Epileptogenesis In Patients Research Articles

Prevention of epileptogenesis - are we there yet?

To review recent progress in preventing epileptogenesis in patients with epilepsy. The recent success of epilepsy prevention and disease modification in tuberous sclerosis using simple EEG biomarkers to guide treatment initiation, and the identification of biomarkers to enrich the targeted patient population has made clinical trials of epilepsy prevention after acquired central nervous system (CNS) insults such as traumatic brain injury, stroke or infection both feasible and timely. Two such trials are currently on-going to prevent poststroke epilepsy. No disease-modifying or preventive treatments exist for epilepsy, and their development remains a major unmet need.. We have entered though the era of change in the treatment of epilepsy from symptomatic only to disease prevention. In this review, we summarize developments and review opportunities, challenges, and potential solutions to develop preventive treatment for acquired epilepsies in humans. The 'Holy Grail' of epilepsy is within our reach.

Common Pathways of Epileptogenesis in Patients With Epilepsy Post-Brain Injury: Findings From a Systematic Review and Meta-analysis.

Epilepsy may result from various brain injuries, including stroke (ischemic and hemorrhagic), traumatic brain injury, and infections. Identifying shared common biological pathways and biomarkers of the epileptogenic process initiated by the different injuries may lead to novel targets for preventing the development of epilepsy. We systematically reviewed biofluid biomarkers to test their association with the risk of post-brain injury epilepsy. We searched articles until January 25, 2022, in MEDLINE, Embase, PsycInfo, Web of Science, and Cochrane. The primary outcome was the difference in mean biomarker levels in patients with and without post-brain injury epilepsy. We used the modified quality score on prognostic studies for risk of bias assessment. We calculated each biomarker's pooled standardized mean difference (SMD) and 95% CI. Molecular interaction network and enrichment analyses were conducted in Cytoscape (PROSPERO CRD42021297110). We included 22 studies with 1,499 cases with post-brain injury epilepsy and 7,929 controls without post-brain injury epilepsy. Forty-five biomarkers in the blood or CSF were investigated with samples collected at disparate time points. Of 22 studies, 21 had a moderate-to-high risk of bias. Most of the biomarkers (28/45) were investigated in single studies; only 9 provided validation data, and studies used variable definitions for early-onset and late-onset seizures. A meta-analysis was possible for 19 biomarkers. Blood glucose levels in 4 studies were significantly higher in patients with poststroke epilepsy (PSE) than those without PSE (SMD 0.44; CI 0.19-0.69). From individual studies, 15 biomarkers in the blood and 7 in the CSF were significantly associated with post-brain injury epilepsy. Enrichment analysis identified that the significant biomarkers (interleukin [IL]-6, IL-1β]) were predominantly inflammation related. We cannot yet recommend using the reported biomarkers for designing antiepileptogenesis trials or use in the clinical setting because of methodological heterogeneity, bias in the included studies, and insufficient validation studies. Although our analyses indicate the plausible role of inflammation in epileptogenesis, this is likely not the only mechanism. For example, an individual's genetic susceptibilities might contribute to his/her risk of epileptogenesis after brain injury. Rigorously designed biomarker studies with methods acceptable to the regulatory bodies should be conducted.

Dynamics of AMPA receptors regulate epileptogenesis in patients with epilepsy

The excitatory glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) contribute to epileptogenesis. Thirty patients with epilepsy and 31 healthy controls are scanned using positron emission tomography with our recently developed radiotracer for AMPARs, [11C]K-2, which measures the density of cell-surface AMPARs. In patients with focal-onset seizures, an increase in AMPAR trafficking augments the amplitude of abnormal gamma activity detected by electroencephalography. In contrast, patients with generalized-onset seizures exhibit a decrease in AMPARs coupled with increased amplitude of abnormal gamma activity. Patients with epilepsy had reduced AMPAR levels compared with healthy controls, and AMPARs are reduced in larger areas of the cortex in patients with generalized-onset seizures compared with those with focal-onset seizures. Thus, epileptic brain function can be regulated by the enhanced trafficking of AMPAR due to Hebbian plasticity with increased simultaneous neuronal firing and compensational downregulation of cell-surface AMPARs by the synaptic scaling.

The state of the lumen of the major cerebral vessels and systems of regulation of cerebral circulation in patients with cerebral ischemia with the development of epileptic seizures

Introduction. Cerebrovascular diseases are often associated with the development of epileptic seizures. It was suggested that in the implementation of epileptogenesis in patients with ischemic brain damage, a hemodynamic factor, namely the state of the perfusion reserve, may be important.Objective. The examination of the state of cerebrovascular reactivity of different cerebral vascular basins in patients with the development of epileptic seizures affected by cerebral ischemia.Materials and methods. 772 patients with acute and chronic cerebral ischemia (265 stroke patients with epileptic seizures and 174 patients with seizures on the background of chronic cerebral ischemia and 203 patients with stroke and 130 patients with chronic cerebral ischemia without seizures) was comprehensively examined.Results. In patients with cerebral ischemia, focal seizures prevail. Cortical localization of ischemic foci prevailed in patients with both acute and chronic cerebral ischemia. Stenosis of the main arteries were more often detected as in patients with ischemic stroke with the development of epileptic seizures – 218 (82.3%) compared with patients with stroke in the comparison group – 151 (74.4%) patients, р < 0.05), and in patients with CBI (chronic brain ischemia) with the development of epileptic seizures – 121 (69.5%) people, p < 0.05) compared with patients in the comparison group – 74 (56.9%) patients. The prevalence of stenosisof the main cerebral arteries was revealed in more than 70% in patients with pre-stroke epileptic seizures – 77 (33.5%) compared with patients without precursor seizures, who have been diagnosed with stenosis of more than 70% were found in only 4 (11.5%) patients (χ2 = 10.1; p = 0.03). In the comparison group of patients, there was no significant difference in CVR (cerebrovascular reactivity) changes in the carotid system and in the VBS (vertebrobasilar system) – 30 (36.6%) and 42 (47.7%) examined, respectively.Conclusion. The revealed decrease in cerebrovascular reactivity in the vertebrobasilar basin can be considered as one of the risk factors for the development of epilepsy in conditions of brain ischemia.

IDH-mutated gliomas promote epileptogenesis through d-2-hydroxyglutarate-dependent mTOR hyperactivation.

Uncontrolled seizures in patients with gliomas have a significant impact on quality of life and morbidity, yet the mechanisms through which these tumors cause seizures remain unknown. Here, we hypothesize that the active metabolite d-2-hydroxyglutarate (d-2-HG) produced by the IDH-mutant enzyme leads to metabolic disruptions in surrounding cortical neurons that consequently promote seizures. We use a complementary study of in vitro neuron-glial cultures and electrographically sorted human cortical tissue from patients with IDH-mutant gliomas to test this hypothesis. We utilize micro-electrode arrays for in vitro electrophysiological studies in combination with pharmacological manipulations and biochemical studies to better elucidate the impact of d-2-HG on cortical metabolism and neuronal spiking activity. We demonstrate that d-2-HG leads to increased neuronal spiking activity and promotes a distinct metabolic profile in surrounding neurons, evidenced by distinct metabolomic shifts and increased LDHA expression, as well as upregulation of mTOR signaling. The increases in neuronal activity are induced by mTOR activation and reversed with mTOR inhibition. Together, our data suggest that metabolic disruptions in the surrounding cortex due to d-2-HG may be a driving event for epileptogenesis in patients with IDH-mutant gliomas.

NCMP-07. IDH MUTANT GLIOMAS PROMOTE EPILEPTOGENESIS VIA D-2-HYDROXYGLUTARATE DEPENDENT MTOR HYPER-ACTIVATION

Abstract Uncontrolled seizures in patients with low grade gliomas have a significant impact on quality of life and morbidity, yet the mechanisms through which these tumors cause seizures remain unknown. Albeit there are multiple features that contribute to tumor related epileptogenesis, IDH mutations are determined to be an independent factor, although the pathogenesis remains poorly understood. Here, we hypothesize that the active metabolite D-2-hydroxyglutarate (D-2-HG) produced by the IDH-mutant enzyme leads to metabolic disruptions in surrounding cortical neurons that consequently promote seizures. We use a complementary study of in vitro cortical cultures and electrographically sorted human cortical tissue from patients (n=5) with IDH-mutant gliomas to test this hypothesis. We demonstrate that D-2-HG leads to increased neuronal spiking activity (p< 0.0001) and promotes a distinct metabolic profile in surrounding neurons and upregulation of mTOR signaling (p< 0.0001), which is consistent in human epileptic cortex compared to peritumoral nonepileptic cortex. Furthermore, increases in neuronal activity are induced by mTOR activation and reversed with mTOR inhibition. Together, our data suggest that metabolic disruptions and mTOR signaling upregulation in the surrounding cortex due to D-2-HG may be a driving event for epileptogenesis in patients with IDH-mutant low grade gliomas.

Reactive astrocytes contribute to epileptogenesis in patients with cavernous angioma

ObjectivePatients with cavernous angioma (CA) often suffer from severe epilepsy, and surgical resection is often performed to attenuate these epileptic seizures. Several studies have suggested that surgical removal of the surrounding hemosiderin-pigmented tissues adjacent to CA achieves better seizure control than restricted lesionectomy. Pathological examination of the resected foci reveals not only hemosiderin pigmentation but also various degrees of inflammatory change, such as hemosiderin-laden macrophages, gliosis and fibrosis. However, there is some controversy regarding the epileptogenic potential of these regions due to the uncertain nature of the mechanisms contributing to these histopathological changes. MethodsTo investigate the correlations between neuron hyperexcitability and evident pathological changes, we performed ex vivo flavoprotein fluorescence imaging using surgically resected epileptogenic foci surrounding CA. The mirror surfaces of the tissues used for the physiological experiment were also subjected to morphological examination. ResultsHemosiderin-laden macrophages and many gemistocytic astrocytes were observed in the area adjacent to CA, where horizontal spreading excitations were detected significantly more frequently. Outside these areas, we found fine granular iron deposits and only a few fibrillary astrocytes, and weakly propagating excitations were detected. Furthermore, areas of enhanced activation were more clearly correlated with the glial proliferation index than with iron deposition. ConclusionThese results suggest that the epileptogenesis in patients with CA may be based on a biological process, such as alteration of glial function, rather than direct chemical reactions involving iron deposition.

OTME-4. IDH mutated gliomas promote epileptogenesis via D-2-hydroxyglutarate dependent mTOR hyperactivation

Epilepsy in the context of brain tumors provides a great burden in these patients, yet mechanisms underlying this process are poorly understood. It has been demonstrated that isocitrate dehydrogenase (IDH) mutations are an independent factor in epileptogenesis in patients with low grade gliomas. Here, using electrographically sorted human cortical tissue from patients with IDH mutated tumor related epilepsy and in vitro cortical cultures, we explore a metabolic paradigm and its impact on increased neuronal excitability. We hypothesize the IDH mutation promotes epileptogenesis through its neomorphic activity of D-2-hydroxyglutarate (D-2-HG) production in turn interrupts surrounding normal neuronal circuitry potentially through metabolic perturbations. We demonstrate D-2-HG increases neuronal spiking activity, promotes distinct metabolic profiles independent of neuronal spiking activity, as well as increases neuronal mTOR signaling, which is reflected in human peritumoral epileptic cortex. Increased mTOR signaling is sufficient to upregulate neuronal spiking activity and, reciprocally, inhibition of mTOR corrects neuronal activity as well as partially corrects metabolic reprogramming. Our results suggest D-2-HG can lead to mTOR activation within the peritumoral neurons, thereby suggesting an additional possible mechanism of epileptogenesis in patients with IDH mutated low grade gliomas. Ultimately, our results raise the possibility of mTOR inhibition may be a promising treatment of seizures in patients with these tumors.

Sensory profile alterations in patients with insular epilepsy surgery: Preliminary findings

The insular cortex is now well-established as a potential site of epileptogenesis in patients with drug-resistant epilepsy, and its resection has been associated with good outcomes in terms of seizure control. However, given the role of the insula in sensory processing and in visceral information integration, it remains unclear whether insular cortex epilepsy and its surgery are associated with disturbances in sensory information processing and visceral sensation processes as experienced in daily life. In the present study, we examined such sensory disturbances in a group of patients (n = 17) who underwent epilepsy surgery involving a resection of the insula and compared them to a lesion-control group of patients with temporal epilepsy surgery (n = 22) and a healthy control group (n = 29) matched for age, gender, and education. Participants were assessed on the self-report “Adolescent/Adult Sensory Profile” questionnaire at least four months after surgery. Our series of one-way analyses of variance (ANOVAs) revealed that insular and temporal resections in patients with drug-refractory epilepsy were associated with a low “sensation seeking” behavior reflecting a lack of engagement with sensory inputs from the environment. Furthermore, insular resections were associated with impairments in the “active behavioral responses” for the gustatory/olfactory modalities. These preliminary findings suggest that insular resections may be associated with mild to moderate alterations in sensory processing.

Biomarkers for epileptogenesis in patients with autoimmune epilepsy

OAE Publishing Inc. is an international scholarly publisher specializing in peer-reviewed academic journals. To promote academic exchange and knowledge sharing, OAE provides an outstanding academic platform for biomedical experts and scholars all over the world.

Kininogen Level in the Cerebrospinal Fluid May Be a Potential Biomarker for Predicting Epileptogenesis.

Purpose: Epilepsy is a highly disabling neurological disorder. Brain insult is the most critical cause of epilepsy in adults. This study aimed to find reliable and efficient biomarkers for predicting secondary epilepsy.Materials and methods: The LiCl-pilocarpine (LiCl-Pilo) chronic epilepsy rat model was used, and rat cerebrospinal fluid (CSF) was collected 5 days after status epilepticus (SE). The CSF was analyzed using the label-free LC-ESI-Q-TOF-MS/MS. Differential expression of proteins was confirmed using enzyme-linked immunosorbent assay (ELISA) and Western blotting. The corresponding protein level in the CSF of patients with encephalitis in the postacute phase was determined using ELISA and compared between patients with and without symptomatic epilepsy after encephalitis during a 2-year follow-up.Results: The proteomics and ELISA results showed that the protein level of kininogen (KNG) was obviously elevated in both CSF and hippocampus, but not in serum, 5 days after the onset of SE in LiCl-Pilo chronic epilepsy model rats. In patients with encephalitis, the protein level of KNG in the CSF in the postacute phase was significantly elevated in patients with a recurrent epileptic seizure during a 2-year follow-up than in patients without a recurrent seizure.Conclusion: KNG in the CSF may serve as a potential biomarker for predicting epileptogenesis in patients with encephalitis.

Pathophysiological Characteristics Associated With Epileptogenesis in Human Hippocampal Sclerosis

Mesial temporal lobe epilepsy (MTLE) is the most frequent focal epileptic syndrome in adults, and the majority of seizures originate primarily from the hippocampus. The resected hippocampal tissue often shows severe neuronal loss, a condition referred to as hippocampal sclerosis (HS). In order to understand hippocampal epileptogenesis in MTLE, it seems important to clarify any discrepancies between the clinical and pathological features of affected patients. Here we investigated epileptiform activities ex vivo using living hippocampal tissue taken from patients with MTLE. Flavoprotein fluorescence imaging and local field potential recordings revealed that epileptiform activities developed from the subiculum. Moreover, physiological and morphological experiments revealed possible impairment of K+ clearance in the subiculum affected by HS. Stimulation of mossy fibers induced recurrent trans-synaptic activity in the granule cell layer of the dentate gyrus, suggesting that mossy fiber sprouting in HS also contributes to the epileptogenic mechanism. These results indicate that pathophysiological alterations involving the subiculum and dentate gyrus could be responsible for epileptogenesis in patients with MTLE.

DETECTING FEATURES OF EPILEPTOGENESIS IN EEG AFTER TBI USING UNSUPERVISED DIFFUSION COMPONENT ANALYSIS.

Epilepsy is among the most common serious disabling disorders of the brain, and the global burden of epilepsy exerts a tremendous cost to society. Most people with epilepsy have acquired forms, and the development of antiepileptogenic interventions could potentially prevent or cure these epilepsies [3, 13]. The discovery of potential antiepileptogenic treatments is currently a high research priority. Clinical validation would require a means to identify populations of patients at particular high risk for epilepsy after a potential epileptogenic insult to know when to treat and to document prevention or cure. We investigate the development of post-traumatic epilepsy (PTE) following traumatic brain injury (TBI), because this condition offers the best opportunity to know the time of onset of epileptogenesis in patients. Epileptogenesis is common after TBI, and because much is known about the physical history of PTE, it represents a near-ideal human model in which to study the process of developing seizures. Using scalp and depth EEG recordings for six patients, the goal of our analysis is to find a way to quantitatively detect features in the EEG that could potentially help predict seizure onset post trauma. Unsupervised Diffusion Component Analysis [5], a novel approach based on the diffusion mapping framework [4], reduces data dimensionality and provides pattern recognition that can be used to distinguish different states of the patient, such as seizures and non-seizure spikes in the EEG. This method is also adapted to the data to enable the extraction of the underlying brain activity. Previous work has shown that such techniques can be useful for seizure prediction [6]. Some new results that demonstrate how this algorithm is used to detect spikes in the EEG data as well as other changes over time are shown. This nonlinear and local network approach has been used to determine if the early occurrences of specific electrical features of epileptogenesis, such as interictal epileptiform activity and morphologic changes in spikes and seizures, during the initial week after TBI predicts the development of PTE.

Blocking GluN2B subunits reverses the enhanced seizure susceptibility after prolonged febrile seizures with a wide therapeutic time-window

Febrile seizures (FSs), the most common type of convulsive events in infants, are closely associated with temporal lobe epilepsy (TLE) in adulthood. It is urgent to investigate how FSs promote epileptogenesis and find the potential therapeutic targets. In the present study, we showed that the phosphorylation of GluN2B Tyr1472 gradually reached peak level at 24h after prolonged FSs and remained elevated during 7days thereafter. IL-1β treatment alone, which in previous study mimicked the effect of prolonged FSs on adult seizure susceptibility, increased GluN2B Tyr1472 phosphorylation. Both IL-1 receptor antagonist (IL-1Ra) and IL-1R1 deletion were sufficient to reverse the prolonged FSs induced hyper-phosphorylation of GluN2B Tyr1472. GluN2B antagonist ifenprodil showed a wide therapeutic time-window (3days) to reverse the enhanced seizure susceptibility after prolonged FSs or IL-1β treatment. Our study demonstrated that GluN2B phosphorylation at Tyr1472 site mediated by the transient increase of IL-1β was involved in the enhanced adult seizure susceptibility after prolonged FSs, implicating GluN2B-containing NMDAR is a new potential drug target with a wide therapeutic time window to prevent epileptogenesis in patients with infantile FSs.

Long-range and short-range tumor-stroma networks synergistically contribute to tumor-associated epilepsy.

Epileptic seizures are frequently caused by brain tumors. Traditional anti-epileptic treatments do not acquire satisfactory responses. Preoperative and postoperative seizures seriously influence the quality of life of patients. Thus, tumor-associated epilepsy (TAE) is an important subject of the current research. The delineation of the etiology of epileptogenesis in patients with primary brain tumor may help to find the novel and effective drug targets for treating this disease. In this review, we describe the current status of treatment of TAE. More importantly, we focus on the factors that are involved in the functional connectivity between tumors and stromal cells. We propose that there exist two modes, namely, long-range and short-range modes, which likely trigger neuronal hyperexcitation and subsequent epileptic seizures. The long-range mode is referred to as factors released by tumors including glutamate and GABA, binding to the corresponding receptor on the cellular membrane and causing neuronal hyperactivity, while the short-range mode is considered to involve direct intracellular communication between tumor cells and stromas. Gap junctions and tunneling nanotube network are involved in cellular interconnections. Future investigations focused on those two modes may find a potential novel therapeutic target for treating TAE.

Fractalkine/CX3CL1 modulates GABAA currents in human temporal lobe epilepsy

The chemokine fractalkine/CX3CL1 and its receptor CX3CR1 are widely expressed in the central nervous system (CNS). Recent evidence showed that CX3CL1 participates in inflammatory responses that are common features of CNS disorders, such as epilepsy. Mesial temporal lobe epilepsy (MTLE) is the prevalent form of focal epilepsy in adults, and hippocampal sclerosis (HS) represents the most common underlying pathologic abnormality, as demonstrated at autopsy and postresection studies. Relevant features of MTLE are a characteristic pattern of neuronal loss, as are astrogliosis and microglia activation. Several factors affect epileptogenesis in patients with MTLE, including a lack of γ-aminobutyric acid (GABA)ergic inhibitory efficacy. Therefore, experiments were designed to investigate whether, in MTLE brain tissues, CX3CL1 may influence GABAA receptor (GABAA R) mediated transmission, with a particular focus on the action of CX3CL1 on the use-dependent decrease (rundown) of the GABA-evoked currents (IGABA ), a feature underlying the reduction of GABAergic function in epileptic tissue. Patch-clamp recordings were obtained from cortical pyramidal neurons in slices from six MTLE patients after surgery. Alternatively, the cell membranes from epileptic brain tissues of 17 MTLE patients or from surgical samples and autopsies of nonepileptic patients were microtransplanted into Xenopus oocytes, and IGABA were recorded using the standard two-microelectrode voltage-clamp technique. Immunohistochemical staining and double-labeling studies were carried out on the same brain tissues to analyze CX3CR1 expression. In native pyramidal neurons from cortical slices of patients with MTLE, CX3CL1 reduced IGABA rundown and affected the recovery of IGABA amplitude from rundown. These same effects were confirmed in oocytes injected with cortical and hippocampal MTLE membranes, whereas CX3CL1 did not influence IGABA in oocytes injected with nonepileptic tissues. Consistent with a specific effect of CX3CL1 on tissues from patients with MTLE, CX3CR1 immunoreactivity was higher in MTLE sclerotic hippocampi than in control tissues, with a prominent expression in activated microglial cells. These findings indicate a role for CX3CL1 in MTLE, supporting recent evidence on the relevance of brain inflammation in human epilepsies. Our data demonstrate that in MTLE tissues the reduced GABAergic function can be modulated by CX3CL1. The increased CX3CR1 expression in microglia and the modulation by CX3CL1 of GABAergic currents in human epileptic brain suggests new therapeutic approaches for drug-resistant epilepsies based on the evidence that the propagation of seizures can be influenced by inflammatory processes.

Managing Common Complex Symptomatic Epilepsies: Tumors and Trauma

Head trauma and brain tumors are inextricably linked to epilepsy. Both traumatic brain injury and brain tumors are overrepresented in newly diagnosed patients with epilepsy, as well as in patients with drug-resistant focal epilepsy. Indeed, chronic seizures are the most cited problem associated with either of these conditions. However, managing complex cases of posttraumatic epilepsy or tumor-based epilepsy can be a challenge for many epilepsy specialists. Currently, there is no clear understanding of the basic science that underpins the mechanism for epileptogenesis in patients with tumors or trauma so at present one cannot identify appropriate targets that could help prevent seizures and epilepsy from occurring. Because of these challenges, complex lesional epilepsy was chosen as the theme for this year’s 2012 American Epilepsy Society Annual Course. The objectives for the course included understanding models for preventing epileptogenesis, creating best evidence algorithms that describe how to best manage patients with epilepsy related to brain tumors, including novel intraoperative monitoring techniques. Risk analyses were summarized to benefit treatment decisions regarding the prophylactic use of antiepileptic drugs in patients with CNS tumors or traumatic brain injury and to present the best management options with patients with metastatic brain tumors based on current knowledge. Throughout two half-day sessions, post-traumatic epilepsy and tumoral epilepsy were explored in detail. Each session was framed by clinical cases involving adults and children. Through a variety of learning methodologies that included lectures, debates, and panel sessions, clinical management was highlighted, illuminating basic science and practice gaps. This discussion summarizes the salient take-home points of the session that are clinically useful for the practicing clinician.

Focal cortical dysplasia type IIa underlying epileptogenesis in patients with epilepsy associated with Sturge‐Weber syndrome

In patients with epilepsy associated with Sturge-Weber syndrome (SWS), epileptogenesis has been suggested to be caused by chronic ischemia in cortical areas affected by leptomeningeal angiomatosis or by ischemia-related cortical malformations. However, this has not been fully verified electrophysiologically. We herein present two cases of SWS with medically intractable epilepsy in which the epileptogenic area involved focal cortical dysplasia (FCD) type IIa near the region of leptomeningeal angiomatosis. In both cases, the ictal-onset zones were identified by chronic subdural electrodes, and the presence of FCD type IIa was shown histopathologically. In SWS, especially in association with focal leptomeningeal angiomatosis, FCD may thus play a major role in epileptogenesis. FCD should therefore be demonstrated by the collective findings of perioperative neurophysiologic examination, anatomic and functional neuroimaging, and histopathologic examination.

Epilepsy in patients with a brain tumour: focal epilepsy requires focused treatment

Brain tumours frequently cause epileptic seizures. Medical antiepileptic treatment is often met with limited success. Pharmacoresistance, drug interactions and adverse events are common problems during treatment with antiepileptic drugs. The unpredictability of epileptic seizures and the treatment-related problems deeply affect the quality of life of patients with a brain tumour. In this review, we focus on both clinical and basic aspects of possible mechanisms in epileptogenesis in patients with a brain tumour. We provide an overview of the factors that are involved in epileptogenesis, starting focally at the tumour and the peritumoral tissue and eventually extending to alterations in functional connectivity throughout the brain. We correlate this knowledge to the known mechanisms of antiepileptic drugs. We conclude that the underlying mechanisms of epileptogenesis in patients with a brain tumour are poorly understood. The currently available antiepileptic drugs have little to no influence on the known epileptogenic mechanisms that could contribute to the poor efficacy. Better understanding of focal changes that are involved in epileptogenesis may provide new tools for optimal treatment of both the seizures and the underlying tumour. In our opinion, therapy for every patient with a brain tumour suffering from epilepsy should first and foremost aim at eliminating the tumour as well as the epileptic focus through resection combined with postoperative treatment, and only if this strategy does not result in adequate seizure control should medical antiepileptic treatment be intensified. If this strategy, however, results in sustained seizure freedom, tapering of antiepileptic drugs should be considered in the long term.

The methylation hypothesis: Do epigenetic chromatin modifications play a role in epileptogenesis?

Any structural brain lesion can provoke epilepsy, although onset and progression of seizures as well as response to antiepileptic drug (AED) treatment remain difficult to predict in each patient. Tremendous work has focused on the development of new AED compounds with the intention to treat seizures. However, these efforts have not yet discovered a "magic bullet" that cures epilepsy in every patient or modifies disease progression. With the "methylation hypothesis" we propose that epigenetic mechanisms play a pivotal role in epileptogenesis in patients with structural lesions. "Epigenetics" is defined as information that is heritable during cell division other than the DNA sequence itself, that is, DNA methylation or histone tail modifications, which can produce lasting alterations in chromatin structure and gene expression. They are increasingly recognized as fundamental regulatory processes in central nervous system development, synaptic plasticity, and memory, and also play a role in neurologic disorders such as schizophrenia and spinal muscular atrophy. The methylation hypothesis suggests that seizures by themselves can induce epigenetic chromatin modifications, thereby aggravating the epileptogenic condition. The impact of the methylation hypothesis for new-onset epilepsy will be discussed. Unravelling of epigenetic pathomechanisms will also open new strategies to identify molecular targets for pharmacologic treatment in epilepsies.