Human clinical trails in antiepileptogenesis

doi:10.1016/j.neulet.2011.03.010

Neuroscience Letters

Volume 497, Issue 3, 27 June 2011, Pages 251-256

https://doi.org/10.1016/j.neulet.2011.03.010 Get rights and content

Abstract

Blocking the development of epilepsy (epileptogenesis) is a fundamental research area with the potential to provide large benefits to patients by avoiding the medical and social consequences that occur with epilepsy and lifelong therapy. Human clinical trials attempting to prevent epilepsy (antiepileptogenesis) have been few and universally unsuccessful to date. In this article, we review data about possible pathophysiological mechanisms underlying epileptogenesis, discuss potential interventions, and summarize prior antiepileptogenesis trials. Elements of ideal trials designs for successful antiepileptogenic intervention are suggested.

Highlights

► Blocking epileptogenesis in those at risk is critical for controlling this serious disorder. ► Animal models are beginning to demonstrate that this can be done although much more research is needed in this area. ► Human trials to date have been unsuccessful. ► Designing clinical trials for epileptogenesis is challenging and requires more research.

Introduction

There is a widely quoted phrase somewhat adapted from the Hippocratic oath that all physicians take before entering their profession: “first, do no harm.” rarely, does anyone ask, “what is second?” In many areas of medicine, emphasis is placed on diagnosing and treating illness. This is particularly true in epilepsy. Unfortunately, what should be “second” is preventing illness, so that it becomes unnecessary to diagnose or treat that which does not exist in the first place. For the most part, preventing epilepsy in those with known risk has not been possible. In order for this unacceptable situation to be corrected, we need to understand the mechanisms by which epilepsy develops in an injured or genetically susceptible brain, demonstrate in some preclinical model that the process can be prevented, and then demonstrate in a well designed clinical trial that the proposed preventive strategy is effective and safe.

Epilepsy affects more than 45 million people worldwide. In the US, the prevalence of epilepsy is approximately 6–8 per 1000 people, and the incidence is approximately 26–40 per 100,000 person-years [10]. Treatment of epilepsy has focused on preventing recurrence of seizures after the onset of epilepsy. Surgical cure is an option for some medication-refractory patients, but even then the treatment may be onerous and is usually delayed sufficiently that there often is irreparable biological and psychosocial comorbidity, even if the patient becomes seizure free [1]. In all, approximately 40% of patients that develop epilepsy continue to have life-long seizures [25]. It is common for antiepileptic drugs (AED) to have side effects, with those effects being highest among patients who need a large number and high dosage of AEDs [7]. Avoiding all of this whenever possible is a major advantage to individuals destined to develop epilepsy.

In this article, we will review the concept of epileptogenesis as it relates to man. We will review clinical trials of epileptogenesis prevention and describe steps for creation of future trials of antiepileptogenesis in humans. Special emphasis will be placed on the prevention of epilepsy development after symptomatic brain insults.

Section snippets

Definitions

Epilepsy: chronic disorder of the nervous system characterized by recurrent unproved seizures; there should at least two or more seizures greater than 24 h apart [16].

Acute (or early) symptomatic seizures: seizures that occur soon after a brain insult. Usually, this time period is specified as 1–2 weeks after the insult. Some authors use 7 days as the cutoff; some use 2 weeks. These are provoked seizures. The pathophysiology that underlies these provoked seizures (e.g. neuronal calcium influx,

Models

Animal models to investigate mechanisms of epileptogenesis and the critical period for application of specific therapies to prevent epileptogenesis are particularly important. Models based on kindling, prolonged hyperthermia-induced seizures, post-status epilepticus, traumatic brain injury (TBI) and cortical dysplasias produced by tuberous sclerosis have provided a wealth of information about the cellular and biochemical changes that occur during epileptogenesis. However, they have not yet

Postulated antiepileptogenic interventions

Unless a key universal epileptogenic cascade can be identified, it is likely that different epilepsies will require different preventative strategies. Several different categories of interventions hold promise for blocking epileptogenesis. Traditional antiepileptic drugs have been the most commonly used in human clinical trials and will remain the most investigated interventions to block epileptogenesis due to their safety and efficacy as seizure suppressing agents. Their use in these studies

Epileptogenesis

Epileptogenesis is often viewed in different phases. The latent interval exists from the time of brain insult until the development of recurrent spontaneous seizures. Different pathologic mechanisms that have been reliably associated with epilepsy have been observed in this latent period, and they may be the subject of antiepileptogenic interventions. Glutamatergic enhancement has been observed in kindling models associated with mossy fiber sprouting [35]. GABAergic disruption has also been

Risk of epilepsy development (RED syndrome)

The risk of epilepsy development (RED) syndrome is a condition that recognizes that a variety of neurologic conditions precede the process of development of later unprovoked seizures [8]. This syndrome was created to better identify patients at high risk for epilepsy development so that therapies can be targeted for primary disease prevention. The intent is to focus on research leading to therapies for primary prevention of unprovoked seizures and the onset of epilepsy. An apt analogy is the

Past clinical trials in epileptogenesis

A number of human clinical trials have been conducted in preventing epilepsy development in subjects at risk for epilepsy, but only a few of these have been randomized, double blind placebo controlled studies. These trials have generally included patients with brain injuries or brain tumors, and all have failed to discover useful preventative treatments. A landmark human clinical trial showed that phenytoin administration after moderate to severe TBI does not decrease the chance of unprovoked

Antiepileptogenic morbidity

One factor that complicates trials is that the AEDs, especially the older ones, can cause substantial morbidity. Phenytoin caused significant neurobehavioral impairment months after traumatic brain injury compared to patients with similar injury receiving placebo [9]. Post-stroke recovery in animal models has been shown to be impaired by GABA-ergic drugs [13]. Similarly, in a trial where recovery of function after intracerebral hemorrhage was studied, patients on antiepileptic drugs fared more

Biomarkers

Given the long duration until clinical detection of epileptogenesis after brain injury and the lack of promising results from human antiepileptogenesis trials, development and validation of biomarkers for human epileptogenesis will be extremely important to better detect beneficial effects of interventions. Surface EEG spikes, specific intracranial EEG spike patterns, and intracranial EEG seizures may be present before development of clinical seizures and serve as biomarkers.

High frequency

An ideal human antiepileptogenesis trial

Selecting the appropriate patient population is the most important factor in designing a study of antiepileptogenesis in humans [Table 1]. The ideal population would be subjects with very high epilepsy risk (high RED scores) to maximize the chance of detecting a difference between the treatment and placebo arms. Further, the risk factor for epilepsy must be readily identifiable in origin and time in order to establish a relatively homogeneous population with a similar starting point. In

Conclusion

Preventing epilepsy in those known to be at risk should be a very high priority for the medical community and epilepsy specialists in particular. Curing epilepsy once it develops or stopping existing seizures with medications or devices will also continue to be crucial. In order for us to develop the ability to prevent epileptogenesis, we will need to understand the process better and to employ appropriate animal models to test therapeutic hypotheses. However, it needs to be recognized that

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New approaches for developing multi-targeted drug combinations for disease modification of complex brain disorders. Does epilepsy prevention become a realistic goal?
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Citation Excerpt :
This period roughly corresponds to the typical duration of time that patients with severe brain injury spend in the intensive care unit (ICU). Parenteral (i.v.) treatment with drug combinations in the ICU would prevent nonadherence to medication, which was a significant bias in previous epilepsy prevention trials (Mani, Pollard, & Dichter, 2011). Translation of preclinical findings to clinical trials would be facilitated by validated surrogate markers for epileptogenesis, which, however, are not yet available (Pitkänen et al., 2016).
Over decades, the prevailing standard in drug discovery was the concept of designing highly selective compounds that act on individual drug targets. However, more recently, multi-target and combinatorial drug therapies have become an important treatment modality in complex diseases, including neurodegenerative diseases such as Alzheimer's and Parkinson's disease. The development of such network-based approaches is facilitated by the significant advance in our understanding of the pathophysiological processes in these and other complex brain diseases and the adoption of modern computational approaches in drug discovery and repurposing. However, although drug combination therapy has become an effective means for the symptomatic treatment of many complex diseases, the holy grail of identifying clinically effective disease-modifying treatments for neurodegenerative and other brain diseases remains elusive. Thus, despite extensive research, there remains an urgent need for novel treatments that will modify the progression of the disease or prevent its development in patients at risk. Here we discuss recent approaches with a focus on multi-targeted drug combinations for prevention or modification of epilepsy. Over the last ~10 years, several novel promising multi-targeted therapeutic approaches have been identified in animal models. We envision that synergistic combinations of repurposed drugs as presented in this review will be demonstrated to prevent epilepsy in patients at risk within the next 5–10 years.
Statins in primary prevention of poststroke seizures and epilepsy: A systematic review
2020, Epilepsy and Behavior
Cerebrovascular disease is the most common cause of seizures in adults and the elderly. So far, no drug is recommended as primary prevention of acute symptomatic poststroke seizures (ASPSS) or poststroke epilepsy (PSE). This systematic review aimed to evaluate the association between the use of statins after stroke and the risk of developing ASPSS or PSE following cerebral infarct or hemorrhage (primary prevention).
We included studies evaluating the poststroke use of statins as primary prevention of ASPSS or PSE, irrespective of stroke type. We excluded uncontrolled studies and studies with prestroke statin use. The main outcome included the occurrence of ASPSS or PSE and the effect of statins by type and dose. The odds ratios (ORs) or hazard ratios (HR) with 95% confidence intervals (CIs) were used as the measures of association between treatment and outcome.
Four studies were included. One study showed a reduced risk of ASPSS after ischemic stroke (OR: 0.25; 95% CI: 0.10–0.59; p = 0.0016). Three studies consistently reported a reduced risk of PSE after ischemic stroke, and one study a reduced risk of PSE after hemorrhagic stroke (HR: 0.62; 95% CI: 0.42–0.90; p = 0.01).
Data from the literature suggest an association between statin use and a reduced risk of ASPSS after ischemic stroke and a reduced risk of PSE after ischemic and hemorrhagic stroke. Although the certainty of the evidence is low, these findings appear promising and worthy of further investigation.
Modifying genetic epilepsies – Results from studies on tuberous sclerosis complex
2020, Neuropharmacology
Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder affecting approximately 1 in 6,000 in general population and represents one of the most common genetic causes of epilepsy. Epilepsy affects 90% of the patients and appears in the first 2 years of life in the majority of them. Early onset of epilepsy in the first year of life is associated with high risk of cognitive decline and neuropsychiatric problems including autism.
Recently TSC has been recognized as a model of genetic epilepsies. TSC is a genetic condition with known dysregulated mTOR pathway and is increasingly viewed as a model for human epileptogenesis. Moreover, TSC is characterized by a hyperactivation of mTOR (mammalian target of rapamycin) pathway, and mTOR activation was showed to be implicated in epileptogenesis in many animal models and human epilepsies. Recently published studies documented positive effect of preventive or disease modifying treatment of epilepsy in infants with high risk of epilepsy with significantly lower incidence of epilepsy and better cognitive outcome. Further studies on preventive treatment of epilepsy in other genetic epilepsies of early childhood are considered.
This article is part of the special issue entitled ‘New Epilepsy Therapies for the 21st Century – From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy’.
The need to incorporate aged animals into the preclinical modeling of neurological conditions
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Neurological conditions such as traumatic brain injury, stroke, Parkinson’s disease, epilepsy, multiple sclerosis, and Alzheimer’s disease are serious clinical problems that affect millions of people worldwide. The majority of clinical trials for these common conditions have failed, and there is a critical need to understand why treatments in preclinical animal models do not translate to patients. Many patients with these conditions are middle-aged or older, however, the majority of preclinical studies have used only young-adult animals. Considering that aging involves biological changes that are relevant to the pathobiology of neurological diseases, the lack of aged subjects in preclinical research could contribute to translational failures. This paper details how aging affects biological processes involved in neurological conditions, and reviews aging research in the context of traumatic brain injury, stroke, Parkinson’s disease, epilepsy, multiple sclerosis, and Alzheimer’s disease. We conclude that aging is an important, but often overlooked, factor that influences biology and outcomes in neurological conditions, and provide suggestions to improve our understanding and treatment of these diseases in aged patients.
Mechanisms of epileptogenesis and preclinical approach to antiepileptogenic therapies
2018, Pharmacological Reports
Citation Excerpt :
Administration of the AED (once daily for 6 weeks, 150 mg/kg or 300 mg/kg) after pilocarpine-induced SE in mice, resulted in a significant decrease in seizure activity at the chronic state, 8 weeks after the end of treatment, decrease in mossy fiber sprouting into the inner molecular layer of the DG and attenuated neuronal loss (dose 150 mg/kg) in pilocarpine-injected mice [110]. The results of antiepileptogenesis clinical studies concerning older AEDs (phenytoin, phenobarbital, diazepam, carbamazepine, valproate) are rather disappointing [8,10,111,112]. Reasons for these disappointing results may be due to the possibility that studied AEDs, despite suppressing seizure activity, do not interfere in any substantial way with the “epileptogenic” process and/or they may have been examined at the wrong doses, for the wrong duration, or at the wrong time after brain injury [9].
The prevalence of epilepsy is estimated 5–10 per 1000 population and around 70% of patients with epilepsy can be sufficiently controlled by antiepileptic drugs (AEDs). Epileptogenesis is the process responsible for converting normal into an epileptic brain and mechanisms responsible include among others: inflammation, neurodegeneration, neurogenesis, neural reorganization and plasticity. Some AEDs may be antiepileptiogenic (diazepam, eslicarbazepine) but the correlation between neuroprotection and inhibition of epileptogenesis is not evident. Antiepileptogenic activity has been postulated for mTOR ligands, resveratrol and losartan. So far, clinical evidence gives some hope for levetiracetam as an AED inhibiting epileptogenesis in neurosurgical patients. Biomarkers for epileptogenesis are needed for the proper selection of patients for evaluation of potential antiepileptogenic compounds.
Status epilepticus does not induce acute brain inflammatory response in the Amazon rodent Proechimys, an animal model resistant to epileptogenesis
2018, Neuroscience Letters
Mesial temporal lobe epilepsy is a serious brain disorder in adults that is often preceded by an initial brain insult, such as status epilepticus (SE), that after a latent period leads to recurrent seizures. Post-SE models are widely used for studies on epileptogenic processes. Previous findings of our laboratory suggested that the Neotropical rodents Proechimys exhibit endogenous antiepileptogenic mechanisms in post-SE models. Strong body of research supports that SE triggers a rapid and dramatic upregulation of inflammatory mediators and vascular endothelial growth factor (VEGF). In this work we found that, in the epilepsy-resistant Proechimys, hippocampal and cortical levels of inflammatory cytokines (IL-1β, IL-6, IL-10, TNF-α) and VEGF remained unchanged 24 h after SE, strongly contrasting to the high levels of post-SE changes observed in Wistar rats. Furthermore, substantial differences in the brain baseline levels of these proteins were encountered between animal species studied. Since inflammatory cytokines and VEGF have been recognized as major orchestrators of the epileptogenic process, our results suggest their role in the antiepileptogenic mechanisms previously described in Proechimys.

View all citing articles on Scopus

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ReviewHuman clinical trails in antiepileptogenesis

Abstract

Highlights

Introduction

Section snippets

Definitions

Models

Postulated antiepileptogenic interventions

Epileptogenesis

Risk of epilepsy development (RED syndrome)

Past clinical trials in epileptogenesis

Antiepileptogenic morbidity

Biomarkers

An ideal human antiepileptogenesis trial

Conclusion

Epilepsy Behav.

NeuroRX

Arch. Phys. Med. Rehabil.

Epilepsy Res.

Clin. Neurophysiol.

Prog. Brain Res.

Lancet Neurol.

Brain Behav. Immun.

Dormancy of inhibitory interneurons in a model of temporal lobe epilepsy

Science

Early treatment suppresses the development of spike-wave epilepsy in a rat model

Epilepsia

High-frequency oscillations after status epilepticus: epileptogenesis and seizure genesis

Epilepsia

Epilepsy

N. Engl. J. Med.

Neuroprotection and antiepileptogenesis

Neurology

Reappraisal of polytherapy in epilepsy: a critical review of drug load and adverse effects

Epilepsia

Emerging concepts in the pathogenesis of epilepsy and epileptogenesis

Arch. Neurol.

Neurobehavioral effects of phenytoin prophylaxis of posttraumatic seizures

JAMA

Initial management of epilepsy

N. Engl. J. Med.

Epidemiology of posttraumatic epilepsy: a critical review

Epilepsia

Is epilepsy a preventable disorder? New evidence from animal models

Neuroscientist

Risk factors for epilepsy

Epilepsy Res. Suppl.

Review
Human clinical trails in antiepileptogenesis