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.

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.

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.

Brain-responsive neurostimulation in patients with medically intractable mesial temporal lobe epilepsy.

OBJECTIVE: Evaluate the seizure-reduction response and safety of mesial temporal lobe (MTL) brain-responsive stimulation in adults with medically intractable partial-onset seizures of mesial temporal lobe origin. METHODS: Subjects with mesial temporal lobe epilepsy (MTLE) were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. RESULTS: There were 111 subjects with MTLE; 72% of subjects had bilateral MTL onsets and 28% had unilateral onsets. Subjects had one to four leads placed; only two leads could be connected to the device. Seventy-six subjects had depth leads only, 29 had both depth and strip leads, and 6 had only strip leads. The mean follow-up was 6.1 ± (standard deviation) 2.2 years. The median percent seizure reduction was 70% (last observation carried forward). Twenty-nine percent of subjects experienced at least one seizure-free period of 6 months or longer, and 15% experienced at least one seizure-free period of 1 year or longer. There was no difference in seizure reduction in subjects with and without mesial temporal sclerosis (MTS), bilateral MTL onsets, prior resection, prior intracranial monitoring, and prior vagus nerve stimulation. In addition, seizure reduction was not dependent on the location of depth leads relative to the hippocampus. The most frequent serious device-related adverse event was soft tissue implant-site infection (overall rate, including events categorized as device-related, uncertain, or not device-related: 0.03 per implant year, which is not greater than with other neurostimulation devices). SIGNIFICANCE: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including patients with unilateral or bilateral MTLE who are not candidates for temporal lobectomy or who have failed a prior MTL resection.

Brain-responsive neurostimulation in patients with medically intractable seizures arising from eloquent and other neocortical areas.

OBJECTIVE: Evaluate the seizure-reduction response and safety of brain-responsive stimulation in adults with medically intractable partial-onset seizures of neocortical origin. METHODS: Patients with partial seizures of neocortical origin were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. Additional analyses considered safety and seizure reduction according to lobe and functional area (e.g., eloquent cortex) of seizure onset. RESULTS: There were 126 patients with seizures of neocortical onset. The average follow-up was 6.1 implant years. The median percent seizure reduction was 70% in patients with frontal and parietal seizure onsets, 58% in those with temporal neocortical onsets, and 51% in those with multilobar onsets (last observation carried forward [LOCF] analysis). Twenty-six percent of patients experienced at least one seizure-free period of 6 months or longer and 14% experienced at least one seizure-free period of 1 year or longer. Patients with lesions on magnetic resonance imaging (MRI; 77% reduction, LOCF) and those with normal MRI findings (45% reduction, LOCF) benefitted, although the treatment response was more robust in patients with an MRI lesion (p = 0.02, generalized estimating equation [GEE]). There were no differences in the seizure reduction in patients with and without prior epilepsy surgery or vagus nerve stimulation. Stimulation parameters used for treatment did not cause acute or chronic neurologic deficits, even in eloquent cortical areas. The rates of infection (0.017 per patient implant year) and perioperative hemorrhage (0.8%) were not greater than with other neurostimulation devices. SIGNIFICANCE: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including adults with seizures of neocortical onset, and those with onsets from eloquent cortex.

Potentially preventable complications in epilepsy admissions: The "weekend effect".

INTRODUCTION: Epilepsy affects approximately 1% of the population in the United States with frequent hospital admissions accounting for a significant burden on patients and society as a whole. Weekend admissions have generally been found to have poorer outcomes compared to weekday admissions with increased rates of preventable complications, such as nationally identified "hospital-acquired conditions" (HAC). OBJECTIVE: This study aimed to assess the impact of weekend admission on HACs and mortality in the adult epilepsy population. PARTICIPANTS: All adult patients with epilepsy hospitalized in the U.S. from 2000 to 2010 in the Nationwide Inpatient Sample. RESULTS: There were 12,997,181 admissions for epilepsy with 10,106,152 (78%) weekday, 2,891,019 (22%) weekend, and 10 (<0.1%) missing admissions. Weekend admissions saw a 10% increased likelihood of both HACs (RR=1.10, 95% CI:1.09, 1.11, p<0.01) and mortality (RR=1.10, 95% CI: 1.09, 1.11, p<0.01) compared to weekday admissions. The occurrence of HAC was associated with higher inpatient charges (RR=1.36, 95% CI: 1.35, 1.36, p<0.01), pLOS (RR=1.21, 95% CI: 1.21, 1.22, p<0.01), and higher mortality (RR=1.13, 95% CI: 1.12, 1.14, p<0.01). CONCLUSION: Prior studies have shown weekend admissions are usually associated with higher rates of complications leading to higher costs and a longer hospital stay. Likewise, weekend admissions for epilepsy were associated with increased rates of HACs and mortality; however, they were also negatively associated with LOS and total charge. Thus, weekend admissions for epilepsy should be considered high risk with greater effort made to mitigate these risks.

Lateralization of mesial temporal lobe epilepsy with chronic ambulatory electrocorticography.

OBJECTIVE: Patients with suspected mesial temporal lobe (MTL) epilepsy typically undergo inpatient video-electroencephalography (EEG) monitoring with scalp and/or intracranial electrodes for 1 to 2 weeks to localize and lateralize the seizure focus or foci. Chronic ambulatory electrocorticography (ECoG) in patients with MTL epilepsy may provide additional information about seizure lateralization. This analysis describes data obtained from chronic ambulatory ECoG in patients with suspected bilateral MTL epilepsy in order to assess the time required to determine the seizure lateralization and whether this information could influence treatment decisions. METHODS: Ambulatory ECoG was reviewed in patients with suspected bilateral MTL epilepsy who were among a larger cohort with intractable epilepsy participating in a randomized controlled trial of responsive neurostimulation. Subjects were implanted with bilateral MTL leads and a cranially implanted neurostimulator programmed to detect abnormal interictal and ictal ECoG activity. ECoG data stored by the neurostimulator were reviewed to determine the lateralization of electrographic seizures and the interval of time until independent bilateral MTL electrographic seizures were recorded. RESULTS: Eighty-two subjects were implanted with bilateral MTL leads and followed for 4.7 years on average (median 4.9 years). Independent bilateral MTL electrographic seizures were recorded in 84%. The average time to record bilateral electrographic seizures in the ambulatory setting was 41.6 days (median 13 days, range 0-376 days). Sixteen percent had only unilateral electrographic seizures after an average of 4.6 years of recording. SIGNIFICANCE: About one third of the subjects implanted with bilateral MTL electrodes required >1 month of chronic ambulatory ECoG before the first contralateral MTL electrographic seizure was recorded. Some patients with suspected bilateral MTL seizures had only unilateral electrographic seizures. Chronic ambulatory ECoG in patients with suspected bilateral MTL seizures provides data in a naturalistic setting, may complement data from inpatient video-EEG monitoring, and can contribute to treatment decisions.

Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: final results of the RNS System Pivotal trial.

OBJECTIVE: To demonstrate the safety and effectiveness of responsive stimulation at the seizure focus as an adjunctive therapy to reduce the frequency of seizures in adults with medically intractable partial onset seizures arising from one or two seizure foci. METHODS: Randomized multicenter double-blinded controlled trial of responsive focal cortical stimulation (RNS System). Subjects with medically intractable partial onset seizures from one or two foci were implanted, and 1 month postimplant were randomized 1:1 to active or sham stimulation. After the fifth postimplant month, all subjects received responsive stimulation in an open label period (OLP) to complete 2 years of postimplant follow-up. RESULTS: All 191 subjects were randomized. The percent change in seizures at the end of the blinded period was -37.9% in the active and -17.3% in the sham stimulation group (p = 0.012, Generalized Estimating Equations). The median percent reduction in seizures in the OLP was 44% at 1 year and 53% at 2 years, which represents a progressive and significant improvement with time (p < 0.0001). The serious adverse event rate was not different between subjects receiving active and sham stimulation. Adverse events were consistent with the known risks of an implanted medical device, seizures, and of other epilepsy treatments. There were no adverse effects on neuropsychological function or mood. SIGNIFICANCE: Responsive stimulation to the seizure focus reduced the frequency of partial-onset seizures acutely, showed improving seizure reduction over time, was well tolerated, and was acceptably safe. The RNS System provides an additional treatment option for patients with medically intractable partial-onset seizures.

Developing a hippocampal neural prosthetic to facilitate human memory encoding and recall of stimulus features and categories.

Objective: Here, we demonstrate the first successful use of static neural stimulation patterns for specific information content. These static patterns were derived by a model that was applied to a subject's own hippocampal spatiotemporal neural codes for memory. Approach: We constructed a new model of processes by which the hippocampus encodes specific memory items via spatiotemporal firing of neural ensembles that underlie the successful encoding of targeted content into short-term memory. A memory decoding model (MDM) of hippocampal CA3 and CA1 neural firing was computed which derives a stimulation pattern for CA1 and CA3 neurons to be applied during the encoding (sample) phase of a delayed match-to-sample (DMS) human short-term memory task. Main results: MDM electrical stimulation delivered to the CA1 and CA3 locations in the hippocampus during the sample phase of DMS trials facilitated memory of images from the DMS task during a delayed recognition (DR) task that also included control images that were not from the DMS task. Across all subjects, the stimulated trials exhibited significant changes in performance in 22.4% of patient and category combinations. Changes in performance were a combination of both increased memory performance and decreased memory performance, with increases in performance occurring at almost 2 to 1 relative to decreases in performance. Across patients with impaired memory that received bilateral stimulation, significant changes in over 37.9% of patient and category combinations was seen with the changes in memory performance show a ratio of increased to decreased performance of over 4 to 1. Modification of memory performance was dependent on whether memory function was intact or impaired, and if stimulation was applied bilaterally or unilaterally, with nearly all increase in performance seen in subjects with impaired memory receiving bilateral stimulation. Significance: These results demonstrate that memory encoding in patients with impaired memory function can be facilitated for specific memory content, which offers a stimulation method for a future implantable neural prosthetic to improve human memory.

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.

Altered adult neurogenesis and gliogenesis in patients with mesial temporal lobe epilepsy.

The hippocampus is the most common seizure focus in people. In the hippocampus, aberrant neurogenesis plays a critical role in the initiation and progression of epilepsy in rodent models, but it is unknown whether this also holds true in humans. To address this question, we used immunofluorescence on control healthy hippocampus and surgical resections from mesial temporal lobe epilepsy (MTLE), plus neural stem-cell cultures and multi-electrode recordings of ex vivo hippocampal slices. We found that a longer duration of epilepsy is associated with a sharp decline in neuronal production and persistent numbers in astrogenesis. Further, immature neurons in MTLE are mostly inactive, and are not observed in cases with local epileptiform-like activity. However, immature astroglia are present in every MTLE case and their location and activity are dependent on epileptiform-like activity. Immature astroglia, rather than newborn neurons, therefore represent a potential target to continually modulate adult human neuronal hyperactivity.

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.

A sparse multiscale nonlinear autoregressive model for seizure prediction.

Objectives.Accurate seizure prediction is highly desirable for medical interventions such as responsive electrical stimulation. We aim to develop a classification model that can predict seizures by identifying preictal states, i.e. the precursor of a seizure, based on multi-channel intracranial electroencephalography (iEEG) signals.Approach.A two-level sparse multiscale classification model was developed to classify interictal and preictal states from iEEG data. In the first level, short time-scale linear dynamical features were extracted as autoregressive (AR) model coefficients; arbitrary (usually long) time-scale linear and nonlinear dynamical features were extracted as Laguerre-Volterra AR model coefficients; root-mean-square error of model prediction was used as a feature representing model unpredictability. In the second level, all features were fed into a sparse classifier to discriminate the iEEG data between interictal and preictal states.Main results. The two-level model can accurately classify seizure states using iEEG data recorded from ten canine and human subjects. Adding arbitrary (usually long) time-scale and nonlinear features significantly improves model performance compared with the conventional AR modeling approach. There is a high degree of variability in the types of features contributing to seizure prediction across different subjects.Significance. This study suggests that seizure generation may involve distinct linear/nonlinear dynamical processes caused by different underlying neurobiological mechanisms. It is necessary to build patient-specific classification models with a wide range of dynamical features.

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.

Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy.

OBJECTIVE: To prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years. METHODS: Adults treated with brain-responsive neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL with the Quality of Life in Epilepsy (QOLIE-89) inventory. RESULTS: Of 256 patients treated in the initial trials, 230 participated in the LTT. At 9 years, the median percent reduction in seizure frequency was 75% (p < 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency. We found that 18.4% (47 of 256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-up and an average seizure-free period of 3.2 years (range 1.04-9.6 years). Overall QOL and epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved (p < 0.05). There were no serious AEs related to stimulation, and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators (p < 0.05, 1-tailed χ2). CONCLUSIONS: Adjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS with improved QOL. Stimulation was well tolerated; implantation-related AEs were typical of other neurostimulation devices; and SUDEP rates were low. CLINICALTRIALSGOV IDENTIFIER: NCT00572195. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.

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.

The Weekend Effect on Morbidity and Mortality Among Pediatric Epilepsy Admissions.

BACKGROUND: Pediatric epilepsy is one of the most common neurological disorders with low mortality and high morbidity, often requiring hospitalization. Weekend admissions have been shown to be associated with worse outcomes compared with their weekday counterparts. To date, no study has assessed the impact of weekend admission on clinical and quality outcomes in the pediatric epilepsy population. METHODS: Children with epilepsy were identified from the 2000, 2003, 2006, and 2009 Kids Inpatient Database. Quality outcomes were identified using the Centers of Medicare and Medicaid Services' hospital acquired conditions International Classification of Diseases, Ninth Edition; Clinical Modification (ICD-9CM) codes. Multivariable analyses were conducted to assess the association between weekend admission and inpatient mortality and hospital acquired condition occurrence. RESULTS: A total of 526,765 pediatric epilepsy discharges were identified, with 80% occurring on weekdays and 20% on weekends. Overall, the hospital acquired condition rate was 3.6% (3.2% vs 5.2% for weekday versus weekend) and inpatient mortality was 1.5% (1.2% vs 1.7%). Patients admitted on the weekend had 28% higher rates of hospital acquired conditions and 21% higher inpatient mortality rates compared with their weekday counterparts. Patients seen at nonpediatric centers had 10% to 28% lower rates of mortality, but 5% to 13% higher hospital acquired condition rates than those at pediatric centers. CONCLUSIONS: Weekend admission is significantly associated with worse clinical and quality outcomes compared with weekday admissions among pediatric epilepsy inpatients. Weekend admissions likely represent unplanned, at risk admissions, coupled with less staffing. Further study is needed to isolate clinical and systemic factors to decrease this disparity in this highly comorbid pediatric subgroup.

Dysregulation of PINCH signaling in mesial temporal epilepsy.

Mounting evidence suggests that inflammation is important in epileptogenesis. Particularly Interesting New Cysteine Histidine-rich (PINCH) protein is a highly conserved, LIM-domain protein known to interact with hyperphosphorylated Tau. We assessed PINCH expression in resected epileptogenic human hippocampi and further explored the relationships among PINCH, hpTau and associated kinases. Resected hippocampal tissue from 7 patients with mesial temporal lobe epilepsy (MTLE) was assessed by Western analyses to measure levels of PINCH and hyperphosphorylated Tau, as well as changes in phosphorylation levels of associated kinases AKT and GSK3ß in comparison to normal control tissue. Immunolabeling was also conducted to evaluate PINCH and hpTau patterns of expression, co-localization and cell-type specific expression. Hippocampal PINCH was increased by 2.6 fold in the epilepsy cases over controls and hpTau was increased 10 fold over control. Decreased phospho-AKT and phospho-GSK3ß in epilepsy tissue suggested involvement of this pathway in MTLE. PINCH and hpTau co-localized in some neurons in MTLE tissue. While PINCH was expressed by both neurons and astrocytes in MTLE tissue, hpTau was extracellular or associated with neurons. PINCH was absent from the serum of control subjects but readily detectable from the serum of patients with chronic epilepsy. Our study describes the expression of PINCH and points to AKT/GSK3ß signaling dysregulation as a possible pathway in hpTau formation in MTLE. In view of the interactions between hpTau and PINCH, understanding the role of PINCH in MTLE may provide increased understanding of mechanisms leading to inflammation and MTLE epileptogenesis and a potential biomarker for drug-resistant epilepsy.

Preventable complications in epilepsy admissions: The "July effect".

BACKGROUND: Inpatient hospital stays for patients with epilepsy represent a significant burden on patients and society. Identifying factors that contribute to such costs aides in developing effective strategies to address this burden. July admissions have been associated with higher rates of complications and worse outcomes, attributed to the presence of new physicians. This study aims to evaluate whether epilepsy patients admitted in July have higher preventable complication rates and mortality than during the rest of the year. METHODS: Data was derived from the Nationwide Inpatient Sample (NIS) for epilepsy admissions for the years 2000-2010. Multivariable analyses assessed the effect of July against non-July admission on "hospital acquired complications" (HAC), which are complications identified as owing to preventable causes and mortality. Additionally, the total adjusted charges and prolonged length of stay (pLOS) for July admissions were compared to the 50th percentile. RESULTS: A total of 12,997,181 admissions for epilepsy were identified with 993,619 (8%) occurring in July, 10,810,900 (83%) were non-July months, and 1,192,662 (9%) were missing data. Patients admitted in July showed an increased association for HAC events (RR=1.02, [1.01,1.03], p<0.01), but a decrease in mortality (RR=0.96, [0.95,0.97], p<0.01). There was no difference in rates of higher total adjusted charges for July admissions (RR=1.00, [1.00,1.00], p<0.01) and a decrease in rates of pLOS (RR=0.99, [0.98,0.99], p<0.01). CONCLUSION: In the epilepsy population, although July admissions were associated with a slight increase in HAC events, there was a non-significant or decreased rate of mortality, LOS, and total charge. Our results suggest that although complications were increased in July, possibly due to new staff, supervision is sufficient to prevent significant burden on patients and hospitals.