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Find video protocols related to scientific articles indexed in Pubmed.
Transition issues for benign epilepsy with centrotemporal spikes, nonlesional focal epilepsy in otherwise normal children, childhood absence epilepsy, and juvenile myoclonic epilepsy.
Epilepsia
PUBLISHED: 05-30-2014
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This chapter covers the syndromes of benign epilepsy with centrotemporal spikes (BECTS), nonlesional focal epilepsy in otherwise normal children (NLFN), and the genetic generalized epilepsies. BECTS is an epilepsy syndrome that always enters terminal remission before the general age of a planned transition of adolescents. This is also the case for the majority (65%) of those with childhood absence epilepsy (CAE). Approximately 15% of patients with CAE who initially remit during their childhood years later develop juvenile myoclonic epilepsy (JME) as teenagers. They will have many issues for continuing medical care and transition, because their seizure disorder generally persists into adulthood. A significant minority of NLFN (~35%) and most patients with JME continue to have active epilepsy into adulthood. In addition, CAE, JME, and NLFN patients are at risk of a number of significant adverse social outcomes that require ongoing advice and counseling.
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EEG-fMRI in myoclonic astatic epilepsy (Doose syndrome).
Neurology
PUBLISHED: 04-02-2014
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To identify neuronal networks underlying generalized spike and wave discharges (GSW) in myoclonic astatic epilepsy (MAE).
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Evaluation of health-care utilization in patients with Dravet syndrome and on adjunctive treatment with stiripentol and clobazam.
Epilepsy Behav
PUBLISHED: 02-28-2014
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Dravet syndrome (DS) is a rare, severe childhood epilepsy syndrome that imposes a substantial burden on patients and their caregivers. This study evaluated health-care utilization over a 2-year period in patients with DS at an outpatient clinic of a German epilepsy center. Data on the course of epilepsy, anticonvulsant treatment, and direct costs were recorded using the electronic seizure diary Epivista and patients' files. We enrolled 13 patients with DS (6 females, mean age: 12.3±7.5 years) between 2007 and 2010 and evaluated them during a 1-year baseline. All patients had drug-resistant epilepsy and their seizures failed to improve with a mean number of 6.7±3.4 anticonvulsants. They had an overall mean seizure frequency of 102.1 seizures per year (median: 31, range: 3-538) with 43.2 GTCSs per year (median: 14, range: 0-228). We estimated the annual total direct costs at €6506±3974 (range: €1174-11,783) per patient with hospitalization (68.9% of total direct costs) as the major cost factor ahead of costs for anticonvulsants (24.0%). For the 1-year follow-up period, less severely affected patients were continued on conventional anticonvulsants (n=4) or switched to adjunctive treatment with stiripentol and clobazam (n=9). In the latter group, six patients (67%) were long-term responders, with between 25% and 100% seizure reduction with respect to either GTCSs or the overall seizure frequency. This reduction in seizure frequency was associated with a shift in the distribution of cost components towards higher medication costs and decreased hospitalization costs. The total direct costs increased by 42.7%, mainly due to the newly introduced stiripentol, with an annual cost of €6610. This study showed that direct costs of patients with DS were above the average European costs of drug-resistant epilepsy in children. Treatment with new anticonvulsants resulted in reduction of seizures and inpatient admissions.
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Phenotypic spectrum of eleven patients and five novel MTFMT mutations identified by exome sequencing and candidate gene screening.
Mol. Genet. Metab.
PUBLISHED: 01-28-2014
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Defects of mitochondrial oxidative phosphorylation (OXPHOS) are associated with a wide range of clinical phenotypes and time courses. Combined OXPHOS deficiencies are mainly caused by mutations of nuclear genes that are involved in mitochondrial protein translation. Due to their genetic heterogeneity it is almost impossible to diagnose OXPHOS patients on clinical grounds alone. Hence next generation sequencing (NGS) provides a distinct advantage over candidate gene sequencing to discover the underlying genetic defect in a timely manner. One recent example is the identification of mutations in MTFMT that impair mitochondrial protein translation through decreased formylation of Met-tRNA(Met). Here we report the results of a combined exome sequencing and candidate gene screening study. We identified nine additional MTFMT patients from eight families who were affected with Leigh encephalopathy or white matter disease, microcephaly, mental retardation, ataxia, and muscular hypotonia. In four patients, the causal mutations were identified by exome sequencing followed by stringent bioinformatic filtering. In one index case, exome sequencing identified a single heterozygous mutation leading to Sanger sequencing which identified a second mutation in the non-covered first exon. High-resolution melting curve-based MTFMT screening in 350 OXPHPOS patients identified pathogenic mutations in another three index cases. Mutations in one of them were not covered by previous exome sequencing. All novel mutations predict a loss-of-function or result in a severe decrease in MTFMT protein in patients' fibroblasts accompanied by reduced steady-state levels of complex I and IV subunits. Being present in 11 out of 13 index cases the c.626C>T mutation is one of the most frequent disease alleles underlying OXPHOS disorders. We provide detailed clinical descriptions on eleven MTFMT patients and review five previously reported cases.
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Risk factors of cognitive outcome in patients with atypical benign partial epilepsy/pseudo-Lennox syndrome (ABPE/PLS) and continues spike and wave during sleep (CSWS).
Eur. J. Paediatr. Neurol.
PUBLISHED: 01-26-2014
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Atypical benign partial epilepsy/pseudo-Lennox syndrome (ABPE/PLS) and continues spike and wave during sleep (CSWS) belong to a spectrum of idiopathic focal epilepsy syndromes ranging from benign Rolandic epilepsy to more severe seizure disorders, which are commonly characterized by the association of various epileptic seizure types, aggravation of spike-wave discharges during slow sleep, and cognitive and/or behavioral disturbances. The Aim of our study was to evaluate the risk factors that influence cognitive outcome in patients with ABPE/PLS and CSWS in a retrospective analysis.
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Cortical Thickness Changes Associated with Photoparoxysmal Response.
Brain Topogr
PUBLISHED: 01-18-2014
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Photoparoxysmal response (PPR) is an EEG trait of spike and spike-wave discharges in response to photic stimulation that is closely linked to idiopathic generalized epilepsy (IGE). In our previous studies we showed that PPR is associated with functional alterations in the occipital and frontal cortices. The aim of the present study was to determine structural changes associated with PPR. For this purpose we analysed the cortical thickness as derived from T1 MRI images in PPR-positive-subjects (n = 12; 15.5 ± 8.6 years; 4 males), PPR-positive-IGE-patients (n = 12; 14.9 ± 2.7 years; 4 males) and compared these groups with a group of PPR-negative-healthy-controls (HC, n = 17; 15.3 ± 3.6 years; 6 males). Our results revealed an increase of cortical thickness in the occipital, frontal and parietal cortices bilaterally in PPR-positive-subjects in comparison to HC. Moreover PPR-positive-subjects presented a significant decrease of cortical thickness in the temporal cortex in the same group contrast. IGE patients exhibited lower cortical thickness in the temporal lobe bilaterally and in the right paracentral region in comparison to PPR-positive-subjects. Our study demonstrates structural changes in the occipital lobe, frontoparietal regions and temporal lobe, which also show functional changes associated with PPR. Patients with epilepsy present changes in the temporal lobe and supplementary motor area.
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Developmental changes of neuronal networks associated with strategic social decision-making.
Neuropsychologia
PUBLISHED: 01-09-2014
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One of the important prerequisites for successful social interaction is the willingness of each individual to cooperate socially. Using the ultimatum game, several studies have demonstrated that the process of decision-making to cooperate or to defeat in interaction with a partner is associated with activation of the dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), anterior insula (AI), and inferior frontal cortex (IFC). This study investigates developmental changes in this neuronal network.
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MEG-EEG fusion by Kalman filtering within a source analysis framework.
Conf Proc IEEE Eng Med Biol Soc
PUBLISHED: 10-11-2013
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The fusion of data from multiple neuroimaging modalities may improve the temporal and spatial resolution of non-invasive brain imaging. In this paper, we present a novel method for the fusion of simultaneously recorded electroencephalograms (EEG) and magnetoencephalograms (MEG) within the framework of source analysis. This method represents an extension of a previously published spatio-temporal inverse solution method to the case of MEG or combined MEG-EEG signals. Moreover, we use a state-of-the-art realistic finite element (FE) head model especially calibrated for the MEG-EEG fusion problem. Using a real data set containing an epileptic spike, we validate the source analysis results of the spatio-temporal inverse solution using the results of the LORETA method and the findings from other structural and functional modalities. We show that the proposed fusion method, despite the low signal-to-noise ratio (SNR) of single spikes, points to the same brain area that was found by the other modalities. Furthermore, it correctly identifies the same source as the main generator for the MEG and EEG spikes.
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DBS artifact suppression using a time-frequency domain filter.
Conf Proc IEEE Eng Med Biol Soc
PUBLISHED: 10-11-2013
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Electroencephalogram (EEG) is a useful tool for brain research. However, during Deep-Brain Stimulation (DBS), there are large artifacts that obscure the physiological EEG signals. In this paper, we aim at suppressing the DBS artifacts by means of a time-frequency-domain filter. As a pre-processing step, Empirical-Mode Decomposition (EMD) is applied to detrend the raw data. The detrended signals are then filtered iteratively until, by visual inspection, the quality is good enough for interpretation. The proposed algorithm is demonstrated by an application to a clinical DBS-EEG data set in resting state and in finger-tapping condition. Moreover, a comparison with a Low-Pass filter (LPF) is provided, by visual inspection and by a quantitative measure.
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Atypical Vitamin B6 Deficiency: A Rare Cause of Unexplained Neonatal and Infantile Epilepsies.
J. Child Neurol.
PUBLISHED: 10-10-2013
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ALDH7A1 and PNPO deficiencies are rare inborn errors of vitamin B6 metabolism causing perinatal seizure disorders. The phenotypic variability, however, is broad. To assess the frequency of these deficiencies in unexplained infantile epilepsy, we screened 113 patients for mutations in both genes. We identified 1 patient with an epilepsy phenotype resembling Dravet syndrome and likely pathogenic mutations in ALDH7A1. Presenting features were highly atypical of pyridoxine-dependent epilepsy, including febrile seizures, response to anticonvulsive drugs, and periods of seizure freedom without pyridoxine treatment. "Hidden" vitamin B6 deficiencies might be rare but treatable causes of unexplained epilepsy extending beyond the classical phenotypes.
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Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes.
Nat. Genet.
PUBLISHED: 07-18-2013
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Idiopathic focal epilepsy (IFE) with rolandic spikes is the most common childhood epilepsy, comprising a phenotypic spectrum from rolandic epilepsy (also benign epilepsy with centrotemporal spikes, BECTS) to atypical benign partial epilepsy (ABPE), Landau-Kleffner syndrome (LKS) and epileptic encephalopathy with continuous spike and waves during slow-wave sleep (CSWS). The genetic basis is largely unknown. We detected new heterozygous mutations in GRIN2A in 27 of 359 affected individuals from 2 independent cohorts with IFE (7.5%; P = 4.83 × 10(-18), Fishers exact test). Mutations occurred significantly more frequently in the more severe phenotypes, with mutation detection rates ranging from 12/245 (4.9%) in individuals with BECTS to 9/51 (17.6%) in individuals with CSWS (P = 0.009, Cochran-Armitage test for trend). In addition, exon-disrupting microdeletions were found in 3 of 286 individuals (1.0%; P = 0.004, Fishers exact test). These results establish alterations of the gene encoding the NMDA receptor NR2A subunit as a major genetic risk factor for IFE.
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Reoperation for refractory epilepsy in childhood: a second chance for selected patients.
Neurosurgery
PUBLISHED: 07-12-2013
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Reoperations account for >10% in pediatric epilepsy surgery cohorts, and they are especially relevant in young children with catastrophic epilepsy.
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Consensus on diagnosis and management of JME: From founders observations to current trends.
Epilepsy Behav
PUBLISHED: 06-13-2013
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An international workshop on juvenile myoclonic epilepsy (JME) was conducted in Avignon, France in May 2011. During that workshop, a group of 45 experts on JME, together with one of the founding fathers of the syndrome of JME ("Janz syndrome"), Prof. Dr. Dieter Janz from Berlin, reached a consensus on diagnostic criteria and management of JME. The international experts on JME proposed two sets of criteria, which will be helpful for both clinical and scientific purposes. Class I criteria encompass myoclonic jerks without loss of consciousness exclusively occurring on or after awakening and associated with typical generalized epileptiform EEG abnormalities, with an age of onset between 10 and 25. Class II criteria allow the inclusion of myoclonic jerks predominantly occurring after awakening, generalized epileptiform EEG abnormalities with or without concomitant myoclonic jerks, and a greater time window for age at onset (6-25years). For both sets of criteria, patients should have a clear history of myoclonic jerks predominantly occurring after awakening and an EEG with generalized epileptiform discharges supporting a diagnosis of idiopathic generalized epilepsy. Patients with JME require special management because their epilepsy starts in the vulnerable period of adolescence and, accordingly, they have lifestyle issues that typically increase the likelihood of seizures (sleep deprivation, exposure to stroboscopic flashes in discos, alcohol intake, etc.) with poor adherence to antiepileptic drugs (AEDs). Results of an inventory of the different clinical management strategies are given. This article is part of a supplemental special issue entitled Juvenile Myoclonic Epilepsy: What is it Really?
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EEG-fMRI in atypical benign partial epilepsy.
Epilepsia
PUBLISHED: 05-01-2013
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Atypical benign partial epilepsy (ABPE) is a subgroup among the idiopathic focal epilepsies of childhood. Aim of this study was to investigate neuronal networks underlying ABPE and compare the results with previous electroencephalography (EEG)-functional magnetic resonance imaging (fMRI) studies of related epilepsy syndromes. Ten patients with ABPE underwent simultaneous EEG-fMRI recording. In all 10 patients several types of interictal epileptiform discharges (IEDs) were recorded. Individual IED-associated blood oxygen level-dependent (BOLD) signal changes were analyzed in a single subject analysis for each IED type (33 studies). A group analysis was also performed to determine common BOLD signal changes across the patients. IED-associated BOLD signal changes were found in 31 studies. Focal BOLD signal changes concordant with the spike field (21 studies) and distant cortical and subcortical BOLD signal changes (31 studies) were detected. The group analysis revealed a thalamic activation. This study demonstrated that ABPE is characterized by patterns similar to studies in rolandic epilepsy (focal BOLD signal changes in the spike field) as well as patterns observed in continuous spikes and waves during slow sleep (CSWS) (distant BOLD signal changes in cortical and subcortical structures), thereby underscoring that idiopathic focal epilepsies of childhood form a spectrum of overlapping syndromes.
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Seizure and cognitive outcomes of epilepsy surgery in infancy and early childhood.
Eur. J. Paediatr. Neurol.
PUBLISHED: 03-20-2013
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To investigate seizure and developmental outcomes following epilepsy surgery in very young children and determine their predictive factors.
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Simultaneous EEG and fMRI recordings (EEG-fMRI) in children with epilepsy.
Epilepsia
PUBLISHED: 03-12-2013
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By combining electroencephalography (EEG) with functional magnetic resonance imaging (fMRI) it is possible to describe blood oxygenation level-dependent (BOLD) signal changes related to EEG patterns. This way, EEG-pattern-associated networks of hemodynamic changes can be detected anywhere in the brain with good spatial resolution. This review summarizes EEG-fMRI studies that have been performed in children with epilepsy. EEG-fMRI studies in focal epilepsy (structural and nonlesional cases, benign epilepsy with centrotemporal spikes), generalized epilepsy (especially absence epilepsy), and epileptic encephalopathies (West syndrome, Lennox-Gastaut syndrome, continuous spike and waves during slow sleep, and Dravet syndrome) are presented. Although EEG-fMRI was applied mainly to localize the region presumably generating focal interictal discharges in focal epilepsies, EEG-fMRI identified underlying networks in patients with generalized epilepsies and thereby contributed to a better understanding of these epilepsies. In epileptic encephalopathies a specific fingerprint of hemodynamic changes associated with the particular syndrome was detected. The value of the EEG-fMRI technique for diagnosis and investigation of pathogenetic mechanisms of different forms of epilepsy is discussed.
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Iterative phenotyping of 15q11.2, 15q13.3 and 16p13.11 microdeletion carriers in pediatric epilepsies.
Epilepsy Res.
PUBLISHED: 02-18-2013
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Microdeletions at 15q11.2, 15q13.3 and 16p13.11 are known genetic risk factors for idiopathic generalized epilepsies and other neurodevelopmental disorders. The full phenotypic range of this microdeletion triad in pediatric epilepsies is unknown. We attempted to describe associated phenotypes in a cohort of pediatric epilepsy patients. We screened 570 patients with pediatric epilepsies including idiopathic generalized epilepsies, focal epilepsies and fever-associated epilepsy syndromes for microdeletions at 15q11.2, 15q13.3 and 16p13.11 using quantitative polymerase chain reaction. Identified microdeletions were confirmed using array comparative hybridization. Ten microdeletions in 15q11.2 (n=3), 15q13.3 (n=3) and 16p13.11 (n=4) were identified (1.8%). 9/10 microdeletions were identified in patients with IGE (6/101, 6.0%) or patients with generalized EEG patterns without seizures (3/122, 2.5%). 6/10 microdeletion carriers had various degrees of ID; the frequency of microdeletions in patients with epilepsy and ID was higher (4.6%) compared to patients with normal intellect (0.9%). Iterative phenotyping revealed a wide range of generalized epilepsy phenotypes. In our pediatric cohort, recurrent microdeletions at 15q11.2, 15q13.3 and 16p13.11 are mainly associated with phenotypes related to idiopathic generalized epilepsies or related EEG patterns. In contrast to previous reports, these recurrent microdeletions are virtually absent in focal epilepsies, FS, FS+ and GEFS+. Microdeletion carriers have a five-fold risk to present with various degrees of ID compared to patients without these risk factors. This microdeletion triad might help delineate a novel spectrum of epilepsy phenotypes classifiable through clinical, electrographic and genetic data.
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Everolimus in tuberous sclerosis patients with intractable epilepsy: a treatment option?
Eur. J. Paediatr. Neurol.
PUBLISHED: 02-07-2013
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Tuberous Sclerosis Complex (TSC) is an often severe neurodevelopmental disorder caused by overactivation of the mTOR pathway due to mutations in either the TSC1 or TSC2 genes. Seizures are the primary cause of neurologic morbidity and often refractory. The mTOR inhibitor everolimus was recently approved for the treatment of giant cell astrocytomas and renal angiomyolipomas in TSC. Whether everolimus has any direct effect on epilepsy in TSC is not known.
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Seizure control and developmental trajectories after hemispherotomy for refractory epilepsy in childhood and adolescence.
Epilepsia
PUBLISHED: 02-05-2013
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To evaluate the seizure control and developmental outcomes after hemispherotomy for refractory epilepsy in childhood and to identify their predictive factors.
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Structural genomic variation in childhood epilepsies with complex phenotypes.
Eur. J. Hum. Genet.
PUBLISHED: 01-27-2013
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A genetic contribution to a broad range of epilepsies has been postulated, and particularly copy number variations (CNVs) have emerged as significant genetic risk factors. However, the role of CNVs in patients with epilepsies with complex phenotypes is not known. Therefore, we investigated the role of CNVs in patients with unclassified epilepsies and complex phenotypes. A total of 222 patients from three European countries, including patients with structural lesions on magnetic resonance imaging (MRI), dysmorphic features, and multiple congenital anomalies, were clinically evaluated and screened for CNVs. MRI findings including acquired or developmental lesions and patient characteristics were subdivided and analyzed in subgroups. MRI data were available for 88.3% of patients, of whom 41.6% had abnormal MRI findings. Eighty-eight rare CNVs were discovered in 71 out of 222 patients (31.9%). Segregation of all identified variants could be assessed in 42 patients, 11 of which were de novo. The frequency of all structural variants and de novo variants was not statistically different between patients with or without MRI abnormalities or MRI subcategories. Patients with dysmorphic features were more likely to carry a rare CNV. Genome-wide screening methods for rare CNVs may provide clues for the genetic etiology in patients with a broader range of epilepsies than previously anticipated, including in patients with various brain anomalies detectable by MRI. Performing genome-wide screens for rare CNVs can be a valuable contribution to the routine diagnostic workup in patients with a broad range of childhood epilepsies.European Journal of Human Genetics advance online publication, 27 November 2013; doi:10.1038/ejhg.2013.262.
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The role of SLC2A1 in early onset and childhood absence epilepsies.
Epilepsy Res.
PUBLISHED: 01-08-2013
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Early Onset Absence Epilepsy constitutes an Idiopathic Generalized Epilepsy with absences starting before the age of four years. Mutations in SLC2A1, encoding the glucose transporter, account for approximately 10% of EOAE cases. The role of SLC2A1 mutations in absence epilepsies with a later onset has not been assessed. We found two mutation carriers in 26 EOAE patients, while no mutations were found in 124 probands affected by CAE or JAE.
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Variability of EEG-fMRI findings in patients with SCN1A-positive Dravet syndrome.
Epilepsia
PUBLISHED: 01-07-2013
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Dravet syndrome (DS) or severe myoclonic epilepsy of infancy is an intractable epileptic encephalopathy of early childhood that is caused by a mutation in the SCN1A gene in most patients. The aim of this study was to identify a syndrome-specific epileptic network underlying interictal epileptiform discharges (IEDs) in patients with DS.
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Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy.
Epilepsia
PUBLISHED: 01-07-2013
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Neurexins are neuronal adhesion molecules located in the presynaptic terminal, where they interact with postsynaptic neuroligins to form a transsynaptic complex required for efficient neurotransmission in the brain. Recently, deletions and point mutations of the neurexin 1 (NRXN1) gene have been associated with a broad spectrum of neuropsychiatric disorders. This study aimed to investigate if NRXN1 deletions also increase the risk of idiopathic generalized epilepsies (IGEs).
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Dynamic imaging of coherent sources reveals different network connectivity underlying the generation and perpetuation of epileptic seizures.
PLoS ONE
PUBLISHED: 01-01-2013
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The concept of focal epilepsies includes a seizure origin in brain regions with hyper synchronous activity (epileptogenic zone and seizure onset zone) and a complex epileptic network of different brain areas involved in the generation, propagation, and modulation of seizures. The purpose of this work was to study functional and effective connectivity between regions involved in networks of epileptic seizures. The beginning and middle part of focal seizures from ictal surface EEG data were analyzed using dynamic imaging of coherent sources (DICS), an inverse solution in the frequency domain which describes neuronal networks and coherences of oscillatory brain activities. The information flow (effective connectivity) between coherent sources was investigated using the renormalized partial directed coherence (RPDC) method. In 8/11 patients, the first and second source of epileptic activity as found by DICS were concordant with the operative resection site; these patients became seizure free after epilepsy surgery. In the remaining 3 patients, the results of DICS / RPDC calculations and the resection site were discordant; these patients had a poorer post-operative outcome. The first sources as found by DICS were located predominantly in cortical structures; subsequent sources included some subcortical structures: thalamus, Nucl. Subthalamicus and cerebellum. DICS seems to be a powerful tool to define the seizure onset zone and the epileptic networks involved. Seizure generation seems to be related to the propagation of epileptic activity from the primary source in the seizure onset zone, and maintenance of seizures is attributed to the perpetuation of epileptic activity between nodes in the epileptic network. Despite of these promising results, this proof of principle study needs further confirmation prior to the use of the described methods in the clinical praxis.
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Methodology of photic stimulation revisited: updated European algorithm for visual stimulation in the EEG laboratory.
Epilepsia
PUBLISHED: 11-16-2011
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Intermittent photic stimulation (IPS) is a common procedure performed in the electroencephalography (EEG) laboratory in children and adults to detect abnormal epileptogenic sensitivity to flickering light (i.e., photosensitivity). In practice, substantial variability in outcome is anecdotally found due to the many different methods used per laboratory and country. We believe that standardization of procedure, based on scientific and clinical data, should permit reproducible identification and quantification of photosensitivity. We hope that the use of our new algorithm will help in standardizing the IPS procedure, which in turn may more clearly identify and assist monitoring of patients with epilepsy and photosensitivity. Our algorithm goes far beyond that published in 1999 (Epilepsia, 1999a, 40, 75; Neurophysiol Clin, 1999b, 29, 318): it has substantially increased content, detailing technical and logistical aspects of IPS testing and the rationale for many of the steps in the IPS procedure. Furthermore, our latest algorithm incorporates the consensus of repeated scientific meetings of European experts in this field over a period of 6 years with feedback from general neurologists and epileptologists to improve its validity and utility. Accordingly, our European group has provided herein updated algorithms for two different levels of methodology: (1) requirements for defining photosensitivity in patients and in family members of known photosensitive patients and (2) requirements for tailored studies in patients with a clear history of visually induced seizures or complaints, and in those already known to be photosensitive.
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Abnormal changes of synaptic excitability in migraine with aura.
Cereb. Cortex
PUBLISHED: 11-11-2011
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Migraine patients are characterized by altered cortical excitability and information processing between attacks. The relationship between these abnormalities is still poorly understood. In this study, visual evoked potentials (VEP) and proton magnetic resonance spectroscopy were recorded simultaneously in migraineurs and healthy subjects. In order to investigate the homeostatic-like plasticity in the visual cortex, cortical excitability was modified using transcranial direct current stimulation (tDCS). Before any stimulation, migraineurs showed significantly higher glutamate/creatine ratios (Glx/Cr) than healthy subjects. In healthy subjects, excitatory (anodal) tDCS caused an increase and inhibitory (cathodal) tDCS a decrease in the Glx/Cr ratio. Subsequent photic stimulation (PS) reversed the changes in Glx/Cr ratios, which returned back to baseline, demonstrating homeostatic-like metaplasticity in the control group. In migraine patients, both anodal and cathodal tDCS decreased the Glx/Cr ratio, which did not return to baseline after PS. While healthy subjects showed an increase in VEP amplitude under anodal and a reduction under cathodal tDCS, the modifiability of VEP under tDCS was reduced in migraineurs. The results demonstrate a reduced responsiveness of the occipital cortex to interventions that change cortical excitability in migraine. Moreover, altered glutamatergic neurotransmission seems to mediate the relation between abnormal cortical information processing and excitability in migraineurs.
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Absence seizures with intellectual disability as a phenotype of the 15q13.3 microdeletion syndrome.
Epilepsia
PUBLISHED: 11-02-2011
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15q13.3 microdeletions are the most common genetic findings identified in idiopathic generalized epilepsies to date, and they are present in up to 1% of patients. In addition, 15q13.3 microdeletions have been described in patients with epilepsy as part of a complex neurodevelopmental phenotype. We analyzed a cohort of 570 patients with various pediatric epilepsies for 15q13.3 microdeletions. Screening was performed using quantitative polymerase chain reaction; deletions were confirmed by array comparative genomic hybridization (CGH). We carried out detailed phenotyping of deletion carriers. In total, we identified four pediatric patients with 15q13.3 microdeletions, including one previously described patient. Two of four deletions were de novo, one deletion was inherited from an unaffected parent, and for one patient the inheritance is unknown. All four patients had absence epilepsy with various degrees of intellectual disability. We suggest that absence epilepsy accompanied by intellectual disability may represent a common phenotype of the 15q13.3 microdeletion in pediatric patients with epilepsy.
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Comprehensive analysis of candidate genes for photosensitivity using a complementary bioinformatic and experimental approach.
Epilepsia
PUBLISHED: 08-29-2011
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Photoparoxysmal response (PPR) is a highly heritable electroencephalographic trait characterized by an increased sensitivity to photic stimulation. It may serve as an endophenotype for idiopathic generalized epilepsy. Family linkage studies identified susceptibility loci for PPR on chromosomes 5q35.3, 8q21.13, and 16p13.3. This study aimed to identify key candidate genes within these loci. We used bioinformatics tools for gene prioritization integrating information on biologic function, sequence data, gene expression, and others. The prime candidate gene from this analysis was sequenced in 48 photopositive probands. Presumed functional implications of identified polymorphisms were investigated using bioinformatics methods. The glutamate receptor subunit gene GRIN2A was identified as a prime candidate gene. Sequence analysis revealed various new polymorphisms. None of the identified variants was predicted to be functionally relevant. We objectified the selection of candidate genes for PPR without an a priori hypothesis. Particularly among the various ion channel genes in the linkage regions, GRIN2A was identified as the prime candidate gene. GRIN2A mutations have recently been identified in various epilepsies. Even though our mutation analysis failed to demonstrate direct involvement of GRIN2A in photosensitivity, in silico gene prioritization may provide a useful tool for the identification of candidate genes within large genomic regions.
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Impact of ABCC2 genotype on antiepileptic drug response in Caucasian patients with childhood epilepsy.
Pharmacogenet. Genomics
PUBLISHED: 07-30-2011
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Antiepileptic treatment response has been suggested to be modulated by genetic polymorphisms of drug efflux transporters, in particular ABCB1. Recently, we found a significant association of ABCC2 -24C>T with nonresponse, primarily in the context of generalized epilepsy. Moreover, ABCC2 1249G>A was reported to alter transmembranal carbamazepine transport. Therefore, we aimed to confirm the association of ABCC2 variants with pharmacotherapy-resistance in Caucasians mainly affected by partial epilepsy.
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A retrospective population-based study on seizures related to childhood vaccination.
Epilepsia
PUBLISHED: 06-21-2011
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Cases of severe childhood epilepsies in temporal association with vaccination have great impact on the acceptance of vaccination programs by parents and health care providers. However, little is known about the type and frequency of seizures and epilepsy syndromes following vaccination. This study aims to describe the clinical features of children presenting with seizures after vaccination using a register-based cohort.
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Transcranial magnetic stimulation reveals high test-retest reliability for phosphenes but not for suppression of visual perception.
Clin Neurophysiol
PUBLISHED: 05-05-2011
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To investigate test-retest reliability of visual cortical excitatory and inhibitory phenomena.
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Valproate reduces spontaneous generalized spikes and waves but not photoparoxysmal reactions in patients with idiopathic generalized epilepsies.
Epilepsia
PUBLISHED: 04-11-2011
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Patients with idiopathic generalized epilepsies (IGEs) often present with interictal spike-wave discharges (SWDs) at rest (spontaneous SWDs), during hyperventilation, and in response to photic stimulation (photoparoxysmal response or PPR). Valproic acid (VPA) is a first-line antiepileptic drug for therapy of patients with IGE. Herein we investigated the effect of VPA on all three types of SWDs in children and adolescents with IGE.
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A de novo 1.1Mb microdeletion of chromosome 19p13.11 provides indirect evidence for EPS15L1 to be a strong candidate for split hand split foot malformation.
Eur J Med Genet
PUBLISHED: 03-11-2011
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We describe a 3.5 year old girl presenting with short stature, developmental delay, marked muscular hypotonia with ataxia, premature pubarche, and dysmorphic features. A 1.07-1.12Mb-sized de novo microdeletion of chromosome 19p13.11 is most likely the cause for the clinical phenotype. The patient did not show any abnormalities of the extremities which contrasts with the finding of one previously reported patient with an overlapping deletion presenting with split hand and foot malformation (SHFM). The remarkable difference is that in the previously described patient but not in the patient reported herein the genes EPS15L1 and CALR3 were deleted. As EPS15L1 has been associated with limb development previously, the presented case provides indirect evidence that this may be a new candidate gene for SHFM. A possible genotype-phenotype correlation is provided based on literature review and comparison of our patient to the previously reported patients with overlapping or partly overlapping copy number variations in 19p13.11.
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EEG-fMRI reveals activation of brainstem and thalamus in patients with Lennox-Gastaut syndrome.
Epilepsia
PUBLISHED: 01-28-2011
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Even if etiologies of Lennox-Gastaut syndrome (LGS) are diverse, the multiple causes converge into a final common pathway that results in this specific epilepsy phenotype. There is little knowledge, however, about neuronal networks that may be a part of this pathway.
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Improving sensitivity of EEG-fMRI studies in epilepsy: the role of sleep-specific activity.
Neurosci. Lett.
PUBLISHED: 01-12-2011
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Using simultaneous recordings of EEG and functional MRI (EEG-fMRI) in patients with focal epilepsy, recent studies have revealed insufficient sensitivity and a lack of correspondence between epileptic EEG foci and activation patterns in some patients. In this study of children with focal epilepsy, we explore whether sleep-specific activity (sleep spindles, k-complexes and vertex sharp waves) may increase the sensitivity of EEG-fMRI of interictal epileptiform discharges (IED). When considering the sleep-specific activity in a statistical model, it was possible to increase the statistical significance of the activated voxels inside of the expected source of the IED and to reduce the number of activated voxels outside of it. According to this study, it could be worthwhile to include sleep-specific activity into the model by analyzing EEG-fMRI data in epilepsy.
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A 2 Mb deletion in 14q13 associated with severe developmental delay and hemophagocytic lymphohistiocytosis.
Eur J Med Genet
PUBLISHED: 01-09-2011
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Interstitial deletions of chromosome 14 have rarely been described. We report on a boy in whom a 2 Mb deletion in 14q13 was discovered by array CGH. The deletion was a de novo event. The boy presented with asymmetrical growth retardation at birth. There was severe developmental delay with muscular hypotonia and focal epilepsy with apneic episodes progressing to serial tonic seizures. At the age of 3 3/12 years he was diagnosed with pneumonia. In the further course he developed symptoms of hemophagocytic lymphohistiocytosis. He died due to organ failure. Herein the clinical findings are compared to patients with cytogenetic visible deletions encompassing the region deleted in the proband and the possible connection with the deleted genes.
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A retrospective study of the relation between vaccination and occurrence of seizures in Dravet syndrome.
Epilepsia
PUBLISHED: 01-04-2011
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Dravet syndrome is a severe epileptic encephalopathy starting in the first year of life. Mutations in SCN1A can be identified in the majority of patients, and epileptic seizures in the setting of fever are a clinical hallmark. Fever is also commonly seen after vaccinations and provocation of epileptic seizures by vaccinations in patients with Dravet syndrome has been reported, but not systematically assessed. In a retrospective evaluation of 70 patients with Dravet syndrome and SCN1A mutations, seizures following vaccinations were reported in 27%. In 58% of these patients vaccination-related seizures represented the first clinical manifestation. The majority of seizures occurred after DPT vaccinations and within 72 h after vaccination. Two-thirds of events occurred in the context of fever. Our findings highlight seizures after vaccinations as a common feature in Dravet syndrome and emphasize the need for preventive measures for seizures triggered by vaccination or fever in these children.
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Behavioural treatment programme contributes to normalization of contingent negative variation in children with migraine.
Cephalalgia
PUBLISHED: 11-08-2010
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Migraine is a disorder of central information processing which may be characterized by increased amplitudes and reduced habituation of evoked and event-related potentials. In this pilot study, special behavioural training of habituation to aversive stimuli (MIPAS-Family?=?Migraine Patient Seminar for Families) was developed and proven effective in children suffering from migraine without aura.
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A duplication in 1q21.3 in a family with early onset and childhood absence epilepsy.
Epilepsia
PUBLISHED: 09-24-2010
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Early onset absence epilepsy (EOAE) starting before the age of 4 years constitutes a rare subgroup of the idiopathic generalized epilepsies (IGEs). A strong genetic component in IGE has been suggested by twin and family studies. We describe a boy with absence seizures starting at the age of 9 months whose parents both had childhood absence epilepsy. A 192-kb duplication in 1q21.3 was identified in the proband and his father, encompassing the gene CHRNB2 coding for the ?-2 subunit of the nicotinic acetylcholine receptor and the gene ADAR coding for adenosine deaminase, an enzyme responsible for RNA editing. Both are candidate genes for seizure disorders. The duplication was not identified in 191 independent IGE patients (93 EOAE; 98 classical IGE) or in 1,157 population controls.
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Absence seizures: individual patterns revealed by EEG-fMRI.
Epilepsia
PUBLISHED: 08-17-2010
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Absences are characterized by an abrupt onset and end of generalized 3-4 Hz spike and wave discharges (GSWs), accompanied by unresponsiveness. Although previous electroencephalography-functional magnetic resonance imaging (EEG-fMRI) studies showed that thalamus, default mode areas, and caudate nuclei are involved in absence seizures, the contribution of these regions throughout the ictal evolution of absences remains unclear. Furthermore, animal models provide evidence that absences are initiated by a cortical focus with a secondary involvement of the thalamus. The aim of this study was to investigate dynamic changes during absences.
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Neuronal networks in children with continuous spikes and waves during slow sleep.
Brain
PUBLISHED: 08-05-2010
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Epileptic encephalopathy with continuous spikes and waves during slow sleep is an age-related disorder characterized by the presence of interictal epileptiform discharges during at least >85% of sleep and cognitive deficits associated with this electroencephalography pattern. The pathophysiological mechanisms of continuous spikes and waves during slow sleep and neuropsychological deficits associated with this condition are still poorly understood. Here, we investigated the haemodynamic changes associated with epileptic activity using simultaneous acquisitions of electroencephalography and functional magnetic resonance imaging in 12 children with symptomatic and cryptogenic continuous spikes and waves during slow sleep. We compared the results of magnetic resonance to electric source analysis carried out using a distributed linear inverse solution at two time points of the averaged epileptic spike. All patients demonstrated highly significant spike-related positive (activations) and negative (deactivations) blood oxygenation-level-dependent changes (P < 0.05, family-wise error corrected). The activations involved bilateral perisylvian region and cingulate gyrus in all cases, bilateral frontal cortex in five, bilateral parietal cortex in one and thalamus in five cases. Electrical source analysis demonstrated a similar involvement of the perisylvian brain regions in all patients, independent of the area of spike generation. The spike-related deactivations were found in structures of the default mode network (precuneus, parietal cortex and medial frontal cortex) in all patients and in caudate nucleus in four. Group analyses emphasized the described individual differences. Despite aetiological heterogeneity, patients with continuous spikes and waves during slow sleep were characterized by activation of the similar neuronal network: perisylvian region, insula and cingulate gyrus. Comparison with the electrical source analysis results suggests that the activations correspond to both initiation and propagation pathways. The deactivations in structures of the default mode network are consistent with the concept of epileptiform activity impacting on normal brain function by inducing repetitive interruptions of neurophysiological function.
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Optimal HRF and smoothing parameters for fMRI time series within an autoregressive modeling framework.
J. Integr. Neurosci.
PUBLISHED: 08-01-2010
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The analysis of time series obtained by functional magnetic resonance imaging (fMRI) may be approached by fitting predictive parametric models, such as nearest-neighbor autoregressive models with exogeneous input (NNARX). As a part of the modeling procedure, it is possible to apply instantaneous linear transformations to the data. Spatial smoothing, a common preprocessing step, may be interpreted as such a transformation. The autoregressive parameters may be constrained, such that they provide a response behavior that corresponds to the canonical haemodynamic response function (HRF). We present an algorithm for estimating the parameters of the linear transformations and of the HRF within a rigorous maximum-likelihood framework. Using this approach, an optimal amount of both the spatial smoothing and the HRF can be estimated simultaneously for a given fMRI data set. An example from a motor-task experiment is discussed. It is found that, for this data set, weak, but non-zero, spatial smoothing is optimal. Furthermore, it is demonstrated that activated regions can be estimated within the maximum-likelihood framework.
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Association study of TRPC4 as a candidate gene for generalized epilepsy with photosensitivity.
Neuromolecular Med.
PUBLISHED: 04-19-2010
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Photoparoxysmal response (PPR) is characterized by abnormal visual sensitivity of the brain to photic stimulation. Frequently associated with idiopathic generalized epilepsies (IGEs), it might be an endophenotype for cortical excitability. Transient receptor potential cation (TRPC) channels are involved in the generation of epileptiform discharges, and TRPC4 constitutes the main TRPC channel in the central nervous system. The present study investigated an association of PPR with sequence variations of the TRPC4 gene. Thirty-five single nucleotide polymorphisms (SNP) within TRPC4 were genotyped in 273 PPR probands and 599 population controls. Association analyses were performed for the broad PPR endophenotype (PPR types I-IV; n = 273), a narrow model of affectedness (PPR types III and IV; n = 214) and PPR associated with IGE (PPR/IGE; n = 106) for each SNP and for corresponding haplotypes. Association was found between the intron 5 SNP rs10507456 and PPR/IGE both for single markers (P = 0.005) and haplotype level (P = 0.01). Three additional SNPs (rs1535775, rs10161932 and rs7338118) within the same haplotype block were associated with PPR/IGE at P < 0.05 (uncorrected) as well as two more markers (rs10507457, rs7329459) located in intron 3. Again, the corresponding haplotype also showed association with PPR/IGE. Results were not significant following correction for multiple comparisons by permutation analysis for single markers and Bonferroni-Holm for haplotypes. No association was found between variants in TRPC4 and other phenotypes. Our results showed a trend toward association of TRPC4 variants and PPR/IGE. Further studies including larger samples of photosensitive probands are required to clarify the relevance of TRPC4 for PPR and IGE.
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Deletions in 16p13 including GRIN2A in patients with intellectual disability, various dysmorphic features, and seizure disorders of the rolandic region.
Epilepsia
PUBLISHED: 04-14-2010
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Seizure disorders of the rolandic region comprise a spectrum of different epilepsy syndromes ranging from benign rolandic epilepsy to more severe seizure disorders including atypical benign partial epilepsy/pseudo-Lennox syndrome,electrical status epilepticus during sleep, and Landau-Kleffner syndrome. Centrotemporal spikes are the unifying electroencephalographic hallmark of these benign focal epilepsies, indicating a pathophysiologic relationship between the various epilepsies arising from the rolandic region. The etiology of these epilepsies is elusive, but a genetic component is assumed given the heritability of the characteristic electrographic trait. Herein we report on three patients with intellectual disability, various dysmorphic features, and epilepsies involving the rolandic region, carrying previously undescribed deletions in 16p13. The only gene located in the critical region shared by all three patients is GRIN2A coding for the alpha-2 subunit of the neuronal N-methyl-D-aspartate(NMDA) receptor.
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Four patients with speech delay, seizures and variable corpus callosum thickness sharing a 0.440 Mb deletion in region 1q44 containing the HNRPU gene.
Eur J Med Genet
PUBLISHED: 04-02-2010
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Structural genome aberrations are frequently associated with highly variable congenital phenotypes involving mental retardation and developmental delay. Although some of these aberrations may result in recognizable phenotypes, a high degree of phenotypic variability often complicates a comprehensive clinical and genetic diagnosis. We describe four patients with overlapping deletions in chromosomal region 1q44, who show developmental delay, in particular of expressive speech, seizures, hypotonia, CNS anomalies, including variable thickness of the abnormal corpus callosum in three of them. High resolution oligonucleotide and SNP array-based segmental aneuploidy profiling showed that these three patients share a 0.440 Mb interstitial deletion, which does not overlap with previously published consensus regions of 1q44 deletions. Two copies of AKT3 and ZNF238, two previously proposed dosage sensitive candidate genes for microcephaly and agenesis of the corpus callosum, were retained in two of our patients. The deletion shared by our patients encompassed the FAM36A, HNRPU, EFCAB2 and KIF26B genes. Since HNRPU is involved in the regulation of embryonic brain development, this represents a novel plausible candidate gene for the combination of developmental delay, speech delay, hypotonia, hypo- or agenesis of the corpus callosum, and seizures in patients with 1q44 deletions. Since only one of the two patients with deletions including the ZNF124 gene showed a vermis hypoplasia, mere hemizygosity for this gene is not sufficient to cause this anomaly. Moreover, to reconcile the variability in the corpus callosum thickness, additional mechanisms, such as unmasking of hemizygous mutations, position effects and possible interactions with other loci need consideration.
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Decomposition of neurological multivariate time series by state space modelling.
Bull. Math. Biol.
PUBLISHED: 03-30-2010
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Decomposition of multivariate time series data into independent source components forms an important part of preprocessing and analysis of time-resolved data in neuroscience. We briefly review the available tools for this purpose, such as Factor Analysis (FA) and Independent Component Analysis (ICA), then we show how linear state space modelling, a methodology from statistical time series analysis, can be employed for the same purpose. State space modelling, a generalization of classical ARMA modelling, is well suited for exploiting the dynamical information encoded in the temporal ordering of time series data, while this information remains inaccessible to FA and most ICA algorithms. As a result, much more detailed decompositions become possible, and both components with sharp power spectrum, such as alpha components, sinusoidal artifacts, or sleep spindles, and with broad power spectrum, such as FMRI scanner artifacts or epileptic spiking components, can be separated, even in the absence of prior information. In addition, three generalizations are discussed, the first relaxing the independence assumption, the second introducing non-stationarity of the covariance of the noise driving the dynamics, and the third allowing for non-Gaussianity of the data through a non-linear observation function. Three application examples are presented, one electrocardigram time series and two electroencephalogram (EEG) time series. The two EEG examples, both from epilepsy patients, demonstrate the separation and removal of various artifacts, including hum noise and FMRI scanner artifacts, and the identification of sleep spindles, epileptic foci, and spiking components. Decompositions obtained by two ICA algorithms are shown for comparison.
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Febrile infection-related epilepsy syndrome (FIRES): a nonencephalitic encephalopathy in childhood.
Epilepsia
PUBLISHED: 03-18-2010
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Encephalitis is generally presumed, even when seizures follow banal febrile infection, and pathogen detection in cerebrospinal fluid fails. This retrospective multicenter case series reports on 22 previously healthy children aged 3-15 years (median 6.5 years) with prolonged or recurrent seizures occurring 2-14 days (median 5 days) after fever onset (19 children with respiratory or nonspecific infections). Cerebrospinal fluid studies revealed 2-42 cells/microl (median 5 cells/microl) and no pathogens. Electroencephalography showed diffuse slowing or multifocal discharges. Neuroimaging demonstrated normal findings in 10 children. Brain biopsies were performed in seven children showing gliosis but no inflammation. Anesthetic barbiturates were used in 14 children with refractory status epilepticus, and immunotherapy in 9. Two children died, eight remained in a state of impaired consciousness, eight developed therapy-refractory epilepsies, two had behavioral disturbances, and two recovered. The lack of evidence for encephalitis suggests another infection-related pathogenesis of this disastrous epileptic encephalopathy. Therefore, we propose the term "febrile infection-related epilepsy syndrome" (FIRES).
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EEG-fMRI study of generalized spike and wave discharges without transitory cognitive impairment.
Epilepsy Behav
PUBLISHED: 02-06-2010
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Generalized spike and wave discharges (GSW) are often accompanied by transitory cognitive impairment (TCI). As a possible neurophysiological correlate of TCI, activation in the thalamus and deactivation in the frontoparietal brain regions associated with GSW were discussed in previous studies which used simultaneous recordings of EEG and functional MRI (EEG-fMRI) in patients with absence epilepsy. We report on a girl having GSW up to 10seconds without any clinical concomitants. The girl underwent an EEG-fMRI investigation with simultaneous behavioral testing (continuous performance task). Although GSW repeatedly occurred during the task, no TCI was observed. EEG-fMRI revealed bilateral deactivation in frontoparietal brain areas and activation in the thalamus in association with GSWs. This study challenges the relation between cognitive impairment during absences and the characteristic pattern of thalamic activation and deactivation in frontoparietal areas associated with GSW.
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Role of GRM4 in idiopathic generalized epilepsies analysed by genetic association and sequence analysis.
Epilepsy Res.
PUBLISHED: 02-02-2010
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GRM4 encoding the group III metabotropic glutamate receptor 4 (mGluR4), is located on the chromosomal segment 6p21.3 where tentative susceptibility loci for Juvenile Myoclonic Epilepsy (JME) and Photoparoxysmal Response (PPR) have been mapped. The present candidate gene study examined if variation in GRM4 confers susceptibility to IGE.
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Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies.
PLoS Genet.
PUBLISHED: 01-28-2010
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Epilepsy is one of the most common neurological disorders in humans with a prevalence of 1% and a lifetime incidence of 3%. Several genes have been identified in rare autosomal dominant and severe sporadic forms of epilepsy, but the genetic cause is unknown in the vast majority of cases. Copy number variants (CNVs) are known to play an important role in the genetic etiology of many neurodevelopmental disorders, including intellectual disability (ID), autism, and schizophrenia. Genome-wide studies of copy number variation in epilepsy have not been performed. We have applied whole-genome oligonucleotide array comparative genomic hybridization to a cohort of 517 individuals with various idiopathic, non-lesional epilepsies. We detected one or more rare genic CNVs in 8.9% of affected individuals that are not present in 2,493 controls; five individuals had two rare CNVs. We identified CNVs in genes previously implicated in other neurodevelopmental disorders, including two deletions in AUTS2 and one deletion in CNTNAP2. Therefore, our findings indicate that rare CNVs are likely to contribute to a broad range of generalized and focal epilepsies. In addition, we find that 2.9% of patients carry deletions at 15q11.2, 15q13.3, or 16p13.11, genomic hotspots previously associated with ID, autism, or schizophrenia. In summary, our findings suggest common etiological factors for seemingly diverse diseases such as ID, autism, schizophrenia, and epilepsy.
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MIPAS-Family-evaluation of a new multi-modal behavioral training program for pediatric headaches: clinical effects and the impact on quality of life.
J Headache Pain
PUBLISHED: 01-12-2010
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Several meta-analyses have demonstrated that the combination of electrical muscle activity and Temperature Biofeedback could be regarded as gold standard in chronic pediatric headaches. However, these techniques seem to be uneconomical and furthermore they are not directed to improve the social competence as well as resolve possible impairments in daily activities of the child. Therefore, multi-modal behavioral techniques have been proposed, but no studies comparing these with the gold standard were conducted. The present study compared the impact of a new multi-modal behavioral education and training program--MIPAS-Family--with a combined Biofeedback treatment, evaluating clinical efficacy as well as the effect on the quality of life (QoL) of children with chronic headaches. Thirty-four children and adolescents with recurrent headache, ranging from 7 to 16 years, were randomly assigned to the MIPAS-Family (N = 19) or the Biofeedback (N = 15) condition. All patients were diagnosed by the criteria of the International Headache Society. The children and their parents completed headache diaries, diaries of daily living activities and a QoL questionnaire (KINDL). Both groups showed significant improvements concerning the headache intensity and headache duration. We found no significant differences in the main headache parameters between both treatments. After the treatments, the children were less disturbed by their headaches in the domains school, homework, and leisure time. In conclusion, MIPAS-Family is as effective as Biofeedback but it is more cost-effective and addresses the whole family and the daily activities.
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Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies.
Brain
PUBLISHED: 10-20-2009
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Idiopathic generalized epilepsies account for 30% of all epilepsies. Despite a predominant genetic aetiology, the genetic factors predisposing to idiopathic generalized epilepsies remain elusive. Studies of structural genomic variations have revealed a significant excess of recurrent microdeletions at 1q21.1, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 in various neuropsychiatric disorders including autism, intellectual disability and schizophrenia. Microdeletions at 15q13.3 have recently been shown to constitute a strong genetic risk factor for common idiopathic generalized epilepsy syndromes, implicating that other recurrent microdeletions may also be involved in epileptogenesis. This study aimed to investigate the impact of five microdeletions at the genomic hotspot regions 1q21.1, 15q11.2, 16p11.2, 16p13.11 and 22q11.2 on the genetic risk to common idiopathic generalized epilepsy syndromes. The candidate microdeletions were assessed by high-density single nucleotide polymorphism arrays in 1234 patients with idiopathic generalized epilepsy from North-western Europe and 3022 controls from the German population. Microdeletions were validated by quantitative polymerase chain reaction and their breakpoints refined by array comparative genomic hybridization. In total, 22 patients with idiopathic generalized epilepsy (1.8%) carried one of the five novel microdeletions compared with nine controls (0.3%) (odds ratio = 6.1; 95% confidence interval 2.8-13.2; chi(2) = 26.7; 1 degree of freedom; P = 2.4 x 10(-7)). Microdeletions were observed at 1q21.1 [Idiopathic generalized epilepsy (IGE)/control: 1/1], 15q11.2 (IGE/control: 12/6), 16p11.2 IGE/control: 1/0, 16p13.11 (IGE/control: 6/2) and 22q11.2 (IGE/control: 2/0). Significant associations with IGEs were found for the microdeletions at 15q11.2 (odds ratio = 4.9; 95% confidence interval 1.8-13.2; P = 4.2 x 10(-4)) and 16p13.11 (odds ratio = 7.4; 95% confidence interval 1.3-74.7; P = 0.009). Including nine patients with idiopathic generalized epilepsy in this cohort with known 15q13.3 microdeletions (IGE/control: 9/0), parental transmission could be examined in 14 families. While 10 microdeletions were inherited (seven maternal and three paternal transmissions), four microdeletions occurred de novo at 15q13.3 (n = 1), 16p13.11 (n = 2) and 22q11.2 (n = 1). Eight of the transmitting parents were clinically unaffected, suggesting that the microdeletion itself is not sufficient to cause the epilepsy phenotype. Although the microdeletions investigated are individually rare (<1%) in patients with idiopathic generalized epilepsy, they collectively seem to account for a significant fraction of the genetic variance in common idiopathic generalized epilepsy syndromes. The present results indicate an involvement of microdeletions at 15q11.2 and 16p13.11 in epileptogenesis and strengthen the evidence that recurrent microdeletions at 15q11.2, 15q13.3 and 16p13.11 confer a pleiotropic susceptibility effect to a broad range of neuropsychiatric disorders.
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Voltage-gated calcium channels in the etiopathogenesis and treatment of absence epilepsy.
Brain Res Rev
PUBLISHED: 09-03-2009
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Voltage-gated calcium channels are key elements in regulating neuronal excitability and are thus of central importance in the pathogenesis of various forms of epilepsies. Among these, absence epilepsies represent about 10% of epileptic seizures in humans. They are electroencephalographically characterized by bilateral synchronous spike-wave discharge activity associated with loss or severe impairment of consciousness. Extensive studies during the last decades revealed that pathophysiologically increased oscillatory activity, i.e., hyperoscillation within the reticulothalamocortical circuitry, is the electrophysiological correlate of absence epilepsy, with extrathalamocortical structures, e.g., brainstem and cerebellum, projecting to the thalamocortical circuitry, thereby modulating its activity. Voltage-gated calcium channels are one of the central players regulating the transition from tonic to rebound burst-firing modes in both thalamic relay and reticular thalamic nucleus neurons, the burst-firing mode being the substrate of the thalamocortical oscillation. Thus, pharmacological interference with these channels enables effective control of spike-wave discharge activity in patients suffering from absence seizures. In this review, we summarize the medical history of absence epilepsies, their classification and terminology, the diagnostic armamentarium available today and the etiopathogenesis of absences. Finally, various antiepileptic drugs that have been proven to or are supposed to exert anti-absence effects are discussed with respect to their pharmacodynamics and pharmacokinetics.
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Developmental changes of the contingent negative variation in migraine and healthy children.
J Headache Pain
PUBLISHED: 08-17-2009
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It has been hypothesized that abnormalities of information processing in migraine may be attributed to impairment of cerebral maturation. However, the most evidences for this hypothesis have come from cross-sectional studies during childhood. We performed a longitudinal study and recorded contingent negative variation (CNV), an event-related slow cortical potential, in migraine children (n = 27) and age-matched healthy individuals (n = 23) in 1998 and 8 years later (2006). Amplitudes of all CNV components were reduced and habituation of the initial CNV (iCNV) increased in the observed time. However, the reduction of the iCNV amplitude was more pronounced in migraine patients who were in remission in 2006 and in healthy subjects and less pronounced in migraineurs with persisting headaches. Patients with the worsened migraine demonstrated the most pronounced loss of iCNV habituation in 1998 and significantly increased iCNV amplitudes in 2006. This longitudinal study supports the hypothesis of impaired cerebral maturation in migraine and shows that migraine manifestation is a key factor interfering with the natural maturation process of central information processing.
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Clinical variability in distal spinal muscular atrophy type 1 (DSMA1): determination of steady-state IGHMBP2 protein levels in five patients with infantile and juvenile disease.
J. Mol. Med.
PUBLISHED: 07-01-2009
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Distal spinal muscular atrophy type 1 (DSMA1) is caused by mutations in the immunoglobulin mu-binding protein 2 (IGHMBP2) gene. Patients with DSMA1 present between 6 weeks and 6 months of age with progressive muscle weakness and respiratory failure due to diaphragmatic palsy. Contrary to this "classic" infantile disease, we have previously described a DSMA1 patient with juvenile disease onset. In this paper, we present (1) a second juvenile case and (2) the first study of DSMA1 on protein level in patients with infantile (n = 3) as well as juvenile (n = 2) disease onset observing elevated residual steady-state IGHMBP2 protein levels in the patients with late onset DSMA1 as compared to those with classic DSMA1. Mutation screening in IGHMBP2 revealed two patients compound heterozygous for a novel missense mutation (c.1478C-->T; p.T493I) and another previously described mutation. In lymphoblastoid cells of both patients, steady-state IGHMBP2 protein levels were reduced. In comparison to wild-type IGHMBP2, the p.T493I variant protein had an increased tendency to aggregate and spontaneously degrade in vitro. We verified a change in the physicochemical properties of the p.T493I variant which may explain the pathogenicity of this mutation. Our data further suggest that the age of onset of DSMA1 is variable, and we discuss the effect of residual IGHMBP2 protein levels on the clinical course and the severity of the disease.
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Dyschromatosis ptychotropica: an unusual pigmentary disorder in a boy with epileptic encephalopathy and progressive atrophy of the central nervous system-a novel entity?
Eur. J. Pediatr.
PUBLISHED: 06-09-2009
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The skin and the central nervous system are tissues of common ectodermal origin and share a close ontogenetic relationship. Genetic diseases primarily affecting both organ systems are regularly encountered in both dermatological and neurological settings. Here, we report on a boy with epileptic encephalopathy, severe intellectual disability, optic atrophy, and progressive cerebellar and supratentorial atrophy, reminiscent of progressive encephalopathy with edema and hypsarrythmia (PEHO) syndrome displaying a previously undescribed dyschromatosis in the form of progressive reticulate and mottled hyper- and hypopigmentation of the neck and the inguinal and axillary regions. We hypothesised that this combination of neurological and cutaneous findings has a common aetiology and represents a novel recognisable entity. Because of the unusual dermatological findings, we suggest the term dyschromatosis ptychotropica. Recognition of further cases may help elucidate the aetiology of this condition and give insight into the pathophysiology of both pigmentation disorders and epileptic encephalopathies.
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Non-response to antiepileptic pharmacotherapy is associated with the ABCC2 -24C>T polymorphism in young and adult patients with epilepsy.
Pharmacogenet. Genomics
PUBLISHED: 05-06-2009
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We aimed to evaluate the association of non-response to antiepileptic pharmacotherapy with the frequency of variant alleles in the drug transporter genes ABCB1 and ABCC2 or in the CYP2C locus in young patients with epilepsy and an independent cohort of adults with drug-refractory epilepsy.
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fMRI activation during spike and wave discharges evoked by photic stimulation.
Neuroimage
PUBLISHED: 04-06-2009
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Photoparoxysmal response (PPR) is an electroencephalographic (EEG) trait characterized by the occurrence of epileptiform discharges in response to visual stimulation. Studying this trait helps to learn about mechanisms of epileptogenicity. While simultaneous recordings of EEG and functional MRI (EEG-fMRI) in patients with spontaneous generalised spike-wave discharges (GSW) have revealed activation of the thalamus and deactivation in frontoparietal areas, EEG-fMRI studies on evoked GSW such as PPR are lacking. In this EEG-fMRI study, 30 subjects with reported generalised PPR underwent intermittent photic stimulation (IPS) in a 3 T MR scanner. PPR was elicited in 6 subjects, four diagnosed with idiopathic generalised epilepsy and two with tension-type headache. Because PPR is preceded by synchronization of cortical gamma oscillations, blood oxygenation level-dependent (BOLD) signal changes were analysed at the onset of the PPR (standard regressor) and 3 s before the onset of PPR (early regressor) in one model. In all subjects, IPS led to a significant activation of the visual cortex. Based on the early regressor, PPR associated activation was found in the parietal cortex adjacent to the intraparietal sulcus in five and in the premotor cortex in all 6 subjects. The standard regressor revealed deactivation in early activated areas in all subjects and thalamic activation in one subject. In contrast to spontaneous GSW, these results suggest that PPR is a cortical phenomenon with an involvement of the parietal and frontal cortices. Pronounced haemodynamic changes seen with the early regressor could mirror gamma activity that is known to precede PPR.
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Peri-ictal changes of cortical excitability in children suffering from migraine without aura.
Pain
PUBLISHED: 04-02-2009
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In adult patients with migraine, transcranial magnetic stimulation (TMS) has been used to examine cortical excitability between attacks, but there have been discrepant results. No TMS study has examined cortical excitability in children or adolescents with migraine. Here, we employed TMS to study regional excitability of the occipital (phosphene threshold [PT] and suppression of visual perception) and motor (resting motor threshold and cortical silent period) cortex in ten children suffering from migraine without aura and ten healthy age-matched controls. Patients were studied 1-2 days before and after a migraine attack as well as during the inter-migraine interval. The motion aftereffect was also investigated at each time-point as an index of cortical reactivity to moving visual stimuli. Migraineurs had lower PTs compared to healthy participants at each time-point, indicating increased occipital excitability. This increase in occipital excitability was attenuated 1-2 days before a migraine attack as indicated by a relative increase in PTs. The increase in PTs before the next attack was associated with a stronger TMS-induced suppression of visual perception and a prolongation of the motion aftereffect. Motor cortex excitability was not altered in patients and did not change during the migraine cycle. These findings show that pediatric migraine without aura is associated with a systematic shift in occipital excitability preceding the migraine attack. Similar systematic fluctuations in cortical excitability might be present in adult migraineurs and may reflect either a protective mechanism or an abnormal decrease in cortical excitability that predisposes an individual to a migraine attack.
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Mapping brain activity on the verge of a photically induced generalized tonic-clonic seizure.
Epilepsia
PUBLISHED: 03-12-2009
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In a photosensitive patient intermittent photic stimulation (IPS) accidentally provoked a generalized tonic-clonic seizure during simultaneous recordings of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). Before seizure onset, IPS consistently induced generalized photoparoxysmal responses (PPRs). These PPRs were associated with increases in blood oxygen level dependent (BOLD) signal in the visual cortex, the thalamus, and both superior colliculi, and a decrease in BOLD signal in the frontoparietal areas. The BOLD signal in the visual cortex increased in magnitude during consecutive epochs of IPS associated with PPRs. We propose that repeated IPS led to an excessive amount of neuronal activity in the visual cortex that evoked PPRs and finally exceeded a critical threshold and triggered a generalized seizure.
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Combination of EEG-fMRI and EEG source analysis improves interpretation of spike-associated activation networks in paediatric pharmacoresistant focal epilepsies.
Neuroimage
PUBLISHED: 02-12-2009
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Simultaneous recording of EEG and functional MRI (EEG-fMRI) is a promising tool that may be applied in patients with epilepsy to investigate haemodynamic changes associated with interictal epileptiform discharges (IED). As the yield of the EEG-fMRI technique in children with epilepsy is still unclear, the aim of this study was to evaluate whether the combination of EEG-fMRI and EEG source analysis could improve localization of epileptogenic foci in children. Six children with an unambiguous focus localization were selected based on the criterion of the consistency of ictal EEG, PET and ictal SPECT. IEDs were taken as time series for fMRI analysis and as averaged sweeps for the EEG source analysis based on the distributed linear local autoregressive average (LAURA) solution. In four patients, the brain area with haemodymanic changes corresponded to the epileptogenic zone. However, additional distant regions with haemodynamic response were observed. Source analysis located the source of the initial epileptic activity in all cases in the presumed epileptogenic zone and revealed propagation in five cases. In three cases there was a good correspondence between haemodynamic changes and source localization at both the beginning and the propagation of IED. In the remaining three cases, at least one area of haemodynamic changes corresponded to either the beginning or the propagation. In most children analysed, EEG-fMRI revealed extended haemodynamic response, which were difficult to interpret without an appropriate reference, i.e. a priori hypothesis about epileptogenic zone. EEG source analysis may help to differentiate brain areas with haemodynamic response.
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Noninvasive determination of the tension-time index in Duchenne muscular dystrophy.
Am J Phys Med Rehabil
PUBLISHED: 02-05-2009
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Noninvasive determination of the tension-time index of the inspiratory muscles (TT MUS) can identify predisposition to respiratory muscle fatigue in neuromuscular disease. We correlated TT MUS with age and extent of need of ventilator use for patients with Duchenne muscular dystrophy.
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Hashimoto encephalopathy in a 15-year-old-girl: EEG findings and follow-up.
Pediatr. Neurol.
PUBLISHED: 01-26-2009
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Hashimoto encephalopathy is characterized by severe neuropsychiatric findings, including psychosis, confusion, seizures, stupor, stroke-like episodes, tremor, and myoclonus. The combination of findings is variable. Hashimoto encephalopathy constitutes an important differential diagnosis in patients with encephalopathy. The triad of encephalopathy, corresponding electroencephalographic slowing, and increased protein content in cerebrospinal fluid should prompt testing of anti-thyroid antibodies in blood and cerebrospinal fluid. Elevated antibody levels support the diagnosis. We describe a 15-year-old girl with a fluctuating course of Hashimoto encephalopathy. Electroencephalograms revealed no specific alterations, but widespread slowing of the background activity occurred during two episodes of fluctuating encephalopathy. Cortical edema was indicated by cranial magnetic resonance imaging during the first episode of encephalopathy, in the context of cerebral seizures. Laboratory findings were in accordance with Hashimoto encephalopathy, which was steroid-responsive.
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15q13.3 microdeletions increase risk of idiopathic generalized epilepsy.
Nat. Genet.
PUBLISHED: 01-11-2009
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We identified 15q13.3 microdeletions encompassing the CHRNA7 gene in 12 of 1,223 individuals with idiopathic generalized epilepsy (IGE), which were not detected in 3,699 controls (joint P = 5.32 x 10(-8)). Most deletion carriers showed common IGE syndromes without other features previously associated with 15q13.3 microdeletions, such as intellectual disability, autism or schizophrenia. Our results indicate that 15q13.3 microdeletions constitute the most prevalent risk factor for common epilepsies identified to date.
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Hemodynamic changes preceding the interictal EEG spike in patients with focal epilepsy investigated using simultaneous EEG-fMRI.
Neuroimage
PUBLISHED: 01-05-2009
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EEG-fMRI is a non-invasive technique that allows the investigation of epileptogenic networks in patients with epilepsy. Lately, BOLD changes occurring before the spike were found in patients with generalized epilepsy. The study of metabolic changes preceding spikes might improve our knowledge of spike generation. We tested this hypothesis in patients with idiopathic and symptomatic focal epilepsy. Eleven consecutive patients were recorded at 3 T: five with idiopathic focal and 6 with symptomatic focal epilepsy. Thirteen spike types were analyzed separately. Statistical analysis was performed using the timing of spikes as events, modeled with HRFs peaking between -9 s and +9 s around the spike. HRFs were calculated the most focal BOLD response. Eleven of the thirteen studies showed prespike BOLD responses. Prespike responses were more focal than postspike responses. Three studies showed early positive followed by later negative BOLD responses in the spike field. Three had early positive BOLD responses in the spike field, which remained visible in the later maps. Three others had positive BOLD responses in the spike field, later propagating to surrounding areas. HRFs peaked between -5 and +6 s around the spike timing. No significant EEG changes could be identified prior to the spike. BOLD changes prior to the spike frequently occur in focal epilepsies. They are more focal than later BOLD changes and strongly related to the spike field. Early changes may result from increased neuronal activity in the spike field prior to the EEG spike and reflect an event more localized than the spike itself.
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Muscle artifact suppression using independent-component analysis and state-space modeling.
Conf Proc IEEE Eng Med Biol Soc
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In this paper, we aim at suppressing the muscle artifacts present in electroencephalographic (EEG) signals with a technique based on a combination of Independent Component Analysis (ICA) and State-Space Modeling (SSM). The novel algorithm uses ICA to provide an initial model for SSM which is further optimized by the maximum-likelihood approach. This model is fitted to artifact-free data. Then it is applied to data with muscle artifacts. The state space is augmented by extracting additional components from the data prediction errors. The muscle artifacts are well separated in the additional components and, hence, a suppression of them can be performed. The proposed algorithm is demonstrated by application to a clinical epilepsy EEG data set.
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Exome sequencing in a family with restless legs syndrome.
Mov. Disord.
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Restless legs syndrome (RLS) has a high familial aggregation. To date, several loci and genetic risk factors have been identified, but no causative gene mutation has been found.
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Myoclonic astatic epilepsy (Doose syndrome) - a lamotrigine responsive epilepsy?
Eur. J. Paediatr. Neurol.
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Myoclonic astatic epilepsy (MAE, Doose syndrome) is a difficult to treat idiopathic generalized epilepsy of early childhood. MAE frequently shows the course of an epileptic encephalopathy and may result in permanent cognitive impairment. Systematic analyses on clinical effects of different AED combinations are still needed. The purpose of our study was to analyze the therapeutic effect of adjunctive lamotrigine (LTG) in pharmacoresistant MAE patients.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.