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1.  Focal cortical dysplasia is more common in boys than girls 
Epilepsy & behavior : E&B  2013;27(1):121-123.
Genetics and environment likely contribute to the development of medically intractable epilepsy, however, in most patients the specific combination of etiologies remains unknown. Here we undertook a multicenter retrospective cohort study of sex distribution in pediatric patients undergoing epilepsy surgery, and carried out a secondary analysis of the same population subdivided by histopathologic diagnosis. In the multicenter cohort of intractable epilepsy patients undergoing surgery regardless of etiology (n=206), 63% were boys, which is significantly more boys than expected for the general population (Fisher exact two-tailed p=0.017). Subgroup analysis found that of the 90 patients with a histopathologic diagnosis of focal cortical dysplasia, 72% were boys, giving an odds ratio (OR) of 2.5 (95% CI, 1.34 to 4.62) for male sex. None of the other etiologies had a male sex predominance. Future studies could examine the biological relevance and potential genetic and pathophysiological mechanisms of this observation.
PMCID: PMC3930197  PMID: 23416281
focal cortical dysplasia; pediatric epilepsy; epilepsy surgery; gender; sex
2.  Leaving tissue associated with infrequent intracranial EEG seizure onsets is compatible with post-operative seizure freedom 
Journal of pediatric epilepsy  2012;1(4):211-219.
Identify seizure onset electrodes that need to be resected for seizure freedom in children undergoing intracranial electroencephalography recording for treatment of medically refractory epilepsy. All children undergoing intracranial electroencephalography subdural grid electrode placement at the Children’s Hospital of Philadelphia from 2002-2008 were asked to enroll. We utilized intraoperative pictures to determine the location of the electrodes and define the resection cavity. A total of 15 patients had surgical fields that allowed for complete identification of the electrodes over the area of resection. Eight of 15 patients were seizure free after a follow up of 1.7 to 8 yr. Only one seizure-free patient had complete resection of all seizure onset associated tissue. Seizure free patients had resection of 64.1% of the seizure onset electrode associated tissue, compared to 35.2% in the not seizure free patients (p=0.05). Resection of tissue associated with infrequent seizure onsets did not appear to be important for seizure freedom. Resecting ≥ 90% of the electrodes from the predominant seizure contacts predicted post-operative seizure freedom (p=0.007). The best predictor of seizure freedom was resecting ≥ 90% of tissue involved in majority of a patient’s seizures. Resection of tissue under infrequent seizure onset electrodes was not necessary for seizure freedom.
PMCID: PMC3930198  PMID: 24563805
Epilepsy; epilepsy surgery; cortical dysplasia; neocortical epilepsy; intracranial electroencephalography
3.  Delayed Myelination in an Intrauterine Growth Retardation Model Is Mediated by Oxidative Stress Upregulating Bone Morphogenetic Protein 4 
Intrauterine growth retardation (IUGR) is associated with neurological deficits including cerebral palsy and cognitive and behavioral disabilities. The pathogenesis involves oxidative stress that leads to periventricular white matter injury with a paucity of mature oligodendrocytes and hypomyelination. The molecular mechanisms underlying this damage remain poorly understood. We employed a rat model of IUGR created by bilateral ligation of the uterine artery at embryonic day 19 that results in fetal growth retardation and oxidative stress in the developing brain. The IUGR rat pups showed significant delays in oligodendrocyte differentiation and myelination that resolved by 8 weeks. Bone morphogenetic protein 4 (BMP4), which inhibits oligodendrocyte maturation, was elevated in IUGR brains at postnatal time points and returned to near normal by adulthood. Despite the apparent recovery, behavioral deficiencies were found in 8-week-old female animals, suggesting that the early transient myelination defects have permanent effects. In support of these in vivo data, oligodendrocyte precursor cells cultured from postnatal IUGR rats retained increased BMP4 expression and impaired differentiation that was reversed with the BMP inhibitor noggin. Oxidants in oligodendrocyte cultures increased BMP expression, which decreased differentiation; however, abrogating BMP signaling with noggin in vitro and in BMP-deficient mice prevented these effects. Together, these findings suggest that IUGR results in delayed myelination through the generation of oxidative stress that leads to BMP4 upregulation.
PMCID: PMC3390978  PMID: 22710965
Bone morphogenetic protein (BMP); Intrauterine growth retardation; Myelin; Oligodendrocytes; Oxidative stress; Periventricular white matter injury
4.  Mapping and mining interictal pathological gamma (30–100 Hz) oscillations with clinical intracranial EEG in patients with epilepsy 
Expert systems with applications  2012;39(8):7355-7370.
Localizing an epileptic network is essential for guiding neurosurgery and antiepileptic medical devices as well as elucidating mechanisms that may explain seizure-generation and epilepsy. There is increasing evidence that pathological oscillations may be specific to diseased networks in patients with epilepsy and that these oscillations may be a key biomarker for generating and indentifying epileptic networks. We present a semi-automated method that detects, maps, and mines pathological gamma (30–100 Hz) oscillations (PGOs) in human epileptic brain to possibly localize epileptic networks. We apply the method to standard clinical iEEG (<100 Hz) with interictal PGOs and seizures from six patients with medically refractory epilepsy. We demonstrate that electrodes with consistent PGO discharges do not always coincide with clinically determined seizure onset zone (SOZ) electrodes but at times PGO-dense electrodes include secondary seizure-areas (SS) or even areas without seizures (NS). In 4/5 patients with epilepsy surgery, we observe poor (Engel Class 4) post-surgical outcomes and identify more PGO-activity in SS or NS than in SOZ. Additional studies are needed to further clarify the role of PGOs in epileptic brain.
PMCID: PMC3480232  PMID: 23105174
Epileptic network; Interictal epileptic discharge; Pathological gamma oscillation; Detection; Mapping; Data-mining
5.  Copy number variants and infantile spasms: evidence for abnormalities in ventral forebrain development and pathways of synaptic function 
European Journal of Human Genetics  2011;19(12):1238-1245.
Infantile spasms (ISS) are an epilepsy disorder frequently associated with severe developmental outcome and have diverse genetic etiologies. We ascertained 11 subjects with ISS and novel copy number variants (CNVs) and combined these with a new cohort with deletion 1p36 and ISS, and additional published patients with ISS and other chromosomal abnormalities. Using bioinformatics tools, we analyzed the gene content of these CNVs for enrichment in pathways of pathogenesis. Several important findings emerged. First, the gene content was enriched for the gene regulatory network involved in ventral forebrain development. Second, genes in pathways of synaptic function were overrepresented, significantly those involved in synaptic vesicle transport. Evidence also suggested roles for GABAergic synapses and the postsynaptic density. Third, we confirm the association of ISS with duplication of 14q12 and maternally inherited duplication of 15q11q13, and report the association with duplication of 21q21. We also present a patient with ISS and deletion 7q11.3 not involving MAGI2. Finally, we provide evidence that ISS in deletion 1p36 may be associated with deletion of KLHL17 and expand the epilepsy phenotype in that syndrome to include early infantile epileptic encephalopathy. Several of the identified pathways share functional links, and abnormalities of forebrain synaptic growth and function may form a common biologic mechanism underlying both ISS and autism. This study demonstrates a novel approach to the study of gene content in subjects with ISS and copy number variation, and contributes further evidence to support specific pathways of pathogenesis.
PMCID: PMC3230360  PMID: 21694734
infantile spasms; autism; bioinformatics; copy number variation; deletion 1p36 syndrome
6.  Data mining neocortical high-frequency oscillations in epilepsy and controls 
Brain  2011;134(10):2948-2959.
Transient high-frequency (100–500 Hz) oscillations of the local field potential have been studied extensively in human mesial temporal lobe. Previous studies report that both ripple (100–250 Hz) and fast ripple (250–500 Hz) oscillations are increased in the seizure-onset zone of patients with mesial temporal lobe epilepsy. Comparatively little is known, however, about their spatial distribution with respect to seizure-onset zone in neocortical epilepsy, or their prevalence in normal brain. We present a quantitative analysis of high-frequency oscillations and their rates of occurrence in a group of nine patients with neocortical epilepsy and two control patients with no history of seizures. Oscillations were automatically detected and classified using an unsupervised approach in a data set of unprecedented volume in epilepsy research, over 12 terabytes of continuous long-term micro- and macro-electrode intracranial recordings, without human preprocessing, enabling selection-bias-free estimates of oscillation rates. There are three main results: (i) a cluster of ripple frequency oscillations with median spectral centroid = 137 Hz is increased in the seizure-onset zone more frequently than a cluster of fast ripple frequency oscillations (median spectral centroid = 305 Hz); (ii) we found no difference in the rates of high frequency oscillations in control neocortex and the non-seizure-onset zone neocortex of patients with epilepsy, despite the possibility of different underlying mechanisms of generation; and (iii) while previous studies have demonstrated that oscillations recorded by parenchyma-penetrating micro-electrodes have higher peak 100–500 Hz frequencies than penetrating macro-electrodes, this was not found for the epipial electrodes used here to record from the neocortical surface. We conclude that the relative rate of ripple frequency oscillations is a potential biomarker for epileptic neocortex, but that larger prospective studies correlating high-frequency oscillations rates with seizure-onset zone, resected tissue and surgical outcome are required to determine the true predictive value.
PMCID: PMC3187540  PMID: 21903727
high-frequency oscillations; epilepsy; intracranial EEG
7.  Interobserver reproducibility of electroencephalogram interpretation in critically ill children 
Correct outcome prediction after cardiac arrest in children may improve clinical decision making and family counseling. Various investigators have used EEG to predict outcome with varying success, but one limiting issue is the potential lack of reproducibility of EEG interpretation. Therefore, we aimed to evaluate interobserver agreement using standardized terminology in the interpretation of EEG tracings obtained from critically ill children following cardiac arrest.
3 pediatric neurophysiologists scored 74 EEG samples using standardized categories, terminology, and interpretation rules. Interobserver agreement was evaluated using kappa and intra-class correlation coefficients.
Agreement was substantial for the categories of continuity, burst suppression, sleep architecture, and overall rating. Agreement was moderate for seizure occurrence and inter-ictal epileptiform discharge type. Agreement was fair for inter-ictal epileptiform discharge presence, beta activity, predominant frequency, and fastest frequency. Agreement was slight for maximum voltage and focal slowing presence.
The variability of inter-rater agreement suggests that some EEG features are superior to others for use in a predictive algorithm. Using only reproducible EEG features is needed to ensure the most accurate and consistent predictions. Since even seizure identification had only moderate agreement, studies of non-convulsive seizures in critically ill patients must be conducted and interpreted cautiously.
PMCID: PMC3107383  PMID: 21221016
Electroencephalogram; Interobserver variability; Seizure; Pediatric; Hypoxic Ischemic Encephalopathy; Cardiac Arrest
8.  Interictal EEG spikes identify the region of seizure onset in some, but not all pediatric epilepsy patients 
Epilepsia  2009;51(4):592-601.
The role of sharps and spikes, interictal epileptiform discharges (IEDs), in guiding epilepsy surgery in children remains controversial, particularly with intracranial EEG (IEEG). While ictal recording is the mainstay of localizing epileptic networks for surgical resection, current practice dictates removing regions generating frequent IEDs if they are near the ictal onset zone. Indeed, past studies suggest an inconsistent relationship between IED and seizure onset location, though these studies were based upon relatively short EEG epochs.
We employ a previously validated, computerized spike detector, to measure and localize IED activity over prolonged, representative segments of IEEG recorded from 19 children with intractable, mostly extra temporal lobe epilepsy. Approximately 8 hours of IEEG, randomly selected thirty-minute segments of continuous interictal IEEG per patient were analyzed over all intracranial electrode contacts.
When spike frequency was averaged over the 16-time segments, electrodes with the highest mean spike frequency were found to be within the seizure onset region in 11 of 19 patients. There was significant variability between individual 30-minute segments in these patients, indicating that large statistical samples of interictal activity were required for improved localization. Low voltage fast EEG at seizure onset was the only clinical factor predicting IED localization to the seizure onset region.
Our data suggest that automated IED detection over multiple representative samples of IEEG may be of utility in planning epilepsy surgery for children with intractable epilepsy. Further research is required to better determine which patients may benefit from this technique a priori.
PMCID: PMC2907216  PMID: 19780794
Spike density; intracranial EEG; Seizure onset; Pediatric Epilepsy
9.  Targeted loss of Arx results in a developmental epilepsy mouse model and recapitulates the human phenotype in heterozygous females 
Brain  2009;132(6):1563-1576.
Mutations in the X-linked aristaless-related homeobox gene (ARX) have been linked to structural brain anomalies as well as multiple neurocognitive deficits. The generation of Arx-deficient mice revealed several morphological anomalies, resembling those observed in patients and an interneuron migration defect but perinatal lethality precluded analyses of later phenotypes. Interestingly, many of the neurological phenotypes observed in patients with various ARX mutations can be attributed, in part, to interneuron dysfunction. To directly test this possibility, mice carrying a floxed Arx allele were generated and crossed to Dlx5/6CRE-IRES-GFP(Dlx5/6CIG) mice, conditionally deleting Arx from ganglionic eminence derived neurons including cortical interneurons. We now report that Arx−/y;Dlx5/6CIG (male) mice exhibit a variety of seizure types beginning in early-life, including seizures that behaviourally and electroencephalographically resembles infantile spasms, and show evolution through development. Thus, this represents a new genetic model of a malignant form of paediatric epilepsy, with some characteristics resembling infantile spasms, caused by mutations in a known infantile spasms gene. Unexpectedly, approximately half of the female mice carrying a single mutant Arx allele (Arx−/+;Dlx5/6CIG) also developed seizures. We also found that a subset of human female carriers have seizures and neurocognitive deficits. In summary, we have identified a previously unrecognized patient population with neurological deficits attributed to ARX mutations that are recapitulated in our mouse model. Furthermore, we show that perturbation of interneuron subpopulations is an important mechanism underling the pathogenesis of developmental epilepsy in both hemizygous males and carrier females. Given the frequency of ARX mutations in patients with infantile spasms and related disorders, our data unveil a new model for further understanding the pathogenesis of these disorders.
PMCID: PMC2685924  PMID: 19439424
Epilepsy; development; conditional knockout; genetic model; interneurons
10.  Identification of Arx transcriptional targets in the developing basal forebrain 
Human Molecular Genetics  2008;17(23):3740-3760.
Mutations in the aristaless-related homeobox (ARX) gene are associated with multiple neurologic disorders in humans. Studies in mice indicate Arx plays a role in neuronal progenitor proliferation and development of the cerebral cortex, thalamus, hippocampus, striatum, and olfactory bulbs. Specific defects associated with Arx loss of function include abnormal interneuron migration and subtype differentiation. How disruptions in ARX result in human disease and how loss of Arx in mice results in these phenotypes remains poorly understood. To gain insight into the biological functions of Arx, we performed a genome-wide expression screen to identify transcriptional changes within the subpallium in the absence of Arx. We have identified 84 genes whose expression was dysregulated in the absence of Arx. This population was enriched in genes involved in cell migration, axonal guidance, neurogenesis, and regulation of transcription and includes genes implicated in autism, epilepsy, and mental retardation; all features recognized in patients with ARX mutations. Additionally, we found Arx directly repressed three of the identified transcription factors: Lmo1, Ebf3 and Shox2. To further understand how the identified genes are involved in neural development, we used gene set enrichment algorithms to compare the Arx gene regulatory network (GRN) to the Dlx1/2 GRN and interneuron transcriptome. These analyses identified a subset of genes in the Arx GRN that are shared with that of the Dlx1/2 GRN and that are enriched in the interneuron transcriptome. These data indicate Arx plays multiple roles in forebrain development, both dependent and independent of Dlx1/2, and thus provides further insights into the understanding of the mechanisms underlying the pathology of mental retardation and epilepsy phenotypes resulting from ARX mutations.
PMCID: PMC2581427  PMID: 18799476
11.  Human and Automated Detection of High-Frequency Oscillations in Clinical Intracranial EEG Recordings 
Recent studies indicate that pathologic high-frequency oscillations (HFOs) are signatures of epileptogenic brain. Automated tools are required to characterize these events. We present a new algorithm tuned to detect HFOs from 30 – 85 Hz, and validate it against human expert electroencephalographers.
We randomly selected 28 3-minute single-channel epochs of intracranial EEG (IEEG) from two patients. Three human reviewers and three automated detectors marked all records to identify candidate HFOs. Subsequently, human reviewers verified all markings.
A total of 1,330 events were collectively identified. The new method presented here achieved 89.7% accuracy against a consensus set of human expert markings. A one-way ANOVA determined no difference between the mean F-measures of the human reviewers and automated algorithm. Human Kappa statistics (mean κ = 0.38) demonstrated marginal identification consistency, primarily due to false negative errors.
We present an HFO detector that improves upon existing algorithms, and performs as well as human experts on our test data set. Validation of detector performance must be compared to more than one expert because of interrater variability.
This algorithm will be useful for analyzing large EEG databases to determine the pathophysiological significance of HFO events in human epileptic networks.
PMCID: PMC2020804  PMID: 17382583
high-frequency oscillation; HFO; intracranial EEG; epilepsy

Results 1-11 (11)