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Epilepsy is one of the most common chronic brain diseases and is often associated with cognitive, behavioral, or other medical conditions. The need for therapies that would prevent, ameliorate, or cure epilepsy and the attendant comorbidities is a priority for both epilepsy research and public health. In 2018, the National Institute of Neurological Disease and Stroke (NINDS) convened a workshop titled “Accelerating the Development of Therapies for Antiepileptogenesis and Disease Modification” that brought together preclinical and clinical investigators and industry and regulatory bodies’ representatives to discuss and propose a roadmap to accelerate the development of antiepileptogenic (AEG) and disease‐modifying (DM) new therapies. This report provides a summary of the discussions and proposals of the Preclinical Science working group. Highlights of the progress of collaborative preclinical research projects on AEG/DM of ongoing research initiatives aiming to improve infrastructure and translation to clinical trials are presented. Opportunities and challenges of preclinical epilepsy research, vis‐à‐vis clinical research, were extensively discussed, as they pertain to modeling of specific epilepsy types across etiologies and ages, the utilization of preclinical models in AG/DM studies, and the strategies and study designs, as well as on matters pertaining to transparency, data sharing, and reporting research findings. A set of suggestions on research initiatives, infrastructure, workshops, advocacy, and opportunities for expanding the borders of epilepsy research were discussed and proposed as useful initiatives that could help create a roadmap to accelerate and optimize preclinical translational AEG/DM epilepsy research.

Neurocysticercosis (NCC) is a rare central nervous system infection that is preventable and is caused by the Taenia solium tapeworm larval stage. This disorder is the world’s most common cause of acquired epilepsy and a significant cause of neurological morbidity. This disease is pleomorphic due to several complex factors such as cysticerci characteristics, stages of development, and many more which leads to difficulties in inaccurate diagnosis and adequate stage-wise care. The introduction of cystidical medications, however, has led to a stronger prognosis of NCC-affected patients with an increase in the patient’s clinical course of the disease. After diagnosis most seizure patients do not experience epilepsy. Since Neurocysticercosis remains a neglected tropical disease, the management, and prevention of T. so ilium transmission and strategies for eradicating NCC from endemic areas should be highlighted and prioritized in global healthcare to minimize the significant burden on healthcare and the economy.

Whether genetic factors contribute to acquired epilepsies has long been controversial. Supporters observe that, among individuals exposed to seemingly the same brain insult, only a minority develops unprovoked seizures. Yet, only in relatively recent years have studies started to build a case for genetic contributions. Here, we appraise this emerging evidence, by providing a critical review of studies published in the field.

In Vivo CRISPRa Decreases Seizures and Rescues Cognitive Deficits in a Rodent Model of Epilepsy Colasante G, Qiu Y, Massimino L, et al. Brain. 2020;143(3):891-905. doi:10.1093/brain/awaa045Epilepsy is a major health burden, calling for new mechanistic insights and therapies. CRISPR-mediated gene editing shows promise to cure genetic pathologies, although hitherto it has mostly been applied ex vivo. Its translational potential for treating nongenetic pathologies is still unexplored. Furthermore, neurological diseases represent an important challenge for the application of CRISPR because of the need in many cases to manipulate gene function of neurons in situ. A variant of CRISPR, CRISPRa, offers the possibility to modulate the expression of endogenous genes by directly targeting their promoters. We asked if this strategy can effectively treat acquired focal epilepsy, focusing on ion channels because their manipulation is known to be effective in changing network hyperactivity and hypersynchronization. We applied a doxycycline-inducible CRISPRa technology to increase the expression of the potassium channel gene Kcna1 (encoding Kv1.1) in mouse hippocampal excitatory neurons. CRISPRa-mediated Kv1.1 upregulation led to a substantial decrease in neuronal excitability. Continuous video electroencephalogram telemetry showed that AAV9-mediated delivery of CRISPRa, upon doxycycline administration, decreased spontaneous generalized tonic–clonic seizures in a model of temporal lobe epilepsy and rescued cognitive impairment and transcriptomic alterations associated with chronic epilepsy. The focal treatment minimizes concerns about off-target effects in other organs and brain areas. This study provides the proof-of-principle for a translational CRISPR-based approach to treat neurological diseases characterized by abnormal circuit excitability.

Stroke is the main cause of acquired epilepsy in elderly people. Poststroke epilepsy (PSE) not only affects functional recovery after stroke but also brings considerable social consequences. While some factors such as cortical involvement, hemorrhagic transformation, and stroke severity are associated with increased seizure risk, so far that remains controversial. In recent years, there are an increasing number of studies on potential biomarkers of PSE as tools for diagnosing and predicting epileptic seizures. Biomarkers such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), glutamate, and S100 calcium-binding protein B (S100B) in blood are associated with the occurrence of PSE. This review is aimed at summarizing the progress on potential biomarkers of PSE.

Acute intoxication with organophosphates (OPs) can cause a potentially fatal cholinergic crisis characterized by peripheral parasympathomimetic symptoms and seizures that rapidly progress to status epilepticus (SE). While current therapeutic countermeasures for acute OP intoxication significantly improve the chances of survival when administered promptly, they are insufficient for protecting individuals from chronic neurologic outcomes such as cognitive deficits, affective disorders, and acquired epilepsy. Neuroinflammation is posited to contribute to the pathogenesis of these long-term neurologic sequelae. In this review, we summarize what is currently known regarding the progression of neuroinflammatory responses after acute OP intoxication, drawing parallels to other models of SE. We also discuss studies in which neuroinflammation was targeted following OP-induced SE, and explain possible reasons why such therapeutic interventions have inconsistently and only partially improved long-term outcomes. Finally, we suggest future directions for the development of therapeutic strategies that target neuroinflammation to mitigate the neurologic sequelae of acute OP intoxication.

Brain glucose hypometabolism is an early symptom of acquired epilepsy, its causative mechanism yet unclear. We suggest that a bidirectional positive feedback linking seizures and hypometabolism (hypometabolism induces seizures while seizures disrupt glucose metabolism) may be a primary cause for acquired epileptogenesis. We reported recently that chronic partial inhibition of brain glycolysis triggers epileptogenesis in healthy rats. Here, by monitoring dynamic electrical and multiple metabolic parameters before and following seizure generation in mouse hippocampal slices using the 4-aminopyridine model of epileptiform activity, we show that in turn seizures are followed by a long-lasting glucose hypometabolism, indicating possible existence of a positive feedback in the mechanism of epileptogenesis. Seizures were associated with acute oxidative stress that may contribute to the subsequent glucose metabolism impairment, since exogenous application of H2O2 replicated the post-seizure metabolic effects. Exogenous pyruvate, the principal mitochondrial energy substrate with a broad spectrum of neuroprotective properties, effectively normalized the post-seizure glucose consumption. We have shown recently that pyruvate exhibited a strong antiepileptic action in three rodent chronic epilepsy models, while in the present study we find that pyruvate effectively normalizes impaired glucose metabolism following seizures. Together, our results provide the mechanistic basis for the metabolic concept of acquired epileptogenesis and an efficient treatment strategy.

Neurocysticercosis (NCC) results from the localization in the central nervous system (CNS) of larval stages of the cestode parasite Taenia solium. NCC is the most common helminthic parasitic disease of the nervous system and the main cause of acquired epilepsy. This literature review presents an update in NCC diagnostic techniques, including neuroimaging, immunological assays, molecular assays, and clinical manifestations. NCC can cause a wide array of neurological manifestations, most of them being non-pathognomonic. Diagnosis of this infection represents a challenge due to its nonspecific symptoms and limited resources in endemic regions. Diagnoses by neuroimaging and immunological assessment are the current criteria used to diagnose NCC. Current diagnostic techniques continue to be non-affordable and non-available in most endemic regions. The development of novel and affordable standardized diagnostic techniques is of urgent need in order to determine the actual global burden caused by NCC.

Traumatic brain injury, a common cause of acquired epilepsy, is typical to find necrotic cell death within the injury core. The dynamic changes in astrocytes surrounding the injury core contribute to epileptic seizures associated with intense neuronal firing. However, little is known about the molecular mechanisms that activate astrocytes during traumatic brain injury or the effect of functional changes of astrocytes on seizures. In this comprehensive review, we present our cumulated understanding of the complex neurological affection in astrocytes after traumatic brain injury. We approached the problem through describing the changes of cell morphology, neurotransmitters, biochemistry, and cytokines in astrocytes during post-traumatic epilepsy. In addition, we also discussed the relationship between dynamic changes in astrocytes and seizures and the current pharmacologic agents used for treatment. Hopefully, this review will provide a more detailed knowledge from which better therapeutic strategies can be developed to treat post-traumatic epilepsy.

International audience; The recent definition of a network of lymphatic vessels in the meninges surrounding the brain and the spinal cord has advanced our knowledge on the functional anatomy of fluid movement within the central nervous system (CNS). Meningeal lymphatic vessels along dural sinuses and main nerves contribute to cerebrospinal fluid (CSF) drainage, integrating the cerebrovascular and periventricular routes, and forming a circuit that we here define as the CNS-lymphatic unit. The latter unit is important for parenchymal waste clearance, brain homeostasis, and the regulation of immune or inflammatory processes within the brain. Disruption of fluid drain mechanisms may promote or sustain CNS disease, conceivably applicable to epilepsy where extracellular accumulation of macromolecules and metabolic by-products occur in the interstitial and perivascular spaces. Herein we address an emerging concept and propose a theoretical framework on: (a) how a defect of brain clearance of macromolecules could favor neuronal hyperexcitability and seizures, and (b) whether meningeal lymphatic vessel dysfunction contributes to the neuroimmune cross-talk in epileptic pathophysiology. We propose possible molecular interventions targeting meningeal lymphatic dysfunctions, a potential target for immune-mediated epilepsy.

Gender differences in the incidence and clinical course of acquired and “cryptogenic” epilepsy are reviewed based on a literature search. We emphasized incidence and population-based studies because they are best suited to assess the effect of gender on susceptibility and clinical evolution of these epilepsies and may control for potential confounding factors. However, such studies were only available for a few acquired etiologies. These included tumor, prenatal and perinatal brain insults, cerebrovascular disease, infection, trauma, neurodegenerative disease, and autoimmune disorders. None of these acquired causes has been consistently shown to affect women or men to a greater or lesser degree, although some of the literature is contradictory or inadequate. There is almost no literature that addresses the effect of gender on the clinical course of epilepsy associated with these acquired causes. In addition, most studies of acquired causes do not take into account the incidence of the cause in the population with or without associated epilepsy. In children, “cryptogenic” epilepsy (non-syndromic and without causative MRI lesion) does not appear to have a gender preference and gender does not seem to affect the likelihood of remission. As further population-based studies of the etiology and clinical course of epilepsy are undertaken, it may be worthwhile to more specifically define the role of gender.

Introduction: Temporal lobe epilepsy (TLE) is a form of acquired epilepsy characterized as an electro-clinical syndrome in which seizures emanate from the limbic system [1,2]. TLE is particularly disabling due to the unpredictable and recurrent nature of seizures and incidence of antiepileptic drug resistance [3] many times an indication for resection surgery [4,5]. Pre-surgical identification of the seizure onset zone relies on multimodal methods based on different pathophysiological principles. The golden standard technique is long-term intracranial electroencephalogram (EEG) [6] combined neuroimaging techniques, which explore brain hemodynamics as a surrogate signal for brain activity [7,8]. To date, no single sensor approach allows simultaneous and seamless recording of electrical and hemodynamic responses. Materials and methods: We used multisite ceramic-based Pt microelectrode arrays (MEAs) to perform high-frequency amperometric recording of pO(2) and local field potential (LFP)-related currents in the CNS of chronically implanted freely-moving rats during pilocarpine-evoked status epilepticus. Using fast Fourier transform (FFT) filtering of the raw electrochemical signal we separated into the low frequency component (1 Hz) frequency component, corresponding to the LFP currents. Results: We determined the mean resting level of pO(2) in two subregions of the hippocampus as well as in the striatum and the cortex of freely moving rats. The hippocampal DG showed lowest (p

Introduction Poststroke epilepsy (PSE) is the most common form of acquired epilepsy after middle age. The primary aim of this study was to study the impact of PSE on prognosis. A secondary aim was to validate recent findings from smaller studies on the risk of developing PSE on a nationwide scale. Patients and methods We performed a nationwide cohort study based on comprehensive national registries and included patients without a prior epilepsy diagnosis surviving more than 2 months after stroke, identified by the Swedish Stroke Register (Riksstroke) and linked to the National Patient Register and Cause of Death Register. Cox proportional time-updated hazard model was used to assess the risk of death, with or without multivariable adjustment for possible confounders, and multiple Cox regression was used to examine associations between PSE and clinical characteristics. Results In 106,455 patients, PSE (defined as a seizure diagnosis more than 7 days after stroke) was detected in 7.3%, with lower cumulative incidence after ischemic stroke (6.4%) than after intracerebral haemorrhage (12.4%). Stroke severity, intracerebral haemorrhage and young age were associated with a risk of PSE. The risk of death was increased in patients with PSE (hazard ratio: 1.68, 95% confidence interval: 1.25–1.53). Also with adjustments for age, comorbidities and stroke severity, an increased risk of death associated with PSE remained. Discussion Studies are needed on potential causes of increased mortality in PSE, such as a direct seizure-related mortality, less ambitious secondary stroke prophylaxis or rehabilitation, or impact of antiepileptic drugs on cardiovascular risk.

This study tested the hypothesis that acquired epileptogenesis is accompanied by DNA methylation changes independent of etiology. We investigated DNA methylation and gene expression in the hippocampal CA3/dentate gyrus fields at 3 months following epileptogenic injury in three experimental models of epilepsy: focal amygdala stimulation, systemic pilocarpine injection, or lateral fluid-percussion induced traumatic brain injury (TBI) in rats. In the models studies, DNA methylation and gene expression profiles distinguished controls from injured animals. We observed consistent increased methylation in gene bodies and hypomethylation at non-genic regions. We did not find a common methylation signature in all three different models and few regions common to any two models. Our data provide evidence that genome-wide alteration of DNA methylation signatures is a general pathomechanism associated with epileptogenesis and epilepsy in experimental animal models, but the broad pathophysiological differences between models (i.e. pilocarpine, amygdala stimulation and post-TBI) are reflected in distinct etiology-dependent DNA methylation patterns.

Current treatments for epilepsy suffer from significant limitations, including medical intractability and lack of disease-modifying or anti-epileptogenic actions. As most current seizure medications modulate ion channels and neurotransmitter receptors, more effective therapies likely need to target completely different mechanisms of action. The mammalian target of rapamycin (mTOR) pathway represents a potential novel therapeutic target for epilepsy. mTOR inhibitors can suppress seizures and prevent epilepsy in animal models of certain genetic epilepsies, such as tuberous sclerosis complex. mTOR inhibitors may also be effective in some models of acquired epilepsy related to brain injury, but these effects are more variable and dependent on a number of factors. Some clinical data suggest that mTOR inhibitors decrease seizures in tuberous sclerosis complex patients, but controlled trials are lacking and no clinical data on potential anti-epileptogenic actions exist. Future basic and clinical research will help to determine the full potential of mTOR inhibitors for epilepsy.

Mitochondrial dysfunction and oxidative stress contribute to several neurologic disorders and have recently been implicated in acquired epilepsies such as temporal lobe epilepsy (TLE). Acquired epilepsy is typically initiated by a brain injury followed by a “latent period” whereby molecular, biochemical and other cellular alterations occur in the brain leading to chronic epilepsy. Mitochondrial dysfunction and oxidative stress are emerging as factors that not only occur acutely as a result of precipitating injuries such as status epilepticus (SE), but may also contribute to epileptogenesis and chronic epilepsy. Mitochondria are the primary site of reactive oxygen species (ROS) making them uniquely vulnerable to oxidative damage that may affect neuronal excitability and seizure susceptibility. This mini-review provides an overview of evidence suggesting the role of mitochondrial dysfunction and oxidative stress as acute consequences of injuries that are known to incite chronic epilepsy and their involvement in the chronic stages of acquired epilepsy.

D'Ambrosio and Miller argue that brief (i.e., one to a few seconds), rhythmic electrographic events accompanied by behavioral arrest, which they have observed in rats after lateral fluid percussion (i.e., in an animal model of traumatic brain injury), should be considered seizures in this model of posttraumatic epilepsy (1). A counter argument is that these events are not characteristic of the seizures seen clinically in posttraumatic epilepsy or in other forms of acquired epilepsy. Furthermore, several types of brief, rhythmic activity can be recorded in the electroencephalogram (EEG) of animals and humans without epilepsy. One cannot exclude the possibility that such events represent normal electrical activity, which may (or even may not) occur more often after brain injury. Thus, caution is required. In this counterpoint to “What Is an Epileptic Seizure?” by D'Ambrosio and Miller, the assertion is made that experimental studies on animal models of acquired epilepsy that claim electrographic events to be seizures, when the possibility exists that they may not be seizures characteristic of human acquired epilepsy, could be counterproductive, since research resources could be focused on animal models that may not actually demonstrate acquired epilepsy.

Prevention of epileptogenesis is an unmet need in medicine. During the last 3 years, however, several preclinical studies have demonstrated remarkable favorable effects of novel treatments on genetic and acquired epileptogenesis. These include the use of immunosuppressants and treatments that modify cellular adhesion, proliferation, and/or plasticity. In addition, the use of antiepileptic drugs in rats with genetic epilepsy or proconvulsants in acquired epilepsy models has provided somewhat unexpected favorable effects. This review summarizes these studies, and introduces some caveats when interpreting the data. In particular, the effect of genetic background, the severity of epileptogenic insult, the method and duration of seizure monitoring, and size of animal population are discussed. Furthermore, a novel scheme for defining epileptogenesis-related terms is presented.

This report examines several concepts concerning the latent period to the first convulsive seizure, subsequent increases in seizure frequency, and possible mechanisms of epileptogenesis after kainate-induced status epilepticus. Previous data concerning the latent period and seizure progression from intermittent and continuous behavioral monitoring are compared, and hypothetical mechanisms of acquired epilepsy are discussed. Data involving electrographic recordings with tethered animals or with radiotelemetry are assessed in terms of their potential for addressing different hypotheses concerning the latent period and progressive changes in seizure frequency. Experimental analyses of the time course of occurrence of spontaneous seizures are interpreted in terms of possible cellular mechanisms underlying epileptogenesis.

La neurocisticercosis es la primera causa de parasitosis del sistema nervioso central y de epilepsia adquirida en países en vía de desarrollo. Las manifestaciones clínicas de la neurocisticercosis, especialmente la variante racemosa, son pleomórficas e inespecíficas, características que dificultan el diagnóstico y lo convierten en un desafío para el clínico. El objetivo de este informe es describir dos casos de neurocisticercosis racemosa, en los cuales las neuroimágenes guiaron al diagnóstico definitivo. El primer caso se trató de una paciente con cefalea persistente y signos neurológicos focales, requirió múltiples ayudas paraclínicas que llevaron al diagnóstico definitivo de neurocisticercosis racemosa con vasculitis cerebral secundaria, a pesar del tratamiento médico y quirúrgico la paciente falleció después de múltiples complicaciones. El segundo caso se trató de una paciente con antecedente de neurocisticerosis, que consultó por vómito crónico incoercible, requirió múltiples ayudas paraclínicas que llevaron al diagnóstico de vómito de origen central secundario a neurocisticercosis racemosa y atrapamiento del cuarto ventrículo, después del tratamiento médico y quirúrgico la paciente presentó leve mejoría. En estos dos casos se evidencia como la adecuada interpretación de las neuroimágenes es fundamental para llegar al diagnóstico de la neurocisticercosis racemosa.

Literature is sparse about seizures in adult horses and this affection often carries a poor prognosis for further riding or athletic use. The authors present a case of an adult horse showing recurrent focal seizures and neurological deficits indicative of central blindness occurring during an episode of colic which was resolved surgically. Clinical signs occurred soon after an episode of colic, then resolved by laparotomy with an uneventful general anaesthesia. The investigations undertaken to find the cause of the seizures concluded finally a tentative diagnosis of a cortical lesion associated with amaurosis due to possible brain hypoxia and/or trauma. The outcome of the presented case was satisfactory, as four months later on a control examination no further seizures had been reported, most neurological deficits had disappeared and vision had at least partially been restored.

Neurocysticercosis (NCC) is caused by the larva of Taenia solium, when it is lodged in the central nervous system (CNS). NCC is identified as the major cause of community acquired epilepsy, especially in the developing countries. It is also increasingly being reported in the developed world due to human migration from the disease endemic countries. However, some individuals with similar NCC lesions may remain asymptomatic and the reason for this asymptomatic status largely remains unknown. However, studies from our center suggest that cytokines play important role in disease pathogenesis. In the present review, we have discussed the role of different cytokines in the pathogenesis of NCC in human.

Interictal spikes are periodic, very brief bursts of neuronal activity that are observed in the electroencephalogram of patients with chronic epilepsy. These spikes are useful diagnostically, but we do not know why they are so strongly associated with the spontaneous seizures that characterize chronic epilepsy. Interictal spikes appear before the first spontaneous seizures in animal models of acquired epilepsy, and spikes are sufficient to induce long-term changes in synaptic connections between neurons. Thus, spikes may guide the development of the neuronal circuits that initiate spontaneous seizures. If so, then attempts to prevent or cure epilepsy may best be directed at spikes rather than seizures.

Summary: Since 1993, nine new antiepileptic drugs (AEDs) have been introduced into the U.S. market for the symptomatic treatment of partial epilepsy. Their antiepileptic activity was, for the most part, defined by acute seizure models such as the maximal electroshock (MES) and subcutaneous pentylenetetrazol (scPTZ) seizure tests and the kindled rat. Unfortunately, the clinical evidence to date would suggest that none of these models, albeit useful, are likely to identify those therapeutics that will effectively manage the patient with refractory seizures. In recent years, a number of in vivo and in vitro models have been developed that display varying degrees of pharmacoresistance. As such, they may provide a unique opportunity for identifying the truly novel AED. Through a greater understanding of the pathophysiology of acquired epilepsy at the molecular and genetic level, it may be possible to identify a new therapeutic approach that reaches beyond the symptomatic treatment of epilepsy to modify the progression, or, dare we suggest, prevent the development of epilepsy in the susceptible patient. The realization of such a possibility will necessitate a change in our current AED discovery approach. The present review describes the current approach used in the search for new AEDs and offers some insight into future directions incorporating new and emerging models of therapy resistance and epileptogenesis.

Neurocysticercosis is a major health problem for a large proportion of the developing world where it has been found to be the most common cause of acquired epilepsy. This central nervous system parasite is also quite common in many parts of India because of lack of hygiene, clean drinking water and the lack of knowledge regarding modes of acquiring this infection. Diagnosis of this condition can be accomplished with a fair deal of accuracy only when various laboratory-based immunodiagnostic test results are used in conjunction with clinical features. Imaging methods like CT and MRI also play pivotal roles in the diagnosis of this condition. Both antibody detection as well as antigen detection tests have been found to be vital in the diagnosis of this condition, and each of them has their own advantages as well as short comings. Recombinant DNA technology has made it possible to develop many different recombinant antigens which have potential for designing various immunodiagnostic tests in the diagnosis of neurocysticercosis.

Moderate to severe traumatic brain injury (TBI) is one of the leading causes of acquired epilepsy. Prophylaxis for seizures is the standard of care for individuals with moderate to severe injuries at risk for developing seizures, though relatively limited comparative data is available to guide clinicians in their choice of agents. There have however been experimental studies which demonstrate potential neuroprotective qualities of levetiracetam after TBI, and in turn there is hope that eventually such agents may improve neurobehavioral outcomes post-TBI. This mini-review summarizes the available studies and suggests areas for future studies.

Neurocysticercosis (NCC) is an infection of the central nervous system by the Taenia solium larvae, and is the most common cause of acquired epilepsy in endemic regions. The natural history of parenchymal NCC lesions can be divided into 4 stages with unique imaging and clinical features. Evaluation of cysticerci is challenging on conventional magnetic resonance (MR) imaging and computed tomography, and is significantly improved with MR cysternography techniques. Differentiation of NCC lesions from metastatic disease and pyogenic abscesses can be improved with advanced MR imaging including (1)H nuclear MR spectroscopy, diffusion-weighted imaging, and MR perfusion imaging.

Background: Neurocysticercosis is the most common parasitic infestation of the central nervous system and an important cause of acquired epilepsy. Although endemic in developing countries, with an increased immigration from the endemic regions, it is also seen progressively in other parts of the world. Hence, there is an increased need for awareness of neurocysticercosis in the non-endemic areas. Case Description: The case described here is of a 13-year-old girl who presented with refractory seizures. She had been on antiepileptic medication and had also received anti-parasitic treatment for neurocysticercosis. Surgical intervention was recommended because the seizures were resistant to treatment and also because the diagnosis could not be clearly established. Following surgery, the seizures have been under control and the patient has been doing well. Conclusion: Neurocysticercosis can be a potential cause of refractory seizure even in non-endemic countries. Some cases may be difficult to diagnose. Clinical presentation of seizure and brain imaging should be given priority over blood investigations for diagnosing neurocysticercosis and advanced neurosurgical intervention can be considered in suitable cases for better outcome.

There are essentially two potential treatment options for any acquired disorder: symptomatic or prophylactic. For acquired epilepsies that follow a variety of different brain insults, there remains a complete lack of prophylactic treatment options, whereas at the same time these epilepsies are notoriously resistant, once they have emerged, to symptomatic treatments with antiepileptic drugs. The development of prophylactic strategies is logistically challenging, both for basic researchers and clinicians. Nevertheless, cannabinoid-targeting drugs provide a very interesting example of a system within the central nervous system (CNS) that can have very different acute and long-term effects on hyperexcitability and seizures. In this review, we outline research on cannabinoids suggesting that although cannabinoid antagonists are acutely proconvulsant, they may have beneficial effects on long-term hyperexcitability following brain insults of multiple etiologies, making them promising candidates for further investigation as prophylactics against acquired epilepsy. We then discuss some of the implications of this finding on future attempts at prophylactic treatments, specifically, the very short window within which prevention may be possible, the possibility that traditional anticonvulsants may interfere with prophylactic strategies, and the importance of moving beyond anticonvulsants-even to proconvulsants-to find the ideal preventative strategy for acquired epilepsy.

Acquired symptomatic epilepsy is the most common form of epilepsy in adults. In these patients, epilepsy typically develops in three phases: brain-damaging insult (BDI) such as traumatic brain injury or stroke, epileptogenesis or latency phase, and occurrence of spontaneous seizures or epilepsy. Neurodegeneration caused by epileptogenic BDI is often a major component of the changes in neuronal networks that take place during epileptogenesis. After epilepsy diagnosis, recurrent seizures can also contribute to further damage in a subpopulation of patients. Therefore, neurodegeneration represents one of the most attractive targets for treatments aimed at improving the outcome of patients with acquired epilepsy. We review the current understanding regarding the following questions: where does neurodegeneration occur in epileptic brain, when does it occur, what are the mechanisms of neurodegeneration, and finally, do current treatments of epilepsy affect the neurodegeneration?

Neurocysticercosis, the infection caused by the larval form of the tapewormTaenia solium, is the most common parasitic disease of the central nervous system and the most common cause of acquired epilepsy worldwide. This has primarily been a disease that remains endemic in low-socioeconomic countries, but because of increased migration neurocysticercosis is being diagnosed more frequently in high-income countries. During the past three decades improved diagnostics, imaging, and treatment have led to more accurate diagnosis and improved prognosis for patients. This article reviews the current literature on neurocysticercosis, including newer diagnostics and treatment developments.

Interictal spikes are widely accepted diagnostically as a sign of epilepsy, but reasons for the presence of interictal activity in the epileptic brain are unknown. Interictal spikes are easily generated in normal brain by pharmacologically reducing inhibition, and experimental studies of acquired epilepsy indicate that spikes precede seizures. These data lead to the hypothesis that interictal spikes are correlated with epilepsy because they play a fundamental role in epileptogenesis following brain injury. Spikes may guide sprouting axons back to their network of origin, increase and sustain the strength of the synapses formed by sprouted axons, and alter the balance of ion channels in the epileptic focus, such that seizures become possible. This hypothesis has implications that are testable: altering spiking or the calcium signals generated by spikes should alter epileptogenesis and spikes should precede seizures in brain-injured human patients.

Neurocysticercosis, the infection of the human brain by the larvae of Taenia solium, is a major cause of acquired epilepsy in most low-income countries. Cases of neurocysticercosis are becoming more common in high-income countries because of increased migration and travel. Diagnosis by neuroimaging and serological assessment has greatly improved over the past decade, and the natural progression of the disease and response to antiparasitic drugs is now much better understood. Neurocysticercosis is potentially eradicable, and control interventions are underway to eliminate this infection. Meanwhile, updated information on diagnosis and management of neurocysticercosis is required, especially for clinicians who are unfamiliar with its wide array of clinical presentations.

Neurocysticercosis is a major cause of acquired epilepsy around the globe. The racemose form of this disease, which has a predilection for the subarachnoid space, is rare in the US. The patient described here had a combination of intraventricular and subarachnoid cysticercal cysts. In the following report, the CT and MR characteristics of this rare form of neurocysticercosis both before and after treatment are described, and the current issues surrounding management are briefly discussed.

Animal models of injury-induced epilepsy may provide insight into the mechanisms of acquired epilepsy. Previous animal models of temporal lobe epilepsy (TLE) were produced by acute treatments that often have high mortality rates and/or are associated with a low proportion of animals developing spontaneous, chronic motor seizures. In this unit, a protocol is provided for inducing chronic epilepsy in rats using multiple, low-dose, intraperitoneal injections of an excitotoxic agent, kainic acid. This protocol reliably induces TLE in nearly all treated rats (97% had at least two observed spontaneous motor seizures) with a relatively low mortality rate (

Epilepsy is a prevalent neurological disease estimated to afflict approx 1% of the US population (1). Epileptic seizures are the clinical manifestation of epilepsy and result from excessive, synchronous, abnormal electrical firing patterns of neurons (2). Many persons with epilepsy manifest idiopathic epilepsy involving partial or generalized seizures without signs of a structural brain disorder (2–4). This contrasts with symptomatic or acquired epilepsy, in which seizures arise from brain injury or disease associated with obvious neurostructural changes. Although some idiopathic epilepsies are inherited as simple Mendelian traits, most idiopathic epilepsies are multifactorial and involve complex gene-environment interactions (5,6).

Cysticercosis, the infection of the larval tissue stage of the pork tapeworm, Taenia solium, is endemic to most developing countries and increasingly is seen in industrialized countries because of immigration. Human infection is a major cause of acquired epilepsy, and porcine infection causes important economic losses to farm workers. Clinical manifestations vary because of the variable number, size, and location of the cysts and the immune response of the host. Diagnosis is based on imaging techniques (CT and MR imaging) and serology (immunoblot). Current research efforts are centered on control and eradication of the taeniasis cysticercosis complex in endemic areas.

The incidence of sudden unexplained death (SUD) among patients less than 50 years old with refractory epilepsy was determined at Boston University Medical Center, Lexington, MA, and Department of Epidemiology, Glaxo Wellcome, Research Triangle Park, NC.

Study of the incidence of epilepsy among 12,119 of the near relatives of 2130 epileptics and among 55 twin pairs affected by seizures, together with analysis of the brain wave records of 470 relatives and of the 55 twins, leads to the conclusion that epilepsy per se is not inherited but a tendency or predisposition usually is inherited. The terms, genetic and acquired epilepsy, should replace the meaningless conventional terms essential and symptomatic. Probably in most patients both genetic and acquired factors are present. The incidence of epilepsy is higher among the near relatives of epileptics if pathology of the brain did not antedate the onset of seizures, if the patient's epilepsy began early in life, if he was mentally abnormal at birth, if he has petit mal and if the patient is female. The electroencephalogram is an hereditary trait and brain wave tracings, properly made and interpreted, may be of positive value in visualizing a transmitted quality which (with the possible help of acquired patho...

The most common forms of acquired epilepsies arise following acute brain insults such as traumatic brain injury, stroke, or central nervous system infections. Treatment is effective for only 60%-70% of patients and remains symptomatic despite decades of effort to develop epilepsy prevention therapies. Recent preclinical efforts are focused on likely primary drivers of epileptogenesis, namely inflammation, neuron loss, plasticity, and circuit reorganization. This review suggests a path to identify neuronal and molecular targets for clinical testing of specific hypotheses about epileptogenesis and its prevention or modification. Acquired human epilepsies with different etiologies share some features with animal models. We identify these commonalities and discuss their relevance to the development of successful epilepsy prevention or disease modification strategies. Risk factors for developing epilepsy that appear common to multiple acute injury etiologies include intracranial bleeding, disruption of the blood-brain barrier, more severe injury, and early seizures within 1 week of injury. In diverse human epilepsies and animal models, seizures appear to propagate within a limbic or thalamocortical/corticocortical network. Common histopathologic features of epilepsy of diverse and mostly focal origin are microglial activation and astrogliosis, heterotopic neurons in the white matter, loss of neurons, and the presence of inflammatory cellular infiltrates. Astrocytes exhibit smaller K+ conductances and lose gap junction coupling in many animal models as well as in sclerotic hippocampi from temporal lobe epilepsy patients. There is increasing evidence that epilepsy can be prevented or aborted in preclinical animal models of acquired epilepsy by interfering with processes that appear common to multiple acute injury etiologies, for example, in post-status epilepticus models of focal epilepsy by transient treatment with a trkB/PLCγ1 inhibitor, isoflurane, or HMGB1 antibodies and by topical administration of adenosine, in the cortical fluid percussion injury model by focal cooling, and in the albumin posttraumatic epilepsy model by losartan. Preclinical studies further highlight the roles of mTOR1 pathways, JAK-STAT3, IL-1R/TLR4 signaling, and other inflammatory pathways in the genesis or modulation of epilepsy after brain injury. The wealth of commonalities, diversity of molecular targets identified preclinically, and likely multidimensional nature of epileptogenesis argue for a combinatorial strategy in prevention therapy. Going forward, the identification of impending epilepsy biomarkers to allow better patient selection, together with better alignment with multisite preclinical trials in animal models, should guide the clinical testing of new hypotheses for epileptogenesis and its prevention.

Summary: In a longitudinal study of patients with epilepsy in Rochester, Minnesota, we found that the probability of being in remission (at least 5 consecutive years seizure-free, and continuing) at 20 years after diagnosis was 70%. The rates for remission we encountered were generally higher than those previously reported. We believe that the better prognosis in our series results from inclusion of all incidence cases in a defined population, beginning at the initial diagnosis of epilepsy. Prognosis for remission of epilepsy is poor in patients with' associated neurologic dysfunction identified from birth. Patients with idiopathic seizures and survivors of postnatally acquired epilepsy have better prospects for eventual remission. The probability of remission is highest in patients with generalized-onset seizures diagnosed before 10 years of age. Prognosis is less favorable for those with partial complex seizures and adult-onset epilepsy. RESUME A L'occasion d'une etude longitudinale des malades Epileptiques de Rochester (Minesota) nous avons trouve que la probabilitye d'une remission (au moins 5 annees consecutives sans crises) 20 annees apres le diagnostic etait de 70%. Ce taux est plus eleve que ceux precedemment rapportes. Nous pensons que le meilleurs pronostic dans notre serie tient a ce que nous avons inclus tous les cas incidents dans une population definie, a partir du diagnostic initial d'epilepsie. Le pronostic concernant la remission est moins bon pour les patients qui presentent des troubles neurologiques associes d'origine obstetricale; il est meilleurs pour les patientsavec des crises idiopathiques ou ayant une epilepsie acquise apres la naissance. Ce pronostic est le meilleur pour les malades qui presentent des crises generalisees d'emblee diagnostiquees avant L';age de 10 ans; il est moins favorables chez ceux qui presentent des crises partielles a semiologie complexe et chez ceux dont L';epilepsie est survenue a L';age adulte. RESUMEN En un estudio longitudinal de enfermos con epilepsia realizado en Rochester, Minnesota, encontramos que la probabilidad de estar en remision (por lo menos 5 anos consecutivos sin ataques y continuar asi), 20 anos despues del diagnostico, era de un 70%. Las cifras de remisiones son generalmente mas elevadas que las publicadas previamente. Pensamos que el mejor pronostico de nuestras series se basa en la inclusion de todos los casos que inciden en una poblacion definida desde el momento del diagnostico de epilepsyia. El pronostico con respecto a la remision de la epilepsyia es pobre en los pacientes con disfuncion neurologica asociada identificada desde el nacimiento. Tienen mejor posibilidad de eventual remision aquellos enfermos con ataques idiopaticos y los supervivientes de epilepsyia adquirida en el periodo postnatal. La mayor posibilidad de remision la tienen los enfermos con ataques de comienzo generalizado diagnosticados antes de los 10 anos. El pronostico es menos favorable en los que presentan ataques parciales complejos y epilepsyia de comienzo en edad adulta. ZUSAMMENFASSUNG In einer Langzeitstudie uberPatienten mit Epilepsie in Rochester, Minnesota, fander wir das die Wahrs-cheinlichkeit einer Remission (mindestens 5 und mehr Jahre Anfallsfreiheit) 20 Jahre nach der Diagnosestel-lung bei 70% lag. Die Remissionsrate lag allgemein hoher als in fruheren Arbeiten angegeben wird. Wir glauben, das die bessere Prognose in unserer Gruppe dadurch zustande kommt, das, bei einer definierten Population, alle Falle mit dem Zeitpunkt der Diagnos-estellung Epilepsie in die Studie aufgenommen wur-den. Die Prognose bzgl. Anfallsfreiheit ist schlecht bei Patienten mit zusatzlich neurologischen Storungen, die seit Geburt bestehen. Sie ist besser bei Patienten mit idiopathischen Anfallen und bei uber-lebenden einer postnatal erworbenen Epilepsie. Die Wahrscheinlichkeit einer Remission ist besonders hoch bei Patienten mit generalisierten Anfallen, die vor dem 10. Lebensjahr diagnostiziert wurden. Weni-ger gunstig ist die Prognose bei Patienten mit parti-ellen Anfallen mit komplexer Symptomatik und Beginn im Erwachsenenalter.

The similarity of certain animal diseases to human epilepsy has been recognized for at least 300 years. In the seventeenth century Paracelsus said that epilepsy “exists not only in man but in all living creatures.” Paracelsus also recognized the disease could be inherited and, in stating that “some species of animals suffer the disease by heredity,” has permitted us to deduce that he believed some species might suffer diseases now termed “acquired epilepsy” (for Paracelsus’ quotations, see Lennox and Lennox 1960).