Cortical hyperexcitability and epileptogenesis: Understanding the mechanisms of epilepsy – Part 1

Epilepsy encompasses a diverse group of seizure disorders caused by a variety of structural, cellular and molecular alterations of the brain primarily affecting the cerebral cortex, leading to recurrent unprovoked epileptic seizures. In this two-part review we examine the mechanisms underlying normal neuronal function and those predisposing to recurrent epileptic seizures starting at the most basic cellular derangements (Part 1) and working up to the highly complex epileptic networks (Part 2). We attempt to show that multiple factors can modify the epileptic process and that different mechanisms underlie different types of epilepsy, and in most situations there is an interplay between multiple genetic and environmental factors.     

Desentrañando los misterios de la muerte súbita en epilepsia

IntroductionSudden unexpected death in epilepsy (SUDEP) is the most frequent cause of premature death in epileptic patients. Most SUDEP events occur at night and frequently go unnoticed; the exact pathophysiological mechanisms of this phenomenon therefore remain undetermined. Nevertheless, most cases of SUDEP are attributed to an infrequent yet extremely severe complication of epileptic seizures.DevelopmentWe conducted a systematic literature search on PubMed. Our review article summarises scientific evidence on the classification, pathophysiological mechanisms, risk factors, biomarkers, and prevention of SUDEP. Likewise, we propose new lines of research and critically analyse findings that are relevant to clinical practice.ConclusionsCurrent knowledge suggests that SUDEP is a heterogeneous phenomenon caused by multiple factors. In most cases, however, SUDEP is thought to be due to postictal cardiorespiratory failure triggered by generalised tonic-clonic seizures and ultimately leading to cardiac arrest. The underlying pathophysiological mechanism involves multiple factors, ranging from genetic predisposition to environmental factors. Risk of SUDEP is higher in young adults with uncontrolled generalised tonic-clonic seizures. However, patients apparently at lower risk may also experience SUDEP. Current research focuses on identifying genetic and neuroimaging biomarkers that may help determine which patients are at high risk for SUDEP. Antiepileptic treatment is the only preventive measure proven effective to date. Night-time monitoring together with early resuscitation may reduce the risk of SUDEP.     

Efficacy of current antiepileptics to prevent neurodegeneration in epilepsy models

Results of experiments performed in animal epilepsy models and human epilepsy during the past decade indicate that the epileptic brain is not a stable neuronal network, but undergoes modifications caused by the underlying etiology and/or recurrent seizures. In many forms of epilepsy, such as temporal lobe epilepsy, the underlying etiologic factor triggers a cascade of events (epileptogenesis) leading to spontaneous seizures and cognitive decline. In some patients, the condition progresses, due in part to recurrent seizures. The current treatment of epilepsy focuses exclusively on preventing or suppressing seizures, which are symptoms of the underlying disease. Now, however, we are beginning to understand the underlying neurobiology of the epileptic process, as well as factors that might predict the risk of progression in individual patients. Thus, there are new opportunities to develop neuroprotective and antiepileptogenic treatments for patients who, if untreated, would develop drug-refractory epilepsy associated with cognitive decline. These treatments might improve the long-term outcome and quality-of-life of patients with epilepsy. Here we review the available data regarding the neuroprotective effects of antiepileptic drugs (AEDs) at different phases of the epileptic process. Analysis of published data suggests that initial-insult modification and prevention of the progression of seizure-induced damage are candidate indications for treatment with AEDs. An understanding of the molecular mechanisms underlying the progression of epileptic process will eventually show what role AEDs have in the neuroprotective and antiepileptogenic treatment regimen.     

Concepts of Epilepsy

Summary: The word “epilepsy” refers to a group of disorders characterized by recurrent epileptic seizures. Differential diagnosis first requires distinction between epileptic seizures and the many systemic, neurologic, and psychiatric disorders associated with paroxysmal behaviors that might be mistaken for epilepsy. By definition, isolated epileptic seizures that occur as a natural reaction to a noxious insult are not sufficient evidence for a diagnosis of epilepsy. Many factors contribute to the appearance of an epileptic condition, including nonspecific predisposing factors that alter the threshold for epilepsy and specific epileptogenic disturbances that cause chronic epilepsy to become manifest in susceptible individuals, both of which can be either genetic or acquired. Endogenous or exogenous precipitating factors determine when specific ictal events occur. The many clinical expressions of epileptic seizures reflect the location and extent of the cerebral disturbance, as well as diverse fundamental mechanisms that involve alterations of excitatory and inhibitory influences, resulting in hyperexcitability, hypersynchronization, or both. The various forms of epilepsy and epileptic syndromes are defined by a constellation of signs and symptoms that include characteristic seizure types, other clinical features, and family history. Whereas treatment is largely based on seizure type, identification of a specific epileptic syndrome often provides additional insights into management and prognosis. An example of the usefulness of syndromic classification is the existence of surgically remediable syndromes that have a known poor prognosis with pharmacotherapy, but an excellent prognosis with surgical intervention. Research on underlying basic mechanisms of the epilepsies, particularly molecular genetics designed to identify specific biological defects in idiopathic epilepsies and invasive investigations carried out in the epilepsy surgery setting to elucidate the pathophysiology of symptomatic epilepsies, may reveal definitive substrates that will ultimately permit epileptic syndromes to be reclassified as diseases.     

Update on the mechanisms and roles of high‐frequency oscillations in seizures and epileptic disorders

High‐frequency oscillations (HFOs) are a type of brain activity that is recorded from brain regions capable of generating seizures. Because of the close association of HFOs with epileptogenic tissue and ictogenesis, understanding their cellular and network mechanisms could provide valuable information about the organization of epileptogenic networks and how seizures emerge from the abnormal activity of these networks. In this review, we summarize the most recent advances in the field of HFOs and provide a critical evaluation of new observations within the context of already established knowledge. Recent improvements in recording technology and the introduction of optogenetics into epilepsy research have intensified experimental work on HFOs. Using advanced computer models, new cellular substrates of epileptic HFOs were identified and the role of specific neuronal subtypes in HFO genesis was determined. Traditionally, the pathogenesis of HFOs was explored mainly in patients with temporal lobe epilepsy and in animal models mimicking this condition. HFOs have also been reported to occur in other epileptic disorders and models such as neocortical epilepsy, genetically determined epilepsies, and infantile spasms, which further support the significance of HFOs in the pathophysiology of epilepsy. It is increasingly recognized that HFOs are generated by multiple mechanisms at both the cellular and network levels. Future studies on HFOs combining novel high‐resolution in vivo imaging techniques and precise control of neuronal behavior using optogenetics or chemogenetics will provide evidence about the causal role of HFOs in seizures and epileptogenesis. Detailed understanding of the pathophysiology of HFOs will propel better HFO classification and increase their information yield for clinical and diagnostic purposes.     

Neurobiology of Behavior: Anatomic and Physiological Implications Related to Epilepsy

Summary: Controversy exists concerning whether epileptic seizures can produce enduring alterations in neuronal function that cause interictal behavioral disturbances. Although arguments favoring the occurrence of epilepsy-induced disorders of behavior must not be presented in a way that adds to the stigmata associated with epilepsy, it is not in the best interest of epileptic patients to deny this possible relationship and overlook an opportunity to prevent or treat a major cause of disability. There is evidence to suggest that psychosocial factors cannot account for all the behavioral problems suffered by patients with epilepsy. Behavioral disturbances ascribed to antiepileptic drugs and specific structural lesions may also be due, in part, to epileptogenic mechanisms. Some interictal behavioral disturbances may actually reflect unrecognized ictal events. Most importantly, data obtained from clinical research and animal investigations suggest testable hypotheses of how recurrent epileptic seizures can alter neuronal function in ways that would predispose to specific disruptive interictal behaviors, such as aggression, depression and schizophrenia.     

Recurrent seizures do not cause hippocampal damage

Abstract. Neuronal consequences of recurrent single epileptic seizures have been discussed controversially for some time. Various cross-sectional magnetic resonance imaging (MRI) studies have shown a positive correlation between the severity of epilepsy and the extent of hippocampal damage. However, the open question whether recurrent epileptic seizures induce hippocampal structural pathology can be assessed only in longitudinal studies. The few recent follow-up studies have revealed conflicting results. In the current MRI study we have employed volumetry and T2 relaxometry to quantify hippocampal structural changes of patients with chronic partial epilepsies over a period of 3 years. Our main findings demonstrate that these patients who experience continuing epileptic seizures do no show any development of new pathology or any relevant deterioration of pre-existing hippocampal structural lesions. This argues against the assumption that recurrent epileptic seizures cause or increase structural hippocampal damage.     

神经外科患者癫痫反复发作处理分析

目的 探讨神经外科患者出现癫痫反复发作的临床特点、处理原则与方法.方法 回顾性分析沈阳军区总医院神经外科自2011年1月至6月收治的9例癫痫反复发作患者的临床资料,分析其加重的原因、发作特点及治疗方法和结果.结果 9例患者中3例合并胶质瘤、1例蛛网膜囊肿、1例海绵状血管瘤、1例脑软化灶;7例有癫痫病史,2例既往无癫痫病史;7例为额叶癫痫,2例颞叶癫痫.癫痫发作加重的原因:减药3例,新诊断的脑肿瘤2例,手术(颅内电极置入术)1例,原因不明3例.癫痫发作类型包括部分性发作与全面性发作,发作频率从间隔3min至间隔数小时发作一次.患者经给予多种抗癫痫药物联合用药治疗,包括口服与注射给药,癫痫得到控制,其中添加左乙拉西坦口服有较好的疗效.结论 神经外科患者出现癫痫反复发作多呈药物难治性,发作不易控制,其处理应使用对部分性癫痫发作有较好疗效的多种抗癫痫药物联合用药,剂量应高于常规初始剂量,包括静脉注射及肌注给药,以尽快控制癫痫发作.左乙拉西坦因口服吸收快、起效迅速及有较好的抗癫痫作用,对癫痫反复发作有较好的疗效.     

Audiogenic kindling and secondary subcortico-cortical epileptogenesis: Behavioral correlates and electrographic features

Human epilepsy is usually considered to result from cortical pathology, but animal studies show that the cortex may be secondarily involved in epileptogenesis, and cortical seizures may be triggered by extracortical mechanisms. In the audiogenic kindling model, recurrent subcortical (brainstem-driven) seizures induce secondary epileptic activation of the cortex. The present review focuses on behavioral and electrographic features of the subcortico-cortical epileptogenesis: (1) behavioral expressions of traditional and mild paradigms of audiogenic kindling produced by full-blown (generalized) and minimal (focal) audiogenic seizures, respectively; (2) electrographic manifestations of secondary epileptic activation of the cortex — cortical epileptic discharge and cortical spreading depression; and (3) persistent individual asymmetry of minimal audiogenic seizures and secondary cortical events produced by their repetition. The characteristics of audiogenic kindling suggest that this model represents a unique experimental approach to studying cortical epileptogenesis and network aspects of epilepsy.This article is part of a Special Issue entitled "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic".     

Epileptic Seizures Due to Thrombotic and Embolic Cerebrovascular Disease in Older Patients

Thromboembolic vascular disease is a frequent precipitant of seizures, and is the most common etiology in older patients. The occurrence of seizures shortly after a stroke, however, does not necessarily indicate that the patient will continue to have seizures following initial recovery. This is true even when patients present in epileptic status. This may be because early and late seizures are produced by different pathophysiologic mechanisms.     

Motor correlates of models of secondary bilateral synchrony and multiple epileptic foci.

Bilateral synchronous epileptiform discharges registered in patients with partial epilepsies may be generated by different pathophysiological mechanisms. Differentiation between underlying mechanisms is often crucial for correct diagnosis and adequate treatment in clinical epileptology. The aim of this study was to model in rats two possible mechanisms--secondary bilateral sychrony and interaction between multiple epilepic foci. Furthermore, to describe in detail semiology, laterality and differences in motor phenomena. Secondary bilateral synchrony was modeled by unilateral topical application of bicuculline methiodide (BMI) over the sensorimotor cortex. Bilateral symmetric application of BMI was used as a model of multiple epileptic foci. Electrographic and behavioural phenomena were recorded for 1h following the application of BMI. Electroencephalogram in both groups was characterized by presence of bilateral synchronous discharges. Myoclonic and clonic seizures involving forelimb and head muscles represented the most common motor seizure pattern in both groups. Significant differences were found in the laterality of motor phenomena. Motor seizures in unilateral foci always started in the contralateral limbs whereas symmetrical foci exhibited bilateral independent onset of convulsions. Similar lateralization was observed in interictal motor phenomena (myoclonic jerks). An important influence of posture on epileptic motor phenomena was demonstrated. Active or passive changes in animal posture (verticalization to bipedal posture) caused conversion from unilateral myoclonic jerks or clonic seizures to bilaterally synchronous (generalized) motor phenomena in both groups.     

Disruption of the neurogenic potential of the dentate gyrus in a mouse model of temporal lobe epilepsy with focal seizures

Adult hippocampal neurogenesis is enhanced in response to multiple stimuli including seizures. However, the relationship between neurogenesis and the development of temporal lobe epilepsy (TLE) remains unclear. Unilateral intrahippocampal injection of kainate in adult mice models the morphological characteristics (e.g. neuronal loss, gliosis, granule cell dispersion and hypertrophy) and occurrence of chronic, spontaneous recurrent partial seizures observed in human TLE. We investigated the influence of a kainate-induced epileptogenic focus on hippocampal neurogenesis, comparing neural stem cell proliferation following status epilepticus and spontaneous recurrent partial seizures. Cell proliferation in the subgranular zone was transiently increased bilaterally after kainate treatment. As a result, neurogenesis was stimulated in the contralateral dentate gyrus. In contrast, the epileptic hippocampus exhibited a strongly reduced neurogenic potential, even after onset of spontaneous recurrent partial seizures, possibly due to an alteration of the neurogenic niche in the subgranular zone. These results show that neurogenesis does not contribute to the formation of the epileptic focus and may be affected when dispersion of dentate gyrus granule cells occurs. Therefore, in patients with TLE, hippocampal sclerosis and granule cell dispersion may play a significant role in disrupting the potential for hippocampal neurogenesis.     

Severe epilepsy: Diagnostic and epidemiological aspects

ABSTRACT— Epidemiological parameters of epilepsy have been estimated in a large number of studies. Reported annual incidence rates for recurrent seizures vary between 30 and 50/100 000, and prevalence rates in most studies between 500 and 1000/100 000. Varying findings are mostly due to different case ascertainment methods and definitions of epilepsy applied in different surveys. These aspects will be discussed in this paper. A special emphasis is laid on differential diagnosis of seizure disorders, and on the prevalence and causes of complex partial epilepsy. This epileptic disorder is one of the most common forms of epilepsy, and also difficult to treat in many cases. Many recent reports show that prognosis of seizures in patients with epilepsy is better than suggested in earlier studies. However, 25–30% of epileptics seem to have frequent (<1/month) seizures. Our own study, in accordance with earlier findings suggests that prevalence of patients with severe complex partial epilepsy is about 80–90/100 000. Available literature provides several predictive factors for the prognosis of seizures and assessment of prognosis is possible quite early after the onset of seizures. Treatment choices for patients with intractable epilepsy will be discussed.     

Finding a better drug for epilepsy: Antiepileptogenesis targets

For several decades, both in vitro and in vivo models of seizures and epilepsy have been employed to unravel the molecular and cellular mechanisms underlying the occurrence of spontaneous recurrent seizures (SRS)—the defining hallmark of the epileptic brain. However, despite great advances in our understanding of seizure genesis, investigators have yet to develop reliable biomarkers and surrogate markers of the epileptogenic process. Sadly, the pathogenic mechanisms that produce the epileptic condition, especially after precipitating events such as head trauma, inflammation, or prolonged febrile convulsions, are poorly understood. A major challenge has been the inherent complexity and heterogeneity of known epileptic syndromes and the differential genetic susceptibilities exhibited by patients at risk. Therefore, it is unlikely that there is only one fundamental pathophysiologic mechanism shared by all the epilepsies. Identification of antiepileptogenesis targets has been an overarching goal over the last decade, as current anticonvulsant medications appear to influence only the acute process of ictogenesis. Clearly, there is an urgent need to develop novel therapeutic interventions that are disease modifying—therapies that either completely or partially prevent the emergence of SRS. An important secondary goal is to develop new treatments that can also lessen the burden of epilepsy comorbidities (e.g., cognitive impairment, mood disorders) by preventing or reducing the deleterious changes during the epileptogenic process. This review summarizes novel antiepileptogenesis targets that were critically discussed at the XIth Workshop on the Neurobiology of Epilepsy (WONOEP XI) meeting in Grottaferrata, Italy. Further, emerging neurometabolic links among several target mechanisms and highlights of the panel discussion are presented.     

Neuropathologic consequences of status epilepticus]

Although the results of a number of histopathological studies have unequivocally shown that epileptic seizures are frequently associated with neurodegenerative mechanisms or other alterations in the brain structure, as it is not possible to carry out longitudinal studies the interpretation of these observations remains speculative. It is not clear whether these brain alterations are the cause or the result of epileptic seizures. It is now widely accepted that epileptic seizures correspond to the synchronization of neuronal activity and increase in their discharge frequency. It has been shown that this abnormal firing activity can lead to increase in intracellular calcium concentration in the nerve cells. A rise in intracellular calcium levels can trigger other processes within the cell, or be cytotoxic if these levels are sufficiently high. In this study, in the light of the most recent findings on cell death (apoptosis), the authors have examined the mechanisms whereby epileptic seizures can result in neuronal cell loss.     

Comparative clinical characteristics of early- and adult-onset multiple sclerosis patients with seizures

Multiple sclerosis (MS) and epilepsy are common disorders, the co-occurrence of which has been of considerable interest. This study aimed to evaluate the prevalence and clinical features of epileptic seizures in patients with definite MS including those with pediatric onset (≤16 years of age). Out of 2,300 patients with definite MS followed in our outpatient clinic, 36 with epileptic seizures were identified. In this cohort, 8 out of 146 pediatric cases had seizures. The clinical and demographic features of the patients were recorded. Multiple logistic regression model with the occurence of seizures as the dependent variable was performed to identify the risk factors for seizure occurrence in MS patients. The prevalence of epileptic seizures was 1.5 % in definite MS patients, 1.3 % in adult-onset (comparable to seizure prevalence in the general population) and 5.5 % in pediatric MS patients (≤16 years old). Twenty-six of 36 (72 %) patients with MS and epilepsy developed recurrent seizures after the first epileptic seizure. Mean annual relapse rate (p ≤ 0.001), mean expanded disability status scale (EDSS) score (p = 0.004) and the ratio of patients with pediatric onset (p = 0.01) were higher in MS patients with seizures. In the multiple logistic regression analysis, age at MS onset and EDSS at the last examination were found to be predictors of seizure occurrence. Occurrence of seizures during the clinical course of MS appears to be associated with early-onset and increased disease severity and might be coincidental in adults.     

Incidence of newly diagnosed epileptic seizures in a French South Indian Ocean Island, La Réunion (EPIREUN)

Purpose:   To assess the incidence of newly diagnosed epileptic seizures in the population of La Réunion.
Methods:   From July 1, 2004 to June 30, 2005, we conducted a prospective, observational, and multicenter epidemiologic study to identify patients with newly diagnosed epileptic seizures. Febrile and neonatal seizures were excluded.
Results:   Seven hundred sixty-six patients were included. The standardized (2000 U.S. population) incidence rate of all suspected cases of newly diagnosed (provoked and unprovoked) epileptic seizures was 115.4/100.000 person-years [95% confidence interval (CI) 106.7–124.0]. We observed a bimodal distribution: The crude incidence was 99.5/100,000 in the group aged 0–14 years and 330.8/100,000 in those older than 65 years. One hundred thirty-five cases were classified as provoked seizures (17.6%; incidence 17.7/100,000). Alcohol consumption, cranial trauma, and cerebrovascular disease were the most frequent causes (27.4%, 11.1%, and 10.4%, respectively). Six hundred twenty cases were classified as unprovoked seizures (single and recurrent) (80.9%; incidence, 81.2/100,000). Two hundred sixty cases of seizures were due to stable neurologic conditions (incidence, 34.1/100,000) and the most common causes were cerebrovascular disease (46.2%), alcoholism (20.4%), and cranial trauma (5.4%). Evolutive neurologic conditions contributed to 23 cases (incidence, 3.0/100,000). Lastly, unprovoked seizures with unknown etiology were 337 (incidence, 44.2/100,000).
Conclusions:   The global incidence rate of newly diagnosed epileptic seizures in La Réunion was clearly higher than those observed in industrialized countries and similar to those observed in developing countries. The major risk factors were represented by cerebrovascular disease, alcohol consumption, and cranial trauma. Surprisingly, there were few infections.     

Modern perspectives on epilepsy in relation to psychiatry: classification and evaluation

This paper begins a two-part series on current psychiatric aspects of epilepsy. Part I focuses on the current classification of epileptic seizures; the possible relationships of epilepsy, especially temporal lobe epilepsy, with psychopathology; and the difficulties of evaluating epileptic conditions through electroencephalography. Part II, to be published in the April issue, will cover the management of epilepsy that is accompanied by behavior disturbance.     

Incidence of seizures in patients with multiple sclerosis treated with intrathecal baclofen

Oral and intrathecal baclofen (ITB) have been associated with epileptic seizures. The authors observed a higher incidence of epileptic seizures in 99 patients with multiple sclerosis (MS) treated with ITB vs a matched control group (7% vs 1%, p < 0.05). Three patients with MS on ITB developed status epilepticus. Seizures were often associated with additional triggering factors.