Seizure freedom after laser amygdalohippocampotomy guided by bilateral responsive neurostimulation in pediatric epilepsy: illustrative case.

BACKGROUND: For patients with difficult-to-lateralize temporal lobe epilepsy, the use of chronic recordings as a diagnostic tool to inform subsequent surgical therapy is an emerging paradigm that has been reported in adults but not in children. OBSERVATIONS: The authors reported the case of a 15-year-old girl with pharmacoresistant temporal lobe epilepsy who was found to have bitemporal epilepsy during a stereoelectroencephalography (sEEG) admission. She underwent placement of a responsive neurostimulator system with bilateral hippocampal depth electrodes. However, over many months, her responsive neurostimulation (RNS) recordings revealed that her typical, chronic seizures were right-sided only. This finding led to a subsequent right-sided laser amygdalohippocampotomy, resulting in seizure freedom. LESSONS: In this case, RNS chronic recording provided real-world data that enabled more precise seizure localization than inpatient sEEG data, informing surgical decision-making that led to seizure freedom. The use of RNS chronic recordings as a diagnostic adjunct to seizure localization procedures and laser ablation therapies in children is an area with potential for future study.

Resting-state functional MRI connectivity impact on epilepsy surgery plan and surgical candidacy: prospective clinical work.

OBJECTIVE: The authors' goal was to prospectively quantify the impact of resting-state functional MRI (rs-fMRI) on pediatric epilepsy surgery planning. METHODS: Fifty-one consecutive patients (3 months to 20 years old) with intractable epilepsy underwent rs-fMRI for presurgical evaluation. The team reviewed the following available diagnostic data: video-electroencephalography (n = 51), structural MRI (n = 51), FDG-PET (n = 42), magnetoencephalography (n = 5), and neuropsychological testing (n = 51) results to formulate an initial surgery plan blinded to the rs-fMRI findings. Subsequent to this discussion, the connectivity results were revealed and final recommendations were established. Changes between pre- and post-rs-fMRI treatment plans were determined, and changes in surgery recommendation were compared using McNemar's test. RESULTS: Resting-state fMRI was successfully performed in 50 (98%) of 51 cases and changed the seizure onset zone localization in 44 (88%) of 50 patients. The connectivity results prompted 6 additional studies, eliminated the ordering of 11 further diagnostic studies, and changed the intracranial monitoring plan in 10 cases. The connectivity results significantly altered surgery planning with the addition of 13 surgeries, but it did not eliminate planned surgeries (p = 0.003). Among the 38 epilepsy surgeries performed, the final surgical approach changed due to rs-fMRI findings in 22 cases (58%), including 8 (28%) of 29 in which extraoperative direct electrical stimulation mapping was averted. CONCLUSIONS: This study demonstrates the impact of rs-fMRI connectivity results on the decision-making for pediatric epilepsy surgery by providing new information about the location of eloquent cortex and the seizure onset zone. Additionally, connectivity results may increase the proportion of patients considered eligible for surgery while optimizing the need for further testing.

A systematic review of deep brain stimulation for the treatment of drug-resistant epilepsy in childhood.

OBJECTIVE Drug-resistant epilepsy (DRE) presents a therapeutic challenge in children, necessitating the consideration of multiple treatment options. Although deep brain stimulation (DBS) has been studied in adults with DRE, little evidence is available to guide clinicians regarding the application of this potentially valuable tool in children. Here, the authors present the first systematic review aimed at understanding the safety and efficacy of DBS for DRE in pediatric populations, emphasizing patient selection, device placement and programming, and seizure outcomes. METHODS The systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and recommendations. Relevant articles were identified from 3 electronic databases (MEDLINE, Embase, and Cochrane CENTRAL) from their inception to November 17, 2017. Inclusion criteria of individual studies were 1) diagnosis of DRE; 2) treatment with DBS; 3) inclusion of at least 1 pediatric patient (age ≤ 18 years); and 4) patient-specific data. Exclusion criteria for the systematic review included 1) missing data for age, DBS target, or seizure freedom; 2) nonhuman subjects; and 3) editorials, abstracts, review articles, and dissertations. RESULTS This review identified 21 studies and 40 unique pediatric patients (ages 4­18 years) who received DBS treatment for epilepsy. There were 18 patients with electrodes placed in the bilateral or unilateral centromedian nucleus of the thalamus (CM) electrodes, 8 patients with bilateral anterior thalamic nucleus (ATN) electrodes, 5 patients with bilateral and unilateral hippocampal electrodes, 3 patients with bilateral subthalamic nucleus (STN) and 1 patient with unilateral STN electrodes, 2 patients with bilateral posteromedial hypothalamus electrodes, 2 patients with unilateral mammillothalamic tract electrodes, and 1 patient with caudal zona incerta electrode placement. Overall, 5 of the 40 (12.5%) patients had an International League Against Epilepsy class I (i.e., seizure-free) outcome, and 34 of the 40 (85%) patients had seizure reduction with DBS stimulation. CONCLUSIONS DBS is an alternative or adjuvant treatment for children with DRE. Prospective registries and future clinical trials are needed to identify the optimal DBS target, although favorable outcomes are reported with both CM and ATN in children. ABBREVIATIONS ATN = anterior thalamic nucleus; CM = centromedian nucleus of the thalamus; DBS = deep brain stimulation; DRE = drug-resistant epilepsy; RNS = responsive neurostimulation; STN = subthalamic nucleus; VNS = vagus nerve stimulation.

Deep brain stimulation for seizure control in drug-resistant epilepsy.

Antiepileptic drugs prevent morbidity and death in a large number of patients suffering from epilepsy. However, it is estimated that approximately 30% of epileptic patients will not have adequate seizure control with medication alone. Resection of epileptogenic cortex may be indicated in medically refractory cases with a discrete seizure focus in noneloquent cortex. For patients in whom resection is not an option, deep brain stimulation (DBS) may be an effective means of seizure control. Deep brain stimulation targets for treating seizures primarily include the thalamic nuclei, hippocampus, subthalamic nucleus, and cerebellum. A variety of stimulation parameters have been studied, and more recent advances in electrical stimulation to treat epilepsy include responsive neurostimulation. Data suggest that DBS is effective for treating drug-resistant epilepsy.

Robot-guided pediatric stereoelectroencephalography: single-institution experience.

OBJECTIVEStereoelectroencephalography (SEEG) has increased in popularity for localization of epileptogenic zones in drug-resistant epilepsy because safety, accuracy, and efficacy have been well established in both adult and pediatric populations. Development of robot-guidance technology has greatly enhanced the efficiency of this procedure, without sacrificing safety or precision. To date there have been very limited reports of the use of this new technology in children. The authors present their initial experience using the ROSA platform for robot-guided SEEG in a pediatric population.METHODSBetween February 2016 and October 2017, 20 consecutive patients underwent robot-guided SEEG with the ROSA robotic guidance platform as part of ongoing seizure localization and workup for medically refractory epilepsy of several different etiologies. Medical and surgical history, imaging and trajectory plans, as well as operative records were analyzed retrospectively for surgical accuracy, efficiency, safety, and epilepsy outcomes.RESULTSA total of 222 leads were placed in 20 patients, with an average of 11.1 leads per patient. The mean total case time (± SD) was 297.95 (± 52.96) minutes and the mean operating time per lead was 10.98 minutes/lead, with improvements in total (33.36 minutes/lead vs 21.76 minutes/lead) and operative (13.84 minutes/lead vs 7.06 minutes/lead) case times/lead over the course of the study. The mean radial error was 1.75 (± 0.94 mm). Clinically useful data were obtained from SEEG in 95% of cases, and epilepsy surgery was indicated and performed in 95% of patients. In patients who underwent definitive epilepsy surgery with at least a 3-month follow-up, 50% achieved an Engel class I result (seizure freedom). There were no postoperative complications associated with SEEG placement and monitoring.CONCLUSIONSIn this study, the authors demonstrate that rapid adoption of robot-guided SEEG is possible even at a SEEG-naïve institution, with minimal learning curve. Use of robot guidance for SEEG can lead to significantly decreased operating times while maintaining safety, the overall goals of identification of epileptogenic zones, and improved epilepsy outcomes.

Strategic hospital partnerships: improved access to care and increased epilepsy surgical volume.

OBJECTIVE Surgical treatment of patients with medically refractory focal epilepsy is underutilized. Patients may lack access to surgically proficient centers. The University of California, Irvine (UCI) entered strategic partnerships with 2 epilepsy centers with limited surgical capabilities. A formal memorandum of understanding (MOU) was created to provide epilepsy surgery to patients from these centers. METHODS The authors analyzed UCI surgical and financial data associated with patients undergoing epilepsy surgery between September 2012 and June 2016, before and after institution of the MOU. Variables collected included the length of stay, patient age, seizure semiology, use of invasive monitoring, and site of surgery as well as the monthly number of single-surgery cases, complex cases (i.e., staged surgeries), and overall number of surgery cases. RESULTS Over the 46 months of the study, a total of 104 patients underwent a total of 200 operations; 71 operations were performed in 39 patients during the pre-MOU period (28 months) and 129 operations were performed in 200 patients during the post-MOU period (18 months). There was a significant difference in the use of invasive monitoring, the site of surgery, the final therapy, and the type of insurance. The number of single-surgery cases, complex-surgery cases, and the overall number of cases increased significantly. CONCLUSIONS Partnerships with outside epilepsy centers are a means to increase access to surgical care. These partnerships are likely reproducible, can be mutually beneficial to all centers involved, and ultimately improve patient access to care.

Treatment of medically refractory seizures with responsive neurostimulation: 2 pediatric cases.

The responsive neurostimulation (RNS) system, an adjunctive treatment for pharmacoresistant partial-onset seizures with 1 or 2 foci, has been available to patients aged 18 years or older since the device's FDA approval in 2013. Herein, the authors describe their off-label application of this technology in 2 pediatric patients and the consequent therapeutic benefit without surgical complications or treatment side effects. A 14-year-old nonambulatory, nonverbal male with severe developmental delay was considered for RNS therapy for medically and surgically refractory epilepsy with bilateral seizure onsets in the setting of a normal radiological examination and a known neuropathological diagnosis of type I cortical dysplasia. The RNS system was implanted with strip electrodes placed on the left lateral frontal and right lateral temporal neocortex. At 19 months' follow-up, cortical stimulation resulted in sustained reduction in both seizure frequency-3 seizures per day down from 15 to 30 per day-and seizure severity. The patient subsequently underwent a trial of corticothalamic stimulation with a right temporal cortical strip and a left thalamic depth electrode, which resulted in a further 50% reduction in seizure frequency. In a second case, a 9-year-old right-handed female with radiological evidence of a small watershed infarct on the left and medically refractory seizures was referred for presurgical evaluation. Invasive monitoring revealed an unresectable seizure focus in the eloquent cortex of the left posterior frontal and parietal lobes. The RNS device was implanted with cortical leads placed at the putative seizure focus. At 21 months after surgery, the patient had been seizure free for 4 months, following a 17-month period in which the seizure frequency had decreased from 12 per month to 2 per month, with associated functional and behavioral improvement. The authors' results suggest that RNS may be a palliative option for children with intractable seizures whose condition warrants off-label use of the surgical device. The improved therapeutic effect noted with time and sustained RNS treatment points to a possible neuromodulatory effect.

Chronic subthreshold cortical stimulation for adult drug-resistant focal epilepsy: safety, feasibility, and technique.

OBJECTIVE Epilepsy surgery is effective for lesional epilepsy, but it can be associated with significant morbidity when seizures originate from eloquent cortex that is resected. Here, the objective was to describe chronic subthreshold cortical stimulation and evaluate its early surgical safety profile in adult patients with epilepsy originating from seizure foci in cortex that is not amenable to resection. METHODS Adult patients with focal drug-resistant epilepsy underwent intracranial electroencephalography monitoring for evaluation of resection. Those with seizure foci in eloquent cortex were not candidates for resection and were offered a short therapeutic trial of continuous subthreshold cortical stimulation via intracranial monitoring electrodes. After a successful trial, electrodes were explanted and permanent stimulation hardware was implanted. RESULTS Ten patients (6 males) who underwent chronic subthreshold cortical stimulation between 2014 and 2016 were included. Based on radiographic imaging, intracranial pathologies included cortical dysplasia (n = 3), encephalomalacia (n = 3), cortical tubers (n = 1), Rasmussen encephalitis (n = 1), and linear migrational anomaly (n = 1). The duration of intracranial monitoring ranged from 3 to 20 days. All patients experienced an uneventful postoperative course and were discharged home with a median length of stay of 10 days. No postoperative surgical complications developed (median follow-up length 7.7 months). Seizure severity and seizure frequency improved in all patients. CONCLUSIONS The authors' institutional experience with this small group shows that chronic subthreshold cortical stimulation can be safely and effectively performed in appropriately selected patients without postoperative complications. Future investigation will provide further insight to recently published results regarding mechanism and efficacy of this novel and promising intervention.

Epilepsy surgery in patients with autism.

OBJECTIVE The purpose of this study was to report outcomes of epilepsy surgery in 56 consecutive patients with autism spectrum disorder. METHODS Medical records of 56 consecutive patients with autism who underwent epilepsy surgery were reviewed with regard to clinical characteristics, surgical management, postoperative seizure control, and behavioral changes. RESULTS Of the 56 patients with autism, 39 were male, 45 were severely autistic, 27 had a history of clinically significant levels of aggression and other disruptive behaviors, and 30 were considered nonverbal at baseline. Etiology of the epilepsy was known in 32 cases, and included structural lesions, medical history, and developmental and genetic factors. Twenty-nine patients underwent resective treatments (in 8 cases combined with palliative procedures), 24 patients had only palliative treatments, and 3 patients had only subdural electroencephalography. Eighteen of the 56 patients had more than one operation. The mean age at surgery was 11 ± 6.5 years (range 1.5-35 years). At a mean follow-up of 47 ± 30 months (range 2-117 months), seizure outcomes included 20 Engel Class I, 12 Engel Class II, 18 Engel Class III, and 3 Engel Class IV cases. The age and follow-up times are stated as the mean ± SD. Three patients were able to discontinue all antiepileptic drugs (AEDs). Aggression and other aberrant behaviors observed in the clinical setting improved in 24 patients. According to caregivers, most patients also experienced some degree of improvement in daily social and cognitive function. Three patients had no functional or behavioral changes associated with seizure reduction, and 2 patients experienced worsening of seizures and behavioral symptoms. CONCLUSIONS Epilepsy surgery in patients with autism is feasible, with no indication that the comorbidity of autism should preclude a good outcome. Resective and palliative treatments brought seizure freedom or seizure reduction to the majority of patients, although one-third of the patients in this study required more than one procedure to achieve worthwhile improvement in the long term, and few patients were able to discontinue all AEDs. The number of palliative procedures performed, the need for multiple interventions, and continued use of AEDs highlight the complex etiology of epilepsy in patients with autism spectrum disorder. These considerations underscore the need for continued analysis, review, and reporting of surgical outcomes in patients with autism, which may aid in better identification and management of surgical candidates. The reduction in aberrant behaviors observed in this series suggests that some behaviors previously attributed to autism may be associated with intractable epilepsy, and further highlights the need for systematic evaluation of the relationship between the symptoms of autism and refractory seizures.

Chronic unlimited recording electrocorticography-guided resective epilepsy surgery: technology-enabled enhanced fidelity in seizure focus localization with improved surgical efficacy.

OBJECT: Epilepsy surgery is at the cusp of a transformation due to the convergence of advancements in multiple technologies. Emerging neuromodulatory therapies offer the promise of functionally correcting neural instability and obviating the need for resective or ablative surgery in select cases. Chronic implanted neurological monitoring technology, delivered as part of a neuromodulatory therapeutic device or as a stand-alone monitoring system, offers the potential to monitor patients chronically in their normal ambulatory setting with outpatient medication regimens. This overcomes significant temporal limitations, pharmacological perturbations, and infection risks inherent in the present technology comprising subacute percutaneous inpatient monitoring of presurgical candidates in an epilepsy monitoring unit. METHODS: As part of the pivotal study for the NeuroPace Responsive Neurostimulation (RNS) System, the authors assessed the efficacy of the RNS System to control seizures in a group of patients with medically refractory epilepsy. Prior to RNS System implantation, these patients were not candidates for further resective surgery because they had temporal lobe epilepsy with bilateral temporal sources, frontal lobe reflex epilepsy with involvement of primary motor cortex, and occipital lobe epilepsy with substantial involvement of eloquent visual cortex. Without interfering with and beyond the scope of the therapeutic aspect of the RNS System study, the authors were able to monitor seizure and epileptiform activity from chronically implanted subdural and depth electrodes in these patients, and, in doing so, they were able to more accurately localize the seizure source. In 5 of these study patients, in whom the RNS System was not effective, the notion of resective surgery was revisited and considered in light of the additional information gleaned from the chronic intracranial recordings obtained from various permutations of electrodes monitoring sources in the frontal, temporal, parietal, and occipital lobes. RESULTS: Through long-term analysis of chronic unlimited recording electrocorticography (CURE) from chronically implanted electrodes, the authors were able to further refine seizure source localization and sufficiently increase the expected likelihood of seizure control to the extent that 4 patients who had previously been considered not to be candidates for surgery did undergo resective surgery, and all have achieved seizure freedom. A fifth patient, who had a double-band heterotopia, underwent surgery but did not achieve significant seizure reduction. CONCLUSIONS: Chronic unlimited recording electrocorticography-guided resective epilepsy surgery employs new monitoring technology in a novel way, which in this small series was felt to improve seizure localization and consequently the potential efficacy of resective surgery. This suggests that the CURE modality could improve outcomes in patients who undergo resective surgery, and it may expand the set of patients in whom resective surgery may be expected to be efficacious and therefore the potential number of patients who may achieve seizure freedom. The authors report 4 cases of patients in which this technique and technology had a direct role in guiding surgery that provided seizure freedom and that suggest this new approach warrants further study to characterize its value in presurgical evaluation. Clinical trial no.: NCT00572195 (ClinicalTrials.gov).