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Kaalund S.S.,Copenhagen University | Kaalund S.S.,Bispebjerg Hospital | Veno M.T.,University of Aarhus | Bak M.,Copenhagen University | And 19 more authors.
Epilepsia | Year: 2014

Objective Mesial temporal lobe epilepsy (MTLE) is one of the most common types of the intractable epilepsies and is most often associated with hippocampal sclerosis (HS), which is characterized by pronounced loss of hippocampal pyramidal neurons. microRNAs (miRNAs) have been shown to be dysregulated in epilepsy and neurodegenerative diseases, and we hypothesized that miRNAs could be involved in the pathogenesis of MTLE and HS. Methods miRNA expression was quantified in hippocampal specimens from human patients using miRNA microarray and quantitative real-time polymerase chain reaction RT-PCR, and by RNA-seq on fetal brain specimens from domestic pigs. In situ hybridization was used to show the spatial distribution of miRNAs in the human hippocampus. The potential effect of miRNAs on targets genes was investigated using the dual luciferase reporter gene assay. Results miRNA expression profiling showed that 25 miRNAs were up-regulated and 5 were down-regulated in hippocampus biopsies of MTLE/HS patients compared to controls. We showed that miR-204 and miR-218 were significantly down-regulated in MTLE and HS, and both were expressed in neurons in all subfields of normal hippocampus. Moreover, miR-204 and miR-218 showed strong changes in expression during fetal development of the hippocampus in pigs, and we identified four target genes, involved in axonal guidance and synaptic plasticity, ROBO1, GRM1, SLC1A2, and GNAI2, as bona fide targets of miR-218. GRM1 was also shown to be a direct target of miR-204. Significance miR-204 and miR-218 are developmentally regulated in the hippocampus and may contribute to the molecular mechanisms underlying the pathogenesis of MTLE and HS. © Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.


Van Der Meer D.H.,Isala Medical Center | Wieringa A.,Isala Medical Center | Wegner I.,SEIN Stichting Epilepsie Instellingen Nederland | Wilffert B.,Isala Medical Center | And 2 more authors.
British Journal of Clinical Pharmacology | Year: 2015

Aim The aim of this review was to investigate the quality of the current literature on the transfer of anticonvulsants to breast milk to provide an overview of which anticonvulsants are in need of further research. Methods We reviewed the quality of the available lactation studies for 19 anticonvulsants against the guidelines of the Food and Drug Administration (FDA) and the International Lactation Consultant Association (ILCA). Results Except for one study on lamotrigine and one case report on gabapentin, no study on anticonvulsants had both the absolute infant dose (AID) and milk to plasma ratio (M : P) correctly assessed. Only one study on carbamazepine, phenytoin and vigabatrin was found that correctly assessed the AID. The main cause for this low number is the lack of essential details in published studies, since 25 of 62 studies were case reports, letters or abstracts. Other major shortcomings were the lack of information on sampling methods, the number of samples in a particular dose interval as well as the low number of study participants. Conclusion The quality of the current literature on the transfer of anticonvulsants to breast milk is low, except for lamotrigine, which makes it hard to draw conclusions about the safety of the use of anticonvulsants during the lactation period. Therefore, further research is needed. © 2014 The British Pharmacological Society.


Lamberts R.J.,SEIN Stichting Epilepsie Instellingen Nederland | Gaitatzis A.,SEIN Stichting Epilepsie Instellingen Nederland | Sander J.W.,SEIN Stichting Epilepsie Instellingen Nederland | Sander J.W.,University of London | And 5 more authors.
Neurology | Year: 2013

Objective: To determine the consistency and facilitating cofactors of postictal generalized EEG suppression (PGES) of .20 seconds after convulsive seizures (CS), a suggested predictor of sudden unexpected death in epilepsy risk. Methods: We retrospectively reviewed video-EEG data of people with $2 recorded CS. Presence and duration of PGES were assessed by 2 independent observers blinded to patient status. Intraindividual consistency of PGES .20 seconds was determined and correlations with clinical characteristics were analyzed after correction for individual effects and the varying number of seizures. Results: One hundred fifty-four seizures in 59 people were analyzed. PGES .20 seconds was found in 37 individuals (63%) and 57 (37%) of CS. The proportion of persons in whom PGES occurred consistently (presence or absence of PGES .20 seconds in all CS) was lower in those withmore CS. PGES of .20 seconds was more frequent in seizures arising from sleep (odds ratio 3.29, 95% confidence interval 1.21-8.96) and when antiepileptic medication was tapered (odds ratio 4.80, 95% confidence interval 1.27-18.14). Conclusion: Apparent PGES consistency was less frequent in people with more CS recorded, suggesting that PGES is an inconsistent finding in any one individual. Thus, we believe that PGES .20 seconds is not a reliable predictor of sudden unexpected death in epilepsy. Sleep and antiepileptic drug reduction appear to facilitate the occurrence of PGES. © 2013 American Academy of Neurology.


Wegner I.,SEIN Stichting Epilepsie Instellingen Nederland | Wegner I.,University Utrecht | Sander J.W.,SEIN Stichting Epilepsie Instellingen Nederland | Sander J.W.,University College London | And 2 more authors.
Epilepsy and Behavior | Year: 2013

Age as well as estrogen levels may have an impact on the pharmacokinetics of lamotrigine (LTG) and monohydroxycarbazepine (MHD), the active metabolite of oxcarbazepine (OXC). To assess the effects of age and menopause, we evaluated retrospectively a therapeutic drug-monitoring database. Samples from 507 women and 302 men taking LTG and 464 women and 319 men taking OXC were used to develop a population pharmacokinetic model. Data were analyzed using NONMEM software and were compared with a population pharmacokinetic model based on samples of 1705 women and 1771 men taking carbamazepine (CBZ). Age was a significant factor contributing to pharmacokinetic variability in individuals using LTG, OXC, and CBZ with increasing clearance as a function of bioavailability (Cl/F) over age 18, a maximum Cl/F at 33. years (CBZ) and 36. years (LTG and OXC), and a gradual decrease of Cl/F towards older age. We found no effect of perimenopausal age range on LTG and MHD clearance. © 2013 Elsevier Inc.


Van't Klooster M.A.,University Utrecht | Huiskamp G.,University Utrecht | Zijlmans M.,University Utrecht | Debets R.M.,SEIN Stichting Epilepsie Instellingen Nederland | And 6 more authors.
Epilepsy Research | Year: 2014

Purpose: [18F] Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) is a semi-invasive, interictal method of localization of hypometabolic epileptic foci. FDG-PET can be useful in the clinical work-up prior to epilepsy surgery, especially in equivocal cases. We investigated whether we could increase the yield of presurgical FDG-PET in patients with difficult epilepsy requiring chronic subdural electrocorticography (ECoG). Methods: We retrospectively studied patients with refractory focal epilepsy in whom there was uncertainty about the focus localization and who underwent FDG-PET and ECoG. Two experts (epileptologist and nuclear medicine radiologist) together systematically re-assessed the scans visually (PETRE), blinded to their initial reports. Scans were also re-analyzed by comparing them to a normal control dataset with Statistical Parametric Mapping (SPM), using a liberal (PETSPM1), and strict (PETSPM2) statistical threshold. Regions with hypometabolism and regions containing the seizure onset zone (SOZ) in ECoG were marked as positive anatomical regions (PARs). We compared the concordance of these PARs for the different PET re-assessments. We calculated the sensitivity, specificity and accuracy of the PET results for the SOZ. The added value of the re-assessments was evaluated with emphasis on scans initially reported as negative. Results: 41 Patients (63% extra-temporal) were included. PETRE identified the SOZ best, with a sensitivity of 62% and specificity of 93%. PETSPM1 had a sensitivity of 62% and specificity 69%, for PETSPM2 this was 35% and 85% respectively. The overlap between PETRE vs. PETSPM1 and vs. PETSPM2 was 71% and 37%. Visual re-assessment and PETSPM1 identified the SOZ in four out of five scans that were initially reported as negative. Conclusions: Pre-surgical re-assessment of PET scans is worthwhile in epilepsy patients who undergo ECoG, especially when results were reported as negative before. Visual re-assessment itself has a higher combined specificity, sensitivity and accuracy than SPM analysis alone. SPM analysis could be used as a guide for visual (re-)assessment, because of its high sensitivity. © 2014 Elsevier B.V.


Gaitatzis A.,SEIN Stichting Epilepsie Instellingen Nederland | Sander J.W.,SEIN Stichting Epilepsie Instellingen Nederland
CNS Drugs | Year: 2013

Antiepileptic drugs (AEDs) are used by millions of people worldwide for the treatment of epilepsy, as well as in many other neurological and psychiatric conditions. They are frequently associated with adverse effects (AEs), which have an impact on the tolerability and success of treatment. Half the people who develop intolerable AEs discontinue treatment early on after initiation, while the majority of people will continue to be exposed to their effects for long periods of time. The long-term safety of AEDs reflects their potential for chronic, cumulative dose effects; rare, but potentially serious late idiosyncratic effects; late, dose-related effects; and delayed, teratogenic or neurodevelopmental effects. These AEs can affect every body system and are usually insidious. With the exception of delayed effects, most other late or chronic AEs are reversible. To date, there is no clear evidence of a carcinogenic effect of AEDs in humans. While physicians are aware of the long-term AEs of old AEDs (the traditional liver enzyme-inducing AEDs and valproate), information about AEs of new AEDs (such as lamotrigine, levetiracetam, oxcarbazepine, topiramate or zonisamide), particularly of their teratogenic effects, has emerged over the years. Sporadic publications have raised issues about AEs of the newer AEDs eslicarbazepine, retigabine, rufinamide, lacosamide and perampanel but their long-term safety profiles may take years to be fully appreciated. Physicians should not only be aware of the late and chronic AEs of AEDs but should systematically enquire and screen for these according to the individual AED AE profile. Care should be taken for individuals with comorbid conditions that may render them more susceptible to specific AEs. Prevention and appropriate management of long-term AED AEs is expected to improve adherence to treatment, quality of life and control of epilepsy. © 2013 Springer International Publishing Switzerland.


Van Iterson L.,SEIN Stichting Epilepsie Instellingen Nederland
Psychological Reports | Year: 2010

A differential impact of hemispheric side (left vs right) on cognitive measures, specifically Verbal and Performance IQ, has been described previously for both focal onset seizures and lateralized brain lesions. This study revealed a differential effect on intra-individual variability, measured as subtest scaled-score range, on the Dutch WISC-R and WISC-III, in children with epilepsy. The presence of documented brain lesion was associated with elevated variability on the Verbal Scale for the left hemisphere seizure group and with decreased variability on the Verbal and Full Scales for the right hemisphere seizure group. © Psychological Reports 2010.

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