Neuroimaging the Epileptogenic Process

Epilepsy is one of the most common chronic neurological conditions worldwide. Anti-epileptic drugs (AEDs) can suppress seizures, but do not affect the underlying epileptic state, and many epilepsy patients are unable to attain seizure control with AEDs. To cure or prevent epilepsy, disease-modifying interventions that inhibit or reverse the disease process of epileptogenesis must be developed. A major limitation in the development and implementation of such an intervention is the current poor understanding, and the lack of reliable biomarkers, of the epileptogenic process. Neuroimaging represents a non-invasive medical and research tool with the ability to identify early pathophysiological changes involved in epileptogenesis, monitor disease progression, and assess the effectiveness of possible therapies. Here we will provide an overview of studies conducted in animal models and in patients with epilepsy that have utilized various neuroimaging modalities to investigate epileptogenesis.     

Biomarkers of Epileptogenesis: Psychiatric Comorbidities (?)

The last decade has witnessed a significant shift on our understanding of the relationship between psychiatric disorders and epilepsy. While traditionally psychiatric disorders were considered as a complication of the underlying seizure disorder, new epidemiologic data, supported by clinical and experimental research, have suggested the existence of a bidirectional relation between the two types of conditions: not only are patients with epilepsy at greater risk of experiencing a psychiatric disorder, but patients with primary psychiatric disorders are at greater risk of developing epilepsy. Do these data suggest that some of the pathogenic mechanisms operant in psychiatric comorbidities play a role in epileptogenesis? The aim of this article is to review the epidemiologic data that demonstrate that primary psychiatric disorders are more frequent in people who develop epilepsy, before the onset of the seizure disorder than among controls. The next question looks at the available data of pathogenic mechanisms of primary mood disorders and their potential for facilitating the development and/or exacerbation in the severity of epileptic seizures. Finally, we review data derived from experimental studies in animal models of depression and epilepsy that support a potential role of pathogenic mechanisms of mood disorders in the development of epileptic seizures and epileptogenesis. The data presented in this article do not yet establish conclusive evidence of a pathogenic role of psychiatric comorbidities in epileptogenesis, but raise important research questions that need to be investigated in experimental, clinical, and population-based epidemiologic research studies.     

MicroRNAs and target genes in epileptogenesis

Epilepsy is a chronic brain dysfunction. Current antiepileptic medicines cannot prevent epileptogenesis. Increasing data have shown that microRNAs (miRNAs) are selectively altered within the epileptic hippocampi of experimental models and human tissues, and these alterations affect the genes that control epileptogenesis. Furthermore, manipulation of miRNAs in animal models can modify epileptogenesis. As a result, miRNAs have been proposed as promising targets for treating epilepsy. We searched PubMed using the terms “microRNAs/miRNAs AND epilepsy”, “microRNAs/miRNAs AND epileptogenesis”, and “microRNAs/miRNAs AND seizure”. We selected the articles in which the relationship between miRNAs and target gene(s) was validated and manipulation of miRNAs in in vivo epilepsy models modified epileptogenesis during the chronic phase via gene regulation. A total of 13 miRNAs were found in the present review. Based on the current analysis of miRNAs and their target gene(s), each miRNA has limitations as a potential epilepsy target. Importantly, miR-211 or miR-128 transgenic mice displayed seizures. These findings highlight new developments for epileptogenesis prevention. Developing novel strategies to modify epileptogenesis will be effective in curing epilepsy patients. This article provides an overview of the clinical application of miRNAs as novel targets for epilepsy.     

Long-term alteration of calcium homeostatic mechanisms in the pilocarpine model of temporal lobe epilepsy

The pilocarpine model of temporal lobe epilepsy is an animal model that shares many of the clinical and pathophysiological characteristics of temporal lobe or limbic epilepsy in humans. This model of acquired epilepsy produces spontaneous recurrent seizure discharges following an initial brain injury produced by pilocarpine-induced status epilepticus. Understanding the molecular mechanisms mediating these long lasting changes in neuronal excitability would provide an important insight into developing new strategies for the treatment and possible prevention of this condition. Our laboratory has been studying the role of alterations in calcium and calcium-dependent systems in mediating some of the long-term neuroplasticity changes associated with epileptogenesis. In this study, [Ca(2+)](i) imaging fluorescence microscopy was performed on CA1 hippocampal neurons acutely isolated from control and chronically epileptic animals at 1 year after the induction of epileptogenesis with two different fluorescent dyes (Fura-2 and Fura-FF) having high and low affinities for [Ca(2+)](i). The high affinity Ca(2+) indicator Fura-2 was utilized to evaluate [Ca(2+)](i) levels up to 900 nM and the low affinity indicator Fura-FF was employed for evaluating [Ca(2+)](i) levels above this range. Baseline [Ca(2+)](i) levels and the ability to restore resting [Ca(2+)](i) levels after a brief exposure to several glutamate concentrations in control and epileptic neurons were evaluated. Epileptic neurons demonstrated a statistically significantly higher baseline [Ca(2+)](i) level in comparison to age-matched control animals. This alteration in basal [Ca(2+)](i) levels persisted up to 1 year after the induction of epileptogenesis. In addition, the epileptic neurons were unable to rapidly restore [Ca(2+)](i) levels to baseline following the glutamate-induced [Ca(2+)](i) loads. These changes in Ca(2+) regulation were not produced by a single seizure and were not normalized by controlling the seizures in the epileptic animals with anticonvulsant treatment. Peak [Ca(2+)](i) levels in response to different concentrations of glutamate were the same in both epileptic and control neurons. Thus, glutamate produced the same initial [Ca(2+)](i) load in both epileptic and control neurons. Characterization of the viability of acutely isolated neurons from control and epileptic animals utilizing standard techniques to identify apoptotic or necrotic neurons demonstrated that epileptic neurons had no statistically significant difference in viability compared to age-matched controls. These results provide the first direct measurement of [Ca(2+)](i) levels in an intact model of epilepsy and indicate that epileptogenesis in this model produced long-lasting alterations in [Ca(2+)](i) homeostatic mechanisms that persist for up to 1 year after induction of epileptogenesis. These observations suggest that altered [Ca(2+)](i) homeostatic mechanisms may underlie some aspects of the epileptic phenotype and contribute to the persistent neuroplasticity changes associated with epilepsy.     

Peritumoral epilepsy: Relating form and function for surgical success

Seizures are a prominent symptom in patients with both primary and secondary brain tumors. Medical management of seizure control in this patient group is problematic as the mechanisms linking tumorigenesis and epileptogenesis are poorly understood. It is possible that several mechanisms contribute to tumor-associated epileptic zone formation. In this review, we discuss key candidates that may be implicated in peritumoral epileptogenesis and, in so doing, hope to highlight areas for future research. Furthermore, we summarize the current role of antiepileptic medications in this type of epilepsy and examine the changes in surgical practice which may lead to improved seizure rates after tumor surgery. Lastly, we speculate on possible future preoperative and intraoperative considerations for improving seizure control after tumor resection.This article is part of a Special Issue entitled “NEWroscience 2013”.     

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.     

Public awareness, attitude, and understanding of epilepsy in Hong Kong Special Administrative Region, China

PURPOSE: Because of the nature of the epileptic seizure, the social stigma attached to epilepsy is a major handicap to persons with epilepsy compared with the disability associated with seizures or the side effects from medications. Measuring the awareness, attitude, and understanding of epilepsy is the first step in alleviating discrimination. METHODS: We conducted a face-to-face questionnaire interview survey in five different locations (HKSAR) that represented the population structure, administrative function, and occupations of inhabitants. Subjects with epilepsy or with relatives who had epilepsy were excluded. RESULTS: We interviewed 1,128 subjects; 58.2% had heard about epilepsy before. Of these, 55% had witnessed one or more epileptic seizure, and 18.9% knew one or more persons with epilepsy; 52.7% would put an object into a patient's mouth during an epileptic seizure to prevent injury of the tongue (32.2% learned this from a local television program), and 94.1% agreed that persons with epilepsy could be married. However, only 72.5% considered pregnancy to be appropriate; 11.2% would not let their children play with others with epilepsy; 32.2% would not allow their children to marry persons with epilepsy. Employers (22.5%) would terminate the employment contract after an epileptic seizure in an employee with unreported epilepsy. CONCLUSIONS: This study documented the public attitude toward epilepsy in HKSAR; although it was more negative than that in Western societies, it was more positive than that of the Chinese in China or Taiwan. We suggest that more effort be made to improve public awareness of, attitude toward, and understanding of epilepsy through school education and epilepsy-related organizations in HKSAR.     

Public knowledge and attitudes toward epilepsy in Kuwait

PURPOSE: The study was conducted to determine the familiarity with, knowledge of, misunderstandings, and attitudes toward epilepsy among the Kuwaiti population. METHODS: A pretested questionnaire was used to collect data from a sample of 784 Kuwaiti individuals, selected from five governorates in Kuwait using a multistage stratified clustered sampling. RESULTS: Seven hundred fifty-five subjects were interviewed, and 97.6% reported their awareness about epilepsy. Of these, 51.8% knew someone who had epilepsy, 56.4% had witnessed an epileptic seizure, 45.9% believed that epilepsy is a hereditary disease, 60.4% reported that "all epileptic fits manifest symptoms of generalized tonic-clonic seizure," 88.3% indicated that putting an object into the patient's mouth to prevent tongue biting during a seizure is appropriate, and 57.1% stated that drug therapy was the only treatment available for epilepsy. Objections to shake hands with, working with, marrying, and employing epileptic patients were reported by 16.0%, 24.8%, 71.6%, and 45.2%, respectively. Childbirth by epileptic women and allowing children to play with an epileptic child were opposed by 56.3% and 27.7%, respectively. A total of 370 (50.2%) agreed that epilepsy is equivalent to psychiatric disorder. DISCUSSION: The present findings have demonstrated that epilepsy is a well-known disease in Kuwait, and that negative attitudes toward epilepsy do prevail in Kuwait. The majority of the negative attitudes were significantly associated with the misunderstanding of epilepsy. Continuing effective educational interventions would be needed in order to improve the appropriate understanding of epilepsy, and to ameliorate the social discrimination and misconceptions against epileptic patients.     

Conceptual relevance of new-onset epilepsy

The definitions of "first seizure" and "new-onset epilepsy" are arbitrary and rather simple for use to describe the beginning of a complex brain disease in which seizures are only one symptom. A diligent study of early stages in epilepsy including detailed clinical information, psychiatric comorbidities, sophisticated advanced neuroimaging, and timely functional brain tests may provide a better understanding of epileptogenesis. The goal will be to understand the process of evolution to chronic epilepsy and eventually to prevent refractory epilepsy.     

Surgery for extratemporal nonlesional epilepsy in children: a meta-analysis

Purpose

Previous small studies have demonstrated that seizure outcomes following surgery for extratemporal lobe epilepsy (ETLE) in children are worse than those for temporal lobe epilepsy. We have conducted a meta-analysis of the available literature to better understand ETLE surgical outcomes in children.

Methods

We searched PubMed (1990–2009) for appropriate studies using the following terms: ETLE, ETLE surgery, ETLE surgery outcome, frontal lobe epilepsy, occipital lobe epilepsy, and parietal lobe epilepsy. Our collected data included patient age at seizure onset and surgery, the cerebral lobe involved with epileptogenesis, MRI findings, predominant seizure semiology, intracranial monitoring use (electrode implantation), epileptic region histopathology, and postoperative seizure outcome. Statistical analysis was performed to determine associations among these variables and postoperative outcome.

Results

Ninety-five patients from 17 studies satisfied the inclusion criteria. Pathological findings (p?=?0.039) and seizure type (p?=?0.025) were significantly associated with outcome: A larger proportion of patients with cortical dysplasia and complex partial seizures experienced better outcomes. Age at surgery (p?=?0.073) and the cerebral resection site (p?=?0.059) were marginally associated with seizure outcome.

Conclusions

This study confirms previous reports: Surgical outcomes for ETLE epilepsy are significantly worse than those for temporal lobe epilepsy. The reasons for this difference may include the diffuse nature of the pathology involved in ETLE, difficulty in localizing the seizure focus in young children, and involvement of “eloquent” nonresectable cortex in epileptogenesis. Because of the reporting variability among different epilepsy centers, more uniform protocols are necessary for fair evaluation and comparison of outcomes among the different centers.     

Basic Mechanisms of Epilepsy: Targets for Therapeutic Intervention

Summary: Although a wide variety of drugs are available for treatment of epilepsy, many patients with epilepsy still experience uncontrolled seizures. In addition, there is a need for new drugs that can halt epileptogenesis after brain injury. Mechanisms that underlie seizure processes constitute potential target areas for the development of new antiepileptic drugs (AEDs). An understanding of the underlying mechanisms of interictal spike discharge and seizure spread is critical for the development of AEDs for treatment of partial seizures. Suppression of specific forms of voltage-dependent calcium currents and inhibition of GABA_B receptor-mediated inhibition are two key target areas for new AEDs to treat primary generalized seizures. As researchers gain more understanding of the cellular, molecular, and genetic mechanisms underlying seizure propagation, we should be better able to develop therapeutic agents designed to suppress seizure-provoking mechanisms and to enhance the brain's natural protective mechanisms.     

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.     

The pathophysiology of focal epilepsy: neurophysiological considerations.

The study of epilepsy serves to emphasize the importance of integrating basic research with clinical data. In this selective review, the results of recent experiments using intracellular recording techniques, ion-specific microelectrodes, and a methodology suitable for studying mammalian cortex in vitro are discussed in terms of cellular phenomena which underlie clinical observations made in epileptic patients. This information has begun to clarify: (1) the changes in neuronal behavior associated with interictal and ictal events; (2) alterations in local ionic microenvironment which occur during focal epileptogenesis; (3) intrinsic control mechanisms which serve to restrict seizure spread; (4) neuronal characteristics which account for the differences in seizure patterns seen in infants and adults; and (5) the possible long-term consequences of recurrent local neuronal hyperexcitability.     

Temporal patterns and mechanisms of epilepsy surgery failure

Epilepsy surgery is an accepted treatment option in patients with medically refractory focal epilepsy. Despite various advances in recording and localization noninvasive and invasive techniques (including electroencephalography (EEG), magnetic resonance imaging (MRI), positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetoencephalography (MEG), subdural grids, depth electrodes, and so on), the seizure outcome following surgical resection remains suboptimal in a significant number of patients. The availability of long‐term outcome data on an increasing number of patients suggests two major temporal patterns of seizure recurrence (early vs. late) that implicate the following two different mechanisms for seizure recurrence: (1) a failure to either define/resect the epileptogenic zone, and (2) the nonstatic nature of epilepsy as a disease through the persistence of proepileptic cortical pathology. We describe the temporal patterns of epilepsy surgery failures and discuss their potential clinical, histopathologic, genetic, and molecular mechanisms. In addition, we review predictors of successful surgical interventions and analyze the natural history of epilepsy following surgical intervention. We hypothesize that the acute/early postoperative failures are due to errors in localizing and/or resecting the epileptic focus, whereas late recurrences are likely due to development/maturation of a new and active epileptic focus (de novo epileptogenesis).     

Early life stress in epilepsy: A seizure precipitant and risk factor for epileptogenesis

Stress can influence epilepsy in multiple ways. A relation between stress and seizures is often experienced by patients with epilepsy. Numerous questionnaire and diary studies have shown that stress is the most often reported seizure-precipitating factor in epilepsy. Acute stress can provoke epileptic seizures, and chronic stress increases seizure frequency. In addition to its effects on seizure susceptibility in patients with epilepsy, stress might also increase the risk of epilepsy development, especially when the stressors are severe, prolonged, or experienced early in life. Although the latter has not been fully resolved in humans, various preclinical epilepsy models have shown increased seizure susceptibility in naïve rodents after prenatal and early postnatal stress exposure.In the current review, we first provide an overview of the effects of stress on the brain. Thereafter, we discuss human as well as preclinical studies evaluating the relation between stress, epileptic seizures, and epileptogenesis, focusing on the epileptogenic effects of early life stress. Increased knowledge on the interaction between early life stress, seizures, and epileptogenesis could improve patient care and provide a basis for new treatment strategies for epilepsy.This article is part of a Special Issue entitled “NEWroscience 2013”.     

Current management for epilepsy in tuberous sclerosis complex

PURPOSE OF REVIEW: This article reviews the most significant advances in the field of epilepsy associated with tuberous sclerosis complex, with emphasis on new advances in the knowledge of the pathophysiological mechanisms of epileptogenicity, progress in identifying the epileptogenic zone, and the rationale for surgical management in individuals with intractable seizures. RECENT FINDINGS: Advances in our understanding of the mechanisms and genetics underlying infantile spasms and catastrophic epilepsy associated with tuberous sclerosis complex may facilitate more effective interventions. Early effective seizure control could significantly reduce the adverse developmental effects of chronic epilepsy in tuberous sclerosis. Vigabatrin is the first choice in the short-term treatment of infantile spasms. Some individuals, however, develop seizures that remain highly intractable. The factors that influence the intractability of epilepsy associated with tuberous sclerosis complex remain poorly understood. Multimodality neuroimaging has improved detection of epileptogenic foci, allowing an increased number of individuals to be evaluated for resective surgery. Epilepsy surgery is often associated with significant improvement of the neurologic outcome. SUMMARY: Epilepsy in tuberous sclerosis seems to arise from the interaction between multiple areas, all of which have increased excitability and reduced inhibition. Understanding the mechanisms of epileptogenesis might increase the availability of development of a more specific and efficacious treatment. New evidence suggests that it is possible to noninvasively identify children with tuberous sclerosis who are highly likely to become seizure free following surgical treatment.     

Current possibilities of the operative treatment of epilepsy

Interest in surgical treatment for epileptic seizures has increased considerably over the last decades. Better understanding of the epileptic process itself and the advent of new functional diagnostic means have led to the recognition that 11%-50% of patients with partial seizures might benefit from surgery. The major aspects of this review article include a discussion of the criteria that must be met before considering surgery and the need to establish a proper diagnosis. Together with immaculate surgical techniques, these factors provide the basis for a successful outcome following operation. Surgical therapy has three objectives: (1) seizure control, (2) functional and behavioral improvement, and (3) interruption of an otherwise ongoing process. As the study of epileptogenesis and localization of the epileptic focus, besides information derived from the clinical pattern of the typical seizure itself, depends more on the techniques that reveal abnormalities of neuronal function, as opposed to structure, presurgical evaluation continues to depend largely on electrophysiological measurements. Special recording techniques and particularly long-term monitoring, using CCTV and stereotactically implanted depth electrodes (stereo EEG), are often mandatory. Other modern diagnostic means, such as single photon-emission computed tomography and positron computed tomography for functional abnormalities, as well as CT scan and NMR tomography for identification of structural abnormalities, add valuable information. The most common surgical resection performed today for epilepsy is anterior temporal lobectomy. About 60% of patients with partial epilepsy may become seizure-free after this procedure, with minimal side effects. Over 90% may achieve worthwhile benefit. Mesiobasal-limbic epilepsy can be successfully operated on by microsurgical "selective amygdalohippocampectomy".(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Effect of war on the occurrence of epileptic seizures in children

We studied the occurrence of epileptic seizures in 72 children from war-affected and 39 children from non-war-affected areas during and after the 1991-1992 war in Croatia. During the war, children from war-affected areas who had "stable" epilepsy before the war and regularly took antiepilepsy medications had epileptic seizures more often than children from areas not affected by the war. In 2002, all children (n=10) whose first epileptic seizure was related to a stressful event had a "stable" condition, whereas 4 of 10 children whose first epileptic seizure was not stress-related had an "unstable" condition. Typical absence seizures were observed in 6 of 10 children in the stress-related group and none in the non-stress-related patient group. Stressful life events can be provocative factors for the occurrence of epileptic seizures. Typical absence seizures are more likely to be provoked by stress then other types of epileptic seizures.