Physician distress when treatments fail. Survey on physician distress when treating persons with drug-resistant epilepsy and knowledge of neuropalliative care.

OBJECTIVE: Drug-resistant epilepsy can be difficult to cure and may pose emotional challenges for epilepsy providers. Neuropalliative care (NPC) can augment quality of life (QOL) in persons with neurological diseases and may add meaningful elements to the treatment repertoire of epilepsy specialists even if seizures continue. However, NPC has not been widely implemented in epilepsy. Our study aimed to determine whether physicians of persons with drug-resistant epilepsy (PWDRE) experience distress when faced with treatment failure (Engel class ≥ 2), either failure of medications-only (PWDREmo) or of both medications and surgery (procedures with curative intent (PWDREms)). Furthermore, we evaluated physician knowledge about and referrals to NPC following treatment failures to help improve patient QOL despite ongoing seizures. METHODS: An anonymous online survey was distributed to US epilepsy physicians through the American Epilepsy Society website and personal email to assess levels of distress experienced when caring for PWDREmo and PWDREms (7-point Likert scale ["1" = "no distress", "7" = "most distress ever felt"]), and knowledge and use of NPC. RESULTS: Eighty-two physicians completed the survey. Most experienced distress when epilepsy treatments failed: 59% felt moderate distress (≥4) with PWDREmo (median "4", mean 3.74, range 1-7), 90% suffered moderate to severe distress (5, 5.17, 1-7) with PWDREms. Distress over PWDREms was significantly greater than distress over PWDREmo (p < 0.0001). Forty-three percent reported confidence in their knowledge about NPC. Only 15% were likely to refer PWDREmo to NPC, while 44% would consider it for PWDREms. CONCLUSION: Among survey responders, physician distress was high when confronted with treatment failures, especially the failure of epilepsy surgery. Fewer than half of responders were likely to refer patients to NPC. Further research is necessary to determine extent, reasons, and effects of physician distress and whether improved understanding of and patient access to NPC would help alleviate physician distress when faced with treatment failures in PWDRE.

Concurrent brain-responsive and vagus nerve stimulation for treatment of drug-resistant focal epilepsy.

OBJECTIVE: Clinical trials of a brain-responsive neurostimulator, RNS® System (RNS), excluded patients with a vagus nerve stimulator, VNS® System (VNS). The goal of this study was to evaluate seizure outcomes and safety of concurrent RNS and VNS stimulation in adults with drug-resistant focal-onset seizures. METHODS: A retrospective multicenter chart review was performed on all patients with an active VNS and RNS who were treated for a minimum of 6 months with both systems concurrently. Frequency of disabling seizures at baseline before RNS, at 1 year after RNS placement, and at last follow-up were used to calculate the change in seizure frequency after treatment. Data on adverse events and complications related to each device were collected. RESULTS: Sixty-four patients from 10 epilepsy centers met inclusion criteria. All but one patient received RNS after VNS. The median follow-up time after RNS implantation was 28 months. Analysis of the entire population of patients with active VNS and RNS systems revealed a median reduction in seizure frequency at 1 year post-RNS placement of 43% with a responder rate of 49%, and at last follow-up a 64% median reduction with a 67% responder rate. No negative interactions were reported from the concurrent use of VNS and RNS. Stimulation-related side-effects were reported more frequently in association with VNS (30%) than with RNS (2%). SIGNIFICANCE: Our findings suggest that concurrent treatment with VNS and RNS is safe and that the addition of RNS to VNS can further reduce seizure frequency.

Quantitative [18]FDG PET asymmetry features predict long-term seizure recurrence in refractory epilepsy.

OBJECTIVE: Fluorodeoxyglucose-positron emission tomography (FDG-PET) is an established, independent, strong predictor of surgical outcome in refractory epilepsy. In this study, we explored the added value of quantitative [18F]FDG-PET features combined with clinical variables, including electroencephalography (EEG), [18F]FDG-PET, and magnetic resonance imaging (MRI) qualitative interpretations, to predict long-term seizure recurrence (mean post-op follow-up of 5.85 ±â€¯3.77 years). METHODS: Machine learning predictive models of surgical outcome were created using a random forest classifier trained on quantitative features in 89 patients with drug-refractory temporal lobe epilepsy evaluated at the Hospital of the University of Pennsylvania epilepsy surgery program (2003-2016). Quantitative features were calculated from asymmetry features derived from image processing using Advanced Normalization Tools (ANTs). RESULTS: The best-performing model used quantification and had an out-of-bag accuracy of 0.71 in identifying patients with seizure recurrence (Engel IB or worse) which outperformed that using qualitative clinical data by 10%. This model is shared through open-source software for research use. In addition, several asymmetry features in temporal and extratemporal regions that were significantly associated with seizure freedom are identified for future study. SIGNIFICANCE: Complex quantitative [18F]FDG-PET imaging features can predict seizure recurrence in patients with refractory temporal lobe epilepsy. These initial retrospective results in a cohort with long-term follow-up suggest that using quantitative imaging features from regions in the epileptogenic network can inform the clinical decision-making process.

Would people living with epilepsy benefit from palliative care?

Palliative care (PC) is an approach to the care of persons living with serious illness and their families that focuses on improving quality of life and reducing suffering by addressing complex medical symptoms, psychosocial needs, spiritual well-being, and advance care planning. While PC has traditionally been associated with hospice care for persons with cancer, there is now recognition that PC is relevant to many noncancer diagnoses, including neurologic illness, and at multiple points along the illness journey, not just end of life. Despite the recent growth of the field of neuropalliative care there has been scant attention paid to the relevance of PC principles in epilepsy or the potential for PC approaches to improve outcomes for persons living with epilepsy and their families. We believe this has been a significant oversight and that PC may provide a useful framework for addressing the many sources of suffering facing persons living with epilepsy, for engaging patients and families in challenging conversations, and to focus efforts to improve models of care for this population. In this manuscript we review areas of significant unmet needs where a PC approach may improve patient and family-centered outcomes, including complex symptom management, goals of care, advance care planning, psychosocial support for patient and family and spiritual well-being. When relevant we highlight areas where epilepsy patients may have unique PC needs compared to other patient populations and conclude with suggestions for future research, clinical, and educational efforts.

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.

Seizure outcome with responsive neurostimulation (RNS) comparing strip versus depth leads.

OBJECTIVE: This study aimed to compare seizure outcomes and complication rates in patients treated with only responsive neurostimulation (RNS) strip leads with those treated with only RNS depth leads. METHODS: A retrospective cohort study was performed using the institutional epilepsy surgery database. Included was any patient implanted with the RNS system between August 2015 and May 2018 with either two depth (2D) or two strip (2S) leads connected to the device and at least 6 months follow-up. Excluded were those with a combination of active depth and strip leads. Data extracted from the charts comprised demographic information, duration of epilepsy, presence of a magnetic resonance imaging (MRI) lesion, prior resective surgery, clinically disabling seizures at baseline and follow-up, prior invasive monitoring, location (mesial temporal or neocortical) and number of seizure foci, unilateral or bilateral RNS lead placement, and postoperative complications. RESULTS: Of 48 screened patients, 34 met study inclusion criteria. Of these, 15 were treated with 2D leads and 19 with 2S leads. Groups 2D and 2S were comparable with respect to age at onset, duration of epilepsy, baseline seizure frequency, and exposure time to RNS. After adjustment for patient age and duration of epilepsy, seizure frequency in 2S patients was noted to be decreased by 83% (p = 0.046), while it was reduced by 51% (p = 0.080) in 2D patients. The complication rate was not significantly different between the two groups. CONCLUSION: In our small retrospective population, patients with RNS strip leads experienced a significantly greater seizure reduction than patients with RNS depth leads, without a difference in complication rate.

RNS modifications to eliminate stimulation-triggered signs or symptoms (STS): Case series and practical guide.

Responsive neurostimulation (RNS) for intractable epilepsy involves placement of electrodes onto or into the brain that detect seizure activity and then deliver a current to abort a seizure before it spreads. Successful RNS treatment can deliver hundreds of stimulations per day, which are generally unnoticeable to patients. Uncommonly, RNS electrodes may result in stimulation of brain regions or peripheral structures that causes uncomfortable sensory or motor effects, a phenomenon we refer to as stimulation-triggered signs or symptoms (STS). Occurrence of STS may limit the ability to use RNS to full capacity to reduce seizures. In this case series, we describe STS in six out of 58 (10.3%) RNS patients at our institution. To eliminate or minimize STS, we developed a protocol for modification of RNS parameters. Modifying RNS stimulation was associated with reduced STS in all six patients, five had adjustment of stimulation settings, one of lead position. Five out of six patients were able to undergo further optimization of RNS for improved seizure control after reduction of symptoms. One patient had recurrent STS that prevented further increase of RNS stimulation current. This study may help other medical teams in identifying and reducing STS in patients with epilepsy receiving RNS devices.

Curative and palliative MRI-guided laser ablation for drug-resistant epilepsy.

Epilepsy is a common neurological disorder occurring in 3% of the US adult population. It is characterised by seizures resulting from aberrant hypersynchronous neural activity. Approximately one-third of newly diagnosed epilepsy cases fail to become seizure-free in response to antiseizure drugs. Optimal seizure control, in cases of drug-resistant epilepsy, often requires neurosurgical intervention targeting seizure foci, such as the temporal lobe. Advances in minimally invasive ablative surgical approaches have led to the development of MRI-guided laser interstitial thermal therapy (LITT). For refractory epilepsy, this surgical intervention offers many advantages over traditional approaches, including real-time lesion monitoring, reduced morbidity, and in some reports increased preservation of cognitive and language processes. We review the use of LITT for epileptic indications in the context of its application as a curative (seizure freedom) or palliative (seizure reduction) measure for both lesional and non-lesional forms of epilepsy. Furthermore, we address the use of LITT for a variety of extratemporal lobe epilepsies. Finally, we describe clinical outcomes, limitations and future applications of LITT for epilepsy.

Endocarditis is a common stroke mechanism in hemodialysis patients.

BACKGROUND AND PURPOSE: Hemodialysis patients are at high risk for ischemic stroke, and previous studies have noted a high rate of cardioembolism in this population. The aim of this study was to determine ischemic stroke causes among hemodialysis patients and elucidate specific cardioembolic stroke mechanisms. METHODS: This study is a retrospective cross-sectional study of hemodialysis patients admitted with acute stroke to the University of Pennsylvania Health System between 2003 and 2010. Strokes were classified using modified Trial of Org 10,172 in Acute Stroke Treatment (TOAST) criteria as large vessel, cardioembolism, small vessel, atypical, multiple causes, or cryptogenic. Cardioembolic strokes were further characterized for specific mechanism. RESULTS: We identified 52 patients hospitalized with acute stroke while receiving hemodialysis. Mean age was 64±13 years, 56% were female, and 67% were black. Stroke subtypes included 3 (6%) large vessel, 20 (38%) cardioembolism, 6 (11%) small vessel, 3 (6%) other, 4 (8%) with multiple causes, and 16 (31%) were unknown. Among patients who had an echocardiogram performed, 5 of 52 (10%; 95% confidence interval, 1%-18%) had a patent foramen ovale. Cardioembolic stroke mechanisms included 6 with infective endocarditis (accounting for 12% of all strokes). CONCLUSIONS: Cardioembolism and cryptogenic stroke are the predominant stroke mechanisms among hemodialysis patients. Infective endocarditis was identified frequently relative to other stroke cohorts, and a raised index of suspicion is warranted in the hemodialysis population.

The diagnosis and treatment of attention deficit hyperactivity disorder in patients with epilepsy.

Attention deficit/hyperactivity disorder (AD/HD) can cause significant impairment in psychosocial and scholastic achievement. AD/HD should be appropriately managed even if patients have comorbid epilepsy. The diagnosis and treatment of AD/HD in patients with epilepsy presents several challenges. Differentiating independent problems in attention from frequent epileptic seizures is the first step in evaluating these individuals. Once this is accomplished the formal independent diagnosis of AD/HD can be pursued. Data from non-epileptic AD/HD populations should be applied with caution to patients with epilepsy. Once attention deficit disorder has been diagnosed formally, choices in treatment can create other problems as some pharmacological treatments for AD/HD pose a risk of exacerbating seizures. This article serves as a review for the diagnosis and treatment of AD/HD spectrum disorders in patients with epilepsy.

Brain-Responsive Neurostimulation for the treatment of adults with epilepsy in tuberous sclerosis complex: A case series.

OBJECTIVE: Tuberous sclerosis complex (TSC) is a genetic disorder primarily characterized by the development of multisystem benign tumors. Epilepsy is the most common neurologic manifestation, affecting 80%-90% of TSC patients. The diffuse structural brain abnormalities and the multifocal nature of epilepsy in TSC pose diagnostic challenges when evaluating patients for epilepsy surgery. METHODS: We retrospectively reviewed the safety experience and efficacy outcomes of five adult TSC patients who were treated with direct brain-responsive neurostimulation (RNS System, NeuroPace, Inc). RESULTS: The average follow-up duration was 20 months. All five patients were responders (≥50% disabling seizure reduction) at last follow-up. The median reduction in disabling seizures was 58% at 1 year and 88% at last follow-up. Three of the five patients experienced some period of seizure freedom ranging from 3 months to over 1 year. SIGNIFICANCE: In this small case series, we report the first safety experience and efficacy outcomes in patients with TSC-associated drug-resistant focal epilepsy treated with direct brain-responsive neurostimulation.

International Recommendations for the Management of Adults Treated With Ketogenic Diet Therapies.

OBJECTIVE: To evaluate current clinical practices and evidence-based literature to establish preliminary recommendations for the management of adults using ketogenic diet therapies (KDTs). METHODS: A 12-topic survey was distributed to international experts on KDTs in adults consisting of neurologists and dietitians at medical institutions providing KDTs to adults with epilepsy and other neurologic disorders. Panel survey responses were tabulated by the authors to determine the common and disparate practices between institutions and to compare these practices in adults with KDT recommendations in children and the medical literature. Recommendations are based on a combination of clinical evidence and expert opinion regarding management of KDTs. RESULTS: Surveys were obtained from 20 medical institutions with >2,000 adult patients treated with KDTs for epilepsy or other neurologic disorders. Common side effects reported are similar to those observed in children, and recommendations for management are comparable with important distinctions, which are emphasized. Institutions differ with regard to recommended biochemical assessment, screening, monitoring, and concern for long-term side effects, and further investigation is warranted to determine the optimal clinical management. Differences also exist between screening and monitoring practices among adult and pediatric providers. CONCLUSIONS: KDTs may be safe and effective in treating adults with drug-resistant epilepsy, and there is emerging evidence supporting the use in other adult neurologic disorders and general medical conditions as well. Therefore, expert recommendations to guide optimal care are critical as well as further evidence-based investigation.

Epilepsy Benchmarks Area IV: Limit or Prevent Adverse Consequence of Seizures and Their Treatment Across the Life Span.

Epilepsy represents a complex spectrum disorder, with patients sharing seizures as a common symptom and manifesting a broad array of additional clinical phenotypes. To understand this disorder and treat individuals who live with epilepsy, it is important not only to identify pathogenic mechanisms underlying epilepsy but also to understand their relationships with other health-related factors. Benchmarks Area IV focuses on the impact of seizures and their treatment on quality of life, development, cognitive function, and other aspects and comorbidities that often affect individuals with epilepsy. Included in this review is a discussion on sudden unexpected death in epilepsy and other causes of mortality, a major area of research focus with still many unanswered questions. We also draw attention to special populations, such as individuals with nonepileptic seizures and pregnant women and their offspring. In this study, we review the progress made in these areas since the 2016 review of the Benchmarks Area IV and discuss challenges and opportunities for future study.

Preoperative evaluation for epilepsy surgery: Process improvement.

BACKGROUND: Epilepsy surgery (ES) can improve seizure outcome. A prolonged duration of presurgical evaluation contributes to epilepsy-related morbidity and mortality. We introduced process changes to decrease evaluation time (ET) and increase ES numbers (excluding vagus nerve stimulation). METHODS: The University of Colorado Hospital patient database was searched for ESs between January 2009 and May 2016. Measures to reduce ET included (1) increasing patient care conference (PCC) frequency; (2) faster intracarotid amobarbital test (IAT) scheduling; (3) dedicated ES clinic; and (4) adding a nurse navigator. ET from noninvasive video-EEG monitoring (P1) to IAT, PCC, and ES, and ES volume were determined and compared for a baseline group (P1 January 2009-March 2013) and a group exposed to process changes (P1 after March 2013), the postchanges group, to assess the effect of these measures. RESULTS: ES number was 61 for the baseline group and 77 for the postchanges group, increasing the annual rate at 3 years after changes from 14.4 to 36.8 (p = 0.0008; 37% yearly increase postchanges). Interventions lowered average ET by 96 days (p ≤ 0.0001), P1 to IAT by 39 days (p = 0.0011), and P1 to PCC by 58 days (p = 0.0002). CONCLUSIONS: Simple process changes, including more frequent patient care conferences, faster scheduling, a dedicated ES clinic, and a nurse navigator significantly decreased evaluation times and increased ES numbers. Centers could utilize similar strategies to improve process and surgical volume and thereby increase patient seizure control and safety.

A novel seizure detection algorithm informed by hidden Markov model event states.

OBJECTIVE: Recently the FDA approved the first responsive, closed-loop intracranial device to treat epilepsy. Because these devices must respond within seconds of seizure onset and not miss events, they are tuned to have high sensitivity, leading to frequent false positive stimulations and decreased battery life. In this work, we propose a more robust seizure detection model. APPROACH: We use a Bayesian nonparametric Markov switching process to parse intracranial EEG (iEEG) data into distinct dynamic event states. Each event state is then modeled as a multidimensional Gaussian distribution to allow for predictive state assignment. By detecting event states highly specific for seizure onset zones, the method can identify precise regions of iEEG data associated with the transition to seizure activity, reducing false positive detections associated with interictal bursts. The seizure detection algorithm was translated to a real-time application and validated in a small pilot study using 391 days of continuous iEEG data from two dogs with naturally occurring, multifocal epilepsy. A feature-based seizure detector modeled after the NeuroPace RNS System was developed as a control. MAIN RESULTS: Our novel seizure detection method demonstrated an improvement in false negative rate (0/55 seizures missed versus 2/55 seizures missed) as well as a significantly reduced false positive rate (0.0012 h versus 0.058 h(-1)). All seizures were detected an average of 12.1 ± 6.9 s before the onset of unequivocal epileptic activity (unequivocal epileptic onset (UEO)). SIGNIFICANCE: This algorithm represents a computationally inexpensive, individualized, real-time detection method suitable for implantable antiepileptic devices that may considerably reduce false positive rate relative to current industry standards.

Focal Seizures Induced by Intracranial Electroencephalogram Grids.

Here we present a unique, but important seizure variant directly related to placement of subdural grids. Two distinct epileptogenic zones were identified, one which correlated with the patient's baseline seizures and a separate zone associated with atypical semiology and localization. Inspection of this zone at surgery revealed cortical deformation from the grid itself. The patient underwent successful surgical resection of the primary epileptogenic zone, but not that of the atypical zone. She remains seizure free at two years following surgery. Recognition of grid-induced seizures is important as they may confound the interpretation of intracranial electroencephalograms (iEEG) and mislead resective surgery.