Impairment of inhibitory control of the hypothalamic pituitary adrenocortical system in epilepsy

Excess comorbidity between depression and epilepsy proposes common pathophysiological patterns in both disorders. Neuroendocrine abnormalities were often observed in depression as well as in epilepsy. Lack of inhibitory control of the hypothalamic pituitary adrenocortical (HPA) system is a core feature of depression; main relay stations of this system are located in the amygdala and hippocampus, which are key regions for both disorders. Therefore we explored the feedback mechanism of the HPA system in epilepsy. In order to control for the impact of depression we focused on epilepsies without depression. We compared patients with epilepsy (subdivided by medication with or without hepatic enzyme inducing antiepileptic medication) with 16 healthy controls and 16 patients with unipolar major depression but without epilepsy. We observed a lack of inhibitory control of the HPA system in patients with epilepsy, also in the absence of enzyme inducing medication. An impact of the temporal lobe location of the epileptic focus could not be observed. Thus, epilepsies share with depression the deficiencies in the feedback mechanism of the HPA system, proposing common pathophysiological features of up to now unknown nature.     

Are some idiopathic epilepsies disorders of ion channels?: A working hypothesis

Epilepsy is a common neurological disease and encompasses a variety of disorders with paroxysms. Although there is a genetic component in the pathogenesis of epilepsy, the molecular mechanisms of this syndrome remains poorly understood. Linkage analysis and positional cloning have not been sufficient tools for determining the pathogenic mechanisms of common idiopathic epilepsies, and hence, novel approaches, based on the etiology of epilepsy, are necessary. Recently, many paroxysmal disorders, including, epilepsy, have been considered to be due to ion channel abnormalities or channelopathies. Results of recent studies employing gene analysis in animal models of epilepsy and human familial epilepsies support the hypothesis that at least some of the so called idiopathic epilepsies, i.e. epilepsies currently, classified as idiopathic could be considered as a channelopathy. This hypothesis is consistent with the putative prerequisites for genes responsible for the majority of idiopathic epilepsies that can adequately explain the following characteristics of epilepsy. Neuronal hyperexcitability, dominant inheritance with various penetrance, pharmacological role of some conventional antiepileptic drugs, age dependency in the onset of epilepsy, and the involvement of genetic factors in the pathogenesis of post-traumatic epilepsy. Search for mutations in ion channels expressed in the central nervous system may help in finding defects underlying some of idiopathic epilepsies, thereby enhancing, our understanding of the molecular pathogenesis of epilepsy. A working hypothesis to view certain idiopathic epilepsies as disorders of ion channels should provide a new insight to our understanding of epilepsy and allow the design of novel therapies.     

Genes and mutations in human idiopathic epilepsy

Thirteen genes have already been identified in human idiopathic epilepsies since 1995, but they account only for a minority of all epilepsy cases. Most of these genes are associated with rare monogenic epilepsy syndromes, but some of them contribute to the common epilepsy subtypes. The questions remains to be answered how many more epilepsy genes exist in brain. Idiopathic epilepsies are common neurological disorders, and it can therefore be expected that the total number of genes associated with an increased seizure susceptibility is much higher than 13. Most of the known genes code for either voltage-gated or ligand gated ion channels, but recently two epilepsy genes have been found which do not fit into the concept of epilepsies as channelopathies. It can therefore be suspected that more than one pathogenetic concept exists in epileptogenesis.     

Focal epilepsies: Update on diagnosis and classification

Correctly diagnosing and classifying seizures and epilepsies is paramount to ensure the delivery of optimal care to patients with epilepsy. Focal seizures, defined as those that originate within networks limited to one hemisphere, are primarily subdivided into focal aware, focal impaired awareness, and focal to bilateral tonic–clonic seizures. Focal epilepsies account for most epilepsy cases both in children and adults. In children, focal epilepsies are typically subdivided in three groups: self-limited focal epilepsy syndromes (e.g., self-limited epilepsy with centrotemporal spikes), focal epilepsy of unknown cause but which do not meet criteria for a self-limited focal epilepsy syndrome, and focal epilepsy of known cause (e.g., structural lesions—developmental or acquired). In adults, focal epilepsies are often acquired and may be caused by a structural lesion such as stroke, infection and traumatic brain injury, or brain tumors, vascular malformations, metabolic disorders, autoimmune, and/or genetic causes. In addition to seizure semiology, neuroimaging, neurophysiology, and neuropathology constitute the cornerstones of a diagnostic evaluation. Patients with focal epilepsy who become drug-resistant should promptly undergo assessment in an epilepsy center. After excluding pseudo-resistance, these patients should be considered for presurgical evaluation as a means to identify the location and extent of the epileptogenic zone and assess their candidacy for a surgical procedure. The goal of this seminar in epileptology is to summarize clinically relevant information concerning focal epilepsies. This contributes to the ILAE's mission to ensure that worldwide healthcare professionals, patients, and caregivers continue to have access to high-quality educational resources concerning epilepsy.     

Sunday July 2, 20067:30 – 9:00Hall 5BTeaching SessionEpilepsy and genetics

¹ O. Steinlein (   ¹ Institute of Human Genetics, University of Munich, Germany )
The term epilepsy describes a heterogeneous group of disorders, with a lifetime cumulative incidence of 3%. In the majority of epilepsies genes are a minor if not even the only etiological factor. There is a large subgroup of epilepsies that are suspected or proofed to be mainly genetic in origin. This group of epilepsies has been named idiopathic, and during the last decade several genes have already been identified for various idiopathic epilepsies. On the other hand there is a large group of epilepsies and disorders with epilepsy that have been termed "symptomatic" because they are due to known metabolic, neurodegenerative or structural brain damage. Many of these disorders have by now shown to be caused by clearly defined genetic factors. Seizures and myoclonus are common to many neurodegenerative and metabolic disorders, but are also a major feature in patients with structural chromosomal arrangements or neuronal migration disorders. In this talk exemplary members of both groups will be discussed to illustrate principal etiological categories of the disorder "epilepsy" and trace the various genetic pathways to epileptogenesis.     

The utility of omega-3 fatty acids in epilepsy: more than just a farmed tilapia!

The epilepsies are one of the most common serious brain disorders and 20 to 30% of people developing epilepsy continue to have seizures and are refractory to treatment with the currently available therapies. Approximately one in a 1000 patients with chronic epilepsy will die suddenly, unexpectedly, and without explanation, even with post-mortem examination and this phenomenon is called sudden unexplained death in epilepsy (SUDEP). Understanding the mechanisms underlying SUDEP may lead to the identification of previously unrecognized risk factors that are more amenable to correction. We discuss here the possible implications of omega-3 fatty acids consumption on SUDEP prevention.     

Diagnosis and treatment of mood disorders in persons with epilepsy

PURPOSE OF REVIEW: Epilepsy is a common, disabling neurological disorder associated with increased rates of comorbid psychiatric disorders as compared with the general population. RECENT FINDINGS: Mood disorders, especially major depression, appear to be more prevalent in persons with epilepsy than in those with the other chronic disorders and the general population. Depression may have more influence on quality of life than do cognitive and seizure factors. Although psychological, social, and vocational disabilities contribute to mood dysfunction in epilepsy, functional neuroimaging studies have consistently shown correlation of presence of cerebral abnormalities with increased severity of symptoms of depression. Most persons with epilepsy are not routinely screened for depression, and depression is subsequently treated in only a minority of patients. Although serotonin receptor density is greatest in brain regions commonly associated with epilepsy, such as the mesial temporal and prefrontal areas, no controlled trials have investigated the efficacy of serotonin reuptake inhibitors in persons with epilepsy. Optimal methods to identify and treat depression in epilepsy require substantial further research. SUMMARY: Depression is a common comorbid condition with significant negative effects on health status in persons with epilepsy, but additional understanding of the disorder is needed to improve diagnosis and treatment.     

Neuropsychiatric complications of epilepsy

Psychiatric complications of epilepsy are multiple and result from the complex interaction between endogenous, genetic, therapeutic, and environmental factors. The relationship between epilepsy and psychiatric disorders may be much closer than previously appreciated. Recent studies have suggested the existence of a bi-directional relationship between depression and epilepsy, whereby patients with epilepsy have a higher risk than the general population of suffering from depression, not only after, but also before the onset of epilepsy. Furthermore, similar neurotransmitter changes have been identified in depression and epilepsy, suggesting the possibility that these two disorders share common pathogenic mechanisms. Although the clinical manifestations of psychiatric disorders in epilepsy are often indistinguishable from those of nonepileptic patients, certain types of depression and psychotic disorders may present with clinical characteristics that are particular to epilepsy patients. These include the psychosis of epilepsy, postictal psychotic disorders, alternative psychosis (or forced normalization), and certain forms of interictal depressive disorders.     

Immune-mediated epilepsies

A pathogenic role of immunity in epilepsies has long been suggested based on observations of the efficacy of immune-modulating treatments and, more recently, by the finding of inflammation markers including autoantibodies in individuals with a number of epileptic disorders. Clinical and experimental data suggest that both innate and adaptive immunity may be involved in epilepsy. Innate immunity represents an immediate, nonspecific host response against pathogens via activation of resident brain immune cells and inflammatory mediators. These are hypothesized to contribute to seizures and epileptogenesis. Adaptive immunity employs activation of antigen-specific B and T lymphocytes or antibodies in the context of viral infections and autoimmune disorders. In this article we critically review the evidence for pathogenic roles of adaptive immune responses in several types of epilepsy, and discuss potential mechanisms and therapeutic targets. We highlight future directions for preclinical and clinical research that are required for improved diagnosis and treatment of immune-mediated epilepsies.     

Modern management of epilepsy: a practical approach

The epilepsies are among the most common serious brain disorders, can occur at all ages, and are characterized by a variety of presentations and causes. Diagnosis of epilepsy remains clinical, and neurophysiological investigations support the diagnosis of the syndrome. Brain imaging is able to identify many of the structural causes of the epilepsies. Current antiepileptic drugs (AEDs) block seizures without influencing the underlying tendency to generate seizures, and are effective in 60-70% of individuals. Several modern drugs are as efficacious as the older medications, but have important advantages including the absence of adverse drug interactions and hypersensitivity reactions. Epilepsy is associated with an increased prevalence of mental health disorders including anxiety, depression, and suicidal thoughts. An understanding of the psychiatric correlates of epilepsy is important to the adequate management of people with epilepsy. Anticipation of common errors in the diagnosis and management of epilepsy is important. Frequent early diagnostic errors include nonepileptic psychogenic seizures, syncope with myoclonus, restless legs syndrome, and REM behavioral disorders, the last mostly in elderly men. Overtreatment with too rapid titration and too high doses or too many AEDs should be avoided. For people with refractory focal epilepsy, vagus nerve stimulation offers palliative treatment with possible mood improvement and neurosurgical resection offers the possibility of a life-changing cure. Potential advances in the management of epilepsy are briefly discussed. This short review summarizes the authors' how-to-do approach to the modern management of people with epilepsy.     

Syndromes at risk of status epilepticus in children: genetic and pathophysiological issues

Status epilepticus (SE) is a medical emergency with increased risk of morbidity and mortality in all age groups. Recent research has identified a variety of new genes implicated in disorders with severe epilepsies as a prominent feature. Autoimmune mechanisms have also been recently recognised as a cause of epilepsies with SE as a characteristic symptom. Knowledge about the aetiology potentially underlying SE may help to guide diagnostics and eventually influence treatment decisions. This review recapitulates, in brief, the risk of SE in specific clinical settings, provides an overview of paediatric epilepsy syndromes more commonly, or by definition, associated with SE, and summarizes some recent research data on genetic defects and disease mechanisms implicated in the pathogenesis of epilepsies frequently accompanied by SE.     

Understanding the association of neurocysticercosis and mesial temporal lobe epilepsy and its impact on the surgical treatment of patients with drug-resistant epilepsy

Mesial temporal lobe epilepsy associated with hippocampal sclerosis (MTLE-HS) is one of the most common types of focal epilepsies. This is an epileptic syndrome commonly associated with treatment-resistant seizures, being also the most prevalent form of drug-resistant epilepsy which is treated surgically in most epilepsy surgery centers. Neurocysticercosis (NCC) is one of the most common parasitic infections of the central nervous system, and one of the most common etiological agents of focal epilepsy, affecting millions of patients worldwide. Recently, researchers reported a curious association between MTLE-HS with NCC, but this association remains poorly understood. Some argue that calcified NCC lesions in MTLE-HS patients is only a coincidental finding, since both disorders are prevalent worldwide. However, others suppose there might exist a pathogenic relationship between both disorders and some even suspect that NCC, by acting as an initial precipitating injury (IPI), might cause hippocampal damage and, eventually, MTLE-HS. In this review, we discuss the various reports that examine this association, and suggest possible explanations for why calcified NCC lesions are also observed in patients with MTLE-HS. We also propose mechanisms by which NCC could lead to MTLE-HS. Finally, we discuss the implications of NCC for the treatment of pharmacologically-resistant focal epilepsies in patients with calcified NCC or in patients with MTLE-HS and calcified NCC lesions. We believe that investigations in the relationship between NCC and MTLE-HS might offer further insights into how NCC may trigger epilepsy, and into how MTLE-HS originates. Moreover, observations in patients with drug-resistant epilepsy with both NCC and hippocampal sclerosis may not only aid in the understanding and treatment of patients with MTLE-HS, but also of patients with other forms of dual pathologies aside from NCC.This article is part of a Special Issue titled Neurocysticercosis and Epilepsy.     

Genetics of epilepsy

Epilepsy is a common and very heterogeneous neurologic disorder. Genetic factors are likely to play a role in most cases, either because the underlying cause of epilepsy is primarily genetic or because genes modulate susceptibility to an epileptogenic insult. Primarily genetic epilepsies include conditions in which altered brain development or neurodegeneration are at the basis of seizures, but also conditions in which the brain is grossly normal, and the main, if not only, clinical feature is epilepsy. These are called idiopathic epilepsies, though this definition may change in the future. A few idiopathic epilepsies are monogenic disorders due to mutations in a variety of genes affecting neuronal excitability, synaptic transmission, or network development. Most cases have a complex etiology that combines predisposing genetic variants with nongenetic factors. Few of these have been identified so far and only in very few affected individuals, consisting mostly of deletions of critical chromosomal regions. Genetic factors also play a role in the response to antiepileptic drugs, affecting both their efficacy and their tolerability. There have been recent advances in discovering such factors, in particular those underlying risk to medication toxicity.     

Convulsing toward the pathophysiology of autism

The autisms and epilepsies are heterogeneous disorders that have diverse etiologies and pathologies. The severity of impairment and of symptoms associated with autism or with particular epilepsy syndromes reflects focal or global, structurally abnormal or dysfunctional neuronal networks. The complex relationship between autism and epilepsy, as reflected in the autism–epilepsy phenotype, provides a bridge to further knowledge of shared neuronal networks that can account for both the autisms and the epilepsies. Although epilepsy is not a causal factor for autism, increased understanding of common genetic and molecular biological mechanisms of the autism–epilepsy phenotype has provided insight into the pathophysiology of the autisms. The autism–epilepsy phenotype provides a novel model to the study of interventions that may have a positive modulating effects on social cognitive outcome.     

Genetics of epilepsy

Understanding the molecular biology of epilepsy is a challenge for modern science. Epilepsy results from alternations in fundamental mechanisms of brain and membrane function. Although an understanding of the mode of inheritance and the etiology of genetic epilepsy syndromes forms the basis for genetic counseling, the development of specific therapies will come from knowing the basic mechanisms of epilepsy. Defining the genes causing epilepsy requires an unambiguous definition of seizure phenotype, along with the stability of that trait, an unremitting clinical course, and an abundance of clinical material. This article reviews the task of defining the genetics of epilepsy and discusses genetic methodology, idiopathic generalized and localization-related partial epilepsies, neuronal migration disorders, progressive myoclonus epilepsies, molecular biology of epileptogenesis, and future research.     

Genetic approach to the pathogeneses of epilepsy]

Recently, genetic causes have been identified in certain epilepsy syndromes in which the phenotypes are similar to common idiopathic epilepsies. Interestingly, almost all such genetic abnormalities were detected in genes encoding ion channels expressed in the brain. Thus such epilepsy syndromes are disorders of ion channels, i.e., "channelopathies". The list of ion channel abnormalities that are associated with childhood epilepsy is expanding and includes the followings. Mutations of the genes encoding two subunits of the neuronal nicotinic acetylcholine receptor, a ligand-gated ion channel, were found in autosomal dominant nocturnal frontal lobe epilepsy. Mutations of two KCNQ K+-channel genes were identified in benign familial neonatal convulsions. Mutations of the genes encoding several subunits of the voltage-gated Na+-channel and GABA(A) receptor, a ligand-gated ion channel, were also identified as underlying causes of various epilepsy syndromes, such as autosomal dominant epilepsy with febrile seizures plus or generalized epilepsy with febrile seizures plus, benign familial neonatal infantile seizures and autosomal dominant juvenile myoclonic epilepsy. Mutations within the same gene can result in different epilepsy phenotypes. Abnormalities of Na+-channel alpha1 subunit were also associated with severe myoclonic epilepsy in infancy. Epilepsy syndromes mentioned above, except for severe myoclonic epilepsy in infancy, were familial epilepsy syndromes showing dominant inheritance with high penetrance while common idiopathic epilepsies do not show obvious inheritance. However, the similarities in symptomatology between such familial epilepsies and common idiopathic epilepsy may provide us with clues to the genetics of common idiopathic epilepsies.     

Immunology and epilepsy

Immune mechanisms play a critical role in systemic disorders (systemic lupus erythematosus, Sj?gren's syndrome, Crohn's disease, and sarcoidosis) and in localized central nervous system (CNS) disorders (CNS vasculitis, multiple sclerosis, acute disseminated encephalomyelitis, and encephalitides). Both humoral and cell-mediated mechanisms are involved in the systemic and CNS-limited disorders. Immune mechanisms may also be a factor in a number of epilepsies such as Rasmussen's encephalitis, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, and temporal lobe epilepsy. Immunologic abnormalities are found in routine epilepsy surgical specimens, suggesting a broader role of immunopathology in the etiology of epilepsy. The prevalence and impact of immunopathology in epilepsy syndromes remains to be determined by future research.     

Advances in the pathophysiology of developmental epilepsies

Pediatric epilepsies display unique characteristics that differ significantly from epilepsy in adults. The immature brain exhibits a decreased seizure threshold and an age-specific response to seizure-induced brain injury. Many idiopathic epilepsy syndromes and symptomatic epilepsies commonly present during childhood. This review highlights recent advances in the pathophysiology of developmental epilepsies. Cortical development involves maturational regulation of multiple cellular and molecular processes, such as neurogenesis, neuronal migration, synaptogenesis, and expression of neurotransmitter receptors and ion channels. These normal developmental changes of the immature brain also contribute to the increased risk for seizures and unique responses to seizure-induced brain injury in pediatric epilepsies. Recent technological advances, especially in genetics and imaging, have yielded exciting discoveries about the pathophysiology of specific pediatric epilepsy syndromes, such as the emergence of channelopathies as the cause of many idiopathic epilepsies and identification of malformations of cortical development as a major source of symptomatic epilepsies in children.     

Epilepsy and the frontal lobes

Although the frontal lobes contain a large proportion of the total cerebral cortex in human brain, the epilepsies arising in this region are less studied and less well characterised than epilepsies arising in the mesial temporal lobe. Detailed studies of seizure semiology have identified a number of patterns of frontal lobe seizure, but with inconsistency across studies, and with limited evidence that specific patterns arise in specific discrete frontal lobe regions. In contrast to mesial temporal lobe epilepsy, there is no consistent pattern of cognitive impairment seen in patients with frontal lobe epilepsy, although some evidence exists to support the notion that cognitive function may be impaired. Given the rich interconnectivity between frontal lobes and many other brain regions, it is not surprising to find functional deficits in the frontal lobes in patients with epilepsy arising in other sites; this is best studied in patients with temporal lobe epilepsy. Current concepts in epilepsy suggest that epilepsies hitherto regarded as idiopathic generalised (rather than focal) may in fact have a focal origin of seizure activity; this may be supported by increasing evidence for focal structural and functional frontal lobe abnormalities in idiopathic generalised epilepsies.     

Behavioral Aspects of Frontal Lobe Epilepsy

There is growing interest in disorders of behavior, personality, and mood associated with focal epilepsies, though the neuropsychological and behavioral or psychiatric aspects of epilepsy have usually been treated separately. The causes of behavioral disorders in patients with focal epilepsies are multifactorial, though the positive effects of seizure control on behavior suggest that state dependency is a major contributing factor. Patients with temporal lobe epilepsy manifest depression, anxiety, neuroticism, and social limitations, as well as impaired memory. By contrast, studies of cognitive function in patients with frontal lobe epilepsy show executive dysfunctions in response selection/initiation and inhibition, as well as cognitive impairment, hyperactivity, conscientiousness, obsession, and addictive behaviors.