Is There a Role for Environmental and Metabolic Factors Predisposing to Severe COVID-19?

The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic affects people around the world. However, there have been striking differences in the number of infected individuals and deaths in different countries. Particularly, within Central Europe in countries that are similar in ethnicity, age, and medical standards and have performed similar steps of containment, such differences in mortality rates remain inexplicable. We suggest to consider and explore environmental factors to explain these intriguing variations. Countries like Northern Italy, France, Spain, and UK have suffered from 5 times more deaths from the corona virus infection than neighboring countries like Germany, Switzerland, Austria, and Denmark related to the size of their respective populations. There is a striking correlation between the level of environmental pollutants including pesticides, dioxins, and air pollution such as NO2 known to affect immune function and healthy metabolism with the rate of mortality in COVID-19 pandemic in these European countries. There is also a correlation with the use of chlorination of drinking water in these regions. In addition to the improvement of environmental protective programs, there are possibilities to lower the blood levels of these pollutants by therapeutic apheresis. Furthermore, therapeutic apheresis might be an effective method to improve metabolic inflammation, altered vascular perfusion, and neurodegeneration observed as long-term complications of COVID-19 disease.

Neurocognition in childhood epilepsy: Impact on mortality and complete seizure remission 50 years later.

OBJECTIVE: To study associations of the severity of impairment in childhood neurocognition (NC) with long-term mortality and complete seizure remission. METHODS: A population-based cohort of 245 subjects with childhood onset epilepsy was followed up for 50 years (median = 45, range = 2-50). Childhood NC before age 18 years was assessed as a combination of formal intelligence quotient scores and functional criteria (school achievement, working history, and psychoneurological development). Impaired NC was categorized with respect to definitions of intellectual functioning in International Classification of Diseases, 10th revision (R41.83, F70-F73). The outcome variables, defined as all-cause mortality and 10-year terminal remission with the 5 past years off medication (10YTR), were analyzed with Cox regression models. RESULTS: Of the 245 subjects, 119 (49%) had normal childhood NC, whereas 126 (51%) had various degrees of neurocognitive impairment. During the 50-year observation period, 71 (29%) of the subjects died, 13% of those with normal and 44% of those with impaired NC. The hazard of death increased gradually in line with more impaired cognition, reaching significance in moderate, severe, and profound impairment versus normal NC (hazard ratio [Bonferroni corrected 95% confidence interval] = 3.3 [1.2-9.2], 4.2 [1.2-14.2], and 5.5 [2.4-12.3], respectively). The chance for 10YTR was highest among subjects with normal NC (61%), whereas none of those with profound impairment reached 10YTR. In the intermediate categories, the chance was, however, not directly related to the increasing severity of impairment. SIGNIFICANCE: The severity of neurocognitive impairment during childhood shows a parallel increase in the risk of death. In comparison with normal NC, subjects with lower childhood NC are less likely to enter seizure remission. However, normal NC does not guarantee complete remission or prevent premature death in some individuals with childhood onset epilepsy.

Overrepresentation of epilepsy in children with type 1 diabetes is declining in a longitudinal population study in Finland.

AIM: The aim was to determine temporal changes in increased risk of epilepsy among children with type 1 diabetes. METHODS: The incidence of epilepsy up to age 15 in children with prior type 1 diabetes was analysed regarding the general Finnish child population using data from the Finnish nationwide hospital register. Type 1 diabetes and epilepsy were identified by the International Classification of Diseases 9th and 10th revision codes. Epilepsy was defined according to ILAE guidelines. The analyses were done using negative binomial regression models. RESULTS: Preceding type 1 diabetes was diagnosed in 6162 (0.91%) of the 679 375 general children population. Incidence rate of new-onset epilepsy among children with type 1 diabetes was higher than in controls (140 vs 82 per 100 000 person-years at risk, respectively). The excess incidence diminished with time (P = 0.033 for diabetes to birth cohort interaction), from over twofold in birth cohort 1990-1993 [incidence rate ratio 2.2 (95% CI 1.7-2.9)] to 40% in birth cohort 1998-2000 [1.4 (95% CI 1.001-1.9)]. CONCLUSION: In a population study setting, children with type 1 diabetes had an increased, but slowly declining risk of developing epilepsy. Future research may elucidate the underlying mechanisms.

Commonalities in epileptogenic processes from different acute brain insults: Do they translate?

The most common forms of acquired epilepsies arise following acute brain insults such as traumatic brain injury, stroke, or central nervous system infections. Treatment is effective for only 60%-70% of patients and remains symptomatic despite decades of effort to develop epilepsy prevention therapies. Recent preclinical efforts are focused on likely primary drivers of epileptogenesis, namely inflammation, neuron loss, plasticity, and circuit reorganization. This review suggests a path to identify neuronal and molecular targets for clinical testing of specific hypotheses about epileptogenesis and its prevention or modification. Acquired human epilepsies with different etiologies share some features with animal models. We identify these commonalities and discuss their relevance to the development of successful epilepsy prevention or disease modification strategies. Risk factors for developing epilepsy that appear common to multiple acute injury etiologies include intracranial bleeding, disruption of the blood-brain barrier, more severe injury, and early seizures within 1 week of injury. In diverse human epilepsies and animal models, seizures appear to propagate within a limbic or thalamocortical/corticocortical network. Common histopathologic features of epilepsy of diverse and mostly focal origin are microglial activation and astrogliosis, heterotopic neurons in the white matter, loss of neurons, and the presence of inflammatory cellular infiltrates. Astrocytes exhibit smaller K+ conductances and lose gap junction coupling in many animal models as well as in sclerotic hippocampi from temporal lobe epilepsy patients. There is increasing evidence that epilepsy can be prevented or aborted in preclinical animal models of acquired epilepsy by interfering with processes that appear common to multiple acute injury etiologies, for example, in post-status epilepticus models of focal epilepsy by transient treatment with a trkB/PLCγ1 inhibitor, isoflurane, or HMGB1 antibodies and by topical administration of adenosine, in the cortical fluid percussion injury model by focal cooling, and in the albumin posttraumatic epilepsy model by losartan. Preclinical studies further highlight the roles of mTOR1 pathways, JAK-STAT3, IL-1R/TLR4 signaling, and other inflammatory pathways in the genesis or modulation of epilepsy after brain injury. The wealth of commonalities, diversity of molecular targets identified preclinically, and likely multidimensional nature of epileptogenesis argue for a combinatorial strategy in prevention therapy. Going forward, the identification of impending epilepsy biomarkers to allow better patient selection, together with better alignment with multisite preclinical trials in animal models, should guide the clinical testing of new hypotheses for epileptogenesis and its prevention.

Remission in epilepsy: How long is enough?

OBJECTIVE: The International League Against Epilepsy (ILAE) has proposed to expand the definition of remission to 10 years seizure-free with the last 5 years off antiepileptic drugs (AEDs). We examined if a 10-year remission is needed to predict the lowest recurrence risk. METHODS: The population-based study cohort consisted of 148 patients with new-onset childhood epilepsy living in the catchment area of Turku University Hospital. They were prospectively followed for 44 years (median). Patients in first remission were prospectively followed for the duration of remission or possible relapse at 2 years in remission with the last year without antiepileptic drugs (AEDs), at 5 years in remission with the last 2 years without AEDs, and at 10 years with the last 5 years without AEDs. For comparison of the proportions of relapsed patients within each remission category exact Clopper Pearson 95% confidence intervals were used. RESULTS: The magnitude of the relapse rate estimates off AEDs did not significantly improve when remission increased from 2 years (2YR) to 5 years (5YR) and further to 10 years (10YR). However, 10YR was a more sensitive measure of no relapse than 2YR. Among patients with remission on or off AEDs, the ability to predict lower relapse rate increased markedly from 2 to 5 years, and again from 5 to 10 years. The risk of relapse was virtually the same estimated after 2YR off AEDs as after 10YR on or off AEDs, except for patients with generalized epilepsy whose 2YR off AEDs was a weaker predictor than 10YR on or off AEDs. SIGNIFICANCE: Given the modest differences in relapse rates between the 5 years seizure-free with last 2 years off medications definition and the 10 years seizure-free with last 5 years off medications, and the adverse impact of not being considered in remission, we propose that a return to the 5-year definition may be warranted.

Do traditional anti-seizure drugs have a future? A review of potential anti-seizure drugs in clinical development.

Currently information is available for 20 potential anti-seizure drugs in clinical development. They include candidates with mechanisms of action similar to those of marketed AEDs (allopregnanolone, brivaracetam, ganaxolone, ICA-105665, NS1209, selurampanel); those with new mechanisms of action (beprodon, VX-765); compounds repurposed for the treatment of epilepsy (biperiden, bumetanide, fenfluramine, melatonin, nalutozan, pitolisant, quinidine, valnoctamide, verapamil); and finally candidates with currently unknown mechanisms of action (JNJ-26489112, UCB0942, YKP3089 (Cenobamate). Clinical development of anti-seizure drugs is still active but unexciting. Potential anti-seizure drugs continue to be largely identified by their activity against seizures provoked by electrical or chemical procedures in animals with normal brains. As in the past, this may lead to new drugs whose efficacy is not better than that of those already on the market.

Prevention of Epilepsy: Issues and Innovations.

Epilepsy is a common brain disease and preventing epilepsy is a very relevant public health concern and an urgent unmet need. Although 40 % of all epilepsy cases are thought to have acquired causes, there is a roadblock for successful prevention. Efforts to protect the brain from epileptogenic insults are severely hampered by our lack of biomarkers to identify the few percent at high risk meriting treatment among those exposed. Preventing brain injury has been moderately effective from around birth to middle age; however, the strategy has failed to stop a substantial increase over the last decades in symptomatic epilepsy in those aged 65 and above. The traditional concept of repurposing anti-seizure drugs used for symptomatic seizure relief to prevent the onset of epilepsy has completely failed up to now. More recently, however, hope is on the horizon with a search for biomarkers and discovery of a new class of agents, called anti-epileptogenic drugs, which were specifically developed for prevention of epilepsy.

Long-term changes in the incidence of childhood epilepsy. A population study from Finland.

BACKGROUND: The incidence of childhood epilepsy has changed during the past decades, but it is unclear whether it increased or decreased. METHODS: Changes in drug-treated childhood epilepsy between 1968 and 2012 were evaluated using the Finnish nationwide register of all children, aged ≤15years, on antiepileptic drugs (AEDs) prescribed for the treatment of epilepsy. The first registered entitlement to full-refundable AEDs was used as a proxy for newly diagnosed epilepsy. Incidence densities were calculated as ratios of annual new cases per 100,000person-years in each calendar year during 1968 to 2012. RESULTS: The annual incidence density of newly treated childhood epilepsy increased from 35 in the 1960s to 87 per 100,000person-years in the 1990s and decreased thereafter to 61 per 100,000person-years. Since 1996, the incidence density decreased 1-2% per year in children aged <1, 1-5, or 6-10years (all 95% confidence intervals within 0.3%-3%), while no substantial change was seen in older children. CONCLUSION: The incidence of drug-treated childhood epilepsy from the late 1960s to the early 1990s distinctly increased. The reasons for the increase are not fully understood but may include increasing ascertainment through improved diagnosis and a wider acceptance of AED treatment. Since the 1990s, a slight decline can be seen, probably reflecting the recent improvement in child health and safety.

WITHDRAWN: Oxcarbazepine add-on for drug-resistant partial epilepsy.

BACKGROUND: Most people with epilepsy have a good prognosis and their seizures can be well controlled with the use of a single antiepileptic drug, but up to 30% develop refractory epilepsy, especially those with partial seizures. In this review we summarize the current evidence regarding oxcarbazepine when used as an add-on treatment for drug-resistant partial epilepsy. OBJECTIVES: To evaluate the effects of oxcarbazepine when used as an add-on treatment for drug-resistant partial epilepsy. SEARCH METHODS: We searched the Cochrane Epilepsy Group's Specialized Register (28 March 2006), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2006), MEDLINE (1966 to March 2006). No language restrictions were imposed. We checked the reference lists of retrieved studies for additional reports of relevant studies. We also contacted Novartis (manufacturers of oxcarbazepine) and experts in the field. SELECTION CRITERIA: Randomized, placebo-controlled, double-blinded, add-on trials of oxcarbazepine in patients with drug-resistant partial epilepsy. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and extracted the relevant data. The following outcomes were assessed : (a) 50% or greater reduction in seizure frequency; (b) treatment withdrawal (any reason); (c) side effects. Primary analyses were intention-to-treat. Summary odds ratios were estimated for each outcome. MAIN RESULTS: Two trials were included representing 961 randomized patients.Overall Odds Ratio (OR) (95% Confidence Interval (CIs)) for 50% or greater reduction in seizure frequency compared to placebo 2.96 (2.20, 4.00).Treatment withdrawal OR (95% CIs) compared to placebo 2.17 (1.59, 2.97).Side effects: OR (99% CIs) compared to placebo, ataxia 2.93 (1.72, 4.99); dizziness 3.05 (1.99, 4.67); fatigue 1.80 (1.02, 3.19); nausea 2.88 (1.77, 4.69); somnolence 2.55 (1.84, 3.55); diplopia 4.32 (2.65, 7.04), were significantly associated with oxcarbazepine. AUTHORS' CONCLUSIONS: Oxcarbazepine has efficacy as an add-on treatment in patients with drug-resistant partial epilepsy, both in adults and children. However, trials reviewed were of relatively short duration, and provide no evidence about the long-term effects of oxcarbazepine. Results cannot be extrapolated to monotherapy or to patients with other epilepsy types.

Placebo and nocebo responses in drug trials of epilepsy.

Placebo response can be defined as any therapeutic change on placebo, while the nocebo response is any ill effect during placebo exposure. Several meta-analytic approaches have investigated the extent of placebo response in randomized, placebo-controlled, clinical trials of focal epilepsies. Placebo response rates (proportion of patients with ≥50% improvement of seizures versus baseline) ranging from 9.9% up to 15.2% have been reported. Interestingly, a sham response of 15.8% has been noted in trials of transcranial magnetic stimulation. Recently, nocebo response rates of 60.3% and 3.9% were noted, which were defined as the proportion of patients with adverse events (AEs) and those withdrawing because of intolerable AEs, respectively. Factors which were found to influence placebo response were as follows: the year of publication (with more recent studies showing higher rates of placebo response), some clinical characteristics of recruited patients (lower placebo response rates with a history of 7 or more prior lifetime AEDs, a high baseline seizure frequency, prior epilepsy surgery, and higher age at diagnosis), trial design and statistical analysis, and whether studies have been conducted in children or adults. Furthermore, placebo and nocebo rates were correlated with respective seizure outcome and adverse events of the experimental AED. Several mechanisms of placebo and nocebo responses are discussed. Specifically, the role of positive or negative expectations of patients and of investigators may influence the placebo and the nocebo response. Finally, recommendations are given on how to address placebo and nocebo responses in clinical practice.

The enigma of the latent period in the development of symptomatic acquired epilepsy - Traditional view versus new concepts.

A widely accepted hypothesis holds that there is a seizure-free, pre-epileptic state, termed the "latent period", between a brain insult, such as traumatic brain injury or stroke, and the onset of symptomatic epilepsy, during which a cascade of structural, molecular, and functional alterations gradually mediates the process of epileptogenesis. This review, based on recent data from both animal models and patients with different types of brain injury, proposes that epileptogenesis and often subclinical epilepsy can start immediately after brain injury without any appreciable latent period. Even though the latent period has traditionally been the cornerstone concept representing epileptogenesis, we suggest that the evidence for the existence of a latent period is spotty both for animal models and human epilepsy. Knowing whether a latent period exists or not is important for our understanding of epileptogenesis and for the discovery and the trial design of antiepileptogenic agents. The development of antiepileptogenic treatments to prevent epilepsy in patients at risk from a brain insult is a major unmet clinical need.

Stopping antiepileptic drugs in seizure-free patients.

PURPOSE OF REVIEW: Based on the available evidence, we aim to balance risks and benefits of antiepileptic drug (AED) withdrawal in medically and surgically treated adults and children who achieved remission. We summarize risks and predictors of seizure relapse after AED withdrawal and chances of not regaining seizure freedom. Finally, we discuss how AED discontinuation can inform us on the natural course of the epileptic disorder. RECENT FINDINGS: In medically treated patients, the risk of recurrence after AED withdrawal is increased until 2 years after withdrawal, although long-term seizure outcomes seem to be unaffected by drug policies. Most relapses occur during the first year after withdrawal. Several predictors of postwithdrawal relapse have been identified. The risk of developing uncontrollable epilepsy following withdrawal is less than one in five. Whether AED withdrawal after epilepsy surgery contributes to seizure outcome has never been studied in a randomized controlled manner. Recent studies suggested that AED reduction merely unmasks incomplete surgical success. The risk of not regaining seizure freedom after postoperative relapse is around 30% and probably not affected by AED reduction. Timing of AED discontinuation does not influence eventual seizure outcomes. SUMMARY: There is no proof that AED withdrawal itself negatively affects long-term seizure outcomes in patients who became seizure-free under AED treatment or after epilepsy surgery. AED discontinuation unveils the natural history of the epilepsy in medically treated patients, and the completeness of resection of the epileptogenic network in patients who underwent epilepsy surgery.

Clinical conditions of long-term cure in childhood-onset epilepsy: a 45-year follow-up study.

Clinical conditions of long-term cure in childhood-onset epilepsy, defined as sustained remission off antiepileptic drug (AED) treatment, are not well known. To address that clinically important question, we determined clinical factors predictive of long-term seizure cure in a population-based cohort of 133 patients followed up since their first seizure before the age of 16 years. At the end of the 45-year follow-up (mean=39.8, median=44, range=11-47), 81 (61%) of the 133 patients had entered at least 5-year remission off AEDs, meeting our definition of cure. The 81 patients were seizure-free off AEDs for a mean of 34.4 (median=38, range=6-46) years and 59 (73%) of the 81 patients following the first standard medication until the end of follow-up (mean=36.5, median=39, range=14-46 years). Four independent factors were found to be associated with cure compared with having seizures while on AEDs: seizure frequency less than weekly during the first 12 months of AED treatment (p=0.002), pretreatment seizure frequency less than weekly (p=0.002), higher IQ (>70; p=0.021), and idiopathic or cryptogenic vs. symptomatic etiology (p=0.042). Patients with seizure frequency of less than once a week during early treatment and idiopathic etiology had a ninefold chance to of being cured since the onset of the first adequate antiepileptic therapy until the end of follow-up compared with patients who a symptomatic etiology had at least weekly seizures while on AEDs (RR=8.7, 95% CI=2.0-37.0; p<0.001). In conclusion, IQ, etiology, and seizure frequencies both in the first year of AED treatment and prior to medication appear to be clinical predictors of cure in childhood-onset epilepsy.

The administration of rescue medication to children with prolonged acute convulsive seizures in a non-hospital setting: an exploratory survey of healthcare professionals' perspectives.

UNLABELLED: Timely administration of rescue medication for prolonged convulsive seizures lasting more than 5 min is necessary to prevent progression to status epilepticus in children. The Practices in Emergency and Rescue Medication for Epilepsy Managed with Community Administered Therapy (PERFECT™) initiative was set up to gain a better understanding of how prolonged convulsive seizures in children are managed when they occur outside of the hospital. We present the findings from an exploratory telephone survey of 128 healthcare professionals (HCPs) (85 pediatric neurologists and neurologists, 28 community pediatricians, and 15 epilepsy nurses) from six EU countries, conducted as part of the PERFECT™ initiative. Among HCPs, there was greater awareness of local protocols and lesser awareness of national or international guidelines. HCPs were not very aware of how prolonged convulsive seizures were managed outside of the hospital and had few professional links to schools or other settings where these seizures were most likely to occur. Approximately one third believed that lack of confidence and fear of liability were barriers to caregivers administering treatment in schools, as was insufficient training of caregivers in the wider community on the management of prolonged convulsive seizures. CONCLUSION: Results of this HCP survey have identified several clear gaps that need to be addressed: clearer guidance that spans all settings of care, greater dissemination of such guidelines across the chain of care, more open communication and better links between HCPs and schools, and systematic training of all relevant caregivers on the appropriate management of prolonged convulsive seizures.

Time to relapse after epilepsy surgery in children: AED withdrawal policies are a contributing factor.

AIM: It was recently suggested that early postoperative seizure relapse implicates a failure to define and resect the epileptogenic zone, that late recurrences reflect the persistence or re-emergence of epileptogenic pathology, and that early recurrences are associated with poor treatment response. Timing of antiepileptic drugs withdrawal policies, however, have never been taken into account when investigating time to relapse following epilepsy surgery. METHODS: Of the European paediatric epilepsy surgery cohort from the "TimeToStop" study, all 95 children with postoperative seizure recurrence following antiepileptic drug (AED) withdrawal were selected. We investigated how time intervals from surgery to AED withdrawal, as well as other previously suggested determinants of (timing of) seizure recurrence, related to time to relapse and to relapse treatability. Uni- and multivariable linear and logistic regression models were used. RESULTS: Based on multivariable analysis, a shorter interval to AED reduction was the only independent predictor of a shorter time to relapse. Based on univariable analysis, incomplete resection of the epileptogenic zone related to a shorter time to recurrence. Timing of recurrence was not related to the chance of regaining seizure freedom after reinstallation of medical treatment. CONCLUSION: For children in whom AED reduction is initiated following epilepsy surgery, the time to relapse is largely influenced by the timing of AED withdrawal, rather than by disease or surgery-specific factors. We could not confirm a relationship between time to recurrence and treatment response. Timing of AED withdrawal should be taken into account when studying time to relapse following epilepsy surgery, as early withdrawal reveals more rapidly whether surgery had the intended curative effect, independently of the other factors involved.

[Michal Borysiekiewicz (1848-1899)--ophthalmology professor, head of departments in Innsbruck and Graz]. / Michal Borysiekiewicz (1848-1899)--profesor okulistyki, kierownik Klinik Okulistycznych w Innsbrucku i Grazu.

Michal Borysiekiewicz (1848-1899) was an ophthalmology professor, head of the Eye Clinics in Innsbruck (1887-1892) and Graz (1892-1899). He studied medicine at the University of Vienna, where he was awarded the M.D. title in 1872. A student of Carl Ferdinand von Arlt and Carl Stellwag von Carion, the author of several clinical and research projects published in German, he focused his work on pharmacology, cataract surgery and retinal examination techniques. He also published some clinical cases. In his research, he particularly emphasized the comparative anatomy and physiology of the retina.

Enzyme induction with antiepileptic drugs: cause for concern?

Several commonly prescribed antiepileptic drugs (AEDs)-including phenobarbital, phenytoin, and carbamazepine-stimulate the synthesis of a broad range of monooxygenase and conjugating enzymes. These agents are well known to reduce the duration and action of many lipid- and non-lipid-soluble drugs, including anticoagulants, cytotoxics, analgesics, antiretrovirals, glucocorticoids, statins, antihypertensives, oral contraceptives, psychoactive drugs, immunosuppressants, and of course, other AEDs. This process, therefore, may be associated with a number of clinical problems including higher cancer mortality, progressive AIDS, transplant rejection, and unwanted pregnancy. Withdrawal of enzyme-inducing AEDs will increase the concentration of induced drugs, bringing with it substantial risk of toxicity if doses are not concomitantly reduced. Yet the potential widespread adverse health consequences of these interactions, both with AED initiation and withdrawal, remain largely underappreciated. Furthermore, induction also affects enzymes involved in endogenous metabolic pathways, and can alter bone biochemistry, gonadal steroids, and lipid markers. Therefore, enzyme-inducing AEDs may contribute to the development of a number of comorbidities, including osteoporosis, sexual dysfunction, and vascular disease. This process continues as long as the patient takes the inducer. Modern AEDs that do not possess this property have similar efficacy for the common epilepsies. Accordingly, perhaps consideration should be given to starting treatment with, or even switching patients to, non-enzyme-inducing AEDs.

Development of new treatment approaches for epilepsy: unmet needs and opportunities.

A working group was created to address clinical "gaps to care" as well as opportunities for development of new treatment approaches for epilepsy. The working group primarily comprised clinicians, trialists, and pharmacologists. The group identified a need for better animal models for both efficacy and tolerability, and noted that animal models for potential disease-modifying or antiepileptogenic effect should mirror conditions in human trials. For antiseizure drugs (ASDs), current animal models have not been validated with respect to their relationship to efficacy in common epilepsy syndromes. The group performed an "expert opinion" survey of perceived efficacy of the available ASDs, and identified a specific unmet need for ASDs to treat tonic-atonic and myoclonic seizures. No correlation has as yet been demonstrated between animal models of tolerability and adverse effects (AEs), versus tolerability in humans. There is a clear opportunity for improved therapies in relation to dose-related AEs. The group identified common and rare epilepsy syndromes that could represent opportunities for clinical trials. They identified opportunities for antiepileptogenic (AEG) therapies in both adults and children, acknowledging that the presence of a biomarker would substantially improve the chances of a successful trial. However, the group acknowledged that disease-modifying therapies (given after the first seizure or after the development of epilepsy) would be easier to study than AEG therapies.

Issues related to development of antiepileptogenic therapies.

Several preclinical proof-of-concept studies have provided evidence for positive treatment effects on epileptogenesis. However, none of these hypothetical treatments has advanced to the clinic. The experience in other fields of neurology such as stroke, Alzheimer's disease, or amyotrophic lateral sclerosis has indicated several problems in the design of preclinical studies, which likely contribute to failures in translating the positive preclinical data to the clinic. The Working Group on "Issues related to development of antiepileptogenic therapies" of the International League Against Epilepsy (ILAE) and the American Epilepsy Society (AES) has considered the possible problems that arise when moving from proof-of-concept antiepileptogenesis (AEG) studies to preclinical AEG trials, and eventually to clinical AEG trials. This article summarizes the discussions and provides recommendations on how to design a preclinical AEG monotherapy trial in adult animals. We specifically address study design, animal and model selection, number of studies needed, issues related to administration of the treatment, outcome measures, statistics, and reporting. In addition, we give recommendations for future actions to advance the preclinical AEG testing.