. had epileptic seizures for the first time (intravenous penicillin 5, intramuscular insulin 4, lignocaine 4, psychopharmaceuticals 4, We wished to determine the effect of valproate (VPA) on ce- and aminophylline 2, prednisone, vitamin K, ephedrine, atro- rebral central benzodiazepine receptors (BZR) in patients with pine, INH, 1 each). The drug-induced seizure rate in this inpa- idiopathic generalized epilepsy (IGE). VPA is known to result in tient group was only 0.8 in 1,000. The psychotropic drugs prob- reduced y-aminobutyric acid (GABA) concentrations in cerebro- ably have greater ability to decrease the epileptic threshold than spinal fluid. In a previous cross-sectional study, we showed that do drugs used in internal medicine. patients with IGE receiving VPA had a mean 8% reduction in "C-Flumazenil volume of distribution ("C-Fmz-V,). In a longitudinal study, we have now calculated "C-Fmz-V, in 5 patients with IGE aged 19-56 years, using tracer-alone high- Discontinuation of Antiepileptic Drugs in Children with Epilepsy: specific "C-Fmz-positron emission tomography scans. The first Results of a Prospective Follow-Up Study. I. Fineza, C. Robalo, scan was performed when the patient was not taking VPA; the A. Mirante, G. Oliveira, and I. Borges (Hospital PediBtrico de second was performed 4 weeks after addition of VPA up to the Coirnbra, Coimbra, Portugal)4121. clinically indicated dose. V, before and after treatment was com-

Epilepsia, Vol. 35, Suppl. 7, 1994 84 EUROPEAN CONGRESS PROCEEDINGS pared in each patient and with a group of 5 age-matched controls. twitches, clonic seizures, and tonus. HEPES Ringer's solution Addition of VPA was associated with an 8% reduction in "C- with pH 6.7 significantly decreased latency to onset of clonic Fmz-V,. These preliminary results suggest that chronic VPA seizures (317 f 39 s; n = 5) as compared with that of pH 7.4 (563 therapy results in downregulation of the GABAA-BZR complex, ? 72 s, n = 5). There were no significant differences in latency possibly by increasing local GABA levels. to onset of twitches or tonus, but the proconvulsant trend of the more acidic pH was preserved. The data indicate that SNR is an important site for regulation of flurothyl seizures and that local Quantitative Analysis of Benzodiazepine Receptor Density in Tem- changes in pH may significantly affect seizure susceptibility. poral Lobe Epilepsies: Preoperative Results and Postoperative Out- come. S. Venz, H. B. Straub, H.-J. Meencke, J. Hierholzer, and M. Cordes (Department of Radiology and Neurology, UK R. Involvement of Nigral Low-Affinity Gaba, Receptors in Control of Virchow, Free University of Berlin, Berlin, Germany)-6124. Flurothyl-Induced Seizures in Rat Pups and Adult Rats. Jana Vel- lSkova and Solomon L. MoshC (Albert Einstein College of Med- To compare specific binding (SB) of ['Z31]Iomazenil (IMZ), a icine, Bronx, NY, U.S.A.)-6126. benzodiazepine receptor (BR) antagonist suitable for SPECT examination, in the epileptogenic area and the normal contralateral Substantia nigra pars reticularis (SNR) appears to be a gate in hemisphere, we performed IMZ-single photon emission com- controlling seizure propagation. Furthermore, involvement of puted tomography (SPECT) in 17 patients with unilateral tem- SNR is mediated by GABAergic transmission. Previous studies poral lobe epilepsies confirmed by ictal video/EEG-monitoring. showed that bilateral microinfusions of muscimol (a high-affinity The electrodes were placed according to the International 10-20 GABA, receptor agonist) into SNR of 15-day-old rat pups were system, with additional sphenoidal electrodes if necessary. All proconvulsant, i.e., facilitated onset of clonic flurothyl-induced patients were examined 5 and 90 rnin after intravenous (Lv.) seizures. In contrast, in adult rats, muscimol was anticonvulsant, application of 111 MBq IMZ. SPECT data were evaluated by i.e., delayed onset of clonic flurothyl seizures. In present exper- irregular anatomic regions of interest (ROI) which were drawn iments, we studied the action of ZAPA, a low-affinity GABA, ipsilaterally and mirrored to the contralateral side. Total binding receptor agonist. In 15-day-old rat pups, bilateral microinfusions (TB) of IMZ in every region was normalized to whole brain of ZAPA into SNR (2 mg/0.25 ml) significantly increased latency activity and body surface. TB of IMZ in the white matter region to onset of both clonic and tonic-clonic flurothyl seizures. ZAPA was considered nonspecific binding (NB) since this area is free of (2-4 mg/0.25 ml) had no significant effect on either clonic or BR. SB was expressed as the difference in TB - NB. All pa- tonic-clonic seizures in adult rats as compared with saline- tients had magnetic resonance imaging scans and 99mTcHMPAO infused controls. The data suggest that the low-affinity GABA, SPECT examinations. receptors in SN are involved in control of clonic and tonic-clonic The difference in TB (%) in the epileptogenic area as compared flurothyl seizures in 15-day-old rat pups, but not in adult rats. with that of the contralateral normal side was higher in IMZ SPECT as compared with HMPAO SPECT (p = 0.03; Wilcoxon sign test), yielding a higher sensitivity in detecting the epileptogenic area that was confirmed by findings of video/EEG moni- Ontogeny of Pro- and Anticonvulsant Actions of GABA, Agonists toring. Furthermore, the increase in SB of IMZ from 5 rnin to 90 in Substantia Nigra. Douglas Garant, Ellen Sperber, and Solo- rnin pi. was lower in the ipsilateral area as compared with the mon Mosht (Laboratory of Developmental Epilepsy, Albert Ein- contralateral side (p = 0.03; Mann-Whitney U test). A strong stein College of Medicine, Bronx, NY, U.S.A.)-6127. correlation was evident between the difference in SB ipsilaterally (90 min - 5 min. pi.) in the area containing the epileptogenic GABA, receptor-mediated GABA transmission in substantia focus according to video/EEG monitoring and side-to-side dif- nigra pars reticulata (SNR) protects against a variety of experi- ference in SB of IMZ 90 rnin p.i. (r = 0.80; p = 0.0005). Thirteen mental seizures in both mature and immature rats. Curiously, of 17 patients showed decreased BR density >lo% in the ROI in SNR infusions of the GABA, receptor agonists muscimol and the epileptogenic area as compared with the contralateral side; 7 THIP yield biphasic dose-response curves in adults: intermedi- of the 13 underwent classic resection of the epileptogenic tem- ate doses are anticonvulsant, but high doses are proconvulsant. poral lobe, resulting in a 12-month seizure-free period with no In rat pups, only proconvulsant effects of agonists are observed, relapse as yet. and at lower doses than in adults, suggesting that higher concen- SB of IMZ is significantly decreased in the epileptogenic area, trations of these drugs antagonize GABA, receptors in both ma- indicating an alteration in the GABA-BR complex as a functional ture and immature SNR and that pups are more sensitive to this correlate of focal epilepsies. Furthermore, the increase in SB in action. On the other hand, the absence of anticonvulsant effects IMZ SPECT (5 and 90 min p.i.) is another helpful parameter to of agonists in pups demonstrates that in immature SNR these support lateralization of the epileptogenic area. IMZ SPECT is a agonists lack the anticonvulsant efficacy that GABA possesses useful tool in preoperative diagnostic workup of temporal lobe at GABA, receptors. We hypothesize that these profound de- epilepsies and is superior to HMPAO SPECT. velopmental differences in GABAergic response are the result of ontogenic differences in the composition of GABA, receptors in SNR, which may contribute to the well-documented increased Changes in Extracellular pH in Substantia Nigra Pars Reticularis susceptibility of the immature brain to seizures. Modulate Flurothyl-Induced Seizures. Libor VelisCk, Jana VeliSk- ova, and Solomon L. Moshe (Albert Einstein College of Medi- cine, Bronx, NY, U.S.A.)4125. Microdialysis Study of Lamotrigine Kinetics in Rat Brain. Moham- med S. Alavijeh, Matthew C. Walker, and Philip N. Patsalos, Evidence shows that microinjections of neuroactive sub- (Department of Clinical Neurology, Institute of Neurology, stances (such as y-aminobutyric acid and N-methyl-D-aspartate Queen Square, London, England)dl28. (NMDA) receptor agonists and antagonists) into substantia nigra pars reticularis (SNR) modify the outcome of experimental sei- In management of status epilepticus (SE), rapid and effective zures. Recent studies showed that extracellular acidosis can de- treatment is essential if patient morbidity and mortality are to be crease NMDA receptor conductances. Rats were stereotaxally improved. Lamotrigine (LTG) may be clinically useful in treat- implanted with cannulas in anterior SNR and after recovery were ment of SE, and because SE is associated with selective pathol- infused with 0.25 ml of either HEPES Ringer's solution of (pH = ogy involving hippocampus and cortex, we studied its neuro- 7.4 .+ 0.05) or with HEPES Ringer's solution with pH adjusted pharmacokinetics in these brain regions using microdialysis. by 1 N H,S04 to 6.7 t 0.05. Rats were tested in the flurothyl Male Sprague Dawley rats weighing 250-300 g were anesthe- chamber after I rnin and observed for occurrence of myoclonic tized, microdialysis probes were stereotaxically implanted, and a

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 85 catheter was placed in the right jugular vein. Two days later, a decrease in alanine concentrations in hippocampus was ob- LTG 10 mg/kg was administered intraperitoneally to freely be- served. Other amino acids did not change. having rats and sampled for an 8-h period. Dialysate and serum samples were analyzed for LTG content by high-performance liquid chromatography, and neuropharmacokinetic/pharmacokinetic parameters were computed with PCNONLIN. Parameters Piracetam Kinetics in Blood and Cerebrospinal Fluid. Mary H. for serum and dialysate of frontal cortex and hippocampus were Doheny, Mohammed S. Alavijeh, Neville Ratnaraj, and Philip (mean f SEM n = 4-5); T,,, (h): 0.23 * 0.03, 1.00 f 0.45, 0.79 N. Patsalos (Department of Clinical Neurology, Institute of Neu- 5 0.24; C,,, (pIM): 46.2 -C 1.5, 19.9 f 3.5, 28.8 ? 5.5; areaunder rology, Queen Square, London, Englandj-6131. the curve (pw: 599 f 78, 187 f 26, 899 f 174; and t% (h): 9.0 ? 1.4, 5.9 2 0.6, 22.7 * 3.6, respectively. Piracetam, a “nootropic” drug, was recently marketed in the Using microdialysis to monitor brain extracellular environ- United Kingdom for treatment of myoclonus. Although it is a ment and thus events at the neuronal level, we observed that cyclic analogue of the inhibitory neurotransmitter y-aminobu- LTG entry into frontal cortex and hippocampus is similar but tyric acid, its mechanism of action is unknown. Because pirac- that its removal from hippocampus is approximately fourfold etam is very polar, its passage through the blood-brain barrier slower. These data may be important in studies of LTG in rat SE might be expected to be limited; therefore, to elucidate its mech- models. anism of action, we first studied its kinetics with a model that allows simultaneous sampling of blood (pharmacokinetics) and cerebrospinal fluid (CSF, neuropharmacokinetics) (Patsalos et al., J Pharmacol Toxicol Methods 1992;28:21-8. Cerebrospinal Fluid and Blood Kinetics of Acute and Chronic Phe- Male Sprague-Dawley rats weighing 250-300 g (n = 5-8) were nytoin. Philip N. Patsalos, Yvette I. Lolin, and Neville Ratnaraj administered 300 or 600 mgikg piracetam intraperitoneally, and (Department of Clinical Neurology, Institute of Neurology, CSF (30 p1) and blood (100 pl) were collected at intervals for 8 h Queen Square, London, England)dl29. and analyzed for piracetam content. Piracetam C,,, values increased linearly and dose dependently in blood and peaked by The temporal pharmacokinetic (blood) and neuropharmacoki- 14-24 min. Concentrations then decreased exponentially with netic (cerebrospinal fluid, CSF) interrelation of phenytoin (PHT) elimination half-life (t%) values of 1.3-1.8 h. CSF piracetam con- was studied after acute and during chronic (65 days) intraperi- centrations peaked at 80 min and then decreased exponentially toneal administration of PHT 30, 50, or 100 mglkg, using a new with elimination t% values of 3.445 h. Although piracetam freely behaving rat model (Patsalos et al., 1993). After adminis- readily enters brain, its egress is relatively slow. tration, PHT rapidly appeared in both serum (T,,, mean range 0.15-0.38 h) and CSF (T,,, mean range 0.9-1.4 h), suggesting ready penetration of the blood-brain barrier (BBB). However, transport across the BBB may be rate limiting since although Primidone Metabolism and Kinetics in Blood and Cerebrospinal PHT concentrations increased dose dependently in serum, CSF Fluid. Neville Ratnaraj, Shigeru Nagaki, and Philip N. Patsalos concentrations did not. Furthermore, the divergence between (Department of Clinical Neurology, Institute of Neurology, blood and CSF compartments increased with chronic dosing. Queen Square, London, Englandj-6132. C,,,, area under the curve, and half-life values for serum increased nonlinearly, suggesting accumulation kinetics. The kinetics and metabolism of primidone (PRM) were studied These data indicate that high initial PHT blood concentrations with a model that allows simultaneous sampling of blood (phar- are essential if PHT entry into brain is to be facilitated. This may macokinetics) and cerebrospinal fluid (CSF, neuropharmacoki- be important in studies of PHT in animal models of status epi- netics) in freely behaving rats (Patsalos et al., J Pharmacol Tox- lepticus (Patsalos PN et al. J Pharmacol Toxicol Methods 1992; icol Methods 1992;28:21-28). Male Sprague-Dawley rats weigh- 28: 2 1-8). ing 25&300 g (n = 3-6) were administered 50, 100, or 200 mg/kg PRM intraperitoneally, and CSF (30 pl) and blood (100 p1) were collected at intervals for an 8-h period and 24 h later and analyzed for content of PRM and its primary pharmacologically ac- Brain Microdialysis Study of Milacemide, a Glycine Prodrug. Mary tive metabolites phenylethylmalonamide (PEMA) and phenobar- H. Doheny, Shigeru Nagaki, and Philip N. Patsalos (Department bital (PB). PRM and PEMA C,,, values increased linearly and of Clinical Neurology, Institute of Neurology, Queen Square, dose dependently in both blood and CSF. In contrast, PB C,,, London, England)--6130. values for blood were not linearly related and values for CSF were indistinguishable for the three PRM doses. Furthermore, Milacemide is a glycine prodrug whose exact mechanism of whereas half-life values for PRM and PEMA were higher in anticonvulsant action is unknown, but y-aminobutyric acid blood as compared with CSF, the opposite pertained for PB. (GABA) and dopamine (DA) may play a role (Semba et al., These data suggest that derived PB may enteddistribute in the 1992,1993; Semba and Patsalos, 1993). Using microdialysis to CNS through a rate-limiting process. monitor brain extracellular environment, and thus events at the neuronal level, we further investigated the mechanism of action of milacemide. Microdialysis probes were stereotaxically implanted in frontal Influence of Valproate and Carbamazepine on Rat Biliary Secre- cortex and hippocampus of male Sprague-Dawley rats, weighing tion: Effects of Ursodeoxycholate Supplementation. Jean Claude 250-300 g under halothane anesthesia. One day later, artificial Montet, Alfredo J. Zamora, Joelle Bonneton, M. Guitaoui, Anne cerebrospinal fluid was perfused through the probes at a flow Mane Montet, Pierre Genton, and Edouard Mesdjian (INSERM, rate of 2 pl/min. Dialysate samples (40 p1) were collected every Centre Saint-Paul, Marseille, France)4133. 20 min for 2 h. Animals were then injected with milacemide (400 or 800 mg/kg), and sampling was continued for 8 h. Samples were Clinical and experimental studies have shown that valproate analyzed for glycinamide (primary metabolite), glycine, and (VPA) and carbamazepine (CBZ) can cause hepatotoxicity. We other amino acid content. report results of a biochemical and histologic study of rats In both frontal cortex and hippocampus, glycinamide in- treated for 8 days with VPA (200 mg/kg/day), CBZ (200 mg/kgl creased linearly and dose dependently. In contrast, while glycine day) or VPA + CBZ. Ursodeoxycholate (UDC) (60 mg/kg/day), concentrations were increased dose dependently in hippocampus a new hepatoprotective agent, was used as supplement as com- (400 mg/kg = 24%; 800 mg/kg = 35%), glycine was unaffected in pared with in VPA + CBZ-treated rats. Choleresis was signifi- frontal cortex. A concomitant increase in serine and taurine and cantly increased in all groups as compared with controls. VPA 86 EUROPEAN CONGRESS PROCEEDINGS had the strongest choleretic effect, and hepatocytes showed in- be well suited for determination of the full time course of drug tense subplasmalemmal vacuolization. UDC did not modify bile action in conjunction with blood concentration monitoring in in- flow. Biliary bile salt secretion was greatest with CBZ and least dividual animals after a single dosage. with VPA, but the changes did not differ significantly from controls. VPA strongly inhibited biliary phospholipid secretion, whereas CBZ induced greater lipid secretion than VPA or VPA + CBZ. Ultrastructurally, CBZ induced outstanding prolifera- Antiseizure Effects of N-3 Polyunsaturated Fatty Acids on Differ- tion of smooth endoplasmic reticulum in hepatocytes. UDC sig- ent Epilepsy Models in Wistar Rats. Ruslan F. Makulkin, Serge A. nificantly increased lipid output as compared with VPA and VPA Novitsky, Alexander V. Tischenko, Valentine P. Babiy, and + CBZ. UDC did not change biliary secretion as compared with Tatiana V. Korneyenko (Pirogov Medical Institute, Odessa, controls. VPA appears to be the most disturbing antiepileptic Ukraine)dl36. drug, inducing hypercholeresis and hyposecretion of biliary phospholipids. Addition of CBZ to VPA reduced these effects. We examined the influence of N-3 polyunsaturated fatty acids UDC tended to regularize biliary secretion and normalized phos- (PUFA 200 mglkg orally daily for 4 weeks before testing) on pholipid secretion. severity of acute pentylenetetrazol (PTZ) seizures (60 mg/kg intraperitoneally, i.p.) and development of convulsive reactions in bemegrid kindling (11 mglkg i.p. daily) conditions. Biliary Excretion of Carbamazepine and Valproate in Rats. Joelle After a previous N-3 PUFA course, mean severity of PTZ Bonneton, Jean Claude Montet, Anne Marie Montet, Pierre Gen- seizures were significantly reduced (1.35-fold, p < 0. I), general ton, and Edouard Mesdjian (INSERM, Centre Saint-Paul, tonic-clonic seizures ceased in 60% of patients, and repeated Marseille, France)d134. seizures were prevented completely. N-3 PUFA administration made kindling development difficult, reduced intensity of seizure Carbamazepine (CBZ) and valproate (VPA) are now often severity > 1.43-fold (p < 0.02), and decreased severity of maxi- used in combination in treatment of severe epilepsy. Plasma mal seizure reactions 1.32-fold (p < 0.001). The approach time of pharmacokinetic interactions between CBZ and VPA have been maximal seizure reaction was also significantly longer (p < widely studied. We evaluated the kinetics of biliary excretion of 0.001) than that in control observation. Our data show clear an- oral CBZ and intraperitoneal VPA and biliary interactions of tiepileptic effects of N-3 PUFA on acute and chronic epilepsy these drugs in rats. Five groups were studied: controls, CBZ, models, suggesting that N-3 PUFA may be considered a new VPA, CBZ + VPA, and CBZ + VPA in association with oral additional anticonvulsive remedy in neurologic practice. ursodeoxycholate (UDC), a novel hepatoprotector, respectively. Animals were treated for 8 days; hourly fractions of bile were collected on day 8 for 4 h after drug administration; blood was collected at the end of the experiment. Kinetics study showed *Abstract 6137 appears on page 72 that biliary excretion of CBZ, CBZ-epoxide (CBZ-E), and VPA decreased over time in all animals. Computing of biliary flow of CBZ, CBZ-E, and VPA for 4 h showed that VPA had no effect on total amount of secreted CBZ, but significantly increased biliary excretion of CBZ-E. CBZ significantly decreased biliary Topic VII: Video Session-Difficult to excretion of VPA, with or without associated UDC. These changes reproduced those observed in plasma: VPA inhibiting Classify Seizures epoxide hydrolase and CBZ inducing metabolism of VPA. Ad- dition of UDC did not influence these interactions. Video Session I

Efficacy of Antiepileptic Drugs in a Cortical Stimulation Model. R. A. Voskuyl, A. Hoogerkamp, and M. Danhof (Department of Reflex Epilepsy: Touch Absences in a 1-Year-Old Infant. F. X. Physiology, University of Leiden, Leiden, The Netherlands)- Sanmarti, J. Montalvo, and M. Pineda (Hospital Sant Joan de 6135. Deu, Barcelona, Spain)-7009.

The efficacy of treatment with antiepileptic drugs (AEDs) may In 1987, Deonna and Revol independently described cases of change in time owing to several factors, including development cryptogenic reflex epilepsy whose evolution was favorable. We of tolerance, changes in pathologic condition, and interactions report a new case of touch-absence reflex epilepsy. with other drugs (both AEDs and other drugs). To investigate the The patient was a 13-month-old infant who, in a 1-week pe- underlying mechanisms, one should compare concentration- riod, was subject to increasingly frequent episodes of contact effect relation established under various conditions. As a first block lasting a few seconds. The patient was particularly prone step, we determined the concentration-effect relation in freely to these bouts on awakening. Symptoms included fixed stare, moving rats for several established and experimental AEDs us- blinking, lip clonias, and clonias of the extremities which, unless ing a model based on cortical stimulation with a ramp-shaped he was supporting himself, could cause him to fall over. The pulsetrain through chronically implanted electrodes. In this family observed that having his cheeks kissed or rubbed evoked model, two behavioral endpoints have been defined: the thresh- the same symptoms. Family and personal background showed olds for localized and generalized seizure activity (TLS and no antecedents. After his admission to the hospital, neurologic TGS, respectively). Carbamazepine, phenytoin, flunarizine, and exploration proved negative, except to confirm the phenomena lamotrigine selectively increased TGS, with little or no effect on described. Video-EEG confirmed absence seizures and 6-s 3-Hz TLS. Valproate increased only TLS and did not affect the dif- spike and wave discharges. Some of the seizures were sponta- ference between TGS and TLS. Phenobarbital, benzodiazepines, neous, but most were provoked. loreclezole, and N-methyl-D-aspartate antagonists increased Response to treatment with valproate 30 mg/kg/day was spec- both TLS and TGS independently. Finally, vigabatrin increased tacular. The infant remains asymptomatic at age 3 years 4 TGS for an extremely long time (>2 weeks), whereas ethosuxi- months. His physical and mental development is adequate. The mide had no effect. Comparison with standard screening models illness had a favorable course although myoclonic absences were indicates that increase in TLS reflects suppression of seizure originally suspected, although diagnoses of reflex epilepsy are initiation and increase in TGS over TLS reflects suppression of generally reserved, and although the ?a<&was one of cryptogenic seizure propagation. The cortical stimulation model appears to epilepsy.

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 87

Startle Benign Myoclonic Epilepsy in Infancy. S. Ricci, F. Vige- sleep; once, they occurred on awakening. Although evidence of vano, L. Fusco, M. R. Cilio, and R. Cusmai (Section of Neuro- an epileptic disorder was provided, its classification into one of physiology, Bambino Gesu Children’s Hospital, Rome, Italy)- age-related epileptic syndrome should await further follow-up 7008. study and recordings with use of long-term video/EEG.

Benign myoclonic epilepsy in infancy (BMEI) is an idiopathic epilepsy characterized by brief myoclonic attacks with onset in the first 2 years of life, with good prognosis. We report a video- Differential Diagnosis of Epilepsy in Children. A. Levy Gomes EEG and polygraphic study of 6 children with startle BMEI (SB- (ServiCo de Pediatria, Hospital Santa Maria, Lisbon, Portugal)- MEI), which is characterized by symmetric myoclonic jerks 7003. identical to those of BMEI, appearing as reflex responses to sudden unexpected acoustic and tactile stimuli. All children were We report four different cases that can be mistaken for epi- neurologically normal; 5 of 6 had a family history of epilepsy or leptic seizures and the findings of interest on video EEG. Hy- of febrile convulsions. Age at onset ranged from 6 to 21 months; perekplexia or excessive startle disease is a rare genetically de- manifestations disappeared in a period ranging from 4 to 12 termined disorder that causes an excessive startle response. We months. Jerks disappeared spontaneously in 3 patients and in the show the evolution of 2 children of different ages who both were other 3 after valproate therapy. Four children also had rare spon- considered epileptic in the newborn period, during which they taneous myoclonic jerks. The attacks consisted of isolated jerks had tonic episodes and startle movements precipitated by loud or of brief bouts of two-8 symmetric myoclonic jerks of the arms voices and movement. One boy had extreme breath-holding or the entire body. Ictal EEGs showed brief generalized spike- or spells with anoxic evidence on EEG during clinical manifesta- polyspike-and-wave discharges. SBMEI is a new age-dependent tions. Limpness was followed by a stiffening of the body and two idiopathic generalized epileptic syndrome with good prognosis. or three jerks that could be confused with epileptic seizure. In older age, subacute sclerosing panencephalitis is frequently confused with absence status or myoclonic epileptic status on EEG, and video-EEG is pathognomonic. Night terrors may be difficult Tonic Spasm Seizures: A Particular and Previously Unreported to differentiate from epilepsy. In 1 child with frontal sleep epi- Type of Seizure. Lucia Fusco and Federico Vigevano (Section of lepsy, we delineated the differences between epilepsy and night Neurophysiology, Children’s Hospital Bambino Gesu, Rome, It- terrors. Video-EEG monitoring and videotapes taken at home aly)-7006. are of great value in difficult cases. Video/polygraphic EEG recording of pediatric seizures provided recordings of apparently tonic seizures, in which detailed analysis showed peculiar features. Seizures began with a rapid, Neonatal Myoclonic Encephalopathy. A. Levy Gomes and J. P. brief contraction of upper limbs and neck, followed by sustained Vieira (ServiCo de Pediatria, Hospital Santa Maria, Lisbon, Por- contraction of the same segments. Electromyographic recording tugal)-7002. of the attack showed the initial phase spasm-like and the subsequent phase to be similar to tonic seizure. The EEG counterpart We report a video-EEG and clinical study of a newborn with was a high-amplitude slow wave corresponding to the spasm, myoclonic encephalopathy that began in first minutes of life. The followed by a discharge of rhythmical spikes corresponding to child had nonketotic hyperglycemia with recessive inheritance. the tonic phase. This attack therefore resulted from a combina- Tonic spasms, erratic fragmentary myoclonus, and partial motion of an epileptic spasm and a tonic seizure. tor seizures were observed since birth. EEG clearly showed two The 7 patients who exhibited this type of seizures, were aged different patterns: During the first 2 days, EEG showed periods 2-14 years; all had had West syndrome in the first year of life, of truly hypsarrythmic abnormalities during myoclonias and par- and 6 had no known etiology. All had simple spasm seizures as tial motor seizures; during tonic spasms, EEG showed profound well, manifesting mainly in clusters on awakening. Interictal voltage alteration as in infantile spasms. By the third day, EEG EEG showed spike-and-wave activity, bilateral or with predom- clearly showed a suppression-burst pattern that persisted until inance over one hemisphere, mainly in the anterior regions. The death. tonic spasm seizures exhibit a unique clinical and EEG pattern and constitute an unreported seizure type that the classification does not yet specifically recognize. Benign Familial Neonatal Seizures: An Ictal Video-EEG Record- ing. Emilio Franzoni, Valentina Marchiani, and Filomena Cate- rina Moscano (Pediatric Neurology, Bologna University, Bolo- Contemporary Diagnostic Approach to Nocturnal Epilepsy: Video gna, Italy)-7012. Presentation. Slobodanka IliC-TasiC, Milivoje MihajloviC, zarko MartinoviC, D. VukiC, and Bosanka JociC (Medical Faculties of Benign familial neonatal seizures (BFNS) occur in normal NiS University and Beograd University, VMA Beograd, newborns without perinatal neurologic damage or metabolic ab- Beograd, Yugoslavia)-7013. normalities who have a positive family history for neonatal seizures. This autosomal dominant disorder has excellent progno- Epileptic seizures occurring at night and paroxysmal sleep dis- sis. orders represent very difficult problems in differential diagnosis. We report a female infant who showed seizures on the third The differentiation of these disorders is especially difficult in day of life. The seizures had tonic onset with staring and lip childhood. cyanosis, lasting 62 min and occurring three to four times daily. In a 5-year-old girl, paroxysmal and stereotyped head and On day 5, phenobarbital (PB) was started, with complete seizure body movements were associated with emission of guttural control attained. During her admission on the neonatal unit, he- sounds during sleep and were first noted when she aged 2 years. matochemical investigations, lumbar puncture, and cerebral ul- EEG during wakefulness then showed normal activities for her trasonography showed no abnormalities. Family history in the age and no epileptiform abnormalities. Her disorder was consid- mother and the maternal grandmother was positive for seizures ered atypical “jactatio capitis nocturna” or “benign (physio- in infancy. logic) sleep myoclonus.” Three years later, when clinical mani EEG is of little assistance in diagnosing BFNS, since BFNS festations became more frequent, overnight polysomnographic may or may not cause abnormal EEG and has no known diag- study showed frequent bilateral epileptiform paroxysms, fre- nostic features. Ictal recordings are very rare. We witnessed one quently evident during light sleep stages (1 and 2) of NREM seizure episode during a video-EEG recording and can confirm phase or in transitional phase between stage 1 NREM and REM focal onset of the discharge with subsequent spread mainly over

Epilepsia, Vol. 35, Suppl. 7, 1994 88 EUROPEAN CONGRESS PROCEEDINGS

centrotemporooccipital regions of both hemispheres. Interictal panied by bursts of sharp EEG activity predominating centrally EEG was normal. with the same frequency as the tremor. The movement disorder in AS appears to be caused by a genetically determined dysfunction of motor cortex that sustains a spectrum of manifestations of cortical myoclonus. Video Session 2 Diagnostic Problems in Classifying Some Rare Clinical Forms of Epileptic Seizures. Dragoslav V. Ercegovac, Zoran JovanoviC, Is This Primary Generalized or Partial Epilepsy? E. R. Newton, Zorica CiriC, and Marko D. Ercegovac (Institute of Mental S. W. Brown, S. P. Whitfield, and C. Gifford (The David Lewis Health, Belgrade, Yugoslavia)-70 14. Centre, Manchester, England)-7004. Since 1989, in our Department for Psychophysiology and We present the video and EEG records of an 11-year-old boy Clinic of Neurophysiology (Outpatient Epileptic Center, Bel- with seizure onset at age 5 years. Initially, seizures consisted grade), we have used an audiovisual technique with Vidigraph solely of loss of contact with reality for 20 s (these he called (Viekers Medical) TV camera and split-screen monitoring. We “blinkies”), but in 2 months he developed attacks in which his simultaneously recorded EEG, electrocardiogram, respiration, color drained and he became agitated (these he called “frights”). patient’s face and body, and patient’s and examiner’s voices. We Both types of seizure have continued to occur, although frights report 4 patients with questionable seizure classification and, at times develop into tonic-clonic seizures. Neither has been possibly, questionable diagnosis of epilepsy. satisfactorily controlled with medication. Since December 1993, a 46-year-old man has slowly changed With time, his blinkies have lasted longer, now lasting 50-80 his behavior, becoming disinterested in his family and work and min and occurring four to six times a day. His level of conscious- showing aggression. From age 20-30 years, he had had four to ness varies during a “blinky,” from being totally unresponsive to five tonic-clonic seizures, but EEG was always normal. In the being in varying degrees of contact with his environment. At last 20 years antiepileptic medication has prevented seizures. times he can walk and eat during such periods. He is also able to The first recent EEG showed 5- to 10-min generalized 3-Hz recall information, e.g., arrangement of furniture of rooms that spike-and-wave discharges with no clinical manifestations other he has visited only during blinkies. than eye opening (on request) and visible discreet clonic move- Observation of both seizure types suggests a focal origin, but ment. Basic cognitive functions were not impaired. during both types EEG shows generalized changes. The changes A 7-year-old girl had 1- to 2-min paroxysmal strange behavior during a blinky are characteristic of atypical absence status with impairment of consciousness and amnesia 8-15 times a rather than complex partial status. night. Awake EEG showed generalized epileptiform discharges. A 20-year-old man had spontaneous and “startle” complex partial seizures (clinically) with no epileptiform discharges on EEG. A 16-year-old girl had paroxysmal behavioral events, re- Prolonged Seizures States Characterized by Generalized Epilepti- sembling partial complex seizures, with impairment of con- form Discharges and Cognitive Impairment with Possible Focal sciousness, provoked by simple auditory stimuli. Differential di- Origin: Case Reports with Video Presentation. P. Halasz, Olga agnosis was reflex epilepsy/pseudoseizures. Eider, N. Donauer, G. Barcs, and A. Ho116 (National Institute of Psychiatry and Neurology, Budapest, Hungary)-7005.

We report 2 patients, both of whom had prolonged (several Epileptic Myoclonia or Movement Disorder? Piet H. A. Voskuil minutes to >30 min) cognitive impairment coincidentally with (Dr Hans Berger Kliniek, Epilepsycenter, Breda, The Nether- generalized epileptiform discharges (spike-waves, multiple lands)-7015. spikes in periodic bursts, or more or less continuous form). The degree of cognitive impairment was variable, detected by neuro- We present EEG videotapes and the case history of a mentally psychological investigation during simultaneously registered par- retarded girl now aged 24 years whose symptoms had onset at oxysms. age 4 months. Change in her development caused change in di- Electroclinical symptoms could be influenced by intrave- agnosis from myoclonic epilepsy to kinesiogenic choreoathetosis nously and/or or~llyadministered antiepileptic drugs. Morpho- to symptomatic epilepsy which may be either focal or general- logic and functional neuroimaging showed focal frontal features ized, with both generalized (myoclonic) and simple partial sei- in both patients. The nosology of the electroclinical symptoms zures. was assessed in the framework of a broader spectrum of ictal cognitive symptoms characterized by violent EEG discharges without or with sparse overt epileptic seizures. Topic VIII: Miscellaneous

Status Myoclonicus and Cortical Tremor in Angelman Syndrome. Poster Session (8001-8066) Renzo Guerrini, Paolo Bonanni, *Pierre Thomas, and *Georges Suisse (INPE-IRCCS Stella Maris, Pisa, Italy; and *Service de Neurologie, CHU, Nice, France)-7010. Reflex Seizures. J. Salas-Puig, V. Mateos, D. Campos, J.A. Angelman syndrome (AS) is characterized by mental retarda- Vidal, and C.H. Laboz (Neurological Department, Hospital tion, a typical facial expression, a characteristic “puppetlike” General Asturias, Oviedo, Spain)-8001. motor pattern and, often, epilepsy. With video-EEG, we studied 4 patients with AS with movement disorder characterized by Five to 6% of epileptic patients have reflex seizures (RS). We subcontinuous rhythmic limb jerking of fluctuating amplitude. In studied prospectively a group of epileptic patients to determine 2 patients, the jerking was coarse at -2 Hz and worsened peri- the proportion of RS and their correspondence to the epileptic odically, becoming status myoclonicus, with each jerk being re- syndromes according to the classification of the International lated to a cortical spike on EEG. In the other 2, jerks occurred at League Against Epilepsy. From January 1991 to January 1994, 7-12 Hz and were limited to hands and feet, resembling subcon- we studied 531 epileptic patients (males, 52%; and females 48%) tinuous paroxysms of distal tremor. Each episode was accom- with a mean age of 36.4 years (range <1-84). Thirty patients (16

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 89 males, 14 females) with a mean age of 20.1 (range 5-34) had RS. ing slow wave sleep is characteristic of two specific syndromes In 22 (73%), paroxysmal EEG activities during the specific stim- in childhood: Landau-Kleffner syndrome (LKS) and epilepsy ulus exposure were recorded. with continuous spike waves during slow wave sleep (CSWS), RS occurred in the following epileptic syndromes: generalized which are believed to have a common pathogenesis. We describe Idiopathic 15 patients (14 photogenic, 1 decision making), gen- in four new cases the association of acquired nonverbal disability eralized cryptogenic 1 (eye closure), focal idiopathic 2 (primary and a peculiar neurolinguistic aspect similar to semantic prag- reading), focal cryptogenic 3 (1 decision-making, 1 hot water matic syndrome, with typical epilepsy with CSWS. immersion, 1 Musicogenic), focal symptomatic: 7 (4 startle, 2 The neuropsychological deterioration is characterized by three eating, 1 unknown), unclassified 2 (1 eye closure, 1 drawing). deficits: severe attention disorder, considerable visuospatial def- The figures and proportion of RS were idiopathic generalized 108 icit with agraphia and decrease in PI 6 (WISC-R), and particular patients (14% RS), cryptogenic generalized 14 (7% RS), symp- language behavior (logarrheic with uncontrolled flow and asso- tomatic generalized 14 (0% RS), idiopathic focal 15 (13% RS), ciation in ideas, inappropriate commentaries making narrative cryptogenic focal 158 (1.9% RS), symptomatic focal 155 (4.5% almost valueless despite normal phonology, and expressive syn- RS), undetermined 12 (0% RS), and unclassified 53 (3.8% RS). tax structure. This association suggests a deficit in right hemi- Of epileptic patients, 5.6% had RS. In some, knowledge of the sphere function and is more similar to right-side predominance of precipitating factor was beneficial in preventing seizures. PA in these 4 righthanded children. It appears to resemble the semantic pragmatic syndrome described by Rourke, with major visuospatial deficit and relation to right hemisphere dysfunction. Mathematical Epilepsy: A Case of Association of Partial and Reflex This neuropsychological semiology deteriorating with CSWS Seizures. L. Minotti, L. Guidolin, V. Sgro, M.P. Canevini, A. and improving with EEG amelioration suggests a mechanism Saltarelli, and R. Canger (Regional Epilepsy Centre, S. Paolo similar to that of LKS but involving the right hemisphere. Hospital, University of Milan, Milan, Italy)-8002.

Since the report by Ingvar and Nyman in 1962 of a case of seizures evoked by mathematical tasks, several additional cases Attention Deficit Hyperactivity Disorder as the Single Clinical Fea- have been reported in the literature under a variety of terms. ture in a Case of Continuous Spikes and Waves During Slow Sleep. Review of the literature showed no patient with partial epilepsy M.N. Metz-Lutz, E. Hirsch, P. Maquet, J. Motte, S. Finck, and associated with reflex seizures and/or partial seizures activated C. Marescaux (INSERM U398, Clinique Neurologique, HGpi- by spatial or mathematical tasks. The diagnosis was always one taux Universitaires de Strasbourg, Strasbourg, Universit6 de of idiopathic generalized epilepsy. Neurologie Pediatrie de Reims, Reims, France, and UniversitC We report a woman who has had epilepsy since age 14 years, de Li&ge,Belgium)-8005. with generalized tonic-clonic seizures, complex partial seizures of probable temporal lobe origin, and myoclonic jerks evoked by In the syndrome of epilepsy with continuous spike and wave various occupations such as playing piano, writing arithmetic discharges during slow wave sleep (CSWS), EEG abnormalities calculations, or using a personal computer. Furthermore, the are associated with various acquired neuropsychological defi- patient has a history of 24-h coma of unknown etiology at age 3 cits. These deficits are often associated with attention deficit and years. We discuss the possibility of occurrence of this type of behavioral disorders. We describe a young girl who at age 7 reflex seizures in partial epilepsy or the coexistence of two forms years developed severe behavioral disturbances with hyperac- of epilepsy in our patient. tivity, impulsivity, and attention deficits, associated with few partial seizures. The excessive activity level, with irritability, disinhibition, and inappropriate postures and speech, suggested Continuous Spikes and Waves During Slow Wave Sleep and Its childhood mania. The EEG recordings evidenced right temporal Relation to Landau-Kleffner Syndrome: Consideration of Three spike and wave discharges during wakefulness that generalized Cases. E.R. Newton, S.P. Whitfield, and G. Parkinson (The and became continuous during slow sleep. Neuropsychological David Lewis Centre, Manchester, England)-8003. testing showed severe attention deficits that impaired her performance in different tests, particularly those requiring auditory Kellerman (1978) suggested a close relation between continu- and sustained attention. Treatment with clobazam and valproate ous spikes and waves during slow wave sleep (CSWS) and ac- suppressed the partial seizures and improved the EEG. How- quired aphasia. Although not originally supported by Tassinari et ever, hyperactivity and manic behavior regressed only when me- al. (1982), this view was later modified (Tassinari et al., 1985, thylphenidate was added to antiepileptic drugs. Repeated neuro- 1992) to suggest that language functions were severely impaired psychological evaluations still demonstrated persisting attention in children with this condition. Billiard et al. (1982) and Dulac et disorders that regressed slowly after complete disappearance of al. (1983) concur with this view. Hirsch et al. (1990) considered spike and wave discharges in sleep EEG recordings. In this, the CSWS to represent the most severe form of Landau-Kleffner clinical feature was consistent with attention deficit hyperactiv- syndrome (LKS). We report our experience with three patients ity disorder as defined in DSM 111, but this clinical state ap- with CSWS who show considerable variation in language flu- peared in a lefthanded child who had functioned normally in ency: from severe impairment of speech production to no de- early schooling with no noticeable behavioral or attention dis- tectable evidence of impaired fluency and consider how such turbance. From the various neuropsychological and neurophys- cases bear on differential diagnosis between CSWS and LKS. iologic findings, we assessed the role of an age-dependent right We also describe the psychiatric and behavioral aspects of hemisphere dysfunction in the acquired attention deficits. CSWS.

Acquired Nonverbal Deficit and Semantic Pragmatic Syndrome As- Continuous Spikes and Waves During Slow Wave Sleep Associated sociated with Continuous Spike Waves During Slow Wave Sleep in with Acquired and Reversible Apraxia. J. Motte, M.N. Metz- Four Cases. C. Billard, M.L. Loisel, P. Gillet, B. Lucas, M.M. Lutz, C. Marescaux, P. Maquet, J. Jouot, C. Billard, E. Hirsch, Barthez, J. Motte, and A. Autret (Department of Child Neurol- J. Couchot, and P. Sabouraud (Unit6 de Neurologie Pkdiatrique, ogy and Neurosurgery, HGpital Clocheville, CHU Tours, Reims, American Memorial Hospital, CHU de Reims, Reims, and France)-8004. INSERM U398, Strasbourg and Tours, France)--8006.

The association of acquired changes in higher functions and of We report a boy with no previous personal or familial neuro- diffuse bilateral continuous paroxysmal abnormalities (PA) dur- logic antecedent who at age 7 years began to have nocturnal

Epilepsia, Vol. 35, Suppl. 7, 1994 90 EUROPEAN CONGRESS PROCEEDlNGS tonic partial seizures. Simultaneously, this usually good school- Correlations Between Sleep Quality and Seizures: Polygraphic boy showed sharp regression in his school performance, with a Study. Ph. Derambure, E. Josien, M. D. Lamblin, J.M. Jac- modification in writing. He also exhibited a severe attention def- quesson, and J.D. Guieu (Clinical Neurophysiology, HBpital B, icit with hyperkinetic disorder. CHU, Lille, France)-8009. Neurologic examination showed global apraxia with left hemisphere dysfunction. Awake EEG showed synchronous bilateral Interactions between sleep and epileptic paroxysmal abnor- discharges, predominant in right frontorolandic region. Sleep malities remain unclear. The hypothesis which suggests that EEG was characterized by continuous spikes and waves in 90% their basic mechanisms may be linked could explain the closed of sleep time (CSWS). Such anomalies were also predominant in relation between seizures and either vigilance level or sleep qual- right frontorolandic region. ity. Computed tomography and magnetic resonance imaging scans Polysomnography was performed in 150 patients with active were normal. Positron emission tomography showed hyperme- epilepsy. Multiple Sleep Latency Test was performed on the tabolism in right temporoparietal region during sleep. following day. Quality of sleep was also assessed by a personal The child clearly improved with treatment with clobazam and diary maintained by patients for 2 weeks. We analyzed sleep ritalin. CSWS may predominate on the right side with clear ac- organization by using the Rechtschaffen and Kales classification quired and reversible symptomatology of associative cortex of of stages; EEG paroxysmal abnormalities were quantified ac- the right hemisphere. cording to sleep stages. Polygraphic data were evaluated in relation to the type of epilepsy (partial or generalized; idiopathic, cryptogenic, or symptomatic) and seizure frequency. The results showed correlation between sleep disturbances, frequency of seizures, and type of epilepsy. Paroxysmal abnor- Continuous Spikes and Waves During Slow Sleep in Children. A. mality patterns were influenced by stage changes and number of Levy Gomes (Servico Pediatria, H. Santa Maria, Lisbon, Por- arousals. These data suggest that sleep recording can be a useful tugal)-8007. tool to evaluate active epilepsy to improve both sleep efficiency and epilepsy stability. Continuous spikes and waves during slow wave sleep (CWSW) is a syndrome that appears in very diverse clinical settings in normal or previously developmentally delayed children. We have observed this pattern in children with true Landau- Bilateral Occipital Calcifications and Epilepsy in Celiac Disease. Kleffner syndrome (LKS) and in patients with mental retardation Adriana Magaudda, *Giuseppe Magazzu, tMarcello Longo, without identifiable brain pathology and myoclonic epilepsies. *Claudio Romano, and Raoul Di Perri (Departments of Neurol- The boy with LKS is a very special case because he is steroid ogy, *Pediatrics, and tRadiology, University of Messina, dependent with multiple relapses. Messina, ltaly)-8010. In patients with benign rolandic epilepsy, the paroxysms become increasingly frequent during drowsiness and all stages of More than 50% of patients with bilateral occipital calcification sleep and diffuse to the contralateral hemisphere. In other benign (BOC) and epilepsy also have celiac disease (CD), but the fre- epilepsies, the interictal EEG shows a pattern similar to that of quency of both BOC and epilepsy in CD is not yet well defined. CSWS. We describe these 4 different types of patients with CD patients (n = 451; average age 45 years, range 10-53) fol- CSWS to illustrate their clinical, EEG, and psychological differ- lowed at our hospital underwent cerebral computed tomography ences. (CT) scanning and complete neurologic examination. They included CD patients with different age at diagnosis: <2 years, 2-18 years, and >I8 years. Thirty patients who underwent CT for head trauma constituted the control group. CT failed to show Nocturnal Seizures in Adults: A Benign Partial Epileptic Syn- BOC in 44 patients; it demonstrated cortico subcortical puncti- drome. Basim Yaqub, Ghazala Waheed, Mohammed Kabiraj, form calcification localized in the left occipital lobe in an 18-year- Abdulkader Daif, Mohammed Abduljabbar, Abdulrahman old girl. No case of BOC was noted in the control group. None Tahan, and Tahir Obeid (Department of Neurosciences, Riyadh of the 45 CD patients had epilepsy. Of 451 CD patients, 3 (0.66%) Military Hospital, Riyadh, Saudi Arabia)-8008. had epilepsy without BOC, 3 with BOC and epilepsy without gastrointestinal symptoms were shown to have CD. The incidence of BOC in CD is not high, and the frequency of epilepsy The pattern of seizure occurrence in most epileptic persons is without BOC in CD is not different from that observed in the random, without cycling or clustering. Seizures in benign child- general population in our region; the frequency of epilepsy in CD hood epilepsy with centrotemporal spikes occur only during is increased twofold when patients with BOC and epilepsy are sleep; other nocturnal seizures are difficult to classify and, ac- taken into account. Our data suggest a relation between BOC cording to the proposal for the revised Classification of Epilep- and epilepsy but not between CD and epilepsy. The high fre- sies (1989), are considered under “epilepsies and syndromes un- quency of CD in patients with BOC and epilepsy may be ex- determined whether focal or generalized” owing to lack of un- plained by a common genetic background. equivocal generalized or focal features. We evaluated clinical characteristics and EEG findings by long video split-screen EEG monitoring in 64 successive patients with definite nocturnal seizures. Mental state, neurologic examination, neuroimaging, and EEG background were normal in all patients. Classification of Sturge-Weber-Krabbe and Klippel-Trenaunay Syndromes in a Fe- seizures was possible in 42 of 64 (66%) patients according to the male. Nedko Tchoudomirov and Krasimira Tchoudomirova (De- revised Classification of Epilepsies and Epileptic Syndromes by partments of Neurology and Dermatology, Plovdiv, Bulgaria)- the Commission on Classification and Terminology of the Inter- 8011. national League Against Epilepsy (1989). Of the 42 patients, 33 (79%) had partial epilepsies, and 9 (21%) had generalized epilep- We report a rare case of Sturge-Weber-Krabbe syndrome in sies. Response to antiepileptic drugs (AEDs) was excellent, and combination with Klippel-Trenaunay syndrome in a 30-year-old only 4 (6%) patients had one seizure attack a year; 2 of them woman. Since birth, she has had flat blue-red hemangiomas on were receiving two antiAEDs and the others were seizure-free the left arm and hand and on the corresponding half of the chest, while treated with one AED during 2-year follow-up. Nocturnal and a flat particularly tuberous, hemangioma covering half of her seizures in adults apparently constitute a new distinctive benign face. She has hypertrophy of the left arm, which is longer and partial epileptic syndrome. larger than the right arm. Radiographs of the arms and hands EUROPEAN CONGRESS PROCEEDINGS 91 showed that the bones of the left extremity are larger. Radio- A 60-year-old woman had had daily drug-resistant complex graphs of the bones of the cranium showed bone angioma. She partial seizures since age 34 years. Interictal EEG showed asyn- has glaucoma, with anomaly of the vessels on the left, and initial chronous bitemporal spike and wave discharges, with greater hypertonia (155/85 mm Hg). Contralateral to the skin lesions is frequency on the left. Functional neurosurgery for diffuse and latent hemiparesis and homonymous hemianopia. EEG showed bilateral ischemic lesions was excluded by brain nuclear mag- focal paroxysmal activity secondarily generalized. netic resonance studies. In July 1993, a drop during a seizure caused a left hemispheric cerebellar hematoma with diplopia, dysarthria, and ataxic gait; 21 days after head trauma, seizures disappeared. The patient has since been seizure-free (follow-up 7 Long-Duration Transient Epileptic Amnesia. J. G6mez-Alons0, months), and interictal EEG is normal. Behavior disturbances D. Mufioz, C. Andrade, and A. Koukoulis (S. Neurologia, Hos- appeared at seizure cessation as depression and a prepsychotic pital Xeral, Vigo, Spain)-8012. state. Chronic cerebellar stimulation as therapy for drug-resistant Transient epileptic amnesia (TEA) is a recently recognized seizures in humans was based on experimental animal research. entity whose differential features are still being delineated. A 38 Cerebellar stimulation can both decrease and increase neocorti- year-old woman had a history of spells of arrest of activity and cal epileptic discharges. In clinical use, however, results are con- oroalimentary automatisms. In recent years, she had eight am- troversial, and this method as treatment for epileptic seizures has nestic episodes, usually lasting 6-24 h; one that occurred during been abandoned. her vacation lasted 72 h. During this time, she had been able to dress herself, to go shopping, to eat, and to make two plane trips, although she required some help from friends. She had only fragmentary recollection of the events. Basal EEG showed slow ac- Features of CNS Involvement in Progressive Facial Hemiatrophy: tivity was recorded in left temporal region. After sleep depriva- Further Evidence of Chronic Localized Meningoencephalitis. K. tion, some spike and wave discharges were noted mainly in cen- Terstegge, S. Felber, W. Vermaasen, S. Venz, and I.N. Averi- tral areas. Magnetic resonance imaging showed questionable anov (Strahlenklinik U K. Rudolf Virchow, Freie Universitat atrophy of the left temporal lobe. Our case, which meets the Berlin, Berlin, Germany; Innsbruck, Austria; and Moscow)- requirements of TEA, proves that the amnestic episodes may 8016. last <3 days. Progressive facial hemiatrophy (PFH), a sporadic disease occurring mainly in childhood, is characterized by local loss of subcutaneous fat, and results in sometimes disabling deforma- Strabismus or Atypical Absence? Mariana Dimitrova Dimitrova tion of one side of the face. Whether the atrophy is secondary to (Department of Neurology, Plovdiv, Bulgaria)-8013. localized scleroderma of the skin in all or only in some patients is not clear. Radiologic and clinical features from earlier reports We studied a child with convergent monocular strabismus, of neurologically symptomatic patients led to the recent sugges- accompanied by unmotivated absentmindedness. The case is an tion of a chronic localized meningoencephalitis as hitherto un- appropriate internosologic model on the border between neurol- recognized pathologic correlate of occasional CNS involvement. ogy and ophthalmology. We describe our method for systemic We prospectively analyzed clinical and cranial radiomorphologic ophthalmologic, neurologic, and EEG analysis. We suggest the features of CNS involvement in PFH to detect support for or possibility of another form of atypical absence strabismus. refutation of this hypothesis. Fifteen patients with CNS symptoms in PFH were included in the study. We did not differentiate between PFH in “Romberg’s disease” or PFH concomitant with facial localized scleroderma. Autistic Spectrum Disorder and Lennox-Gastaut Syndrome: Two We analyzed the histories, clinical findings, and magnetic reso- Case Reports. Ekkehart F. A. Staufenberg and Stephen W. nance imaging (MRI) findings. (T2- and T,-weighted plain and Brown (The David Lewis Centre for Epilepsy, Cheshire, En- Gd-DTPA-enhanced examinations in axial and coronal planes). gland)-8014. Additional computed tomography scans were available for most patients. We report lifetime follow-up of a 26-year-old man and an 18- CNS symptoms and morphologic abnormalities are a faculta- year-old woman with autistic syndromes preceding (case 1) and tive phenomenon in PFH. Clinical and MRI findings in our se- occurring contemporaneously (case 2) with development of elec- lected group of patients proved that brain involvement usually troclinical signs characteristically associated with Lennox- appears on the homolateral side relative to the facial process. Gastaut syndrome (LGS). Neither patient developed West syn- Irritative symptoms (seizures) were almost always present, drome. whereas a single neurologic dysfunction appears to be rare. In- Case 1 has had an abnormal developmental history from birth; flammation in cerebrospinal fluid and posterior uveitis were Case 2 showed only profound motor, cognitive, and behavior common in our selected patient group. Largely variable expres- regression since age 3 years, including expressive aphasia. She sions of homolateral hemiatrophy, white matter lesion, and cor- showed significant temporary improvement at 13 years when ticomeningeal dysmorphia were noted on MRI. Inconstant seizure control was better. phase-dependent features were parenchymal, meningeal, and in- We describe EEG data from 24-h ambulatory recordings and traosseous Gd-DTPA enhancement. These clinical and radio- etiologic aspects of the apparent comorbidity of pervasive de- logic features, especially CSF findings, uveitis, and phase- velopmental disorders with LGS. We suggest that the epileptic dependent Gd-DTPA enhancement, appear to be consistent with syndrome plays a neuropathophysiologic role in autistic disor- the hypothesis of localized inflammatory disease. ders rather than being the epiphenomenon of a common underlying neuropathologic process.

Epilepsy in Children with Myelomeningocele. Olavo GonCalves and Luis Borges (Neuropediatria; Hospital Pediiitrico de Coim- Abatement of Drug-Resistant Complex Partial Seizures After Trau- bra, Coimbra, Portugal)-80 17. matic Cerebellar Hematoma. Angelina Cerullo, Federica Provini, Carla Marini, Giuseppe Plazzi, *Mario Amore, *Nicoletta Every child born in the central region of Portugal who has Zazzeri, and Paolo Tinuper (Neurological Institute, and *Psychi- myelomeningocele is treated at the Hospital Pediiitrico of Coim- atric Institute, Bologna University, Bologna, Italy)--8015. bra. The incidence of neural tube defects in the zone is 10.9/

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS

10,000, representing 7 in 10,000 of cases of myelomeningocele. Nonconvulsive Status Epilepticus: A Follow-Up Study. JosC In all, 103 children are treated in our service; 70% had hydro- Ribeiro, Dina Pinto, Isabel Pires, Teresa Sonim, Georgina cephalus requiring ventriculoperitoneal shunt. Eight of them Sousa, and Maria Luiza Guimarfies (Neurophysiology Depart- have epilepsy (4 boys and 4 girls), classified as generalized in 2 ment, S. Jodo Hospital. Porto Portugal)-8020. and partial in 4. All received a shunt (11.5% of patients with a shunt have epilepsy); 7 of 8 had shunt revisions. Nonconvulsive status epilepticus (NCSE), representing nearly In 1 patient with partial epilepsy, seizure control has not been 20% of all SE in adults, comprises two subgroups: absence and attained despite the antiepileptic drugs used. The boy has a mo- complex partial SE (CPSE). The issue of prognosis of these two tor level of Ll-L2, mental retardation, and EEG with polyspikes conditions is still debated. Twenty cases of NCSE, I I CPSE, and and spike waves (1.5-2.5 HZ mx maximum amplitude 280 u, 9 absence status were studied in an 8-year period in the EEG predominantly in the right hemisphere and anteriorly demon- Department of S. Jo50 Hospital, Porto, Portugal. strated by magnetic resonance imaging. In the other children, CPSE and absence status subgroups were analyzed, according seizure control was easily achieved. to clinical and EEG parameters, as follows (with values for CPSE versus absence status): age (mean age 38.9 vs. 36 years, age range 19-76 vs. 9-73 years, median age 31 vs. 40 years), sex ratio (M/F:2.7 vs. OS), duration of status (mean value 5 vs. 2.4 days), duration of preexisting epilepsy (10.5 vs. 22.9 years), sei- Radiologic Findings in 303 Patients with Lennox-Gastaut Syn- zure frequency before NCSE; type of seizures and epileptic syndrome. Silke Ehlers, Gudrun Gohlich-Ratmann, and Gert Jacobi drome, neuroimaging findings; ictal EEG; and underlying medi- (Department of Pediatric Neurology, Children’s University Hos- cal conditions. pital, Frankfurt, Germany)-8018. A clinical and EEG follow-up was performed with a mean time of 39 months for CPSE groups (range 6-84 months, median 41 We investigated 303 children with Lennox-Gastaut syndrome, months) and 51 months for the absence status group (range 12- diagnosed between 1965 and 1992. Case history was perinatal 108 months, median 45 months). events (18%), meningitis or encephalitis (7%), postnatal circula- Despite the small size of our series, overall prognosis in terms tory arrest (4%), tuberous sclerosis (4%), neurodegenerative dis- of seizure control was better in the CPSE subgroup (5 of 8 pa- eases (4%), head injuries (2%), and brain tumor (1 patient). Clin- tients still living became seizure-free in the 6 months preceding ically they had seizures, primarily astatic and tonic, followed by the follow-up visit) than in the absence status subgroup (only 1 of myoclonic and atypical absence seizures. They had typical 8 patients still living achieved complete seizure control). Mor- EEGs with diffuse bilateral synchronous sharp and slow waves. tality appeared to be associated with old age and severity of the Some had had West syndrome. Outcome with regard to educa- underlying medical and/or neurologic conditions. tion was poor in most patients. Of 218 children who underwent radiologic examination, 127 (58%) had pathologic results: hydrocephalus (49%), generalized cerebral atrophy (39%), microcephaly (24%), unilateral cerebral Status Epilepticus: A One-Year Experience in a Pediatric Intensive atrophy (21%), brain malformation (19%), porencephaly (16%), Care Unit. Anabela Ferrfio, ManuCla Correia, A. Levy Comes, macrocephaly (5%), and ataxia (1%). Helena Almeida, Ana Carvalho, Gustavo Rodrigues, and Silva To determine histories, we performed proportionally more Sequeira (Hospital Santa Maria, ServiCo de Pediatria, UCEP, PEG studies than computed tomography or magnetic resonance Lisbon, Portugal)-8021. imaging (MRI). With PEG one can see atrophies, cysts, poren- cephalies, and other malformations of the brain, but nothing can Status epilepticus is an important cause of admission in a pe- be determined about gyration. Eighty percent of MRIs were diatric intensive care unit (PICU). We studied children admitted pathologic, which raises the question of whether one could de- to our unit with status epilepticus retrospectively for 1 year tect more patients with primary impaired brain development by (March 1993 to February 1994), evaluating 10 cases (2.2% of MRI in this type of epilepsy. PICU admissions): 6 females and 4 males aged 3 months to 8 years (mean 2 years 10 months). Three had prediagnosed epilepsy (psychomotor delayed I, Rett syndrome I), and 7 had acute cerebral disease. Among the 5 CRF studies, 3 showed Cognitive Regression and Epilepsy in Children. Eulilia Calado augmented cellular elements for age; 6 of the 9 cerebral scans and Karin Dias (Unidade de Neurologia PediBtrica, H.D. Este- showed abnormal findings. Mean duration of status epilepticus ffinia, Lisbon, Portugal)-8019. was 3.8 h (1-9 h). Therapeutic management consisted of phenytoin (PHT) 2, phenobarbital (PB) 1, PB plus PHT 2, and thiopental after failure Cognitive regression is often the main feature of continuous of PHT plus pentobarbital 5. All patients were maintained on spikes and waves in slow wave sleep (CSSW) and Landau- antiepileptic drugs (PHT5, PB3, valproate 1, and clonazepam Kleffner syndrome. Recently, investigators reported several plus vigabatrin 1). Five of the children are well, and 5 have cases of reversible cognitive regression associated with other neurologic abnormalities (tetraparesis 2, psychomotor delayed 2, types of epilepsy with unrecognized clinical seizures and differ- Rett syndrome 1). ently localized foci on EEG. We report the clinical cases of 2 boys aged 5 and 7 years who, before referral to the hospital, had been under psychiatric treatment for several months for disruptive behavior and/or dementia. Seizures became apparent only after a few months and ini- Epilepsia Partialis Continua: An Analysis of 32 Cases Ascertained tially were considered psychogenic. The first child had very fre- Through a Nationwide Scheme in the United Kingdom. Oliver C. quent bilateral frontotemporal spike-wave activity on EEG and Cockerell, John Rothwell, Josemir W. Sander, and Simon D. interictal EEG of the second child was noninformative, whereas Shorvon (Epilepsy Research Group and the MRC Human Move- his ictal EEG showed left frontal paroxysmal activity. Treatment ment and Balance Unit, The Institute of Neurology, Queen with valproate and clobazam in 1 and with carbamazepine in the Square, London, and the Chalfont Centre for Epilepsy, Chalfont other was successful; both children became seizure-free and St Peter, Bucks, England)--8022. gradually exhibited their normal behavior and cognitive level, with simultaneous EEG normalization. We describe the complex Epilepsia partialis continua (EPC) is a rare syndrome of con- relation between subclinical abnormal electric activity and sus- tinuous localized muscle jerking that may occur in all age groups. tained abnormal behavior in children. Interest in the diagnostic definition of EPC, the nature of the

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 93 jerks, and the cerebral origin of the jerks has been considerable. sotomy. A second operation was needed in 2, resulting in total EPC is a rare syndrome, but exact incidence and prevalence callosotomy. Follow-up time is 6 months and 4 years. A ques- figures are completely unknown in the United Kingdom or else- tionnaire was sent to all parents. A good result with significantly where. We used a system of prospective active surveillance of all reduced seizure frequency and in most cases near-complete elim- neurologists and associated specialists in the United Kingdom (n ination of astatic seizures was achieved. Behavior improved in = 450) for 1 year. Forty-eight cases were identified; of these, 9 almost all patients. were incident cases and had started in that year (age range 45-84 years; duration of EPC, mean 16 days; etiology was stroke 2, cortical vein thrombosis I, diabetic hyperglycemia 1, drug abuse angiitis 1, trauma 1, and other 3). The chronic cases showed a Results of Epilepsy Surgery for Cavernous Venous Malformations. different disorder (age range 2-55 years, mean 30 years; age at Magnus Olivecrona and Herbert Silfvenius (Department of Neu- onset of EPC range 1-48 years, mean 15 years; number of years rosurgery, University Hospital, Umed, Umed Sweden)-8025. with EPC mean 13 years; etiology was Rasmussen’s 6, arterial venous malformation 1, multisystem degeneration 3, birth injury Since 1981, 13 patients with epilepsy and cavernous venous 2, and unknown 2). Neurophysiologic tests and volumetric mag- malformations (CMVs) have been operated on at the Department netic resonance imaging were performed. of Neurosurgery, University Hospital. Umed, Sweden: 10 females (mean age 30.9 years, range 20-44) and 3 males (mean age 38.4 years, range 22-60). Mean duration of epilepsy at time of operation was -6.5 years. Seizures were generalized (l), simple Seizure Outcome in Frontal Lobe Epilepsy: Correlation with Sur- partial (2), and complex partial (10). All patients had neuroradio- gical Removal. Fernando Cendes, Felipe Quesney , Andre Oliv- logic findings indicating CVM. EEG findings were negative in 2 ier , Francois Dubeau, and Frederick Andermann (Montreal Neu- patients, nonlateralizing in 1, lateralizing in 4, and regional in 6. rological Institute and Hospital, McGill University, Montreal, CVM was in sensory motor hand region in 2 and in Wernicke’s Canada)-8023. area in I. In 4 stereotaxic localization and in 4 intraoperative cortical stimulation was used. Four patients underwent an- We correlated seizure onset localization, extent of surgical terotemporal lobe resection for deep-seated CVMs; in 10, le- removal, and seizure outcome in 23 patients with frontal lobe sionectomy was performed. epilepsy investigated with stereotaxically implanted intracere- Outcome with regard to seizures with mean follow-up time of bra1 and epidural electrodes (SEEG). Depth electrodes were 3.6 years (range 0.1-10.75) was group I69%, group I1 23%, and placed bilaterally in the orbitofrontal, cingular, and superiofron- group IV 8%. Three patients have been reoperated owing to tal regions, and in the. temporal lobes. Epidural electrodes were persisting seizures and remaining hemosiderin gliosis; 2 became implanted along the first, second, and third frontal gyri. Extent seizure free. Pathologic examination confirmed the CVM. No of surgical removal was assessed based on the surgeon’s opera- surgical complications or postoperative neurologic deficits were tive map and on postoperative magnetic resonance imaging noted. Surgery for epilepsy and CVM achieves very good results (MRI) (available in 5 patients). and is even possible in vital cortical regions. Not only the CVM Five of the 18 patients had frontal lobe lesions evident on but also the surrounding hemosiderin-stained gliosis must be re- computed tomography or MRI. In only 1 of these patients was sected. SEEG seizure onset focal/regional. Surgical outcome in 14 patients with >2 years postoperative follow-up (mean 7.8 years) was 74% class I or I1 and 36% class I11 or IV (Engel’s classification). Predictors of good outcome were predominant focal SEEG seizure onset (39% of patients), complete or nearly com- Seizures and Treated Cerebral Arteriovenous Malformations. Elia plete removal of the epileptogenic brain tissue based on ictal Baeta, Jorge Campos, Leonor Gomes, Alvaro Almeida, Teresa SEEG and electrocorticographic findings in the nonlesional Paiva, Isabel Martins, and Francisco Pinto (S. Neurologia, H. cases, and removal of structural lesions. Regional or widespread Garcia de Orta-Almada; H. St. Maria, Lisbon, Portugal)-8026. SEEG seizure onset in these patients did not worsen surgical outcome. In more than one third of patients, seizures are the initial symptom of a cerebral arteriovenous malformation (AVM). They can also accompany or follow an intracranial hemorrhage secondary to AVM rupture. With new therapeutic techniques (sur- Callosotomy in Children with Therapy-Resistant Epilepsy. Staffan gical and neuroradiologic), AVM morbidity and mortality can be Lundberg, Orvar Eeg-Olofsson, Hans Carlsson, and Bo decreased, but functional results of treatment and subsequent Spannare (University Children’s Hospital and Department of long-term follow-up have seldom been reported and little is Neurosurgery, Neuro Centre, Uppsala, Sweden)-8024. known about clinical evolution of epileptic manifestations. Since 1990, we have treated 22 patients with endovascular About 25-30% of epilepsies in childhood are resistant to med- therapy and with radiotherapy or neurosurgery. Seventeen had ical therapy. Most children with such disease are severely mul- epilepsy. In 10 patients, AVM was diagnosed during determina- tihandicapped. Usually, they have several seizure types, such as tion of the etiology of late-onset epilepsy. After treatment, 9 complex partial seizures with secondarily generalized, myoclon- remained seizure-free, 4 had reduction in seizure frequency, and ic, and atonidastatic seizures, and atypical absences. Consider- 4 were unchanged. None developed epilepsy after treatment. We ation of a neurosurgical alternative to reduce seizure frequency analyzed clinical characteristics and the possibility of difference in these children, at least to improve the quality of life, is rea- in prognosis related to AVM size, location, time of evolution, sonable. Such a neurosurgical procedure is corpus callosotomy. and previous hemorrhage. Fifteen children and adolescents aged 18 months to 17 years were selected for this palliative operation. Indications for callosotomy were epilepsy resistant to medical therapy, multiple seizure types, frequent atonic or astatic events, and no epileptiform Remission After Hemispherectomy in a Patient with Symptomatic focal discharges on EEG. Preoperative MRT examination and, if Epilepsy, Psychogenic Seizures, and Behavioral Disorder. C. Ben- possible, neuropsychological observation were performed. Two ninger, G. Mittermaier, *C.E. Elger, and tJ. Schramm patients had a diagnosis of West syndrome of symptomatic, (Abteilung Padiatrische Neurologie der Universitats Heidelberg, probably prenatal, type. In 12, the diagnosis was Lennox- Heidelberg; *Klinik fur Epileptologie der Universitats Bonn; and Gastaut syndrome with unknown etiology in 8, and Sturge- TNeurochirurgische Universitats Klinik Bonn, Bonn, Ger- Weber syndrome in 1. All underwent anterior or subtotal callo- many)-8027.

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS

A 20-year-old man had had drug-resistant epilepsy with tonic- with locally related syndromes have more frequentkonstant clonic and partial seizures since his third year of life. He devel- headaches than do those with generalized syndromes (52 vs. oped hemiparesis with progressive atrophy of the contralateral 39%). The patients classified as having frequent/constant head- cerebral hemisphere, e.g., Rasmussen encephalitis. In recent aches also have more idiopathic headaches (90 vs. 73%). These years, behavioral problems and psychogenic seizures developed findings suggest that idiopathic headaches are a risk factor for that prevented social integration and further diagnostic proce- having headache-related seizures. dures (long-term EEG monitoring, Wadatest). After hemispherectomy, this patient became completely seizure-free, and psychogenic seizures as well as the behavioral disorder disappeared. We describe the indications for epilepsy surgery with Primary Headaches in Epileptic Patients. Jose Barros, Rui special regard to psychosocial problems. Chorao, Joaquim Pinheiro, Joio Lopes, Ana P. Correia, Joiio Ramalheira, Pereira Monteiro, and J. Lopes Lima (Epilepsy and Headache Outpatient Clinics, Department of Neurology, Hospi- tal St. Antonio, Porto, Portugal)-803 1. Stereotaxic Surgery of Epilepsy Among Children and Teenagers. Nickolay Solovih and Aleksey Korotkov (Saratov, Russia)- The possible relation between migraine and epilepsy remains 8028. controversial. Investigators have noted a high incidence of migraine in epileptic patients, but the association may be caused by Ninety-eight stereotaxic operations were performed on 86 pa- the coincidence of two common diseases. tients with different forms of epilepsy. Patients were aged 8-18 We mailed a standardized questionnaire to 200 randomized years and had rather prolonged frequent attacks of increasing patients of our epilepsy outpatient clinic with idiopathic or cryp- duration that were refractory to therapy despite repeated differ- togenic syndromes according to the International Classification ent treatments for many years. Twenty-two operated patients of Epilepsies and Epileptic Syndromes of the International had tonic-clonic seizures, 19 had petit mal, 33 had temporal ep- League Against Epilepsy. Patients with symptomatic or benign ilepsy, and 12 had Jacksonian and sensory epilepsy. With im- epilepsies were excluded, as were those who were mentally re- planted electrodes we tape recorded the deepest structures of tarded, illiterate, or aged <16 years. Answers were evaluated brain (stereo EEG). Both electric and other types of stimulation blindly by two of the authors, and headaches were classified were used to localize the epileptic focus and mechanism of gen- according to the Classification of the International Headache eralization of epileptic activity (subsequently destroyed with an- Society. In all, 62.5% of the patients have partial seizures. Re- ode current). The most frequent targets for destruction were sponse rate was 88.5%. Of this population, 80.79% reported hav- nidea thalamus and subthalamus formations and amydalohippoc- ing headaches not related to seizure episodes; in 50%, headaches ampal complex. In 62 patients (72.1%), epileptic attacks ceased were severe enough to interfere with the capacity to work. Me- or occurred rarely. Electrode implantation was well tolerated by dian age at the first headache episode was 16.47 years (SD 8.78) patients. Stereotaxic operation offers great potential for deter- and at first seizure was 17.74 years (SD 12.06). The two were mination of pathogenetic factors and in complex treatment of coincident in 26.6% of the study population. Migraine was the epilepsy. diagnosis in 40 (22.6%), and 86 (48.58%) had tension-type headaches. The prevalencekeverity of idiopathic headaches was greater than that of the general population, and headaches also Epileptic Seizures During Migraine Attack. G. Lekkou, C. started earlier. Derdelakou, Th. Thomaides, S. Tsiara, and C. L. Karageorgiou (Neurology Department, General Hospital of Athens, Athens, Greece)-8029. Centrotemporal Spike Epilepsy and Headache. J. Pinheiro, J. We examined the frequency and profile of epileptic seizures Lopes, J. Ramalheira, A.P. Correia, J. Barros, R. Chorio, P. during a migraine attack in 1,500 patients in the Headache Clinic Monteiro, and J. Lopes Lima (Headache and Epilepsy Outpa- of Athens General Hospital. Ten patients had an epileptic attack tient Clinics; Department of Neurology, Hospital St. Antonio, during the migraine attack, a partial complex seizure that began Porto, Portugal)-8032. after onset of headache. An increased frequency of migraine has been described in patients with centrotemporalspike epilepsy (CTSE) and in their first-degree relatives. From our outpatient epilepsy clinic, we Headaches Associated with Epileptic Seizures. Ana P. Correia, selected 86 possible cases of CTSE. Their charts were reviewed Jose Barros, Joao Lopes, Joaquim Pinheiro, Rui Choriio, Joao blindly by three of the authors, and only patients with diagnosis Ramalheira, Pereira Monteiro and J. Lopes Lima (Epilepsy and considered positive by the three authors were included. The cri- Headache Outpatient Clinics, Department of Neurology, Hospi- terion used was the Classification of Epilepsies and Epileptic tal St. Antonio, Porto, Portugal)-8030. Syndromes of the International Leagues Against Epilepsy. The answers were also evaluated by two independent researchers The combined occurrence of epileptic seizures and migraine and were based on the Classification of the International Head- has prompted discussion about a possible relation between mi- ache Society and separated into three groups: migraine, tension- graine and epilepsy. The headache that follows a generalized type, and other. convulsion is a known phenomenon that may be caused by gen- We selected 36 patients with CTSE (22 males and 14 females) eral metabolic changes and an increase in cerebral blood flow. with a median age of 13.04 years. We obtained 21 responses Investigators demonstrated that migrainelike episodes associ- (58.3%): 42.86% patients had no headache, 33.33% had tension- ated with partial seizures may be central in origin. type headache, 14.29 had migraine, and 9.52% had other types. Two hundred randomized patients of our epilepsy outpatient We analyzed the data from the first-degree relatives and com- clinic with cryptogenic and idiopathic epilepsies received a ques- pared them with results in the literature. tionnaire by mail. Patients with benign epilepsies and those who were mentally retarded, illiterate, and aged <16 years were excluded. One hundred seventy patients responded; 62.94% had partial seizures. Median age was 33 years (SD 14.27); 51.5% National Hospital Seizure Severity Scale (NHS3): Validation. M.F. were female. Headaches were “constant” in 56 and “frequent” O’Donoghue, J.S. Duncan, and J.W.A.S. Sander (The Epilepsy in 24; headaches occurred “seldom” in 18 and “never” in 62. Research Group, Institute of Neurology, London, England)- The four groups had the same age of onset of epilepsy. Patients 8033.

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS 95

The National Hospital Seizure Severity Scale (NHS3) is a pleted basic education, level and who had seizures of various new, easily applicable, physician-administered, seizure severity severity levels and types or were seizure-free. scale based on the Chalfont Seizure Severity Scale (J Neurol Neurosurg Psychiatry 1991;54:873-6). It contains seven factors reported by patients in open interviews as being relevant to seizure severity. We validated the scaling of the NHS3 by two Diagnosing Low-Grade Astrocytomas in Epileptic Patients. Per methods. First, 70 patients were asked to rank five prototypic Schmidt Splrensen, Jesper Krusell, Allan Mortensen, and Kurt seizures, from a written description, in terms of seizure severity Virring SZrensen (Department of Neurology, Central Hospital, (a typicdl absence, a brief complex partial seizure (CPS), an Viborg, Denmark)-8036. atonic seizure with a resultant scalp laceration, an embarrassing CPS, and a generalized tonic-clonic convulsion with prolonged We conducted a retrospective study among patients with epi- recovery). The rankings were compared with that predicted by lepsy with the dual purpose of detecting structural CNS abnor- the NHS3. Concordance was excellent (weighted K = 0.8). Sec- malities and comparing the efficacy of two different radiologic ond, 42 patients judged the relative severity of the prototypic techniques; computed tomography (CT) and magnetic resonance seizures on a visual analogue scale (VAS), and mean VAS se- imaging (MRI). In a 3-year period, 163 patients were included in verity score was compared with the NHS3 predicted score. the study. In 11 of these (3 women and 8 men), we diagnosed and Again excellent agreement was obtained. Our findings suggest histologically verified grade I or I1 astrocytoma. These patients that NHS3 has both content and construct validity. were the subject of a separate study designed to describe the natural history of low-grade astrocytomas in epileptic persons. Mean age of these patients at time of first seizure was 31.3 +- 8.6 years (range 16.9-51.1 years), with delay ranging from 1 Methodologic Problems with Assessment of Seizure Severity. M.F. month to 11 years for the final diagnosis of a CNS neoplasm. O'Donoghue, J.S. Duncan, and J.W.A.S. Sander (The Epilepsy Eight patients had partial seizures, 6 with simple or complex Research Group, Institute of Neurology, London, England)- symptoms and 2 with seizures secondarily generalized. In 3 pa- 8034. tients, the seizures were instantly generalized. Nine received medical treatment, 6 of these as monotherapy. Only 2 patients, Several recent trials of new antiepileptic drugs (AEDs) have however, had an acceptable seizure frequency of two or fewer included seizure severity (SS) as an outcome measure. During seizures a year. The remaining 7 patients had seizure frequency development of a new SS scale based on the Chalfont Seizure ranging from eight a year to several a day. With MRI, we were Severity Scale (J Neurol Neurosurg Psychiatry 1991;54:873-6), able to diagnose 7 patients, suggesting that MRI is more efficient we encountered several methodologic difficulties. In a compar- than CT in this particular tumor type. Benign astrocytomas have ison of the Liverpooland Chalfont scales in the context of a new a recognizable pattern in epileptic persons. With prompt referral AED trial, we realized that a significant proportion of epilepsy to MRI of relevant patients we established correct diagnosis patients cannot reliably complete self-report SS scales owing to early in the disease, thereby influencing prognosis favorably. cognitive impairment. In an attempt to produce a scale with individualized weightings for each severity factor, we discovered that most patients find this counterintuitive and difficult. We also noted that subjectively rated items (e.g., my seizures are: mild, Epilepsy in Patients with Brain Tumor. Saleh Al Deeb, Basim moderate, severe) correlate poorly with objective measures of Yaqub, Nabil Biary, Waleed Khoja, Osama Koreich, and Khalaf severity (e.g., reported injuries or duration of recovery). We Al Moutaery (Department of Neurosciences, Riyadh Military recommend that as an assessment of drug efficacy the SS scale Hospital, Riyadh, Saudi Arabia)-8037. be restricted to a physician-administered measure of objective aspects of SS such as presence of seizure warning, falls, injuries, Three hundred fifty patients with brain tumor were reviewed urinary incontinence, convulsions, automatisms, and duration of at the Riyadh Armed Forces Hospital in the last 6 years: 33% had recovery. epilepsy and 9% had epilepsy as a first symptom. Type of epilepsy was simple partial in 21%, complex partial in lo%, and secondarily generalized in 69%; 33% required more than one antiepileptic drug. Phenytoin was used in 63% of patients, with Validation of Seizure Severity Scale: An Exploratory Study. "T.I.L. 28% failure; carbamazepine was used in 21%, with 57% failure. Ribeiro, S"D. MendonGa, 71. Comes, TL. GonGalves, tJ. Lopes We evaluated the relation between tumor, type, grade, and lo- Lima, and *$A. Martins da Silva (*ServiGo de Neurofisiologia cation and epilepsy. and tServiGo de Neurologia, Hospital de Santo Ant6nio; $Lab- oratorio de Biometria and OUnidade de Fisiologia Humana, In- stituto de CiCncias Biomkdicas Abel Salazar; 'IUnidade de Neu- rofisiologia e Psicofisiologia do IBMC, Universidade do Porto; Bitemporal Epilepsy: Clinical, EEG, and Magnetic Resonance Im- and YFaculdade de Psicologia e Cihcias de EducaGBo da Uni- aging Findings. Felipe Quesney , Antonio Gambardella, Andre versidade do Porto, Porto, Portugal)-8035. Olivier, FranGois Dubeau, and Frederick Andermann (Montreal Neurological Institute and Hospital, McGill University, Montre- The Seizure Severity Scale (SSS) (Baker et al., 1991) is a pa- al, Canada)-8038. tient-based scale on which patients classify their seizures according to their subjective experience. The SSS was designed as an Clinical, EEG, or magnetic resonance imaging (MRI) predic- outcome measure in evaluation of treatment of intractable epi- tors of bilateral independent temporal lobe seizure onsets were lepsy. We wished to adapt the SSS to the Portuguese population studied in patients with temporal lobe epilepsy (TLE) investi- to explore the relation (a) between epilepsy characteristics (age gated with chronically implanted depth electrodes in amygdaloid of onset, duration, frequency, type) and SSS item response; (b) and hippocampal structures bilaterally. Among 70 patients with between epilepsy characteristics and total outcome measure of TLE who underwent depth EEG investigation, we selected 11 SSS; (c) between treatment and outcome measure of SSS; and patients (mean age 31.9 years, range 2148) with bilateral inde- (d) between personal characteristics (sex, age, education, pro- pendent temporal lobe seizure onsets without side predomi- fessional status) and outcome measure of SSS; and (e) to explore nance. We reviewed clinical, scalp EEG, and neuroradiologic SSS as a descriptive tool or as a quality-of-life tool. This research data for each patient. was started early in 1993, with patients followed at the epileptic Eight of 11 patients had a previous history of encephalitis or outpatient clinic of Hospital Geral de Santo Antonio at Porto. severe head trauma. No history of febrile convulsions was doc- The study was based on analysis of data collected from a sample umented. On serial scalp EEGs, bitemporal independent interic- of 50 patients, men and women aged 15-65 years, who had com- tal spiking was documented in all patients. Ictal onsets using

Epilepsia, Vol. 35, Suppl. 7, 1994 96 EUROPEAN CONGRESS PROCEEDINGS extracranial electrodes were bitemporal independent in 5 of 11 levels and an EEG were obtained. A detailed history including patients and simultaneously bitemporal in 2 patients. No clinical age of onset, cause, type and duration of epilepsy, seizure-free differentiation between left and right temporal lobe seizures was period, duration of AED treatment, and family history were detected. MRI investigation showed predominantly unilateral taken; a neurologic examination also was performed. Medication temporal lobe atrophy in 7 of 11 patients and bitemporal atrophy was gradually discontinued in 12 months; for patients treated in 1. A history of encephalitis and bitemporal independent ictal with more than one AED, one drug was completely discontinued onset on scalp EEG are reliable predictors of bitemporal epi- before the next was tapered. Of the 144 patients in the study, 58 lepsy. (40.5%) remained seizure-free after drug withdrawal, wit follow- up periods of 6 months to 4 years; 26 (18%) relapsed during or after the discontinuation period; 56 (38.8%) have not yet finished the discontinuation period. and 4 (0.03%) were excluded based Hungarian Multisite Study of Warning Signs of Epileptic Seizures: on special clinical data. Preliminary Results. Peter Rajna and Judit Veres (Department of Psychiatry, Semmelweis University of Medicine, Budapest, Hungary)-8039. Seizures and Menstrual Cycle in Women with Epilepsy. Amelia A 25-item questionnaire focusing on prodromal (aura) initial Tartara, Carlo A. Galimberti, Rosanna Murelli, Raffaele Manni, symptoms of epileptic seizures was filled out by every second and Enrico Marchione (Epilepsy Centre, Neurological Institute person with epilepsy with the assistance of the responsible pro- “C. Mondino,” Pavia, Italy)-8042. fessionals of nine Hungarian outpatient clinics for persons with epilepsy. Preliminary results of evaluation (n = 432) of the first Seizure exacerbation in relation to the menstrual cycle has 6 months (total study duration is 16 months) show that more than been reported in the literature. To evaluate seizure frequency half of the investigated population have some somatic and/or during the menstrual cycle, we selected 25 women of reproduc- psychic symptoms indicating the occurrence of common epilep- tive age (mean 30.3 -+ 7 years, range 20-44 years) with epilepsy tic seizure. Predicting signs are most frequent in focal than in [idiopathic generalized epilepsy (IGE) 2, cryptogenic or symp- generalized mechanisms. The phenomena are quite stable in- tomatic partial epilepsy (PE) 231 treated with antiepileptic drugs traindividually, but their presence without subsequent seizures is (AEDs). Ten patients were receiving monotherapy and 15 were relatively rare. receiving two AEDs. All patients had maintained an accurate During the prodromal state, one third of patients retain their seizure diary, including occurrence of menstruation. Globally, ability to accomplish spontaneous and instructed activity, and 397 menstrual cycles were studied (5-30 for each patient). Sta- some have already been successful in using warning signs to tistical analysis (evaluation of contingency coefficient) showed a prevent or avoid the seizures. Based on our results, we deter- significant increase in seizures during menstrual flow in 5 pa- mined possible ways in which patients may attempt to inhibit tients (20%; l with IGE and 4 with PE). In 3 (12%) other patients seizures. with PE, seizures increased significantly during a premenstrual 5-day period. No menstrual disturbances were reported by 7 of these 8 patients; 1 patient had irregular cycles. Ovulatory function, monitored by progesterone determination in luteal phase Epilepsy and Muscle Calcifications. Jost Leal Loureiro, Maria during one cycle during study admittance, was normal in 4 and CCu Branco, Francisco Esteves, Margarida Costa, and A. Trigo uncertain in 4. Pelvic echotomography, performed in 7 patients, Faria (Hospital S. Pedro-Vila Real, Vila Real, Portugal)--8040. showed polycystic ovaries in 1. Seventy patients with acquired epilepsy with onset after age 15 years, normal clinical neurologic examination, and no suspicion of other neurologic disease, underwent standard roentgenogram Plasma Levels of Progesterone Metabolites in Women with Partial of the thighs. Six percent had muscle calcifications, strongly Epilepsy in Intercritical Phase. Renato Galli, *Stefan0 Michelini, suggestive of parasites. To establish the semiologic value of a ‘I’Luigi Bartalena, Roberto Massetani, Enrica Bonanni, Maurizio single roentgenogram of the thighs in diffential diagnosis of ac- Petri, $Robert Purdy, *Giovan Battista Cassano, TEnnio Mar- quired epilepsy, we compared the rate with that of a normal tino, and Luigi Murri (Department of Clinical Neurophysiology, population sample. Institutes of Neurology, *Psychiatry, tEndocrinology, Pisa, It- aly; and $Department of Organic Chemistry, San Antonio, TX, U .S.A.)-8043.

Discontinuation of Antiepileptic Drugs. 1. Luzeiro, H. Gens, J. A relation is considered to exist between ovarian hormones Gads, M.G. Alves, J.L. Opes Lima, and Carolina G. Silva and epilepsy. Estradiol (E2) decreases epilepsy threshold, (ServiGo de Neurologia, Centro Hospitalar, Coimbra, Portu- whereas progesterone (P) has an opposite effect. Recently, some gal)-804 1. hydroxy metabolites of P, i.e., allopregnanolone (A) and preg- nanolone (Pn), were shown to have an inhibitory interaction with In most patients with epilepsy, remission of seizures is possi- GABAA receptors in CNS. We evaluated hormonal plasma pro- ble with antiepileptic drug (AED) therapy. Because of concern files in 15 women with partial epilepsy in intercritical phase and about the various chronic and teratogenetic adverse effects of compared them with those of age-matched healthy volunteers. AEDs, as well as some more subtle effects on behavioral and Plasma concentrations of follicle-stimulating hormone, PRL, cognitive function, several prospective studies have been per- luteinizing hormone, E2, P, A and Pn were measured on the formed to determine risk of relapse after AED discontinuation; morning of the study day during luteal phase by radioimmuno- however, information about the risk of seizure recurrence and assay. the factors that influence recurrence, is still controversial. No statistically significant differences were noted between ep- We report preliminary data of a prospective study of 144 pa- ileptic patients and controls for any study variable. Moreover, tients (59.4% males and 40.6% females) selected from the Out- hormonal plasma levels did not differ significantly between patient Epileptic Clinic of the Neurology Service of Centro Hos- women aged <30 and those aged >30 years or between patients pitalar de Coimbra and Santo Antonio General Hospital who with and without seizure frequency deterioration during luteal were recruited between January 1989 and January 1994. We eval- phase of the menstrual cycle. However, patients with lesions uated the risk of seizure relapse in our patients. detectable by computed tomography and/or nuclear magnetic Eligible patients had to have been free of seizures for at least resonance showed higher concentrations of P and Pn than those 2 years while treated with AEDs and had to agree to enter the without lesions (p < 0.05, t test for unpaired data). Our results discontinuation protocol. Before discontinuation, serum drug suggest that metabolites of P do not behave abnormally in EUROPEAN CONGRESS PROCEEDINGS 97 women with partial epilepsy in intercritical phase, but some dif- number of spikes was reduced during LTG treatment, as were ferences detected deserve further consideration. epileptic complexes on EEG. LTG had few side effects (10% of patients).

Classification of Noncompliant Epileptic Patients. J. Beaussart- Defaye, M. Beaussart, J.M. Lamiaux, and J.C. Grubar (Labo- Anticonvulsant Effects of Loreclazole and Valproate on Electrically ratoire de Psychologie Cognitive, Unit6 de Recherches sur les Induced Seizures in Rats. Wojciech Kulak, Wojciech Sobaniec, Epilepsies, Universitt Charles de Gaulle, Lille, France)-8044. Henryka Sobaniec, and Maria Sobaniec-Lotowska (Department of Neurology, Medical Academy, Bialystok, Poland)-8047. A representative sample of 3,088 outcome patients was classified according to their compliance with medical recommenda- The effects of loreclazole (a triazole derivative with potent tions; 1,101 (35.65%) of them were noncompliant. The reasons antiepileptic properties) and valproate (VPA) on duration of elec- given by the families (for patients aged <18 years) by patients trically induced seizures and protection rate against tonic exten- themselves (aged >I8 years), or observed by their neurologist, sion were assessed in 70 rats. Administration of loreclazole (20 were refusal to take treatment (fear of dependence and side ef- or 40 mg/kg intraperitoneally, i.p.) significantly reduced seizure fects), 16% (<18 years), 16% (>18); resorting to alternative med- duration: the drug protected 40 and 50% of rats, respectively, icine only, 8% (<18), 4% (>I@; taking the prescribed treatment from the tonic phase of seizures. VPA 200 mg orally (p.0.) a intermittently, 18% (<18), 23% (>I@; trying to give up treat- significant decreased seizure duration and protected against ment in untimely manner, 15% (<18), 9% (>18); and consulting tonic extension. Combined treatment with VPA 100 mg/kg p.0. their neurologist irregularly, 43% (18). and loreclazole 20 or 40 mglkg i.p. reduced seizure duration sig- Data on the noncompliant patients were also classified accord- nificantly and protected 50 and 30% of rats, respectively, from ing to sex (no significant difference), etiology (34.75% of symp- tonic seizures. The anticonvulsant efficacy achieved with com- tomatic cases), seizure types (41.57% complex partial, 36.39% bined VPA and loreclazole apparently results from the combined generalized), and other descriptive epileptologic variables in- effects of the two drugs. cluding the influence of noncompliant behavior on development of the different types of epilepsy. Our results indicate the need for educational program to inform patients of the risks of inappropriate treatment and of noncompliance with medical recom- Periodontium in Epileptic Patients Treated with Mono- or Poly- mendations. therapy. Henryka Sobaniec, Wojciech Sobaniec, Wojciech Ku- lak, and Maria totowska-Sobaniec (Department of Prosthetics, Medical Academy, Bialystok, Poland)-8048.

Getting to Know Epilepsy as an Art Therapist. J. Sumner (The Recent epilepsy therapy differs markedly from that used sev- David Lewis Centre for Epilepsy, Cheshire, England)-8045. eral years ago. In the seventies, polytherapy was quite common and the more frequently used drugs were phenytoin (PHT) and This poster presentation is the purely personal view of a new- phenobarbital (PB) combined with another, such as a benzodi- comer to epilepsy. It presents a fresh impression of established azepine. Monotherapy is now preferred. Depending on seizure theories and philosophies relating to epilepsy. Because it is sub- type, the so-called first-line drugs are valproate VPA and its jective, the presentation includes a personal history of the ther- derivatives and carbamazepine (CBZ). apist to indicate the origin of the opinions. It outlines the views We assessed the periodontium of 50 epileptic patients treated encountered while considering the questions: “What is epi- for >3 years. Thirty (group 1) were treated with polytherapy lepsy?” and “What is the role of Art Therapy in Epilepsy?” (PHT, PB), and 20 (group 11) were treated with monotherapy (Cregeen S, Inscape, Spring 1992: 17-26). (VPA or CBZ). Hyperplastic gingivitis was noted in 43.3% of Some misconceptions about the role of art therapy in epilepsy group 1 patients; group I1 patients did not show these changes. are considered: e.g., that art therapy is recreational and that art Gingivitis was detected in 76.6% in group I and 40.0% in group therapy is involved only in treatment of individuals with none- 11; 40.0% in group 1 and 35% in group 2 had gingival bleeding. pileptic seizures. It outlines how therapy may be used to provide Periodontosis was evident in 20% in group I, possibly owing to input into epilepsy research, e.g., in treatment of sexually the advanced age of the patients. Hyperplastic changes were abused adults with epilepsy (Grieg and Betts, Seizure, 1991;l: observed in those treated with PHT and were dependent on dose 269-74) and in evaluating reduction in epileptic seizures in indi- and duration of therapy. New antiepileptic drugs (VPA, CBZ, viduals who attend art therapy sessions. vigabatrin) do not cause gingival hyperplasia.

Treatment of Epilepsy with Lamictal Among Children and Teen- Defining Seizures. Nancy C. Schumacher (Bloomington, MN, agers. Vjacheslav Galasheskiy and Aleksey Korotkov (Saratov, U .S. A.)-8049. RussiaL-8046. Complex partial seizures may become an embarrassment to an We studied the antiepileptic effect of Lamictal (lamotrigine, epileptic person if they are allowed to continue unabated over an LTG) in 12 children and teenagers, 7 with partial secondarily extended time, possibly leading to depression. It is important generalized seizures/temporal lobe epilepsy (TLE), 2 with gen- that physicians explain expected side effects of drugs. Drug ther- eralized tonic-clonic seizures, and 3 with absence epilepsy. Four apy is not always successful, and such side effects are sometimes patients received LTG as monotherapy; 8 also received other awkward and menacing. traditional antiepileptic drugs. Anamnesis of the disease was 2- Natural changes that accompany menopause become exacer- 10 years. bated by stress and may be confused with reactions to new an- LTG had antiepileptic effect in 75% of cases of TLE and in tiepileptic drugs (AEDs). Both patients and physicians find it 50% of cases of generalized epilepsy. Improvement usually was difficult to sort out the cause of night sweats, insomnia, anemia, apparent during the second and third week of treatment, the anorexia, constipation, and hot flashes when they occur imme- acute form of the convulsive component, as well as seizure du- diately after a major drug change. Some side effects may be due ration, was reduced. In 80% of cases, postepileptic state was to menopause but not to AEDs, and vice versa. When a person shorter. Epileptic episodes did not increase during LTG treat- is unaware of the origin of the side effects, the effects become ment. No changes were noted in the sleep-wake cycle. LTG had more threatening. Continuing treatment with a drug that causes no depressive effect on CNS; instead, it improved mood. The discomfort becomes difficult.

Epilepsia, Vol. 35, Suppl. 7, 1994 EUROPEAN CONGRESS PROCEEDINGS

Why change medication? Change is needed when control is adult units. In 25 (17.9%), resective surgery was considered, but inadequate when toxicity occurs, or when side effects interfere in 9 it was abandoned (patient too demented, no discernible fo- with a person’s life style. cus based on noninvasive ictal EEGs combined with neuroimaging, bilateral foci, pseudoseizures, and other psychiatric con- traindications). At present (February 1994, 3% years after the end of the eval- Retrospective Evaluation of a 5-Day Epilepsy Program. W. Nelen, uation period), 15 (10.7%) had been operated on. If the 140 pa- A. Achterberg, and P. Voskuil (Dr. Hans Berger Kliniek, Epi- tients form a representative sample of the population with intrac- lepsycenter, Breda, The Netherlands)-8050. table epilepsy, and if the prevalence of such epilepsy is estimated to 25%, the prevalence of “surgical candidates” among patients The 5-day epilepsy program is a unique approach to epilepsy with epilepsy is -2.5% (95% confidence limit 1.44.196). Thus, care in Holland. Six patients with their partners are admitted for for more than -95% of all epilepsy we can reasonably estimate 5 days to a special unit in our epilepsy clinic. The multidisci- that the hope for the future lies in progress in medical treatment. plinary program consists of a complete medical and psychosocial evaluation; exchange of views and experiences with other patients and partners; social assessment through group observations and extensive interviews of patients and partners by a so- Bilateral Periodic Lateralized Epileptiform Discharge in Patients cial worker and a psychologist; presentation of all results to the Aged 13-20 Years Treated with Glutamate. Dennis Roberto Arel- patient and partner by a neurologist, psychologist, and social lano Hoffman (EEG Department, N. Villaran Clinic, Lima, worker on the fifth day, with details about diagnosis, etiology, Peru)-8054. and prognosis and specific advice with regard to life style, social activities, treatment programs, and necessary further investiga- We are performing continuing study of the occurrence of bi- tion. The discussion is tape-recorded and is taken home by the lateral epileptiform discharge (BIPLED) in routine EEG of per- participants. The most important aim of the program is to im- sons who habitually use monosodium glutamate (MSG) as a food prove the ability of patients and their partners to cope with ep- additive. Using chi-square test, we assessed 619 EEGs of pa- ilepsy. tients aged 13-20 years with regard to sex and percentage. The effects of the program are evaluated retrospectively with Results showed 213 males and 261 females who could be di- a “one group posttest-only design” 6 years after patients partic- vided into two groups: users and nonusers of MSG. More EEG ipate. Participants (n = 361) completed two questionnaires con- abnormalities [deficient organization of background activity cerning their coping behavior before and after participating in the (DO), presence of paroxysms, and compatibility with BIPLED] program and reported the extent to which they followed advice. were determined in greater percentages in MSG users. No sig- Patients and their partners gave high ratings regarding being nificance differences were noted with regard to slow alpha informed about all questions they had had before participation. rhythm. Chi-square analysis showed >90% significance (mainly Their feelings of fear and tension were reduced after the pro- in females) in EEG abnormality in persons consuming MSG. gram. Patients and their partners coped better with epilepsy (not More cases of abnormal EEG and compatibility with BIPLED including the year of participation). Patients, but not their part- were detected, mainly in females, in patients aged 13-20 years ners, had significantly better social adaptation. The program was who habitually used MSG as a food additive. Clinicians perform- highly effective: 77% of advice was followed. After participating ing EEGs should be aware that MSG is a substance that can in the 5-day epilepsy program, patients and partners were better provoke subclinical bioelectrical manifestations and increase B1- able to cope with the epilepsy. PLEDs.

Gelastic Epilepsy: A Follow-Up Study. DuSan VranjeSeviC (Clinic Lamictal as Add-on Antiepileptic Drug in 210 Patients with Resis- for Child Neurology, Belgrade, Yugoslavia)-8051. tant Epilepsy. C. Bisgaard, M. Dalby, and J. Mai (Neurological Department, Aarhus University Hospital, Aarhus, Denmark)- We made a follow-up (2-28 years) study of 28 children with 8057. gelastic epilepsy. Ten children had only gelastic seizures; in the remaining 18, such seizures occurred together, occasionally, or Lamictal (lamotrigine, LTG) was used as add-on antiepileptic permanently with other types of epilepsy. Neurologic and endo- drug (AED) for 3-25 months (average 9 months), on a named- crinologic investigations indicated disorder of the hypothalamic patient basis, in 210 patients with long-standing resistant epi- region in one-third of these patients. In 3, detailed clinical inves- lepsy (average duration 19 years). Daily LTG dose was gradually tigation showed a tumor, which is often reported to be an im- increased in 4-21 days from 25 mg initially to a maintenance dose portant etiologic factor. EEG results were in full accord with of 50-900 rng (average 195 mg). Side effects were reported by 54 those described in the literature. patients and resulted in LTG discontinuation in 19 patients (skin Good therapeutic results of treatment were obtained with an- rash 8, sedation 3, dizziness 2, sleep disturbance 3, hyperhydro- tiepileptic drugs (tegretol, phenytoin), although only 12 children sis 2, and galactorrhea with excessive prolactin levels I). Skin became seizure-free. Gelastic seizures often go unrecognized or rash occurred only in patients with rapid increase in LTG (<7 misdiagnosed despite their typical features a 28-year-old man days). Treatment was discontinued in 19 other patients owing to whose seizures at age 13 years were photographed and whose lack of effect. ictal EEG was recorded now has only rare seizures and mild Eighty-seven patients had <75% reduction in seizure fre- intellectual insufficiency. quency, 119 patients (56%) had 275% reduction in monthly seizure frequency, and 55 patients (26%) became seizure-free. Dif- ferences were noted in response rates (seizure reduction >75%) for partial seizures (61 of 104 patients), Lennox-Gastaut syn- How Many Patients with Epilepsy are Candidates for Resective drome (17 of 20 patients), and juvenile myoclonic epilepsy (6 of Surgery? An Estimate Based on Evaluation of 140 Intractable 21 patients). In a subpopulation of 82 severely physically and Cases. J@rgen Alving (Dianalund Epilepsy Hospital, Dianalund, mentally handicapped patients, responses were very good and of Denmark)-8053. benefit with regard to caretaking in 52 (63%). A valuable effect of LTG, apparent as maintained wellbeing, was reported by pa- From January 1, 1989 to April 7, 1990, 140 patients with in- tients or relatives (82 patients, 39%). LTG is a safe and effective tractable epilepsy were evaluated in our pediatric and short-stay drug in resistant epilepsy.

Epilepsia, Vol. 35, Suppl. 7. 1994 EUROPEAN CONGRESS PROCEEDINGS 99

Epileptic Seizures in Patients with Alzheimer’s Disease. discharge while augmenting the convulsive threshold (possibly Shota Bibileishvili (Sarajishvili Institute of Neurology, Tbilisi, due to a connection with the site of glycine on the N-methyl-D- The Republic of Georgia)-8058. aspartate receptor. We assessed preliminary results of a ‘H nuclear magnetic res- Epileptic seizures are uncommon in patients with Alzheimer’s onance spectroscopy study of patients with drug-resistant epi- disease. We studied 36 patients. Of these, only 7 (19.4%) showed lepsy treated with LTG or FBM. Variations in endogenous generalized tonic-clonic and partial epileptic seizures. All pa- amino acid concentration were studied in symmetrical frontal tients were subjected to EEG, computed tomography (CT), and cortex volumes in two patient groups (7 LTG and 5 FBM pa- magnetic resonance imaging (MRI). Focal neurologic symptoms tients) before and after treatment, as well as in a control group. werc absent. EEG of most patients showed excessive general- Four patients treated with LTG who experienced a 50% de- ized asynchronous slow waves, marked slowing, reduction in crease in epileptic crises also had a significant decrease (from 20 amplitude, and disorganization of alpha rhythm. Eight of 36 pa- to 50%) in total peak levels of glutamate, GABA, and gluatmine. tients showed different types of seizure discharges: high- On the contrary, no significant spectroscopic changes were ev- amplitude sharp waves in frontal regions, 1; spikes and spike- ident in patients with static frequency of crises or in the control wave complexes in frontotemporal regions, 5; and bilateral syn- group. We are now attempting to quantify the variations in brain chronous discharges of polyspikes, 2. Seven of these 8 patients aspartate concentrations in the same patient and control groups had clinical seizures. CT and MRI registered dilatation of the and are elaborating on spectroscopic data obtained in FBM pa- subarachnoid area and of the ventricle system, in particular of tients. the frontal and occipital horns of the lateral ventricles. Cortical atrophic foci were more often observed in the frontal and parietal lobes. The atrophic process was less marked in temporal and occipital regions. However, patients with epileptic seizures showed atrophic process mainly in the temporal region. Emer- Nursing Treatment of Nonepileptic Seizures. Phillip Aspinall gence of epileptic seizures in patients with Alzheimer’s disease (Maudsley Hospital, London, England)-8061. was associated with predominance of the atrophic process in the temporal region; increased epileptogeneity is a typical feature of The Maudsley Epilepsy Unit is used for tertiary referrals, and temporal lobe structures. its patients are complex and need considerable care. We have devised an assessment and treatment program for patients diagnosed with nonepileptic seizures. Treatment is part of a contin- uum that includes assessment, treatment, and follow-up. As- pects of treatment include involving the patient and family in all Vigabatrin in Add-on Therapy in Partial, Drug-Resistant Epilep- stages of care, the validation of the patient’s seizures, and the sies: Are There any Predictive Criteria for Its Efficacy? Salvatore development of a trusting therapeutic relationship with the pri- Striano, Leonilda Bilo, Roberta Meo, Patrizia Ruosi, Angela Ca- mary nurse and the multidisciplinary team. It also includes porella, Cristofaro Nocerino, Teresa Cuomo, and Anna Estraneo teaching the patient techniques for self-management of seizures (Clinica Neurologica, Universita Federico 11, Napoli, Italy)- and working with the patient to try to identify any maintaining 8059. factors that perpetuate the seizures. All patients maintain a detailed Antecedants, Behavior, and Consequences seizure diary. The efficacy of vigabatrin (VGB) as add-on therapy in drug- A study is in progress to assess response to treatment and its resistant partial epilepsies was established in several studies, in outcome. all of which seizures were markedly reduced -50% of patients. However, only a few patients (-7%) enter remission when VGB therapy is initiated. Except for some rare conditions, such as tuberous sclerosis, we lack predictive criteria for the efficacy of LTG in individual patients. Therefore, we evaluated the clinical Open Clinical Trial of Vigabatrin as Add-on Therapy in Severely characteristics of a small group (15 patients) of good responders Intractable Partial Seizures. B.J. Lee, K. Huh, S.C. Park, *J.Y. (seizure-free or with seizure reduction >75%). No significant Chung, and *Y.K. Chun (Department of Neurology, Yonsei Uni- differences were noted among the entire (77 patients) group in versity College of Medicine, Seoul, Korea; and *Marion Merrell regard to duration and severity of epilepsy, the number of asso- Dow Korea)-8062. ciated antiepileptic drugs, or the nature (symptomatic or cryptogenic) of the epilepsy. As a unique feature, we noted a sugges- The antiepileptic effect of vigabatrin (VGB) in children has tive high frequency of intracerebral calcifications of various eti- been demonstrated in a number of controlled studies. In adults, ology among symptomatic good responders. the effect of VGB (gamma vinyl, GABA) has only been investigated to a limited extent. To assess the long-term effect and safety of VGB in patients with severe epilepsy, an open, add-on, dose-ranging study was initiated. Thirty-two patients with severely medically intractable partial seizures with or without sec- [ 1H]-Nuclear Magnetic Resonance Spectroscopy Study of Varia- ondarily generalized tonic-clonic seizures were included. tions in Endogenous Brain Amino Acids in Epileptic Patients due to Study protocol consisted of 2 months of phase 1 (VGB:2.0 Lamotrigine and Felbamate. G.F. Perticoni, P. Brunori, *O. mg/day) and 4 months of phase I1 (VGB:3.0-4.0 mg/day). VGB Presciutti, *R. Tarducci, *G. Gobbi, and C. Tiacci (Neurophys- was added to the patients’ former anticonvulsants for 3-6 months iopathology Unit and *Department of Medical Physics, Regional and the changes in seizure frequency were checked regularly for Hospital, Perugia, Italy)-8060. 1 month. During the study period 9 patients dropped out for various reasons: 3 patients due to side effects, and 1 patient due Lamotrigine (LTG) and felbamate (FBM) have recently been to the development of tuberculous meningitis. used as antiepileptic drug treatment but have not yet been mar- At the end of the study, >50% improvement in reduction of keted in Italy. In in vitro experiments, LTG inhibits amino acid seizure frequency was observed in 12 of 28 patients (43%) who release induced by veratrine in rat cerebral cortex. This inhibi- did not development serious side effects. Dizziness was the most tion mainly affects glutamate and aspartate systems and to a frequent side effect having been found in 10 patients, and psy- lesser extent that of y-aminobutyric acid (GABA). This effect is chosis was seen in two patients. On long-term treatment of VGB, due to a membrane stabilization mechanism of LTG, similar to about 70% of the patients continued to experience its beneficial that of phenytoin. The mechanism of action FBM is less well effect. Out study suggests that VGB is a new antiepileptic drug defined: In animal models, it inhibits progression of the epileptic useful for severely refractory partial seizures.

Epitepsia. Vol. 35, Suppl. 7, 1994 100 EUROPEAN CONGRESS PROCEEDINGS

Efficacy and Tolerability of Vigabatrin as Add-on Therapy to Val- in mental performance. Because their disorder has a lesional proate in Severely Intractable Partial Epilepsy. Y.M. Whang, J.G. etiology and their prolonged spike-wave status persists during Kang, M.C. Lee, and *J.Y. Chung (Department of Neurology, wakefulness, these patients should be distinguished from those Asan Medical Center, Ulsan University, Seoul, Korea; and with continuous spike-waves during sleep. Our observations sug- *Marion Merrell Dow Korea)-8063. gest a causal role for congenital lesions of the left hemisphere and long-lasting spike-wave encephalopathies. We investigated the efficacy and safety of vigabatrin (VGB) (24 g/day) as add-on therapy to valproate (VPA) in 20 adult patients (mean age 26.3 years, range 13-36 years) with partial Aphasic Status: Clinical and EEG Study of One Patient. S. A. seizures in an open clinical trial. All patients were receiving VPA Musumeci, M. Elia, R. Ferri, A. Castano, S. Del Gracco, and C. combined with other conventional antiepileptic drugs (AEDs). Seuder (Department of Neurology, Oasi Institute (IRCCS), The mean number of AEDs before ingestion of VGB was 2.67. Troina, Italy)-8065. The mean plasma concentration of AEDs before VGB was within therapeutic ranges. Seizure counts and safety data were We report the clinical and EEG features of a 36-year-old assessed at intervals during a 6-month follow-up period. Twelve woman with drug-resistant epilepsy and moderate mental retar- of 20 (60%) patients showed a decrease in seizure frequency > dation who had long-lasting aphasic “status” as clinical expres- 50%, and one patient became seizure free. The mean number of sion of occurrence of numerous subsequent partial seizures. Ce- seizures per month decreased from 11.9 to 5.5. Eight patients rebral computed tomography scan was normal. During such an discontinued VGB for lack of efficacy or worsening. Long-term episode, the patient answered questions with a verbal stereo- effect was also evaluated after 1 year in 9 patients with improve- typy. Concurrently, EEG showed numerous ictal discharges of ment, and 8 patients were found to still experience the beneficial spike-and-wave complexes, followed by delta waves and lasting effects of VGB. Discontinuation of preexisting VPA without -6-10 s. Such discharges were often preceded by short se- changing the state of improvement was possible in 2 (10%) pa- quences of theta waves or by significant reduction in EEG volt- tients and decreases in dosage of VPA was possible in 3 (15%) age for 2-3 s. These discharges were always focal, being better or patients. VGB was very well tolerated. No patients had impor- exclusively represented over left frontotemporal regions. After tant changes in hematology or biochemistry values. Psychotic -3 h, administration of intravenous diazepam abolished this sta- effect was not observed. The side effects were dizziness (3 tus and the patient was able to answer questions correctly. We cases), weight gain (2 cases), drowsiness (1 case), headache (1 conclude that in our patient the aphasic status was a well-defined case), skin rash (1 case), and GI symptom (1 case). clinical entity with speech arrest episodes observed before it VGB appears to be a well-tolerated drug with antiepileptic occurred; it showed a peculiar EEG picture characterized by efficacy as add-on .therapy to VPA in severely refractory partial paroxysmal potentials over left frontotemporal regions (over the epilepsy, and long-term efficacy is also sufficient. dominant hemisphere), and its etiology was different from vascular or tumoral pathology.

Congenital Left Hemispheric Lesions and Spike-Wave Sleep- Dependent Encephalopathy. s. Ricci, M. Di Capua, and F. Vige- Epileptic Seizures due to P-Cell Adenoma. A. Tahmasebi and J. van0 (Section of Neurophysiology , Bambino Gesu Children’s Ziaiy (Kashany Hospital, Isfahan University of Medical Sci- Hospital, Rome, Italy)4064. ences, Isfahan, Iran)4066.

Congenital unilateral hemispheric lesions arising from prenatal Metabolic abnormalities are the major cause of pathologic con- brain damage may cause epileptic seizures and epileptic enceph- ditions that give rise to epileptic seizures and that are reversible. alopathies. We observed 3 girls in whom epileptic encephalopa- We studied 4 patients with epileptic seizures but no improvement thy, characterized by persistent spike-wave activity during sleep after 2-year treatment with antiepileptic drugs (AEDs). These 4 and wakefulness, started at age -6 years. All had left poroen- patients (2 males and 2 females) were evaluated for blood sugar cephaly and right spastic hemiparesis since birth. All underwent and hormonal (including insulin) changes in basal state and after repeated ambulatory EEG monitoring. All had partial motor sei- activation tests. Hypoglycemia and hyperinsulinemid were de- zures and atypical absences. In all, sleep induced continuous tected in 3 of the patients (after abdominal computed tomogra- spike-wave activity that persisted after awakening, as well as phy scan showed a p-cell adenoma (2 cm in diameter) in the head daily prolonged, spike-wave status. The symptoms during status of the pancreas; all underwent pancreatectomy. Postoperatively, differed markedly between patients, and in each patient at dif- the patients are seizure-free). Epileptic seizures in 1 patient (a ferent times, but EEG features remained unchanged over the 21-year-old man) were due to isolated ACTH deficiency; after years. daily levothyroxine (1 50 pg/day) plus hydrocortisone (20 mg/ The appearance of encephalopathy coincided with a decrease day) treatment, epileptic seizures subsided.

Epilepsia, Vol. 35, Suppl. 7, 1994