Mechanisms of epileptogenesis in tuberous sclerosis complex and related malformations of cortical development with abnormal glioneuronal proliferation

Malformations of cortical development (MCDs) are increasingly recognized as causes of medically intractable epilepsy. In order to develop more effective, rational therapies for refractory epilepsy related to MCDs, it is important to achieve a better understanding of the underlying mechanisms of epileptogenesis, but this is complicated by the wide variety of different radiographic, histopathological, and molecular features of these disorders. A subset of MCDs share a number of characteristic cellular and molecular abnormalities due to early defects in neuronal and glial proliferation and differentiation and have a particularly high incidence of epilepsy, suggesting that this category of MCDs with abnormal glioneuronal proliferation may also share a common set of primary mechanisms of epileptogenesis. This review critically analyzes both clinical and basic science evidence for overlapping mechanisms of epileptogenesis in this group of disorders, focusing on tuberous sclerosis complex, focal cortical dysplasia with balloon cells, and gangliogliomas. Specifically, the role of lesional versus perilesional regions, circuit versus cellular/molecular defects, and nonneuronal factors, such as astrocytes, in contributing to epileptogenesis in these MCDs is examined. An improved understanding of these various factors involved in epileptogenesis has direct clinical implications for optimizing current treatments or developing novel therapeutic approaches for epilepsy in these disorders.     

Tuberous sclerosis and epilepsy: role of astrocytes

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that is among the most common genetic causes of epilepsy. Focal brain lesions in TSC, known as cortical tubers, have been implicated in promoting epileptogenesis in TSC. Histological, cellular, and molecular abnormalities in astrocytes are characteristic features of tubers and perituberal cortex, suggesting that astrocyte dysfunction may contribute to the pathophysiology of epilepsy in TSC. Numerous astrocytes can be seen histologically in tubers expressing glial fibrillary acidic and S100 proteins. In some analyses, astrocytes exhibit enhanced activation of the mammalian target of rapamycin suggesting a link between TSC1 and TSC2 mutations and astrocytic proliferation. Astrocytic proliferation in subependymal giant cell astrocytoma is associated with progressive growth and compression of surrounding brain structures by these lesions. Increased numbers of enlarged astrocytes has been observed in several TSC mouse models and may be intimately linked to epileptogenesis. Impairment of astrocytic buffering mechanisms for glutamate and potassium has been identified in TSC animal models and human tuber tissue and likely promotes neuronal excitability and seizures in TSC. Targeting these defects in astrocytes may represent a novel therapeutic strategy for epilepsy in patients with TSC.     

Pathology and pathophysiology of the amygdala in epileptogenesis and epilepsy

Acute brain insults, such as traumatic brain injury, status epilepticus, or stroke are common etiologies for the development of epilepsy, including temporal lobe epilepsy (TLE), which is often refractory to drug therapy. The mechanisms by which a brain injury can lead to epilepsy are poorly understood. It is well recognized that excessive glutamatergic activity plays a major role in the initial pathological and pathophysiological damage. This initial damage is followed by a latent period, during which there is no seizure activity, yet a number of pathophysiological and structural alterations are taking place in key brain regions, that culminate in the expression of epilepsy. The process by which affected/injured neurons that have survived the acute insult, along with well-preserved neurons are progressively forming hyperexcitable, epileptic neuronal networks has been termed epileptogenesis. Understanding the mechanisms of epileptogenesis is crucial for the development of therapeutic interventions that will prevent the manifestation of epilepsy after a brain injury, or reduce its severity. The amygdala, a temporal lobe structure that is most well known for its central role in emotional behavior, also plays a key role in epileptogenesis and epilepsy. In this article, we review the current knowledge on the pathology of the amygdala associated with epileptogenesis and/or epilepsy in TLE patients, and in animal models of TLE. In addition, because a derangement in the balance between glutamatergic and GABAergic synaptic transmission is a salient feature of hyperexcitable, epileptic neuronal circuits, we also review the information available on the role of the glutamatergic and GABAergic systems in epileptogenesis and epilepsy in the amygdala.     

Epileptogenesis in the Developing Brain: What Can We Learn from Animal Models?

Summary:  Knowledge of the processes by which epilepsy is generated (epileptogenesis) is incomplete and has been a topic of major research efforts. Animal models can inform us about these processes. We focus on the distinguishing features of epileptogenesis in the developing brain and model prolonged febrile seizures (FS) that are associated with human temporal lobe epilepsy. In the animal model of FS, epileptogenesis occurs in ∼35% of rats. Unlike the majority of acquired epileptogeneses in adults, this process early in life (in the febrile seizures model as well as in several others) does not require "damage" (cell death). Rather, epileptogenesis early in life involves molecular mechanisms including seizure-evoked, long-lasting alterations of the expression of receptors and ion channels. Whereas transient changes in gene expression programs are common after early-life seizures, enduring effects, such as found after experimental FS, are associated with epileptogenesis. The ability of FS to generate long-lasting molecular changes and epilepsy suggests that mechanisms, including cytokine activation that are intrinsic to FS generation, may play a role also in the epileptogenic consequences of these seizures.     

Aquaporin-4 and epilepsy

Recent studies have implicated glial cells in modulation of synaptic transmission, so it is plausible that glial cells may have a functional role in the hyperexcitability characteristic of epilepsy. Indeed, alterations in distinct astrocyte membrane channels, receptors, and transporters have all been associated with the epileptic state. This review focuses on the potential roles of the glial water channel aquaporin-4 (AQP4) in modulation of brain excitability and in epilepsy. We will review studies of mice lacking AQP4 (Aqp4(-/-) mice) or α-syntrophin (an AQP4 anchoring protein) and discuss the available human studies demonstrating alterations of AQP4 in human epilepsy tissue specimens. We will conclude with new studies of AQP4 regulation and discuss the potential role of AQP4 in the development of epilepsy (epileptogenesis). While many questions remain unanswered, the available data indicate that AQP4 and its molecular partners may represent important new therapeutic targets.     

Mammalian target of rapamycin (mTOR) inhibition as a potential antiepileptogenic therapy: From tuberous sclerosis to common acquired epilepsies

Most current treatments for epilepsy are symptomatic therapies that suppress seizures but do not affect the underlying course or prognosis of epilepsy. The need for disease-modifying or "antiepileptogenic" treatments for epilepsy is widely recognized, but no such preventive therapies have yet been established for clinical use. A rational strategy for preventing epilepsy is to target primary signaling pathways that initially trigger the numerous downstream mechanisms mediating epileptogenesis. The mammalian target of rapamycin (mTOR) pathway represents a logical candidate, because mTOR regulates multiple cellular functions that may contribute to epileptogenesis, including protein synthesis, cell growth and proliferation, and synaptic plasticity. The importance of the mTOR pathway in epileptogenesis is best illustrated by tuberous sclerosis complex (TSC), one of the most common genetic causes of epilepsy. In mouse models of TSC, mTOR inhibitors prevent the development of epilepsy and underlying brain abnormalities associated with epileptogenesis. Accumulating evidence suggests that mTOR also participates in epileptogenesis due to a variety of other causes, including focal cortical dysplasia and acquired brain injuries, such as in animal models following status epilepticus or traumatic brain injury. Therefore, mTOR inhibition may represent a potential antiepileptogenic therapy for diverse types of epilepsy, including both genetic and acquired epilepsies.     

Animal models of focal cortical dysplasia and tuberous sclerosis complex: Recent progress toward clinical applications

Focal cortical dysplasia (FCD) and related malformations of cortical development (MCDs) represent an increasingly recognized cause of medically intractable epilepsy. However, the underlying mechanisms of epileptogenesis are poorly understood, and treatments for epilepsy due to various cortical malformations are often limited or ineffective. Animal models offer a number of advantages for investigating cellular and molecular mechanisms of epileptogenesis and developing novel, rational therapies for MCD-related epilepsy. This review highlights specific examples of how animal models have been useful in addressing several clinically relevant issues about epilepsy due to FCDs and related cortical malformations, including the pathologic and clinical features, etiologic factors, localization of the epileptogenic zone, neuronal and astrocytic contributions to epileptogenesis, and the development of antiepileptogenic therapies.     

Neurocysticercosis and pharmacoresistant epilepsy: possible role of calcified lesions in epileptogenesis

Neurocysticercosis is a neglected and usually poverty‐related disease of high public importance. The mechanisms by which the calcified lesions cause epilepsy are not known, but have been attributed to residual perilesional gliosis or an inflammatory process. This case shows that an inflammatory response to a calcified granuloma may be associated with the development of epilepsy. The increase in glutamate and kinin B1 (pro‐epileptogenic) receptors added by reduced expression of kinin B2 (anti‐epileptogenic) receptors may explain the chronic epileptogenesis associated with the lesion, corroborating the hypothesis of inflammatory mechanisms involved in the pathophysiology of epilepsy in these patients.     

The hypothalamic hamartoma: a model of subcortical epileptogenesis and encephalopathy

Although uncommon, the hypothalamic hamartoma (HH) is often associated with a devastating clinical syndrome, which may include refractory epilepsy, progressive cognitive decline, and deterioration in behavioral and psychiatric functioning. Contrary to conventional thinking which attributed seizure origin to cortical structures, the hamartoma itself has now been firmly established as the site of intrinsic epileptogenesis for the gelastic seizures (i.e., characterized by unusual mirth) peculiar to this disorder. It also appears that the HH contributes to a process of secondary epileptogenesis, with eventual cortical seizure onset of multiple types in some patients. Anticonvulsant medications are known to be poorly effective in this disorder. Treatment, including some innovative approaches to surgical resection, is now targeted directly at the HH itself, with impressive results. Younger patients, in particular, may avoid the deteriorating course described earlier. Access to tissue from larger numbers of patients at single or collaborating centers specializing in HH surgery will allow for research into the fundamental mechanisms producing this little understood disorder. Refractory epilepsy associated with HH is the premier human model for subcortical epilepsy and an excellent model for secondary epileptogenesis and epileptic encephalopathy.     

Glial source of nitric oxide in epileptogenesis: A target for disease modification in epilepsy

Epileptogenesis is the process of developing an epileptic condition and/or its progression once it is established. The molecules that initiate, promote, and propagate remarkable changes in the brain during epileptogenesis are emerging as targets for prevention/treatment of epilepsy. Epileptogenesis is a continuous process that follows immediately after status epilepticus (SE) in animal models of acquired temporal lobe epilepsy (TLE). Both SE and epileptogenesis are potential therapeutic targets for the discovery of anticonvulsants and antiepileptogenic or disease-modifying agents. For translational studies, SE targets are appropriate for screening anticonvulsive drugs prior to their advancement as therapeutic agents, while targets of epileptogenesis are relevant for identification and development of therapeutic agents that can either prevent or modify the disease or its onset. The acute seizure models do not reveal antiepileptogenic properties of anticonvulsive drugs. This review highlights the important components of epileptogenesis and the long-term impact of intervening one of these components, nitric oxide (NO), in rat and mouse kainate models of TLE. NO is a putative pleotropic gaseous neurotransmitter and an important contributor of nitro-oxidative stress that coexists with neuroinflammation and epileptogenesis. The long-term impact of inhibiting the glial source of NO during early epileptogenesis in the rat model of TLE is reviewed. The importance of sex as a biological variable in disease modification strategies in epilepsy is also briefly discussed.     

Pathophysiology of epilepsy

This work reviews the current knowledge on epileptogenesis and pathophysiology of epilepsy. Recently, gene defects underlying four monogenic epilepsies (generalized epilepsy with febrile seizures, autosomal dominant nocturnal frontal lobe epilepsy, benign familial neonatal convulsions and episodic ataxia type 1 with partial seizures) have been identified, shedding new light on the pathophysiology of epilepsy as these diseases are caused by ion channel mutations. Although epileptic syndromes differ pathophysiologically, common ictogenesis-related characteristics as increased neuronal excitability and synchronicity are shared as well as mechanisms involved in interictal-ictal transition. Emerging insights point to alterations of synaptic functions and intrinsic properties of neurons as common mechanisms underlying hyperexcitability. This work also reviews the neurochemical mechanisms of epilepsy. An imbalance between glutamate and gamma-aminobutyric acid neurotransmitter systems can lead to hyperexcitability but catecholaminergic neurotransmitter systems and opioid peptides were shown to play a role in epileptogenesis as well. An overview of currently available anti-epileptic drugs and their presumed mechanisms of action is given as an illustration of the neurochemistry of epileptogenesis. Most anti-epileptic drugs exert their anti-epileptic properties through only a few neurochemical mechanisms that are meanwhile basic pathophysiological mechanisms thought to cause seizures.     

Etiologic and Preventive Aspects of Epilepsy in the Child–Bridging the Gap Between Laboratory and Clinic

Summary: Four broad categories of basic phenomena are pertinent to developing ways to prevent epilepsy. These include mechanisms of epileptogenesis, ictal initiation and temporary entrainment by the seizure discharge of normally functioning brain, seizure propagation, and control mechanisms that function both to restrain the cascade of epileptic events culminating in a seizure and to arrest the epileptic event and restore the interictal state. In newborns and children, hypoxia-ischemia is a major factor leading to epileptogenesis, and several schemes are proposed to classify, quantify, and prevent hypoxic-ischemic encephalopathy. Control mechanisms must be better understood in order to develop prophylactic recommendations for epilepsy, and an experimental model of "kindling antagonism" may increase our understanding of these. Programs of prevention of seizures in children will evolve only if basic researchers and clinicians work productively together to develop an adequate understanding of factors important in epileptogenesis and antiepileptogenic control mechanisms.     

Epileptogenic roles of astroglial death and regeneration in the dentate gyrus of experimental temporal lobe epilepsy

Recent studies have demonstrated that blockade of neuronal death in the hippocampus cannot prevent epileptogenesis in various epileptic models. These reports indicate that neurodegeneration alone is insufficient to cause epilepsy, and that the role of astrocytes in epileptogenesis should be reconsidered. Therefore, the present study was designed to elucidate whether altered morphological organization or the functionalities of astrocytes induced by status epilepticus (SE) is responsible for epileptogenesis. Glial responses (reactive microgliosis followed by astroglial death) in the dentate gyrus induced by pilocarpine-induced SE were found to precede neuronal damage and these alterations were closely related to abnormal neurotransmission related to altered vesicular glutamate and GABA transporter expressions, and mossy fiber sprouting in the dentate gyrus. In addition, newly generated astrocytes showed down-regulated expressions of glutamine synthase, glutamate dehydrogenase, and glial GABA transporter. Taken together, our findings suggest that glial responses after SE may contribute to epileptogenesis and the acquisition of the properties of the epileptic hippocampus. Thus, we believe that it is worth considering new therapeutic approaches to epileptogenesis involving targeting the inactivation of microglia and protecting against astroglial loss.     

Mechanisms of depression in epilepsy from a clinical perspective

The epilepsies are a complex group of disorders commonly associated with brain dysfunction, social isolation, and vocational difficulty. Each of these factors may contribute to increased prevalence of depressive disorders in epilepsy, but the specific mechanisms are not completely understood. The brain regions commonly involved in various types of epilepsies, such as the hippocampus and amygdala in temporal lobe epilepsy and subcortical nuclei in idiopathic generalized epilepsies, are important components of current models of depression. Increased understanding of mechanisms of depression in epilepsy is not only crucial for improving care of many persons with seizures, but may also yield useful information about principal mechanisms underlying both depression and epileptogenesis.     

Toothbrushing-induced epilepsy with structural lesions in the primary somatosensory area

We report three patients with reflex toothbrushing-induced epilepsy associated with small circumscribed structural lesions in the primary somatosensory cortex in close proximity to the hand and speech motor areas. Sensory symptoms were observed at clinical onset with localizing focal ictal and interictal epileptiform discharges on EEG. These cases refine the localization, possible mechanisms of epileptogenesis, and classification of this reflex epilepsy.     

Epilepsy

PURPOSE OF REVIEW: To provide a critical review of studies published between December 2005 and November 2006, and detect the advances of basic and clinical research in epilepsy. RECENT FINDINGS: The complexity of the mechanisms underlying epileptogenesis and drug resistance was repeatedly highlighted. Seizure diagnosis and classification are still difficult, despite the use of valid and reliable instruments. Even well defined epilepsy syndromes may exhibit complex genetic patterns and atypical electroencephalogram features. Low prevalence rates of active epilepsy have been reported from several countries, suggesting underreporting for sociocultural reasons. Several pregnancy and neonatal factors can be found to increase the risk of epilepsy when accurate data are available from well defined populations. Early remission of seizures does not always predict terminal remission after prolonged follow-up. Cognitive regression may be associated with the presence of interictal electroencephalographic epileptiform abnormalities. A Cochrane review showed lamotrigine to be less frequently withdrawn than carbamazepine. However, these findings are contrasted by clinical practice, which showed no individual drug to be more likely to confer seizure freedom than any other. SUMMARY: Recent research highlights the complexity of the mechanisms of epileptogenesis and drug response, and the difficulties with the classification of epilepsy into separate phenotypic categories.     

Epilepsy Related to Traumatic Brain Injury

Post-traumatic epilepsy accounts for 10–20 % of symptomatic epilepsy in the general population and 5 % of all epilepsy. During the last decade, an increasing number of laboratories have investigated the molecular and cellular mechanisms of post-traumatic epileptogenesis in experimental models. However, identification of critical molecular, cellular, and network mechanisms that would be specific for post-traumatic epileptogenesis remains a challenge. Despite of that, 7 of 9 proof-of-concept antiepileptogenesis studies have demonstrated some effect on seizure susceptibility after experimental traumatic brain injury, even though none of them has progressed to clinic. Moreover, there has been some promise that new clinically translatable imaging approaches can identify biomarkers for post-traumatic epileptogenesis. Even though the progress in combating post-traumatic epileptogenesis happens in small steps, recent discoveries kindle hope for identification of treatment strategies to prevent post-traumatic epilepsy in at-risk patients.