Epilepsy Research - Articles in Press

Variability of sclerosis along the longitudinal hippocampal axis in epilepsy: A post mortem study - Corrected Proof

2012-05-18

Summary: Detailed neuropathological studies of the extent of hippocampal sclerosis (HS) in epilepsy along the longitudinal axis of the hippocampus are lacking. Neuroimaging studies of patients with temporal lobe epilepsy support that sclerosis is not always localised. The extent of HS is of relevance to surgical planning and poor outcomes may relate to residual HS in the posterior remnant. In 10 post mortems from patients with long histories of drug refractory epilepsy and 3 controls we systematically sampled the left and right hippocampus at seven coronal anatomical levels along the body to the tail. We quantified neuronal densities in CA1 and CA4 subfields at each level using Cresyl Violet (CV), calretinin (CR), calbindin (CB) and Neuropeptide Y (NPY) immunohistochemistry. In the dentate gyrus we graded the extent of granule cell dispersion, patterns of CB expression, and synaptic reorganisation with CR and NPY at each level. We identified four patterns of HS based on patterns of pyramidal and interneuronal loss and dentate gyrus reorganisation between sides and levels as follows: (1) symmetrical HS with anterior–posterior (AP) gradient, (2) symmetrical HS without AP gradient, (3) asymmetrical HS with AP gradient and (4) asymmetrical cases without AP gradient. We confirmed in this series that HS can extend into the tail. The patterns of sclerosis (classical versus atypical or none) were consistent between all levels in less than a third of cases. In conclusion, this series highlights the variability of HS along the longitudinal axis. Further studies are required to identify factors that lead to focal versus diffuse HS.

Discontinuation of antiepileptic drugs after successful epilepsy surgery. A Canadian survey - Corrected Proof

2012-05-17

Summary: Introduction: To identify the perceived practice among Canadian epileptologists regarding discontinuation of antiepileptic drugs (AEDs) following successful resective surgery for temporal and extratemporal surgery.Methods: We performed a survey of pediatric and adult epileptologists in Canada, using a 77-item questionnaire to explore attitudes, timing, rate of withdrawal, and factors contributing to the decision to withdraw AEDs after successful epilepsy surgery. Surveys were mailed with a postage-paid return envelope. Two subsequent surveys were mailed to non-respondents at 15 days intervals. All procedures received institutional review board approval.Results: Surveys were sent to 82 epileptologists in all the Canadian provinces. Sixty-six physicians answered the survey (80.5%), representing all epilepsy centers across Canada. The minimum seizure free period required after epilepsy surgery before withdrawing AEDs, varied substantially among responders: <6 months in 10%, 6–11 months in 21%, >1 year in 50%, >2 years in 12%, >2 years in 3% after. The most important factors influencing the decision to withdraw AEDs a negative EEG before discontinuation (71%), patients’ preferences (78%) and the presence of unilateral mesial temporal sclerosis (70%). The most important factors against reduction were the following: patients’ wishes to resume driving (67%), focal (65%) or generalized (78%) epileptiform activity on EEG after surgery, persistent isolated auras (78%), any seizures after hospital discharge (81%), and presurgical multifocal/bilateral/diffuse findings (78%).Discussion: Canadian epileptologists indicated that AED levels, EEG and MRI are typically done before discontinuing AEDs. Generally, a good candidate for stopping AEDs has focal pathology, is completely seizure free, had an anterior temporal lobe resection, complete resection of seizure focus, and has no epileptiform discharges on postoperative EEG. The data pertaining to self-reported practice styles, and actual practice may differ.

Pilocarpine-induced status epilepticus increases Homer1a and changes mGluR5 expression - Corrected Proof

2012-05-16

Summary: Homer1a regulates expression of group I metabotropic glutamate receptors type I (mGluR1 and mGluR5) and is involved in neuronal plasticity. It has been reported that Homer1a expression is upregulated in the kindling model and hypothesized to act as an anticonvulsant. In the present work, we investigated whether pilocarpine-induced status epilepticus (SE) would alter Homer1a and mGluR5 expression in hippocampus. Adult rats were subjected to pilocarpine-model and analyzed at 2h, 8h, 24h and 7 d following SE. mRNA analysis showed the highest expression of Homer1a at 8h after SE onset, while immunohistochemistry demonstrated that Homer1a protein expression was significantly increased in hippocampus, amygdala and piriform and entorhinal cortices at 24h after SE onset when compared to control animals. The increased Homer1a expression coincided with a significant decrease of mGluR5 protein expression in amygdala and piriform and entorhinal cortices. The data suggest that during the critical periods of epileptogenesis, overexpression of Homer1a occurs to counteract hyperexcitability and thus Homer1a may be a molecular target in the treatment of epilepsy.

Acute encephalopathy with a novel point mutation in the SCN2A gene - Corrected Proof

2012-05-16

Summary: Mutations of the neuronal voltage-gated sodium channel alpha subunit type II (SCN2A) cause various epileptic syndromes, but have never been reported in association with acute encephalopathy. To validate the involvement of SCN2A mutations in acute encephalopathy, we screened 25 patients and found a novel missense mutation (Met1128Thr) in a patient with acute encephalitis with refractory, repetitive partial seizures (AERRPS). This finding suggests that SCN2A mutation is a predisposing factor for acute encephalopathy.

Stereotactic radiofrequency amygdalohippocampectomy for the treatment of temporal lobe epilepsy: Do good neuropsychological and seizure outcomes correlate with hippocampal volume reduction? - Corrected Proof

2012-05-16

Summary: Temporal lobe surgery bears the risk of a decline of neuropsychological functions. Stereotactic radiofrequency amygdalohippocampectomy (SAHE) represents an alternative to mesial temporal lobe epilepsy (MTLE) surgery. This study compared neuropsychological results with MRI volumetry of the residual hippocampus.We included 35 patients with drug-resistant MTLE treated by SAHE. MRI volumetry and neuropsychological examinations were performed before and 1 year after SAHE. Each year after SAHE clinical seizure outcome was assessed.One year after SAHE 77% of patients were assessed as Engel Class I, 14% of patients was classified as Engel II and in 9% of patients treatment failed. Two years after SAHE 76% of subjects were classified as Engel Class I, 15% of patients was assessed as Engel II and in 9% of patients treatment failed. Hippocampal volume reduction was 58±17% on the left and 54±27% on the right side. One year after SAHE, intelligence quotients of treated patients increased. Patients showed significant improvement in verbal memory (p=0.039) and the semantic long-term memory subtest (LTM) (p=0.003). Patients treated on the right side improved in verbal memory, delayed recall and LTM. No changes in memory were found in patients treated on the left side. There was a trend between the larger extent of the hippocampal reduction and improvement in visual memory in speech-side operated.

Costs, work absence, and adherence in patients with partial onset seizures prescribed gabapentin or pregabalin - Corrected Proof

Nathan L. Kleinman, Alesia Sadosky, Jaren Seid, Roy C. Martin, David M. Labiner — 2012-05-16

Summary: Background/objective: Few studies have examined cost of illness of epileptic partial onset seizures (POS) from the employer perspective or compared users of gabapentin and pregabalin in treatment of POS. This study compares pharmacotherapy, direct/indirect costs, and work absences of patients with POS newly started on gabapentin or pregabalin.Methods: Data from employees and dependent spouses with POS starting treatment (index date) with either gabapentin or pregabalin were analyzed. Patients were required to have at least 6 months of health plan enrollment pre- and post-index. Regression modeling compared medical and prescription costs, sick leave (SL), short-term disability (STD), workers’ compensation (WC) costs and absence days during the 6-month post-index period. Persistence, adherence (percent of days covered), impact on adherence of copay, and copay as a percent of salary were modeled.Results: Semiannual medical, drug, SL, STD, and WC costs for gabapentin vs. pregabalin cohorts were $10,306 vs. $9186, $2353 vs. $3387 (P=0.01), $552 vs. $342, $1280 vs. $580, and $170 vs. $30, respectively. SL days (10.8 vs. 1.5, P=0.04) and STD days (9.8 vs. 6.2) were lower in the pregabalin cohort. Persistence (median 94 vs. 70 days) and proportion with ≥80% adherence (30% vs. 15%, P=0.049) were greater in the pregabalin cohort. Adherence decreased as copay or copay as a percent of salary increased beyond specific levels in both cohorts.Conclusion: Despite higher acquisition costs for branded pregabalin over generic gabapentin, overall direct and indirect costs trended lower for pregabalin users. Additionally, pregabalin users had significantly fewer sick leave days and significantly higher adherence rates than gabapentin users.

Effects of adrenal dysfunction and high-dose adrenocorticotropic hormone on NMDA-induced spasm seizures in young Wistar rats - Corrected Proof

Ya-Jie Wang, Ying Zhang, Xian-Hong Liang, Guang Yang, Li-Ping Zou — 2012-05-14

Summary: Infantile spasms (IS) is a devastating epilepsy syndrome treated with adrenocorticotropic hormone (ACTH). To demonstrate the effects of adrenal dysfunction, adrenalectomy (ADX) and N-methyl-d-aspartate (NMDA)-induced rat model studies of IS were performed. The latency of the seizure in the ADX group decreased and the severity of seizures increased significantly. Hippocampal corticotropin-releasing hormone (CRH) mRNA was overexpressed in ADX rats. After ACTH administration, the latency increased and the severity of seizures decreased significantly. ADX increased seizure susceptibility of the rats to NMDA. Pretreatment with a single high dose of ACTH caused an obvious reduction in susceptibility to NMDA-induced seizures and suppressed CRH mRNA expression. These findings are especially useful for IS patients with adrenal diseases and worthy of further clinical study.

Failure to find association between febrile seizures and SCN1A rs3812718 polymorphism in south Indian patients with mesial temporal lobe epilepsy and hippocampal sclerosis - Corrected Proof

2012-05-14

Summary: We compared the allele and genotype frequencies of SCN1A SNP rs3812718 between patients with MTLE-HS of south Indian ancestry with and without febrile seizures (FS) and with ethnically matched controls. While we observed no significant difference in allele and genotype frequencies of rs3812718 between MTLE-HS patients with and without FS, A allele and AA genotype were overrepresented in MTLE-HS patients when compared to controls. We conclude that in the population studied, although rs3812718 polymorphism increases the susceptibility to MTLE-HS, this is not by increasing the susceptibility to FS.

Behavioral, cognitive, and safety profile of 2-deoxy-2-glucose (2DG) in adult rats - Corrected Proof

2012-05-14

Summary: 2-Deoxy-d-glucose (2DG), a glucose analog that transiently inhibits glycolysis, has anticonvulsant and antiepileptic disease-modifying properties in experimental in vivo models of seizures and epilepsy. Here we evaluated the effects of 2DG across the range of doses (50–500mg/kg i.p.) shown previously to exert anticonvulsant and antiepileptic effects in rats, on spatial learning and memory using the Morris water maze and on exploratory behavior using the open field test. For water maze testing, both acute and chronic protocols were tested. For acute testing, 2DG was injected for 15min prior to the water maze trial only on testing days. For chronic testing, 2DG was injected daily for 14days before water maze testing began. Neither protocol altered the latency to platform acquisition or retention of platform location by the probe test. For open field testing, 2DG was given at doses of 50–250mg/kg 15 or 30min prior to testing on each testing day. When given 30min prior to testing, exploratory activity in the open field was transiently and reversibly decreased by 2DG at doses of 250mg/kg/day but there were no effects on open field activity at 50mg/kg/day. When given 15min prior to testing, 2DG decreased exploratory activity in a dose-dependent fashion at both 50 and 250mg/kg. There were no toxic effects of 2DG at doses of 500mg/kg/day on body weight or general health. In summary, 2DG is well tolerated at doses associated with anticonvulsant and antiepileptic effects, supporting its potential as an anticonvulsant and antiepileptic agent with a novel mechanism of action.

Do gene polymorphism in IL-1β, TNF-α and IL-6 influence therapeutic response in patients with drug refractory epilepsy? - Corrected Proof

2012-05-14

Summary: Purpose: Pro-inflammatory cytokines may play an important pathophysiological role in patients with epilepsy. To understand the role of genes encoding pro-inflammatory cytokines in epilepsy, this study aimed to evaluate the polymorphisms of the promoter regions of IL-1β-511C>T (rs16944), TNF-α–308G>A (rs1800629) and IL-6-174G>C (rs1800795) genes and to look into the interaction between these genes in influencing seizure susceptibility, seizure frequency and response to therapy.Methods: The comparative frequency of polymorphism was determined in rs16944, rs1800629 and rs1800795 using PCR-RFLP in a group of 120 persons with epilepsy (PWE) and 110 ethnically matched healthy subjects of comparable age and sex in the North Indian population.Results: Alleles and genotypes of rs16944, rs1800629 and rs1800795 were not found to influence the odds ratio of having susceptibility to epilepsy. Also gene–gene interaction of possible nine combinations of these genes did not show any positive association with epilepsy. The genotype and allelic frequency of rs1800795 showed a significant association (p<0.05) in seizure frequency (number of seizures/6-months) and drug refractory epilepsy. However, the genotype and allelic frequency of rs16944 and rs1800629 were not found to have such effect.Conclusion: This study demonstrates that the rs16944, rs1800629 and rs1800795 polymorphism does not act as a strong susceptibility factor for epilepsy in North Indian population. The genotypic association of rs1800795 with seizure frequency and drug-refractory epilepsy raises the issue that a specific set of polymorphic genes can influence seizures and therapeutic response in epilepsy.

Spectral analysis of bilateral or alternate-site kindling-induced afterdischarges in the rabbit hippocampi - Corrected Proof

Komei Tsuchiya, Shinichi Kogure — 2012-05-11

Summary: Kindling is one of the popular animal models of temporal lobe epilepsy. In the present study following the previous results obtained using unilateral hippocampal kindling (UK), we performed spectral analysis of bilateral or alternate-site kindling-induced afterdischarges (ADs) in the rabbit hippocampi. Eight and ten adult rabbits were used for bilateral kindling (BK) and alternate-site kindling (AK), respectively. Kindling stimuli consisted of a train of biphasic pulses (1ms duration each) of 50Hz for 1s, with suprathreshold intensity for AD. The stimulations were applied simultaneously to the bilateral hippocampi in the BK and were delivered to the right and left hippocampus once every 24h in the AK. Motor responses were classified into five stages according to the conventional criteria. All animals in BK as well as AK developed stage 5 convulsions. This contrasts to the result of UK (kindled: 50%; incomplete: 50%). We normalized power spectral density (PSD) and monitored the changes in the proportion of lower frequency band component (LFB: 0–9Hz) and the higher frequency band (HFB: 12–30Hz). BK animals showed a significantly large decrement (0.5 times, p<0.01) in LFB component at the final stage compared to the initial stage, but a very large increment (4.7 times) in HFB component. Likewise, AK animals exhibited a significantly large decrement (0.6 times, p<0.01) in LFB component at the final stage, but a very large increment (3.6 times) in HFB component. Correlation analyses were performed between the HFB component and AD duration, interictal discharge frequency, and behavioral stages during kindling progression. Very strong positive correlations were found in both kindling animals. Chronological spectral analysis of seizure discharges, resulting in a pattern of LFB decrement accompanied by HFB increment, is a convenient tool to investigate epileptic disorders and diagnose epileptic states.

5-HT3 receptor mediates the dose-dependent effects of citalopram on pentylenetetrazole-induced clonic seizure in mice: Involvement of nitric oxide - Corrected Proof

2012-05-11

Summary: Citalopram is a selective serotonin reuptake inhibitor (SSRI), widely used in the treatment of depressive disorders. It has been shown that citalopram affects seizure susceptibility. Although the exact mechanism of these effects are not yet fully understood, recent data suggest that 5HT3 receptors and nitric oxide (NO) might participate in the central effects of SSRIs. In this study in a mouse model of clonic seizure induced by pentylenetetrazole we investigated whether 5-HT3 receptors are involved in the effects of citalopram on seizure threshold. In our experiments, citalopram at lower doses (0.5 and 1mg/kg, i.p) significantly increased the seizure threshold and at higher doses (≥25mg/kg) showed proconvulsive effects. Moreover, mCPBG (a 5-HT3 receptor agonist) at low and non-effective doses augmented while non-effective doses of tropisetron prevented the anticonvulsive properties of citalopram.On the other hand, Low doses of nitric oxide synthase inhibitors l-NAME and 7-NI alone or in combination with lower doses of 5-HT3 receptor agonist enhanced the anticonvulsive property of citalopram, while l-arginine (NO precursor) alone or in combination with tropisetron blocked the protective effect of citalopram.In summary, our findings demonstrate that 5-HT3 receptor mediates the anticonvulsant properties of low doses of citalopram, whereas it seems that the proconvulsive effect is mostly mediated through the NO pathway and can be totally blocked by NOS inhibitors. This could propose a new approach toward finding the mechanism of citalopram activity, curtailing the adverse effects of citalopram and perhaps managing the convulsions as a vicious consequence of citalopram overdose.

Characterization of status epilepticus induced by two organophosphates in rats - Corrected Proof

2012-05-11

Summary: Organophosphates (OPs) inhibit the enzyme cholinesterase and cause accumulation of acetylcholine, and are known to cause seizures and status epilepticus (SE) in humans. The animal models of SE caused by organophosphate analogs of insecticides are not well characterized. SE caused by OPs paraoxon and diisopropyl fluorophosphate (DFP) in rats was characterized by electroencephalogram (EEG), behavioral observations and response to treatment with the benzodiazepine diazepam administered at various stages of SE. A method for SE induction using intrahippocampal infusion of paraoxon was also tested. Infusion of 200nmol paraoxon into the hippocampus caused electrographic seizures in 43/52 (82.7%) animals tested; and of these animals, 14/43 (30%) had self-sustaining seizures that lasted 4–18h after the end of paraoxon infusion. SE was also induced by peripheral subcutaneous injection of diisopropyl fluorophosphate (DFP, 1.25mg/kg) or paraoxon (1.00mg/kg) to rats pretreated with atropine (2mg/kg) and 2-pralidoxime (2-PAM, 50mg/kg) 30min prior to OP injection. SE occurred in 78% paraoxon-treated animals and in 79% of DFP-treated animals. Diazepam (10mg/kg) was administered 10min and 30min after the onset of continuous EEG seizures induced by paraoxon and it terminated SE in a majority of animals at both time points. DFP-induced SE was terminated in 60% animals when diazepam was administered 10min after the onset of continuous EEG seizure activity but diazepam did not terminate SE in any animal when it was administered 30min after the onset of continuous seizures. These studies demonstrate that both paraoxon and DFP can induce SE in rats but refractoriness to diazepam is a feature of DFP induced SE.

A parent's perspective on dietary treatments for epilepsy - Corrected Proof

Emma Williams, Jim Abrahams, Alison Maguire, Gerry Harris — 2012-05-10

Summary: Four families gave their accounts of the how Dietary Therapies had impacted on their lives and that of their children who suffered with intractable epilepsy. All with very different stories, experiences and outcomes.Niamh was diagnosed with migrating partial epilepsy of infancy with an underlying metabolic problem was fed via her jejunostomy and the parents overcame every obstacle in their path to have as much time with their daughter as possible. Niamh's family now work with the Matthew's Friends organization to promote dietary awareness and make these treatments available for all those who need them.Carson, who with infantile spasms, was able to access the diet as her first line treatment without any medication being taken. Carson is the inspiration behind the Carson Harris Foundation and her family promote dietary awareness in USA.Matthew, with Dravet Syndrome, was refused for the diet for years, suffered brain damage and was put on a whole host of unsuitable medications before finally managing to get the diet. The diet proved his saving but what could have been the outcome if the family had got the diet when it was first asked for? Matthew is the inspiration behind the Matthew's Friends – Dietary Treatments for Epilepsy organization.Charlie, suffered with intractable epilepsy, was put on a whole host of medications that did not work and underwent brain surgery before finally getting to the diet that cured him of his epilepsy. He is the inspiration behind The Charlie Foundation in the USA and his father, Jim Abrahams made the film ‘First Do No Harm’ which told the true story of a child who was cured of his epilepsy using the Ketogenic Diet, just like Charlie and thousands upon thousands of other children around the world.The Charlie Foundation and Matthew's Friends work side by side in the promotion, education and funding of these treatments and have asked other family organizations to work with them so that families of the future will not have to struggle to gain the information that they so desperately need. Families have the right to make an informed choice and these organizations work together in order to be able to provide this.

Unprovoked seizures in multiple sclerosis and systemic lupus erythematosus: A population-based case–control study - Corrected Proof

Cecilia Adelöw, Tomas Andersson, Anders Ahlbom, Torbjörn Tomson — 2012-05-10

Summary: To study the risk of developing unprovoked seizures among patients with multiple sclerosis (MS) and systemic lupus erythematosus (SLE), we used 1885 new onset seizure cases, 15,080 controls and defined exposure as a hospital discharge diagnosis of MS or SLE. The odds ratio with 95% confidence interval was 3.7 (CI 1.2–11.0) for MS and 8.0 (2.2–30.0) for SLE, suggesting an increased risk of unprovoked seizures in patients with both these diagnoses.

Metabolic brain PET pattern underlying hyperkinetic seizures - Corrected Proof

Eric Guedj, Aileen McGonigal, Lisa Vaugier, Olivier Mundler, Fabrice Bartolomei — 2012-05-03

Summary: This study aims to contribute to the identification of selective brain regions involved in hyperkinetic behaviors.We studied the whole-brain voxel-based interictal metabolic 18FDG-PET pattern of 23 patients with hyperkinetic seizures, in comparison with both 15 healthy subjects similar for age and gender, and 23 patients without hyperkinetic seizures. Patients were in particular similar for the localization of the epileptogenic zone, this having been defined using stereoelectroencephalography (SEEG) when clinically indicated (15/23 patients with hyperkinetic seizures and 13/23 patients without hyperkinetic seizures).Using conjunction voxel-based analysis, patients with hyperkinetic seizures exhibited significant hypometabolism within bilateral midbrain and the right caudate head, in comparison both to healthy subjects (p<0.05, FDR-corrected for the voxel) and to patients without hyperkinetic seizures (p<0.0167, uncorrected for the voxel). Findings were secondarily confirmed separately in each subgroup of patients with frontal, temporal or posterior epilepsy.These findings argue for a specific subcortical metabolic impairment in patients with hyperkinetic seizures, within brain structures supposed to be involved in the generation of primitive motor programs.

Rare protein sequence variation in SV2A gene does not affect response to levetiracetam - Corrected Proof

2012-05-01

Summary: Levetiracetam, a broad spectrum antiepileptic drug, binds to membrane protein SV2A. The protein coding region of SV2A was sequenced in 158 patients with focal or generalized epilepsies divided into three groups based on their response to levetiracetam: responders (>75% decrease), exacerbators (50% increase) and non-responders. Nonsynonymous coding variation within SV2A was extremely rare, suggesting that rare variation is not likely to account for the individual differences in response to levetiracetam.

Investigation of prevalence, clinical characteristics and management of epilepsy in Yueyang city of China by a door-to-door survey - Corrected Proof

2012-04-30

Summary: Background: The aim of this study was to establish the prevalence rate, types and causes of epilepsy, and information on treatment gap of epilepsy in Yueyang city, and to evaluate the diagnosis and treatment status of these patients.Methods: A door-to-door epidemiological survey on epilepsy was conducted by random cluster sampling among the urban and rural populations of Yueyang city, Hunan province, China. The screening questionnaire for epilepsy used in this study was adapted from the WHO and ICBERG standard screening questionnaires. All peoples diagnosed with epilepsy or suspected to be epileptic during screening were rechecked by neurologists. Clinical and treatment data were collected from patients with definitive diagnosis.Results: A total of 32059 peoples were screened. 143 peoples were diagnosed with epilepsy. Lifetime prevalence rate was 4.5‰ and 1-year active prevalence rate was 2.8‰. Prevalence rates were higher in male and rural areas. Secondary generalized tonic–clonic seizure prevailed over other seizure types in frequency. 93.4% of the patients with active epilepsy had treatment gaps without receiving standard and regular antiepileptic drugs before the survey.Conclusions: The prevalence rate of epilepsy in Yueyang is lower than in other areas of China and Asia. The large amount of patients with treatment gaps indicates an urgent need for a rational intervention strategy.

Resting motor threshold in idiopathic generalized epilepsies: A systematic review with meta-analysis - Corrected Proof

2012-04-30

Summary: Resting motor threshold (rMT) assessed by means of Transcranial Magnetic Stimulation (TMS) is thought to reflect trans-synaptic excitability of cortico-spinal neurons. TMS studies reporting rMT in idiopathic generalized epilepsies (IGEs) yielded discrepant results, so that it is difficult to draw a definitive conclusion on cortico-spinal excitability in IGEs by simple summation of previous results regarding this measure. Our purpose was to carry out a systematic review and a meta-analysis of studies evaluating rMT values obtained during single-pulse TMS in patients with IGEs. Controlled studies measuring rMT by single-pulse TMS in drug-naive patients older than 12 years affected by IGEs were systematically reviewed. rMT values were assessed calculating mean difference and odds ratio with 95% confidence intervals (CI). Fourteen trials (265 epileptic patients and 424 controls) were included. Patients with juvenile myoclonic epilepsy (JME) have a statistically significant lower rMT compared with controls (mean difference: −6.78; 95% CI −10.55 to −3.00); when considering all subtypes of IGEs and IGEs other than JME no statistically significant differences were found. Overall considered, the results are indicative of a cortico-spinal hyper-excitability in JME, providing not enough evidence for motor hyper-excitability in other subtypes of IGE. The considerable variability across studies probably reflects the presence of relevant clinical and methodological heterogeneity, and higher temporal variability among rMT measurements over time, related to unstable cortical excitability in these patients.

Risk factors for hyperammonemia associated with valproic acid therapy in adult epilepsy patients - Corrected Proof

2012-04-30

Summary: Hyperammonemia is one of the side effects of treatment with valproic acid (VPA), but the risk factors and mechanisms involved remain obscure. This study analyzed the risk factors for hyperammonemia associated with VPA therapy in adult epilepsy patients.A retrospective analysis of 2724 Japanese patients (1217 males and 1507 females aged from 16 to 76years) treated with VPA between January 2006 and December 2010 were analyzed.The ammonia level increased markedly in a VPA dose-dependent manner, and was significantly elevated in patients who also used hepatic enzyme inducers such as phenytoin (PHT), phenobarbital (PB), carbamazepine (CBZ), and combinations of these drugs. When a blood ammonia level exceeding 200μg/dl was defined as hyperammonemia, the risk factors for hyperammonemia according to multiple regression analysis were a VPA dose >20mg/kg/day (odds ratio (OR): 4.1; 95% confidence interval (CI): 1.6–10.8) and concomitant use of PHT (OR: 11.0; 95% CI: 3.1–38.7), concomitant PB (OR: 4.3; 95% CI: 1.0–17.9), concomitant CBZ (OR: 2.8; 95% CI: 0.6–11.9), and concomitant topiramate (OR: 2.8; 95% CI: 1.2–6.5). Regimens containing multiple inducers were associated with an increased risk of hyperammonemia.Identification of risk factors for hyperammonemia associated with VPA therapy can help to minimize side effects during its clinical use.

Epilepsy surgery can help many more adult patients with intractable seizures - Corrected Proof

2012-04-30

Summary: Purpose: To quantify underreferral for epilepsy surgery in The Netherlands, and reveal its causes.Methods: Cross-sectional sample of medical files of epilepsy patients from eight general hospitals and two tertiary care epilepsy centers. We selected patients, not seizure free despite 3 or more anti-epileptic drugs. Medical records were judged by an expert panel whether referral should have been done according to published Dutch guidelines. The treating neurologists were confronted with the panel's judgement.Key findings: In a sample of 1424 patients, 69 had been referred; another 265 were intractable and not referred; 139 of these 265 patients should have been according to the panel. In 89 of 139 patients, the neurologist gave additional arguments for not referring, mainly the physician's estimate of (low) seizure burden or the patient's psychological condition. In 66 of 89 cases, this could not convince the panel. Attitudes were similar in secondary and tertiary treatment centers. Multivariable data analysis showed independent predictors of incorrectly, versus correctly, not referred patients.Significance: Substantial underreferral exists in The Netherlands, withholding refractory patients seizure freedom. Adherence to existing guidelines, better prioritizing of surgical work-up, and unprejudiced discussion of surgical treatment with the patient, could lead to 2–2.5 times more referrals.

Cerebro-cerebellar functional connectivity profile of an epilepsy patient with periventricular nodular heterotopia - Corrected Proof

2012-04-30

Summary: Periventricular nodular heterotopia (PNH) is a rare malformation of cortical development often associated with drug resistant focal onset epilepsy. The link between nodules and neocortex have been demonstrated with depth electrodes investigations showing that seizures may arise from both structures. In the last years fMRI resting-state (fMRI-RS) have received a surge in interest due to its capability to track non-invasively physiological and pathological relevant differences in brain network organization. We performed a cerebro-cerebellar voxel-wise and region-of-interest resting state fMRI (RS-fMRI) functional connectivity analysis in a seizure-free epilepsy patient with a PNH in the right temporal horn. Our finding confirms a spontaneous synchronization between PNH and its surrounding cortex, specifically in the inferior temporal, fusiform and occipital gyrus. We also found a significant connectivity with bilateral cerebellum, more intense and widespread on the PNH cerebellar contralateral lobule. RS-fMRI confirmed its potential as a promising tool for non-invasive mapping of cortical and subcortical brain functional organization.

Serum magnesium and sudden unexpected death in epilepsy: A curious clinical sign or a necessity of life - Corrected Proof

Fulvio A. Scorza, Esper A. Cavalheiro, Roberta M. Cysneiros, Ricardo M. Arida — 2012-04-30

We read with interest the innovative article titled “Can magnesium supplementation reduce seizures in people with epilepsy? A hypothesis” by Yuen and Sander published in the March issue of Epilepsy Research (). Given the dearth of published data concerning reduction of seizures in people with epilepsy through magnesium supplementation, we applaud Dr. Yuen and Sander for pursuing this topic. Moreover, this proposal cited above also deserves a reflection with respect to sudden unexpected death in epilepsy (SUDEP).

Levetiracetam extended release conversion to monotherapy for the treatment of patients with partial-onset seizures: A double-blind, randomised, multicentre, historical control study - Corrected Proof

2012-04-20

Summary: This double-blind, randomised, multicentre, conversion to monotherapy, historical control study (N01280; NCT00419094) evaluated the efficacy, safety and tolerability of levetiracetam extended release (LEV XR) 2000mg/day once daily for the treatment of patients with partial-onset seizures compared with a historical control. Patients aged 12–75 years with 2–40 partial-onset seizures per 4 weeks, taking 1–2 antiepileptic drugs (AEDs) and receiving a stable dosage for ≥4 weeks prior to screening were randomised in a 3:1 ratio to LEV XR 2000 or 1000mg/day. The study comprised baseline (8 weeks), LEV XR up-titration (2 weeks), baseline AED tapering (6 weeks), LEV XR monotherapy (10 weeks), and entry into open-label follow-up study or down-titration (1 week). The primary efficacy variable was the cumulative exit rate at Day 112 due to predefined exit criteria compared with the historical control. Of the 171 patients randomised to LEV XR 2000mg/day and 57 randomised to 1000mg/day, 141 (82.5%) and 50 (87.7%) completed the study. The cumulative exit rate for patients on LEV XR 2000mg/day (0.375 [95% CI 0.297, 0.453]) was significantly lower than historical control (0.653). Both LEV doses were well tolerated. The most common adverse events during the treatment period were somnolence (21.9%), headache (19.7%) and convulsion (14.9%).

The antidepressant drug fluoxetine inhibits persistent sodium currents and seizure-like events - Corrected Proof

Kajsa M. Igelström, Philip M. Heyward — 2012-04-20

Summary: The antidepressant drug fluoxetine (FLX) has been shown to exert antiepileptic effects in several animal models, but mixed preclinical findings and occasional reports of proconvulsant effects have led to hesitation towards its use in epileptic people. Despite being developed as a selective serotonin reuptake inhibitor, FLX has numerous other targets in the brain. One of the proposed targets is the neuronal sodium channel, which is inhibited by many existing antiepileptic drugs. In this study, we used electrophysiological methods in a brain slice model of seizures to test for anticonvulsant and Na+ channel-blocking effects of FLX. This approach allowed us to use a single biological system to study the effects of FLX on (1) epileptiform activity, (2) Na+-dependent action potential generation, and (3) the persistent Na+ current (INaP). We found that FLX was anticonvulsant in a dose- and time-dependent manner, and that this action was accompanied by strong INaP inhibition and impairment of repetitive firing. These findings suggest that the effect of FLX on active membrane properties is similar to that of many antiepileptic drugs, and that this action may contribute to anticonvulsant effects.

Retigabine as adjunctive therapy in adults with partial-onset seizures: Integrated analysis of three pivotal controlled trials - Corrected Proof

2012-04-18

Summary: We assessed the efficacy and tolerability of retigabine (RTG; international non-proprietary name)/ezogabine (EZG; US adopted name) as adjunctive therapy in adults with partial-onset seizures in an integrated analysis of three trials. Studies 205, 301 (NCT00232596), and 302 (NCT00235755) were randomized, double-blind, placebo-controlled studies in adults having ≥4 partial-onset seizures per 28 days and receiving 1–3 antiepileptic drugs with/without vagus nerve stimulator. Patients underwent titration to RTG/EZG 600, 900, or 1200mg/day or to placebo followed by 8 or 12 weeks maintenance. For efficacy analyses, placebo was compared with RTG/EZG 600 and 900mg/day in Studies 205 and 302, and RTG/EZG 1200mg/day in Studies 205 and 301. Responder rates (≥50% reduction in baseline seizure frequency) were 35% and 45% for RTG/EZG 600 and 900mg/day, respectively (placebo=21%; p<0.001), and 50% for RTG/EZG 1200mg/day (placebo=24%, p<0.001). Reductions in 28-day total partial-seizure frequency (medians: placebo=14%; 600mg/day=26%, p=0.003; 900mg/day=37%, p<0.001; placebo=15%; 1200mg/day=39%, p<0.001) were significantly greater with all RTG/EZG doses vs. placebo from baseline to the double-blind phase, and similarly during the maintenance phase. The most commonly reported (>10%) treatment-emergent adverse events were dizziness, somnolence, headache, and fatigue. RTG/EZG demonstrated efficacy and was generally tolerated as adjunctive therapy in adults with partial-onset seizures in this integrated analysis.

A comparison of quality of life in adolescents with epilepsy or asthma using the Short-Form Health Survey (SF-36) - Corrected Proof

Ji Wang, Yi Wang, Li Bo Wang, Hui Xu, Xiao-lei Zhang — 2012-04-18

Summary: Purpose: To compare the quality of life (QOL) in adolescents with epilepsy or asthma.Methods: Eighty-five epileptic adolescents, 81 adolescents with asthma and 71 normal controls were recruited from the Affiliated Children's Hospital of FuDan University from June, 2007 to December, 2007. These adolescents received the Medical Outcomes Study 36-Item Short-Form Health Survey (MOS F-36) in order to evaluate QOL.Results: Although the onset age for adolescents with asthma was younger (P=0.032), there were no significant differences in clinical characteristics between adolescents with epilepsy and asthma. The results of MOS SF-36 demonstrated the following: (1) For the adolescents with epilepsy, the total QOL score and sub-scores for 8 items were significantly different between epilepsy patients and healthy controls, and the total QOL score and sub-scores for 4 items were significantly different between controlled and uncontrolled epilepsy groups; (2) for the adolescents with asthma, the total QOL score and sub-scores for 4 items were significantly different between asthma patients and healthy controls, and the total QOL score and sub-scores for 4 items were significantly different between controlled and uncontrolled asthma groups; (3) the QOL of adolescents with epilepsy was poorer than that of the adolescents with asthma regardless of the remission stage and disease stage; (4) the emotional and mental health of adolescents with epilepsy was inferior to that of adolescents with asthma.Conclusions: The QOL of adolescents with chronic paroxysmal diseases including epilepsy and asthma deserves close attention and should be included as a key parameter when evaluating disease status.

Clinical evidence for the utility of movement compensation algorithm in magnetoencephalography: Successful localization during focal seizure - Corrected Proof

2012-04-16

Summary: A movement compensation (MC) algorithm may help to evaluate seizure focus in magnetoencephalography despite patient movement. We report a boy whose ictal MEG focus was localized to the same sublobar region before and after head turning when MC was applied, but which was erroneously localized to a different area without MC. This study provides the first clinical evidence for utility of MC in magnetoencephalography for localizing focal seizures.

Metoprine induced behavioral modifications and brain regional histamine increase in WAG/Rij and Wistar rats - Corrected Proof

2012-04-16

Summary: The effects of metoprine, an inhibitor of histamine N-methyltransferase, on open field activity and brain regional histamine (HA) content were examined in rats with mixed, absence and audiogenic, epilepsy (WAG/Rij-AGS), rats with audiogenic epilepsy (Wistar-AGS) and in non-epileptic control rats (Wistar-nAGS). HA content was increased by metoprine (20mg/kg, i.p.) in the cortex, striatum, thalamus, hypothalamus and hippocampus of the rats from all three tested groups. However, WAG/Rij rats showed a lower rate of metoprine-induced HA accumulation in the striatum and thalamus than Wistar rats. For the open field test, the main effect of metoprine (20mg/kg, i.p.) was a general increase of locomotor activity although distinctive features, such as hyperlocomotion and exaggerated sniffing, were characteristic for the epileptic rats (WAG/Rij-AGS and Wistar-AGS, respectively). Individual rats from all the groups showed stereotyped behavior of shuttle type and head bobbing. Electroencephalographic data obtained in WAG/Rij-AGS rats confirmed that metoprine-induced behavioral activation was accompanied by suppression of spike-wave discharges, the main hallmark of absence seizures. Taken together, these results show that inhibition of the histamine catabolism may induce motor activation of particular patterns in epileptic rats and provoke stereotyped behavior.

Seizures and multiple sclerosis in Chinese patients: A clinical and magnetic resonance imaging study - Corrected Proof

Mei-Yun Cheng, Yau-Yau Wai, Long-Sun Ro, Tony Wu — 2012-04-16

Summary: Purpose: Epileptic seizures in Chinese patients with multiple sclerosis (MS) have not been studied extensively. We investigated the clinical, laboratory, and imaging findings for Chinese patients with MS who had experienced seizures.Methods: A total of 93 (57.4%) patients were diagnosed as having conventional MS and 69 (42.6%) patients as having neuromyelitis optica (NMO) over 20years. Data on clinical symptoms, related examinations, and treatment were analyzed retrospectively.Results: Eight patients (8.6%), all of whom were female, had seizures during the course of relapsing–remitting MS. One had seizures as the presenting symptom of MS. The seizure type was focal onset in all the 8 patients, 6 of whom had secondarily generalized seizures. Only 1 patient was recorded as having focal epileptiform discharges by electroencephalography. The frequency of seizures was significantly higher in patients with recurrent seizures than in those with acute-MS-related seizures. Diffuse or extensive lesions were observed in acute-MS-related seizures; focal persistent lesions were related to recurrent seizures or even status epilepticus, both of which need long-term antiepileptic medication.Conclusion: The seizure courses (acute or recurrent) and distribution of lesions (diffuse or localized) might provide information on seizure recurrence and decide antiepileptic treatment strategies.

Analysis of three lamotrigine extended-release clinical trials: Comparison of pragmatic ITT and LOCF methodologies - Corrected Proof

Jacqueline A. French, Anne E. Hammer, Alain Vuong, John A. Messenheimer — 2012-04-12

Summary: Early withdrawal of patients from a clinical trial can compromise the robustness of the data by introducing bias into the analysis. This is most commonly addressed by using the “intent to treat” (ITT) population and “last observation carried forward” (LOCF) methodology, where a patient's last assessment is carried forward. This can lead to overstatement of treatment efficacy especially if events indicative of treatment failure are infrequent. An alternative methodology, labeled “pragmatic ITT” (P-ITT), requires patients to have a positive outcome and to complete the trial in order to be considered a treatment success by that outcome measure. Data from 3 randomized multicenter lamotrigine extended-release (LTG XR) trials were analyzed and response (proportions seizure-free and with 50% response) were compared using LOCF and P-ITT methodologies.In 2 of the 3 trials, a lower response for both seizure freedom and 50% response was seen during the Maintenance phase using the P-ITT methodology. In the trial that did not show a difference, only a small number of patients withdrew early, thus negating the benefit brought by the P-ITT method. Differences between methodologies were not noted when evaluation was applied to the entire treatment period, most likely a reflection of the fact that a therapeutic dose of lamotrigine is not rapidly achieved.We propose that the P-ITT may be a simpler, more informative method for evaluating the effectiveness of a drug, especially in comparison to another active drug(s).

Effect of mild hypothermia on glutamate receptor expression after status epilepticus - Corrected Proof

Lifei Yu, Yuanfeng Zhou, Yi Wang — 2012-04-09

Summary: Hypothermia has been shown to have neuroprotective effects in various models of neurological damage. However, its therapeutic effect on pediatric status epilepticus (SE) is still unknown. We conducted a study to investigate whether hypothermia can have an adjuvant effect on pilocarpine-induced status epilepticus in immature rats when combined with diazepam treatment. Pilocarpine-induced status epilepticus was maintained for either 30min or 60min, which was followed by injection with diazepam (10mg/kg body weight) and/or treatment with mild hypothermia (core temperature to 33°C). We found that the spike-wave amplitude and frequency after SE during treatment with diazepam and hypothermia was significantly lower than treatment with diazepam alone. Mild hypothermia significantly reduced the number of cells undergoing necrosis and apoptosis. In addition, α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor subunit GluR1 was shown to be up-regulated by SE, while GluR2 was shown to be down-regulated. However, after combination therapy with diazepam and mild hypothermia for 8h, the expression of GluR1 was decreased and GluR2 was increased relative to the levels of diazepam alone treated juveniles. We also found that the expression of mGluR-1a was also decreased relative to diazepam alone. These findings suggest that mild hypothermia might further protect against pilocarpine-induced status epilepticus in immature rats by regulating glutamate receptor expression. This study was conducted using a pediatric model of SE so as to gain a better understanding of the role of hypothermia in the developing brain.

Anticonvulsant effect of retigabine during postnatal development in rats - Corrected Proof

Patrick A. Forcelli, Colin Soper, Anand Lakhkar, Karen Gale, Alexei Kondratyev — 2012-04-09

Summary: Retigabine is a new-generation antiepileptic drug that exerts therapeutic action through the activation of KCNQ channel dependent M-type potassium currents. While retigabine has been extensively studied in adult animals using a wide variety of seizure models, its effects in developing animals have not been examined. There has only been one previous report of retigabine efficacy in juvenile rats (), which examined efficacy against kindled seizures and did not examine ages younger than postnatal day (P) 14. To determine the efficacy of retigabine during brain development we pretreated rats with retigabine (0–30mg/kg) at three ages corresponding to the neonatal period through late childhood/early adolescence (i.e., P7, P14, or P25). Seizures were induced 30min later using a chemoconvulsant (pentylenetetrazol, PTZ) model, which has been widely used to determine anticonvulsant efficacy of many other antiepileptic drugs in neonatal animals. In a dose and age-dependent manner, retigabine reduced the severity of PTZ evoked seizures, increased the latency to seizure onset, and decreased the incidence of full maximal seizures. The minimum effective dose was found to be 5mg/kg for P7 animals, 2.5mg/kg for P14 animals, and 1mg/kg for P25 animals. These findings allow a direct comparison between retigabine and previously studied antiepileptic drugs against PTZ seizures during development, and provide the first report of the effective dose range of retigabine in neonatal animals.

Electroclinical overlap of two types of epileptic encephalopathy occurring in the same children in a certain age period? - Corrected Proof

Roberto Horacio Caraballo, Alejandra Soraru, Ricardo Oscar Cersósimo — 2012-04-09

Summary: In this study, we describe three patients who each had an electroclinical overlap of two different epileptic encephalopathies (EE), with onset in a certain age period. Patient 1 had electroclinical features compatible with continuous spikes and waves during slow sleep (CSWSS) syndrome that changed into Lennox–Gastaut syndrome (LGS) (symptomatic, cause porencephalic cyst) at the age of 8.5 years. Patient 2 had LGS which evolved into CSWSS at the age of 6 years (symptomatic, cause polymicrogyria). The third patient had cryptogenic CSWSS syndrome at age the age of 7 years which evolved into LGS at the age of 7.5 years. All three patients could be considered to have two EE: CSWSS syndrome and LGS or to have had overlapping features of these epilepctic syndromes.

Corrigendum to “Levetiracetam clinical pharmacokinetics in elderly and very elderly patients with epilepsy” [Epilepsy Res. 98 (2012) 130–134] - Corrected Proof

M. Contin, S. Mohamed, F. Albani, R. Riva, A. Baruzzi — 2012-04-09

The authors regret that during the publication of the above paper the author's affiliation was published incorrectly. The updated affiliation is reproduced correctly above. The authors would like to apologise for any inconvenience this may have caused to the readers of the journal.

Variability of carbamazepine and valproate concentrations in elderly nursing home residents - Corrected Proof

Angela K. Birnbaum, Jeannine M. Conway, Melissa A. Strege, Ilo E. Leppik — 2012-04-05

Summary: Purpose: Measuring antiepileptic drug (AED) concentrations is common practice in nursing homes. Phenytoin (PHT) concentrations fluctuate substantially in many nursing home residents under constant dose conditions; however, the stability of other AED concentrations has not been studied. We investigated the variability of carbamazepine (CBZ) and valproate (VPA) concentrations under constant dose conditions in US nursing home residents.Methods: A database of elderly persons (≥65 years) in 119 nursing homes throughout the US was reviewed for residents with at least one measurement of total PHT, CBZ or VPA. Inclusion criteria for this study were three or more serum concentration measurements while on the same dose of CBZ or VPA, a two-month minimum stay, and no interfering co-medications (inducers or inhibitors). Enrollment occurred over a 2-year period. Data were collected on residents for a minimum of 6 months.Key findings: Of the 593 residents identified, 245 had CBZ or VPA concentrations measured and 44 (18%) met inclusion criteria (22 on CBZ and 22 VPA). Some subjects had little variability in AED concentrations, others had large fluctuations. Total CBZ concentrations within individuals varied as little as 0mg/L to as much as 6.3mg/L and total VPA concentrations as little as 10.0mg/L to as much as 77.6mg/L.Significance: The variability of PHT, CBZ, and VPA concentrations in many but not all nursing home residents implies that a re-evaluation of the role of AED concentration measurements in the management of patients is needed. Strategies for use and interpretation of AED concentration measurements need to be reevaluated.

Baboon model of generalized epilepsy: Continuous intracranial video-EEG monitoring with subdural electrodes - Corrected Proof

2012-04-05

Summary: The baboon provides a natural non-human primate model for photosensitive, generalized epilepsy. This study describes an implantation procedure for the placement of subdural grid and strip electrodes for continuous video-EEG monitoring in the epileptic baboon to evaluate the generation and propagation of ictal and interictal epileptic discharges. Subdural grid, strip and depth electrodes were implanted in six baboons, targeting brain regions that were activated in functional neuroimaging studies during photoparoxysmal responses. The baboons were monitored with continuous video-EEG monitoring for 2–21 (mean 9) days. Although the animals were tethered, the EEG signal was transmitted wirelessly to optimize their mobility. Spontaneous seizures, interictal epileptic discharges (IEDs), and responses to intermittent light stimulation (ILS) were assessed. Due to cortical injuries related to the electrode implantation and their displacement, the procedure was modified. Habitual myoclonic and generalized tonic–clonic seizures were recorded in three baboons, all associated with a generalized ictal discharge, but were triggered multiregionally, in the frontal, parietal and occipital cortices. IEDs were similarly expressed multiregionally, and responsible for triggering most generalized spike-and-wave discharges. Generalized photoparoxysmal responses were activated only in one baboon, while driving responses recorded in all three photosensitive baboons were 2.5 times the stimulus rate. In contrast to previous intracranial investigations in this model, generalized ictal and interictal epileptic discharges were triggered by parietal and occipital, in addition to the frontocentral cortices. Furthermore, targeted visual areas responded differently to ILS in photosensitive than nonphotosensitive baboons, but further studies are required before mechanisms can be implicated for ILS-induced activation of the epileptic networks.

Antiepileptic drugs and vitamin B6 plasma levels in adult patients - Corrected Proof

2012-04-05

Summary: Treatment with several antiepileptic drugs (AED) is associated with lower serum concentrations of folate or vitamin B12. This prospective monocenter study analyzed vitamin B6 blood levels in 400 serial patients with epilepsy, AED-treated (n=385), untreated (n=15) and healthy controls (n=233). The mean plasma vitamin B6 levels of the AED-treated (12.1±10.1; p=0.093) and the untreated patients (15.6±12.4; p=0.664) were not significantly different from the controls (13.9±15.2). These observations do not support the hypothesis that vitamin B6 blood levels are influenced by AED treatment.

High frequency spectral components after Secobarbital: The contribution of muscular origin—A study with MEG/EEG - Corrected Proof

2012-04-04

Highlights: ► High-frequency activity (wide range gamma) in the surface EEG after administration of benzodiazepines is not of cerebral origin. ► MEG is significantly less susceptible to muscle activity artifacts than surface EEG recording. ► The combination of MEG and EEG help discern cerebral activity from extra-cerebral (muscle) activity.Summary: Objectives: Previously we found that benzodiazepines not only provoke beta-activity in the EEG, but also higher frequency activity. Knowing the origin of this high frequency activity is crucial if localisation of epileptogenic brain tissue is the query. We attempt to differentiate cerebral from muscular origin of such activity.Methods: We postulate that EEG and MEG have similar sensitivity to brain activity, but different sensitivity to muscle activity, and compare co-recorded EEG and MEG signals in a group of five patients who had received short-lasting barbiturates to induce sleep. We performed principal components analysis over time and subtract the results for MEG from the EEG to see where the frequency spectra differ.Results: The EEG showed activity in the gamma bands up to 270Hz for all patients; the MEG significantly less. We find no differences in the lower frequency bands. Topographically the differences localized over the frontotemporal regions.Conclusions: In the EEG benzodiazepines and/or barbiturates are not only associated with frequencies in the beta band, but also with wide range gamma activity. The latter seems to be of muscular origin.Significance: Our study suggests that gamma activity in such measurements may not be cerebral in origin. MEG is less susceptible to contamination from muscle activity than the EEG.

Recruitment for genetic studies of epilepsy - Corrected Proof

Sylwia Misiewicz, Melodie R. Winawer — 2012-04-04

Summary: Virtually nothing has been published about recruitment of adults with sporadic temporal lobe epilepsy (TLE) for genetic studies. We examined eligibility, recruitment, participation rates, and reasons for exclusion in a genetic study of TLE. Participants with non-acquired TLE with onset ≤35 were recruited through review of records and screening of incoming patients at Columbia University Medical Center (CUMC). Eligible patients were asked to participate in an interview about seizures and give a blood sample for DNA extraction. Medical records were sought for each participant. Of 2974 patients screened 252 (8.5%) were eligible, and 40 (15.9% of eligible) participated. Leading reasons for ineligibility included an antecedent cause of epilepsy, syndrome other than TLE, and seizure onset after age 35. Those declining participation cited concerns about confidentiality, lack of compensation, and fear of phlebotomy. Although TLE is common and patients were recruited from a major surgical epilepsy center, a small proportion of potential participants participated. Large numbers need to be screened to reach the target sample size. Obtaining permission from treating physicians to contact their patients directly can improve recruitment. Saliva DNA collection, monetary incentives and patient education can improve participation. This information can facilitate study design in epilepsy genetics.

Predictive model for refractoriness in Temporal Lobe Epilepsy based on clinical and diagnostic test data - Corrected Proof

2012-04-03

Summary: Introduction: Temporal Lobe Epilepsy (TLE) is frequently resistant to drug treatment, but a high percentage of these patients can be free of seizures after epilepsy surgery. Delay in the surgical decision has been related to quality of life impairment, social and work limitations, and increased mortality risk. A predictive model for refractoriness based on clinical and diagnostic factors may allow its earlier detection and a shorter delay before surgery.Material and methods: A case–control study was conducted in TLE patients over 16 years old. The dependent variable was resistance to medical treatment according to ILAE 2010 criteria. Independent variables were clinical, semiological, therapeutic, neurophysiological, radiological, and neuropsychological variables. A multivariate study was conducted to identify the variables associated with refractoriness, calculating the positive and negative predictive values and positive likelihood ratios of these variables individually and in combination. These data were used to construct a refractoriness predictive model.Results: ILAE refractoriness criteria were met by 83 patients (50.9%). In the multivariate analysis, refractoriness was significantly associated with one semiological variable, one neuroradiological variable, one neurophysiological variable, and two therapeutic variables but not with neuropsychological test outcomes. These significant variables were used to construct a predictive model.Conclusion: Assessment of semiological, neurophysiological, and neuroradiological data can serve to stratify the risk of refractory epilepsy in TLE patients.

Coexisting seizures in patients with infantile spasms confirmed by long-term video-electroencephalography monitoring - Corrected Proof

2012-03-30

Summary: Purpose: We performed this study to evaluate the frequency, types, and ictal electroencephalography (EEG) findings of coexisting seizures in patients with infantile spasms at the onset of spasms. We also evaluated the effect of coexisting seizures on short-term seizure control.Methods: We retrospectively reviewed the long-term video-EEG and electronic medical records of 109 patients (58 boys and 51 girls) diagnosed with infantile spasms at the Seoul National University Children's Hospital. Coexisting seizure types were classified according to the International League Against Epilepsy seizure and epilepsy classification. Ictal EEG findings were also reviewed. Short-term seizure control rates were compared between groups with or without coexisting seizures.Results: We identified 27 coexisting seizures in 24 of the 109 patients (22%). The most common type of seizure was generalized tonic seizure followed by myoclonic, focal tonic, tonic-clonic, hypokinetic, and versive seizures. Rates of preterm birth and birth asphyxia were significantly higher in patients with coexisting seizures. Initial anticonvulsant was vigabatrin (103 patients), valproic acid (five patients), and topiramate (one patient). There was no significant difference in short-term seizure freedom (overall seizure-free rates in patients without coexisting seizures vs. those with: 29.2% vs. 11.1% at 2months, 36.1% vs. 22.2% at 4months, and 41.7% vs. 27.8% at 6months). Seizure freedom was significantly lower in the symptomatic groups compared with non-symptomatic groups.Conclusions: Long-term video-EEG monitoring is required as an initial evaluation in patients with infantile spasms, especially when there are reports of coexisting seizures, or a history of preterm birth or birth asphyxia. Presence of coexisting seizures was not related to poor seizure control in the short-term treatment period.

Comparison of heart rate variability among children with well controlled versus refractory epilepsy: A cross-sectional study - Corrected Proof

2012-03-30

Summary: Purpose: Autonomic symptoms frequently occur during seizures. There are reports that the adult group of intractable epilepsy patients have different autonomic profile than the well controlled epilepsy, but there is no clear evidence in the children epilepsy group, therefore, we planned to study the autonomic profile in well controlled and refractory epilepsy children by recording the short-term heart rate variability (HRV).Methods: This cross sectional study was conducted in a tertiary care hospital between July 2008 and June 2009. Children with mean age of 9.1±3.3 years were enrolled. Three groups of children, 40 in each group namely, refractory epilepsy, well controlled epilepsy and normal control children were included. Children who had chronic systemic diseases and were on drugs that cause autonomic dysfunction were excluded. All children underwent short term heart rate variability testing. Data was analyzed in time domain and frequency domain.Results: pNN50 was significantly lower in children with refractory epilepsy than the well control as well as healthy controls. Rest of the parameters of time domain and frequency domain were comparable between the groups.Conclusions: Our study showed that parasympathetic activity is lower in refractory epilepsy children. However, autonomic tone is comparable in well control versus healthy controls.

Surgical treatment for epilepsy in 17 children with tuberous sclerosis-related West syndrome - Corrected Proof

2012-03-29

Summary: The efficacy of surgery for the treatment of epilepsy in patients with West syndrome secondary to tuberous sclerosis is unclear. The charts of 17 patients with tuberous sclerosis and secondary West syndrome who underwent a one-stage surgical resection with a combined palliative operative procedure were reviewed. Engel classification was used to classify the patients with regard to seizure status following surgery. After surgery, 11 patients were in Engel class I, 4 in class II, and 2 in class III. The EEG after surgery was normal in 8 patients, significantly improved in 8, and without significant improvement in 1 patient. Six patients had a recurrence of seizures after surgery, which included 3 patients with continuing spasms and 3 patients where the spasms had resolved but had developed either partial seizures or generalized tonic–clonic seizures. There were significant improvements in the Gesell Developmental Schedules for motor field (P=0.003), adaptive field (P=0.003), language field (P=0.033), and personal–social field (P=0.007). Thus, a one-stage surgical approach can be used to produce satisfactory outcomes in young children with tuberous sclerosis who have secondary West syndrome and seizures that do not respond to conventional antiepileptic therapy, even in when there are multiple epileptogenic foci.

Correlations between ictal propagation and response to electrical cortical stimulation: A cortico-cortical evoked potential study - Corrected Proof

2012-03-29

Summary: Objective: To better understand the process of ictal propagation in epilepsy by using cortico-cortical evoked potential (CCEP), which reveals the brain networks.Methods: Intracranial EEG recordings of 11 seizures from 11 patients with pharmacoresistant focal epilepsy were studied to identify the propagation sites and times. Six patients had a history of secondary generalization (Gen (+) group) and five patients did not (Gen (−) group). Thereafter repetitive 1Hz bipolar electrical stimuli were applied to the ictal onset zones and CCEPs were recorded by averaging electrocorticograms.Results: The propagation of contiguous spread was significantly faster than non-contiguous spread (p=0.033). In four patients, CCEP amplitudes were significantly larger in the ictal propagation area than out of the propagation area. However, the distribution of CCEP responses was not necessarily consistent with the ictal propagation area as a whole. Furthermore, the ictal propagation areas out of CCEP-positive areas were significantly broader in Gen (+) group than Gen (−) group (p=0.017).Conclusion: The present findings suggest that contiguous spread is faster than non-contiguous spread, which can be explained by the enhancement of excitability around the ictal onset area. Furthermore, there is a group of fibers that is “closed” during the seizures and secondary generalization might be more associated with the impairment of cortical inhibition over the broad cortical area rather than direct connection.

Evaluation of different antiepileptic drug strategies in medically refractory epilepsy patients following epilepsy surgery - Corrected Proof

2012-03-22

Summary: Purpose: This study aimed to explore the most appropriate antiepileptic drug strategies after successful epilepsy surgery.Methods: A total of 131 refractory epilepsy patients who underwent epilepsy surgery from January 2005 to December 2008 in the Department of Neurosurgery, West China Hospital, were retrospectively reviewed. Patients were divided into three groups (monotherapy, duotherapy, and polytherapy) according to drug combinations used immediately after epilepsy surgery. Seizure outcomes were followed up for more than 2 years. Engel classification was used to evaluate seizure outcomes.Results: The mean postoperative follow-up period was 3.7±1.0 years. Preoperative baseline data among the three groups were comparable. Seizure recurrence rate in monotherapy was obviously higher than in other groups (34.1% vs. 15.1%, 7.1%) at 6-month follow-up, which showed a statistically significant difference (p=0.02). Seizure outcomes for 2 years were assessed using Engel classification. In the duotherapy group, the rate of Engel class I was definitely higher than in the other two groups (69.9% vs. 47.7%, 57.1%, p=0.02). Seizure relapse rates at the 2-year follow-up, after planned reduction or withdrawal, were 46.4% for monotherapy, 16.9% for duotherapy, and 25.0% for polytherapy (p=0.01).Conclusions: Monotherapy may be not sufficient enough to control seizures completely. It appears to have a higher risk for seizure relapse when considering drug reduction. It suggests that duotherapy may be more effective and safer than monotherapy. Even after successful epilepsy surgery, duotherapy seems preferable to monotherapy or polytherapy for control of residual seizures.

Possible involvement of PPAR-gamma receptor and nitric oxide pathway in the anticonvulsant effect of acute pioglitazone on pentylenetetrazole-induced seizures in mice - Corrected Proof

Razieh Adabi Mohazab, Mehrak Javadi-Paydar, Bahram Delfan, Ahmad Reza Dehpour — 2012-03-22

Summary: Besides the receptor-mediated effects of pioglitazone, the involvement of nitric oxide (NO) has been previously demonstrated in some pioglitazone-induced central and peripheral effects. In the present study, the effects of acutely administered pioglitazone on pentylenetetrazole (PTZ)-induced seizures and involvement of NO were evaluated in mice. To determine the threshold for clonic seizures, PTZ was administered intravenously. A single dose of pioglitazone (10, 20, 40 and 80mg/kg, p.o.) was administered either 2 or 4h prior to induction of seizures. For determination of possible role of peroxisome proliferator activated receptor gamma (PPAR-γ) and nitric oxide pathway in this effect, the effects of a PPAR-γ antagonist, GW9662 (2mg/kg); a non-specific nitric oxide synthase (NOS) inhibitor, NG-nitro-l-arginine methyl ester (l-NAME; 0.3, 1, 3, and 10mg/kg); a specific iNOS inhibitor, aminoguanidine (100mg/kg, i.p.) or a nitric oxide precursor, l-arginine (30, 60, 100 and 200mg/kg, i.p.); each administered 15min prior to pioglitazone, were investigated on the anticonvulsant effect of this drug. Administration of pioglitazone (40 and 80mg/kg) increased the threshold of PTZ-induced seizure in a dose-dependent, and time-dependent manner. GW9662 reversed the anticonvulsant effect of pioglitazone (40mg/kg). Acute administration of l-NAME (1, 3 and 10mg/kg) inhibited the anticonvulsant effect of pioglitazone (40mg/kg), the same result was detected with aminoguanidine (100mg/kg); whereas l-arginine, in the noneffective dose (100mg/kg), potentiated the seizure threshold when co-administered with a subeffective dose of pioglitazone (20mg/kg).Conclusion: The present study demonstrates the anticonvulsant effect of acute pioglitazone on PTZ-induced seizures in mice. This effect was reversed by PPAR-γ antagonist, and both a specific- and a non-specific nitric oxide synthase inhibitors, and augmented by nitric oxide precursor, l-arginine. These results support that the anticonvulsant effect of pioglitazone is mediated through PPAR-γ receptor-mediated pathway and also, at least partly, through the nitric oxide pathway.

Is the ketogenic diet effective in specific epilepsy syndromes? - Corrected Proof

2012-03-19

Summary: Is the ketogenic diet (KD) more effective in certain epilepsy syndromes? The KD has been shown to be effective in treating multiple seizure types and epilepsy syndromes. We review the effectiveness of the KD in Dravet syndrome, epilepsy with myoclonic–atonic seizures, mitochondrial disease, tuberous sclerosis, late infantile and juvenile neuronal ceroid lipofuscinosis, and febrile infection-related epilepsy syndrome. In certain epilepsy syndromes, like epilepsy with myoclonic–atonic seizures, the diet should be considered early in the course of treatment.

Connectivity disruptions in resting-state functional brain networks in children with temporal lobe epilepsy - Corrected Proof

2012-03-15

Summary: Functional resting-state connectivity has been shown to be altered in certain adult epilepsy populations, but few connectivity studies have been performed on pediatric epilepsy patients. Here functional connectivity was measured in pediatric, non-lesional temporal lobe epilepsy patients with normal intelligence and compared with that in age and gender-matched healthy controls using the independent component analysis method. We hypothesized that children with non-lesional temporal lobe epilepsy have disrupted functional connectivity within resting-state networks. Significant differences were demonstrated between the two groups, pointing to a decrease in connectivity. When the results were analyzed according to the interictal electroencephalogram findings, however, the connectivity disruptions were seen in different networks. In addition, increased connectivity and abnormally anti-correlated thalamic activity was detected only in the patients with abnormal electroencephalograms. In summary, connectivity disruptions are already to be seen at an early stage of epilepsy, and epileptiform activity seems to affect connectivity differently. The results indicate that interictal epileptiform activity may lead to reorganization of the resting-state brain networks, but further studies would be needed in order to understand the pathophysiology behind this phenomenon.

Can magnesium supplementation reduce seizures in people with epilepsy? A hypothesis - Corrected Proof

Alan W.C. Yuen, Josemir W. Sander — 2012-03-09

Summary: Magnesium is required for over 300 enzyme systems and is critical for many cellular functions including oxidative phosphorylation, glycolysis, DNA transcription and protein synthesis. Studies suggest that the modern Western diet and lifestyle may lead to magnesium deficiency, and this appears to be associated with a wide range of medical conditions. Magnesium deficiency decreases seizure thresholds in animal models of epilepsy and indeed low magnesium concentration in the perfusate is a common method of generating spontaneous epileptiform discharges from rat hippocampal slices. Magnesium is a potential modulator of seizure activity because of its ability to antagonize excitation through the N-methyl-d-aspartate receptor. Some studies have shown that people with epilepsy have lower magnesium levels than people without epilepsy. There are case reports of seizures being controlled with magnesium supplementation in people with specific conditions, and recently in an open randomized trial, children with infantile spasms responded better to adrenocorticotropic hormone (ACTH) plus magnesium than to ACTH alone. We hypothesise that magnesium supplementation can reduce seizures in people with epilepsy. This hypothesis can be tested in a controlled randomised supplementation trial. If proven, magnesium supplementation needs to be considered in the overall management of people with refractory epilepsy.