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Hernando Rafael

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Jorge A. González-Martínez, William E. Bingaman, Steven A. Toms, and Imad M. Najm

Object

The normal adult human telencephalon does not reveal evidence of spontaneous neuronal migration and differentiation despite the robust germinal capacity of the subventricular zone (SVZ) astrocyte ribbon that contains neural stem cells. This might be because it is averse to accepting new neurons into an established neuronal network, probably representing an evolutionary acquisition to prevent the formation of anomalous neuronal circuits. Some forms of epilepsy, such as malformations of cortical development, are thought to be due to abnormal corticogenesis during the embryonic and early postnatal periods. The role of postnatal architectural reorganization and possibly postnatal neurogenesis in some forms of epilepsy in humans remains unknown. In this study the authors used resected specimens of epileptic brain to determine whether neurogenesis could occur in the diseased tissue.

Methods

The authors studied freshly resected brain tissue obtained in 47 patients who underwent neurosurgical procedures and four autopsies. Forty-four samples were harvested in patients who underwent resection for the treatment of pharmacoresistant epilepsy.

Results

Using organotypic brain slice preparations cultured with 5-bromodeoxyuridine (a marker for cell proliferation), immunohistochemistry, and cell trackers, the authors demonstrate the presence of spontaneous cell proliferation, migration, and neuronal differentiation in the adult human telencephalon that starts in the SVZ and progresses to the adjacent white matter and neocortex in human neocortical pathological structures associated with epilepsy. No cell migration or neuronal differentiation was found in the control group.

Conclusions

The presence of spontaneous neurogenesis associated with some forms of human neocortical epilepsy may represent an erroneous and maladaptive mechanism for neuronal circuitry repair, or it may be an intrinsic part of the pathogenic process.

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Robert A. McGovern, Elia Pestana Knight, Ajay Gupta, Ahsan N. V. Moosa, Elaine Wyllie, William E. Bingaman, and Jorge Gonzalez-Martinez

OBJECTIVE

The goal in the study was to describe the clinical outcomes associated with robot-assisted stereoelectroencephalography (SEEG) in children.

METHODS

The authors performed a retrospective, single-center study in consecutive children with medically refractory epilepsy who were undergoing robot-assisted SEEG. Kaplan-Meier survival analysis was used to calculate the probability of seizure freedom. Both univariate and multivariate methods were used to analyze the preoperative and operative factors associated with seizure freedom.

RESULTS

Fifty-seven children underwent a total of 64 robot-assisted procedures. The patients’ mean age was 12 years, an average of 6.4 antiepileptic drugs (AEDs) per patient had failed prior to implantation, and in 56% of the patients the disease was considered nonlesional. On average, children had 12.4 electrodes placed per implantation, with an implantation time of 9.6 minutes per electrode and a 10-day postoperative stay. SEEG analysis yielded a definable epileptogenic zone in 51 (89%) patients; 42 (74%) patients underwent surgery, half of whom were seizure free at last follow-up, 19.6 months from resection. In a multivariate generalized linear model, resective surgery, older age, and shorter SEEG-related hospital length of stay were associated with seizure freedom. In a Cox proportional hazards model including only the children who underwent resective surgery, older age was the only significant factor associated with seizure freedom. Complications related to bleeding were the major contributors to morbidity. One patient (1.5%) had a symptomatic hemorrhage resulting in a permanent neurological deficit.

CONCLUSIONS

The authors report one of the largest pediatric-specific SEEG series demonstrating that the modern surgical management of medically refractory epilepsy in children can lead to seizure freedom in many patients, while also highlighting the challenges posed by this difficult patient population.

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Jorge A. González-Martínez, Gabriel Möddel, Zhong Ying, Richard A. Prayson, William E. Bingaman, and Imad M. Najm

Object

Nitric oxide has been associated with epileptogenesis. Previous studies have shown increased expression of N-methyl-d-aspartate (NMDA) subunit NR2B receptors in epileptic dysplastic human neocortex. The expression of neuronal nitric oxide synthase (nNOS), and its relation to this subunit NR2B in epileptic dysplastic tissue has never been addressed.

Methods

Ten patients with medically intractable epilepsy caused by focal cortical dysplasia (CD), and 2 patients with mesial temporal sclerosis (control group) underwent pre- and/or intraoperative invasive monitoring evaluations. Cortical samples from epileptogenic and nonepileptogenic areas were collected from each patient intraoperatively. Samples were processed for cresyl violet staining, immunocytochemical tests with nNOS, NeuN, and NR2B, and immunofluorescence analyses to evaluate colocalized immunoreactivity between nNOS and NR2B.

Results

. All samples obtained in the patients with epilepsy revealed CD in various degrees. In the nonepileptic sample group, cresyl violet staining revealed normal cortical architecture in 9 samples, but a mild degree of CD in 3. The density and intensity of nNOS-stained neurons was remarkably increased in the epileptic tissue compared with nonepileptic samples (p < 0.05). Two types of nNOS-stained neurons were identified: Type I, expressing strong nNOS immunoreactivity in larger neurons; and Type II, expressing weak nNOS immunoreactivity in slightly smaller neurons. Different from Type I neurons, Type II nNOS-stained neurons revealed immunoreactivity colocalized with NR2B antibody.

Conclusions

The overexpression of nNOS in the epileptic samples and the immunoreactivity colocalization between nNOS and NR2B may suggest a possible role of nNOS and NO in the pathophysiological mechanisms related to in situ epileptogenicity.

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Thandar Aung, Vineet Punia, Masaya Katagiri, Richard Prayson, Irene Wang, and Jorge A. Gonzalez-Martinez

OBJECTIVE

The objective of this study was to illustrate the feasibility and value of extra- and intraoperative stereoelectroencephalography (SEEG) in patients who underwent resection in rolandic and perirolandic regions.

METHODS

The authors retrospectively reviewed all consecutive patients with at least 1 year of postoperative follow-up who underwent extra- and intraoperative SEEG monitoring between January 2015 and January 2017.

RESULTS

Four patients with pharmacoresistant rolandic and perirolandic focal epilepsy were identified, who underwent conventional extraoperative invasive SEEG evaluations followed by adjuvant intraoperative SEEG recordings. Conventional extraoperative SEEG evaluations demonstrated ictal and interictal epileptiform activities involving eloquent rolandic and perirolandic cortical areas in all patients. Following extraoperative monitoring, patients underwent preplanned staged resections guided by simultaneous and continuous adjuvant intraoperative SEEG monitoring. Resections, guided by electrode contacts of interest in 3D boundaries, were performed while continuous real-time electrographic data from SEEG recordings were obtained. Staged approaches of resections were performed until there was intraoperative resolution of synchronous rolandic/perirolandic cortex epileptic activities. All patients in the cohort achieved complete seizure freedom (Engel class IA) during the follow-up period ranging from 18 to 50 months. Resection resulted in minimal neurological deficit; 3 patients experienced transient, distal plantar flexion weakness (mild foot drop).

CONCLUSIONS

The seizure and functional outcome results of this highly preselected group of patients testifies to the feasibility and demonstrates the value of the combined benefits of both intra- and extraoperative SEEG recordings when resecting the rolandic and perirolandic areas. The novel hybrid method allows a more refined and precise identification of the epileptogenic zone. Consequently, tailored resections can be performed to minimize morbidity as well as to achieve adequate seizure control.

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Jorge A. González-Martínez, Zhong Ying, Richard Prayson, William Bingaman, and Imad Najm

Object

Changes in the expression of glutamate transporters (GLTs) may play a role in the expression of epileptogenicity. Previous studies have shown an increased number of neuronal GLTs in human dysplastic neurons. The expression of glial and neuronal GLTs and glutamine synthetase (GS) in balloon cells (BCs) and BC-containing cortical dysplasia has not been studied.

Methods

The authors analyzed neocortical samples that were resected in 5 patients who had cortical dysplasia–induced medically intractable focal epilepsy and who underwent extraoperative prolonged electrocorticographic (ECoG) recordings. The expressions of glial (GLT1/EAAT2) and neuronal (EAAT3, EAAC1) GLTs and GS proteins were immunohistochemically studied in all 5 resected samples. The authors also assessed in situ colocalization of GLTs and GS with neuronal and glial markers.

Results

Balloon cell–containing cortical dysplasia lesions did not exhibit ictal patterns on prolonged extraoperative ECoG recordings. There was a differential expression of glial and neuronal GLTs in BCs and dysplastic neurons: the majority of BCs highly expressed glial but not neuronal GLTs. Dysplastic neurons showed increased immunohistochemical staining with neuronal EAAT3 but not with EAAT2/GLT1. Moreover, only glial fibrillary acidic protein–positive BCs also expressed GS.

Conclusions

There is a differential GLT expression in dysplastic and balloon cells. The presence of glial GLTs and GS in balloon cell cortical dysplasia suggests a possible antiepileptic role for BCs and is consistent with the reported increased epileptogenicity in GLT1-deficient animals.

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Jorge Gonzalez-Martinez, Jeffrey Mullin, Sumeet Vadera, Juan Bulacio, Gwyneth Hughes, Stephen Jones, Rei Enatsu, and Imad Najm

Object

Despite its long-reported successful record, with almost 60 years of clinical use, the technical complexity regarding the placement of stereoelectroencephalography (SEEG) depth electrodes may have contributed to the limited widespread application of the technique in centers outside Europe. The authors report on a simplified and novel SEEG surgical technique in the extraoperative mapping of refractory focal epilepsy.

Methods

The proposed technique was applied in patients with medically refractory focal epilepsy. Data regarding general demographic information, method of electrode implantation, time of implantation, number of implanted electrodes, seizure outcome after SEEG-guided resections, and complications were prospectively collected.

Results

From March 2009 to April 2012, 122 patients underwent SEEG depth electrode implantation at the Cleveland Clinic Epilepsy Center in which the authors' technique was used. There were 65 male and 57 female patients whose mean age was 33 years (range 5–68 years). The group included 21 pediatric patients (younger than 18 years). Planning and implantations were performed in a single stage. The time for planning was, on average, 33 minutes (range 20–47 minutes), and the time for implantation was, on average, 107 minutes (range 47–150 minutes). Complications related to the SEEG technique were observed in 3 patients. The calculated risk of complications per electrode was 0.18%. The seizure-free rate after SEEG-guided resections was 62% in a mean follow-up period of 12 months.

Conclusions

The authors report on a safe, simplified, and less time-consuming method of SEEG depth electrode implantation, using standard and widely available surgical tools, making the technique a reasonable option for extraoperative monitoring of patients with medically intractable epilepsy in centers lacking the Talairach stereotactic armamentarium.

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Shan Wang, Yingying Tang, Thandar Aung, Cong Chen, Masaya Katagiri, Stephen E. Jones, Richard A. Prayson, Balu Krishnan, Jorge A. Gonzalez-Martinez, Richard C. Burgess, Imad M. Najm, Andreas V. Alexopoulos, Shuang Wang, Meiping Ding, and Zhong Irene Wang

OBJECTIVE

Presurgical evaluation of patients with operculoinsular epilepsy and negative MRI presents major challenges. Here the authors examined the yield of noninvasive modalities such as voxel-based morphometric MRI postprocessing, FDG-PET, subtraction ictal SPECT coregistered to MRI (SISCOM), and magnetoencephalography (MEG) in a cohort of patients with operculoinsular epilepsy and negative MRI.

METHODS

Twenty-two MRI-negative patients were included who had focal ictal onset from the operculoinsular cortex on intracranial EEG, and underwent focal resection limited to the operculoinsular cortex. MRI postprocessing was applied to presurgical T1-weighted volumetric MRI using a morphometric analysis program (MAP). Individual and combined localization yields of MAP, FDG-PET, MEG, and SISCOM were compared with the ictal onset location on intracranial EEG. Seizure outcomes were reported at 1 year and 2 years (when available) using the Engel classification.

RESULTS

Ten patients (45.5%, 10/22) had operculoinsular abnormalities on MAP; 5 (23.8%, 5/21) had operculoinsular hypometabolism on FDG-PET; 4 (26.7%, 4/15) had operculoinsular hyperperfusion on SISCOM; and 6 (30.0%, 6/20) had an MEG cluster (3 tight, 3 loose) within the operculoinsular cortex. The highest yield of a 2-test combination was 59.1%, seen with MAP and SISCOM, followed by 54.5% with MAP and FDG-PET, and also 54.5% with MAP and MEG. The highest yield of a 3-test combination was 68.2%, seen with MAP, MEG, and SISCOM. The yield of the 4-test combination remained at 68.2%. When all other tests were negative or nonlocalizing, unique information was provided by MAP in 5, MEG in 1, SISCOM in 2, and FDG-PET in none of the patients. One-year follow-up was available in all patients, and showed 11 Engel class IA, 4 class IB, 4 class II, and 3 class III/IV. Two-year follow-up was available in 19 patients, and showed 9 class IA, 3 class IB, 1 class ID, 3 class II, and 3 class III/IV.

CONCLUSIONS

This study highlights the individual and combined values of multiple noninvasive modalities for the evaluation of nonlesional operculoinsular epilepsy. The 3-test combination of MAP, MEG, and SISCOM represented structural, interictal, and ictal localization information, and constituted the highest yield. MAP showed the highest yield of unique information when other tests were negative or nonlocalizing.

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Oral Presentations

2010 AANS Annual Meeting Philadelphia, Pennsylvania May 1–5, 2010