Epilepsy Research

Editorial Board

2012-05-01

Non-resective surgery and radiosurgery for treatment of drug-resistant epilepsy

2012-01-16

Summary: Epilepsy surgery is an effective treatment for properly selected patients with intractable seizures. However, many patients with medically intractable epilepsy are not excellent candidates for surgical resection of the epileptogenic zone. Due to recent advances in computer technology and bioengineering, several novel techniques are receiving increasing interest for their role in the care of people with epilepsy. Neuromodulation is an emerging surgical option to be used when conventional resective surgery is not indicated. We review the indications and expected outcomes of neuromodulatory treatments currently available for the treatment of refractory epilepsy, i.e., vagus nerve stimulation, deep brain stimulation, stereotactic radiosurgery, and multiple subpial transections.

Epileptic seizures from abnormal networks: Why some seizures defy predictability

2011-12-14

Summary: Seizure prediction has proven to be difficult in clinically realistic environments. Is it possible that fluctuations in cortical firing could influence the onset of seizures in an ictal zone? To test this, we have now used neural network simulations in a computational model of cortex having a total of 65,536 neurons with intercellular wiring patterned after histological data. A spatially distributed Poisson driven background input representing the activity of neighboring cortex affected 1% of the neurons. Gamma distributions were fit to the interbursting phase intervals, a non-parametric test for randomness was applied, and a dynamical systems analysis was performed to search for period-1 orbits in the intervals. The non-parametric analysis suggests that intervals are being drawn at random from their underlying joint distribution and the dynamical systems analysis is consistent with a nondeterministic dynamical interpretation of the generation of bursting phases. These results imply that in a region of cortex with abnormal connectivity analogous to a seizure focus, it is possible to initiate seizure activity with fluctuations of input from the surrounding cortical regions. These findings suggest one possibility for ictal generation from abnormal focal epileptic networks. This mechanism additionally could help explain the difficulty in predicting partial seizures in some patients.

Ictal MEG onset source localization compared to intracranial EEG and outcome: Improved epilepsy presurgical evaluation in pediatrics

2011-12-19

Summary: Purpose: Magnetoencephalography (MEG) has been shown a useful diagnostic tool for presurgical evaluation of pediatric medically intractable partial epilepsy as MEG source localization has been shown to improve the likelihood of seizure onset zone (SOZ) sampling during subsequent evaluation with intracranial EEG (ICEEG). We investigated whether ictal MEG onset source localization further improves results of interictal MEG in defining the SOZ.Methods: We identified 20 pediatric patients with one habitual seizure during MEG recordings between October 2007 and April 2011. MEG was recorded with sampling rates of 600Hz and 4000Hz for 10 and 2min respectively. Continuous head localization (CHL) was applied. Source localization analyses were applied using multiple algorithms, both at the beginning of ictal onset and for interictal MEG discharges. Ictal MEG onsets were identified by visual inspection and power spectrum using short-time Fourier transform (STFT). Source localizations were compared with ICEEG, surgical procedure and outcome.Key findings: Eight patients met all inclusion criteria. Five of the 8 patients (63%) had concordant ictal MEG onset source localization and interictal MEG discharge source localizations in the same lobe, but the source of ictal MEG onset was closer to the SOZ defined by ICEEG.Significance: Although the capture of seizures during MEG recording is challenging, the source localization for ictal MEG onset proved to be a useful tool for presurgical evaluation in our pediatric population with medically intractable epilepsy.

Increases in seizure latencies induced by subcutaneous docosahexaenoic acid are lost at higher doses

2012-01-30

Summary: Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid (PUFA) which has been found to have anticonvulsant properties. Our group has previously reported in a pilot study that the acute administration of subcutaneous (s.c.) DHA increases seizure latencies in the maximal pentylenetetrazole (PTZ) seizure test, however it loses its effect at higher doses. The purpose of the present experiments was (1) to confirm that DHA loses its effect at higher doses, (2) to correlate the anticonvulsant properties of DHA with DHA levels in the different lipid pools of serum and (3) to evaluate whether an anticonvulsant dose of DHA resulted in an increase in DHA release from the brain phospholipids following induction of seizure.In the first experiment, male Wistar rats were injected s.c. with 200, 300, 400 or 600mg/kg of DHA, or 400mg/kg oleic acid (OA, isocaloric control), and seizure tested with the maximal PTZ test 1h post injection (Experiment 1). In a second experiment, subjects received either: (1) an effective dose of DHA (400mg/kg), (2) a higher, non-effective dose (600mg/kg; based on the findings of Experiment 1), or (3) OA (400mg/kg). Subjects were sacrificed 1h post injection and blood was collected for fatty acid analysis (Experiment 2). In the third experiment, subjects were injected with either the effective dose of DHA (400mg/kg) or OA (400mg/kg). One hour post lipid injection, animals received either PTZ or saline, and animals were euthanized via microwave fixation. Brain were extracted and unesterified fatty acid concentrations were measured (Experiment 3).Experiment 1 confirmed that DHA loses its effects at higher doses in the maximal PTZ test. The 400mg/kg dose was maximally effective but effects were lost at 600mg/kg. Experiment 2 showed that only the unesterified DHA pool in serum was statistically increased by an acute injection of s.c. DHA (P<0.05, as compared to OA), whereas esterified DHA pools were unchanged (P>0.05). Curiously, unesterified DHA levels were similar in both the 400mg/kg and 600mg/kg dosage groups. Experiment 3 showed that an anticonvulsant dose of DHA (400mg/kg) did not increase DHA release from brain phospholipids following seizure induction (P>0.05).In conclusion, DHA has anticonvulsant properties when injected s.c., but these properties are lost at higher doses. The anticonvulsant effects of DHA are accompanied by increased levels of unesterified DHA in the serum, but not in increased DHA release from brain phospholipids.

Beta adrenergic blockade prevents cardiac dysfunction following status epilepticus in rats

Jason G. Little, Steven L. Bealer — 2012-01-03

Summary: Status epilepticus (SE) can result in temporary cardiac dysfunction in patients, characterized by reduced ejection fraction, decreased ventricular contractility, and alterations in electrical activity of the heart. Although reversible, the cardiac effects of seizures are acutely life threatening, and may contribute to the delayed mortality following SE. The precise mechanisms mediating acute cardiac dysfunctions are not known. These studies evaluated effects of self-sustaining limbic SE in rats on cardiac performance 24h following seizures, and determined if sympathetic nervous system activation during seizures contributed to cardiac dysfunction. Rats subjected to SE received either vehicle (saline) or the B1 adrenergic antagonist atenolol (AT) prior to and during 90min of seizure activity. Control rats were similarly treated, except they did not undergo seizures. Twenty-four hours after SE, animals were anesthetized and catheterized for measurement of cardiac performance variables. Animals undergoing SE demonstrated significantly reduced cardiac output, decreased ventricular contractility and relaxation, increased blood pressure, and prolonged QT interval. However, heart rate was not altered. Treatment with AT prevented all changes in cardiac performance due to SE, and attenuated the increase in QT interval. These data demonstrate that SE in the rat results in cardiac dysfunction 24h following seizures, mediated by the sympathetic nervous system.

Clusterin interaction with Bcl-xL is associated with seizure-induced neuronal death

2011-12-26

Summary: Status epilepticus causes significant damage to the brain, and cellular injury due to prolonged seizures may cause the pathogenesis of epilepsy or cognitive deficits. Clusterin mediates several cell signaling pathways, including cell death or survival pathways in the brain. A nuclear form of clusterin protein has been suggested to have pro-apoptotic properties. Bcl-xL functions as a dominant-negative modulator of the pro-apoptotic protein Bax. However, the relationship between clusterin and Bcl-xL in cell death signaling in the brain remains unknown. Therefore, we examined whether clusterin interacts with Bcl-xL after seizures or whether this interaction is related to neuronal death. We found increased levels of nuclear clusterin and cleaved caspase-3 in CA3 neurons after prolonged seizures induced by systemic kainic acid, along with extensive hippocampal cell death, as evidenced by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) and anti-active caspase-3 staining. Furthermore, co-immunoprecipitation and double immunofluorescence analyses revealed that clusterin interacted with Bcl-xL in dying CA3 neurons while the levels of Bcl-xL, Bad or Bax remained constant. These findings provide evidence that nuclear clusterin signals cell death at least via an interaction with Bcl-xL in the hippocampus after seizures, suggesting that targeting nuclear clusterin may be a promising novel strategy to protect against seizure-induced neuronal injury.

Neuroethologically delineated differences in the seizure behavior of Synapsin 1 and Synapsin 2 knock-out mice

Lars Etholm, Elma Bahonjic, Sven Ivar Walaas, Hung-Teh Kao, Paul Heggelund — 2012-01-11

Summary: The highly homologous nerve terminal phosphoproteins synapsin I and synapsin II have been linked to the pathogenesis of epilepsy through associations between synapsin gene mutations and epileptic disease in humans and to the observation of handling induced seizures in mice genetically depleted of one or both of these proteins. Whereas seizure behavior in mice lacking both synapsin I and synapsin II is well characterized, the seizure behavior in mice lacking either is less well studied. Through so called neuroethologically based analyses of fully established seizure behavior in Synapsin 1 and 2 knock-out mice (Syn1KO and Syn2KO mice) aged 4 1/2 months, this study reveals significant differences in the seizure behavior of the two genotypes: whereas Syn1KO mice show both partial and generalized forebrain seizure activity, Syn2KO mice show only fully generalized forebrain seizures. Analysis of seizure behavior at earlier stages shows that the mature seizure pattern in Syn2KO mice establishes rapidly from the age of ∼2 months, when Syn1KO partial seizures are rare, and Syn1KO generalized seizures are almost absent. The specific behavioral phenotypes of the two strains suggest that the slight differences in structure, function and expression of these highly related proteins could be important factors during seizure generating neural activity.

Serotonin gene polymorphisms and psychiatry comorbidities in temporal lobe epilepsy

2012-01-05

Summary: Objective: Neuropsychiatric comorbidities are frequent in temporal lobe epilepsy (TLE). It is biologically plausible that alterations in serotonin-related genes may be involved in higher susceptibility to psychiatric disease in these individuals. Here we report results of an association study of serotonin gene polymorphisms and psychiatry comorbidities in TLE.Methods: Case-control study of 155 patients with temporal lobe epilepsy. We evaluate the influence of 5-HTTLPR and 5-HTTVNTR polymorphisms in the 5-HTT gene and the C-1019G polymorphism in the 5-HT1A gene in psychiatric comorbidities of TLE.Results: After logistic regression, female sex (OR=2.34; 95% CI 1.06–5.17; p=0.035) and the presence of C allele of 5-HT1A C-1019G polymorphism (OR=2.77; 95% CI 1.01–7.63; p=0.048) remained independent risk factors for anxiety disorders in temporal lobe epilepsy.Conclusion: C allele of 5-HT1A C-1019G polymorphism might be an independent risk factor for anxiety disorders in temporal lobe epilepsy. We believe that other studies in this venue will shade some light on molecular mechanisms involved in psychiatric comorbidities in epilepsy.

White matter impairment in the basal ganglia-thalamocortical circuit of drug-naïve childhood absence epilepsy

2012-01-09

Summary: Purpose: It is unknown whether white matter abnormalities exist in childhood absence epilepsy (CAE), a syndrome of idiopathic epilepsy (IGE). Diffusion tensor imaging (DTI) can noninvasively quantify white matter integrity. This study used DTI to investigate abnormal changes in white matter of untreated CAE patients.Methods: Subjects included nine patients with untreated CAE and nine age-and sex-matched healthy controls. Diffusion tensor imaging parameters were voxel based and statistically compared between patients and controls. The correlations between DTI parameters in regions of interest (ROIs) and age of seizure onset or duration of epilepsy were analyzed.Results: Untreated CAE patients had a significantly higher fractional anisotropy (FA) value in the bilateral thalamus, anterior corpus callosum and upper brainstem, while also displaying a lower FA value in prefrontal white matter, anterior cingulate, and bilateral posterior limbs of the internal capsule compared to control subjects. An increase in mean diffusivity (MD) value was observed in parietal lobe white matter, prefrontal white matter, and posterior cerebellar hemispheres, in addition to subcortical structures including bilateral putamen and posterior limb of internal capsule. MD significant correlations between ROI diffusion parameters and the duration of the disease or the age of onset.Conclusions: The results showed white matter integrity impairment in the basal ganglia-thalamocortical circuit of drug-naïve CAE patients. These abnormalities in white matter may be related to increased cortical excitability and cause cognitive, linguistic, and behavioral/emotional deficits both during and between seizures.

Is ictal dystonia associated with an inhibitory effect on seizure propagation in focal epilepsies?

2012-01-25

Summary: Purpose: In focal epilepsy, ictal version and ictal dystonia are thought to reflect seizure spread into the frontal eye field and the basal ganglia, respectively. Here we investigated whether the occurrence of dystonia during seizure evolution reflects mechanisms preventing secondary generalization. To this aim, the evolution of seizures in patients with focal epilepsies was compared as to whether concomitant (1) dystonia, (2) dystonia and version, or (3) version occurred.Methods: Seizure evolutions of 79 patients characterized by either dystonia (n=29; 232 seizures), dystonia and head version in the same seizure evolution (n=9; 83 seizures) or head version (n=41; 330 seizures), were included in the study.Results: The rate of secondary generalization was significant lower in seizures with ictal dystonia (8%, 6 of 72 seizures) compared to seizures with ictal dystonia and version (62%, 13 of 21 seizures, p<0.0001) or compared to seizures with version (95%, 82 of 86 seizures, p<0.0001).Conclusion: This study shows that seizures with unilateral ictal dystonia are less likely to generalize as compared to seizures associated with version. This effect is likely to reflect the involvement of inhibitory mechanisms related to the basal ganglia, which exert an inhibiting effect on secondary seizure generalization.

EEG-LORETA endophenotypes of the common idiopathic generalized epilepsy syndromes

2012-01-12

Summary: Objective: We tested the hypothesis that the cortical areas with abnormal local EEG synchronization are dissimilar in the three common idiopathic generalized epilepsy (IGE) phenotypes: IGE patients with absence seizures (ABS), juvenile myoclonic epilepsy (JME) and epilepsy with generalized tonic–clonic seizures exclusively (EGTCS).Patients and methods: Groups of unmedicated ABS, JME and EGTCS patients were investigated. Waking EEG background activity (without any epileptiform potentials) was analyzed by a source localization method, LORETA (Low Resolution Electromagnetic Tomography). Each patient group was compared to a separate, age-matched group of healthy control persons. Voxel-based, normalized broad-band (delta, theta, alpha, and beta) and very narrow band (VNB, 1Hz bandwidth, from 1 to 25Hz) LORETA activity (=current source density, A/m2) were computed for each person. Group comparison included subtraction (average patient data minus average control data) and group statistics (multiple t-tests, where Bonferroni-corrected p<0.05 values were accepted as statistically significant).Results: Statistically not significant main findings were: overall increased delta and theta broad band activity in the ABS and JME groups; decrease of alpha and beta activity in the EGTCS group. Statistically significant main findings were as follows. JME group: bilaterally increased theta activity in posterior (temporal, parietal, and occipital) cortical areas; bilaterally increased activity in the medial and basal prefrontal area in the 8Hz VNB; bilaterally decreased activity in the precuneus, posterior cingulate and superior parietal lobule in the 11Hz and 21–22Hz VNBs. ABS group: bilaterally increased theta activity emerged in the basal prefrontal and medial temporal limbic areas. Decreased activity was found at 19–21Hz in the right postcentral gyrus and parts of the right superior and medial temporal gyri. EGTCS group: decreased activity was found in the frontal cortex and the postcentral gyrus at 10–11Hz, increased activity in the right parahippocampal gyrus at 16–18Hz.Discussion: Increased theta activity in the posterior parts of the cortex is the endophenotype for JME. Increased theta activity in the fronto-temporal limbic areas is the endophenotype for ABS. Statistically not significant findings might indicate diffuse biochemical abnormality of the cortex in JME and ABS.Significance: EEG-LORETA endophenotypes may correspond to the selective propensity to generate absence and myoclonic seizures in the ABS and JME syndromes.

Hypoxia enhances high-voltage-activated calcium currents in rat primary cortical neurons via calcineurin

2012-01-16

Summary: Hypoxia regulates neuronal ion channels, sometimes resulting in seizures. We evaluated the effects of brief sustained hypoxia (1% O2, 4h) on voltage-gated calcium channels (VGCCs) in cultured rat primary cortical neurons. High-voltage activated (HVA) Ca2+ currents were acquired immediately after hypoxic exposure or after 48h recovery in 95% air/5% CO2. Maximal Ca2+ current density increased 1.5-fold immediately after hypoxia, but reverted to baseline after 48h normoxia. This enhancement was primarily due to an increase in L-type VGCC activity, since nimodipine-insensitive residual Ca2+ currents were unchanged. The half-maximal potentials of activation and steady-state inactivation were unchanged. The calcineurin inhibitors FK-506 (in the recording pipette) or cyclosporine A (during hypoxia) prevented the post-hypoxic increase in HVA Ca2+ currents, while rapamycin and okadaic acid did not. L-type VGCCs were the source of Ca2+ for calcineurin activation, as nimodipine during hypoxia prevented post-hypoxic enhancement. Hypoxia transiently potentiated L-type VGCC currents via calcineurin, suggesting a positive feedback loop to amplify neuronal calcium signaling that may contribute to seizure generation.

Effect of valproic acid treatment on penile structure in prepubertal rats

2012-01-27

Summary: Introduction: The aim of this study was to determine the histological effects of valproic acid (VPA) on the penis in prepubertal rats.Methods: Twelve male Wistar rats (21–24 days old) were divided equally into 2 experimental groups, and given tap water (control group) or 300mg/kg/day VPA via gavage for 30 days. After the penes had been harvested, the antiangiogenic and antifibrogenic properties of VPA were evaluated immunohistochemically using vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS), transforming growth factor-beta 1 (TGF-β1) and Masson's trichrome staining. Apoptosis was determined by caspase-3 and caspase-9 immunoreactions. Results were expressed as histochemical score (HSCORE), a semi-quantitative analysis for the intensity of immunohistochemical reactivity.Results: Immunohistochemical HSCORE decreased for VEGF and TGF-β1 staining and increased for iNOS staining in rats treated with VPA compared with the control group. Intensities of caspase-3 and caspase-9 labeling were also significantly increased by administration of VPA. Masson's trichrome staining exhibited a fairly diminished level of collagen in the corpus cavernosum of rats treated with VPA.Conclusion: In the light of these results, the administration of VPA from prepuberty to adulthood led to increased apoptosis and deterioration of the smooth muscle/collagen ratio in rat's corpus cavernosum.

Triheptanoin in acute mouse seizure models

Nicola K. Thomas, Sarah Willis, Lawrence Sweetman, Karin Borges — 2012-01-20

Abstract: Triheptanoin, the triglyceride of heptanoate, is used to treat certain hereditary metabolic diseases in USA because of its anaplerotic potential. In two chronic mouse seizure models this clear tasteless oil was found to be reproducibly anticonvulsant. Here we investigated the effects of triheptanoin feeding in C3H and CD1 mice using standard acute seizure models. Feeding 30–40% triheptanoin (caloric intake) consistently elevated blood propionyl-carnitines, but inconsistent anticonvulsant effects were observed in the fluorothyl, pentylenetetrazole and 6Hz seizure models. A 2mA consistent increase in the maximal electroshock threshold was found after 3weeks of 35% triheptanoin feeding (p=0.018). In summary, triheptanoin shows a unique anticonvulsant profile in seizure models, compared to other treatments that are in the clinic. Therefore, despite small and/or inconsistent effects of triheptanoin in acute seizure models, triheptanoin remains of interest as a potential add-on treatment for patients with medically refractory epilepsy.

Prevalence of epilepsy in the 15 years and older in Benin: A door-to-door nationwide survey

2012-01-27

Summary: Purpose: Estimate the prevalence of epilepsy in the 15 years and older in Benin.Methods: We used a random multistage sampling design to select a representative sample of the 15 years and older in Benin. From March to May 2010, people were screened door-to-door in the twelve regions of Benin. Screening and data collection were performed using a validated standardised questionnaire of epilepsy in tropical regions. A neurologist examined all people suspected of epilepsy.Results: We identified 174 suspected epilepsy cases from 13,046 screened people; 105 were confirmed by the neurologist (54 men and 51 women). The mean age of PWE was 28.9±14.3 years. The estimate of crude prevalence of epilepsy in the 15 years and older in Benin was 8.05/1000 (95% CI: 6.52–9.58/1000). The crude prevalence of epilepsy among men was 9.77/1000 (95% CI 7.35–12.73/1000) and 6.79/1000 (95% CI 5.06–8.91/1000) for women. The age-adjusted prevalence of epilepsy on sub-Saharan Africa population was 8.25/1000 and 7.33/1000 on world population. Substantial heterogeneity was noted, with differences from one region to another. The most common seizure types were generalised tonic–clonic (80.0%), partial secondary generalised seizures (14.3%) and partial seizures (5.7%).Significance: This nationwide study is the first in West Africa. It provides a low prevalence of epilepsy in Benin compared to previous studies performed in this country and in neighbouring countries. Restricted-area studies are often motivated by the presence of specific risk factors and could overestimate the prevalence, while large-scale studies could underestimate other subtle forms of epilepsy.

Cortical and thalamic resting-state functional connectivity is altered in childhood absence epilepsy

Richard A. Masterton, Patrick W. Carney, Graeme D. Jackson — 2012-01-27

Summary: Purpose: Functional imaging studies have identified a common network of brain regions that activate and deactivate during the generalised spike wave (GSW) discharges of childhood absence epilepsy (CAE). Functional connectivity within this network is also altered during the resting state. In this study our aim was to assess functional connectivity throughout the whole brain of patients with CAE.Methods: We studied a group of eleven patients with untreated CAE and eleven matched controls using resting-state fMRI. We measured functional connectivity between every pair of voxels and generated images of “whole-brain” functional connectivity by counting the number of functional connections of each voxel.Key findings: There were marked differences between CAE patients and controls in whole brain functional connectivity. The patients had decreased connectivity in the thalamus and basal ganglia and increased connectivity in the medial occipital cortex.Significance: These findings suggest enduring changes in function of the thalamus and the cortex in CAE patients even when there is no GSW activity. These human functional connectivity data support the findings in animal models of involvement of cortex as well as thalamus in absence epilepsy.

Occipital lobe epilepsy in children: Characterization, evaluation and surgical outcomes

2012-01-19

Summary: Introduction: Occipital lobe epilepsy (OLE) poses a diagnostic challenge to clinicians. Here, we present our experience in the surgical management of OLE in children using magnetoencephalography (MEG) in the pre-operative evaluation.Methods: Retrospective chart review was performed from 2000 to 2010 to identify patients with OLE. Patients were analyzed in two categories: isolated OLE (11 patients) and extended OLE (parietooccipital, temporooccipital, and temporoparietooccipital; 30 patients). Survival analysis and multivariate Cox proportional hazards regression were used to identify independent predictors of seizure outcome.Results: Forty-one patients with a mean follow-up of 3.1 years were identified with an overall 68% rate of satisfactory seizure outcome. Patients with extended OLE had younger ages at seizure onset and different seizure semiologies compared with those with isolated OLE. None of the latter underwent insertion of subdural grid electrodes for localization of the epileptogenic zone compared with 77% of the former (p<0.001). On multivariate analysis, the strongest independent predictor of unsatisfactory outcome was MEG dipoles in the occipital lobe contralateral to resection.Conclusion: Here, we find similar seizure outcomes for isolated and extended OLE foci despite the use of less invasive strategies for the former. Furthermore, we describe the role of MEG in evaluation, surgical planning and prognostication of children with OLE.

A de novo balanced t(2;6)(p15;p22.3) in a patient with West Syndrome disrupts a lnc-RNA

2012-01-16

Summary: In a male patient with West Syndrome we identified a perfectly balanced, de novo balanced translocation 46,XY,t(2;6)(p15;p22.3). No known protein coding genes were disrupted by the translocation and positional effects on nearby genes were excluded by expression studies. A putative long non-coding RNA, BX118339, spans the breakpoint on chromosome 6. It can be hypothesized that disruption of this non-coding transcript plays a role in the pathogenesis of the patient.