Epilepsy Research - Articles in Press

Histamine 1 receptor knock out mice show age-dependent susceptibility to status epilepticus and consequent neuronal damage - Corrected Proof

2012-02-21

Summary: The central histaminergic neuron system is an important regulator of activity stages such as arousal and sleep. In several epilepsy models, histamine has been shown to modulate epileptic activity and histamine 1 (H1) receptors seem to play a key role in this process. However, little is known about the H1 receptor-mediated seizure regulation during the early postnatal development, and therefore we examined differences in severity of kainic acid (KA)-induced status epilepticus (SE) and consequent neuronal damage in H1 receptor knock out (KO) and wild type (WT) mice at postnatal days 14, 21, and 60 (P14, P21, and P60).Our results show that in P14 H1 receptor KO mice, SE severity and neuronal damage were comparable to those of WT mice, whereas P21 KO mice had significantly decreased survival, more severe seizures, and enhanced neuronal damage in various brain regions, which were observed only in males. In P60 mice, SE severity did not differ between the genotypes, but in KO group, neuronal damage was significantly increased. Our results suggest that H1 receptors could contribute to regulation of seizures and neuronal damage age-dependently thus making the histaminergic system as a challenging target for novel drug design in epilepsy.

Voxel-based relaxometry for cases of an unresolved epilepsy diagnosis - Corrected Proof

Robert K. Kosior, Rachel Sharkey, Richard Frayne, Paolo Federico — 2012-02-20

Summary: Purpose: Voxel-based relaxometry (VBR) is a technique in which a voxel-level statistical comparison of quantitative MR T2 maps is performed to identify regions with significantly elevated T2 relaxation time. Our objective was to assess the performance of single-subject VBR at 3T as a diagnostic tool for patients whose diagnosis of epilepsy or seizure focus location is uncertain.Methods: Fifty-nine patients with possible epilepsy or known epilepsy, but an unknown focus and forty-five healthy controls were studied. All subjects were scanned at 3T using a Carr–Purcell–Meiboom–Gill MR sequence. Single-subject VBR was performed at a significance level of α=0.001. Patients were classified based on whether the diagnosis of epilepsy was in question and whether there was a suspected focus. A VBR score was determined based on the presence of VBR abnormalities in any of 13 predefined regions per hemisphere.Results: All patients exhibited significantly more median VBR abnormalities than controls (p<0.05). VBR abnormalities were seen in 69% and 89% of patients with a normal or questionably abnormal MR scan, respectively. Nineteen of the 27 patients with a suspected focus (70%) had VBR abnormalities in the suspected focus, with additional regions of involvement being elucidated. VBR also correctly predicted the seizure focus in 50% of patients whose seizure foci were confirmed based on follow-up history or clinical investigations.Conclusions: Single subject VBR can help identify potential seizure foci in patients whose seizure foci are uncertain.

The antiepileptic drug mephobarbital is not transported by P-glycoprotein or multidrug resistance protein 1 at the blood–brain barrier: A positron emission tomography study - Corrected Proof

2012-02-20

Summary: Aim of this study was to determine whether the carbon-11-labeled antiepileptic drug [11C]mephobarbital is a substrate of P-glycoprotein (Pgp) and can be used to assess Pgp function at the blood–brain barrier (BBB) with positron emission tomography (PET). We performed paired PET scans in rats, wild-type (FVB) and Mdr1a/b(−/−) mice, before and after intravenous administration of the Pgp inhibitor tariquidar (15mg/kg). Brain-to-blood AUC0–60 ratios in rats and brain AUC0–60 values of [11C]mephobarbital in wild-type and Mdr1a/b(−/−) mice were similar in scans 1 and 2, respectively, suggesting that in vivo brain distribution of [11C]mephobarbital is not influenced by Pgp efflux. Absence of Pgp transport was confirmed in vitro by performing concentration equilibrium transport assay in cell lines transfected with MDR1 or Mdr1a. PET experiments in wild-type mice, with and without pretreatment with the multidrug resistance protein (MRP) inhibitor MK571 (20mg/kg), and in Mrp1(−/−) mice suggested that [11C]mephobarbital is also not transported by MRPs at the murine BBB, which was also supported by in vitro transport experiments using human MRP1-transfected cells. Our results are surprising, as phenobarbital, the N-desmethyl derivative of mephobarbital, has been shown to be a substrate of Pgp, which suggests that N-methylation abolishes Pgp affinity of barbiturates.

Factors associated with behavioral problems in children with idiopathic epilepsy - Corrected Proof

Vaios Dafoulis, Efrosini Kalyva — 2012-02-20

Summary: The present study examined whether the perceived behavioral problems of children with idiopathic epilepsy differed from those of healthy controls according to parent proxy-reports and which factors are associated with these problems. The parents of 106 children with idiopathic epilepsy and 305 healthy controls aged 6–9years old completed the Vanderbilt ADHD Diagnostic Parent Rating Scale and the Strengths and Difficulties Questionnaire. The 106 children with idiopathic epilepsy were also interviewed using the K-SADS-PL. The parents of children with idiopathic epilepsy reported more hyperactivity, emotional and conduct problems than the parents of healthy controls, as well as less prosocial behavior. Parents detected no differences in peer problems, inattention, oppositional/defiant disorder, and anxiety/depression. Age of onset of epilepsy (later), the number of administered antiepileptic drugs (polytherapy), and gender (male) predicted behavioral problems in children with idiopathic epilepsy. The frequency of seizures was associated with behavioral problems, while age was not. Finally, children with benign focal epilepsy were rated by their parents as having less behavioral problems than children with generalized epilepsy.

Anticonvulsant action of GABAB receptor positive modulator CGP7930 in immature rats - Corrected Proof

Pavel Mareš — 2012-02-16

Summary: GABAB receptors mediate inhibition at early stages of development but mixed anti-and proconvulsant action of their agonists affecting all receptors was found in immature rats. Positive allosteric modulators of GABAB receptors potentiate only already active GABAB receptors and therefore more specific action is expected. Possible anticonvulsant action of CGP7930 was studied in a model of pentetrazol-induced seizures previously used for studies with agonists baclofen and SKF97541.Pentetrazol (100mg/kg) was administered subcutaneously in male rats 7, 12, 18, 25 and 90 days old pretreated with CGP7930 in doses 1–40mg/kg i.p.High doses of CGP7930 suppressed generalized tonic–clonic seizures in all five age groups. Animals 18 and less days old exhibited a specific suppression of the tonic phase after lower doses of CGP7930. Twelve-day-old rats were the most sensitive to anticonvulsant effect of CGP7930 (even the 2-mg/kg dose suppressed the tonic phase whereas 20-mg/kg dose was active in other age groups). Minimal clonic seizures (mS) were moderately potentiated by low doses of CGP7930 in 18-day-old but suppressed by the highest dose in 25-day-old rats. The 60-mg/kg dose of PTZ induced only mS in 4 out of 9 25-day-old rats; the 40-mg/kg dose of CGP7930 combined with this lower dose of PTZ resulted in the only proconvulsant effect – generalized tonic–clonic seizures appeared in two rats.Results from 12-day-old rats suggest a possibility to find an age-specific anticonvulsant among positive allosteric modulators of GABAB receptors.

Antiepileptic drugs management and long-term seizure outcome in post surgical mesial temporal lobe epilepsy with hippocampal sclerosis - Corrected Proof

2012-02-16

Summary: Surgery is the treatment of choice for refractory temporal lobe epilepsies, but unexpected seizure recurrences occur and the AEDs management strategy may be an implicated factor. We evaluated the AEDs management's role in the outcome of post surgical epilepsy patients with hippocampal sclerosis (HS).Epileptic patients submitted to amigdalohippocampectomy due to HS in Engel class IA 12months after surgery were selected. The following variables were studied: age, gender, time of post-surgical follow-up, present Engel class, number of antiepileptic AEDs before surgery and at the time of the interview, AED changes after surgery (stopped, increased, decreased, maintained), timing for AED changes after surgery and seizure recurrences.Sixty-seven consecutive patients were studied (mean time of follow-up of 4.9±2.8 years). Among these, 46.3% were tapering AEDs, 38.8% had not changed and 14.9% had increased AEDs. The global recurrence rate was 32.8%. Recurrence rates for patients tapering and not tapering AEDs were similar (34.2% and 31%, respectively). Fifteen patients tapered AEDs before 2 years and 20 at or 2 years after surgery, with similar recurrence rates (33% and 30%, respectively). All patients who recurred due to AED tapering and 66.7% of the patients who recurred with no AED reduction resumed the Engel class I.This study suggests that in HS patients submitted to AHE who are seizure free during the first postsurgical year, AEDs tapering is achieved in a substantial percentage of patients. Tapering AEDs, independently of its timing, will induce seizure recurrence in about a third of patients. However, patients relapsing after tapering AEDs regain control after resuming therapy.

Gender differences in quality of life among Canadian adults with epilepsy - Corrected Proof

John O. Elliott, Alvin S. Mares — 2012-02-10

Summary: The clinical literature suggests epilepsy may impact quality of life in males and females differently. Previous research on gender issues has focused primarily on biological–biomedical factors over psychological and social factors. In this study we compare subjective and objective quality of life in adults persons with epilepsy to persons without epilepsy by gender using the biopsychosocial model in the Canadian Community Health Survey (CCHS), a large epidemiological survey that covers 98% of the Canadian population. Logistic regression analyses were conducted using self-rated health status and the Health Utility Index® 3 (HUI3) as the outcomes. Quality of life was significantly moderated after controlling for the biological–biomedical variables in all analyses except the HUI3. Males with epilepsy were more likely to have HUI3 scores of 0.70 or greater than males without epilepsy (OR=1.61, 95%CI 1.32–1.96). For males with epilepsy the HUI3 was further moderated, but remained significantly better in the final model that controlled for biological, psychological and social factors (OR=1.43, 95%CI 1.17–1.76). Our findings provide support for treatment approaches that focus on the whole person. Such approaches should take into account gender differences when examining objective quality of life.

Alertness network in patients with temporal lobe epilepsy: A fMRI study - Corrected Proof

Jinou Zheng, Bailing Qin, Chao Dang, Wei Ye, Zirong Chen, Lu Yu — 2012-02-06

Summary: Patients with temporal lobe epilepsy (TLE) often suffer from cognitive deficits. However, it remains elusive whether the performance of TLE patients in the attentional networks test (ANT) is impaired. Functional magnetic resonance imaging (fMRI) can accurately reflect the hemodynamics and functional activities in certain regions of the brain. In the current study, we aimed to investigate the characteristics and neural mechanisms of the functions of the alertness network in patients with TLE using the ANT and fMRI. A total of 12 patients with TLE and 8 healthy controls underwent the ANT behavioral tests and subsequent block-design fMRI scanning. The results showed that the response times of the alertness network had no significant difference between the TLE group and the healthy control group. The fMRI data showed that the activation of the cerebellum, right occipital lobe, right frontal and brainstem was significantly weaker in TLE patients than in healthy control. Our data indicate that despite neuropsychological test performance is normal; the alerting network is deficient in the TLE patients. The decreased activation of brain regions of right occipital lobe, cerebellum, right frontal lobe, brain stem and temporal lobe may be the neural basis of altering network impairment in TEL patients.

Non-linear classification of heart rate parameters as a biomarker for epileptogenesis - Corrected Proof

Farshad Kheiri, Anatol Bragin, Jerome Jr. Engel, Joel Almajano, Eamon Winden — 2012-02-06

Summary: Purpose: To characterize a biomarker for epileptogenesis based on cardiac interbeat interval characteristics.Methods: Electrocardiograph (ECG) and electroencephalogram (EEG) signals were recorded from freely moving rats (n=23) before status epilepticus (SE) induced by i.p. pilocarpine (PILO) injection as baseline, and on days 1, 3 and 7 after SE. We assessed several features from cardiac interbeat intervals, including linear, non-linear and frequency parameters of interbeat intervals, and power spectra of interpolated intervals during epileptogenesis. After thresholding, the altered values were applied to a non-linear classifier. The non-linear classifier divided animals into two groups; with and without epilepsy, based on all collected data.Results: We found that none of the single altered parameters in cardiac activity emerged as a sole biomarker for epileptogenesis. However, the non-linear classifier distinguished animals that later developed from those and did not develop epilepsy. The non-linear classification was performed on preliminary findings from 23 animals; six did not develop epilepsy and the rest did. The average positive predictive value (precision rate) was 78%. This was calculated based on the average sensitivity and specificity, which were 80.6% and 35.2% respectively, for the 100 classification passes. We also showed that these numbers would have increased as the number of subjects increased.Conclusion: Changes to the brain caused by status epilepticus that lead to epileptogenesis have systemic effects, and alter cardiac activity. A non-linear classifier performed on several extracted features of cardiac interbeat intervals may be useful as a biomarker to identify animals with low and high probability of developing epilepsy after status epilepticus.

A 21-week open-label clinical trial of pregabalin as adjunctive therapy in partial seizures at multiple centers in Mexico (PREPS Mexico) - Corrected Proof

2012-02-06

Summary: Purpose: To investigate the efficacy of pregabalin in the treatment of refractory partial seizures.Methods: This was a 21-week, open-label study of pregabalin (150–600mg/day) as an adjunctive therapy in adults with refractory partial seizures. The study included an 8-week baseline period, a 9-week dose-optimization period, and a 12-week treatment-observation period. The primary assessment was mean percentage change in 28-day seizure rate between baseline and the last 12 weeks of treatment.Results: In total, 136 Mexican patients were included in this study (55.9% women; mean age/epilepsy duration, 35.2/22.9 years). The median and mean (95% confidence interval [CI]) 28-day baseline seizure rates were 3.9 and 7.8 (5.4–10.2), respectively. The mean (95% CI) reduction in seizure frequency was 51.2% (43.0–59.3) over the last 12 weeks of treatment, while the median reduction was 57.9%. The percentage of patients with a ≥50% or ≥75% reduction in seizure frequency was 63.6% and 48.8%, respectively. The percentage of patients who were seizure-free during the last 4 and 12 weeks of treatment was 40.5% and 20.7%, respectively. The most common adverse events were somnolence (39.7%), dizziness (16.2%), and weight gain (14.0%).Conclusion: Pregabalin was well tolerated and associated with significant reductions in seizure frequency.

Do hyperbaric oxygen-induced seizures cause brain damage? - Corrected Proof

2012-01-31

Summary: It is commonly accepted that hyperbaric oxygen-induced seizures, the most severe manifestation of central nervous system oxygen toxicity, are harmless. However, this hypothesis has not been investigated in depth. We used apoptotic markers to determine whether cells in the cortex and hippocampus were damaged by hyperbaric oxygen-induced seizures in mice. Experimental animals were exposed to a pressure of 6 atmospheres absolute breathing oxygen, and were randomly assigned to two groups sacrificed 1h after the appearance of seizures or 7 days later. Control groups were not exposed to hyperbaric oxygen. Caspase 9, caspase 3, and cytochrome c were used as apoptotic markers. These were measured in the cortex and the hippocampus, and compared between the groups. Levels of caspase 3, cytochrome c, and caspase 9 in the hippocampus were significantly higher in the hyperbaric oxygenexposed groups compared with the control groups 1 week after seizures (p<0.01).The levels of two fragments of caspase 9 in the cortex were higher in the control group compared with the hyperbaric oxygen-exposed group 1h after seizures (p<0.01). Hyperbaric oxygen-induced seizures activate apoptosis in the mouse hippocampus. The reason for the changes in the cortex is not understood. Further investigation is necessary to elucidate the mechanism underlying these findings and their significance.

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

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.

Effect of valproic acid treatment on penile structure in prepubertal rats - Corrected Proof

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.

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

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 - Corrected Proof

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.

Traxoprodil decreases pentylenetetrazol-induced seizures - Corrected Proof

2012-01-27

Summary: Polyamines, including spermidine, facilitate seizures by positively modulating N-methyl-d-aspartate receptors (NMDAr). Although NMDAr antagonists decrease seizures, it remains to be determined whether traxoprodil, a selective antagonist at the NR2B subunit of the NMDAr, decreases seizures and whether spermidine facilitates pentylenetetrazol (PTZ)-induced seizures. Adult male Wistar rats were injected in the lateral ventricle with 0.9% NaCl (1μl, i.c.v.), spermidine (0.02, 0.2 or 2nmol/site, i.c.v.) or traxoprodil (0.2, 2 or 20nmol, i.c.v.) and with PTZ (35 or 70mg/kg, i.p.). The effect of orally administered traxoprodil (60mg/kg, p.o.) on seizures was also investigated. Latencies to clonic and generalized seizures, as well the total time spent in seizures were recorded by behavioral and electrographic methods (EEG). Spermidine (2nmol/site; i.c.v.) facilitated the seizures induced by a sub-threshold dose of PTZ (35mg/kg; i.p.), but did not alter seizure activity induced by a convulsant dose of PTZ (70mg/kg; i.p.). Traxoprodil (20nmol i.c.v.) increased the latency to generalized tonic–clonic seizures induced by PTZ (70mg/kg; i.p.). Traxoprodil (60mg/kg, p.o.) increased the latency to clonic and generalized seizures, and decreased the total time spent in seizures. These results support the role for the NR2B subunit in PTZ-induced seizures.

Influence of N-hydroxymethyl-p-isopropoxyphenylsuccinimide on the anticonvulsant action of different classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model - Corrected Proof

2012-01-27

Summary: Experimental epileptology is mainly focused on searching for some active compounds suppressing seizures that could become efficacious antiepileptic drugs. Accumulating evidence indicates that succinimide derivatives would be good candidates for novel antiepileptic drugs. Therefore, the aim of this study was to determine the effects of N-hydroxymethyl-p-isopropoxyphenyl-succinimide (HMIPPS) on the protective action of four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) in the maximal electroshock-induced seizure test in mice.Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25mA, 500V, 50Hz, 0.2s stimulus duration) delivered via auricular electrodes. Acute adverse-effect profiles with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain antiepileptic drug concentrations.Results indicate that HMIPPS administered intraperitoneally at 100mg/kg significantly elevated the threshold for electroconvulsions in mice (P<0.05). HMIPPS at doses of 12.5, 25 and 50mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, HMIPPS (50mg/kg) significantly enhanced the anticonvulsant activity of phenobarbital and valproate in the mouse maximal electroshock-induced seizure model by reducing their median effective doses (ED50 values) from 23.25mg/kg to 16.82mg/kg (P<0.01; for phenobarbital) and from 259.3mg/kg to 189.7mg/kg (P<0.001; for valproate), respectively. In contrast, HMIPPS (50mg/kg) had no impact on the protective action of carbamazepine or phenytoin in the maximal electroshock seizure test in mice. HMIPPS (25mg/kg) significantly potentiated the anticonvulsant action of valproate by reducing its ED50 value from 259.3mg/kg to 210.6mg/kg (P>0.05), but not that of phenobarbital, phenytoin and carbamazepine in the mouse maximal electroshock-induced seizure model. Pharmacokinetic experiments revealed that HMIPPS did not alter total brain concentrations of phenobarbital or valproate in mice. Moreover, none of the examined combinations of HMIPPS (50mg/kg) with carbamazepine, phenobarbital, phenytoin and valproate (at their ED50 values from the maximal electroshock-induced seizure test) affected motor coordination in the chimney test, long-term memory in the passive avoidance task, and muscular strength in the grip-strength test in mice, indicating no possible acute adverse effects in animals.In conclusion, the enhanced anticonvulsant action of phenobarbital and valproate by HMIPPS in the mouse maximal electroshock-induced seizure model, lack of pharmacokinetic interactions and no potential acute adverse effects make the combinations of HMIPPS with phenobarbital and valproate worthy of consideration for further experimental and clinical studies. The combinations of HMIPPS with carbamazepine and phenytoin are neutral from a preclinical viewpoint.

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

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.

Seizure susceptibility and electroencephalogram power spectra alterations at various phases of the lipopolysaccharide-induced hypothermic response in biotelemetered rats - Corrected Proof

Eyup S. Akarsu, Soner Mamuk — 2012-01-24

Summary: The neuronal excitability has been evaluated at various phases of lipopolysaccharide (LPS; E. coli O111:B4, 250μg/kg, ip)-induced hypothermia including the initial phase, the plateau (including the nadir) and the end of the response in biotelemetered adult Wistar rats. The latency of pentylenetetrazole-induced seizures (60mg/kg, ip) was lower at the initial phase, but a clear anticonvulsive activity was observed at the end of the hypothermic response. Seizure parameters did not change at the nadir. There was no electroencephalogram (EEG) spike-wave activity generation at either phase of the LPS-induced hypothermia. Meanwhile, the power of the 12–32Hz beta band of the EEG spectra increased at the initial phase. This increment persisted at the plateau where there was also a decrease in the 1–4Hz delta power. The data indicate that spike-wave activity is not facilitated during LPS-induced hypothermia but, proconvulsant and anticonvulsant activities occur sequentially depending on the phase of the response. The EEG power spectra also change. These effects may not be attributed merely to the reduction of body temperature. Thus, it is possible that pathophysiological mechanisms involved in the development of hypothermia may also be responsible for neuronal excitability changes in rats.

Triheptanoin in acute mouse seizure models - Corrected Proof

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.

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

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 - Corrected Proof

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.

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

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.

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

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.

CSF levels of dopamine and serotonin, but not norepinephrine, metabolites are influenced by the ketogenic diet in children with epilepsy - Corrected Proof

Maria Dahlin, Jan-Eric Månsson, Per Åmark — 2012-01-12

Summary: The ketogenic diet (KD) is a non-pharmacological treatment of medically refractory epilepsy in children. Its mechanisms of action are still unclear but monoamine neurotransmitters have been proposed to be involved. Norepinephrine, dopamine, and serotonin are known to modulate seizure susceptibility in many animal models. We examined whether the concentrations of norepinephrine, dopamine, and serotonin metabolites were affected by the KD in children with pharmacoresistant epilepsy. The metabolites of norepinephrine, HMPG, of dopamine, HVA, and of serotonin, 5-HIAA, were analyzed in cerebrospinal fluid (CSF) before and 3 months after starting the KD. Twenty-six children (mean age 5.9 years) participated. Twenty-one children had generalized epilepsy and five partial. CSF was sampled by lumbar puncture. Seizure frequency before and during the diet was determined. Highly significant changes were found for HVA (p=0.0002) and 5-HIAA (p=0.004), which were both decreased during the KD compared to before diet. The levels of HMPG were unchanged. However, no differences were found between response groups. Valproate medication affected the levels of HMPG during diet with decreased levels in children on valproate and increased in those not on valproate (p=0.04). Our study indicates that the KD significantly alters the levels of metabolites of dopamine and serotonin but with a stable ratio HVA/5-HIAA in the CSF of children with refractory epilepsy, which finding may be of importance for the mechanism of action.

EEG-LORETA endophenotypes of the common idiopathic generalized epilepsy syndromes - Corrected Proof

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.

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

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.

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

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.

Serotonin gene polymorphisms and psychiatry comorbidities in temporal lobe epilepsy - Corrected Proof

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.

Beta adrenergic blockade prevents cardiac dysfunction following status epilepticus in rats - Corrected Proof

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.

A cross-sectional MRI study of brain regional atrophy and clinical characteristics of temporal lobe epilepsy with hippocampal sclerosis - Corrected Proof

2011-12-26

Summary: Purpose: Applying a cross-sectional design, we set out to further characterize the significance of extrahippocampal brain atrophy in a large sample of ‘sporadic’ mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE+HS). By evaluating the influence of epilepsy chronicity on structural atrophy, this work represents an important step towards the characterization of MRI-based volumetric measurements as genetic endophenotypes for this condition.Methods: Using an automated brain segmentation technique, MRI-based volume measurements of several brain regions were compared between 75 patients with ‘sporadic’ MTLE+HS and 50 healthy controls. Applying linear regression models, we examined the relationship between structural atrophy and important clinical features of MTLE+HS, including disease duration, lifetime number of partial and generalized seizures, and history of initial precipitating insults (IPIs).Results: Significant volume loss was detected in ipsilateral hippocampus, amygdala, thalamus, and cerebral white matter (WM). In addition, contralateral hippocampal and bilateral cerebellar grey matter (GM) volume loss was observed in left MTLE+HS patients. Hippocampal, amygdalar, and cerebral WM volume loss correlated with duration of epilepsy. This correlation was stronger in patients with prior IPIs history. Further, cerebral WM, cerebellar GM, and contralateral hippocampal volume loss correlated with lifetime number of generalized seizures.Conclusion: Our findings confirm that multiple brain regions beyond the hippocampus are involved in the pathogenesis of MTLE+HS. IPIs are an important factor influencing the rate of regional atrophy but our results also support a role for processes related to epilepsy chronicity. The consequence of epilepsy chronicity on candidate brain regions has important implications on their application as genetic endophenotypes.

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

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.

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

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.

Epileptic seizures from abnormal networks: Why some seizures defy predictability - Corrected Proof

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.

Pure bipolar electro-coagulation on functional cortex in the treatment of epilepsy involving eloquent areas - Corrected Proof

Zhiqiang Cui, Guoming Luan, Jian Zhou — 2011-12-12

Summary: Purpose: Although resection of an epileptogenic region remains the main procedure of epilepsy surgery, epileptogenic areas in functionally critical cortex cannot be approached in that manner. Bipolar electro-coagulation on functional cortex (BCFC) was developed to treat such refractory seizures without causing unacceptable neurological deficits. Here we report the outcome of this therapy.Methods: Fifteen patients who underwent pure BCFC without resection between 2002 and 2008 were retrospectively reviewed with regard to seizure outcome, postoperative complications, and predictive factors.Key findings: Seven patients developed hemiparesis after the operation but fully recovered within 1–6 months. One patient developed mild dysphasia, which was resolved within 12 months. All neurological deficits were temporary in the sense that they ultimately did not result in a deficit that would be noticed during a standard clinical examination. There were no subdural hemorrhage and infection. Engel class I outcome was achieved in two (13.3%) patients; class II, in six (40%); class III, in three (20%); and class IV, in four (26.7%).Significance: The BCFC technique is only a palliative surgery, and cannot be applied for all epilepsies, however, this therapy proved to be effective when the epileptogenic foci are located in unresectable cortex. BCFC is safe and easy to use.

Unverricht–Lundborg disease: Homozygosity for a new splicing mutation in the cystatin B gene - Corrected Proof

2011-12-12

Summary: Unverricht–Lundborg disease is the most common form of progressive myoclonic epilepsy (PME). It is due to cystatin B gene (CSTB) mutations. Several mutations in CSTB gene have been published, but few in homozygosity. We describe a patient with a new splicing alteration. Mutation Gln22Gln leads to abnormal splicing and partial inclusion of intronic sequence. This is one of the few cases of homozygosity for a non-classic mutation and adds to mutational heterogeneity of CSTB.

Increased membrane shedding – indicated by an elevation of CD133-enriched membrane particles – into the CSF in partial epilepsy - Corrected Proof

2011-12-02

Summary: Purpose: Recent analyses provided evidence that human adult cerebrospinal fluid (CSF) in addition to soluble proteins also contains membrane particles that moreover carry the somatic stem cell marker CD133. The significance of CD133 as a potential marker of cellular proliferation, including neurogenesis, remains unresolved. As adult neurogenesis has been implicated to be induced by epileptic seizures this study investigated whether patients with partial epilepsy show a varying amount of membrane-associated CD133 in CSF as compared to healthy adults.Methods: CSF samples of 34 partial epilepsy patients were analyzed and compared to 61 healthy controls. Following sequential centrifugation up to 200,000g quantitative immunoblotting was performed using a mouse monoclonal antibody. Antigen-antibody complexes were detected using enhanced chemiluminescence, and visualized and quantified digitally.Results: The overall amount of membrane particle-associated CD133 was significantly increased in epilepsy patients compared to healthy controls (9.6±2.9ng of bound CD133 antibody versus 7.4±3.8ng; p<0.01). There were no differences according to etiology of epilepsy (cryptogenic, neoplasia, dysplasia, ammon's horn sclerosis, and others). Dichotomization of the patients according to temporal versus extratemporal foci revealed a significant increase of membrane particle-associated CD133 in patients with temporal lobe epilepsy (10.88±3.3ng of bound CD133 antibody versus 8.35±3.48ng; p<0.05).Conclusion: The increased amount of membrane particle-associated CD133 in the CSF of patients with partial epilepsy contributes to the ongoing debate of the source of these particles potentially emerging from subventricular zone astrocytes serving as neural stem cells. As neurogenesis in adults is related to the hippocampus, the significance of the increase of membrane particle-associated CD133 especially in temporal lobe epilepsy needs further clinical correlation.

Paradoxical lateralization of non-invasive electroencephalographic ictal patterns in extra-temporal epilepsies - Corrected Proof

Claudia B. Catarino, Christian Vollmar, Soheyl Noachtar — 2011-12-02

Summary: Video-electroencephalographic (EEG) ictal recordings play an important role in the pre-surgical evaluation of patients with medically refractory focal epilepsy. Paradoxical lateralization of the scalp EEG ictal onset patterns, consistently contralateral to the side of the proven epileptogenic lesion is rare but important to recognize, with possible implications on patient management.We searched the database of the University of Munich Epilepsy Monitoring Unit for patients with extratemporal epilepsies, with scalp EEG ictal patterns consistently contralateral to the proven epileptogenic zone. All available clinical, EEG and imaging data were reviewed. Dipole source analysis of EEG seizure onset was performed where possible.Four patients were identified, who had proven paradoxical lateralization of scalp EEG ictal patterns, demonstrated by seizure freedom after epilepsy surgery, data from invasive electroencephalography, or imaging and seizure semiology. Parasagittal lesions on MRI brain scan were found in three cases. Invasive recordings with subdural electrodes were performed in one patient. Dipole source analysis of EEG seizure onset was possible in two patients, helping to correctly lateralize the ictal EEG pattern in one patient.Patients with midline or near midline neocortical seizure foci may show paradoxical lateralization of the ictal EEG, likely due to the spatial orientation of the cortical generators in the medial regions of the cerebral hemispheres. These patients may have excellent surgical outcome despite the apparently discordant EEG findings, making this an important phenomenon to be recognized in clinical practice.

Long-term experience with fractionated stereotactic radiotherapy in pharmacoresistant epilepsy: Neurological and MRI changes - Corrected Proof

2011-11-30

Summary: Purpose: Radiotherapy is an option in patients with difficult-to-treat epilepsy in which pharmacological and surgical alternatives have been exhausted. However, little is known about the long-term efficacy and side effects of radiotherapy in this context. Hence, we report for the first time on the long-term outcome (median 10 years) of fractionated stereotactic radiotherapy (FSRT) in 11 patients with drug-resistant epilepsy in a retrospective study. Primary endpoint is tolerability concerning neurological and MRI findings, secondary endpoint seizure frequency.Patients and methods: FSRT was performed in 11 patients with cryptogenic or symptomatic epilepsy from 1996 to 2009 using a conventional linear accelerator (LINAC) in seven cases and a dedicated NOVALIS® LINAC in four. The biologically equivalent dose ranged from 26.3 to 58.3Gy (α/β=10).Results: (1) None of the patients developed temporary or permanent neurological deficits. No MRI changes occurred. (2)Treatment resulted in improvement of seizure frequency in seven patients, five of them had a decrease in seizure frequency, and two of them were seizure-free at last follow-up.Conclusions: If radiation is administered with proper fractionation, dose prescription and target volume definition, long-term neurological side effects are unlikely. (2) Radiotherapy has the potential to control the frequency and intensity of seizures in epilepsy patients.

Low glycemic index treatment for epilepsy in tuberous sclerosis complex - Corrected Proof

Anna M. Larson, Heidi H. Pfeifer, Elizabeth A. Thiele — 2011-11-28

Summary: Retrospective chart review of 15 patients with tuberous sclerosis complex (TSC) who initiated the low glycemic index treatment (LGIT) for epilepsy management at Massachusetts General Hospital over a five-year period. Prior to dietary therapy, this cohort (average age: 8.5 years) had tried an average of 5.8 anti-epileptic drugs with incomplete seizure control. At 6 months on the LGIT, 7/15 (47%) patients experienced >50% reduction in seizure frequency.

Natural course of epilepsy concomitant with CNS tuberculomas - Corrected Proof

2011-11-28

Summary: Background: Epilepsy is relatively common in CNS tuberculomas, but its natural course is unclear.Aim: To determine the prevalence and prognosis of epilepsy in patients with seizures related to CNS tuberculomas.Methods: We retrospectively reviewed the charts of patients with CNS tuberculomas who presented at our institution between 1983 and 2001.Results: Seizures occurred in 22 of 93 (23.6%) of the patients with CNS tuberculomas. These patients were treated with standard antituberculous therapy for a period varying between 6 and 20 months. Sixty-three out of 93 patients were cured of tuberculosis, and 21 of the 63 (33%) who had concomitant epilepsy became seizure-free. TB recurred in 3 patients, and 1 out of 22 who had concomitant epilepsy continued to have seizures; 3 died and 24 were lost to follow-up. Anti-epileptic medications were discontinued after completion of the anti-TB course.Conclusion: Seizures are commonly associated with CNS tuberculomas and most often resolve after successful treatment of the underlying CNS tuberculosis.

Superoxide dismutase 2 Val16Ala polymorphism is a risk factor for the valproic acid-related elevation of serum aminotransferases - Corrected Proof

2011-11-28

Summary: The association between the superoxide dismutase 2 (SOD2) Val16Ala polymorphism and the serum aminotransferase levels was retrospectively investigated in 207 valproic acid-treated patients with epilepsy. The Val/Val genotype tended to show elevated alanine aminotransferase levels (odds ratio=3.5; P=0.056). In addition, an elevated γ-glutamyltransferase level was associated with the Val/Val genotype (odds ratio=3.1; P=0.022). The SOD2 Val/Val genotype may therefore contribute to a valproic acid-induced elevation in the serum aminotransferase levels.

Dynamics of frequency flow in epileptic brain during extra-temporal partial and idiopathic generalized epilepsy - Corrected Proof

Premananda Indic, Jaishree Narayanan — 2011-11-21

Summary: Temporal lobe epilepsy has been known to be associated with buildup of 4–7Hz activity preceded by attenuation near the seizure focus. Using a wavelet based algorithm, we recently showed that for the patients with temporal lobe epilepsy, frequency flow on the scalp EEG builds up to 5–12Hz range just prior to and during the initial stages of the seizure. Here we present frequency flow analysis on EEG of patients with extra-temporal partial epilepsy and patients with idiopathic generalized epilepsy (IGE) to investigate any characteristic frequency flow patterns in these patients. We found that frequency flow in these patients also stays sustained in the 5–12Hz range for longer periods of time just prior to and during the initial stages of the seizure compared to their respective baseline interictal recordings. The 5–12Hz frequency flow was seen uniformly in all the channels in patients with IGE although it was seen most prominently adjacent to the seizure focus and to a lesser extent in other channels in patients with partial epilepsy.

Cerebral ketone metabolism during development and injury - Corrected Proof

Mayumi L. Prins — 2011-11-21

Summary: Cerebral metabolism of ketones is a normal part of the process of brain development. While the mature brain relies on glucose as a primary fuel source, metabolism of ketone bodies remains an alternative energy source under conditions of starvation. The neuroprotective properties of brain ketone metabolism make this alternative substrate a viable therapeutic option for various pathologies. Since the ability to revert to utilizing ketones as an alternative substrate is greatest in the younger post-weaned brain, this particular therapeutic approach remains an untapped resource particularly for pediatric pathological conditions.

Erratum to “Marked strain and substrain differences in induction of status epilepticus and subsequent development of neurodegeneration, epilepsy, and behavioral alterations in rats” [Epilepsy Res. 96 (2011) 207–224] - Corrected Proof

Melanie Langer, Claudia Brandt, Wolfgang Löscher — 2011-11-21

The publisher regrets that during the publication of the above paper the title was published incorrectly. The updated title is reproduced correctly above. The publisher would like to apologise for any inconvenience this may have caused to the authors of this paper and the readers of the journal.

Eicosanoid levels in the neocortex of drug-resistant epileptic patients submitted to epilepsy surgery - Corrected Proof

2011-11-21

Summary: There is an increasing body of evidence implicating eicosanoids (arachidonic acid metabolites) in the experimental generation of epileptic seizures and the development of epilepsy. Our purpose was to measure the synthesis of eicosanoids from the cyclooxygenase and lipoxygenase pathways in human brain neocortex tissue samples obtained from epileptic patients, and to compare them with non-epileptic control subjects. Epileptic neocortex specimens demonstrated a significant increase (P<0.001) in the levels of three eicosanoids derived from the cyclooxygenase pathway: Prostaglandin E2 (PGE2), Thromboxane A2 (TXA2), and Prostacyclin (PGI2), compared to controls. In the epileptic samples the level of TXA2 was twice as much the levels of PGI2, while in the control samples the levels of PGI2 were slightly higher than TXA2. Conversely, there were no detectable levels of eicosanoids derived from the lipoxygenase pathway: Leukotriene B4 (LTB4) and Leukotriene C4 (LTC4). The lack of leukotrienes synthesis illustrates that COX pathway is dominant in neocortex of epileptic patients. Our human data are consistent with the results obtained in experimental animal models of epilepsy. The important increase in PGE2 and TXA2 suggests that selective inhibition of prostanoid synthesis or blockage of prostanoid receptors might provide novel antiepileptic strategies in human epilepsy.

Non-invasive continuous EEG-fNIRS recording of temporal lobe seizures - Corrected Proof

2011-11-21

Summary: Purpose: Functional near-infrared spectroscopy (fNIRS) is a technique that allows continuous non-invasive monitoring of tissue oxygenation and haemodynamics in the brain. By using combined EEG-fNIRS recordings, we sought to better understand the pathophysiology of temporal lobe seizures.Results: Nine patients (5 males; mean age 35 years; range 11–56 years) with refractory mesial temporal lobe epilepsy underwent combined EEG-fNIRS recordings. Eight complex partial seizures from 3 patients were successfully recorded. All seizures were associated with significant local and remote haemodynamic changes which outlasted the duration of seizures. Over the epileptogenic temporal lobe, increased oxygenation [increase in cerebral blood volume (CBV) and oxyhaemoglobin (HbO), decrease in deoxyhaemoglobin (HbR)] was followed by a deoxygenated state [increase in HbR]. A similar haemodynamic profile was seen over the contralateral temporal lobe (even without evidence of epileptic propagation) though variations generally had lower amplitudes. Heterogeneous haemodynamic changes in remote frontal and/or parietal areas were also noted early on when epileptic activity was limited to the temporal lobe.Conclusion: EEG-fNIRS reveals complex local and remote oxygenation changes during temporal lobe seizures.

Effects of valproate on glutamate metabolism in rat brain slices: A 13C NMR study - Corrected Proof

Maha El Hage, Gabriel Baverel, Guy Martin — 2011-11-16

Summary: Sodium valproate is a drug widely used for the treatment of epilepsy and mood disorders. We studied the effect of valproate on cerebral energy metabolism by incubating rat brain slices with 5mM [3-13C]glutamate in the absence and the presence of 1mM valproate. Substrate removal and product formation were measured by enzymatic and carbon 13 NMR methods. Fluxes through the enzymatic steps involved were calculated with an original mathematical model. We demonstrate that, in the presence of valproate, glutamate consumption and aspartate accumulation and labeling were inhibited, whereas GABA accumulation and labeling were increased. Consistent with these observations, this drug inhibited the unidirectional flux from glutamate to α-ketoglutarate and fluxes through several enzymes (gamma aminobutyric acid aminotransferase, α-ketoglutarate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, aspartate aminotransferase, malic enzyme, pyruvate dehydrogenase, pyruvate carboxylase and citrate synthase). By contrast, glutamic acid decarboxylase flux was increased. With 2mM glutamate+1mM valproate and with 5mM glutamate+2mM valproate, GABA and aspartate labelings were similarly altered. On the basis of the effects of valproate, it is concluded that our cellular model and our cellular metabolomic approach appear suitable to study the beneficial and adverse interactions of neurotropic compounds with the cerebral metabolic pathways.

Changes in the cannabinoid (CB1) receptor expression level and G-protein activation in kainic acid induced seizures - Corrected Proof

2011-11-14

Summary: It has been known for centuries that exogenous cannabinoids, such as tetrahydrocannabinol have anticonvulsant activity. Recent studies have advanced our understanding of the endogenous cannabinoid system and renewed the interest in cannabinoids as a potential treatment for epilepsy. The endogenous cannabinoid system is rapidly activated after seizure activity but still little is known about the molecular mechanisms underlying the role of the cannabinoid system in epilepsy.In this study epileptiform activity was induced by kainic acid (KA) and effects of the CB1 receptor agonists N-(2-Chloroethyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (ACEA) on G-protein signaling using the agonist-stimulated [35S]GTPγS binding assay were evaluated. Control and KA treated rat hippocampus and cortex membranes were used. Our results showed that the ACEA displayed a high potency and efficacy in stimulating the G-proteins and when compared to the control animals, significant enhancements were observed in tissues from the KA treated animals. Potency and efficacy values were in particular increased in the hippocampus tissues. Furthermore, gene expression levels of the cannabinoid receptor 1 (CB1) receptor and cannabinoid receptor interacting protein 1 (CRIP1) were measured by RT-PCR, where both CB1 and CRIP1 expressions were found to be elevated in the KA treated animals.

Effects of amygdala–hippocampal stimulation on interictal epileptic discharges - Corrected Proof

2011-11-14

Summary: Deep brain stimulation (DBS) of different nuclei is being evaluated as a treatment for epilepsy. While encouraging results have been reported, the effects of changes in stimulation parameters have been poorly studied. Here the effects of changes of pulse waveform in high frequency DBS (130Hz) of the amygdala–hippocampal complex (AH) are presented. These effects were studied on interictal epileptic discharge rates (IEDRs).AH-DBS was implemented with biphasic versus pseudo monophasic charge balanced pulses, in two groups of patients: six with temporal lobe epilepsy (TLE) associated with hippocampal sclerosis (HS) and six with non lesional (NLES) temporal epilepsy.In patients with HS, IEDRs were significantly reduced with AH-DBS applied with biphasic pulses in comparison with monophasic pulse. IEDRs were significantly reduced in only two patients with NLES independently to stimulus waveform.Comparison to long-term seizure outcome suggests that IEDRs could be used as a neurophysiological marker of chronic AH-DBS and they suggest that the waveform of the electrical stimuli can play a major role in DBS. We concluded that biphasic stimuli are more efficient than pseudo monophasic pulses in AH-DBS in patients with HS. In patients with NLES epilepsy, other parameters relevant for efficacy of DBS remain to be determined.