Prevention of epileptogenesis-a new goal for epilepsy therapy

Contents lists available at Pediatric Neurology Perspectives in Pediatric NeurologyPrevention of Epileptogenesis A New Goal for Epilepsy Therapy Sergiusz Józwiak MD, PhD Katarzyna Kotulska MD, PhD Department of Neurology and Epileptology, The Children's Memorial Health Institute, Warsaw, Poland Progress in epilepsy treatment in last decades of the discharges on electroencephalography (EEG) were treated twentieth century included a number of new antiepileptic with oral ethosuximide from postnatal day 21 to 5 months of drugs that were expected to reduce the number of patients age. Early treatment with ethosuximide led to a persistent with drug-resistant epilepsy. However, it soon became suppression of seizures, even several months after therapy obvious that, in spite of the improving safety of antiepileptic withdrawal. Prolonged antiepileptogenic treatment in this treatment, the efficacy of new agents was not much better genetic model had a beneficial effect on white matter than the old drugs. The number of patients with drug- microstructure in Wistar Albino Glaxo/Rij rats as observed by resistant epilepsy decreased little, and their outcome has diffusion tensor imaging studies.These experiments with not been improved.
ethosuximide and levetiracetam in genetic models seem to The search for new therapeutic approaches and the demonstrate that epilepsy prevention is possible and that emergence of clinically relevant animal models of epilepsy antiepileptogenic treatment may provide a new strategy for led to a renewed interest in the process of epileptogenesis.
preventing epilepsy in susceptible individuals.
This cascade of molecular and cellular alterations (including Several completed clinical trials in humans have changes in expression and function of receptors and ion demonstrated that administration of conventional antiepi- channels) begins with an insult, brain injury, or genetic leptic drugs, such as phenytoin, phenobarbital, carbamaz- predisposition. There is often a latent period lasting weeks epine, or valproate, in patients after traumatic brain injury to months before the onset of seizures, followed by the failed to prevent the development of epilepsyHowever, it development of clinical epilepsy and its comorbidities. This seems likely that these studies were not properly designed latent period of epilepsy development may offer a time to answer the question at hand, and the drugs were not window when an appropriate medication may stop or selected to have antiepileptogenic activity modify the epileptogenic process.
The immature brain seems to be especially vulnerable to Recent animal studies using the genetic models proved seizures, but it may also be particularly susceptible to that early (antiepileptogenic) therapeutic intervention dur- antiepileptogenic treatment. Talos et used a rodent ing this latent period might prevent the development of model of acute hypoxia-induced neonatal seizures to epilepsy. In an epileptic double mutant rat (spontaneously determine how seizures alter mTOR complex 1 signaling, epileptic rat; zi/zi, tm/tm) that presents recurring tonic and absence-like seizures in response to mild sensory stimula- behavior in later life. They demonstrated that inhibition of tion, Yan et alused levetiracetam for three weeks before the mTOR complex 1 immediately before and after seizures expected time of seizure onset. Such preventative treatment reversed an early increase in glutamatergic neurotrans- with levetiracetam resulted in a significant decrease in the mission and seizure susceptibility and attenuated later life incidence of both types of seizures, indicating a disease- epilepsy and autistic-like behavior.
modifying effecAnother genetic model of human The impact of effective antiepileptogenic treatment on absence epilepsy was used by Blumenfeld et alWistar Al- the immature brain is particularly apparent in children less bino Glaxo/Rij rats that exhibit spontaneous spike-wave than two years of age. Clinical settings provide an especiallygood opportunity to prevent epilepsy and its comorbiditiesin some genetic or developmental defects with a high risk of epilepsy during the first years of life. Prophylactic treatment Received July 30, 2014; Accepted in final form August 26, 2014 with phenobarbitone of 16 infants with Sturge-Weber * Communications should be addressed to: Dr. Jó zwiak; The Children's syndrome resulted in decreased epilepsy (P < 0.01) and Memorial Health Institute; Al. Dzieci Polskich 20; 04-730 Warsaw, mental retardation (P < 0.05) in comparison to 21 children treated in the standard manner (i.e., after the onset of 0887-8994/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved.
S. Józwiak, K. Kotulska / Pediatric Neurology 51 (2014) 758e759 clinical A similar beneficial effect of preventative molecular (genomics, transcriptomics, proteomics, metab- treatment has been observed in our study in infants with olomics, epigenetics) investigations. The project has just begun tuberous sclerosis complex (TSC). A prospective study of 14 and will last for five years.
children treated with vigabatrin due to paroxysmal activity Prevention of epilepsy in individuals at risk or the on EEG in the first months of life demonstrated a lower modification of the disease outcome is one of the major incidence of drug-resistant epilepsy and higher intelligence United States The National Institute of Neurological Disor- quotient score at 24 months of age compared with 31 ders and Stroke/ National Institutes of Health Epilepsy traditionally treated children (7.1% versus 41.9%, P < 0.05; Research benchmarks and also a research priority of the and 92.3% versus 68.7%, P < 0.05, respectiv European scientific community. Such a goal is particularly The recently published "practical clinical definition of meaningful for pediatric neurologists, the physicians who epilepsy" made also a step forward toward anti- are often in the optimal position to alter the natural course epileptogenic treatment by allowing the diagnosis of epi- of disease and improve the quality of life of their patients lepsy after a single seizure in many situations with a and their families.
probability of another seizure exceeding However,there are still no recommendations for pre-emptive man- The work reported in this paper was partially supported by the 7th Framework agement of specific groups of patients with a very high Programme of European Commission within the large-scale integrating project incidence of epilepsy, well recognized natural course of the disease, and established severe epilepsy comorbidities suchas mental retardation and autism. In conditions such as TSC,Sturge-Weber syndrome, Angelman syndrome, and Rett syndrome with an incidence of epilepsy over 60% in the firstyear of life, the antiepileptogenic treatment should be considered before the onset of clinical seizures, when epi- leptogenesis is early in progress.
A search of valid biomarkers to aid the identification of a point of no return in the epileptogenesis process is a major challenge for clinicians. In our experience with over 50 TSC infants followed since soon after birth with video EEGs per- formed every 4 weeks, those who developed paroxysmal ac- determination of EEG characteristics as well as the molecular and neuroimaging biomarkers allowing identification of chil- dren with high risk of epilepsy is critical. Currently, such studies are ongoing within the long-term, prospective study evaluating clinical and molecular biomarkers of EPIlepto- genesiS in a genetic model of epilepsyeTuberous SclerOsis ComPlex (EPISTOP), the large-scale collaborative project within the 7th Framework Programme of European Commu- nity. EPISTOP is a multicenter, prospective study of epilepto- genesis in TSC infants, starting from its latent phase before seizures onset and extending to the development of drug- resistance and epilepsy neuropsychiatric comorbidities. The comprehensive analysis of possible epileptogenesis bio- markers in EPISTOP project includes a wide range of clinical, electrophysiological, neuroimaging, neuropsychologic, and



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Willdenowia 30 – 2000 The inclusion of adventive plants in the second edition of FloraPalaestina Danin, A.: The inclusion of adventive plants in the second edition of Flora Palaestina. – Willdenowia30: 305-314. 2000. – ISSN 0511-9618. Distribution maps for 19 prominent woody adventive gymnosperms, dicots and monocots, which areestablished in the Flora Palaestina area but not included in Flora Palaestina, ed. 1, are presented,showing their presence in grid areas of 5 7 5 km in Israel, and data on their introduction, habitats anddispersal modes are given in this preparatory contribution for the second edition of Flora Palaestina.