Drugs DOI 10.1007/s40265-015-0395-9

REVIEW ARTICLE

Disease Modification in Epilepsy: From Animal Models to Clinical Applications Melissa L. Barker-Haliski1 • Dan Friedman2 • Jacqueline A. French2 H. Steve White1



Ó Springer International Publishing Switzerland 2015

Abstract Several relevant animal models of epileptogenesis and biomarkers have emerged for evaluating the antiepileptogenic potential of an investigational drug. Although several promising candidate compounds and approaches have been identified in these preclinical models, no treatment has yet successfully navigated the path from preclinical efficacy to clinical validation. Until such an agent can move from preclinical proof of concept to clinical success, the need remains to continually develop and optimize preclinical models and clinical trial design in an effort to guide potential clinical investigations. This review describes several available models of disease modification and/or epileptogenesis, preclinical studies in these models and potential biomarkers useful for evaluating the efficacy of a potential therapeutic agent in the preclinical setting. The results that emerge from such efforts may then guide the clinical evaluation of a candidate compound. This review discusses some of the known limitations and hurdles to moving compounds found effective in these models to clinical practice, in the hope that knowledge of this information will facilitate the design and conduct of clinical studies and effectively facilitate the identification of a first-in-class disease-modifying or antiepileptogenic agent.

& Melissa L. Barker-Haliski [email protected] 1

Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology, University of Utah, 417 Wakara Way, Suite 3211, Salt Lake City, UT 84108, USA

2

Comprehensive Epilepsy Center, Department of Neurology, NYU Langone School of Medicine, New York, NY 10016, USA

Key Points Numerous animal models of epileptogenesis exist that recapitulate many aspects of the clinical pathophysiology of epilepsy; however, no one model has yet identified a clinically validated antiepileptogenic agent. Biomarkers of the disease process are essential to inform preclinical and clinical testing strategies. Optimizing animal models and biomarkers may improve the likelihood of a positive clinical outcome in the design and conduct of clinical disease modification and antiepileptogenesis studies.

1 Introduction Although there are over 20 antiseizure drugs (ASDs) currently available to the patient with epilepsy, to date there are no approved treatments that can prevent epileptogenesis [1, 2]. This is not to say that the numerous animal models utilized in the search for novel pharmacotherapies for epilepsy are without use. In fact, the use of various seizure and epilepsy animal models has resulted in numerous clinically useful therapies for the patient with epilepsy [3]. Moreover, one novel treatment for the treatment of epileptic dogs has emerged from the use of these preclinical models [4–6]. For the person with epilepsy, the existing animal models have provided numerous treatments for symptomatic management of their disease, greatly improving quality of life for many individuals. Improving on

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the existing animal models may provide further benefit to the patient with epilepsy. The challenge now is to identify and develop relevant animal models of the disease process that may facilitate the identification of a disease-modifying, or even antiepileptogenic, therapy. Approximately 40 % of epilepsy results from a known brain insult (stroke, infection, tumour, head trauma) and therefore could potentially be prevented [7]. These are the patients who could potentially benefit if an antiepileptogenic treatment could be identified. Studies of potential antiepileptogenic agents have been performed in clinical practice, most notably in patients who have experienced traumatic brain injury (TBI) [8]. To date, these trials have not demonstrated efficacy of any tested compound; additionally, the burden of adverse side effects of the selected drugs substantially outweighed any potential benefit. For these reasons, further study of these drugs was abandoned [8–10]. These studies, while ground-breaking, also demonstrated that studies of antiepileptogenic agents may be plagued by slow and difficult enrolment of eligible patients [11]. In short, the design and conduct of even a welldesigned study to assess disease modification and/or antiepileptogenesis is difficult [12, 13]. Development of preclinical models that would aid in the identification of disease-modifying and antiepileptogenic compounds in at-risk individuals would be of high clinical value to the patient [1, 14–16]. Unfortunately, many of the etiologically relevant animal models (e.g. those that recapitulate most of the clinical pathophysiology) are hampered by the fact that not all animals receiving a precipitating injury will develop epilepsy [17]. A high disease incidence would clearly facilitate the drug discovery process. Thus, studies designed to definitively demonstrate a diseasemodifying or antiepileptogenic effect would benefit from a model where a sufficient number of the injured population developed spontaneous recurrent seizures (SRS). An ideal preclinical model of epileptogenesis should demonstrate many of the characteristics associated with human epilepsy, including seizure-induced cell death, subsequent cognitive impairment and/or other behavioural comorbidities [18]. The epilepsy research community should hold as a primary goal the identification, characterization and optimization of these models for rigorous preclinical evaluation of investigational drugs. Antiepileptogenesis, disease modification and/or comorbidity modification are all potential outcome measures for a preclinical epilepsy study [19]. Epileptogenesis has been exquisitely defined as ‘‘the development and extension of tissue capable of generating spontaneous seizures, resulting in (1) development of an epileptic condition and/ or (2) progression after the condition is established’’ [19]. On the other hand, disease modification suggests the ability

to modify the severity of seizures, when and if they do occur, as well as the ability to alter sensitivity to traditional ASDs and the onset of associated comorbidities [19]. It is generally accepted in the epilepsy research community that etiologically relevant animal models of epileptogenesis and disease modification should thus consist of (adapted from [1]): 1.

2.

3.

A latent phase of varying length following a central nervous system (CNS) insult known to induce epilepsy in humans (i.e. status epilepticus [SE], TBI, stroke, brain tumour or viral meningitis) Onset of behavioural and physiological characteristics classically associated with human epilepsy, including neurodegeneration, neuroinflammation and cognitive disruption High likelihood of development of SRS

Given the plethora of ASDs that manage the symptomatic seizures associated with epilepsy, the challenge for both basic and clinical scientists is to appropriately and rigorously use this clinical knowledge to develop the most useful preclinical models of epileptogenesis and thus bring more preventative therapies to patients at risk of epilepsy. The duration of the latent phase can be utilized as an outcome measure to potentially identify disease-modifying therapies that would be deployed at the point of a CNS insult or shortly thereafter; i.e. during the latent phase (Fig. 1). An agent that prolongs the latent period may be disease modifying in that it alters the normal course of the disease process. The modification of behavioural or physiological end points can be utilized as an outcome measure to identify agents that may minimize behavioural or physiological alterations associated with disease progression. Lastly, the most heavily sought-after outcome of drug development for antiepileptogenesis is prevention of SRS, and that would be a necessary property of an antiepileptogenic agent. As such, animal models that can appropriately model one or more of the above characteristics would play an important role in the search for a disease-modifying or antiepileptogenic agent. This review focuses on some of the models of epileptogenesis/disease modification and discusses the utility of such models in identifying promising agents for subsequent evaluation. The use, relevance and limitations of biomarkers of disease progression for therapy discovery are also discussed. Finally, we discuss the preclinical data considered important when advancing a compound to a clinical trial and the limitations of such a trial. Ultimately, the goal of any model-validation effort should be translation of a promising first-in-class antiepileptogenesis therapy to the patient at risk of developing epilepsy.

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Fig. 1 Animal models of epileptogenesis and disease modification are valuable to model the process by which human patients may develop epilepsy, so as to direct therapy development efforts. Therapeutic intervention approaches should thus also model the process by which human patients may receive therapeutic benefit. These therapeutic intervention approaches can be broken down into three potential scenarios, with all scenarios attempting to minimize spontaneous recurrent seizures, comorbidities of epilepsy and neuroinflammation. a The first scenario is insult (whether genetic or idiopathic) modification. This specifically includes administration of a therapy that may minimize the neurological insult known to induce epileptogenesis, e.g. reducing time in status epilepticus. b The second potential scenario is administration of a therapy during the latent phase following a neurological insult and prior to the onset of overt symptoms associated with epilepsy, e.g. post-insult days after status epilepticus onset. c The third potential scenario is administration of a therapy after overt symptoms have developed, e.g. post-symptom. This final scenario represents the most clinically relevant scenario, as it requires the least information for patient enrolment and selection in a potential clinical trial situation

2 Animal Models of Epileptogenesis and Disease Modification As detailed above, the ideal disease-modifying or antiepileptogenic treatment is likely to be first identified in a relevant and validated animal model of epileptogenesis. This could include models of acquired or genetic epilepsy,

or even a model that displays chronic hyperexcitability. Importantly, such a model should provide several windows of opportunity in which a treatment can be administered and an effect observed [11]. As discussed below (see Fig. 1), there are three typical scenarios that can be modelled in animals to address the impact of treatment on clinical outcome. The first scenario that is probably the easiest to address is as follows: does early treatment exert an insult-modifying effect, and does such an effect modify the onset of disease (see Fig. 1a)? Importantly, insult modification may be a useful strategy to minimize the risk of subsequent development of disease. A good example is a treatment that reduces the severity or duration of SE and is associated with reduced seizure burden and comorbidities [20–22]. Some do not consider this antiepileptogenesis, particularly when the insult consists of seizure activity or SE and the intervention is an ASD, but the result is the same—namely, prevention or a reduction in the severity of the disease state. Insult modification is more difficult when the insult occurs outside the hospital setting (e.g. TBI). In this case, it is important to determine in an animal model the window of opportunity for treatment success (i.e. before, during or slightly after the insult). The second scenario that can be modelled in animals is administration of a treatment during the latent phase, i.e. post-insult and before the onset of disease, such as days to weeks after a moderate–severe TBI (see Fig. 1b) [11]. In this situation, a population or individual at risk could be treated in an attempt to prevent disease onset. This, understandably, represents a very clinically realistic scenario for therapeutic intervention, as epidemiological studies would suggest that patients at risk of developing acquired epilepsy are more easily identified [23]. For example, a child presenting to the emergency department with febrile SE may be at greater risk of subsequent development of epilepsy [24]. Such a patient may make a good candidate for a potential therapeutic intervention study designed to prevent development of epilepsy or to mitigate the longterm seizure burden and comorbidities associated with epilepsy [11]. This is a very frequently utilized treatment scenario, and much preclinical work has also demonstrated a potential window of opportunity for therapeutic intervention [23]. However, even when there may be reason to suspect that a known risk factor will lead to the onset of symptoms, there are issues with treatment at this stage. Just as in animal models, an insult in humans rarely leads to disease in 100 % of patients experiencing the insult; in fact, for most insults, the number who develop epilepsy is substantially less than 50 %. It is often difficult to convince the affected individual to take a medication to prevent a disease they may never experience even without the intervention.

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A third scenario that can be tested using animal models is evaluation of the effects of treatment on disease symptoms and comorbidities when therapies are administered after overt symptoms (i.e. seizures and comorbidities) emerge (see Fig. 1c). This is by far the most widely applicable clinical scenario, yet it is the most difficult to evaluate at the preclinical and clinical stages, because treatment will almost necessarily have to be continued for prolonged periods of time, i.e. months in rodents and years in humans. The outcome measures to be evaluated will most likely include estimates of disease progression, which include seizure burden, cognitive function and/or other neuropsychological measures, as well as pharmacosensitivity status. 2.1 Chronic Seizure and Epilepsy Models Kindling is a well-established experimental model of focal seizures evolving to secondarily generalized seizures wherein the stimulation of a limbic brain structure that is initially nonconvulsive becomes convulsive with repeated stimulations [25]. In addition to increased network hyperexcitability, kindled animals demonstrate much of the neuronal pathophysiology observed in patients with epilepsy, including neurodegeneration [26, 27] and reactive gliosis [28–30]. Kindled seizure models mirror much of the human pathophysiology [31, 32]; therefore, kindled rodents have been tremendously useful in preclinical drug development [33–38]. Over the years, kindling models have provided the basic research community with an important tool to model the process by which brain networks transition to a hyperexcitable state following a focal brain insult [3]. In fact, robust elevations and dysregulation in the expression of effector immediate early genes (IEGs), which are known to be essential to synaptic plasticity and remodelling processes [39–42] likely underlying epileptogenesis [43, 44], have been observed in chemically and electrically induced kindling models. It is interesting to also note that IEG dysregulation is highly conserved in other models and disease states associated with excess glutamate release [45], as well as that seen with recurrent and chronic seizure activity. Additionally, kindled rodents demonstrate neurodegeneration [26, 27], as well as reactive gliosis [28–30], indicative of an inflammatory response associated with epilepsy [46–50]. Kindling-induced hyperexcitability develops over several days to weeks, and this window has been used as an outcome measure to evaluate the disease-modifying potential of a number of drugs [51, 52]. For example, the time (e.g. days) needed to develop the fully kindled state and the number of focal stimulations needed to develop the fully kindled state are two commonly employed measures for these intervention studies.

It is important to keep in mind that therapies administered prior to the kindling stimulation may be insult modifying, i.e. they may decrease the focal afterdischarge associated with the electrical stimulation. As such, drugs or treatments that decrease seizure severity or modify the insult duration can be mistakenly considered to be disease modifying. In contrast, therapies that are administered after the daily stimulation and that prolong the time to reach a fully kindled state would be more appropriately classified as disease modifying. The development of pharmacoresistance is also often a major clinical problem, and therapies that prevent emergence of pharmacoresistance would be an important contribution to the management of epilepsy. Results obtained from the lamotrigine-resistant kindled rat would suggest that pharmacoresistance can develop rapidly and in response to treatment with lamotrigine and other sodium channel blockers, such as carbamazepine [53]. The mechanism underlying the development of this drug-induced pharmacoresistance is not known; however, the kindled rat can be used to identify the mechanisms contributing to the pharmacoresistant state and therapies that do not precipitate a similar level of pharmacoresistance. Important questions that can be asked using the kindled rodent model include the following: do animals that are exposed to a single ASD during kindling/epileptogenesis develop a more clinically relevant seizure phenotype, i.e. pharmacoresistant seizures? Could such studies identify and advance more effective treatments for refractory seizures and relevant treatments that may be disease modifying? In this regard, the lamotrigine-resistant kindled rat model is valuable to the identification and development of a disease-modifying agent because it may more closely mimic the means by which patients with epilepsy are managed clinically [54], e.g. a patient may receive one treatment early in the disease process, only to later switch or add-on an additional treatment upon the re-emergence of seizures. However, the mechanism of pharmacoresistance in humans is still unclear; whether pharmacoresistance is an inherent feature of a given patient’s epilepsy, results as a function of exposure to a particular ASD or is a consequence of the patient’s seizures is still unresolved. Two prevalent theories of pharmacoresistance include the drug target theory, wherein seizures or an ASD may modify the physiological target of the disease, and the drug transporter theory, wherein overexpression of multidrug efflux transporters essential to blood–brain barrier integrity are altered, reducing the levels of ASD available in the CNS [55–59]. Whether pharmacoresistant seizures in the lamotrigine-resistant kindled rat arise because of one of these two theoretical mechanisms remains to be defined. Therefore, the apparent unknown nature of pharmacoresistance in human patients with epilepsy should be carefully considered

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before concrete conclusions are drawn from disease modification studies using animal models with pharmacoresistant seizures. Despite the potential of the kindled rodent as a model for identification of disease-modifying agents, few studies have demonstrated a significant disease-modifying effect with first- and second-generation ASDs. One study in particular, by Silver et al. [60], evaluated the effects of several prototype ASDs in the kindled rat and found that only valproic acid and phenobarbital were able to suppress the rate of kindling acquisition, albeit at doses that induced significant adverse effects on motor behaviour. Other groups had previously demonstrated some prophylactic efficacy with regard to development of kindled seizures with first-generation ASDs [61–63], but these therapeutic effects failed to translate into clinical practice [8]. However, newer-generation ASDs and compounds with novel mechanisms of action may be more useful as diseasemodifying agents. In mice kindled with pentylenetetrazol, levetiracetam was found to inhibit the rate of kindling acquisition in the absence of adverse effects [64]. Eslicarbazepine acetate has also been found to decrease the rate of kindling acquisition and to increase the number of stimulations necessary to reach a fully kindled state in mice [51]. However, these results should be interpreted with caution, as both drugs are effective ASDs and these results may actually reflect an antiseizure effect, i.e. an insultmodifying—versus disease-modifying—effect. The corneal kindled mouse may provide a suitable alternative to the use of large, chronically stimulated kindled rats. This is because kindled rats are often larger in size and thus require more investigational compound for a study to be conducted, making them less amenable to highthroughput drug-testing studies designed for early identification of a promising disease-modifying agent [35, 65, 66]. The corneal kindled mouse also offers investigators the requisite platform to study the effects of genetic modification on the kindling process, making it possible to study disease susceptibility in genetic models of familial epilepsies. For example, Otto et al. [67] demonstrated that mice with mutations in the KCNQ2 gene (A306T) and the KCNQ3 gene (G311V) have accelerated rates of kindling acquisition relative to controls. Similarly, mice with mutations in the SCN9A gene, a modifier of Dravet syndrome, show accelerated rates of kindling acquisition compared with wild-type controls [68]. While there has yet to be a study of the disease-modifying effects of an investigational agent in a genetically susceptible kindled mouse, the opportunity certainly exists. Such combination studies may identify compounds able to reduce disease severity in atrisk individuals with known genetic susceptibility. In addition to their potential for evaluation of the disease-modifying impact of treatment on seizure burden,

kindled rodents may be useful for assessment of the impact of treatment on one or more of the comorbidities associated with human epilepsy; i.e. cognitive dysfunction [18]. For example, Grecksch and colleagues [69, 70] were the first to demonstrate that the pentylenetetrazol-kindled rat demonstrates notable kindling-related cognitive deficits. More recently, Mazarati et al. [71] established that immature rats subjected to the rapid hippocampal kindling protocol exhibited sustained depressive behaviour as measured by performance in the forced swim test and the sucrose-preference test, suggesting that kindled rats develop a similar comorbidity, i.e. depression. 2.2 Etiologically Relevant Models of Post-Insult Acquired Epilepsy Post-insult acquired epilepsy can progress into refractory mesial temporal lobe epilepsy (TLE). TLE represents a common type of human epilepsy. As such, animal models of TLE are important tools in the search for diseasemodifying or antiepileptogenic agents in the at-risk patient population. Several new TLE models are in use within the epilepsy research community, any of which have the potential to provide significant utility for drug testing [3, 72– 74]. While an entire review could be devoted to detailed evaluation of post-insult TLE models, we focus herein on the post-SE model as a relevant preclinical model of epileptogenesis and its potential utility in identification of antiepileptogenic and disease-modifying therapies. 2.3 The Post-Status Epilepticus Model In contrast to the kindling models, where seizures are almost always evoked, the available models of TLE display SRS [73, 74]. Like the kindled rodent models, these models demonstrate much of the neuropathology associated with human TLE: neurodegeneration within the hippocampus and granule cell layer dispersion in the dentate gyrus [75– 77]. Because of the latent period required to develop SRS following a neurological insult in these models, post-insult acquired epilepsy models can be useful to identify both antiepileptogenic and disease-modifying agents. Importantly, the studies that can be envisioned and undertaken in the post-SE models may offer different information regarding the utility of any promising agent. This is because temporally restricted intervention windows are available, e.g. insult-modifying treatments versus post-insult interventions, which can be administered at varying delay times within the latent period (see Fig. 1). Like the kindled rodent models, and as detailed in Fig. 1, studies of disease modification or antiepileptogenesis in SE models could take on two different avenues. The first is their ability to assess the effects of using insult-modifying agents

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administered to dampen the SE insult itself (the severity and duration of SE) on disease initiation and progression. Alternatively, there is also the potential to use SE models to assess post-insult interventions that may delay the onset (i.e. acquisition) of the disease itself or modify the course of the disease if given after SRS onset (see Fig. 1). Both avenues offer essential information that can inform the utility of a potentially disease-modifying and/or preventative agent. Sustained long-term seizure activity in SE is associated with excessive acetylcholine release [78, 79], release of glutamate and secondary overstimulation of glutamate receptors, leading to seizure-induced brain damage [80–82]. This insult and the subsequent hippocampal damage that ensues is widely appreciated as representing a risk factor for the development of epilepsy. As such, therapeutic interventions that can mitigate the SE-associated neuronal damage have been investigated as potential diseasemodifying strategies [83, 84]. For example, treatment with N-methyl-D-aspartate (NMDA)–type glutamate receptor antagonists, such as ketamine or MK-801, may minimize the concomitant surge in acetylcholine release [78, 85] and the resulting neurodegeneration by blocking NMDA receptors [86]. Moreover, NMDA receptor antagonism with ketamine can reduce seizure activity in refractory SE patient populations [87–89]. In addition to modelling much of the neuroanatomical reorganization that arises in patients with epilepsy, the post-SE rodent model of TLE provides an opportunity to evaluate the efficacy of a given treatment with regard to measures of disease severity, including seizure frequency and seizure type (i.e. focal or generalized). Unfortunately, drug trials in animal TLE models are extremely laborious, are time-consuming and require a greater level of technical expertise. As such, there have only been a few pharmacological studies conducted to date [90–94]. One study highlighted the potential role that tropomyosin receptor kinase B (TrkB) receptors may play in the development of epilepsy [95]. Transient inhibition of TrkB receptors for 2 weeks after SE prevented the emergence of SRS and anxiety-like behaviours, and normalized hippocampal pathology weeks to months post-SE [95]. While treatments targeting TrkB have yet to be validated clinically, these results suggest the possibility that post-SE models will lead to identification of a disease-modifying, and potentially even antiepileptogenic, clinical therapy. 2.4 Models of Infection-Induced Epilepsy Models of infection-induced TLE are also potentially useful differentiation tools in identification of new treatments for refractory epilepsy. The evidence suggests that inflammatory processes are upregulated and may, in fact,

be a contributing factor to epileptogenesis [46, 94, 96]. Therefore, identifying and developing models that specifically and consistently demonstrate inflammatory events during epileptogenesis may prove useful in the pursuit of mechanistically novel disease-modifying or antiepileptogenesis therapies. As an example, validation of novel models of viral encephalitis-induced epilepsy may be especially useful for understanding the pathology of epilepsy in the developing world, where infection accounts for a greater number of cases of acquired epilepsy than in the developed world [97]. Indeed, epilepsy is considered an underappreciated long-term complication of CNS infection [98]. In the USA, it is estimated that approximately 19,000 individuals per year are hospitalized with viral encephalitis [99]. The higher incidence of epilepsy in less-developed countries (over 75 % of the 65 million people worldwide with epilepsy) may, in part, be attributable to a higher incidence of CNS infections in these regions [98, 100]. Thus, interventions that may be disease modifying in models of infection-induced encephalitis may provide a significant worldwide public health benefit in the fight against acquired epilepsy. Patients with viral encephalitis who present with seizures are up to 22 times as likely to develop SRS following the infection [101]; thus, blocking acute seizures may minimize the risk of long-term disease onset. One model that clearly has the potential to be useful and relevant in identification of novel treatments for encephalitis-induced epilepsy is the Theiler’s murine encephalomyelitis virus (TMEV) mouse model [102–105]. The TMEV model recapitulates many of the characteristics of human TLE, including neuroinflammation, acute neurodegeneration and behavioural comorbidities [102, 106]. Animals that present with seizures in this model display a lowered seizure threshold [97] and often go on to develop SRS or at least long-term abnormal cortical electroencephalographic activity [102, 107]. Agents with anti-inflammatory properties may differentially alter the disease course and disease severity, whereas compounds with acute antiseizure activity may reduce the presentation of seizures themselves [8, 13]. Interestingly, a repurposed anti-inflammatory agent, minocycline, can prevent development of acute seizures in TMEV-infected mice [103–105]. Furthermore, the prototypical ASD, valproic acid, can also acutely reduce seizure burden in TMEV-infected mice but has no effect on associated long-term comorbidities of epilepsy [108]. Thus, it is entirely possible that agents effective against provoked seizures in this model will differ significantly in terms of their mechanism from agents that are effective in preventing unprovoked seizures long-term. Altogether, these findings highlight the potential value of the TMEV model

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for evaluating novel pharmacological agents. It is presently unknown whether a therapeutic intervention with an as-yetuntested mechanism of action in epilepsy, such as minocycline, can subsequently delay or prevent the onset of chronic SRS or normalize abnormal biomarkers of disease progression, i.e. behavioural comorbidities and an altered seizure threshold in the TMEV model [106, 107]. Only time will tell whether a model with an acute inflammatory response, such as that seen in the TMEV model, will effectively identify and differentiate between antiepileptogenic treatments and antiseizure treatments, and bring forth a new class of disease-modifying therapies for the patient at risk of epilepsy. Nonetheless, identification of an effective treatment in this model may represent a significant opportunity for future clinical investigations. 2.5 Models of Posttraumatic Epilepsy Posttraumatic epilepsy (PTE) can occur in 5–75 % of individuals following TBI, depending on the insult severity, presentation of acute seizures and long-term management of the disease [17, 109, 110]. Given the potential impact that TBI can have on the brain and the potential public health impact of preventing PTE, validating preclinical models of PTE is of great clinical value. In addition to the potential for therapeutic intervention in models of infection-induced encephalitis, targeting inflammatory processes may be an effective disease modification strategy in PTE models [111]. In further support of the role of inflammation in clinical PTE, Diamond et al. [112] demonstrated an intriguing correlation between cerebrospinal fluid (CSF) to serum interleukin (IL)-1b ratios, as measured during the first week after TBI, and the risk of developing PTE. Following analysis of over 256 adults with moderate to severe TBI, a high CSF to serum IL-1b ratio was associated with an increased risk of subsequent development of PTE [112]. Additionally, a single nucleotide polymorphism within the IL1B gene was associated with an increased risk of development of PTE in these patients [112]. This study provides preliminary clinical evidence of the potential role of genetic variation in IL-1b production following TBI and further highlights the contributions that inflammation may make in seizure disorders and epilepsy. More importantly, it suggests a useful clinical biomarker to identify a subset of at-risk individuals and potentially inform the design and conduct of clinical disease prevention studies [11]. Patients with severe TBI have a high risk of seizure recurrence [113], and epilepsy associated with TBI in humans is often drug refractory [114]. Unfortunately, prior clinical efforts to define an antiepileptogenic effect with currently approved ASDs have failed to demonstrate efficacy in controlling unprovoked seizures after TBI [8, 115],

despite some effect on the acute symptomatic seizures associated with TBI [8, 115]. Moreover, in those trials that did demonstrate a certain degree of efficacy in controlling symptomatic seizures [8], adverse side effects severely limited long-term patient compliance and drug adherence, which would have been necessary to truly demonstrate an antiepileptogenic effect [9]. With a notable rise in the numbers of veterans returning from military operations over the last several decades and the concomitant increased prevalence of TBI, there is reason to believe that the incidence of PTE may similarly increase in at-risk patient populations [116]. Such a public health problem will certainly increase the demand for the use of these animal models in the drug development process. While clinical management of PTE with approved ASDs has yet to demonstrate a robust antiepileptogenic effect in humans, other approaches to prevent PTE are under preclinical evaluation. Mild passive focal cooling following TBI has been used as an approach to minimize the associated neuroinflammation in the absence of pharmacological intervention. In one study, D’Ambrosio et al. [117] cooled the brains of rats by approximately 0.5–2 °C, beginning 3 days after a fluid percussion injury to the neocortex. This resulted in a temperature-dependent reduction in the onset of epileptic seizure activity for up to 10 weeks after TBI. While this study may have merely delayed the onset of spontaneous epileptic activity following TBI, these data support the theory that intervention with an effective anti-inflammatory therapy—in this case, post-insult focal cooling—may modify the disease course. Importantly, this study did not require pharmacological intervention to elicit a disease-modifying effect, further emphasizing the potential for disease modification if an insult is minimized or intervention is initiated early in the disease process. Importantly, models that offer intervention windows after an acute insult (e.g. a TBI or SE event) or a chronic insult (e.g. kindling) can be useful in identifying disease-modifying agents. 2.6 Novel Preclinical Models for Evaluating Pharmacological Interventions for Prevention of the Epileptogenesis Process Historical approaches to therapeutic intervention with models of acquired epilepsy and epileptogenesis have relied heavily on investigator-controlled interventions within certain time windows following a neurological insult, e.g. immediately after the insult or during the latent period (see Fig. 1). These approaches are useful to understand the process by which epilepsy develops following a neurological event. However, as noted above, it may not always be possible to identify patients at equivalent time points. This is particularly true in the more than 50 % of epilepsy patients

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where no insult can be identified. Patients either present at the time of their first or second seizure, when epilepsy is diagnosed [118], or they present when they have established epilepsy and their current treatment regimen is failing [119]. These clinical scenarios compel the preclinical scientist to model disease progression after diagnosis. Efforts to reduce the severity of established epilepsy have been useful to understand how therapeutic intervention may lead to diverse responses within a population of experimental subjects. Several studies using the kainic acid-induced SE rat model have demonstrated an improved level of seizure control with traditional ASDs administered long after epilepsy has become chronic [91, 120]. In these studies, the investigators were able to gain significant control of SRS in previously untreated rats [91, 120, 121]. While these approaches are useful as a strategy to identify treatments that may be effective in established epilepsy, they do not closely mimic the means by which patients may initially experience therapeutic intervention after epilepsy is diagnosed, because the treatment was not initiated until long after epilepsy was established [91, 120, 121]. As such, novel approaches designed to evaluate the impact of therapeutic intervention at a more clinically relevant time point could provide valuable information regarding the variability in patient response. One such model in the early stage of development [122] uses a strategy of initiating treatment immediately after the second behavioural seizure, i.e. in the newly diagnosed epileptic rat. This approach can be used for testing novel therapies for symptomatic treatment of epilepsy in the newly diagnosed ‘patient’. This model could also be used to evaluate whether early treatment of the newly diagnosed rat will alter the progression of epilepsy and the associated comorbidities of epilepsy. The ability to evaluate a given treatment for an individual rat by normalizing the treatment response to the initial pretreatment baseline seizure rate and severity provides a level of intervention in preclinical disease modification studies that is presently underutilized and could prove highly useful. 2.7 Summary of Animal Models of Epileptogenesis Increasing the availability of preclinical disease modification data in the above-described models with promising investigational agents and approaches will likely prove productive in the search for revolutionary therapies for the patient at risk of epilepsy. In the future, these patients may benefit from use of etiologically relevant models in preclinical drug development. The above discussion is limited to a few relevant animal models, but the general principles likely apply to many of the other available models reviewed elsewhere [1].

3 Issues Related to Development of Antiepileptogenic and Disease-Modifying Agents There is a clear clinical need to identify agents that may be antiepileptogenic. Demonstrated efficacy in animal models may inform the design and conduct of clinical trials. Should an antiepileptogenic or disease-modifying agent ever make the leap from preclinical efficacy in a model of epileptogenesis to clinical validation, it would become the gold standard by which all future models of epileptogenesis would be validated. Just as evaluation of antiepileptogenic effects in a well-designed clinical trial is difficult to undertake, because of a number of limiting factors, so too is it difficult to execute a ‘clinical trial-like’ study in the preclinical setting with a definitive demonstration of antiepileptogenesis. The length of time to develop epilepsy following a neurological event and the need to fully evaluate any observed effect of treatment for weeks to months following the neurological insult is not conducive to preclinical drug development in the traditional sense, wherein highthroughput screening approaches can quickly identify efficacy in acute or chronic animal models [123]. For these reasons, other useful read-outs that can be more rapidly applied to high-throughput drug testing may expedite early identification of promising antiepileptogenic agents. Evaluation of late biomarkers of epileptogenesis, such as latent phase variation and SRS, is difficult to apply to highthroughput drug development. Other acute biomarkers of disease progression following neurological insult are more readily applicable, including neuroimaging [124] and electrophysiological biomarkers, such as pathological highfrequency oscillations [125], as well as those discussed above, e.g. behavioural comorbidities and neuroinflammation. For example, both neurodegeneration and cognitive testing after SE are useful medium-throughput biomarkers that can be utilized for preclinical evaluation of candidate compounds [123]. Changes in these particular biomarkers have been reported in both animal models and patients with epilepsy [18, 126, 127]. Therefore, they may provide an important surrogate for the labour-intensive and often highly variable use of seizure frequency and the length of the latent phase. These biomarkers address a key National Institute of Neurological Disease and Stroke (NINDS)/American Epilepsy Society (AES) research benchmark [128, 129] and are of great value to preclinical drug development efforts. As interest in—and research efforts into—antiepileptogenesis treatments increase in demand from the patient with epilepsy and his/her clinician, use of biomarkers capable of accelerating the drug development process will similarly increase.

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4 Biomarkers of Disease Modification The ultimate measure of antiepileptogenesis is complete prevention of SRS throughout the lifetime of the patient. Prevention of SRS is a goal of NINDS/AES Epilepsy Research Benchmarks [128]. Long-duration clinical studies of antiepileptogenesis are often difficult to undertake, because of a combination of difficult recruitment and the need to enrol large numbers of patients. Recruitment may be difficult because of both identification of at-risk subjects (depending on how common the insult is) and, as previously mentioned, the need to ask patients who do not yet have a disease to accept treatment. Large enrolment numbers are often required because of the variable (and often low) frequency at which easily identified at-risk patients go on to develop epilepsy following various neurological events (e.g. SE, TBI and encephalitis) [11, 17, 130]. Additionally, monitoring patients for the prolonged periods of time required to demonstrate a true antiepileptogenic effect is less than realistic, e.g. when is an appropriate time to cease monitoring for the first unprovoked seizure? Preclinical studies are similarly limited by several factors: the time needed to sufficiently monitor animals following neurological insult to accurately demonstrate an antiepileptogenic versus disease-modifying effect; the fact that the variability in the percentage of animals at risk of SRS that actually go on to develop epilepsy depends on the model used; and the financial constraints for the preclinical researcher to undertake such lengthy studies. For these reasons, biomarkers that may be predictive of disease modification, or prevention altogether, are of great translational value.

4.1 Behavioural Comorbidities as Surrogates for Disease Modification Increasing evidence suggests that epilepsy is associated with—and may actually be preceded by—cognitive, neuropsychiatric and behavioural comorbidities [18, 131]. Comorbidities of epilepsy can include depression [131], cognitive impairments [126, 132, 133], migraines [134], autistic-like behaviours [135, 136] and even neuropathic pain [137]. Often, the patient with epilepsy might even perceive these comorbidities as being more detrimental to his/her quality of life than the seizures themselves [18]. Thus, use of preclinical models of these behavioural and cognitive comorbidities associated with chronic seizures provides an important surrogate for evaluating diseasemodifying approaches. One of the most commonly used surrogate markers of disease modification is cognitive performance in wellestablished animal models of learning and memory. For

example, the Morris water maze (MWM) [138] is a wellvalidated rodent model of learning and memory [139]. The rodent MWM has been frequently utilized to demonstrate an effect on cognitive performance following a neurological insult, i.e. post-SE. Pharmacological intervention during the insult itself may be neuroprotective and thus improve performance of this task [22, 140]. Such neuroprotection may be predictive of disease modification. In fact, performance of the MWM task is frequently evaluated in other CNS indications wherein cognitive deficits may be indicative of disease progression, including neuroprotection following TBI [141]. Performance of this task is a useful and noninvasive biomarker to inform preclinical studies in disease modification, because patients with hippocampal lesions also demonstrate deficits in cognitive performance of tasks similar to the rodent MWM task [127]. Cognitive performance can then be monitored in longitudinal studies across the length of the epileptogenesis process. Finally, preclinical biomarkers of cognitive performance are highly adaptable to clinical studies. In addition to cognitive deficits in patients with epilepsy [18, 132], there is evidence that patients experience notable anxiety and depression [142]. Activity in an open field represents a valid model of anxiety-like behaviour in rodents [143]. For example, Umpierre et al. [106] monitored the open-field activity of mice with and without a history of TMEV-induced acute behavioural seizures to evaluate measures of disease progression weeks after the viral infection—a point at which SRS are known to develop [102, 107]. Animals at risk of developing epilepsy demonstrated significantly greater anxiety-like behaviours than animals not at risk when evaluated up to 70 days postinfection [106]. This behavioural task offers the added benefit of evaluating cognitive integrity following a neurological insult; animals with hippocampal lesions will ambulate to a greater extent in an open field because of spatial memory deficits [144, 145]. Therefore, open-field activity can be a useful moderate-throughput means to evaluate behavioural comorbidities of epilepsy, especially anxiety-like behavioural comorbidity [142]. 4.2 Biomarkers Associated with Neuroinflammation As detailed above, pro-inflammatory cytokines are expressed in various animal seizure models [46, 146, 147] and patients with epilepsy [48, 49, 96], and they may be essential to epileptogenesis [94, 148, 149]. Cytokines are altered in response to seizures and epilepsy in both patients with epilepsy and animal models. These include IL-1b [94, 112, 150–153], IL-17 [48] and IL-6 [104]. In fact, the general role of IL-1b in epilepsy garnered such significant attention for its hypothesized proconvulsant potential that VX-765, a potent inhibitor of the IL-1b converting enzyme

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[94, 150, 153], was tried in animal models of epilepsy and was able to prevent SRS after SE induced by intrahippocampal kainate [146], as well as suppressing established SRS in the same model. On the basis of these results, a phase II clinical trial of the same agent [ClinicalTrials.gov study identifier NCT01048255] was launched in early 2010 as one of the first efforts to target inflammatory processes underlying chronic partial epilepsy in patients. Unfortunately, VX-765 did not advance beyond initial clinical investigation [21]. However, this should not preclude further clinical evaluation with similar agents. That IL-1b is a potentially novel therapeutic target further highlights the utility of inflammatory cytokines as potential biomarkers of epileptogenesis. Other inflammatory signalling molecules are also heavily implicated in epileptogenesis. Tumour necrosis factor-a [105, 154] may underlie TMEV-induced seizures and epilepsy [102, 107]. Prostaglandins may play a role in post-SE-induced neurodegeneration [149, 155]. There is even emerging evidence of the role of inflammation underlying comorbidities of epilepsy, including depression [156]. Given that depression is often associated with epilepsy and, in fact, may precede the diagnosis of epilepsy itself, the emerging evidence of shared neuroinflammatory pathology in epilepsy and comorbidities thereof suggest the utility and validity of neuroinflammatory markers as biomarkers of certain comorbidities of epilepsy. Altogether, inflammatory mediators represent an important and useful class of biomarkers, as well as being potential therapeutic targets for the modification of epilepsy. Within the brain, expression of these inflammatory signalling molecules occurs primarily within glial cells [47]. However, it is difficult to monitor neuroinflammation or reactive gliosis within a living patient without performing invasive collection procedures. The availability of brain tissue is restricted to a very limited patient population who undergo elective resection surgeries. Importantly, these patients often turn to surgical resection as a last resort in an effort to gain control over pharmacoresistant epilepsy [157]. This may confound any biological data that are collected from resected tissues, because of the longstanding, therapy-resistant nature of the disease in these individuals [158]. Thus, noninvasive neuroimaging techniques to visualize neuroinflammation in heterogeneous populations of patients, regardless of their pharmacosensitivity status, may offer a suitable alternative clinical and preclinical biomarker of epileptogenesis. One approach is to use positron emission tomography (PET). This approach is in use in clinical imaging studies in patients with TLE, using the radioligand [11C]-PBR28 [159], a selective radioligand for translocator protein (18 kDa), which is highly overexpressed by activated microglia and astrocytes under conditions of

neuroinflammation [160]. Dedeurwaerdere et al. [161] conducted similar preclinical studies with in vivo [18F]PBR111 PET imaging in the post-SE rat model. They evaluated the potential preclinical utility of such a noninvasive neuroimaging technique for visualization of disease progression after a neurological insult [161]. Thus, biomarkers of the associated inflammation found in patients with epilepsy offer clinical and preclinical investigators the advantage of being able to truly evaluate markers of epileptogenesis in a longitudinal and noninvasive manner in diverse patient populations, rather than selecting only those individuals with established (and often pharmacoresistant) TLE who elect to undergo surgical resection. Application of a noninvasive biomarker technique could likely play an important role in clinical trial enrolment strategies [11] and clinical management of epilepsy to more appropriately stratify patient populations into cohorts that may or may not respond to relevant treatment approaches.

5 Addressing Deficits in Current Animal Models A number of animal models of epileptogenesis/disease modification with arguable clinical relevance certainly exist [1, 15]. However, there are also notable deficiencies in the design and execution of studies intended to demonstrate a true antiepileptogenic effect of promising agents. The deficit in clinical validation of relevant animal models is, in fact, a common problem and a challenge for many neurological diseases [162]. While animal models that replicate the symptomatic features of epilepsy (i.e. seizures) are well validated and have successfully identified numerous compounds for symptomatic management of seizures [163], animal models of epileptogenesis/disease modification lack clinical validation [1]. There is a clear need to identify novel treatments that are effective in aetiologically relevant animal models of epileptogenesis/disease modification. Developing procedures and protocols that can standardize preclinical research efforts may ultimately improve the likelihood that a promising agent will advance through the gauntlet of a well-designed clinical trial to become the first clinically validated antiepileptogenic/disease-modifying agent. Unfortunately, the few clinical trials that have been conducted have failed to demonstrate a positive antiepileptogenic effect, because the pathophysiology underlying the disease itself likely remains poorly understood [12]. For these reasons, the International League Against Epilepsy (ILAE)/ AES Translational Task Force has charged a collection of working groups to spearhead the unification of preclinical research parameters to lead to new and transformative therapies for the patient with—or at risk of developing— epilepsy [164, 165].

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These working groups will collectively attempt to optimize preclinical research efforts through several methods. One goal identified by this Translational Task Force is development of common data elements (CDEs) to standardize collection of investigational data and minimize variability in results between preclinical research groups [164]. It is anticipated that these steps will allow acquisition of preclinical data in a more cohesive and unified fashion and enhance therapy development for disease modification and antiepileptogenesis [164]. It is anticipated that the preclinical CDEs will, in many ways, mirror the established clinical CDEs for epilepsy [166]. Additional initiatives of the Translational Task Force include systematic review of animal models for their relevance to clinical syndromes and development of an infrastructure to commence multicentre preclinical trials to improve the reproducibility of promising preclinical data [165]. Altogether, establishment of preclinical CDEs, steps to improve our understanding of existing and relevant animal models, and development of multicentre preclinical testing sites may begin to address the limitations of the available animal models of epileptogenesis. It can also be anticipated that these efforts will lead to animal models that better represent the patient at risk of developing epilepsy. These efforts may positively impact translational research efforts and improve the likelihood that an investigational compound identified in one of the above-described animal models of epileptogenesis will someday translate into efficacy in a clinical trial. In addition to the translational research gap in addressing epileptogenesis, there is also a deficiency in preclinical models in addressing the change in the clinical landscape of epilepsy. Much of the early clinical research focused on the treatment of medically refractory TLE. It became apparent that this form of epilepsy was particularly amenable to treatment with resective surgery, and our understanding of the associated neuropathological changes, such as hippocampal sclerosis, mossy fibre sprouting, and selective cell loss and reorganization, was informed by the readily available sources of human brain tissue from en bloc resections to study [167]. This informed the development of rodent models of SRS that mirrored the histopathology of human TLE described above. However, for reasons that are not well understood, patients with refractory TLE, especially mesial TLE with hippocampal sclerosis, are less common in clinical practice than they were in decades past [168], as evidenced by the declining use of temporal lobe resection [169–171] despite guidelines reinforcing its efficacy [172]. The overall utilization of epilepsy surgery has not changed in recent decades [173], nor has the proportion of patients who are treatment resistant declined significantly [174]. In place of patients with refractory TLE, patients with temporal and extra-temporal neocortical

epilepsy, including cases due to cortical malformations and non-acquired cases (often without a clear aetiology), dominate referrals to epilepsy surgery programmes. However, the development of well-validated models of neocortical epilepsy has lagged behind the observed clinical rise. It is not yet well understood how ictogenesis and epileptogenesis differ in TLE and neocortical epilepsy, but it remains a possibility that disease-modifying therapies developed in models of TLE may not have the expected impact in clinical practice, because the targeted condition is much less prevalent.

6 Clinical Applications and Harmonization of Testing Strategies for Improved Clinical Success 6.1 Requirements for Translation of Preclinical Data into Clinical Evaluation While experiments in animal models, using various agents, have demonstrated efficacy in preventing, delaying or modifying the disease course, thus far no agent tested has yet prevented or delayed epilepsy in humans [12]. This failure is likely multifactorial; little rigorous preclinical evaluation preceded human trials, and the studies were underpowered, suffered from poor design or were compromised by recruitment and retention issues [175]. Newer agents and approaches that have demonstrated some potential for disease modification using preclinical models [23, 94, 95, 117] have not yet been evaluated in the clinical setting, making it entirely possible that an agent or an approach for disease modification will be clinically validated in the future. Furthermore, forthcoming success in clinical trials of therapies to prevent or modify epilepsy likely depends as much on designing and executing the proper clinical trials as it does on identifying a breakthrough compound in the laboratory. Prior to undertaking any translational effort with a promising treatment, one must have a thorough understanding of several key factors: first, the goal of therapy—epilepsy prevention in an at-risk population or disease modification in those with the established disorder; second, the epidemiology and clinical course of the disorder in the target population; and third, the treatment window, e.g. the timing and duration of therapy required. Disease modification trials, designed to alter the course of established or emerging epilepsy, are perhaps easier to design and perform. The target clinical population is readily identifiable, as they have come to clinical attention because of their seizures. Recruitment would be relatively easy because subjects already have the disease and the risk to benefit ratio of participation in such a trial would be

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clear. However, to demonstrate a disease-modifying effect (and to obtain such labelling from the US Food and Drug Administration), trials would have to be carefully designed to distinguish antiseizure effects from effects on the course of epilepsy. This may be relatively straightforward for treatments that are given for brief periods of time and then withdrawn, but it is more difficult for chronic therapies [175]. In established and emerging epilepsy, there is a fair understanding of the natural history of the condition, such as the proportion of patients developing pharmacoresistance or disease remission [174]. This information is critical for choosing the optimal trial duration and determining the sample size. Finally, determining the treatment window is more straightforward for disease modification, as it is easier to identify drug targets in established disease. On the other hand, disease prevention trials may be more difficult to perform even if a promising compound is identified in the laboratory. In this type of study, individuals who are at risk of developing epilepsy but have not yet developed the condition would need to be identified and enrolled in prolonged studies that would compare the rates of development of epilepsy between the treatment and control groups. Identifying at-risk populations may be easy in certain conditions such as TBI or viral encephalitis, but, even in these disorders, there are issues. For one, these insults represent incident cases, and it is unlikely that any single centre will see a large number of them, meaning that recruitment will necessarily have to occur across many sites and over a long duration. In addition, as noted above, only a fraction of at-risk individuals actually develop epilepsy. Therefore, a clinical trial would need to recruit and expose many individuals to experimental treatment who would never actually develop epilepsy. Depending on the burden of therapy, including its risks, side effects, costs and invasiveness, a clinical trial may not be acceptable or feasible in the undifferentiated at-risk population [13, 175]. For these reasons, a repurposed therapy, for which the risks and benefits are already known, would be more likely to succeed than a novel therapy with unknown risk potential. Clinical, serum, imaging or electrophysiological biomarkers have the potential to identify individuals in the at-risk population who are most likely to develop epilepsy [176], thereby reducing study sample size requirements and the number of subjects exposed to a potentially harmful drug who might never have developed epilepsy. In addition to standard in vivo and in vitro tests of organ toxicity [177], preclinical evaluation in validated models of common side effects of CNS drugs may be able to identify adverse effects that could limit the feasibility of clinical trials or the ultimate utility of an otherwise promising antiepileptogenic compound. Unfortunately, at present, many side effects and toxicities of ASDs cannot be

modelled in animals, which are often homogenous and are exposed to acute doses of an investigational agent [11]. Finally, a critical aspect of preclinical testing of an antiepileptogenic treatment is determining the optimal timing of treatment. Prior antiepileptogenesis studies in humans have determined the timing of treatment empirically (e.g. as soon as feasible) [178] and were not informed by experimental evidence. However, the ideal situation is for a drug target to be identified in the animal model that can also be easily assessed in humans. Determining the latency of target expression in humans following an epileptogenic insult, and understanding the duration for which that target is expressed, may identify the therapeutic window for humans. However, the timing requirements for drug administration must be feasible in the context of a study or clinical practice. If an antiepileptogenic drug could be given only within 1 h after a brain insult, a therapeutic trial in which subjects are screened, consented, randomized and given experimental treatment all within that hour would be very difficult to perform. However, if the target was expressed (and was able to be engaged) for weeks following the insult, the number of subjects eligible for an interventional trial would increase and, if found effective, the therapy could have broad applicability.

7 Conclusions and Future Directions Several of the animal models described herein have contributed to the advancement of impactful pharmacotherapies for the symptomatic management of seizures in the patient with epilepsy. However, the challenge now is to identify treatments that may achieve the currently unrealized goal of antiepileptogenesis. Identifying and developing more appropriate animal models of the disease course may improve the likelihood of success. Furthermore, initiating well-designed clinical trials may promote the advancement of effective agents to clinical use. The validity of data collected within the preclinical space is an important consideration for any potential clinical study designed to evaluate the antiepileptogenic and/or disease-modifying potential of a candidate therapy. As detailed above, and previously [1], numerous animal models exist that recapitulate important aspects of the epileptogenic process. While there is still much work needed in the identification, application and validation of preclinical models of epileptogenesis, it is important to thoroughly evaluate each one in a calculated and cautious fashion so as to clearly define their potential utility for therapy discovery. One such example that has highlighted the need for critical evaluation of the animal models in use for drug discovery came from the anti-inflammatory agent

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minocycline in amyotrophic lateral sclerosis (ALS) translational research [162]. Despite promising preclinical data suggesting the potential disease-modifying capability of minocycline in animal models of ALS [179], subsequent clinical trials with minocycline actually hastened disease progression and severity [180, 181]. This finding substantiated the need for more thorough evaluation of the state of animal models for this CNS indication [162]. It is hoped that none of the animal models of epileptogenesis would inadvertently advance an agent that actually accelerated disease progression or severity to clinical practice. However, this ALS example emphasizes the need to carefully consider the state and appropriateness of animal models prior to commencement of any clinical evaluation of an investigational agent [162]. In this review, the authors have discussed several relevant animal models of epileptogenesis and highlighted the need for appropriate biomarkers that can be used to guide preclinical and clinical studies, hopefully leading to identification and development of clinically effective diseasemodifying or antiepileptogenic therapies. Until such an agent can move from preclinical proof of concept to clinical success, there is an important need for further characterization and development of animal models, biomarkers and testing procedures to guide preclinical studies that will ultimately inform clinical trials. Acknowledgments Melissa L. Barker-Haliski reports no conflicts of interest. Daniel Friedman receives salary support from the Epilepsy Study Consortium for consulting related to the performance of industrysponsored clinical trials; and serves as a consultant for Alexza, Eisai, Marinus Pharmaceuticals, Pfizer, SK Life Sciences and Upsher-Smith Laboratories. All fees are paid to the Epilepsy Study Consortium, which pays a fixed amount to New York University to support his salary. Dr. Friedman also receives research support from the Centers for Disease Control and Prevention, Epilepsy Foundation, National Institutes of Health/National Institute of Neurological Disease and Stroke (NINDS), Finding a Cure for Epilepsy and Seizures (FACES) and UCB. Jacqueline French is the President of the Epilepsy Study Consortium. All consulting is done on behalf of the consortium, and fees are paid to the consortium. The New York University Comprehensive Epilepsy Center receives salary support from the consortium. Dr. French has acted as a consultant for Acorda, Biotie, Brabant Pharma, Eisai Medical Research, Glaxo Smith-Kline, GW Pharma, Impax, Johnson and Johnson, Marathon Pharmaceuticals, Marinus, Neusentis, Novartis, Pfizer, Sage, Sunovion, SK Life Sciences, Supernus Pharmaceuticals, Takeda, UCB, Upsher-Smith, Ultragenyx, Vertex, Zynerba; has received grants and research from Acorda, Alexza, LCGH, Eisai Medical Research, Lundbeck, Pfizer, SK Life Sciences, UCB, Upsher-Smith and Vertex; has received grants from the National Institute of Neurological Disease and Stroke, Epilepsy Therapy Project, Epilepsy Research Foundation and Epilepsy Study Consortium; is on the editorial boards of Lancet Neurology, Neurology Today and Epileptic Disorders; and is an associate editor of Epilepsia. H. Steve White has served on Scientific Advisory Boards for Upsher-Smith Laboratories and Insero Health; has served as a consultant for Takeda Pharmaceuticals; receives research funding from the National Institute of Neurological Disease and Stroke/

National Institutes of Health; is the Research Director for Citizen’s United for Research in Epilepsy (CURE); and is a scientific cofounder of NeuroAdjuvants, Inc. No funding was received for the publication of this review.

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Disease modification in epilepsy: from animal models to clinical applications.

Several relevant animal models of epileptogenesis and biomarkers have emerged for evaluating the antiepileptogenic potential of an investigational dru...
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