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Epileptogenesis meets Occam's Razor
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ScienceDirect Epileptogenesis meets Occam’s Razor Robert S Sloviter Pharmacological treatment to prevent brain injury-induced temporal lobe epileptogenesis has been generally unsuccessful, raising the issues of exactly when the conversion process to an epileptic brain state occurs and reaches completion, and which cellular or network processes might be the most promising therapeutic targets. The time course of epileptogenesis is a central issue, with recent results suggesting that injury-induced epileptogenesis can be a much more rapid process than previously thought, and may be inconsistent with a delayed epileptogenic mechanism. Simplification of the seemingly complex issues involved in the use of epilepsy animal models might lead to a better understanding of the nature of injury-induced epileptogenesis, the significance of the ‘latent’ period, and whether current strategies should focus on preventing or modifying epilepsy. Address Departments of Neurobiology and Pharmacology/Toxicology, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA 30310, USA Corresponding author: Sloviter, Robert S ([email protected])
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Introduction Seizures occur when populations of neurons generate abnormally prolonged and synchronous discharges as a consequence of genetic influences, developmental anomalies, tumors, infections, toxins, sleep deprivation, hypoxia, metabolic disturbances, or brain injuries. Depending on the brain region involved, epileptiform discharges can produce sensory and motor manifestations, as well as changes in awareness, cognition, and other behaviors. Clinically subtle focal seizures occur when epileptiform discharges are spatially constrained, and more clinically obvious seizures occur if the discharges originate in or spread to motor pathways, or involve the neocortex bilaterally. If spontaneous seizures occur repeatedly, and are not associated with fever, sleep deprivation, hypoxia, or www.sciencedirect.com
any reversible pathophysiological or metabolic disturbance, the condition is ‘epilepsy’ [1,2], and the process that causes epilepsy to develop is called ‘epileptogenesis.’
Defining epileptogenesis as a prelude to understanding it Epileptogenesis is alternately defined to be either the initial and finite process that causes the brain to become ‘epileptic’ in the first place [3], or the sum of all processes that both initiate the epileptic state, and then influence its continuing evolution and progression over time [4–6]. Although much about epilepsy is debatable, it should be possible for all to agree that the word ‘genesis’ unambiguously describes the ‘beginning’ or ‘birth’ of something, and not an entity’s entire lifecycle or duration. The Book of Genesis is a story of the beginning; it is not the entire story. Thus, we define epileptogenesis, as discussed here, to be the initial process that causes epilepsy to develop, with any subsequent influences being different entities in need of a different name. And although the term ‘epileptogenesis’ is often discussed as though it is a specific unidentified mechanism, different epileptic states almost certainly involve different epileptogenic mechanisms. Thus, the term epileptogenesis is simply a general term for any process that causes any epileptic state to develop. If epileptogenesis describes the creation of a brain state with a propensity for generating seizures [2], it presumably does not require a first spontaneous clinical seizure, although clinical diagnosis of epilepsy presumably would. A patient with an unrecognized propensity for photosensitive seizures who has not yet encountered a strobe light of the right frequency, and therefore not yet had a first seizure, has nevertheless already undergone epileptogenesis, although for practical reasons it might be stipulated that epileptogenesis ends with the first seizure event that causes any abnormal behavior (i.e. perhaps an aura, at minimum). This is a complex semantic point because completion of epileptogenesis presumably creates an ‘epileptic network’ before a clinically detectable ‘epileptic state’ exists. Regardless, if epileptogenesis describes the process that causes an epileptic brain state to develop, we suggest the term ‘epileptometagenesis’ (‘meta’ meaning ‘what comes after’) to describe all processes that follow epileptogenesis, and influence the progression or modification of the already established epileptic state (Figure 1). ‘Epileptometagenesis’ replaces the previously suggested ‘epileptic maturation’ [3] because, unlike the growth of an organism, changes that occur in epilepsy are not necessarily a maturation process. ‘Metagenesis’ encompasses all that follows ‘genesis.’ Separate terms for the initial development of epilepsy and for all subsequent changes imply Current Opinion in Pharmacology 2017, 35:1–6
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Figure 1
Epileptogenic brain injury (two alternate hypotheses)
“Epileptogenesis” triggered
“Immediate epileptogenesis”
The “latent” period is a silent, pre-epileptic, gestational state of “epileptogenesis” initiated by brain injury. No subclinical or clinical seizures occur.
“Epileptogenesis” (literally the “birth” of epilepsy) ends with the first spontaneous and unnoticed epileptiform discharge causing abnormal behavior (e.g. an aura).
Onset of epilepsy as “epileptogenesis” reaches a developmental stage that causes the first spontaneous seizure.
“Epileptometagenesis” causes initially subtle focal seizures to become clinically obvious (perhaps via a “kindling” process)
“Epileptogenesis” continues to influence the progression of the established epileptic state throughout life.
“Epileptometagenesis” continues to influence the progression of the established epileptic state throughout life. Current Opinion in Pharmacology
Alternate concepts of ‘delayed’ vs. ‘immediate’ epileptogenesis, and the nature of the ‘latent’ period. Is the ‘latent’ period, when one exists, a seizure-free, pre-epileptic, ‘gestational’ state of epileptogenesis (left), or an immediately-produced subclinical, and frequently unrecognized, focal epileptic state (right) that simply takes time, sometimes decades [15], to cause the first clinically obvious seizures?
that ‘antiepileptogenic’ strategies designed to prevent epilepsy are distinct from ‘disease modification’ strategies designed to modify an already established epileptic state [3,7]. If epilepsy cannot be prevented, it would be beneficial to impede the therapeutically ‘epileptometagenesis’ process by which an initially subtle focal epileptic state becomes increasingly disruptive to a patient’s self-image and their ability to work and function in society.
Genesis of the notion that epileptogenesis involves a time-consuming secondary mechanism Exactly how brain injuries produce epilepsy is still conjectural, and a discussion of possible mechanisms of epileptogenesis is beyond the scope of this review. Generally, however, epileptic network behavior could result from periodic disinhibition/hyperexcitability due to neuron loss or dysfunction [8–11], a change in network excitability caused by the maturation of a delayed secondary epileptogenic process triggered by brain injury [12,13], or the periodic release of unidentified substances that cause transient hyperexcitability without necessarily involving injury, neuron loss, or structural reorganization. Given the plethora of possibilities, why does the prevailing view of epileptogenesis so overwhelmingly favor
involvement of a delayed secondary mechanism that other possibilities are virtually excluded from consideration or discussion? Timing is crucial in this regard. If neuronal or glial cell death or dysfunction, or any other immediate event, were the direct cause of epilepsy, seizures would be expected to start soon after brain injury [14]. The widespread notion of epileptogenesis as a prolonged ‘gestational’ process for an unidentified epileptogenic mechanism is based almost entirely on the clinical assumption that a prolonged and silent ‘latent’ period reliably follows brain injury [15], and that its duration reflects the time needed for the unidentified epileptogenic mechanism to develop [14,16,17]. This is important from a translational perspective because it implies the existence of an extended ‘therapeutic window of opportunity’ when epilepsy might be prevented by a drug that targets this slowly developing epileptogenic mechanism [18]. The concept of the ‘silent’ latent period apparently derives from the observations of Penfield and colleagues, who noted that, “Habitual seizures rarely, if ever, begin at the time of brain injury. There is a ripening period of months or years that follows the initial insult” [19], and that, “insults may result in epilepsy after a silent period of strange ripening. That period lasts for months or years . . . ” [20].
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Epileptogenesis after brain injury Sloviter 3
The notion that the latent period in patients is a silent gestational state of epileptogenesis, rather than a clinically subtle focal epileptic state, was reinforced by early anecdotal reports that spontaneous motor seizures were serendipitously observed months after kainate-induced status epilepticus (SE) in rats [21,22], and by studies using non-continuous monitoring methods that missed early seizures [23–28]. As a result, delayed processes such as mossy fiber sprouting [29] and neurogenesis [30,31] were suggested to be epileptogenic mechanisms, in part, because these processes were as delayed in animals as the onset of epilepsy was presumed to be [18]. Although the earliest animal studies cited above appeared to support the idea of a ‘silent’ latent period, more recent studies of rats monitored continuously after pilocarpineinduced SE have now shown that spontaneous seizures begin coincident with the initial injury [32,33,34], and are not delayed. Immediate epilepsy also follows electrical stimulation-induced convulsive SE [35], which eliminates the issue of residual chemoconvulsant as the cause of early seizures. Importantly, a study that involved continuous monitoring only on days 3 and 6 post-SE found that even after 1 h of convulsive SE, spontaneous clinical seizures began during the first days post-injury [36]. The issue of whether the earliest post-injury seizures are a manifestation of acute brain injury, rather than being the first spontaneous epileptic seizures, is an important one. It is unclear how to differentiate an early injury-associated seizure from the first ‘spontaneous’ epileptic seizure, and it is possible for early post-injury seizures to occur in isolation, and not be followed by spontaneous epileptic seizures [37]. We are specifically referring here to spontaneous seizures that begin and then continue to occur for as long as animals are monitored. Regardless, epilepsy develops coincident with the initial brain injury caused by convulsive SE in rats [35] and mice [38], as it can after prolonged convulsive SE in patients [39]. If prolonged convulsive SE involves no latency to clinical epilepsy [32,33,34,35,36–38,39,40,41], perhaps latent periods are caused by less severe brain injuries, such as non-convulsive SE [40]. Thus, the central question would seem to be: is the latent period, when one exists, a seizurefree, pre-epileptic ‘silent’ period, or a clinically subtle focal epileptic state? If the latent period is a clinically subtle focal epileptic state, support for the concepts of ‘delayed epileptogenesis’ and the anti-epileptogenic ‘therapeutic window’ would presumably collapse. Regardless, the many delayed processes that follow experimental brain injuries cannot be epileptogenic mechanisms in animals that develop clinical epilepsy before the secondary mechanisms have time to develop [41].
Applying Occam’s Razor to the concept of epileptogenesis Whether injury-induced temporal lobe epileptogenesis is a rapid or delayed process has important implications for www.sciencedirect.com
understanding the fundamental nature of this specific epileptogenic process, and for developing pharmacological strategies to prevent or modify it. Resolution of this issue requires an animal model with a latency to the first clinically obvious seizures if the ‘latent’ period is to be revealed as either a ‘silent’ seizure-free interval, or a prolonged interval of subclinical or subtle focal seizures that precedes the onset of clinically obvious seizures [40]. However, even if an extended latent period can be reliably produced in an animal model, and its nature revealed as either an ‘epileptic’ or ‘pre-epileptic’ state, we would still be faced with the challenge of determining which of the many changes caused by brain injury might mediate epileptogenesis, and whether any pharmacological intervention can prevent epilepsy after a potentially epileptogenic brain injury has been sustained. Prolonged convulsive SE and traumatic brain injuries cause excitotoxic and ischemic neuron loss, vascular and glial changes, increased neurogenesis, inflammation, blood/brain barrier breakdown, structural reorganization, epigenetic effects, altered receptor/channel expression, and a multitude of other molecular changes [12,13,42,43]. Which of the hundreds or thousands of changes that follow brain injury actually cause epilepsy? Is a unique combination of changes necessary for epilepsy to develop, or is a single epileptogenic mechanism initiated by a variety of brain injuries? If every newly identified effect of brain injury is going to be suggested to be the epileptogenic mechanism, and none of the many candidate mechanisms can be separated from the other parallel effects of brain injury, how can progress be made? When anything being studied has so many intertwined and inseparable facets, it is useful to consider using Occam’s Razor to cut through the complexity. We suggest that this approach might be effective in trying to understand epileptogenesis. In essence, William of Ockham’s perspective, called ‘nominalism’ (meaning ‘in name only’), addressed the 14th Century question of whether the ability to create names for ideas that exist within the mind (e.g. unicorns or ‘the future’) means that the entities named must have a real and independent existence outside the mind [44]. This became a pressing question because it had been asserted by influential authorities that the presence within the mind of the idea of God proved that God must exist. Ockham’s radical view that a name is just a name, and does not prove the existence of the entity that the name represents, was revolutionary and used to eliminate an accretion of imagined things. Ockham’s original thinking (denying the existence of non-existent things) caused friction with the Papal authorities. Although he was never officially condemned for heresy, Ockham was excommunicated in 1328 and fled Avignon for the safety of Bavaria, where he apparently died peacefully in April of 1347, six months before the arrival Current Opinion in Pharmacology 2017, 35:1–6
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in Sicily of the plague-infected rats that brought the Black Death to Europe. Ockham was officially rehabilitated by Pope Innocent VI in 1359, which permitted his ideas to survive and influence scientific thought during the Renaissance. Ockham’s perspective, as applied to science, states that you should not postulate the existence of entities, mechanisms, or processes without justification, and should not suggest an unnecessarily complex explanation when a simple one suffices [44]. If what originally seemed to be a silent period after brain injury is, in fact, only clinical silence, and focal epilepsy starts soon after injury [35], then there is no need to hypothesize the involvement of a delayed secondary mechanism in the initial epileptogenic process. A multitude of processes triggered by brain injury may affect the progression of the epileptic state, but the initial transformation from a normal to an epileptic brain state could simply be related to initial neuron loss or dysfunction, or other immediate changes. Since spontaneous granule cell-onset seizures may be coincident with initial neuron loss after convulsive or non-convulsive SE [3,35,38,40], there may be little justification for hypothesizing that delayed secondary mechanisms are necessary or likely epileptogenic mechanisms, at least in the animal models studied. If delayed secondary processes are going to continue to be claimed to be epileptogenic mechanisms, experiments should first show that seizures never occur before the candidate mechanism develops. Had this been done prior to suggesting mossy fiber sprouting as the primary cause of epilepsy [29], for example, a great deal of time and resources might have been spared. In addition, any pharmacological treatment that decreases the frequency or severity of spontaneous seizures without stopping them entirely is modifying the disorder, not preventing it. Since correlations fail to establish a causal relationship between any variable studied and ‘epileptogenesis,’ the solution to the complexity of the many parallel effects that brain injuries cause may involve a simpler approach. If, for example, seizure-induced dentate gyrus neuron loss or dysfunction is directly epileptogenic, as we have suggested [45], then selective elimination or silencing of the right neurons should produce granule cell-onset epilepsy without involving brain injury, tissue trauma, inflammation, blood/brain barrier breakdown, synaptic reorganization, neurogenesis, or any other injury-associated phenomenon. This has not yet been demonstrated. Similarly, if inflammation [46] or blood/brain barrier breakdown [47], for example, are epileptogenic mechanisms, rather than tangential or modulating influences, then inflammation alone, or blood/brain barrier breakdown alone, should produce a spontaneous epileptic state in vivo without involving an acute brain injury. Thus, progress might result from experiments specifically designed to demonstrate causality, rather than
correlation, because adding more circumstantial evidence to an existing body of circumstantial evidence does not strengthen the case for causality.
Conclusion The perspective presented here has significant implications for strategies designed to prevent the development of epilepsy, or to modify the disorder once established. If the time course of epileptogenesis is unknown, how can the optimal time of therapeutic intervention be rationally determined [48]? If the injury itself is epileptogenic, whether mediated by neuron loss or neuronal dysfunction, or other immediate changes, then the ‘therapeutic window’ may only be open for a brief period, as in stroke therapy, and pharmacological treatment in the weeks or months after brain injury would be predicted to fail, as some studies have found [49,50]. Conversely, if animal studies poorly reflect the human epileptogenic process, the latent period in humans could, in fact, be a silent ‘gestational’ state, as conceived by Penfield [19,20], although then it would have to be explained why prolonged convulsive SE in humans can produce epilepsy with no apparent latency [38]. We suggest that more extensive injuries cause clinical epilepsy without delay [35,39], whereas less extensive injuries cause an initially subtle focal epileptic state (during the latent period) that can eventually become a clinically obvious epileptic state [10,40]. If there are two distinct processes operating in both animals and humans, one a rapid process that causes the initial epileptic transformation (‘epileptogenesis’), and a second process or series of processes that influence the clinical features and refractoriness of the epileptic state over time (‘epileptometagenesis’), then preventing epileptogenesis may be more challenging than currently assumed, and strategies might more fruitfully focus on keeping focal seizures focal by interrupting or retarding epileptometagenesis, that is, the progressive worsening of the epileptic state when that occurs. It is now important to determine which of the many effects of brain injury mediate the initial process (epileptogenesis), which processes underlie subsequent modifications of the epileptic brain state (epileptometagenesis), and which effects of brain injury are epiphenomena mechanistically related to neither. Finally, it should be emphasized, in a discussion of complexity and simplicity as it applies to epileptogenesis, that although simplicity should be a default setting, it is also possible that epileptogenesis may involve significant complexity, with multiple cascades of mechanisms that can be targeted to prevent or reduce the severity of clinical epilepsy [12,13,51]. Determining exactly when epileptogenesis occurs in any given animal model is a crucial consideration for discriminating between possible epileptogenic and epileptometagenic mechanisms, and
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Epileptogenesis after brain injury Sloviter 5
determining which of the many effects of brain injury may not play significant roles in either process.
15. French JA, Williamson PD, Thadani VM, Darcey TM, Mattson RH, Spencer SS, Spencer DD: Characteristics of medial temporal lobe epilepsy: I. Results of history and physical examination. Ann Neurol 1993, 34:774-780.
Conflict of interest statement
16. Bragin A, Wilson CL, Engel J Jr: Chronic epileptogenesis requires development of a network of pathologically interconnected neuron clusters: a hypothesis. Epilepsia 2000, 41(Suppl. 6):S144-S152.
Nothing declared.
Acknowledgements I thank Drs. Argyle Bumanglag, Marc Dichter, David Henshall, Wolfgang Lo¨scher, and Robert Schwarcz for their insightful comments and constructive criticisms of earlier versions of the manuscript. Special thanks to Dr. Daniel Lowenstein for useful discussions, constructive criticism, and repeated editing of this work. Supported by NIH grant NS083932.
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ScienceDirect Epileptogenesis meets Occam’s Razor Robert S Sloviter Pharmacological treatment to prevent brain injury-induced temporal lobe epileptogenesis has been generally unsuccessful, raising the issues of exactly when the conversion process to an epileptic brain state occurs and reaches completion, and which cellular or network processes might be the most promising therapeutic targets. The time course of epileptogenesis is a central issue, with recent results suggesting that injury-induced epileptogenesis can be a much more rapid process than previously thought, and may be inconsistent with a delayed epileptogenic mechanism. Simplification of the seemingly complex issues involved in the use of epilepsy animal models might lead to a better understanding of the nature of injury-induced epileptogenesis, the significance of the ‘latent’ period, and whether current strategies should focus on preventing or modifying epilepsy. Address Departments of Neurobiology and Pharmacology/Toxicology, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA 30310, USA Corresponding author: Sloviter, Robert S ([email protected])
Current Opinion in Pharmacology 2017, 35:xx–yy This review comes from a themed issue on Tribute to Norman Bowery Edited by David G Trist and Tom Blackburn
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Introduction Seizures occur when populations of neurons generate abnormally prolonged and synchronous discharges as a consequence of genetic influences, developmental anomalies, tumors, infections, toxins, sleep deprivation, hypoxia, metabolic disturbances, or brain injuries. Depending on the brain region involved, epileptiform discharges can produce sensory and motor manifestations, as well as changes in awareness, cognition, and other behaviors. Clinically subtle focal seizures occur when epileptiform discharges are spatially constrained, and more clinically obvious seizures occur if the discharges originate in or spread to motor pathways, or involve the neocortex bilaterally. If spontaneous seizures occur repeatedly, and are not associated with fever, sleep deprivation, hypoxia, or www.sciencedirect.com
any reversible pathophysiological or metabolic disturbance, the condition is ‘epilepsy’ [1,2], and the process that causes epilepsy to develop is called ‘epileptogenesis.’
Defining epileptogenesis as a prelude to understanding it Epileptogenesis is alternately defined to be either the initial and finite process that causes the brain to become ‘epileptic’ in the first place [3], or the sum of all processes that both initiate the epileptic state, and then influence its continuing evolution and progression over time [4–6]. Although much about epilepsy is debatable, it should be possible for all to agree that the word ‘genesis’ unambiguously describes the ‘beginning’ or ‘birth’ of something, and not an entity’s entire lifecycle or duration. The Book of Genesis is a story of the beginning; it is not the entire story. Thus, we define epileptogenesis, as discussed here, to be the initial process that causes epilepsy to develop, with any subsequent influences being different entities in need of a different name. And although the term ‘epileptogenesis’ is often discussed as though it is a specific unidentified mechanism, different epileptic states almost certainly involve different epileptogenic mechanisms. Thus, the term epileptogenesis is simply a general term for any process that causes any epileptic state to develop. If epileptogenesis describes the creation of a brain state with a propensity for generating seizures [2], it presumably does not require a first spontaneous clinical seizure, although clinical diagnosis of epilepsy presumably would. A patient with an unrecognized propensity for photosensitive seizures who has not yet encountered a strobe light of the right frequency, and therefore not yet had a first seizure, has nevertheless already undergone epileptogenesis, although for practical reasons it might be stipulated that epileptogenesis ends with the first seizure event that causes any abnormal behavior (i.e. perhaps an aura, at minimum). This is a complex semantic point because completion of epileptogenesis presumably creates an ‘epileptic network’ before a clinically detectable ‘epileptic state’ exists. Regardless, if epileptogenesis describes the process that causes an epileptic brain state to develop, we suggest the term ‘epileptometagenesis’ (‘meta’ meaning ‘what comes after’) to describe all processes that follow epileptogenesis, and influence the progression or modification of the already established epileptic state (Figure 1). ‘Epileptometagenesis’ replaces the previously suggested ‘epileptic maturation’ [3] because, unlike the growth of an organism, changes that occur in epilepsy are not necessarily a maturation process. ‘Metagenesis’ encompasses all that follows ‘genesis.’ Separate terms for the initial development of epilepsy and for all subsequent changes imply Current Opinion in Pharmacology 2017, 35:1–6
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Figure 1
Epileptogenic brain injury (two alternate hypotheses)
“Epileptogenesis” triggered
“Immediate epileptogenesis”
The “latent” period is a silent, pre-epileptic, gestational state of “epileptogenesis” initiated by brain injury. No subclinical or clinical seizures occur.
“Epileptogenesis” (literally the “birth” of epilepsy) ends with the first spontaneous and unnoticed epileptiform discharge causing abnormal behavior (e.g. an aura).
Onset of epilepsy as “epileptogenesis” reaches a developmental stage that causes the first spontaneous seizure.
“Epileptometagenesis” causes initially subtle focal seizures to become clinically obvious (perhaps via a “kindling” process)
“Epileptogenesis” continues to influence the progression of the established epileptic state throughout life.
“Epileptometagenesis” continues to influence the progression of the established epileptic state throughout life. Current Opinion in Pharmacology
Alternate concepts of ‘delayed’ vs. ‘immediate’ epileptogenesis, and the nature of the ‘latent’ period. Is the ‘latent’ period, when one exists, a seizure-free, pre-epileptic, ‘gestational’ state of epileptogenesis (left), or an immediately-produced subclinical, and frequently unrecognized, focal epileptic state (right) that simply takes time, sometimes decades [15], to cause the first clinically obvious seizures?
that ‘antiepileptogenic’ strategies designed to prevent epilepsy are distinct from ‘disease modification’ strategies designed to modify an already established epileptic state [3,7]. If epilepsy cannot be prevented, it would be beneficial to impede the therapeutically ‘epileptometagenesis’ process by which an initially subtle focal epileptic state becomes increasingly disruptive to a patient’s self-image and their ability to work and function in society.
Genesis of the notion that epileptogenesis involves a time-consuming secondary mechanism Exactly how brain injuries produce epilepsy is still conjectural, and a discussion of possible mechanisms of epileptogenesis is beyond the scope of this review. Generally, however, epileptic network behavior could result from periodic disinhibition/hyperexcitability due to neuron loss or dysfunction [8–11], a change in network excitability caused by the maturation of a delayed secondary epileptogenic process triggered by brain injury [12,13], or the periodic release of unidentified substances that cause transient hyperexcitability without necessarily involving injury, neuron loss, or structural reorganization. Given the plethora of possibilities, why does the prevailing view of epileptogenesis so overwhelmingly favor
involvement of a delayed secondary mechanism that other possibilities are virtually excluded from consideration or discussion? Timing is crucial in this regard. If neuronal or glial cell death or dysfunction, or any other immediate event, were the direct cause of epilepsy, seizures would be expected to start soon after brain injury [14]. The widespread notion of epileptogenesis as a prolonged ‘gestational’ process for an unidentified epileptogenic mechanism is based almost entirely on the clinical assumption that a prolonged and silent ‘latent’ period reliably follows brain injury [15], and that its duration reflects the time needed for the unidentified epileptogenic mechanism to develop [14,16,17]. This is important from a translational perspective because it implies the existence of an extended ‘therapeutic window of opportunity’ when epilepsy might be prevented by a drug that targets this slowly developing epileptogenic mechanism [18]. The concept of the ‘silent’ latent period apparently derives from the observations of Penfield and colleagues, who noted that, “Habitual seizures rarely, if ever, begin at the time of brain injury. There is a ripening period of months or years that follows the initial insult” [19], and that, “insults may result in epilepsy after a silent period of strange ripening. That period lasts for months or years . . . ” [20].
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The notion that the latent period in patients is a silent gestational state of epileptogenesis, rather than a clinically subtle focal epileptic state, was reinforced by early anecdotal reports that spontaneous motor seizures were serendipitously observed months after kainate-induced status epilepticus (SE) in rats [21,22], and by studies using non-continuous monitoring methods that missed early seizures [23–28]. As a result, delayed processes such as mossy fiber sprouting [29] and neurogenesis [30,31] were suggested to be epileptogenic mechanisms, in part, because these processes were as delayed in animals as the onset of epilepsy was presumed to be [18]. Although the earliest animal studies cited above appeared to support the idea of a ‘silent’ latent period, more recent studies of rats monitored continuously after pilocarpineinduced SE have now shown that spontaneous seizures begin coincident with the initial injury [32,33,34], and are not delayed. Immediate epilepsy also follows electrical stimulation-induced convulsive SE [35], which eliminates the issue of residual chemoconvulsant as the cause of early seizures. Importantly, a study that involved continuous monitoring only on days 3 and 6 post-SE found that even after 1 h of convulsive SE, spontaneous clinical seizures began during the first days post-injury [36]. The issue of whether the earliest post-injury seizures are a manifestation of acute brain injury, rather than being the first spontaneous epileptic seizures, is an important one. It is unclear how to differentiate an early injury-associated seizure from the first ‘spontaneous’ epileptic seizure, and it is possible for early post-injury seizures to occur in isolation, and not be followed by spontaneous epileptic seizures [37]. We are specifically referring here to spontaneous seizures that begin and then continue to occur for as long as animals are monitored. Regardless, epilepsy develops coincident with the initial brain injury caused by convulsive SE in rats [35] and mice [38], as it can after prolonged convulsive SE in patients [39]. If prolonged convulsive SE involves no latency to clinical epilepsy [32,33,34,35,36–38,39,40,41], perhaps latent periods are caused by less severe brain injuries, such as non-convulsive SE [40]. Thus, the central question would seem to be: is the latent period, when one exists, a seizurefree, pre-epileptic ‘silent’ period, or a clinically subtle focal epileptic state? If the latent period is a clinically subtle focal epileptic state, support for the concepts of ‘delayed epileptogenesis’ and the anti-epileptogenic ‘therapeutic window’ would presumably collapse. Regardless, the many delayed processes that follow experimental brain injuries cannot be epileptogenic mechanisms in animals that develop clinical epilepsy before the secondary mechanisms have time to develop [41].
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understanding the fundamental nature of this specific epileptogenic process, and for developing pharmacological strategies to prevent or modify it. Resolution of this issue requires an animal model with a latency to the first clinically obvious seizures if the ‘latent’ period is to be revealed as either a ‘silent’ seizure-free interval, or a prolonged interval of subclinical or subtle focal seizures that precedes the onset of clinically obvious seizures [40]. However, even if an extended latent period can be reliably produced in an animal model, and its nature revealed as either an ‘epileptic’ or ‘pre-epileptic’ state, we would still be faced with the challenge of determining which of the many changes caused by brain injury might mediate epileptogenesis, and whether any pharmacological intervention can prevent epilepsy after a potentially epileptogenic brain injury has been sustained. Prolonged convulsive SE and traumatic brain injuries cause excitotoxic and ischemic neuron loss, vascular and glial changes, increased neurogenesis, inflammation, blood/brain barrier breakdown, structural reorganization, epigenetic effects, altered receptor/channel expression, and a multitude of other molecular changes [12,13,42,43]. Which of the hundreds or thousands of changes that follow brain injury actually cause epilepsy? Is a unique combination of changes necessary for epilepsy to develop, or is a single epileptogenic mechanism initiated by a variety of brain injuries? If every newly identified effect of brain injury is going to be suggested to be the epileptogenic mechanism, and none of the many candidate mechanisms can be separated from the other parallel effects of brain injury, how can progress be made? When anything being studied has so many intertwined and inseparable facets, it is useful to consider using Occam’s Razor to cut through the complexity. We suggest that this approach might be effective in trying to understand epileptogenesis. In essence, William of Ockham’s perspective, called ‘nominalism’ (meaning ‘in name only’), addressed the 14th Century question of whether the ability to create names for ideas that exist within the mind (e.g. unicorns or ‘the future’) means that the entities named must have a real and independent existence outside the mind [44]. This became a pressing question because it had been asserted by influential authorities that the presence within the mind of the idea of God proved that God must exist. Ockham’s radical view that a name is just a name, and does not prove the existence of the entity that the name represents, was revolutionary and used to eliminate an accretion of imagined things. Ockham’s original thinking (denying the existence of non-existent things) caused friction with the Papal authorities. Although he was never officially condemned for heresy, Ockham was excommunicated in 1328 and fled Avignon for the safety of Bavaria, where he apparently died peacefully in April of 1347, six months before the arrival Current Opinion in Pharmacology 2017, 35:1–6
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in Sicily of the plague-infected rats that brought the Black Death to Europe. Ockham was officially rehabilitated by Pope Innocent VI in 1359, which permitted his ideas to survive and influence scientific thought during the Renaissance. Ockham’s perspective, as applied to science, states that you should not postulate the existence of entities, mechanisms, or processes without justification, and should not suggest an unnecessarily complex explanation when a simple one suffices [44]. If what originally seemed to be a silent period after brain injury is, in fact, only clinical silence, and focal epilepsy starts soon after injury [35], then there is no need to hypothesize the involvement of a delayed secondary mechanism in the initial epileptogenic process. A multitude of processes triggered by brain injury may affect the progression of the epileptic state, but the initial transformation from a normal to an epileptic brain state could simply be related to initial neuron loss or dysfunction, or other immediate changes. Since spontaneous granule cell-onset seizures may be coincident with initial neuron loss after convulsive or non-convulsive SE [3,35,38,40], there may be little justification for hypothesizing that delayed secondary mechanisms are necessary or likely epileptogenic mechanisms, at least in the animal models studied. If delayed secondary processes are going to continue to be claimed to be epileptogenic mechanisms, experiments should first show that seizures never occur before the candidate mechanism develops. Had this been done prior to suggesting mossy fiber sprouting as the primary cause of epilepsy [29], for example, a great deal of time and resources might have been spared. In addition, any pharmacological treatment that decreases the frequency or severity of spontaneous seizures without stopping them entirely is modifying the disorder, not preventing it. Since correlations fail to establish a causal relationship between any variable studied and ‘epileptogenesis,’ the solution to the complexity of the many parallel effects that brain injuries cause may involve a simpler approach. If, for example, seizure-induced dentate gyrus neuron loss or dysfunction is directly epileptogenic, as we have suggested [45], then selective elimination or silencing of the right neurons should produce granule cell-onset epilepsy without involving brain injury, tissue trauma, inflammation, blood/brain barrier breakdown, synaptic reorganization, neurogenesis, or any other injury-associated phenomenon. This has not yet been demonstrated. Similarly, if inflammation [46] or blood/brain barrier breakdown [47], for example, are epileptogenic mechanisms, rather than tangential or modulating influences, then inflammation alone, or blood/brain barrier breakdown alone, should produce a spontaneous epileptic state in vivo without involving an acute brain injury. Thus, progress might result from experiments specifically designed to demonstrate causality, rather than
correlation, because adding more circumstantial evidence to an existing body of circumstantial evidence does not strengthen the case for causality.
Conclusion The perspective presented here has significant implications for strategies designed to prevent the development of epilepsy, or to modify the disorder once established. If the time course of epileptogenesis is unknown, how can the optimal time of therapeutic intervention be rationally determined [48]? If the injury itself is epileptogenic, whether mediated by neuron loss or neuronal dysfunction, or other immediate changes, then the ‘therapeutic window’ may only be open for a brief period, as in stroke therapy, and pharmacological treatment in the weeks or months after brain injury would be predicted to fail, as some studies have found [49,50]. Conversely, if animal studies poorly reflect the human epileptogenic process, the latent period in humans could, in fact, be a silent ‘gestational’ state, as conceived by Penfield [19,20], although then it would have to be explained why prolonged convulsive SE in humans can produce epilepsy with no apparent latency [38]. We suggest that more extensive injuries cause clinical epilepsy without delay [35,39], whereas less extensive injuries cause an initially subtle focal epileptic state (during the latent period) that can eventually become a clinically obvious epileptic state [10,40]. If there are two distinct processes operating in both animals and humans, one a rapid process that causes the initial epileptic transformation (‘epileptogenesis’), and a second process or series of processes that influence the clinical features and refractoriness of the epileptic state over time (‘epileptometagenesis’), then preventing epileptogenesis may be more challenging than currently assumed, and strategies might more fruitfully focus on keeping focal seizures focal by interrupting or retarding epileptometagenesis, that is, the progressive worsening of the epileptic state when that occurs. It is now important to determine which of the many effects of brain injury mediate the initial process (epileptogenesis), which processes underlie subsequent modifications of the epileptic brain state (epileptometagenesis), and which effects of brain injury are epiphenomena mechanistically related to neither. Finally, it should be emphasized, in a discussion of complexity and simplicity as it applies to epileptogenesis, that although simplicity should be a default setting, it is also possible that epileptogenesis may involve significant complexity, with multiple cascades of mechanisms that can be targeted to prevent or reduce the severity of clinical epilepsy [12,13,51]. Determining exactly when epileptogenesis occurs in any given animal model is a crucial consideration for discriminating between possible epileptogenic and epileptometagenic mechanisms, and
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determining which of the many effects of brain injury may not play significant roles in either process.
15. French JA, Williamson PD, Thadani VM, Darcey TM, Mattson RH, Spencer SS, Spencer DD: Characteristics of medial temporal lobe epilepsy: I. Results of history and physical examination. Ann Neurol 1993, 34:774-780.
Conflict of interest statement
16. Bragin A, Wilson CL, Engel J Jr: Chronic epileptogenesis requires development of a network of pathologically interconnected neuron clusters: a hypothesis. Epilepsia 2000, 41(Suppl. 6):S144-S152.
Nothing declared.
Acknowledgements I thank Drs. Argyle Bumanglag, Marc Dichter, David Henshall, Wolfgang Lo¨scher, and Robert Schwarcz for their insightful comments and constructive criticisms of earlier versions of the manuscript. Special thanks to Dr. Daniel Lowenstein for useful discussions, constructive criticism, and repeated editing of this work. Supported by NIH grant NS083932.
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