Articles and Publications
The Fluid Percussion Model: An Interview with Dr. Raimondo D'Ambrosio
Q: "You’ve just recently been awarded a translational research grant by The Epilepsy Project to explore a new model of epileptogenesis and pharmacoresistant epilepsy. Can you explain the main goal of this study?"
A: "The goal of this study is to begin the validation of a recently developed model of posttraumatic epilepsy in the rat that reproduces many of the features of human posttraumatic epilepsy (PTE). The development of a clinically-relevant model of epilepsy would be an invaluable tool in epilepsy research because it would enable us to investigate the mechanisms of human epileptogenesis, to screen for better antiepileptic drugs and the first antiepileptogenics, and to optimize the design of clinical trials aimed at assessing their effects on patients. All of these efforts currently suffer from the lack of an adequate and validated animal model of acquired epilepsy."
Q: "Can you explain how your model of posttraumatic epilepsy (PTE) differs from the more traditional animal models such as the kindling model?"
A: "This model represents a significant departure from previous models of acquired epilepsy because the initiating insult, a transient compression of the dura mater without penetration, is mechanically very similar to human cases of concussive closed head injury, which may result in complex partial seizures that are resistant to treatment with AEDs. Therefore, fluid percussion injury (FPI)-induced epilepsy is not dependent on the presence of chronic or clinically less relevant stimuli that provide the bases for neurotoxicant- and kindling-based models. Animals just become epileptic after a simple hit on the head, like humans. Because of the simplicity of the model and its similarity to the human condition, we believe it is more likely that the epileptogenic mechanisms recruited by FPI are closer, if not identical, to the ones involved in human posttraumatic epileptogenesis. Indeed, FPI-induced PTE possesses many of the features desirable in an “ideal” animal model for the study of epileptogenesis and pharmacoresistant epilepsy. For example, FPI induces partial-onset seizures that evolve both temporally and spatially as in human cases of acquired epilepsy. The seizures we observed thus far are strikingly similar, in their electrographic and behavioral appearances, to human cases of non-convulsive partial epilepsy, as indeed expected in many cases of human posttraumatic pharmacoresistant epilepsy.
It should be stressed that, contrary to popular belief, the biggest problem in pharmacoresistant epilepsy is complex partial seizures, which may have little no or convulsive component to them, and not the easily recognizable tonic-clonic convulsive seizure which, despite their dramatic behavioral manifestations, can usually be controlled by currently available drugs.
Also of importance is that FPI-induced PTE presents a "seizure-free” latent period between the initiating injury and the onset of epilepsy. In addition, a dramatic progression in seizure type, frequency, and duration have been observed over time after injury.
To the best of our knowledge, of all the models of seizures or acquired epilepsy currently being used to screen for antiepileptic drugs, FPI-induced epilepsy ranks the highest in an ideal “scale of similarity” to the human condition. Moreover, with the FPI-induced epilepsy model clinicians and basic scientists will be able to probe and identify mechanisms of acquired epileptogenesis that are closer, if not identical, to those occurring in humans after injury to the brain.
Of course, this does not mean that other models are not, or have not, been useful. On the contrary, models such as the maximal electroshock, which is not a model of epilepsy but of seizures, has led to the discovery of antiepileptic action of phenytoin, a molecule that has done a lot of good to a lot of people. Similarly, other models such as kindling and subcutaneous injection of neurotoxicants have paved the way to the introduction of newer and better AEDs. However, at the present time, and despite the development of several new AEDs in recent years, one third of all epilepsy patients still suffer from pharmacoresistant seizures. This harsh reality compels us to improve our investigative tools in the quest for a cure. We believe that, in order to move forward and identify new therapeutic interventions able to either control epilepsy currently considered pharmacoresistant, or cure it, a clinically relevant model of acquired epilepsy is not only a valuable tool, it is an irreplaceable one."
Q: "How will this model potentially help human beings with pharmacoresistant epilepsy?"
A: "The new model may be able to serve epileptic patients in several ways. First, if and when it is standardized and optimized, it could be used to identify novel antiepileptic drugs and possibly the first antiepileptogenic drugs. We estimate that, once the model has been optimized, a single trained technician will be able to test, with proper tools and equipment, more than 200 AEDs per year. This would not be a high-throughput screening tool but, when used to identify classes of drugs with antiepileptogenic action, it will be a useful add-on tool to complement current high-throughput screening. Second, the model could serve as a tool to optimize clinical trials because it will help define the appropriate doses, and temporal windows at which to conduct it. Finally, the model could help in identifying novel therapeutic targets at the cellular level, and therefore lead to a better understanding of the mechanisms of epilepsy and to new-concept drugs."
Q: "What expectations, if any, do you have of the outcome from this study?"
A: "Independently from the specific results of the experiments we are conducting with The Epilepsy Project, we expect this work will give us a better understanding of the properties of FPI-induced electrical and behavioral seizures, and as a result enable us to optimize detection of these seizures. Furthermore, this work will begin to show us the location of the epileptic foci, the localization of which is a mandatory first step before attempting interventional studies."
Q: "When do you expect the results from your study will be available?"
A:"Part of the results of this study are available in a recent publication of the journal Brain. In this work we were able to identify the existence of at least two epileptic foci, one in the frontal lobe and one in the hippocampus. Further work is now ongoing to identify their exact location, and the possible existence of a third epileptic focus developing at later times post-injury. We are also determining whether different locations of injury affect the epileptic syndrome, which is a piece of information that helps figuring out the underlying mechanisms and also helps standardizing the model. If everything works out as expected, these results may become available next year. The work already conducted demonstrates that FPI-induced epilepsy is a progressive disorder. Its progression manifests as the increase in frequency, duration, and underlying pathology of partial-onset seizures over time post-injury. This is an exciting result that offers the opportunity, for the first time, to tackle the problem not just of the onset of epilepsy but, more generally, of its progression once it has appeared. In fact, one of the important studies to do in the near future will be the identification of a drug that either prevents posttraumatic epileptogenesis altogether or that, at least, prevents the progression of PTE. Disease-modifying drugs like these would also have a notable impact on the quality of life of posttraumatic epileptic patients."
Q: "What is your opinion regarding the theory that seizures themselves are a way that the brain copes with injury and recovery?"
A: "This is a serious possibility that finds its ground in some clinical and experimental observation, but has not been extensively investigated as yet. The mechanisms that may underlie a functional impairment following seizure-control in an injured brain are not known. The data already available are, however, sufficient to compel preclinical screening of antiepileptogenic drugs to include functional tests, just as neuroprotection studies already routinely do. FPI has been used extensively by the neurotrauma community as a model to investigate neuroprotection and functional recovery following head injury. Therefore, FPI-induced posttraumatic epilepsy presents itself as an ideal animal model to understand the mechanisms of post-injury morbidity - whether caused or not by seizure control - and to design therapies to minimize them."
Raimondo D'Ambrosio, Ph.D.is Associate Professor,Department of Neurological Surgery,Graduate Program in Neurobiology and Behavior at the University of Washington, Seattle. For more information regarding his research please visit: http://depts.washington.edu/neurosur/research/d_ambrosio.html
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