ReviewHuman clinical trails in antiepileptogenesis
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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2022, Pharmacology and TherapeuticsCitation 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).
Statins in primary prevention of poststroke seizures and epilepsy: A systematic review
2020, Epilepsy and BehaviorModifying genetic epilepsies – Results from studies on tuberous sclerosis complex
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2020, Neuroscience and Biobehavioral ReviewsMechanisms of epileptogenesis and preclinical approach to antiepileptogenic therapies
2018, Pharmacological ReportsCitation 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].