Gray Matter Atrophy: The Impacts of Resective Surgery and Vagus Nerve Stimulation in Drug-Resistant Epilepsy.

BACKGROUND: There is great concern for cognitive function after resective temporal lobe surgery for drug-resistant epilepsy. However, few studies have investigated postoperative anatomical changes, and the downstream effects of surgery are poorly understood. This study investigated volumetric changes after resective surgery and vagus nerve stimulation (VNS) for epilepsy. METHODS: Preoperative and latest postoperative (mean, 28 months) structural T1 magnetic resonance imaging scans were retrospectively obtained for 43 patients: 27 temporal lobe resections (TLRs), 6 extratemporal lobe resections, and 10 VNS, undergoing surgery for drug-resistant epilepsy between 2012 and 2017. Automated volumetric analyses of predefined cortical gray matter and subcortical structures were performed. Preoperative and postoperative volumes were compared, and the effects of age, gender, operation type, resection laterality, selectivity, time since surgery, and seizure outcome on volumetric changes were analyzed. RESULTS: After TLRs, there were reductions in contralateral hemispheric gray matter, temporal lobe, entorhinal cortex, parahippocampal, superior temporal, middle temporal, inferior temporal (P = 0.02), lingual, fusiform, precentral, paracentral, postcentral, pericalcarine gyri, and ipsilateral superior parietal gyrus. After VNS, there was bilateral atrophy in the thalamus, putamen, cerebellum, rostral anterior cingulate, posterior cingulate, medial orbitofrontal, paracentral, fusiform, and transverse temporal gyri. There was a significant effect of surgery type but no effect of age, gender, operation type, resection laterality, selectivity, time since surgery, and seizure outcome on contralateral hippocampal gray matter change. CONCLUSION: This is the first study to demonstrate volumetric decreases in temporal and connected regions after TLRs and VNS. These results provide interesting insight into functional network changes.

Real-world experience with direct brain-responsive neurostimulation for focal onset seizures.

OBJECTIVE: The RNS System is a direct brain-responsive neurostimulation system that is US Food and Drug Administration-approved for adults with medically intractable focal onset seizures based on safety and effectiveness data from controlled clinical trials. The purpose of this study was to retrospectively evaluate the real-world safety and effectiveness of the RNS System. METHODS: Eight comprehensive epilepsy centers conducted a chart review of patients treated with the RNS System for at least 1 year, in accordance with the indication for use. Data included device-related serious adverse events and the median percent change in disabling seizure frequency from baseline at years 1, 2, and 3 of treatment and at the most recent follow-up. RESULTS: One hundred fifty patients met the criteria for analysis. The median reduction in seizures was 67% (interquartile range [IQR] = 33%-93%, n = 149) at 1 year, 75% (IQR = 50%-94%, n = 93) at 2 years, 82% (IQR = 50%-96%, n = 38) at ≥3 years, and 74% (IQR = 50%-96%, n = 150) at last follow-up (mean = 2.3 years). Thirty-five percent of patients had a ≥90% seizure frequency reduction, and 18% of patients reported being clinically seizure-free at last follow-up. Seizure frequency reductions were similar regardless of patient age, age at epilepsy onset, duration of epilepsy, seizure onset in mesial temporal or neocortical foci, magnetic resonance imaging findings, prior intracranial monitoring, prior epilepsy surgery, or prior vagus nerve stimulation treatment. The infection rate per procedure was 2.9% (6/150 patients); five of the six patients had an implant site infection, and one had osteomyelitis. Lead revisions were required in 2.7% (4/150), and 2.0% (3/150) of patients had a subdural hemorrhage, none of which had long-lasting neurological consequences. SIGNIFICANCE: In this real-world experience, safety was similar and clinical seizure outcomes exceeded those of the prospective clinical trials, corroborating effectiveness of this therapy and suggesting that clinical experience has informed more effective programming.

Mesial temporal resection following long-term ambulatory intracranial EEG monitoring with a direct brain-responsive neurostimulation system.

OBJECTIVE: To describe seizure outcomes in patients with medically refractory epilepsy who had evidence of bilateral mesial temporal lobe (MTL) seizure onsets and underwent MTL resection based on chronic ambulatory intracranial EEG (ICEEG) data from a direct brain-responsive neurostimulator (RNS) system. METHODS: We retrospectively identified all patients at 17 epilepsy centers with MTL epilepsy who were treated with the RNS System using bilateral MTL leads, and in whom an MTL resection was subsequently performed. Presumed lateralization based on routine presurgical approaches was compared to lateralization determined by RNS System chronic ambulatory ICEEG recordings. The primary outcome was frequency of disabling seizures at last 3-month follow-up after MTL resection compared to seizure frequency 3 months before MTL resection. RESULTS: We identified 157 patients treated with the RNS System with bilateral MTL leads due to presumed bitemporal epilepsy. Twenty-five patients (16%) subsequently had an MTL resection informed by chronic ambulatory ICEEG (mean = 42 months ICEEG); follow-up was available for 24 patients. After MTL resection, the median reduction in disabling seizures at last follow-up was 100% (mean: 94%; range: 50%-100%). Nine patients (38%) had exclusively unilateral electrographic seizures recorded by chronic ambulatory ICEEG and all were seizure-free at last follow-up after MTL resection; eight of nine continued RNS System treatment. Fifteen patients (62%) had bilateral MTL electrographic seizures, had an MTL resection on the more active side, continued RNS System treatment, and achieved a median clinical seizure reduction of 100% (mean: 90%; range: 50%-100%) at last follow-up, with eight of fifteen seizure-free. For those with more than 1 year of follow-up (N = 21), 15 patients (71%) were seizure-free during the most recent year, including all eight patients with unilateral onsets and 7 of 13 patients (54%) with bilateral onsets. SIGNIFICANCE: Chronic ambulatory ICEEG data provide information about lateralization of MTL seizures and can identify additional patients who may benefit from MTL resection.

Dual responsive neurostimulation implants for epilepsy.

Closed-loop brain-responsive neurostimulation via the RNS System is a treatment option for adults with medically refractory focal epilepsy. Using a novel technique, 2 RNS Systems (2 neurostimulators and 4 leads) were successfully implanted in a single patient with bilateral parietal epileptogenic zones. In patients with multiple epileptogenic zones, this technique allows for additional treatment options. Implantation can be done successfully, without telemetry interference, using proper surgical planning and neurostimulator positioning.Trajectories for the depth leads were planned using neuronavigation with CT and MR imaging. Stereotactic frames were used for coordinate targeting. Each neurostimulator was positioned with maximal spacing to avoid telemetry interference while minimizing patient discomfort. A separate J-shaped incision was used for each neurostimulator to allow for compartmentalization in case of infection. In order to minimize surgical time and risk of infection, the neurostimulators were implanted in 2 separate surgeries, approximately 3 weeks apart.The neurostimulators and leads were successfully implanted without adverse surgical outcomes. The patient recovered uneventfully, and the early therapy settings over several months resulted in preliminary decreases in aura and seizure frequency. Stimulation by one of the neurostimulators did not result in stimulation artifacts detected by the contralateral neurostimulator.

Epilepsy surgery in the underserved Hispanic population improves depression, anxiety, and quality of life.

OBJECTIVE: The objective of this study was to investigate the effect of epilepsy surgery on depression, anxiety, and quality of life (QOL) in a Hispanic, primarily immigrant, Spanish-speaking population with intractable epilepsy (IE). METHODS: Patients with IE from a comprehensive epilepsy treatment center in an urban, public healthcare setting who underwent resective brain surgery between 2008 and 2014 (N=47) and completed presurgical and postsurgical neuropsychological evaluation were retrospectively identified. Presurgical and 1-year postsurgical Beck Depression Inventory-II (BDI-II), Beck Anxiety Inventory (BAI), and QOLIE-31 ratings were analyzed as postsurgical outcome measures. One-tailed paired sample t-tests were used to evaluate whether scores improved postoperatively. Established severity level classifications of depression and anxiety (i.e., minimal, mild, moderate, or severe) were used to analyze changes in occurrence of depression and anxiety. RESULTS: Medium to large improvements on the BDI-II and most QOLIE-31 subscales, with a smaller effect on the BAI and remaining QOLIE-31 subscales, were noted 1-year postsurgery. Levels of depression and anxiety were significantly reduced 1-year postsurgery. Depression, anxiety, and QOL improvements were robust and unaffected by gender, levels of education, or hemisphere of surgery. CONCLUSIONS: This study supports the positive benefits of epilepsy surgery on depression, anxiety, and QOL in Hispanic, primarily undocumented immigrant, Spanish-speaking people with epilepsy (PWE) in the US. These results are useful for educating this particular population about the possible benefits of surgery for IE and can enhance presurgical counseling.

Radiosurgery versus open surgery for mesial temporal lobe epilepsy: The randomized, controlled ROSE trial.

OBJECTIVE: To compare stereotactic radiosurgery (SRS) versus anterior temporal lobectomy (ATL) for patients with pharmacoresistant unilateral mesial temporal lobe epilepsy (MTLE). METHODS: This randomized, single-blinded, controlled trial recruited adults eligible for open surgery among 14 centers in the USA, UK, and India. Treatment was either SRS at 24 Gy to the 50% isodose targeting mesial structures, or standardized ATL. Outcomes were seizure remission (absence of disabling seizures between 25 and 36 months), verbal memory (VM), and quality of life (QOL) at 36-month follow-up. RESULTS: A total of 58 patients (31 in SRS, 27 in ATL) were treated. Sixteen (52%) SRS and 21 (78%) ATL patients achieved seizure remission (difference between ATL and SRS = 26%, upper 1-sided 95% confidence interval = 46%, P value at the 15% noninferiority margin = .82). Mean VM changes from baseline for 21 English-speaking, dominant-hemisphere patients did not differ between groups; consistent worsening occurred in 36% of SRS and 57% of ATL patients. QOL improved with seizure remission. Adverse events were anticipated cerebral edema and related symptoms for some SRS patients, and cerebritis, subdural hematoma, and others for ATL patients. SIGNIFICANCE: These data suggest that ATL has an advantage over SRS in terms of proportion of seizure remission, and both SRS and ATL appear to have effectiveness and reasonable safety as treatments for MTLE. SRS is an alternative to ATL for patients with contraindications for or with reluctance to undergo open surgery.

A Single-Center Experience with the NeuroPace RNS System: A Review of Techniques and Potential Problems.

INTRODUCTION: The clinical results for the RNS System (NeuroPace, Mountain View, California, USA) closed-loop responsive neurostimulator for the treatment of medically intractable partial-onset seizures have been encouraging. The University of Southern California (USC) Neurorestoration Center and the Keck Hospital of USC have become the world's first institutions to implant an RNS System post U.S. Food and Drug Administration (FDA) approval. As one of the study centers, we review our experience with our group of patients who have been implanted with the RNS System. METHODS: A total of 40 surgeries by a single surgeon were performed on 10 patients (7 male and 3 female) with an average age of 39.2 years (24-66 years) and were followed for an average of 45 months (30-54 months). The average age at seizure onset was 14 years (birth-37 years) with an average of 4.7 (3-12) failed antiepileptic drugs. We reviewed the patients' charts for complications from the surgeries including infections requiring surgical intervention, hematomas, hardware failures, and death. RESULTS: Of the 40 surgeries, there were 10 initial implantations of the neurostimulator and leads, 24 neurostimulator replacements for expected end of neurostimulator service, 2 incision and drainage procedures (I & Ds) for soft tissue infection followed by 1 explantation and 1 reimplantation (same patient), and 2 revisions because of one lead that was damaged at the exit point between the skull and a titanium mesh and the second lead that was damaged at an acute bend over the skull (same patient). Eight of the patients had no complications and underwent an average of 2.7 neurostimulator replacements over 7 consecutive years to date. Each patient underwent routine postoperative computed tomography imaging of the brain, and none had any intracranial hematomas or misplaced leads requiring revision surgery. Finally, there were no deaths in our patient population. CONCLUSIONS: Our experience with the NeuroPace RNS System over an average follow-up of 45 months suggests that the surgery and device are safe when placed by an experienced surgeon. Although there were no clinically significant hematomas or patient deaths, we did have 1 patient each with infection and lead damage at the point of exit from the skull. We compare the results of this study with other neuromodulation procedures for epilepsy to evaluate the safety and complications associated with the RNS System. Our initial experience suggests that the RNS System can be readily incorporated into an active epilepsy surgical center.

Visual field defects after radiosurgery for mesial temporal lobe epilepsy.

PURPOSE: Gamma knife radiosurgery (RS) may be an alternative to open surgery for mesial temporal lobe epilepsy (MTLE), but morbidities and the anticonvulsant mechanisms of RS are unclear. Examination of visual field defects (VFDs) after RS may provide evidence of the extent of a postoperative fixed lesion. VFDs occur in 52-100% of patients following open surgery for MTLE. METHODS: This multicenter prospective trial of RS enrolled patients with unilateral hippocampal sclerosis and concordant video-electroencephalography (EEG) findings. Patients were randomized to low (20 Gy) or high (24 Gy) doses delivered to the amygdala, hippocampal head, and parahippocampal gyrus. Postoperative perimetry were obtained at 24 months after RS. Visual field defect ratios (VFDRs) were calculated to quantify the degree of VFDs. Results were contrasted with age, RS dose and 50% isodose volume, peak volume of radiation-induced change at the surgical target, quality of life measurements, and seizure remission. KEY FINDINGS: No patients reported visual changes and no patients had abnormal bedside visual field examinations. Fifteen (62.5%) of 24 patients had postoperative VFDs, all homonymous superior quadrantanopsias. None of the VFDs were consistent with injury to the optic nerve or chiasm. Clinical diagnosis of VFDs correlated significantly with VFDRs (p = 0.0005). Patients with seizure remission had smaller (more severe) VFDRs (p = 0.04). No other variables had significant correlations. SIGNIFICANCE: VFDs appeared after RS in proportions similar to historical comparisons from open surgery for MTLE. The nature of VFDs was consistent with lesions of the optic radiations. The findings support the hypothesis that the mechanism of RS involves some degree of tissue damage and is not confined entirely to functional changes in neuromodulation.

Variation of seizure frequency with ovulatory status of menstrual cycles.

PURPOSE: To determine if seizure frequency differs between anovulatory and ovulatory cycles. METHODS: The data came from the 3-month baseline phase of an investigation of progesterone therapy for intractable focal onset seizures. Of 462 women who enrolled, 281 completed the 3-month baseline phase and 92 had both anovulatory and ovulatory cycles during the baseline phase. Midluteal progesterone levels ≥5 ng/ml were used to designate cycles as ovulatory. Among the 92 women, average daily seizure frequency (ADSF) for all seizures combined and each type of seizure considered separately (secondary generalized tonic-clonic seizures - 2°GTCS, complex partial seizures - CPS, simple partial seizures - SPS) were compared between anovulatory and ovulatory cycles using paired t-tests. A relationship between the proportional differences in ADSF and estradiol/progesterone (EP) serum level ratios between anovulatory and ovulatory cycles was determined using bivariate correlational analysis. KEY FINDINGS: ADSF was 29.5% greater for 2°GTCS during anovulatory than during ovulatory cycles. ADSF did not differ significantly for CPS or SPS or for all seizures combined. Proportional differences in anovulatory/ovulatory 2°GTCS ADSF ratios correlated significantly with differences in anovulatory/ovulatory EP ratios. Among the 281 women, the three seizure types did not differ in ovulatory rates, but EP ratios were greater for cycles with 2°GTCS than partial seizures only. SIGNIFICANCE: Seizure frequency is significantly greater for 2°GTCS, but not CPS or SPS, during anovulatory cycles than ovulatory cycles. Because the proportional increases in 2°GTCS frequency during anovulatory cycles correlate with the proportional increases in EP level ratios, these findings support a possible role for reproductive steroids in 2°GTCS occurrence.