Introduction to Epilepsies: Complexity and Comorbidities
Epilepsy & Behavior, Volume 38, September 2014, Pages 1-2, ISSN 1525-5050, http://dx.doi.org/10.1016/j.yebeh.2014.06.035.
Steven C. Schachter, Norberto Garcia-Cairasco, Andres M. Kanner
The NEWroscience 2013 international symposium “Epilepsies: Complexity and Comorbidities” was held at the Ribeirão Preto School of Medicine in Brazil from September 18 to 21, 2013. This unique meeting brought together a multidisciplinary group of basic and clinical biomedical researchers, scientists from the applied sciences, and a wide range of clinicians, and immersed them in a setting that was equal parts science and the arts. As suggested by the symposium’s title, the participants addressed the complexities of epilepsy that currently perplex scientists and the comorbidities of epilepsy, which perhaps, if better understood, could provide a framework for understanding complexities of the epilepsies.
Is depression associated with an increased risk of treatment-resistant epilepsy? Research strategies to investigate this question
Epilepsy & Behavior, Volume 38, September 2014, Pages 3-7, ISSN 1525-5050, http://dx.doi.org/10.1016/j.yebeh.2014.06.027.
Andres M. Kanner
Persons with epilepsy (PWE) have a higher risk of developing depressive disorders (DDs), and people with primary DD have an increased risk of developing epilepsy. Furthermore, a lifetime history of DD has been associated with a worse response of the seizure disorder to pharmacotherapy and epilepsy surgery. The first part of this article reviews the literature of this problem with the intention of highlighting the neurobiologic pathogenic mechanisms operant in DD with a potential to facilitate the epileptogenic process and/or cortical hyperexcitability in humans and experimental animal studies of depression. They include the following: (i) a hyperactive hypothalamic–pituitary–adrenal axis and the associated structural and functional abnormalities of limbic structures, (ii) increased glutamatergic activity and decreased GABAergic and serotonergic activity, and (iii) immunologic disturbances. In the second part of this article, we suggest research strategies to test the hypothesis of whether depression worsens the course of epilepsy and identify the pathogenic mechanisms operant in this process.
Are children affected by epileptic neuropsychiatric comorbidities?
Epilepsy & Behavior, Volume 38, September 2014, Pages 8-12, ISSN 1525-5050, http://dx.doi.org/10.1016/j.yebeh.2013.10.003.
Vera Cristina Terra, Luciano de Paola, Carlos Eduardo Silvado
Childhood-onset epilepsy is associated with psychiatric and cognitive difficulties and with poor social outcomes in adulthood. Some antiepileptic drugs adversely affect behavior in susceptible children with easy-to-control or refractory epilepsies, contributing to a high risk of psychological and psychiatric disturbance. Studies had demonstrated that patients with benign rolandic epilepsy and absence epilepsy had more aggressive behavior, depression, and anxiety disorders than control children. Psychiatric comorbidities are strongly associated with a poor long-term health-related quality of life in childhood-onset epilepsy, which suggests that comprehensive epilepsy care must include screening and long-term treatment for these conditions, even if seizures remit.
Extratemporal lobe circuits in temporal lobe epilepsy
Epilepsy & Behavior, Volume 38, September 2014, Pages 13-18, ISSN 1525-5050, http://dx.doi.org/10.1016/j.yebeh.2014.07.012.
Edward H. Bertram
There is increasing interest in the functional anatomy of epilepsy with the goal to identify the critical nodes in the seizure circuits so that therapy can be directed at them. This goal is especially important because direct delivery of therapy, either through electrical stimulation, drug infusion, or molecular therapies such as optogenetics, has become increasingly possible. In this article, we will review the basic functional anatomy of mesial temporal lobe epilepsy and its primary subcortical connection, the medial dorsal nucleus of the thalamus. Based on its anatomical connections and known physiological interactions, we propose a key role for this thalamic nucleus that is essential for the development of seizures, and this role suggests that this region is a potential therapeutic target.
Posttraumatic epilepsy — Disease or comorbidity?
Epilepsy & Behavior, Volume 38, September 2014, Pages 19-24, ISSN 1525-5050, http://dx.doi.org/10.1016/j.yebeh.2014.01.013.
Asla Pitkänen, Samuli Kemppainen, Xavier Ekolle Ndode-Ekane, Noora Huusko, Joanna K. Huttunen, Olli Gröhn, Riikka Immonen, Alejandra Sierra, Tamuna Bolkvadze
Traumatic brain injury (TBI) can cause a myriad of sequelae depending on its type, severity, and location of injured structures. These can include mood disorders, posttraumatic stress disorder and other anxiety disorders, personality disorders, aggressive disorders, cognitive changes, chronic pain, sleep problems, motor or sensory impairments, endocrine dysfunction, gastrointestinal disturbances, increased risk of infections, pulmonary disturbances, parkinsonism, posttraumatic epilepsy, or their combinations. The progression of individual pathologies leading to a given phenotype is variable, and some progress for months. Consequently, the different post-TBI phenotypes appear within different time windows. In parallel with morbidogenesis, spontaneous recovery occurs both in experimental models and in human TBI. A great challenge remains; how can we dissect the specific mechanisms that lead to the different endophenotypes, such as posttraumatic epileptogenesis, in order to identify treatment approaches that would not compromise recovery?
Do certain signal transduction mechanisms explain the comorbidity of epilepsy and mood disorders?
Epilepsy & Behavior, Volume 38, September 2014, Pages 25-31, ISSN 1525-5050, http://dx.doi.org/10.1016/j.yebeh.2014.01.001.
Luisa Rocha, Mario Alonso-Vanegas, Sandra Orozco-Suárez, David Alcántara-González, Humberto Cruzblanca, Elena Castro
It is well known that mood disorders are highly prevalent in patients with epilepsy. Although several studies have aimed to characterize alterations in different types of receptors associated with both disturbances, there is a lack of studies focused on identifying the causes of this comorbidity. Here, we described some changes at the biochemical level involving serotonin, dopamine, and γ-aminobutyric acid (GABA) receptors as well as signal transduction mechanisms that may explain the coexistence of both epilepsy and mood disorders. Finally, the identification of common pathophysiological mechanisms associated with receptor–receptor interaction (heterodimers) could allow designing new strategies for treatment of patients with epilepsy and comorbid mood disorders.
Focus on desynchronization rather than excitability: A new strategy for intraencephalic electrical stimulation
Epilepsy & Behavior, Volume 38, September 2014, Pages 32-36, ISSN 1525-5050, http://dx.doi.org/10.1016/j.yebeh.2013.12.034.
Daniel de Castro Medeiros, Márcio Flávio Dutra Moraes
Epilepsy is a severely debilitating brain disease, often associated with premature death, which has an urgent need for alternative methods of treatment. In fact, roughly 25% of patients with epilepsy do not have seizures satisfactorily controlled by pharmacological treatment, and 30% of these patients with treatment-refractory seizures are not even eligible for ablative surgery. Epilepsy is most readily identifiable by its seizures and/or paroxysmal events, mostly viewed as spontaneously recurrent and unpredictable, which are caused by stereotyped changes in neurological function associated with hyperexcitability and hypersynchronicity of the underlying neural networks. Treatment has strongly been based on the fixed goal of depressing neuronal activity, working under the veiled assumption that hyperexcitability would lead to synchronous neuronal activity and, therefore, to seizure. Over the last 20–30 years, the emergence of electrical (ES) of deep brain structures, a practicable option for treating patients with otherwise untreatable seizures, has broadened our understanding of anticonvulsant mechanisms that conceptually differ from those of pharmacological treatment. Conversely, the research on ES therapy applied to epilepsy is contributing significantly to untwine the phenomena of excitation from that of synchronization as potential target mechanisms for abolishing seizures and predicting paroxysmal events. This paper is, thus, an addendum to other reviews on the subject of ES therapy in epilepsy which focuses on the desynchronization effect ES has on epileptogenic neural networks rather than its effect on overall brain excitability.
Complex metabolically demanding sensory processing in the olfactory system: Implications for epilepsy
Epilepsy & Behavior, Volume 38, September 2014, Pages 37-42, ISSN 1525-5050, http://dx.doi.org/10.1016/j.yebeh.2013.08.036.
Diego Restrepo, Jennifer L. Hellier, Ernesto Salcedo
Although the olfactory system is not generally associated with seizures, sharp application of odor eliciting activity in a large number of olfactory sensory neurons (OSNs) has been shown to elicit seizures. This is most likely due to increased ictal activity in the anterior piriform cortex—an area of the olfactory system that has limited GABAergic interneuron inhibition of pyramidal output cell activity. Such hyperexcitability in a well-characterized and highly accessible system makes olfaction a potentially powerful model system to examine epileptogenesis.
Nervous and immune systems signals and connections: Cytokines in hippocampus physiology and pathology
Epilepsy & Behavior, Volume 38, September 2014, Pages 43-47, ISSN 1525-5050, http://dx.doi.org/10.1016/j.yebeh.2014.01.017.
Gabriel Maisonnave Arisi
Signaling through secretion of small molecules is a hallmark of both nervous and immune systems. The scope and influence of the intense message exchange between these two complex systems are only now becoming objects of scientific inquiry. Both neurotransmitters and cytokines affect their target cells through surface receptors and also by other molecular mechanisms. Cytokine receptors are present in neurons and glial cell populations in discrete brain regions. This review firstly focuses on the role of cytokines in hippocampal physiological processes, such as memory and learning, and secondly on the pathological involvement of cytokines in diseases like depression and epilepsy. Interleukin-1β is necessary for long-term potentiation (LTP) maintenance in the hippocampus. On the other hand, interleukin-6 has a negative regulatory role in long-term memory acquisition. Astrocyte-secreted tumor necrosis factor plays a role in synaptic strength by increasing surface translocation of glutamate AMPA receptors, and the chemokine CXCL12 can silence the tonic activity of Cajal–Retzius neurons in the hippocampus. Manifold increased concentrations of interleukin-10, interferon-γ, ICAM1, CCL2, and CCL4 are observed in the hippocampi of patients with temporal lobe epilepsy. A contemporary view of the role of cytokines as neuromodulators is emerging from studies in humans and manipulations of experimental animals. Despite the accumulating evidence of the role of cytokines on nervous system physiology and pathology, it is important not to exaggerate its relevance.
Alterations of the microvascular network in the sclerotic hippocampus of patients with temporal lobe epilepsy
Epilepsy & Behavior, Volume 38, September 2014, Pages 48-52, ISSN 1525-5050, http://dx.doi.org/10.1016/j.yebeh.2013.12.009.
Lidia Alonso-Nanclares, Javier DeFelipe
Hippocampal sclerosis is the most frequent pathology encountered in resected tissue obtained from patients with temporal lobe epilepsy. The main hallmarks of hippocampal sclerosis are neuronal loss and gliosis. Several authors have proposed that an increase in blood vessel density is a further indicator, based on interpretations from staining of markers related to both blood–brain barrier disruption and the formation of new blood vessels. However, previous studies performed in our laboratory using correlative light and electron microscopy revealed that many of these “blood vessels” are in fact atrophic vascular structures with a reduced or virtually absent lumen and are often filled with processes of reactive astrocytes. Thus, “normal” vasculature within the sclerotic CA1 field is drastically reduced. Since this decrease is consistently observed in the human sclerotic CA1, this feature can be considered another key pathological indicator of hippocampal sclerosis associated with temporal lobe epilepsy
Peritumoral epilepsy: Relating form and function for surgical success
Epilepsy & Behavior, Volume 38, September 2014, Pages 53-61, ISSN 1525-5050, http://dx.doi.org/10.1016/j.yebeh.2014.05.009.
Christopher J.A. Cowie, Mark O. Cunningham
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.
Computational models of dentate gyrus with epilepsy-induced morphological alterations in granule cells
Epilepsy & Behavior, Volume 38, September 2014, Pages 63-70, ISSN 1525-5050, http://dx.doi.org/10.1016/j.yebeh.2014.02.007.
Julian Tejada, Antonio C. Roque
Temporal lobe epilepsy provokes a number of different morphological alterations in granule cells of the hippocampus dentate gyrus. These alterations may be associated with the hyperactivity and hypersynchrony found in the epileptic dentate gyrus, and their study requires the use of different kinds of approaches including computational modeling. Conductance-based models of both normal and epilepsy-induced morphologically altered granule cells have been used in the construction of network models of dentate gyrus to study the effects of these alterations on epilepsy. Here, we review these models and discuss their contributions to the understanding of the association between alterations in neuronal morphology and epilepsy in the dentate gyrus.
Brain complex network analysis by means of resting state fMRI and graph analysis: Will it be helpful in clinical epilepsy?
Epilepsy & Behavior, Volume 38, September 2014, Pages 71-80, ISSN 1525-5050, http://dx.doi.org/10.1016/j.yebeh.2013.11.019.
Heloisa Onias, Aline Viol, Fernanda Palhano-Fontes, Katia C. Andrade, Marcio Sturzbecher, Gandhimohan Viswanathan, Draulio B. de Araujo
Functional magnetic resonance imaging (fMRI) has just completed 20 years of existence. It currently serves as a research tool in a broad range of human brain studies in normal and pathological conditions, as is the case of epilepsy. To date, most fMRI studies aimed at characterizing brain activity in response to various active paradigms. More recently, a number of strategies have been used to characterize the low-frequency oscillations of the ongoing fMRI signals when individuals are at rest. These datasets have been largely analyzed in the context of functional connectivity, which inspects the covariance of fMRI signals from different areas of the brain. In addition, resting state fMRI is progressively being used to evaluate complex network features of the brain. These strategies have been applied to a number of different problems in neuroscience, which include diseases such as Alzheimer’s, schizophrenia, and epilepsy. Hence, we herein aimed at introducing the subject of complex network and how to use it for the analysis of fMRI data. This appears to be a promising strategy to be used in clinical epilepsy. Therefore, we also review the recent literature that has applied these ideas to the analysis of fMRI data in patients with epilepsy.
Looking for complexity in quantitative semiology of frontal and temporal lobe seizures using neuroethology and graph theory
Epilepsy & Behavior, Volume 38, September 2014, Pages 81-93, ISSN 1525-5050, http://dx.doi.org/10.1016/j.yebeh.2014.07.025.
Poliana Bertti, Julian Tejada, Ana Paula Pinheiro Martins, Maria Luiza Cleto Dal-Cól, Vera Cristina Terra, José Antônio Cortes de Oliveira, Tonicarlo Rodrigues Velasco, Américo Ceiki Sakamoto, Norberto Garcia-Cairasco
Epileptic syndromes and seizures are the expression of complex brain systems. Because no analysis of complexity has been applied to epileptic seizure semiology, our goal was to apply neuroethology and graph analysis to the study of the complexity of behavioral manifestations of epileptic seizures in human frontal lobe epilepsy (FLE) and temporal lobe epilepsy (TLE). We analyzed the video recordings of 120 seizures of 18 patients with FLE and 28 seizures of 28 patients with TLE. All patients were seizure-free > 1 year after surgery (Engel Class I). All patients’ behavioral sequences were analyzed by means of a glossary containing all behaviors and analyzed for neuroethology (Ethomatic software). The same series were used for graph analysis (CYTOSCAPE®). Behaviors, displayed as nodes, were connected by edges to other nodes according to their temporal sequence of appearance. Using neuroethology analysis, we confirmed data in the literature such as in FLE: brief/frequent seizures, complex motor behaviors, head and eye version, unilateral/bilateral tonic posturing, speech arrest, vocalization, and rapid postictal recovery and in the case of TLE: presence of epigastric aura, lateralized dystonias, impairment of consciousness/speech during ictal and postictal periods, and development of secondary generalization. Using graph analysis metrics of FLE and TLE confirmed data from flowcharts. However, because of the algorithms we used, they highlighted more powerfully the connectivity and complex associations among behaviors in a quite selective manner, depending on the origin of the seizures. The algorithms we used are commonly employed to track brain connectivity from EEG and MRI sources, which makes our study very promising for future studies of complexity in this field.
Emergence of semiology in epileptic seizures
Epilepsy & Behavior, Volume 38, September 2014, Pages 94-103, ISSN 1525-5050, http://dx.doi.org/10.1016/j.yebeh.2013.12.003.
Patrick Chauvel, Aileen McGonigal
Semiology, the manifestation of epilepsy, is dependent upon electrical activity produced by epileptic seizures that are organized within existing neural pathways. Clinical signs evolve as the epileptic discharge spreads in both time and space. Studying the relation between these, of which the temporal component is at least as important as the spatial one, is possible using anatomo-electro-clinical correlations of stereoelectroencephalography (SEEG) data. The period of semiology production occurs with variable time lag after seizure onset and signs then emerge more or less rapidly depending on seizure type (temporal seizures generally propagating more slowly and frontal seizures more quickly). The subset of structures involved in semiological production, the “early spread network”, is tightly linked to those constituting the epileptogenic zone. The level of complexity of semiological features varies according to the degree of involvement of the primary or associative cortex, with the former having a direct relation to peripheral sensory and motor systems with production of hallucinations (visual and auditory) or elementary sensorimotor signs. Depending on propagation pattern, these signs can occur in a “march” fashion as described by Jackson. On the other hand, seizures involving the associative cortex, having a less direct relation with the peripheral nervous system, and necessarily involving more widely distributed networks manifest with altered cognitive and/or behavioral signs whose neural substrate involves a network of cortical structures, as has been observed for normal cognitive processes. Other than the anatomical localization of these structures, the frequency of the discharge is a crucial determinant of semiological effect since a fast (gamma) discharge will tend to deactivate normal function, whereas a slower theta discharge can mimic physiological function. In terms of interaction between structures, the degree of synchronization plays a key role in clinical expression, as evidenced, for example, by studies of ictal fear-related behavior (decorrelation of activity between structures inducing “release” phenomena) and of déjà vu (increased synchronization). Studies of functional coupling within networks underlying complex ictal behavior indicate that the clinical semiology of a given seizure depends upon neither the anatomical origin of ictal discharge nor the target areas of its propagation alone but on the dynamic interaction between these. Careful mapping of the ictal network in its full spread offers essential information as to the localization of seizure onset, by deducing that a given network configuration could only be generated by a given area or group of areas.
Hippocampal granule cell pathology in epilepsy — A possible structural basis for comorbidities of epilepsy?
Epilepsy & Behavior, Volume 38, September 2014, Pages 105-116, ISSN 1525-5050, http://dx.doi.org/10.1016/j.yebeh.2013.12.022.
Michael S. Hester, Steve C. Danzer
Temporal lobe epilepsy in both animals and humans is characterized by abnormally integrated hippocampal dentate granule cells. Among other abnormalities, these cells make axonal connections with inappropriate targets, grow dendrites in the wrong direction, and migrate to ectopic locations. These changes promote the formation of recurrent excitatory circuits, leading to the appealing hypothesis that these abnormal cells may by epileptogenic. While this hypothesis has been the subject of intense study, less attention has been paid to the possibility that abnormal granule cells in the epileptic brain may also contribute to comorbidities associated with the disease. Epilepsy is associated with a variety of general findings, such as memory disturbances and cognitive dysfunction, and is often comorbid with a number of other conditions, including schizophrenia and autism. Interestingly, recent studies implicate disruption of common genes and gene pathways in all three diseases. Moreover, while neuropsychiatric conditions are associated with changes in a variety of brain regions, granule cell abnormalities in temporal lobe epilepsy appear to be phenocopies of granule cell deficits produced by genetic mouse models of autism and schizophrenia, suggesting that granule cell dysmorphogenesis may be a common factor uniting these seemingly diverse diseases. Disruption of common signaling pathways regulating granule cell neurogenesis may begin to provide mechanistic insight into the cooccurrence of temporal lobe epilepsy and cognitive and behavioral disorders.
Hippocampal injury-induced cognitive and mood dysfunction, altered neurogenesis, and epilepsy: Can early neural stem cell grafting intervention provide protection?
Epilepsy & Behavior, Volume 38, September 2014, Pages 117-124, ISSN 1525-5050, http://dx.doi.org/10.1016/j.yebeh.2013.12.001.
Ashok K. Shetty
Damage to the hippocampus can occur through many causes including head trauma, ischemia, stroke, status epilepticus, and Alzheimer’s disease. Certain changes such as increased levels of neurogenesis and elevated concentrations of multiple neurotrophic factors that ensue in the acute phase after injury seem beneficial for restraining hippocampal dysfunction. However, many alterations that arise in the intermediate to chronic phase after injury such as abnormal migration of newly born neurons, aberrant synaptic reorganization, progressive loss of inhibitory gamma-amino butyric acid positive interneurons including those expressing reelin, greatly declined neurogenesis, and sustained inflammation are detrimental. Consequently, the net effect of postinjury plasticity in the hippocampus remains inadequate for promoting significant functional recovery. Hence, ideal therapeutic interventions ought to be efficient for restraining these detrimental changes in order to block the propensity of most hippocampal injuries to evolve into learning deficits, memory dysfunction, depression, and temporal lobe epilepsy. Neural stem cell (NSC) grafting into the hippocampus early after injury appears alluring from this perspective because several recent studies have demonstrated the therapeutic value of this intervention, especially for preventing/easing memory dysfunction, depression, and temporal lobe epilepsy development in the chronic phase after injury. These beneficial effects of NSC grafting appeared to be mediated through considerable modulation of aberrant hippocampal postinjury plasticity with additions of new inhibitory gamma-amino butyric acid positive interneurons and astrocytes secreting a variety of neurotrophic factors and anticonvulsant proteins. This review presents advancements made in NSC grafting therapy for treating hippocampal injury in animal models of excitotoxic injury, traumatic brain injury, Alzheimer’s disease, and status epilepticus; potential mechanisms of functional recovery mediated by NSC grafts placed early after hippocampal injury; and issues that need to be resolved prior to considering clinical application of NSC grafting for hippocampal injury.
Gene therapy for epilepsy
Epilepsy & Behavior, Volume 38, September 2014, Pages 125-130, ISSN 1525-5050, http://dx.doi.org/10.1016/j.yebeh.2013.09.013.
Gene therapy may represent an effective alternative to standard pharmacological approaches for certain forms of epilepsy. Currently, the best candidates for this therapeutic approach appear to be epilepsies characterized by a focal lesion. Gene therapy has been attempted to produce antiepileptogenic (prevention of development of epilepsy in subject at risk after having received an epileptogenic insult), antiseizure (reduction of frequency and/or severity of seizures), and disease-modifying (alteration of the natural history of the disease) effects. An example of gene therapy aimed at producing antiepileptogenic effects is a combination therapy based on the supplementation of the neurotrophic factors brain-derived neurotrophic factor (BDNF) and fibroblast growth factor 2 (FGF-2). Antiseizure effects have been obtained by increasing the strength of inhibitory signals (by supplementing specific GABAA receptor subunits or inhibitory neuropeptides like galanin or neuropeptide Y) or by reducing the strength of excitatory signals (by knocking down NMDA receptor subunits). This review summarizes the results obtained to date using gene therapy in epilepsy models and discusses the challenges and the opportunities that this approach can offer for the treatment of human epilepsies.
Systems biology, complexity, and the impact on antiepileptic drug discovery
Epilepsy & Behavior, Volume 38, September 2014, Pages 131-142, ISSN 1525-5050, http://dx.doi.org/10.1016/j.yebeh.2013.08.029.
Doru Georg Margineanu
The number of available anticonvulsant drugs increased in the period spanning over more than a century, amounting to the current panoply of nearly two dozen so-called antiepileptic drugs (AEDs). However, none of them actually prevents/reduces the post-brain insult development of epilepsy in man, and in no less than a third of patients with epilepsy, the seizures are not drug-controlled. Plausibly, the enduring limitation of AEDs’ efficacy derives from the insufficient understanding of epileptic pathology. This review pinpoints the unbalanced reductionism of the analytic approaches that overlook the intrinsic complexity of epilepsy and of the drug resistance in epilepsy as the core conceptual flaw hampering the discovery of truly antiepileptogenic drugs. A rising awareness of the complexity of epileptic pathology is, however, brought about by the emergence of nonreductionist systems biology (SB) that considers the networks of interactions underlying the normal organismic functions and of SB-based systems (network) pharmacology that aims to restore pathological networks. By now, the systems pharmacology approaches of AED discovery are fairly meager, but their forthcoming development is both a necessity and a realistic prospect, explored in this review.
Epilepsy & Behavior, Volume 38, September 2014, Page EX9, ISSN 1525-5050, http://dx.doi.org/10.1016/S1525-5050(14)00565-4.
Mike and Steve Danzer
What are the similarities and differences between schizophrenia and schizophrenia-like psychosis of epilepsy? A neuropathological approach to the understanding of schizophrenia spectrum and epilepsy
Epilepsy & Behavior, Volume 38, September 2014, Pages 143-147, ISSN 1525-5050, http://dx.doi.org/10.1016/j.yebeh.2014.01.005.
Ludmyla Kandratavicius, Jaime Eduardo Hallak, Joao Pereira Leite
Temporal lobe epilepsy (TLE) and psychosis coexist more frequently than chance would predict. In this short review, clinical and neuropathological findings of schizophrenia, TLE, and psychosis of epilepsy are described to enhance our understanding of the noncoincidental association between these conditions. In addition, psychosis of epilepsy was included for the first time in the Diagnostic and Statistical Manual of Mental Disorders (DSM), in the recently launched 5th edition, and improvement in diagnostic criteria was highlighted. Since the hippocampus has long been considered an anatomical area involved in the pathophysiology of TLE and schizophrenia, neuropathological studies of psychoses of epilepsy may contribute to our understanding of the pathophysiology of psychosis in general. The discovery of shared mechanisms and/or affected neurochemicals in TLE and schizophrenia might disclose important clues on the vulnerability of patients with TLE to psychotic symptoms and be an opportunity for new treatment development.
Early-life stress and HPA axis trigger recurrent adulthood depression
Epilepsy & Behavior, Volume 38, September 2014, Pages 148-159, ISSN 1525-5050, http://dx.doi.org/10.1016/j.yebeh.2013.10.020.
Mario F. Juruena
It is now broadly accepted that psychological stress may change the internal homeostatic state of an individual. During acute stress, adaptive physiological responses occur, which include hyperactivity of the HPA axis. Whenever there is an acute interruption of this balance, illness may result. The social and physical environments have an enormous impact on our physiology and behavior, and they influence the process of adaptation or ‘allostasis’. It is correct to state that at the same time that our experiences change our brain and thoughts, namely, changing our mind, we are changing our neurobiology. Increased adrenocortical secretion of hormones, primarily cortisol in major depression, is one of the most consistent findings in neuropsychiatry. A significant percentage of patients with major depression have been shown to exhibit increased concentrations of cortisol, an exaggerated cortisol response to adrenocorticotropic hormone, and an enlargement of both the pituitary and adrenal glands. The maintenance of the internal homeostatic state of an individual is proposed to be based on the ability of circulating glucocorticoids to exert negative feedback on the secretion of hypothalamic-pituitary-adrenal (HPA) hormones through binding to mineralocorticoid (MR) and glucocorticoid (GR) receptors limiting the vulnerability to diseases related to psychological stress in genetically predisposed individuals. The HPA axis response to stress can be thought of as a mirror of the organism’s response to stress: acute responses are generally adaptive, but excessive or prolonged responses can lead to deleterious effects. Evidence indicates that early-life stress can induce persistent changes in the ability of the HPA axis to respond to stress in adulthood. These abnormalities appear to be related to changes in the ability of hormones to bind to GR and MR receptors. First episodes may begin with an environmental stressor, but if the cycles continue or occur unchecked, the brain becomes kindled or sensitized, and future episodes of depression, hypomania, or mania will occur independently of an outside stimulus, with greater frequency and intensity. Generally, HPA axis changes appear in chronic depressive and more severe episodes. Moreover, HPA axis changes appear to be state-dependent, tending to improve upon resolution of the depressive syndrome. Interestingly, persistent HPA dysfunction has been associated with higher rates of relapse and chronicity.
Early life stress in epilepsy: A seizure precipitant and risk factor for epileptogenesis
Epilepsy & Behavior, Volume 38, September 2014, Pages 160-171, ISSN 1525-5050, http://dx.doi.org/10.1016/j.yebeh.2013.09.029.
Jolien S. van Campen, Floor E. Jansen, Pierre N.E. de Graan, Kees P.J. Braun, Marian Joels
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.
Genomic biomarkers of SUDEP in brain and heart
Epilepsy & Behavior, Volume 38, September 2014, Pages 172-179, ISSN 1525-5050, http://dx.doi.org/10.1016/j.yebeh.2013.09.019.
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality, but how to predict which patients are at risk and how to prevent it remain uncertain. The underlying pathomechanisms of SUDEP are still largely unknown, but the general consensus is that seizures somehow disrupt normal cardiac or respiratory physiology leading to death. However, the proportion of SUDEP cases exhibiting cardiac or respiratory dysfunction as a critical factor in the terminal cascade of events remains unresolved. Although many general risk factors for SUDEP have been identified, the development of reliable patient-specific biomarkers for SUDEP is needed to provide more accurate risk prediction and personalized patient management strategies. Studies in animal models and patient groups have revealed at least nine different brain-heart genes that may contribute to a genetic susceptibility for SUDEP, making them potentially useful asgenomic biomarkers. This review summarizes data on the relationship between these neurocardiac genes and SUDEP, discussing their brain-heart expression patterns and genotype-phenotype correlations in mouse models and people with epilepsy. These neurocardiac genes represent good first candidates for evaluation as genomic biomarkers of SUDEP in future studies. The development of validated reliable genomic biomarkers for SUDEP has the potential to transform the clinical treatment of epilepsy by pinpointing patients at risk of SUDEP and allowing optimized, genotype-guided therapeutic and prevention strategies.