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Keywords:

  • Epileptogenesis;
  • Antiepileptogenesis;
  • Epilepsy prevention;
  • Posttraumatic epilepsy

Summary

  1. Top of page
  2. Summary
  3. Identifying the Problems
  4. Can Epilepsy Be Prevented?
  5. Recommendations for Translating Basic Discoveries in the Laboratory to a Pathway Toward a Cure for Posttraumatic Epilepsy
  6. Acknowledgments
  7. References

Translating laboratory discoveries into successful therapies for preventing epilepsy is a difficult task, but preventing epilepsy in those who are known to be at high risk needs to be one of our highest priorities. At present, we need to approach this task as a parallel set of research endeavors—one concentrating on laboratory experiments designed to learn how to prevent epilepsy after brain trauma and the other focusing on how to perform the appropriate clinical research in humans to demonstrate that whatever is discovered in the laboratory can be appropriately tested. It is too important to let the second process await conclusion of the first. Initially, we need to create a consortium of groups in trauma centers that are dedicated to antiepileptogenic studies and develop funding sources for long-term studies. We need to experiment with clinical protocols, making the studies as cost-effective as possible, while performing continuous data mining of outcomes and surrogate markers. The limitations of current technology to assist in antiepileptogenesis trials must be acknowledged: There is no currently available method for continuously monitoring electroencephalography (EEG) over prolonged periods, and there are no validated biomarkers for the process of epileptogenesis. As we learn more about the process of epileptogenesis and its underlying mechanisms, it is hoped that we will be able to prevent the development of epilepsy after traumatic brain injury (TBI) and after many other known epileptogenic lesions.

Translating laboratory discoveries into successful therapies for preventing epilepsy is a very difficult task, much more so than demonstrating that a new drug developed as part of an antiseizure screen can pass muster as a new antiepileptic agent. On the other hand, this is an exceedingly important task and one to which too little attention has been paid in the past. This article discusses some of the reasons that this form of translational research is so difficult, but also offers one example of a “proof of principle” experiment to demonstrate that epilepsy prevention is possible. This article also proposes a pathway, somewhat radical, by which we may be able to achieve the goal of preventing epilepsy after brain trauma, indicates some new technologies that I think will need to be applied to this endeavor, and strongly advocates the need to embark on this pathway now, and not wait for basic “breakthroughs” before beginning.

We can define “curing epilepsy” in two ways: either preventing epilepsy in those who are at risk or eliminating seizures and any other aspects of epilepsy in those who have already developed epilepsy after traumatic brain injury (TBI). This article concentrates on prevention. Why all this fuss about prevention? Why not just treat the seizures after they have developed? First, only clinical seizures are observed, and not even all of them. There is no current method for monitoring subclinical seizures that may have clear electrographic discharges and subsequent consequences. Counting seizures is in some ways like counting stars. It can be done with the naked eyes and have a different count on different nights, depending on whether it’s clear or cloudy. It can be done through a telescope that would reveal many more stars than were thought to exist. But even then, only a fraction of what is there can be observed, because the instruments are not powerful enough. Second, patients with epilepsy have more disability than just seizures, and perhaps by treating the process to prevent epilepsy one might be able to prevent other components of the disorder as well.

Epilepsy is one of the only diseases known to man, where people at risk can be easily identified, and nothing is done to prevent the development of the disorder, even for those at high risk. Instead, one waits until symptoms develop and then attempts are made to treat the symptoms. Why this is remains unclear. Research and treatment strategies for other diseases focus on either prevention or cure, and especially prevention. Epilepsy is a major medical problem. It develops over time, so there is ample opportunity to intervene. Risk factors can be identified, and, if a treatment were available, intervention could be initiated. So why hasn’t the epilepsy community focused more on this issue? Partly, the field is hampered by a lack of basic scientific information about how to intervene. However, the more recent focus on epileptogenesis has increased, and progress should be made in this area soon.

Individuals who are at relatively high risk for developing epilepsy can be identified. These include individuals with moderate to severe head injury (such as we are seeing in the veterans returning from Iraq and Afghanistan), but also individuals with intracerebral hemorrhage, brain tumors, status epilepticus, a variety of chronic neurodegenerative diseases, and children with prolonged febrile seizures, dysplastic lesions, and certain genetic forms of epilepsy but who have not yet become symptomatic. These populations are known; needed now are the tools to change their outcomes.

Identifying the Problems

  1. Top of page
  2. Summary
  3. Identifying the Problems
  4. Can Epilepsy Be Prevented?
  5. Recommendations for Translating Basic Discoveries in the Laboratory to a Pathway Toward a Cure for Posttraumatic Epilepsy
  6. Acknowledgments
  7. References

There are major difficulties in developing strategies for preventing epilepsy after TBI. First, the amount of preclinical data needed must be determined before launching a clinical trial. Which models should be used? Is status epilepticus, the most commonly utilized model for studying epileptogenesis, a good model for TBI, or for epileptogenesis, after other risks? Are rodents appropriate species to use? Is the process of epileptogenesis after different kinds of TBI the same—for example, after blood in the brain, a penetrating injury, or a blast injury?

What kinds of results would be required? Is only completely eliminating seizures an acceptable outcome, or will reducing epilepsy risk or reducing seizure number or intensity or unresponsiveness to antiepileptic drugs (AEDs) be sufficient? What is the “gold standard” when there are no successful animal trials? There have been more than 70 years of successful trials in animal models for testing antiseizure compounds, since Houston Merritt and Tracy Putnam invented the “maximal electroshock model.” However, there has not yet been a successfully implemented model for preventing epilepsy.

At the level of clinical trials, a similar predicament exists. With regard to preventing epilepsy after TBI, there is only one well-established model, that pioneered by Dr. Nancy Temkin and her colleagues in neurosurgery at the University of Washington (Temkin et al., 1990, 1998). They have performed single center, double-blind controlled trials that take about 5 years to complete for one agent. At this time, there is no formal research in clinical trial methodology, especially in this field. We do not know how to optimally do such trials. How should they be funded? It is unlikely, at least initially, that this can be left to the pharmaceutical industry, as there are no very promising drugs identified. In addition, the National Institutes of Health (NIH) does not appear to have sufficient funds to allow support for experimental human clinical trial methodologic research, unless specific funds are set aside for this enterprise. It is possible that alternative sources, such as the Department of Defense, or the Department of Transportation (since so much head trauma occurs from motor vehicle accidents) would be likely funding sources.

If research into the clinical methodology for implementing antiepileptogenesis trials develops, it needs to include the investigation of biomarkers for epileptogenesis, as was done in a National Institute of Neurological Disorders and Stroke (NINDS)–sponsored workshop in 2007. This would involve electroencephalography (EEG) biomarkers, including recordings from both surface and intracranial electrodes; the latter are more likely to reveal spikes, subclinical seizures, developing fast ripples or HFEOs (high frequency epileptiform oscillations) (Bragin et al., 2004). In addition, both standard and new imaging techniques may also be employed to follow the process of epileptogenesis, as is already being done in the Febstat program, where children who have had a bout of prolonged febrile status epilepticus and who are at great risk for developing epilepsy are being followed longitudinally with magnetic resonance imaging (MRI) (S. Shinnar, pers. comm.). In addition, human clinical research may capitalize on the experimental imaging work of Dr. Pitkanen in rats undergoing epileptogenesis after status (Grohn & Pitkanen, 2007), or of Tallie Baram in mice undergoing epileptogenesis after febrile seizures (Dube et al., 2004), to point to new techniques that may be applied to humans. It is also possible that biochemical signatures of the epileptogenic process can be developed. These might detect signals in blood or cerebrospinal fluid (CSF) that would indicate both the ongoing damage after TBI and the synaptic reorganization and altered neuronal phenotypes associated with epileptogenesis.

There are data from experimental studies that illustrate these issues. Dr. Raimondo D’Ambrosio at the University of Washington is investigating posttraumatic epileptogenesis using a fluid-percussion model in rats (D’Ambrosio et al., 2004, 2005). Shortly after TBI, brief focal seizures develop; the seizures are associated with brief behavioral arrests. The surface EEG recordings fail to show any evidence of these seizures, whereas very carefully localized intracranial electrodes clearly demonstrate the seizures. These have been called grade 1 seizures. Grade 2 seizures are more extensive, and can be observed bilaterally. The grade 1 seizures persist for up to 15 weeks, and it takes many weeks before the grade 2 and 3 seizures become manifest. Even then, the grade 3 seizures, with surface EEG changes, occur only infrequently, and may be missed if all that can be monitored is a patient’s, or a witness’s, reporting of seizures. Is this the “latent period” that we commonly see in clinical observations? When grade 3 seizures appear, they can be seen as low amplitude events in the scalp recordings.

Data extrapolated from human intracranial recordings in patients with well-established epilepsy also suggest that interictal spikes, and fast ripples, may possibly occur early during the epileptogenic process, and would likely only be observed with intracranial electrodes, as opposed to routine scalp recordings. Data developed in other experimental laboratories demonstrate that both fast ripples (Bragin et al., 2004) and localized interictal spikes (K. Staley, pers. comm.) may be seen very early after status epilepticus and may serve as markers for those animals destined to develop late epilepsy. At a minimum, these kinds of discharges are likely to be biomarkers of the epileptogenic process, and it would be useful to know how they are affected by any treatment. If any of these events are part of the mechanism by which epileptogenesis occurs, any possible treatment would need to monitor these events to ascertain that they are being appropriately suppressed. Unfortunately, none of these events would be seen with currently used approaches.

Other events recently identified in intracranial recordings from human patients may also serve as signatures of the epileptogenic process and be as important to epileptogenesis as they are to ictogenesis in the already epileptic cortex. New techniques of microwire recording are demonstrating relatively frequent, highly localized seizure-like events (Stead et al., 2007). When these “microseizures” develop in a brain that is injured and is undergoing the process of epileptogenesis is not yet known, but unless these techniques are applied to appropriate clinical settings, this information will never be obtained. Therefore, what is routinely recorded clinically with scalp EEGs may be only the “tip of the iceberg.”

When discussing possible clinical trials to prevent epilepsy after a provocative stimulus, the duration of the treatment must be specified. This will partially depend on the nature of the treatment. A very benign treatment could be continued for a very long time, if necessary, whereas a potentially more toxic treatment may be administered for only a very short period of time. For example, if keeping the brain in a relatively quiescent state is needed to block epileptogenesis after a head injury, one can keep individuals in medically induced comas for days or weeks. This clearly carries risks, but the benefit may outweigh the risks. In most disease modifying paradigms, especially if one is using a symptomatic therapy, such as an antiseizure drug, one must demonstrate that even after cessation of therapy the positive effect persists and that the patients do not “catch up” to the placebo control–treated patients.

Finally, when considering any therapy to prevent epilepsy after a brain injury, one must determine whether such a therapy will inadvertently inhibit recovery of function from the injury. There is evidence from the trauma and ischemia literature, both in animal models and in human patients, that treatment with some antiseizure drugs, notably benzodiazepines and barbiturates, can result in a reduced recovery from the “injury” (Goldstein, 1998, 2003; Perna, 2006). This is not what one would want in an effective mechanism to prevent epilepsy.

Can Epilepsy Be Prevented?

  1. Top of page
  2. Summary
  3. Identifying the Problems
  4. Can Epilepsy Be Prevented?
  5. Recommendations for Translating Basic Discoveries in the Laboratory to a Pathway Toward a Cure for Posttraumatic Epilepsy
  6. Acknowledgments
  7. References

Is there any evidence that epilepsy can be prevented after its development is set in motion? First, it is a matter of faith on the author’s part that this is an achievable goal. Despite the pessimistic data in the literature to date, it is very likely that we are only scratching the surface of research efforts in this area. If one examines a graph of NINDS grant abstracts that contain the word “epileptogenesis” in their titles or key words, it can be seen that there is a dramatic increase in just the last few years! This is very encouraging, although it does remind us about how slow the field has been about catching on to this critical area of research.

Another way to emphasize this point is by examining data from the “Clinicaltrials.gov” website, which describes clinical trials listed for various neurologic disorders, most of which are less common than epilepsy. Note that there are only two clinical trials addressing antiepileptogenesis. Both are pilot clinical trials, one at Penn being conducted by Dr. Susan Herman and the author, and the other at a group of Washington, DC hospitals, being directed by Dr. Pavel Klein.

Is it possible to prevent epilepsy? There are several circumstances in which this has been accomplished. If one can pretreat experimental animals before provoking status epilepticus, both the status-induced damage and the subsequent epilepsy can be prevented. Similarly, if status is significantly shortened, epilepsy may be prevented or made more mild. Recently, a form of genetically determined epilepsy in WAG rats has been prevented by treatment before seizures developed (Blumenfeld et al., 2008). The WAG rats develop a primary generalized epilepsy as they mature. The seizures are controllable by ethosuximide. When the rats were treated with ethosuximide before they developed the spike–wave discharges, the seizures could be prevented, as well as some of the changes in sodium channel gene expression that is associated with the seizures. When the ethosuximide was withdrawn, many of the animals remained seizure-free for months. Maintaining the drug suppressed the seizures in essentially all of the animals. Among those rats that did have seizures, the duration was unchanged. Therefore, the treatment appeared to block seizure occurrence more than modify seizure phenotype.

Recommendations for Translating Basic Discoveries in the Laboratory to a Pathway Toward a Cure for Posttraumatic Epilepsy

  1. Top of page
  2. Summary
  3. Identifying the Problems
  4. Can Epilepsy Be Prevented?
  5. Recommendations for Translating Basic Discoveries in the Laboratory to a Pathway Toward a Cure for Posttraumatic Epilepsy
  6. Acknowledgments
  7. References

It is important to emphasize that clinical trials in antiepileptogenesis is a very difficult issue. There are numerous problems associated with studying epileptogenesis after TBI, as illustrated earlier. Simply determining when the experimental subjects are having seizures is a difficult issue. What is really needed is a mouse that can record seizures. Perhaps such a mouse can be developed with our powerful transgenic technologies!

There are many complex issues when considering protocols for clinical trials in epilepsy prevention after TBI. These include: (1) determining which patients to employ, for example, moderate to severe TBI [e.g., Glasgow coma scale (GCS) ≤12], blood in the brain or subdural hematoma (SDH), and depressed skull fracture; (2) how large a sample to use; (3) what agent to use; (4) how quickly to treat [e.g., hyperacute (hours), acute (1–3 days), subacute (>3 days), any time during “latent period”]; (5) what kind of EEG monitoring to employ, if any; (6) which end points to use; (7) how much follow-up; and (8) how much functional assessment during recovery is needed. There are a number of advantages, however, for starting pilot trials now and not waiting for a laboratory “breakthrough.” Early trials will provide experience with infrastructure, increased knowledge about the epidemiology of risk, the collection of biomarkers, the development of new tools, and will facilitate the establishment of network of experienced investigators who can capitalize on new developments that emerge from the laboratory. Clearly, this is going to be a long and complex program and will not benefit from short-term casual efforts.

Based on these considerations, a plan for developing research in this area and for allowing progress in antiepileptogenesis can be proposed. The initial program would involve creating a consortium of groups in trauma centers that are dedicated to antiepileptogenic studies, developing funding sources for long-term studies, being prepared with new protocols ready to roll out when old ones fail, attempting to make studies as cost-effective as possible, and continuous data mining of outcomes and surrogate markers. Of course, there would need to be an ongoing interaction with basic neuroscientists and the pharmaceutical industry to seek new treatment options.

In this context, the limitations of current technology to accomplish these goals must be acknowledged. Small, highly localized seizures and other electrophysiological events in deep structures cannot be monitored with surface EEGs. There is no current method for continuously monitoring EEGs over prolonged periods. In addition, there are no validated biomarkers for the process of epileptogenesis. Each of these limitations, however, can be overcome with currently available technology or with modest advances in current technology.

In the near future, it is likely that a clinical trial to prevent epilepsy after a TBI will proceed as follows (Fig. 1): An individual with moderate to severe traumatic brain injury has the injury attended to and then has small, safe electrodes implanted around the injured area. These would be connected to an intelligent device that is also implanted and can wirelessly transmit data to a receiver. The device would automatically monitor spikes, fast ripples, and subclinical microseizures, as well as anything else that is determined to be important in the epileptogenic process. The monitoring would occur continuously from the time of implantation. The patient would also be examined intermittently for imaging and biochemical biomarkers.

image

Figure 1.   A modest proposal for future antiepileptogenic studies.

Download figure to PowerPoint

The individual would begin treatment with whatever agent was deemed most appropriate, the results would be monitored, and the protocol would be constantly refined. With luck and good scientific input, it is hoped that future treatments would result in a seizure-free, functionally recovered patient!

Is this all science fiction, or idle fantasy, on the part of someone working in this field for more than 40 years? It doesn’t have to be. Nothing that has been discussed here requires major new scientific breakthroughs; there is nothing here that is not already being investigated at some level. Unfortunately, unless automobiles, guns, slippery patches of ice, wars, and human disputes are eliminated, the problem of posttraumatic epilepsy will not disappear. The disability experienced by patients with epilepsy is also not likely to disappear, unless a dramatically effective new therapy is discovered. Several features of this scheme to “cure” epilepsy by preventing it after a major risk factor, TBI, will require more scientific discoveries and some refinements of currently available technologies. What is mostly missing is the will to do this and the funding.

Acknowledgments

  1. Top of page
  2. Summary
  3. Identifying the Problems
  4. Can Epilepsy Be Prevented?
  5. Recommendations for Translating Basic Discoveries in the Laboratory to a Pathway Toward a Cure for Posttraumatic Epilepsy
  6. Acknowledgments
  7. References

Disclosure: MAD is on the Scientific Advisory Board of NeuroVista but does not receive any compensation for his activities to avoid the appearance of conflict of interest.

References

  1. Top of page
  2. Summary
  3. Identifying the Problems
  4. Can Epilepsy Be Prevented?
  5. Recommendations for Translating Basic Discoveries in the Laboratory to a Pathway Toward a Cure for Posttraumatic Epilepsy
  6. Acknowledgments
  7. References