JLE

Epileptic Disorders

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November 22-25, 2001, Athens, Greece - Abstracts of invited speakers Volume 3, issue 4, December 2001

Organisers

Greek League Against Epilepsy (GrLAE)
Greek National Association Against Epilepsy (GrNAAE)

In collaboration with
International League Against Epilepsy
International Bureau for Epilepsy
Under the Auspices of
Hellenic Neurological Society

Mediterranean Organising Committee

Chairman: Athanasios Covanis, Greece

Members (in alphabetical order)

Giuliano Avanzini, Italy
Michel Baldy-Moulinier, France
Antony Galea Debono, Malta
Esat Eskazan, Turkey
Pierre Genton, France
Farouk Koura, Egypt
Amel Mrabet, Tunisia
Cigdem Ozkara, Turkey
Emilio Perucca, Italy
Antonio Russi, Spain

Local Organising Committee

Chairman: Athanasios Covanis

Members (in alphabetical order)

Alexandros Agathonikou
Athanasios Evangeliou
Kiriakos Garganis
Stilianos Gatzonis
Stylianos Giannakodimos
Marina Katsalouli
Vasilis Kimiskidis
Nomiki Loli
Panagiotis Polychronopoulos
Neophytos - Fivos Prodromou
Panagiotis Sioutos
Constantinos Skiadas
Magda Spilioti
Virginia Theodorou
Nikolaos Triantafyllou
Stephanos Tsounis
Georgios Zacharakis

Secretary of local organising committee:

Anastasia Vassou

Local Scientific Committee

Chairman: Athanasios Covanis

Members (in alphabetical order)

Nikolaos Diamantopoulos
Georgios Georgakakis
Climentini Karageorgiou
Aristides Kazis
Anna Karlovasitou-Koniari
Vasilis Kontopoulos
Georgios Kostopoulos
Evangelos Markakis
Panagiotis Mavrommatis
Ioannis Milonas
Christos Panteliadis
Antigone Papavasiliou
Photios Photiou
Andreas Plaitakis
Damianos Sakkas
Dimitrios Vasilopoulos
Sotirios Yiouroukos m

Abstracts - Invited Speakers

Overview: epilepsy surgery in developing countries

Jerome Engel, Jr., MD, PhD, UCLA, Los Angeles, CA, USA

The Mediterranean region presents unique opportunities for effective biomedical cooperation because of the close association of both highly industrialized and developing countries. Surgery has been an accepted alternative treatment for medically refractory epilepsy for over one hundred years, and is now widely applied in industrialized countries. For those with surgically remediable syndromes in these countries, 70 to 90% can expect to become seizure free postoperatively. However, 90% of patients with medically refractory epilepsy live in the developing world, where surgical treatment has not been considered a feasible means of addressing this overwhelming burden, because of the belief that epilepsy surgery is an expensive high technology-bound therapy beyond the means of countries with limited resources for health care delivery. Recently, advances in presurgical evaluation that have led to new, more cost-effective approaches in the industrialized world are being successfully applied by a number of epilepsy surgery programs in the developing world, including the Mediterranean region, disproving the prevailing impression that epilepsy surgery is beyond the means of these countries. To create epilepsy surgery centers in developing countries, the most important investment, as for industrialized countries, is in properly trained personnel. Collaborative training programs between industrialized and developing countries in the Mediterranean region would help to achieve this objective. Establishing a critical mass of multidisciplinary experts requires commitment but is relatively inexpensive. Most developing countries can afford at least one medical center with the required MRI and video-EEG monitoring unit. Those that cannot may be able to work with neighboring countries to develop regional centers serving several countries. These centers could then limit their practice to patients with surgically remediable syndromes, those who can be easily diagnosed noninvasively and have the greatest potential for becoming seizure free postoperatively. For this patient population in developing countries, surgical treatment may even be more cost-effective than pharmacotherapy.

Interests of EEG sleep studies in epileptology

Michel Baldy-Moulinier MD, Epilepsy Unit Universitary Hospital, Centre Gui-de-Chauliac 34295 Montpellier Cedex 5, France

Interests of sleep studies in Epileptology is explained by the reciprocal influence of sleep on Epilepsy and epilepsy on sleep organization. Sleep may facilitate both interictal epileptiform EEG discharges and seizures. Such effect is very sensitive in sleep-related epilepsies. In contrast a protective effect may be attributed to sleep considering the influence of sleep deprivation on epileptic manifestations.This last effect is a major criteria of awakening-related epilepsies.

Sleep studies may be performed by various protocols including all night polysomnography, nap EEG recordings, sleep recording after sleep deprivation and sleep interrupted by provoked arousals.

Sleep studies have a special interest when wake EEG is normal. Sleep may help diagnosis of benign childhood epilepsy with centrotemporal spikes, autosomal dominant nocturnal frontal lobe epilepsy and symptomatic or cryptogenic frontal lobe epilepsy. Sleep abnormalities characterize Landau-Kleffner and Continuous Spike Wave Activity during Slow Sleep Syndromes.

Sleep deprivation protocols are useful for the diagnosis of Idiopathic Generalized Epilepsies particularly Juvenile Myoclonic Epilepsy and Epilepsy with Generalized Tonic Clonic Seizures on Awakenings.

The effect of Epilepsy on Sleep Organization is of pathophysiological interest in Temporal Lobe Epilepsy.

For an overall benefit, most of sleep studies should be performed with Video-EEG monitorring particularly when epilepsy manifestations must be differenciated with Parasomnia. Polysomnography must be combined with video-EEG when epilepsy is suspected to be associated with Sleep Apnea Syndrome.

Idiopathic generalized epilepsies of adolescence

Dorothée Kasteleijn-Nolst Trenité, The Netherlands

About 50% of all epilepsies can be classified as idiopathic and 25% as generalized idiopathic. Several idiopathic epilepsies have their age at onset in puberty such as juvenile absence epilepsy, juvenile myoclonic epilepsy, epilepsy with grand mal on awakening. Others have a peak prevalence around puberty, like visual sensitive epilepsy.

An overview will be given of the separate syndromes: clinical symptomatology, incidence and prevalence data, evolution of symptomatology and molecular genetic data as far as available.

Because of the special issues involved in adolescent care, it is worthwhile to highlight these epilepsy types.

Praxis-induced seizures in adolescents

J. Salas-Puig, L. Jiménez, S. Calleja. Neurology Department Hospital General Asturias, Oviedo, Spain

Epileptic seizures induced by specific stimuli (reflex seizures) are rare and sometimes very difficult to diagnose. They occur aproximately in 6% of patients with epilepsy. Reflex seizures provoked by intelectual activity such as praxis or decision-making occur in some patients who share the majority of clinical and neurophysiological characteristics of patients with idiopathic generalized epilepsies.

We report on six patients with praxis-induced seizures and we comment on overlapping situations which occurred in three other patients, two of them with reading epilepsy and the other one with juvenile myoclonic epilepsy, who suffered myoclonic seizures during the EEG recordings while they were making the cubes of WAIS test or during drawing or calculation.

1. Patients with praxis-induced seizures

They were five males and one female with a median age of 39.2 years (21-41). Three patients had familial antecedents of epilepsy. Age at onset of tonic-clonic seizures was 14.2 years (10-18). All suffered tonic-clonic seizures, three had absences and three myoclonic seizures. Neurological examination was normal. All had average or above-average intelligence. CT scan and MRI were normal. Standard EEG were normal. Two patients showed a photoparoxysmal response. All patients showed spike and wave discharges on the EEG during different activities: calculation, drawing, playing cards, chess or other similar games, WAIS cubes. No patient had EEG discharges during reading. Five patients followed treatment with sodium valproate on monotherapy. Three did not suffer any more seizures. Two patients continue to suffer rare seizures. One patient needed polytherapy with carbamacepine, sodium valproate and clobazam to be seizure-free. All patients had a clear benefit identifying the reflex nature of their seizures which allowed them to avoid the precipitating factors.

2. Patients with overlaping reflex-seizures

We studied two patients with reading epilepsy who also had EEG discharges when they were drawing or making the WAIS cubes or during calculation. A 28 year-old male patient . His sister had reading epilepsy. He suffered his first seizure during reading when he was 12. Neurological examination was normal. IQ was normal. CT scan and MRI were normal. The EEG recordings during reading showed fast spike and wave discharges predominantly on left hemisphere with corresponding jaw myoclonus. The EEG also showed a photoparoxysmal response increased by eye-closure condition. The EEG recordings during calculation and drawing also showed spike and wave discharges without jaw myoclonus. Sodium valproate was prescribed and he continued to be seizure-free. An 18 year-old female patient with unremarkable family history. At the age of 12 months she suffered a febrile convulsion. When she was 16 year-old, she had a tonic-clonic seizure while she was reading. After several weeks she suffered myoclonic jerks and a tonic-clonic seizure during calculation. Neurological examination, IQ, MRI were normal. Standard EEG recording was normal. During reading aloud the EEG showed left predominating spike and wave discharges accompanied by a myoclonus. During WAIS cubes the EEG also showed spike and wave discharges, sometimes with upper limbs myoclonus. Lamotrigine treatment controlled her seizures.

A 45 year-old female patient with unremarkable familial and personal history. At the age of 18, she begun to suffer myoclonic jerks on awakening. When she was 22, she had a generalized tonic-clonic seizure. Neurological examination was normal. Phenobarbital was prescribed and the patient had rare myoclonic seizures on awakening in relationship with sleep deprivation or discontinuation of treatment. Standard EEG was normal. EEG during sleep showed generalized spike-polyspike and wave discharges during NREM sleep. The diagnosis was juvenile myoclonic epilepsy. When she was 43, she told myoclonus in her right hand while writing. EEG recordings during writing, drawing and making WAIS cubes showed spike and wave discharges some of them with right hand myoclonus. Sodium valproate was prescribed and she became seizure-free.

There are some patients with seizures induced by an intelectual activity such as thinking, calculation, taking spatial decisions, playing cards, draughts, chess or similar games (praxis-induced) who belong to the idiopathic generalized epilepsies. There are also some patients with other kinds of epileptic syndromes who showed EEG paroxysmal discharges during such intelectual activities. In our experience we can find some patients with the myoclonic variant of reading epilepsy with such situation. We can also find some patients with juvenile myoclonic epilepsy who have this peculiarity.

We think that there are some intelectual activities which trigger cortical areas and they are able to induce clinical seizures or paroxysmal EEG activity. In this peculiar form of reflex seizures, parietal lobes, especially non-dominant parietal specific structures, play a crucial role.

The recognition of the triggering factors is very important to become seizure-free.

Adolescents with epilepsy: what is forbidden and what is permitted? Lifestyle issues

Pierre Genton, MD, Centre Saint-Paul, Marseille, France

Adolescents usually face numerous restrictions, all the more if they are treated for epilepsy, but compliance with rules is a major problem in this age class. Adolescents are at odds with figures of authority, including parents, teachers and doctors, and wish their lifestyle to conform with the group behaviour of their fellow teenagers. It is thus both difficult and potentially nefarious to try and impose unpopular restrictions, which might contribute to further the social isolation of young patients with epilepsy during years that are crucial in the development of social and affective relationships. We shall review the data that are available concerning lifestle and consumption habits that are fairly common in adolescents with epilepsy, and to try and delineate a reasonable, evidence-based approach to their specific needs.

Sleep habits change at adolescence, with shorter nights during the week and longer, often delayed sleep periods during week-ends: it is proposed that only patients in whom a clear relationship between sleep deprivation and the occurrence of seizures can be found should be warned and educated, in order for them to observe adequate and regular sleep periods. Mild to moderate consumption of alcohol has never been shown to have a deleterious effect on epilepsy or to provoke occasional seizures, while binge drinking or regular, significant intake of alcohol may indeed provoke seizures or aggravate epilepsy in the long-term. Neither coffee nor tobacco appear as proconvulsant, except in very particular situations including massive intakes. Recreational drugs such as marijuana, LSD or amphetamines, while posing numerous health problems, do not appear to increase the risk of seizures. However, the so-called "hard" illicit drugs are significantly associated with seizures, cocaine being the lesser culprit among the latter.

A reasonable therapeutic and educational attitude is necessary, that will not overstate the nefarious effect of all these supposedly proconvulsive factors, and in all cases, it is better, and more efficient, to explain than to forbid.

Idiopathic generalized epilepsy syndromes in childhood

A. Covanis, Greece

Idiopathic generalized epilepsy (IGE) syndromes in childhood comprise of several groups and subgroups of syndromes with or without photosensitivity. These two syndromes in the neonatal period: benign familiar and non familiar neonatal convulsions.

The classical IGE includes childhood absence epilepsy (spanioepilepsy), Juvenile myoclonic epilepsy with Generalized tonic-clonic seizures on awaking (GTCS-A). However there are a number of other groups or subgroups of syndromes the majority of which are not included in the International classification. These syndromes seem to be phenotypically different and may prove to be also genetically different. Benign myoclonic epilepsy in infancy (Dravet) or childhood (Jeavons), Myoclonic astatic epilepsy (Doose). Epilepsy with myoclonic absences (Tassinari). Eyelid myoclonia with absences (Jeavons) Facial (perioral) myoclonia with absences, Generalised epilepsy with febrile seizures plus and pure photosensitive epilepsy whereas seizures are induced only with the light source/pattern or seizures are induced only in the laboratory.

In the classical childhood absense epilepsy (CAE) there are subgroups of syndromes which may be of genetic importance. The "pure absence epilepsy syndrome" is characterized by the absence of aberrant clinical (spaniolepsy, generalized tonic-clonic seizures, marked clonic/myoclonic component, poor initial response to therapy) and EEG features (focal spikes or slow spike and wave complexes, brief generalized spike- wave discharges, photosensitivity). The typical absence epilepsy of early onset is twice as common in females and includes a variety of clinical features, which are not present in the CAE. There are two different subgroups; the non-myoclonic and myoclonic. In the non-myoclonic group there are cases with spanioleptic and pyknoleptic absences. The spanioleptic are reminiscent of Juvenile absence epilepsy, while the pyknoleptic are either CAE-like or an early expression of JME. Absence seizures in the myoclonic group are pyknoleptic.

Juvenile absence epilepsy can present in childhood with a spanioleptic absences. The onset is less abrupt and the loss of consciousness less profound than in SAE. Generalized tonic-clonic seizures herald absences in 80% and myoclonic jerks occur in 15-20% of the cases.

Eyelid myoclonia with absences (Jeavon's syndrome) is characterized by slight or marked jerking of the eyelids immediately after eye closure, associated with 3c/s spike or polyspike and wave discharge, often irregular and fragmented. This type of discharges is invariably evoked on intermittent photic stimulation perioral myoclonia with absences has been recently described as a separate syndrome. For successful therapy early treatment is necessary in order to avoid the experience of a pleasurable feeling which leads to non-compliance.

Perioral myoclonia with absences has been recently described as a separate syndrome. However, perioral facial or eyebrow myoclonias, erratic, slight or marked are also seen in some other myoclonic or CAE syndromes and are not characteristic of a single syndrome. Some children who present with generalized tonic-clonic seizures occurring either randomly during the day or on awaking, have typical absences which in some may be apparent during detailed video-EEG recording.

Epilepsy with myoclonic absences is rare (0,5-1% of all epilepsies) difficult to treat and in 50% of the cases persists after the age of 20 years.

Benign myoclonic epilepsy in infancy, childhood and the myoclonic astatic epilepsy have cases with similar characteristics not always distinguished from the start and good prognosis. These cases are included by Dravet in the same syndrome.

Juvenile myoclonic epilepsy can present in childhood usually with absences and photosensitivity.

The geneticists who are dealing with epilepsy are confronted with the challenge of complex inheritance and heterogeneity of IGE. Several loci predisposing to IGE have been mapped to different chromosomal segments by some studies (2q36, 3q26, 5p15, 5q22, 6p11, 6p23.1, 8p12, 8q24, 14q23, 15q14, 18q21) but not confirmed by others. The genes for the classical IGE have not been found. Subdividing epileptic syndromes may be of help to the geneticists in identifying genes for pure syndromes or sub-syndromes, where interactions of genes may be involved.

The ion channels in epileptogenesis. Implications for genetic studies and drug development

Giuliano Avanzini, Instituto Nazionale Neurologico C.-Besta, Milano, Italy

Recent results have provided the evidence of genetically - determined alterations in molecular structure of receptor - associated or voltage - gated ionic channels leading to epileptogenic neuronal hyperexcitability. In particular structural abnormalities of nicotine receptors, K+ and Na+ channel subunits have been demonstrated in autosomal dominant nocturnal frontal lobe epilepsy, benign neonatal familial convulsions and generalized epilepsies with febrile convulsions plus respectively. The interest of the new data on ion channels for both genetics of the epilepsies and antiepileptic drug development is shown by studies on Na+ channels.

The current flowing through the fast inactivating Na+ channels is currently defined as fast Na+ current (INaf) and represents the main component of transmembrane Na+ currents. A small percentage of Na+CH which fails to inactivate account for the persistent fraction of Na currents (INap). Although relatively small it is functionally important that it enables the nerve cell to fire the high frequency bursts of AP which are typically found in neurons belonging to epileptic foci. Many clinically effective antiepileptic drugs (AEDs) act on Na+ currents in an use-dependent manner i.e. as higher the action potential frequency as stronger is the counteracting effect of the AED. This highly desirable selectivity is further enhanced by a specific effect on INap which has been demonstrated for phenytoine, sodium valproate, lamotrigine and topiramate. More directly the implication of Na+ channels in epileptogenesis is demonstrated by recent genetic studies. A peculiar type of family epilepsy called generalized epilepsy with febrile seizure plus (GEFS+) has in fact been found to be associated with different mutations affecting either beta1 or alpha subunits of Na+ channels. Interestingly the mutations seem to affect Na+ channel inactivation resulting eventually in an enhancement of the INap. These results provide a unitary pathogenetic interpretation for this genetically heterogenous type of epilepsy confirming the importance of Na+ channels in epileptogenesis.

The genetic epilepsies of infancy and early childhood

Meral Topçu1, Güzide Turanl1, Dilek Yalnizoglu1, Filiz Özbaç-Gerçeker2, Meral Özgüç2

1 Department of Child Neurology, 2TUBITAK DNA/Cell Bank & Gene Research Laboratory, Hacettepe University, Faculty of Medicine, Ankara, Turkey

Epilepsies of infancy and early childhood include; Severe Myoclonic Epilepsy of Infancy (SMEI), Myoclonic Epilepsy of Infancy (EIM), Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE), Pyridoxine-dependent epilepsy (PDE), Benign Familial Neonatal Convulsions (BFNC), Benign Familial Infantile Convulsions (BFIC) and Infantil Convulsions with Paroxysmal Choreoathetosis (ICCA).

SMEI is a rare disorder characterised by generalized tonic, clonic, and tonic-clonic seizures that are initially induced by fever and begin during the first year of life. Mutations in SCN1A gene (2q24) were reported in SMEI patients. EIM, defined by myoclonic seizures, febrile convulsions and tonic-clonic seizures in early infancy, was mapped to chromosome 16p13. Characteristic features of ADNFLE are focal origin of the seizures, almost exclusive occurrence during drowsing or sleep, and the variable severity of symptoms in family members. ADNFLE was mapped to 20q13.2 and the gene responsible for the disorder is Neurotensin receptor 1 (NTSR1). PDE, characterised by a combination of various seizure types, usually occurs in the first hours of life and the gene responsible for PDE was mapped to 5q31.2-q31.3. BFNC, known by brief seizures of a mixed type, starting with tonic posture, ocular symptoms, apnea, and other autonomic features, was mapped to choromosome 20q13.3 and KCNQ2 is the gene responsible for this disorder. BFIC is an autosomal dominant idiopathic epileptic syndrome characterized by seizures of partial type with onset between 3 and 12 months, normal interictal electroencephalogram and normal psycomotor development. Up to now, three loci have been identified for autosomal dominant BFIC; 19q, 16p12-q12, 2q24. We have tested 8 Turkish BFIC families with 25 affected individuals to chromosome 19q. No linkage was found to this locus and other loci will be tested for these families. Previously, autosomal dominant form of ICCA was also mapped to 16p12-q12. Here, we report the first ICCA family with autosomal recessive inheritance linked to the same locus.

Epilepsy surgery in childhood: outcome of 33 patients with resective surgery, 17 patients with corpus callosotomy, and 14 patients with vagus nerve stimulation

G. Turanl?1, D. Yaln?zo?lu1, D. Genç-Aç?kgöz1, E. Erdo?an1, I. Saatçi2, F. Söylemezo?lu3, Y. Renda1, V. Bertan4, A. Erdem5, N. Akalan4, M. Topçu1

Hacettepe University 1Dept. of Pediatric Neurology, 2Dept. of Radiology, 3Dept. of Pathology, 4Dept. of Neurosurgery, 5Ankara University Dept. of Neurosurgery, Ankara, Turkey

Forty-three patients underwent resective surgery for epilepsy between June 1994-February 2001 at Hacettepe University Department of Pediatric Neurology. We present outcome of 33 patients with post-operative follow up duration more than 6 months. Female/male ratio was 14/19. Fifteen patients underwent temporal resection and 13 had extratemporal or multilobar resection, 5 underwent hemispherectomy. Age at the time of surgery ranged between 13 months-18 years of age (mean: 10.8 years). 19 patients were between 1-12 years of age, and 14 patients were 13-17 years of age. Mean age at onset of seizures was 3.4 years for patients with temporal resection , 5.1 years for patients with extratemporal or multilobar resections, and 2.2 years for patients with hemispherectomy. Post operative follow-up duration ranged between 8-75 months (mean: 37 months). 16 patients were seizure free (Class I), 6 patients had good control (Class II), 9 patients had poor control (6 patients Class III, 3 patients Class IV). Two patients with hemispherectomy expired at 24 hours and 10 months. Neuropathologic results revealed tumors in 9 patients (4 of which were DNET), encephalomalasia in 8, temporal gliosis or cysts in 6, Rasmussen encephalitis in 5. The remaining 5 cases showed infarction, hamartoma, cortical dysplasia, pial angiomatosis, and normal features, each in one patient. Excluding the two patients lost following hemispherectomy, overall seizure control is 16/31 (52%). 9/15 patients with temporal resection (60%) were seizure free, where as 6/13 patients with extratemporal or multilobar resections (46%) achieved complete seizure control. 2/5 patients with hemisferectomy were seizure free. Our results showed favorable outcome in patients with temporal resections, and patients with tumors.

Seventeen patients (5 boys and 12 girls) underwent anterior 2/3 corpus callosotomy. Age at onset of seizures ranged between 2-54 months (mean: 12.7 months). Age at the time of surgery was between 1.5-14.5 years of age (mean: 6.5 years). Follow up duration was between 8 months and 7 years (mean: 5.2 years). One patient was seizure free (6%), 9 (43%) had significantly fewer seizures (Class II) and the remaining 9 (Class III) showed no obvious improvement.

Fourteen patients underwent implantation of a vagus nerve stimulator. Age at implant ranged between 11-20 years, and age at seizure onset between newborn period and 8 years. Follow up duration ranged between 3 months and 2 years. Four patients failed corpus callosotomy and two had resective surgery for epilepsy. Nine patients had symptomatic partial epilepsy, 2 had cryptogenic partial epilepsy, one had generalized epilepsy and 2 had Lennox-Gastaut Syndrome. Ten patients had a baseline neuropsychological evaluation and 7 underwent reevaluation at 3 months. At three months four patients had 50% decrease in seizure frequency, one had 60% decrease, and two had more than 90% decrease. Six patients had no significant change in seizure frequency, however seizure severity and duration remarkably decreased. One patient had increased seizures compared to baseline, following an initial improvement. Neuropsychological evaluation of 7 patients at 3 months revealed significant gains in higher cortical functions in one patient and no obvious change in five. VNS has shown efficasy in patients with childhood onset refractory epilepsy. Further studies are required to evaluate long term effects of VNS on cognitive function.

Progressive myoclonus epilepsies (PME)

Miri Neufeld MD, EEG and Epilepsy Unit, Department of Neurology, Sourasky Tel-Aviv Medical Center, Tel-Aviv University, Tel-Aviv, Israel

Progressive Myoclonus Epilepsies (PME), refers to a heterogeneous group of rare inherited secondary epilepsies. There are 5 major and more than 10 very rare diseases classified under PME. The major types include: Unverricht-Lundborg disease (ULD), Lafora-Body disease, Myoclonus epilepsy and Ragged - Red Fibers (MERRF), Neuronal Ceroid Lipofuscinosis (NCL) and the Sialidoses.

These disorders may have distinct geographic and ethnic background.

Clinicaly they are characterized by myoclonic and generalized seizures, and progressive neurologic dysfunction. Myoclonus is stimulus sensitive and can affect different muscle groups in the body. The generalized seizures consists of generalized tonic clonic and absence seizures. Patients with Lafora disease have often also occipital seizures. Most patients develop normally until the onset of the disease whereupon there is a progressive neurologic deterioration including dementia, ataxia, extrapyramidal symptoms and other neurologic manifestations. Helpful neurophysiologic studies include EEG findings with slowing of background rhythms with generalized discharges, photic sensitivity and occipital discharges as well as high voltage somatosensory and visual evoked potentials. Pathologic studies are essential for establishment of a number of disorders: biopsy of skin (e.g., Lafora bodies, fingerprint profiles), skeletal muscle (e.g., ragged red fibers).

Most PME are autosomal recessive disorders with the exceptions of DRPLA and MERRF. In the past few years mutations have been defined in Lafora disease (EPM2A gene coding for laforin ), in NCL (in CLN1-CLN8 genes), MERRF (tRNA Lys mutation in mitochondrial DNA) and Unverricht-Lundborg disease (in cystatin B gene).

As part of systemic study of the genetics of epilepsy in Israel we describe two Israeli Arab families, one with ULD and instability of the expanded dodecamer repeats in the cystatin B gene, in whom a prominent feature was the lack of photosensitivity. An additional family with clinical features concordant with ULD but without mutation in the cystatin B gene. This latter family suggests the existence of genetic heterogeneity for ULD.

The genetic partial epilepsies

Michelucci R, Nobile C*, Tassinari CA

Department of Neurological Sciences, Bellaria Hospital, Bologna, Italy.

* Department of Genetics, Padova, Italy

In recent years, large families with non-lesional and non-age related partial epilepsies showing a clear monogenic autosomal dominant inheritance have been reported.

These families have offered the best chance to discover genes associated with idiopathic epilepsies. So far, three phenotypes have been identified: Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE), Familial Temporal Lobe Epilepsy (FTLE), and Familial Partial Epilepsy with variable foci (FPEVF).

ADNFLE. This is a distinctive epilepsy syndrome with a mean age of onset of 11 years. It is characterized by clusters of motor seizures arising from sleep. Affected individuals may awaken with a non specific aura prior to a motor seizure with hyperkinetic or tonic features. Awareness may be retained during the seizures which occur almost exclusively during sleep and tend to persist through adult life. These seizures have often led to misdiagnosis of parasomnias, night terrors or hysteria. Loci for ADNFLE have been mapped to chromosomes 20, 15, 1. Despite this apparent genetic heterogeneity, all the defective genes encode for different subunits (alpha4, beta2) of the nicotinic acetylcholine receptor.

FTLE. FTLE can be subdivided into mesial and lateral forms. Mesial FTLE is a relatively common disorder with an onset in early adult life. Seizures show typical psychic, autonomic or special sensory auras. The evolution is usually benign but clinical heterogeneity has been described. No loci have been found for mesial FTLE. Autosomal Dominant Lateral Temporal Lobe Epilepsy (ADTLE) has been described in only a few families. The onset ranges from infancy to early adulthood; the seizures are characterized by auditory, visual or aphasic symptoms, sometimes evolving into secondary generalization. The evolution is benign. Most families have been mapped to a locus on chromosome 10q24.

FPEVF. This is an autosomal dominant partial epilepsy with seizures originating from different regions of the cortex in different family members. Loci for FPEVP have been assigned to chromosomes 2 and 22.

Is knowledge of mechanisms of action of AED's important for drug selection?

Dr Santiago Arroyo, Hospital Clínico de Barcelona, Spain

Antiepileptic drug (AED) selection is influenced by multiple considerations: epilepsy syndrome, aetiology, and individual patient's characteristics. Although, it has been postulated that knowledge of AED mechanisms of action could be helpful for AED selection, there is little evidence for it. In fact, it is still scarce the knowledge of the mechanisms underlying the different types of epilepsies in humans, and the mechanisms of most antiepileptic drugs are only partially understood. Moreover, each AED have multiple mechanisms that are only incompletely recognized. In monotherapy for newly onset epilepsy (with generalized or partial seizures), most drugs with very different mechanisms of action will be similarly effective as long as there is no generalised spike-wave discharges or myoclonus. In this later situation, certain AEDs could induce seizures (carbamazepine, phenytoin, vigabatrin), but other sodium-channel acting drugs (lamotrigine, topiramate) or GABAergic drugs (phenobarbital, benzodiacepines, valproic acid) are effective. In add-on therapy, knowledge of the pharmacokinetic AEDs profile is of utmost importance to avoid unwanted interactions. Some authors have stated that certain AED combinations with different or similar mechanisms of action could improve efficacy. This has been called "rational polytherapy". However, most of the evidence underlying this "rational" way of proceeding is based on experimental data on animals (sometimes contradictory) and anecdotal evidence in humans. Different genetic make-up might be at the core of the different response to the same AED observed in humans with a similar type of epilepsy and aetiology. Knowledge of the of the genetic profile of the responders versus the non-responders to a drug in each type of epilepsy could be more relevant for AED selection than knowledge of the mechanism of action of the drug. In conclusion, under our current level of understanding, knowledge of AED mechanisms does not appear to be useful for choosing the right medication for an individual patient.

Antiepileptic drug trials: can evidence-based medicine be misleading?

E. Perucca, Clinical Pharmacology Unit, Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy

Rational choice and utilization of available antiepileptic drugs (AEDs) requires adequate knowledge of their pharmacological properties and full awareness of the large body of evidence that is continuously accumulating on their relative efficacy, safety and tolerability in different types of epilepsy. While informal observations such as retrospective surveys and case reports can be useful under special circumstances, prospective randomized clinical trials represent by far the most important tool by which objective information can be obtained about the clinical value of existing drugs. Even randomized trials, however, can lead to misleading conclusions because of inherent weaknesses or bias in study design, analysis, and interpretation.

Some of the most common deficiencies identified in many recent AED trials include: 1) recruitment of heterogeneous patients' groups (for example, patients with partial and primarily generalized epilepsies) without differentiating clinical response in relation to syndromic form; 2) low statistical power due to insufficient sample size (for trials designed or expected to show therapeutic equivalence); 3) inappropriate titration rates or suboptimal dosages or dosing schedules (often favoring the sponsor's product over the comparator); 4) duration of treatment insufficient to assess meaningful outcome measures at optimized dosages; 5) choice of endpoints of questionable clinical significance. Some of these deficiencies can be explained by the fact that most large-scale AED trials have been designed to address regulatory needs rather than to provide the type of information, which is required for rational prescribing. Doctors need to be aware of these issues, and they should make every possible effort to interpret critically the evidence, which they utilize to make therapeutic decisions in everyday's clinical practice.

Epilepsy, genes and drugs

Meir Bialer, Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel

Patients or individuals respond differently to drugs due to pharmacokinetic (PK) and/or pharmacodynamic (PD) differences. PK differences are associated with altered metabolism and variable distribution and tissue uptake. Metabolism is the major source of altered pharmacokinetics and, consequently, altered response in terms of pharmacological and/or toxicological effects. PD differences are associated with altered sensitivity to equal drug concentrations. Inheritance accounts for a large part of the variability among individuals mediated through the basic biological unit of heredity, the gene. Genotype is the fundamental assortment of genes of an individual, while phenotype is the outward characteristic expression of an individual. Drugs in general and AEDs in particular are subject to oxidative metabolism by the cytochrome P-450 mixed function oxidase system located primarily within the liver but also in the GI tract and elsewhere in the body. The cytochrome P-450 superfamily in humans is divided into three major families designated as CYP 1, 2 and 3 which are further divided into subfamilies, A through E. Individual isozymes or CYP (P-450) enzymes (gene products) are then designated by adding a number to the subfamily. Most AEDs are eliminated by P-450 (CYP)-mediated hepatic metabolism.

The three principal P-450 isozymes associated with genetic polymorphism are CYP2D6, CYP2C19 and CYP2C9. Genetic polymorphism is generated by mutations or duplication in the genes for these enzymes resulting in decreased, increased or absent enzyme expression or activity. Alleles coding for inactive enzymes or those with diminished or amplified activity contribute to interindividual variability. CYP2D6 was the first CYP isozyme to be associated with genetic polymorphism for which the poor metabolizer phenotype is caused by loss of several functional alleles whereas the ultrarapid metabolizer phenotype is the result of duplication or amplification of the active CYP2D6 gene. Although many drugs are CYP2D6 substrates, the involvement of CYP2D6 in AED metabolism is rather minimal. Phenytoin (PHT) is predominately eliminated through CYP2C9 and CYP2C19 hepatic metabolism and thus is susceptible to genetic polymorphism. The metabolic ratio of PHT to its major metabolite (S)-p-hydroxy-PHT is a putative probe (marker) for CYP2C9 genetic polymorphism. The frequency of CYP2C9 poor metabolizers is 1-2% among Orientals and 8-10% among Caucasians.

The AED analogue of phenytoin, mephenytoin, has been utilized as a probe for CYP2C19 genetic polymorphism. Mephenytoin undergoes stereoselective pharmacokinetics whereby the S-enantiomer undergoes CYP2C19-mediated hydroxylation while the R-enantiomer undergoes N-demethylation which is not susceptible to genetic polymorphism. Consequently, the ratio of the urinary excretion of the two mephenytoin enantiomers serves to phenotype patients. The frequency of CYP2C19 poor metabolizers is 13-20% among Orientals and 3-5% among Caucasians. To date, there are no reports of genetic polymorphism of the most abundant isozyme CYP3A4 which accounts for about 30% of the total hepatic CYP and is involved in the metabolism of more than 50% of all drugs including carbamazepine, felbamate and tiagabine. Pharmacogenetics or genotyping of patients can explain variability in pharmacodynamic response to drugs, may assist in prediction of drug response and may have a role in future pharmacotherapy of AEDs in patients.

Age related adverse effects of AEDS

Alexis Arzimanoglou, MD, Head of the Epilepsy Program, Child Neurology and Metabolic Diseases Dpt., University Hospital Robert- Debré, Paris, France

Treatment of epilepsy can only be a reasonable compromise between expected efficacy and acceptable side effects of the AEDs. Adverse effects of AEDs can include idiosyncratic, dose-rated, chronic, teratogenic, and drug interactions. As a physician considers the use of AEDs for a patient, knowledge of the drugs' efficacy and safety is critical. However, variability in response may be correlated not only with the patient's epilepsy syndrome but also with maturation, age, sex and pregnancy.

Idiosyncratic disorders are the most serious but relatively rare and in the majority of cases not age-dependent. In very young children suspected to suffer from metabolic derangements or neurodegenerative disorders some AEDs should be avoided (phenytoin with Unverricht- Lundborg disease, the ketogenic diet with pyruvate carboxylase deficiency and organic acidurias, and valproate with fatty acid oxidation defects). Fatal hepatic dysfunction was reported in children under the age of 3 years, receiving valproate as part of anticonvulsant polytherapy. Dermatologic and other hypersensitivity reactions may not be the same at different ages.

Alteration of the pharmacokinetic profile of a drug may be at the origin of adverse events. In the management of paediatric seizures, the effects of age and maturation on the pharmacokinetic profile are primary concerns; in the neonate, oral absorption of drugs is poor and erratic. Even absorption from IM administration may vary with age. Body composition influences the distribution of drugs and, for those that are highly bounded to plasma proteins, the total plasma drug concentrations. Changes in hepatic, renal, gastrointestinal and cardiovascular physiology during pregnancy also alter the pharmacokinetics of AEDs. As for elderly epileptic patients, concomitant medications can alter absorption, distribution, and metabolism of AEDs, thereby increasing the risk of toxicity or therapeutic failure. The presence of hepatic or renal failure may also potentialize an existing adverse effect.

Dose-related adverse effects are common but may vary, or may be differently perceived, according to age. Excessive weight gain seems to be less of a problem in children. Even moderate weight gain may be badly perceived from an adolescent patient, this also applying to some cosmetic side-effects. Drugs facilitating weight loss may have to be avoided, or the dose must be adapted, in very young children or low-weight adolescents. Sedation, drowsiness, hyperactivity and irritability may also prove to be age-dependent. When present, their consequences, in terms of social impact, are not the same when dealing with children, adolescents or adults. Similarly, even mild cognitive effects may have more severe consequences when present in a school-age patient as compared to a well inserted adult patient, although evaluation of the consequences in the later must also take into account the patient's profession.

Issues related to contraception can be challenging for neurologists. Physiologic changes of pregnancy, noncompliance, stress and sleep deprivation may lead to breakthrough seizures. Differential diagnosis with an aggravating effect of a drug is necessary.

A variety of adverse outcomes are increased among offspring of women with epilepsy compared with the general population. These include congenital malformations, intrauterine growth retardation, developmental delay and mental retardation.

Presence of an associated pathology, particularly in elderly patients, should influence the choice of an AED. For example, if terror is an issue, valproate may not be the best AED. If sodium balance is a concern, then carbamazepine may not be the first choice. Finally, when the AED is prescribed for a long period of time, chronic adverse effects and their age-related consequences must be considered (induction of decreased bone mineralisation in children or elder patients, peripheral neuropathy, etc.).

The majority of epilepsy syndromes have their onset in childhood. A very effective drug for an adult patient with partial epilepsy may have an aggravating effect in a child with a generalised epilepsy syndrome.

Photosensitive epilepsies

Peter Wolf, Bielefeld, Germany

Photosensitivity is the most frequent mode of sensory precipitation of epileptic seizures. It is a genetic trait which is not only found in humans but also in certain animal species like chickens and baboons. The photosensitive epilepsies in the various species are similar up to a point, but there are also important differences in their appearance and pathophysiology. In human epilepsy, at least two types of photosensitivity must be differentiated: one (to slow flicker frequencies) is a frequent finding in progressive myoclonus epilepsies where it is not bound to one particular genotype. The other (with a peak response at 12-20 Hz) is an age-dependent reflex epileptic trait which is mostly found in patients with idiopathic generalized epilepsies. In Juvenile Myoclonic Epilepsy up to 50% of the patients have it.

Photosensitivity may already be apparent from the conditions in which the seizures occur (e.g. looking at a glittering water surface; watching television) but often it is first discovered at EEG investigation. It is rare that a patient only has reflex seizures, and only in these cases the term "Photensitive Epilepsy" is truly justified. The majority have also spontaneous seizures. Avoidance and attenuation of the precipitating stimuli (use of dark lenses; precautions at television) are an integral part of the management of all these patients. In pure photosensitive epilepsy it can be successfully applied as the only therapy. Usually, AEDs are also required, and VPA is the drug of first choice, with lamotrigine and perhaps levetiracetam as possible alternatives. CBZ may worsen the condition.

Mesial temporal lobe epilepsy

Cigdem Ozkara, University of Istanbul, Cerrahpasa Medical Faculty, Department of Neurosurgery, Istanbul, Turkey

Among the localisation-related epilepsies temporal lobe epilepsy (TLE) is by far the most common when the medically refractory patients are especially considered. Tumoral or non tumoral lesions particularly involving the mesial temporal structures give rise to complex partial seizures with a relatively characteristic semiology comprising an aura, a motionless stare and automatisms with additional features as a result of preferential propagation patterns. It has also been known for many years that the most common pathologic substrate of mesial TLE is hippocampal sclerosis (HS) although there are still controversial opinions about its occurrence and relation to the seizures. However, data accumulated from surgical series strongly suggests that TLE associated with HS represents a discrete clinical entity. Scalp and intracranial EEG characteristics, neuropsychological profile, historical relation to early risk factors, MRI findings and poor response to medical treatment have been documented although some conflicts exist. Early diagnosis of the situation is important because disabling seizures and their consequences may be prevented by surgical intervention either by anterior temporal lobectomy or selective amygdalohippocampectomy in well selected cases. However, there are several pitfalls to be taken into consideration from pathogenesis to pathology and from clinical evolution to prognosis implicating a heterogenety amongst the patients to some extend.

This assumption lead us to review the patient files of epilepsy clinics in Cerrahpasa Medical Faculty. Two hundred fifty patients with HS demonstrated by MRI or confirmed after surgery were analysed. The results of this study will also be discussed to search for differences amongst the patients form the clinical point of view.

Intracranial electrical stimulation (ICES) in epilepsy

Demetrios N. Velis, MD, Department of Clinical Neurophysiology and the Epilepsy Monitoring Unit, SEIN, "Meer en Bosch" Campus, Heemstede, The Netherlands

Intracranial electrical stimulation (ICES) has been used both to cause epileptic seizures to occur in various experimental animal models of epilepsy and in attempting to prevent the occurrence of seizures in the same animal models and patients. These patients have been recruited from the pool of potential candidates for epilepsy surgery.

ICES is safe. Stringent criteria for delivering electrical charge to neuronal tissue have been established on the basis of the past decades of intraoperative electrical stimulation during resective epilepsy surgery. Surgical risks are similar to those for the implantation of indwelling electrodes. Targets for ICES include thalamic nuclei, the subthalamic nucleus, the pes hippocampi close to the amygdala, and the part of the parahippocampal gyrus close to the entorhinal cortex. Thalamic and subthalamic nucleus stimulation rely on paradigms developed for deep brain stimulation (DBS) in debilitating Parkinsonism. DBS for epilepsy may be considered a palliative procedure. Mesial temporal lobe ICES has been reported to cause total freedom from seizures in certain mesial temporal lobe epilepsy (MTLE) cases. Persisting beneficial effects of ICES in MTLE have been observed for several months following termination of stimulation. No untoward neurocognitive, neurotoxic or epileptogenic effects of ICES in patients have been reported. The need for ICES is manifest and the expected patient supply is guaranteed if only by the rejection rates of screening programs for epilepsy surgery worldwide.

Additional experimental animal model work is currently under way leading to a better selection of targets and stimulation parameters for ICES and in defining the criteria for implantation in pharmacoresistant epilepsy. ICES is potentially most effective in combination with expected advances in the field of seizure anticipation, in the immediate preictal period, to prevent or suppress the occurrence of impending seizures thereby minimizing the potential for as yet unknown untoward neurotoxic, neurocognitive, and/or epileptogenic effects of ICES.

ICES for epileptic seizure prevention has been earmarked as a priority topic in the March 2000 "Benchmarks for Epilepsy Research" a report of the US National Institute of Neurological Disorders and Stroke.