Clinical trials for prevention of epileptogenesis
Introduction
Currently available antiepileptic drugs (AEDs) suppress seizures without altering the underlying course of epilepsy. We need to take a step backward in the process to search for treatments that could prevent epileptogenesis in subjects at risk (Jacobs et al., 2001). Epileptogenesis involves progressive biochemical, anatomic, and physiologic changes which eventually generate spontaneous clinical seizures. Epileptogenic changes occur during the latent or clinically silent period (between the initial brain insult and the development of the first unprovoked seizure) in symptomatic epilepsies where there is a clear cause for epileptic seizures. Development of epilepsy after a brain injury depends on a variety of factors, including age at the time of injury, genetic background, severity of the injury, brain structures damaged, and the occurrence of acute symptomatic seizures.
Section snippets
Epileptogenesis
Epileptogenesis after brain insults is an incompletely understood process. An initial precipitating injury such as stroke or traumatic brain injury results in brain damage. Acute symptomatic seizures occur within the first one to 2 weeks after the brain injury. These early seizures are not epilepsy, but are likely caused by alterations in the blood-brain barrier, parenchymal hemorrhage, release of excitotoxic neurotransmitters, and changes in energy metabolism (Vaughan and Delanty, 2002). Acute
Issues in antiepileptogenesis trial design
Prevention of epilepsy has been an elusive target. Antiepileptogenesis trials in experimental animals (Pitkanen, 2002) and in humans (Temkin, 2001) have been disappointing. Well-designed prospective clinical trials for epilepsy prevention demonstrated that phenytoin and valproate can suppress early seizures after severe traumatic brain injury, but that treatment had no effect on the development of late epilepsy (Temkin et al., 1990, Temkin et al., 1999). All human epilepsy prevention trials to
Populations at risk for epilepsy
Clinical trials of possible antiepileptogenic agents would enroll patients at high risk for developing epilepsy immediately after a brain insult or during the latent period, with the goal of preventing epilepsy. This eligibility criterion would minimize the sample size needed for the trial. The study population should have at least a 20% risk for the development of late seizures or epilepsy. If the study population has a 20% risk of developing epilepsy, and the study treatment decreases the
Biomarkers of epileptogenesis
Clinical trials for epilepsy prevention should also begin to examine potential biomarkers of epileptogenesis. Possible biomarkers include magnetic resonance imaging (MRI) to identify local and global structural abnormalities, functional MRI and positron emission tomography (PET) to examine changes in neuronal and receptor functioning, and electroencephalography (EEG) to screen for ictal and interictal epileptiform abnormalities. Although none of these are yet validated as surrogate markers,
Conclusion
Rigorous clinical trial design will be necessary to demonstrate antiepileptogenesis and epilepsy prevention. This will include recruitment of carefully selected subjects at very high risk for seizures following brain injury, long follow-up duration, post-treatment observation periods, and good compliance. Identification of potential antiepileptogenic agents in experimental animals, exploration of possible biomarkers of epileptogenesis, and determination of the optimal treatment window for
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