The Experts below are selected from a list of 10146 Experts worldwide ranked by ideXlab platform
Gabriella D'arcangelo - One of the best experts on this subject based on the ideXlab platform.
-
Rapamycin suppresses seizures and neuronal hypertrophy in a mouse model of Cortical Dysplasia
Disease Models & Mechanisms, 2009Co-Authors: M. C. Ljungberg, C. N. Sunnen, A. E. Anderson, Joaquin N Lugo, Gabriella D'arcangeloAbstract:Malformations of the cerebral cortex known as Cortical Dysplasia account for the majority of cases of intractable childhood epilepsy. With the exception of the tuberous sclerosis complex, the molecular basis of most types of Cortical Dysplasia is completely unknown. Currently, there are no good animal models available that recapitulate key features of the disease, such as structural Cortical abnormalities and seizures, hindering progress in understanding and treating Cortical Dysplasia. At the neuroanatomical level, Cortical abnormalities may include dyslamination and the presence of abnormal cell types, such as enlarged and misoriented neurons and neuroglial cells. Recent studies in resected human brain tissue suggested that a misregulation of the PI3K (phosphoinositide 3-kinase)-Akt-mTOR (mammalian target of rapamycin) signaling pathway might be responsible for the excessive growth of dysplastic cells in this disease. Here, we characterize neuronal subset (NS)-Pten mutant mice as an animal model of Cortical Dysplasia. In these mice, the Pten gene, which encodes a suppressor of the PI3K pathway, was selectively disrupted in a subset of neurons by using Cre-loxP technology. Our data indicate that these mutant mice, like Cortical Dysplasia patients, exhibit enlarged Cortical neurons with increased mTOR activity, and abnormal electroencephalographic activity with spontaneous seizures. We also demonstrate that a short-term treatment with the mTOR inhibitor rapamycin strongly suppresses the severity and the duration of the seizure activity. These findings support the possibility that this drug may be developed as a novel antiepileptic treatment for patients with Cortical Dysplasia and similar disorders.
-
Activation of mammalian target of rapamycin in cytomegalic neurons of human Cortical Dysplasia.
Annals of neurology, 2006Co-Authors: M. C. Ljungberg, Meenakshi B. Bhattacharjee, Dawna L. Armstrong, Daniel Yoshor, John W. Swann, Michael Sheldon, Gabriella D'arcangeloAbstract:Objective The cortex of patients with Cortical Dysplasia contains several abnormal cell types. Among the dysplastic cells, cytomegalic neurons are known to be electrically hyperactive and may contribute to epileptic activity. In this study, we sought to identify molecular markers of cytomegalic neurons in focal or hemispheric Cortical Dysplasia and to determine whether the activity of the mammalian target of rapamycin (mTOR) kinase is abnormally high in these cells. Methods Microarray analysis of gene expression in large dysplastic cells microdissected from Cortical Dysplasia surgical specimens was used to identify markers of cytomegalic neurons. Immunohistochemistry and immunofluorescence analysis of Cortical sections was used to validate the microarray results and to probe the activity of mTOR in cytomegalic neurons using phospho-specific antibodies directed against known mTOR targets. Results We demonstrate that the neurofilament heavy chain is a reliable marker of cytomegalic neurons and that targets of the mTOR kinase, such as the ribosomal protein S6, eIF4G, and Akt, are hyperphosphorylated in these dysplastic neurons. Interpretation We conclude that mTOR kinase hyperactivation is a molecular mechanism underlying the development of cytomegalic neurons. This finding may lead to the development of novel therapeutic approaches for childhood epilepsy associated with Cortical Dysplasia. Ann Neurol 2006
Julia Jacobs - One of the best experts on this subject based on the ideXlab platform.
-
high frequency oscillations mirror disease activity in patients with focal Cortical Dysplasia
Epilepsia, 2013Co-Authors: Karolin Kerber, Pierre Levan, Matthias Dümpelmann, Susanne Fauser, Rudolf Korinthenberg, Andreas Schulzebonhage, Julia JacobsAbstract:Summary Purpose The study analyzes the occurrence of high frequency oscillations in different types of focal Cortical Dysplasia in 22 patients with refractory epilepsy. High frequency oscillations are biomarkers for epileptic tissue, but it is unknown whether they can reflect increasingly dysplastic tissue changes as well as epileptic disease activity. Methods High frequency oscillations (80–450 Hz) were visually marked by two independent reviewers in all channels of intracranial implanted grid, strips, and depth electrodes in patients with focal Cortical Dysplasia and refractory epilepsy. Rates of high frequency oscillations in patients with pathologically confirmed focal Cortical Dysplasia of Palmini type 1a and b were compared with those in type 2a and b. Key Findings Patients with focal Cortical Dysplasia type 2 had significantly more seizures than those with type 1 (p < 0.001). Rates of high frequency oscillations were significantly higher in patients with focal Cortical Dysplasia type 2 versus type 1 (p < 0.001). In addition, it could be confirmed that rates of high frequency oscillations were significantly higher in presumed epileptogenic areas than outside (p < 0.001). Significance Activity of high frequency oscillations mirrors the higher epileptogenicity of focal Cortical Dysplasia type 2 lesions compared to type 1 lesions. Therefore, rates of high frequency oscillations can reflect disease activity of a lesion. This has implications for the use of high frequency oscillations as biomarkers for epileptogenic areas, because a detailed analysis of their rates may be necessary to use high frequency oscillations as a predictive tool in epilepsy surgery.
-
High frequency oscillations mirror disease activity in patients with focal Cortical Dysplasia.
Epilepsia, 2013Co-Authors: Karolin Kerber, Pierre Levan, Matthias Dümpelmann, Susanne Fauser, Rudolf Korinthenberg, Andreas Schulze-bonhage, Julia JacobsAbstract:Summary Purpose The study analyzes the occurrence of high frequency oscillations in different types of focal Cortical Dysplasia in 22 patients with refractory epilepsy. High frequency oscillations are biomarkers for epileptic tissue, but it is unknown whether they can reflect increasingly dysplastic tissue changes as well as epileptic disease activity. Methods High frequency oscillations (80–450 Hz) were visually marked by two independent reviewers in all channels of intracranial implanted grid, strips, and depth electrodes in patients with focal Cortical Dysplasia and refractory epilepsy. Rates of high frequency oscillations in patients with pathologically confirmed focal Cortical Dysplasia of Palmini type 1a and b were compared with those in type 2a and b. Key Findings Patients with focal Cortical Dysplasia type 2 had significantly more seizures than those with type 1 (p
Gary W Mathern - One of the best experts on this subject based on the ideXlab platform.
-
surgical treatment of epilepsy associated with Cortical Dysplasia 2012 update
Epilepsia, 2012Co-Authors: Jason S Hauptman, Gary W MathernAbstract:Summary Cortical Dysplasia is the most common etiology in children and the third most frequent finding in adults undergoing epilepsy neurosurgery. The new International League Against Epilepsy (ILAE) classification grades isolated Cortical Dysplasia into mild type I (Cortical dyslamination), severe type II (dyslamination plus dysmorphic neurons and balloon cells), and Dysplasia associated with other epileptogenic lesions (type III). Multilobar type II lesions present at an earlier age and with more severe epilepsy compared with focal type I abnormalities, often in the temporal lobe, and these findings are reflected in types and age of operations for Cortical Dysplasia. Presurgical evaluation of patients with epilepsy from Cortical Dysplasia can be challenging. Interictal and ictal scalp electroencephalography (EEG) accurately localizes Cortical Dysplasia with 50–66% accuracy. Structural magnetic resonance imaging (MRI) is negative in roughly 30% of cases, most often linked with mild type I cases. FDG-PET can be 80–90% accurate, but is not 100% sensitive. Chronic intracranial electrodes are used in about 50% of cases with Cortical Dysplasia, but often do not capture restricted ictal-onset zones. About 60% of patients with Cortical Dysplasia are seizure free after epilepsy neurosurgery, with much higher rates of becoming seizure free with complete (80%) compared with incomplete (20%) resections. The most common reason for incomplete resection is the risk of an unacceptable neurologic deficit. Future challenges include better tools in identifying subtle forms of type I Cortical Dysplasia, and development of adjunctive treatments from basic research for those undergoing incomplete resections.
-
Epilepsy surgery patients with Cortical Dysplasia Present and future therapeutic challenges
Neurology, 2008Co-Authors: Gary W MathernAbstract:Cortical Dysplasia is the most common substrate in pediatric and the second or third most frequent etiology in adult epilepsy surgery patients.1 The histopathology was first described less than 30 years ago,2 and we are still learning about the clinical features of this disorder. Early surgical series involved few patients or focused on MRI positive cases,3,4 and reported inconsistent predictors of therapeutic success. Only recently have single centers published surgical cohorts of over 100 patients.5,6 This issue of Neurology® publishes two studies that together report on 315 epilepsy surgery patients with Cortical Dysplasia: Krsek et al., a mostly pediatric cohort from Miami Children's Hospital, and Kim et al., a generally adult population from Seoul, Korea.7,8 Both centers have previously published on their cohorts.9,10 From these and other reports emerges a clearer image of the electro-clinico-pathologic characteristics of patients with Cortical Dysplasia. For example, most surgical patients have mild compared with severe forms of Cortical Dysplasia on histopathology. This is defined as mild malformations of Cortical development (mMCD; 16%) or mild type I (59%) Cortical Dysplasia using the Palmini classification system …
-
infantile spasm associated microencephaly in tuberous sclerosis complex and Cortical Dysplasia
Neurology, 2007Co-Authors: P S Chandra, Snow T Nguyen, Julia W Chang, Joao Pereira Leite, Luciano Neder, Noriko Salamon, Carlos Cepeda, Harry V Vinters, My N Huynh, Gary W MathernAbstract:Objective: In children with and without infantile spasms, this study determined brain volumes and cell densities in epilepsy surgery patients with tuberous sclerosis complex (TSC) and Cortical Dysplasia with balloon cells (CD). Methods: We compared TSC (n = 18) and CD (n = 17) patients with normal/autopsy controls (n = 20) for MRI gray and white matter volumes and neuronal nuclei (NeuN) cell densities. Results: In patients without a history of infantile spasms, TSC cases showed decreased gray and white matter volumes (−16%). In cases with a history of infantile spasms, both CD (−25%) and TSC (−35%) patients showed microencephaly. This was confirmed in monozygotic twins with TSC, where the twin with a history of spasms had cerebral volumes less (−16%) than the twin without a history of seizures. Regardless of seizure history, TSC patients showed decreased NeuN cell densities in lower gray matter (−36%), whereas CD patients had increased densities in upper Cortical (+52%) and white matter regions (+65%). For TSC patients, decreased lower gray matter NeuN densities correlated with reduced MRI volumes. Conclusions: Patients with tuberous sclerosis without spasms showed microencephaly associated with decreased Cortical neuronal densities. In contrast, Cortical Dysplasia patients without spasms were normocephalic with increased cell densities. This supports the concept that tuberous sclerosis and Cortical Dysplasia have different pathogenetic mechanisms despite similarities in refractory epilepsy and postnatal histopathology. Furthermore, a history of infantile spasms was associated with reduced cerebral volumes in both Cortical Dysplasia and tuberous sclerosis patients, suggesting that spasms or their treatment may contribute to microencephaly independent of etiology.
Richard B. Morawetz - One of the best experts on this subject based on the ideXlab platform.
-
Rasmussen's Encephalitis with Concomitant Cortical Dysplasia: The Role of GluR3
Epilepsia, 1999Co-Authors: Cheryl A. Palmer, Ruben Kuzniecky, Richard B. Morawetz, James D. Geyer, Janice M. Keating, Frank Gilliam, E. Martina BebinAbstract:Summary: The role of the glutamate receptor GluR3 in Rasmussen's encephalitis is actively under investigation. Autoimmune processes with this receptor as the target are currently theorized. We provide an additional case of pathologically proved Rasmussen's encephalitis (with concomitant Cortical Dysplasia) in the presence of antibodies against the GluR3 receptor.
-
Cortical Dysplasia in temporal lobe epilepsy: magnetic resonance imaging correlations.
Annals of neurology, 1991Co-Authors: Ruben Kuzniecky, J. H. Garcia, Edward Faught, Richard B. MorawetzAbstract:Cortical Dysplasia has been documented in histological specimens surgically removed for treatment of refractory temporal lobe epilepsy. We studied 10 patients with Cortical Dysplasia and complex partial seizures who underwent temporal lobectomy. Magnetic resonance imaging revealed abnormalities in 5 of the patients who had microscopically detectable major abnormalities. Magnetic resonance imaging revealed an abnormal Cortical-white matter architectonic pattern in 2 patients with moderate Cortical Dysplasia. In the remaining 3 patients, magnetic resonance imaging findings were unremarkable. These observations suggest that magnetic resonance imaging is sensitive in the detection of certain dysplastic lesions in temporal lobe epilepsy. Preoperative identification of these abnormalities by magnetic resonance imaging may permit early and optimal surgical treatment in patients with refractory epilepsy.
M. C. Ljungberg - One of the best experts on this subject based on the ideXlab platform.
-
Rapamycin suppresses seizures and neuronal hypertrophy in a mouse model of Cortical Dysplasia
Disease Models & Mechanisms, 2009Co-Authors: M. C. Ljungberg, C. N. Sunnen, A. E. Anderson, Joaquin N Lugo, Gabriella D'arcangeloAbstract:Malformations of the cerebral cortex known as Cortical Dysplasia account for the majority of cases of intractable childhood epilepsy. With the exception of the tuberous sclerosis complex, the molecular basis of most types of Cortical Dysplasia is completely unknown. Currently, there are no good animal models available that recapitulate key features of the disease, such as structural Cortical abnormalities and seizures, hindering progress in understanding and treating Cortical Dysplasia. At the neuroanatomical level, Cortical abnormalities may include dyslamination and the presence of abnormal cell types, such as enlarged and misoriented neurons and neuroglial cells. Recent studies in resected human brain tissue suggested that a misregulation of the PI3K (phosphoinositide 3-kinase)-Akt-mTOR (mammalian target of rapamycin) signaling pathway might be responsible for the excessive growth of dysplastic cells in this disease. Here, we characterize neuronal subset (NS)-Pten mutant mice as an animal model of Cortical Dysplasia. In these mice, the Pten gene, which encodes a suppressor of the PI3K pathway, was selectively disrupted in a subset of neurons by using Cre-loxP technology. Our data indicate that these mutant mice, like Cortical Dysplasia patients, exhibit enlarged Cortical neurons with increased mTOR activity, and abnormal electroencephalographic activity with spontaneous seizures. We also demonstrate that a short-term treatment with the mTOR inhibitor rapamycin strongly suppresses the severity and the duration of the seizure activity. These findings support the possibility that this drug may be developed as a novel antiepileptic treatment for patients with Cortical Dysplasia and similar disorders.
-
Activation of mammalian target of rapamycin in cytomegalic neurons of human Cortical Dysplasia.
Annals of neurology, 2006Co-Authors: M. C. Ljungberg, Meenakshi B. Bhattacharjee, Dawna L. Armstrong, Daniel Yoshor, John W. Swann, Michael Sheldon, Gabriella D'arcangeloAbstract:Objective The cortex of patients with Cortical Dysplasia contains several abnormal cell types. Among the dysplastic cells, cytomegalic neurons are known to be electrically hyperactive and may contribute to epileptic activity. In this study, we sought to identify molecular markers of cytomegalic neurons in focal or hemispheric Cortical Dysplasia and to determine whether the activity of the mammalian target of rapamycin (mTOR) kinase is abnormally high in these cells. Methods Microarray analysis of gene expression in large dysplastic cells microdissected from Cortical Dysplasia surgical specimens was used to identify markers of cytomegalic neurons. Immunohistochemistry and immunofluorescence analysis of Cortical sections was used to validate the microarray results and to probe the activity of mTOR in cytomegalic neurons using phospho-specific antibodies directed against known mTOR targets. Results We demonstrate that the neurofilament heavy chain is a reliable marker of cytomegalic neurons and that targets of the mTOR kinase, such as the ribosomal protein S6, eIF4G, and Akt, are hyperphosphorylated in these dysplastic neurons. Interpretation We conclude that mTOR kinase hyperactivation is a molecular mechanism underlying the development of cytomegalic neurons. This finding may lead to the development of novel therapeutic approaches for childhood epilepsy associated with Cortical Dysplasia. Ann Neurol 2006
