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Keywords:

  • Antiepileptic drug;
  • Epileptogenesis;
  • Fluid-percussion injury;
  • Recovery;
  • Surrogate marker

Summary

  1. Top of page
  2. Summary
  3. Heterogeneity of TBI in Humans—A Challenge for Animal Model Development
  4. Using TBI Models for Modeling PTE
  5. Epileptogenesis versus Recovery
  6. Preclinical Trials in Experimental Models of TBI— Do They Pave the Way for Finding Antiepileptogenic or Disease-Modifying Treatments for PTE?
  7. Use of AEDs at Early Postinjury Phase—Any Harm?
  8. Future Challenges
  9. Acknowledgments
  10. References

A large number of animal models of traumatic brain injury (TBI) are already available for studies on mechanisms and experimental treatments of TBI. Immediate and early seizures have been described in many of these models with focal or mixed type (both gray and white matter damage) injury. Recent long-term video-electroencephalography (EEG) monitoring studies have demonstrated that TBI produced by lateral fluid-percussion injury in rats results in the development of late seizures, that is, epilepsy. These animals develop hippocampal alterations that are well described in status epilepticus–induced spontaneous seizure models and human posttraumatic epilepsy (PTE). In addition, these rats have damage ipsilaterally in the cortical injury site and thalamus. Although studies in the trauma field provide a large amount of information about the molecular and cellular alterations corresponding to the immediate and early phases of PTE, chronic studies relevant to the epileptogenesis phase are sparse. Moreover, despite the multiple preclinical pharmacologic and cell therapy trials, there is no information available describing whether these therapeutic approaches aimed at improving posttraumatic recovery would also affect the development of lowered seizure threshold and epilepsy. To make progress, there is an obvious need for information exchange between the trauma and epilepsy fields. In addition, the inclusion of epilepsy as an outcome measure in preclinical trials aiming at improving somatomotor and cognitive recovery after TBI would provide valuable information about possible new avenues for antiepileptogenic interventions and disease modification after TBI.


Heterogeneity of TBI in Humans—A Challenge for Animal Model Development

  1. Top of page
  2. Summary
  3. Heterogeneity of TBI in Humans—A Challenge for Animal Model Development
  4. Using TBI Models for Modeling PTE
  5. Epileptogenesis versus Recovery
  6. Preclinical Trials in Experimental Models of TBI— Do They Pave the Way for Finding Antiepileptogenic or Disease-Modifying Treatments for PTE?
  7. Use of AEDs at Early Postinjury Phase—Any Harm?
  8. Future Challenges
  9. Acknowledgments
  10. References

Traumatic brain injury (TBI) in humans is a heterogeneous disorder that can differ in the type of injury, distribution of damage, or mechanisms of damage (Gennarelli & Graham, 2005). Regarding the type of injury, TBI can be classified into those injuries that result from a direct mechanical force to the head occurring at the time of injury (primary TBI, Table 1), or those that result from nonmechanically induced secondary complications that were or were not initiated by the primary damage (secondary TBI, Table 1). The extent and distribution of damage can vary from focal to diffuse, comprising a variety of different types of lesions (Table 1). Mechanisms of damage can vary from the direct impact to the skull/brain (e.g., a fall) to the acceleration/deceleration type of injury (e.g., rapid head rotation in a car accident) (Table 1). This variability challenges not only modelers of TBI, but in particular those who wish to develop models for posttraumatic epilepsy (PTE). This relates to the fact that information about the risk factors for PTE originates mostly from retrospective epidemiologic studies rather than prospective studies that would have carefully characterized the details of injury type, distribution, or the mechanisms of damage associated with subsequent epileptogenesis using novel imaging and other methodologies (see Pitkänen & McIntosh, 2006).

Table 1.   Classification of traumatic brain injury, type of damage, and mechanisms of damage according to Gennarelli and Graham (2005)
Traumatic brain injury
Primary
 Injury to scalp
 Skull fracture
 Surface contusion/laceration
 Intracranial hematoma
 Diffuse axonal injury
 Diffuse vascular injury
 Injury to cranial nerves and pituitary stalk
Secondary
 Hypoxia–ischemia
 Swelling/edema
 Raised intracranial pressure and associated vascular changes
 Meningitis/abscess
Damage after brain injury
Focal
 Injury to scalp
 Skull fracture
 Surface contusion/laceration
 Intracranial hematoma
 Raised intracranial pressure and associated vascular changes
Diffuse (multifocal)
 Diffuse axonal injury
 Hypoxic–ischemic damage
 Meningitis
 Vascular injury
Mechanisms of damage
Contact
 Injury to scalp
 Fracture of skull with or without an associated extradural hematoma
 Surface contusions and lacerations and associated intracerebral hematomas
Acceleration/deceleration
 Tearing of bridging veins with formation of subdural hematoma
 Diffuse axonal injury, tissue tears, and associated intracerebral hematomas
 Diffuse vascular injury

Currently available TBI models can be divided into focal models of TBI, diffuse brain injury models, mixed models of focal and diffuse brain injury, combined injury models, experimental models of coma, and models of repetitive concussive injury (Cernak, 2005; Morales et al., 2005). Most of these models are performed in rodents and utilize a direct impact on the epidural space or the brain tissue (Cernak, 2005). Acceleration models resulting in widespread white matter damage (diffuse axonal injury, DAI) have been successfully applied in primates and miniature swine that have a larger amount of white matter than rodents (Gennarelli et al., 1981; Smith et al., 1997a). Although none of the TBI models recapitulates fully the human syndrome, it is well acknowledged that these models are useful for understanding the molecular mechanisms of TBI and testing the efficacy of novel treatments for TBI (Cernak, 2005; Morales et al., 2005). Therefore, there are plenty of possibilities when planning to use TBI models as a starting point for modeling PTE.

Using TBI Models for Modeling PTE

  1. Top of page
  2. Summary
  3. Heterogeneity of TBI in Humans—A Challenge for Animal Model Development
  4. Using TBI Models for Modeling PTE
  5. Epileptogenesis versus Recovery
  6. Preclinical Trials in Experimental Models of TBI— Do They Pave the Way for Finding Antiepileptogenic or Disease-Modifying Treatments for PTE?
  7. Use of AEDs at Early Postinjury Phase—Any Harm?
  8. Future Challenges
  9. Acknowledgments
  10. References

A PubMed search in April 2008 for the term “TBI model” yielded approximately 900 references, whereas the search for the term “post-traumatic epilepsy model” resulted in only around 40 references. In most of these models, PTE has been triggered by iron injection to the cortex or the amygdala, or by cortical undercut (Willmore et al., 1978; see Prince et al., 2009). Only recently, models developed in the trauma field to investigate human TBI have been used to assess the development of lowered seizure threshold and epilepsy (Table 2). The large majority of these studies have used lateral fluid-percussion (LFP) or central fluid-percussion (CFP) TBI models that produce both gray matter and white matter damage (Fig. 1). Other models used include weight drop, controlled cortical impact, or penetrating ballistic injury models (see Table 2). All of these models belong to mixed type or focal models of TBI (Morales et al., 2005).

Table 2.   Summary of studies that have investigated changes in brain excitability after traumatic brain injury
Injury typePostinjury assessmentPreparationChange in excitabilityReference
  1. CCI, controlled cortical impact; CFP, central fluid-percussion traumatic brain injury (TBI); GABA, γ-amino butyric acid; LFP, lateral fluid-percussion TBI; P, postnatal day; PTZ, pentylenetetrazol; rpFPI, rostral parasagittal fluid-percussion injury. All experiments were performed in rats unless otherwise indicated.

Immediate phase (<24 h)
Weight drop0–2 h post-TBIIn vivo82% of rats had electrographic generalized seizuresNilsson et al. (1994)
LFP1 h post-TBIHippocampal sliceIncreased duration of evoked presynaptic volleys in CA1Reeves et al. (2000)
LFP1–4 h post-TBIHippocampal sliceDepolarizing shift in the resting membrane potential of dentate interneurons (recovers in 4 days)Ross & Soltesz (2000)
LFP1 h post-TBIIn vivoLowered threshold for kainate-induced behavioral seizuresRoncati Zanier et al. (2003)
LFP0–24 h post-TBIIn vivoUp to 30% of rats had behavioral clonic seizuresKharatishvili et al. (2006)
Weight drop2 h and 24 h post-TBIHippocampal sliceCA1 pyramidal cell hyperexcitability (not detected in CA3). Normalized within 3 daysGriesemer & Mautes (2007)
Early phase (≤1 week)
LFP1 week post-TBIIn vivoIncreased granule cell hyperexcitabilityLowenstein et al. (1992)
LFP1 week post-TBIHippocampal-entorhinal slicesIncreased stimulus-induced afterdischarge duration and self-sustained epileptic activity in dentate gyrusCoulter et al. (1996)
LFP2 days post-TBIIn vivoDecreased inhibition in CA1 Increased inhibition in dentate gyrusReeves et al. (1997)
LFP1 week post-TBIHippocampal sliceDecreased feed-forward GABAA receptor-mediated inhibition of granule cellsToth et al. (1997)
LFP1 week post-TBIHippocampal sliceMossy cell and granule cell hyperexcitabilitySanthakumar et al. (2000)
LFP1 week post-TBIHippocampal sliceDentate gyrus hyperexcitability to low-frequency stimulation (recovers in 1 month)Santhakumar et al. (2001)
LFP1 week post-TBIHippocampal sliceCA1 hyperexcitabilityAkasu et al. (2002)
CFP3 h–7 days post-TBICoronal slice with corpus callosumAxonal conductance defect in corpus callosumBaker et al. (2002)
LFP (mice)6–8 days post-TBIHippocampal sliceEnhanced inhibition in CA1 Reduced inhibition in the dentate gyrusWitgen et al. (2005)
Penetrating ballistic-like injury0–72 hIn vivoSeizures in 14% of animalsWilliams et al. (2006)
LFP (mice)7 days post-TBIHippocampal sliceBilateral dentate gyrus hyperexcitabilityTran et al. (2006)
Late Phase (>1 week)
CFPPTZ kindling started 24 h after TBIIn vivoNo difference in kindling rate as compared to controlsHamm et al. (1995)
LFP15 days post-TBIIn vivoIncreased inhibition in dentate gyrusReeves et al. (1997)
LFP3 months post-TBIHippocampal - entorhinal sliceDecrease in the threshold for generation of self-sustaining epileptiform activity to high-frequency stimulation in CA1Santhakumar et al. (2001)
Weight drop3 weeks post-TBIHippocampal sliceBilateral hyperexcitability of the granule cell and molecular layers of dentate gyrusGolarai et al. (2001)
Weight drop15 weeks post-TBIIn vivo Hippocampal sliceIncreased susceptibility to PTZ-induced seizures Bilateral hyperexcitability of the granule cell and molecular layers of dentate gyrusGolarai et al. (2001)
LFP8–10 weeks post-TBICortical sliceCortical hyperexcitabilityD’Ambrosio et al. (2004)
LFP2–16 weeks post-TBIIn vivoSpontaneous seizures originating in the frontoparietal cortexD’Ambrosio et al. (2004)
rpFPIUp to 7 months post-TBIIn vivoSpontaneous hippocampal seizures in addition to cortical seizuresD’Ambrosio et al. (2005)
LFPUp to 1 year post-TBIIn vivoUp to 50% of rats have electrographic seizures clonic seizuresKharatishvili et al. (2006)
LFP (mice)30 days post-TBIHippocampal sliceDentate gyrus hyperexcitability ipsilaterally but not contralaterallyTran et al. (2006)
LFPUp to 1 year post-TBIIn vivoEpileptiform electrographic interictal spiking in 80% of ratsKharatishvili et al. (2007)
CCI (P16-18)2 weeks post-TBI (P34–40) 6 weeks post-TBI (P60–63)In vivoNo change in limbic, hindbrain or forebrain seizure threshold Decreased forebrain (minimal clonic seizure) thresholdStatler et al. (2008)
image

Figure 1.   (A) Location of craniectomy in a model of fluid-percussion (FP) traumatic brain injury (TBI) in the two laboratories that have shown the development of epilepsy in this model of TBI. (B) Injury device that is used for induction of FP injury. The strength of the injury is adjusted by pendulum height. After release, the pendulum hits the cork piston, sealing one end of the saline-filled cylinder that transmits the liquid pulse to the epidural space. (C) The injury develops gradually (see also Fig. 2). Here the location and extent of injury is shown in a T2-weighted image (open arrow) at 9 days after lateral FP injury. (D) A thionin-stained coronal section from the brain of a rat subjected to lateral FP (LFP) brain injury. The animal had been followed for 12 months postinjury and had a total of 11 seizures during seven video-EEG (electroencephalography) monitoring sessions (63 recording days). The first spontaneous seizure was recorded 3 months after injury. Seventy-one percent of seizures were secondarily generalized. In addition to the injury site in the cortex, structural alterations are clear ipsilaterally in the hippocampus (HC) and thalamus (Th). (E) Higher magnification photomicrograph from a thionin-stained hippocampus from a rat with LFP injury–induced posttraumatic epilepsy (PTE). Note the loss of hilar cells (indicated with an arrow). (F) Timm-stained hippocampal section from the rat with PTE demonstrating mossy fiber sprouting in the inner molecular layer (arrows). CA3, CA3 pyramidal cell layer of the hippocampus; g, granule cell layer; f, the dentate gyrus; H, hilus; m, molecular layer.

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In Table 2, we have divided the observations made about the posttraumatic brain excitability into immediate (within 24 h postinjury), early (between 24 h and 1 week postinjury), and late changes (>1 week postinjury) (Frey, 2003). At the immediate phase, a subpopulation of animals that experienced either weight drop or LFP-induced TBI were reported to experience spontaneous postinjury seizures (Nilsson et al., 1994; Kharatishvili et al., 2006). In addition, seizure threshold for induced seizures was reduced (Roncati Zanier et al., 2003) and in vitro studies demonstrated hyperexcitability in the CA1 subfield of the hippocampus (Reeves et al., 2000; Griesemer & Mautes, 2007). In addition, during the first week after TBI (early phase, between 24 h and 1 week postinjury), spontaneous, presumably injury-related seizures can still occur as reported by Williams and coworkers in the new penetrating ballistic-like injury (Williams et al., 2005, 2006). At this later phase, most of the in vitro electrophysiologic studies have demonstrated increased excitability not only in the CA1 (Reeves et al., 1997; Akasu et al., 2002) but also in the dentate gyrus (Lowenstein et al., 1992; Coulter et al., 1996; Reeves et al., 1997; Toth et al., 1997; Santhakumar et al., 2001; Witgen et al., 2005; Tran et al., 2006). In addition to changes in local excitability, Baker et al. (2002) reported an axonal conductance defect in the corpus callosum. Whether it has an effect on seizure spread at later stages remains to be studied.

A survey of conventional animal models in the trauma field indicates that late spontaneous seizures or epilepsy have consistently been reported only in the rat fluid-percussion TBI model, which is the most commonly used model of human closed head TBI (D’Ambrosio et al., 2004, 2005; Kharatishvili et al., 2006). Interestingly, as compared to the most commonly used epileptogenesis models that are induced by status epilepticus (SE), in PTE induced by LFP injury the epileptogenesis phase is longer, seizure frequency is substantially lower, and most of the seizures are secondarily generalized rather than partial (Table 3; Nissinen et al., 2000; Kharatishvili et al., 2006). In the rat weight-drop model the threshold for pentylenetetrazol (PTZ)–induced seizures is reduced but no spontaneous seizures have been reported (Golarai et al., 2001). Recently, Statler et al. (2008) reported lowered minimal clonic seizure threshold in the mouse controlled cortical impact (CCI) model. Although reports about the occurrence of spontaneous seizures have been sparse, which may partly relate to low seizure frequency, observations available from in vitro slice studies support the idea that cortical and hippocampal excitability are chronically increased in a variety of TBI models (Table 2).

Table 3.   Comparison of epilepsy phenotypes in posttraumatic and post–status epilepticus models
Epilepsy phenotypeTBI Lateral fluid-percussion Kharatishvili et al. (2006)SE Amygdala stimulation Nissinen et al. (2000)
  1. AED, antiepileptic drug; SE, status epilepticus; TBI, traumatic brain injury.

Epileptogenesis
 Duration of latencySeveral monthsDays–1 month
 % of rats with seizures50%80–100%
Epilepsy
 Mean seizure frequency0.3/day8/day
 Maximal seizure frequencyUp to 1/dayUp to 30/day
 Mean seizure duration104 s49 s
 Day–night cycle44% lights on57% lights on
 Response to AEDsNo dataYes
Comorbidities
 Memory impairmentYesYes
 Sensorimotor impairmentYesNo data
 Drug-refractorinessNo dataYes

There are several caveats to consider when interpreting the experimental data available. A large majority of the studies characterizing post-TBI changes in excitability have investigated rats with focal or mixed type TBI, that is, models in which white matter damage is not the dominant pathologic feature. This may impose limitations on data interpretation, in particular when assessing the association of type of damage with risk of epileptogenesis (e.g., focal gray matter damage vs. DAI). In addition, little information is available about the development of epilepsy in mice with TBI, although such information would be valuable in guiding the use of genetically modified mice in search of risk genes for PTE. Furthermore, very little information is available about the excitability change after TBI in immature animals, even though childhood PTE is not uncommon (Statler, 2006). Moreover, combining TBI with other factors such as hypoxia, hyperthermia, intracerebral bleeding, infection, or SE that compromise the outcome in the clinical setting could provide useful information about the mechanisms and conditions that increase the risk of PTE. We will focus next on the fluid-percussion TBI model, the only model, so far, where the occurrence of spontaneous seizures has been consistently demonstrated.

Epileptogenesis versus Recovery

  1. Top of page
  2. Summary
  3. Heterogeneity of TBI in Humans—A Challenge for Animal Model Development
  4. Using TBI Models for Modeling PTE
  5. Epileptogenesis versus Recovery
  6. Preclinical Trials in Experimental Models of TBI— Do They Pave the Way for Finding Antiepileptogenic or Disease-Modifying Treatments for PTE?
  7. Use of AEDs at Early Postinjury Phase—Any Harm?
  8. Future Challenges
  9. Acknowledgments
  10. References

LFP injury causes both primary and secondary damage to the brain. The primary damage is caused by the impact itself, and it initiates ionic, molecular, and cellular alterations within seconds. This is followed by secondary damage that is composed of neurodegeneration, neurogenesis, astrocytosis, microgliosis, axonal and myelin injury, axonal sprouting, vascular damage, and angiogenesis (see Reilly, 2001;Thompson et al., 2005; Pitkänen & McIntosh, 2006). Previous histologic analyses of the LFP injury model demonstrated that these alterations can happen in the injured cortex, perifocal area, underlying hippocampus, and/or thalamus (Thompson et al., 2005). Most of the data concerning the progression of damage have been collected during the first 1–2 months postinjury, which corresponds also to the time period when most of the electrophysiologic alterations implying increased excitability of injured tissue have been performed (Thompson et al., 2005). Very few studies have addressed the dynamics of molecular and cellular alterations at the later stages when the spontaneous seizures appear (Kharatishvili et al., 2006). The application of MRI in the analysis of cellular and pathway alterations will likely provide useful information about the association of cellular pathology with epileptogenesis, and help to understand why epileptogenesis is seen only in a subpopulation of animals (Kharatishvili et al., 2007).

Well-documented functional consequences of LFP-induced injury include somatomotor and cognitive impairment (Thompson et al., 2005). Interestingly, somatomotor impairment is partly recoverable within the few weeks or months postinjury. This is associated with regenerative cellular processes in the brain such as axonal sprouting and revascularization. It is important to bear in mind that epileptogenesis is underway in parallel to the physical recovery of animals, at least in subpopulations of animals (Fig. 2).

image

Figure 2.   The brain faces many challenges after traumatic brain injury (TBI). Acute damage related to the primary impact is followed by a myriad of secondary molecular and cellular changes, including delayed neurodegeneration, neurogenesis, axonal injury, axonal sprouting, gliosis, and angiogenesis. Many of these alterations are apparently needed for successful recovery that occurs over the weeks and months postinjury. In parallel to the recovery process, a subpopulation of animals undergo epileptogenesis, culminating in the occurrence of spontaneous seizures. The great challenge is to differentiate those mechanisms that lead to favorable and unfavorable recovery.

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Preclinical Trials in Experimental Models of TBI— Do They Pave the Way for Finding Antiepileptogenic or Disease-Modifying Treatments for PTE?

  1. Top of page
  2. Summary
  3. Heterogeneity of TBI in Humans—A Challenge for Animal Model Development
  4. Using TBI Models for Modeling PTE
  5. Epileptogenesis versus Recovery
  6. Preclinical Trials in Experimental Models of TBI— Do They Pave the Way for Finding Antiepileptogenic or Disease-Modifying Treatments for PTE?
  7. Use of AEDs at Early Postinjury Phase—Any Harm?
  8. Future Challenges
  9. Acknowledgments
  10. References

A large number of different treatments have been tested to enhance posttraumatic recovery. Pharmacologic approaches include use of compounds reducing excitotoxicity, calcium channel blockage, free radical scavengers, antiinflammatory agents, neurotrophic factors, caspase inhibitors, calpain inhibitors, hormonal treatments, augmentation of various neurotransmitter systems, anticoagulants, poly (ADP-ribose) polymerase (PARP) inhibitors, and antiepileptic drugs (AEDs) (for a comprehensive review, see Marklund et al., 2006). More recently, cell transplantation including genetically manipulated cell types have been tested as a recovery-enhancing treatment option (see Pitkänen et al., 2006).

Both in pharmacologic and cell therapy studies, outcome measures have included the effects of treatments on the edema development, volume of cortical lesions, severity and extent of hippocampal neurodegeneration, axonal injury, somatomotor function, and learning and memory. Although positive effects have been obtained in several experimental trials, treatments have not yet been translated to clinical practice. From the epileptogenesis point of view it is, however, conspicuous that the development of late spontaneous seizures has never been an outcome measure in preclinical TBI trials. This creates a question: whether some of these treatments were actually antiepileptogenic or disease-modifying, if epilepsy would have been analyzed as an outcome measure.

Use of AEDs at Early Postinjury Phase—Any Harm?

  1. Top of page
  2. Summary
  3. Heterogeneity of TBI in Humans—A Challenge for Animal Model Development
  4. Using TBI Models for Modeling PTE
  5. Epileptogenesis versus Recovery
  6. Preclinical Trials in Experimental Models of TBI— Do They Pave the Way for Finding Antiepileptogenic or Disease-Modifying Treatments for PTE?
  7. Use of AEDs at Early Postinjury Phase—Any Harm?
  8. Future Challenges
  9. Acknowledgments
  10. References

As discussed by Temkin (see the present volume), there is no evidence that any of the AEDs, when administered after TBI, would have any antiepileptogenic or disease-modifying effects on the development of PTE in humans. Conversely: do AEDs compromise the postinjury recovery?

Table 4 summarizes the effects of AEDs on posttraumatic recovery in animal models. So far, remacemide, topiramate, talampanel, lacosamide, and carisbamate have been investigated. No major harmful or beneficial effects have been reported. However, studies in which AEDs had been administered for a longer period after TBI and in which outcome measures had been assessed months later are not available.

Table 4.   Effects of administration of antiepileptic drugs on posttraumatic recovery in experimental models
AEDBeginning and duration of treatmentOutcome measures (time of analysis)EffectReference
  1. AED, antiepileptic drug.

Remacemide15 min postinjury Rx single doseCortical lesion (48 h postinjury) Learning and memory (48 h postinjury)inline image inline imageSmith et al. (1997b)
Topiramate30 min postinjury Rx for 32 hEdema (48 h postinjury) Neurodegeneration (48 h postinjury) Memory (48 h postinjury) Learning (4 weeks postinjury) Motor recovery (4 weeks postinjury) Rotating pole (4 weeks postinjury) inline image inline image inline image inline image inline image inline imageHoover et al. (2004)
Talampanel30 min postinjury Rx for 3 dayCortical lesion (7 days postinjury) CA1 degeneration (7 days postinjury)inline image inline imageBelayev et al. (2001)
Lacosamide30 min postinjury Rx for 3 dayLesion severity (2 weeks postinjury) Motor function (2 weeks postinjury) Learning and memory (2 weeks postinjury)inline image inline image inline imageNissinen et al. (2006)
Carisbamate (RWJ-333369)15 min postinjury Rx for 1 dayEdema (48 h postinjury) Lesion size (4 week postinjury) Motor function (up to 4 week postinjury) Learning (4 week postinjury)inline image inline image inline image inline imageKeck et al. (2007)

Future Challenges

  1. Top of page
  2. Summary
  3. Heterogeneity of TBI in Humans—A Challenge for Animal Model Development
  4. Using TBI Models for Modeling PTE
  5. Epileptogenesis versus Recovery
  6. Preclinical Trials in Experimental Models of TBI— Do They Pave the Way for Finding Antiepileptogenic or Disease-Modifying Treatments for PTE?
  7. Use of AEDs at Early Postinjury Phase—Any Harm?
  8. Future Challenges
  9. Acknowledgments
  10. References

We already have plenty of information on postinjury neurogenesis, synaptogenesis, and revascularization, which presumably contribute to the repair process. This raises a question: Is epilepsy a concomitant of an effective recovery process, a by-product of aberrant recovery, or a complication that hampers good clinical outcome? Furthermore, would the best recovery enhancements also modify the epileptogenic process? To find the answers it will be necessary to differentiate the molecular mechanisms that lead to favorable recovery from those that compromise it. Data available also show that modeling of PTE is laborious. Therefore, there is an urgent need for development of bio/surrogate markers that would predict epileptogenesis after different types of brain injuries and could be used for selection of animals for studies aimed at understanding the mechanisms of posttraumatic epileptogenesis, preclinical trials testing novel treatments, and also for the follow-up of treatment efficacy.

Disclosure: None of the authors have any conflicts of interest to disclose.

References

  1. Top of page
  2. Summary
  3. Heterogeneity of TBI in Humans—A Challenge for Animal Model Development
  4. Using TBI Models for Modeling PTE
  5. Epileptogenesis versus Recovery
  6. Preclinical Trials in Experimental Models of TBI— Do They Pave the Way for Finding Antiepileptogenic or Disease-Modifying Treatments for PTE?
  7. Use of AEDs at Early Postinjury Phase—Any Harm?
  8. Future Challenges
  9. Acknowledgments
  10. References
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