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Lara E. Jehi, Diosely C. Silveira, William Bingaman and Imad Najm

Object

The authors provide a systematic analysis of electroclinical characteristics in patients with persistent seizures following temporal lobe epilepsy (TLE) surgery and identify ideal candidates for reoperation.

Methods

The authors retrospectively reviewed the records of 68 adult patients (mean follow-up 8.7 years) who underwent a video electroencephalography evaluation and high-resolution imaging after failed TLE surgery performed between 1990 and 2004 at The Cleveland Clinic. Multivariate logistic regression analyses were performed to identify predictors of the yield of a repeat evaluation, location of the recurrence focus, and outcome following reoperation.

Results

Although a focus of recurrence was identified in 44 patients, only 15 underwent reoperation, and only 6 of these became seizure free. Localized foci of recurrence were successfully identified in patients with early (within 1 postoperative year) and frequent (≥ 4 per month) recurrent seizures (yield of 100% if both conditions were fulfilled). Predictors of contiguity of the focus of recurrence to the initial surgical bed were variable depending on the type of the initial surgery: patients with baseline contralateral temporal spiking were 6 times (OR 6.34, p < 0.05) more likely to experience seizure recurrence from the contralateral temporal lobe after a “standard” temporal lobectomy, while the need to use subdural electrodes and the timing of recurrence were more significant following limited temporal resections. The focus of recurrence was distant to the original surgical bed when subdural electrodes were used prior to first surgery (OR 28.0, p = 0.01) or when seizures recurred early (within < 6 postoperative months; OR 12.5, p = 0.04). With reoperation, only patients with mesial and basal extension of the temporal resections became seizure free. Interestingly, seizure freedom was achieved with medical therapy alone in 42% of patients with a nonidentifiable recurrence focus as opposed to 4% of those with an unoperated identifiable focus.

Conclusions

The timing and frequency of recurrent seizures following unsuccessful TLE surgery provide useful guidelines for the yield of a surgical reevaluation, and potentially for the mechanisms of surgical failure.

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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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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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Nitin Tandon, Andreas V. Alexopoulos, Ann Warbel, Imad M. Najm and William E. Bingaman

Object

Occipital resections for epilepsy are rare. Reasons for this are the relative infrequency of occipital epilepsy, difficulty in localizing epilepsy originating in the occipital lobe, imprecisely defined seizure outcome in patients treated with focal occipital resections in the MR imaging era, and concerns about producing visual deficits. The impact of lesion location on vision and seizure biology, the management decision-making process, and the outcomes following resection need elaboration.

Methods

The authors studied 21 consecutive patients who underwent focal occipital resections for epilepsy at Cleveland Clinic Epilepsy Center over a 13-year period during which MR imaging was used. Demographics, imaging, and data relating to the epilepsy and its surgical management were collected. The collateral sulcus, the border between the medial surface and the lateral convexity, and the inferior temporal sulcus were used to subdivide the occipital lobe into medial, lateral, and basal zones. Lesions that did not involve most or all of the occipital lobe (sublobar) were spatially categorized into these zones. Visual function, semiology, and scalp electroencephalography were evaluated in relation to these spatial categories. Preresection and postresection visual function and seizure frequency were evaluated and compared. Lastly, an exhaustive review and discussion of the published literature on occipital resections for epilepsy was carried out.

Results

Five lesions were lobar and 16 were sublobar. Patients with medial or lobar lesions had a much greater likelihood of preoperative visual field defects. Those with basal or lateral lesions had a greater likelihood of having a visual aura preceding some or all of their seizures and a trend (not significant) toward having a concordant lateralized onset by scalp electroencephalography. Invasive recordings were used in 8 cases. All patients had lesions (malformations of cortical development, tumors, or gliosis) that were completely resected, as evaluated on postoperative MR imaging. At last follow-up, 17 patients (81%) were seizure free or had only occasional auras (Wieser Class 1 or 2). The remaining 4 patients (19%) had a worthwhile improvement in seizure control (Class 3 or 4). Of the patients for whom both pre- and postoperative visual testing data were available, 50% suffered no new visual deficits, and 17% each developed a new quadrantanopia or a hemianopia.

Conclusions

Lesional occipital lobe epilepsy can be successfully managed with resection to obtain excellent seizure-free rates. Individually tailored resections (in lateral occipital lesions, for example) may help preserve intact vision in a subset of cases (38% in this series). Invasive recordings may further guide surgical decision-making as delineated by an algorithm generated by the authors. The authors' results suggest that the spatial location of the lesion correlates both with the semiology of the seizure and with the presence of visual deficit.

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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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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 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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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.