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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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Sumeet Vadera, Amar R. Marathe, Jorge Gonzalez-Martinez and Dawn M. Taylor

Stereoelectroencephalography (SEEG) is becoming more prevalent as a planning tool for surgical treatment of intractable epilepsy. Stereoelectroencephalography uses long, thin, cylindrical “depth” electrodes containing multiple recording contacts along each electrode's length. Each lead is inserted into the brain percutaneously. The advantage of SEEG is that the electrodes can easily target deeper brain structures that are inaccessible with subdural grid electrodes, and SEEG does not require a craniotomy. Brain-machine interface (BMI) research is also becoming more common in the Epilepsy Monitoring Unit. A brain-machine interface decodes a person's desired movement or action from the recorded brain activity and then uses the decoded brain activity to control an assistive device in real time. Although BMIs are primarily being developed for use by severely paralyzed individuals, epilepsy patients undergoing invasive brain monitoring provide an opportunity to test the effectiveness of different invasive recording electrodes for use in BMI systems. This study investigated the ability to use SEEG electrodes for control of 2D cursor velocity in a BMI. Two patients who were undergoing SEEG for intractable epilepsy participated in this study. Participants were instructed to wiggle or rest the hand contralateral to their SEEG electrodes to control the horizontal velocity of a cursor on a screen. Simultaneously they were instructed to wiggle or rest their feet to control the vertical component of cursor velocity. The BMI system was designed to detect power spectral changes associated with hand and foot activity and translate those spectral changes into horizontal and vertical cursor movements in real time. During testing, participants used their decoded SEEG signals to move the brain-controlled cursor to radial targets that appeared on the screen. Although power spectral information from 28 to 32 electrode contacts were used for cursor control during the experiment, post hoc analysis indicated that better control may have been possible using only a single SEEG depth electrode containing multiple recording contacts in both hand and foot cortical areas. These results suggest that the advantages of using SEEG for epilepsy monitoring may also apply to using SEEG electrodes in BMI systems. Specifically, SEEG electrodes can target deeper brain structures, such as foot motor cortex, and both hand and foot areas can be targeted with a single SEEG electrode implanted percutaneously. Therefore, SEEG electrodes may be an attractive option for simple BMI systems that use power spectral modulation in hand and foot cortex for independent control of 2 degrees of freedom.

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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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Soha Alomar, Jeffrey P. Mullin, Saksith Smithason and Jorge Gonzalez-Martinez

OBJECTIVE

Insular epilepsy is relatively rare; however, exploring the insular cortex when preoperative workup raises the suspicion of insular epilepsy is of paramount importance for accurate localization of the epileptogenic zone and achievement of seizure freedom. The authors review their clinical experience with stereoelectroencephalography (SEEG) electrode implantation in patients with medically intractable epilepsy and suspected insular involvement.

METHODS

A total of 198 consecutive cases in which patients underwent SEEG implantation with a total of 1556 electrodes between June 2009 and April 2013 were reviewed. The authors identified patients with suspected insular involvement based on seizure semiology, scalp EEG data, and preoperative imaging (MRI, PET, and SPECT or magnetoencephalography [MEG]). Patients with at least 1 insular electrode based on the postoperative 3D reconstruction of CT fused with the preoperative MRI were included.

RESULTS

One hundred thirty-five patients with suspected insular epilepsy underwent insular implantation of a total of 303 electrodes (1–6 insular electrodes per patient) with a total of 562 contacts. Two hundred sixty-eight electrodes (88.5%) were implanted orthogonally through the frontoparietal or temporal operculum (420 contacts). Thirty-five electrodes (11.5%) were implanted by means of an oblique trajectory either through a frontal or a parietal entry point (142 contacts). Nineteen patients (14.07%) had insular electrodes placed bilaterally. Twenty-three patients (17.04% of the insular implantation group and 11.6% of the whole SEEG cohort) were confirmed by SEEG to have ictal onset zones in the insula. None of the patients experienced any intracerebral hemorrhage related to the insular electrodes. After insular resection, 5 patients (33.3%) had Engel Class I outcomes, 6 patients (40%) had Engel Class II, 3 patients (20%) had Engel Class III, and 1 patient (6.66%) had Engel Class IV.

CONCLUSIONS

Insula exploration with stereotactically placed depth electrodes is a safe technique. Orthogonal electrodes are implanted when the hypothesis suggests opercular involvement; however, oblique electrodes allow a higher insular sampling rate.

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Demitre Serletis, Juan Bulacio, William Bingaman, Imad Najm and Jorge González-Martínez

Object

Stereoelectroencephalography (SEEG) is a methodology that permits accurate 3D in vivo electroclinical recordings of epileptiform activity. Among other general indications for invasive intracranial electroencephalography (EEG) monitoring, its advantages include access to deep cortical structures, its ability to localize the epileptogenic zone when subdural grids have failed to do so, and its utility in the context of possible multifocal seizure onsets with the need for bihemispheric explorations. In this context, the authors present a brief historical overview of the technique and report on their experience with 2 SEEG techniques (conventional Leksell frame-based stereotaxy and frameless stereotaxy under robotic guidance) for the purpose of invasively monitoring difficult-to-localize refractory focal epilepsy.

Methods

Over a period of 4 years, the authors prospectively identified 200 patients with refractory epilepsy who collectively underwent 2663 tailored SEEG electrode implantations for invasive intracranial EEG monitoring and extraoperative mapping. The first 122 patients underwent conventional Leksell frame-based SEEG electrode placement; the remaining 78 patients underwent frameless stereotaxy under robotic guidance, following acquisition of a stereotactic ROSA robotic device at the authors' institution. Electrodes were placed according to a preimplantation hypothesis of the presumed epileptogenic zone, based on a standardized preoperative workup including video-EEG monitoring, MRI, PET, ictal SPECT, and neuropsychological assessment. Demographic features, seizure semiology, number and location of implanted SEEG electrodes, and location of the epileptogenic zone were recorded and analyzed for all patients. For patients undergoing subsequent craniotomy for resection, the type of resection and procedure-related complications were prospectively recorded. These results were analyzed and correlated with pathological diagnosis and postoperative seizure outcomes.

Results

The epileptogenic zone was confirmed by SEEG in 154 patients (77%), of which 134 (87%) underwent subsequent craniotomy for epileptogenic zone resection. Within this cohort, 90 patients had a minimum follow-up of at least 12 months; therein, 61 patients (67.8%) remained seizure free, with an average follow-up period of 2.4 years. The most common pathological diagnosis was focal cortical dysplasia Type I (55 patients, 61.1%). Per electrode, the surgical complications included wound infection (0.08%), hemorrhagic complications (0.08%), and a transient neurological deficit (0.04%) in a total of 5 patients (2.5%). One patient (0.5%) ultimately died due to intracerebral hematoma directly ensuing from SEEG electrode placement.

Conclusions

Based on these results, SEEG methodology is safe, reliable, and effective. It is associated with minimal morbidity and mortality, and serves as a practical, minimally invasive approach to extraoperative localization of the epileptogenic zone in patients with refractory epilepsy.

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Rei Enatsu, Jorge Gonzalez-Martinez, Juan Bulacio, John C. Mosher, Richard C. Burgess, Imad Najm and Dileep R. Nair

OBJECT

The frontal and insular fiber network in humans remains largely unknown. This study investigated the connectivity of the frontal and anterior insular network in humans using cortico-cortical evoked potential (CCEP).

METHODS

This retrospective analysis included 18 patients with medically intractable focal epilepsy who underwent stereoelectroencephalography and CCEP. Alternating 1-Hz electrical stimuli were delivered to parts of the frontal lobe and anterior insula (prefrontal cortex [PFC], ventrolateral and dorsolateral premotor area [vPM and dPM, respectively], presupplementary motor area [pre-SMA], SMA, frontal operculum, and anterior insula). A total of 40–60 stimuli were averaged in each trial to obtain CCEP responses. The distribution of CCEP was evaluated by calculating the root mean square of CCEP responses.

RESULTS

Stimulation of the PFC elicited prominent CCEP responses in the medial PFC and PMs over the ipsilateral hemisphere. Stimulation of the vPM and dPM induced CCEP responses in the ipsilateral frontoparietal areas. Stimulation of the pre-SMA induced CCEP responses in the ipsilateral medial and lateral frontal areas and contralateral pre-SMA, whereas stimulation of the SMA induced CCEP responses in the bilateral frontoparietal areas. Stimulation of the frontal operculum induced CCEP responses in the ipsilateral insula and temporal operculum. CCEPs were observed in the ipsilateral medial, lateral frontal, and frontotemporal operculum in the anterior insular stimulation. Stimulation of the vPM and SMA led to the network in the dominant hemisphere being more developed.

CONCLUSIONS

Various regions within the frontal lobe and anterior insula were linked to specific ipsilateral and contralateral regions, which may reflect distinct functional roles.

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Sumeet Vadera, Lara Jehi, Richard C. Burgess, Katherine Shea, Andreas V. Alexopoulos, John Mosher, Jorge Gonzalez-Martinez and William Bingaman

Object

During the presurgical evaluation of patients with medically intractable focal epilepsy, a variety of noninvasive studies are performed to localize the hypothetical epileptogenic zone and guide the resection. Magnetoencephalography (MEG) is becoming increasingly used in the clinical realm for this purpose. No investigators have previously reported on coregisteration of MEG clusters with postoperative resection cavities to evaluate whether complete “clusterectomy” (resection of the area associated with MEG clusters) was performed or to compare these findings with postoperative seizure-free outcomes.

Methods

The authors retrospectively reviewed the charts and imaging studies of 65 patients undergoing MEG followed by resective epilepsy surgery from 2009 until 2012 at the Cleveland Clinic. Preoperative MEG studies were fused with postoperative MRI studies to evaluate whether clusters were within the resected area. These data were then correlated with postoperative seizure freedom.

Results

Sixty-five patients were included in this study. The average duration of follow-up was 13.9 months, the mean age at surgery was 23.1 years, and the mean duration of epilepsy was 13.7 years. In 30 patients, the main cluster was located completely within the resection cavity, in 28 it was completely outside the resection cavity, and in 7 it was partially within the resection cavity. Seventy-four percent of patients were seizure free at 12 months after surgery, and this rate decreased to 60% at 24 months. Improved likelihood of seizure freedom was seen with complete clusterectomy in patients with localization outside the temporal lobe (extra–temporal lobe epilepsy) (p = 0.04).

Conclusions

In patients with preoperative MEG studies that show clusters in surgically accessible areas outside the temporal lobe, we suggest aggressive resection to improve the chances for seizure freedom. When the cluster is found within the temporal lobe, further diagnostic testing may be required to better localize the epileptogenic zone.

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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.