Neuromodulatory Focused Ultrasound for Epilepsy: Are Animal Models Useful?

Ultrasound neuromodulation is a potential alternative therapy for suppressing epileptic discharges. Recently, several human clinical trials have reported promising results from repeated focused ultrasound (FUS) treatments for temporal lobe epilepsy. In this Viewpoint, we highlight the valuable guidance of preclinical validation methods for choosing the optimal FUS parameters, thus ensuring consistency with the outcomes of clinical trials and leading human trials to the safest and most effective approaches.

Comparing the efficacy of anti-seizure medications using matched cohorts on a large insurance claims database.

Epilepsy is a severe chronic neurological disease affecting 60 million people worldwide. Primary treatment is with anti-seizure medicines (ASMs), but many patients continue to experience seizures. We used retrospective insurance claims data on 280,587 patients with uncontrolled epilepsy (UE), defined as status epilepticus, need for a rescue medicine, or admission or emergency visit for an epilepsy code. We conducted a computational risk ratio analysis between pairs of ASMs using a causal inference method, in order to match 1034 clinical factors and simulate randomization. Data was extracted from the MarketScan insurance claims Research Database records from 2011 to 2015. The cohort consisted of individuals over 18 years old with a diagnosis of epilepsy who took one of eight ASMs and had more than a year of history prior to the filling of the drug prescription. Seven ASM exposures were analyzed: topiramate, phenytoin, levetiracetam, gabapentin, lamotrigine, valproate, and carbamazepine or oxcarbazepine (treated as the same exposure). We calculated the risk ratio of UE between pairs of ASM after controlling for bias with inverse propensity weighting applied to 1034 factors, such as demographics, confounding illnesses, non-epileptic conditions treated by ASMs, etc. All ASMs exhibited a significant reduction in the prevalence of UE, but three drugs showed pair-wise differences compared to other ASMs. Topiramate consistently was associated with a lower risk of UE, with a mean risk ratio range of 0.68-0.93 (average 0.82, CI: 0.56-1.08). Phenytoin and levetiracetam were consistently associated with a higher risk of UE with mean risk ratio ranges of 1.11 to 1.47 (average 1.13, CI 0.98-1.65) and 1.15 to 1.43 (average 1.2, CI 0.72-1.69), respectively. Large-scale retrospective insurance claims data - combined with causal inference analysis - provides an opportunity to compare the effect of treatments in real-world data in populations 1,000-fold larger than those in typical randomized trials. Our causal analysis identified the clinically unexpected finding of topiramate as being associated with a lower risk of UE; and phenytoin and levetiracetam as associated with a higher risk of UE (compared to other studied drugs, not to baseline). However, we note that our data set for this study only used insurance claims events, which does not comprise actual seizure frequencies, nor a clear picture of side effects. Our results do not advocate for any change in practice but demonstrate that conclusions from large databases may differ from and supplement those of randomized trials and clinical practice and therefore may guide further investigation.

Functional connectomic profile correlates with effective anterior thalamic stimulation for refractory epilepsy.

BACKGROUND: Deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) is an effective treatment for refractory epilepsy; however, seizure outcome varies among individuals. Identifying a reliable noninvasive biomarker to predict good responders would be helpful. OBJECTIVES: To test whether the functional connectivity between the ANT-DBS sites and the seizure foci correlates with effective seizure control in refractory epilepsy. METHODS: We performed a proof-of-concept pilot study of patients with focal refractory epilepsy receiving ANT-DBS. Using normative human connectome data derived from 1000 healthy participants, we investigated whether intrinsic functional connectivity between the seizure foci and the DBS site was associated with seizure outcome. We repeated this analysis controlling for the extent of seizure foci, distance between the seizure foci and DBS site, and using functional connectivity of the ANT instead of the DBS site to test the contribution of variance in DBS sites. RESULTS: Eighteen patients with two or more seizure foci were included. Greater functional connectivity between the seizure foci and the DBS site correlated with more favorable outcome. The degree of functional connectivity accounted for significant variance in clinical outcomes (DBS site: |r| = 0.773, p < 0.001 vs ANT-atlas: |r| = 0.715, p = 0.001), which remained significant when controlling for the extent of the seizure foci (|r| = 0.773, p < 0.001) and the distance between the seizure foci and DBS site (|r| = 0.777, p < 0.001). Significant correlations were independent of variance in the DBS sites (|r| = 0.148, p = 0.57). CONCLUSION: These findings suggest that functional connectomic profile is a potential reliable non-invasive biomarker to predict ANT-DBS outcomes. Accordingly, the identification of ANT responders could decrease the surgical risk for patients who may not benefit and optimize the cost-effective allocation of health care resources.

Pulsed Focused Ultrasound Reduces Hippocampal Volume Loss and Improves Behavioral Performance in the Kainic Acid Rat Model of Epilepsy.

Focused ultrasound (FUS) has the potential to modulate regional brain excitability and possibly aid seizure control; however, effects on behavior of FUS used as a seizure therapy are unknown. This study explores behavioral effects and hippocampal restoration induced by pulsed FUS in a kainic acid (KA) animal model of temporal lobe epilepsy. Twenty-nine male Sprague-Dawley rats were observed for 20 weeks with anatomical magnetic resonance imaging (MRI) and behavioral performance evaluations, comprising measures of anxiety, limb usage, sociability, and memory. FUS targeted to the right hippocampus was given 9 and 14 weeks after KA was delivered to the right amygdala. Ultrasound pulsations were delivered with the acoustic settings of 0.25 of mechanical index, 0.5 W/cm2 of intensity spatial peak temporal average (ISPTA), 100 Hz of pulse repetition frequency, and 30% of duty cycle, during three consecutive pulse trains of 10 min separated by 5-min rests. Controls included normal animals with sham injections and KA-exposed animals without FUS exposure. Longitudinal MRI observations showed that FUS substantially protected hippocampal and striatal structures from KA-induced atrophy. KA alone increased anxiety, impaired contralateral limb usage, and reduced sociability and learning. Two courses of FUS sonications partially ameliorated these impairments by enhancing exploring and learning, balancing limb usage, and increasing social interaction. The histology results indicated that two sonications enhanced neuroprotection effect and decreased the inflammation markers induced by KA. This study supports existence of both neuroprotective and beneficial behavioral effects from low-intensity pulsed ultrasound in the KA animal model of epilepsy.

Deep brain stimulation of thalamus for epilepsy.

Neuromodulation (neurostimulation) is a relatively new and rapidly growing treatment for refractory epilepsy. Three varieties are approved in the US: vagus nerve stimulation (VNS), deep brain stimulation (DBS) and responsive neurostimulation (RNS). This article reviews thalamic DBS for epilepsy. Among many thalamic sub-nuclei, DBS for epilepsy has been targeted to the anterior nucleus (ANT), centromedian nucleus (CM), dorsomedial nucleus (DM) and pulvinar (PULV). Only ANT is FDA-approved, based upon a controlled clinical trial. Bilateral stimulation of ANT reduced seizures by 40.5% at three months in the controlled phase (p = .038) and 75% by 5 years in the uncontrolled phase. Side effects related to paresthesias, acute hemorrhage, infection, occasional increased seizures, and usually transient effects on mood and memory. Efficacy was best documented for focal onset seizures in temporal or frontal lobe. CM stimulation may be useful for generalized or multifocal seizures and PULV for posterior limbic seizures. Mechanisms of DBS for epilepsy are largely unknown, but animal work points to changes in receptors, channels, neurotransmitters, synapses, network connectivity and neurogenesis. Personalization of therapies, in terms of connectivity of the seizure onset zone to the thalamic sub- nucleus and individual characteristics of the seizures, might lead to improved efficacy. Many questions remain about DBS, including the best candidates for different types of neuromodulation, the best targets, the best stimulation parameters, how to minimize side effects and how to deliver current noninvasively. Despite the questions, neuromodulation provides useful new opportunities to treat people with refractory seizures not responding to medicines and not amenable to resective surgery.

Transcranial direct current stimulation for focal status epilepticus or lateralized periodic discharges in four patients in a critical care setting.

OBJECTIVE: Transcranial direct current stimulation (tDCS) has been advocated for various neurological conditions, including epilepsy. A 1-4-mA cathodal current applied to the scalp over a seizure focus can reduce spikes and seizures. This series of four patients with focal status epilepticus is among the first case series to demonstrate benefit of tDCS in the critical care setting. METHODS: Patients in the intensive care unit were referred for tDCS treatment when focal status epilepticus or clinically relevant lateralized periodic discharges did not resolve with conventional antiseizure medications and anesthetics. Battery-powered direct cathodal current at 2 mA was delivered by an ActivaDose (Caputron) tDCS device via a saline-soaked sponge on the scalp over the seizure focus. Anode was on the contralateral forehead or shoulder. Treatment was for 30 min, repeated twice in a day, then again 1-4 times more over the next few days. RESULTS: Three females and one male, aged 34-68 years, were treated. Etiologies of status epilepticus were posterior reversible encephalopathy syndrome in association with immunosuppressants for a liver transplant, perinatal hypoxic-ischemic injury, a prior cardioembolic parietal stroke, and central nervous system lupus. tDCS led to significant reduction of interictal spikes (.78 to .38/s, p < .0001) in three cases and electrographic seizures (3.83/h to 0/h, p < .001) in two cases. Medication reductions were enabled in all cases subsequent to tDCS. The only side effect of tDCS was transient erythema under the sponge in one case. Two patients died of causes unrelated to tDCS, one was discharged to a nursing home, and one became fully responsive as seizures were controlled with tDCS. SIGNIFICANCE: Spikes and electrographic seizure frequency significantly improved within 1 day of tDCS. Results are potentially confounded by multiple ongoing changes in medications and treatments. These results might encourage further investigation of tDCS in the critical care setting, but verification by controlled studies will be required.

A Robust eLORETA Technique for Localization of Brain Sources in the Presence of Forward Model Uncertainties.

OBJECTIVE: In this paper, we present a robust version of the well-known exact low-resolution electromagnetic tomography (eLORETA) technique, named ReLORETA, to localize brain sources in the presence of different forward model uncertainties. METHODS: We first assume that the true lead field matrix is a transformation of the existing lead field matrix distorted by uncertainties and propose an iterative approach to estimate this transformation accurately. Major sources of the forward model uncertainties, including differences in geometry, conductivity, and source space resolution between the real and simulated head models, and misaligned electrode positions, are then simulated to test the proposed method. RESULTS: ReLORETA and eLORETA are applied to simulated focal sources in different regions of the brain and the presence of various noise levels as well as real data from a patient with focal epilepsy. The results show that ReLORETA is considerably more robust and accurate than eLORETA in all cases. CONCLUSION: Having successfully dealt with the forward model uncertainties, ReLORETA proved to be a promising method for real-world clinical applications. SIGNIFICANCE: eLORETA is one of the localization techniques that could be used to study brain activity for medical applications such as determining the epileptogenic zone in patients with medically refractory epilepsy. However, the major limitation of eLORETA is sensitivity to the uncertainties in the forward model. Since this problem can substantially undermine its performance in real-world applications where the exact lead field matrix is unknown, developing a more robust method capable of dealing with these uncertainties is of significant interest.

Antiseizure Drugs and Movement Disorders.

The relationship between antiseizure drugs and movement disorders is complex and not adequately reviewed so far. Antiseizure drugs as a treatment for tremor and other entities such as myoclonus and restless leg syndrome is the most common scenario, although the scientific evidence supporting their use is variable. However, antiseizure drugs also represent a potential cause of iatrogenic movement disorders, with parkinsonism and tremor the most common disorders. Many other antiseizure drug-induced movement disorders are possible and not always correctly identified. This review was conducted by searching for all the possible combinations between 15 movement disorders (excluding ataxia) and 24 antiseizure drugs. The main objective was to describe the movement disorders treated and worsened or induced by antiseizure drugs. We also summarized the proposed mechanisms and risk factors involved in the complex interaction between antiseizure drugs and movement disorders. Antiseizure drugs mainly used to treat movement disorders are clonazepam, gabapentin, lacosamide, levetiracetam, oxcarbazepine, perampanel, phenobarbital, pregabalin, primidone, topiramate, and zonisamide. Antiseizure drugs that worsen or induce movement disorders are cenobamate, ethosuximide, felbamate, lamotrigine, phenytoin, tiagabine, and vigabatrin. Antiseizure drugs with a variable effect on movement disorders are carbamazepine and valproate while no effect on movement disorders has been reported for brivaracetam, eslicarbazepine, lacosamide, and stiripentol. Although little information is available on the adverse effects or benefits on movement disorders of newer antiseizure drugs (such as brivaracetam, cenobamate, eslicarbazepine, lacosamide, and rufinamide), the evidence collected in this review should guide the choice of antiseizure drugs in patients with concomitant epilepsy and movement disorders. Finally, these notions can lead to a better understanding of the mechanisms involved in the pathophysiology and treatments of movement disorders.

Practical considerations in epilepsy neurostimulation.

Neuromodulation is a key therapeutic tool for clinicians managing patients with drug-resistant epilepsy. Multiple devices are available with long-term follow-up and real-world experience. The aim of this review is to give a practical summary of available neuromodulation techniques to guide the selection of modalities, focusing on patient selection for devices, common approaches and techniques for initiation of programming, and outpatient management issues. Vagus nerve stimulation (VNS), deep brain stimulation of the anterior nucleus of the thalamus (DBS-ANT), and responsive neurostimulation (RNS) are all supported by randomized controlled trials that show safety and a significant impact on seizure reduction, as well as a suggestion of reduction in the risk of sudden unexplained death in epilepsy (SUDEP). Significant seizure reductions are observed after 3 months for DBS, RNS, and VNS in randomized controlled trials, and efficacy appears to improve with time out to 7 to 10 years of follow-up for all modalities, albeit in uncontrolled follow-up or retrospective studies. A significant number of patients experience seizure-free intervals of 6 months or more with all three modalities. Number and location of epileptogenic foci are important factors affecting efficacy, and together with comorbidities such as severe mood or sleep disorders, may influence the choice of modality. Programming has evolved-DBS is typically initiated at lower current/voltage than used in the pivotal trial, whereas target charge density is lower with RNS, however generalizable optimal parameters are yet to be defined. Noninvasive brain stimulation is an emerging stimulation modality, although it is currently not used widely. In summary, clinical practice has evolved from those established in pivotal trials. Guidance is now available for clinicians who wish to expand their approach, and choice of neuromodulation technique may be tailored to individual patients based on their epilepsy characteristics, risk tolerance, and preferences.

Impact of high-density EEG in presurgical evaluation for refractory epilepsy patients.

OBJECTIVE: Electrical source localization (ESI) can help to identify the seizure onset zone or propagation zone, but it is unclear how dipole localization techniques influence surgical planning. METHODS: Patients who received a high density (HD)-EEG from 7/2014-7/2019 at Stanford were included if they met the following inclusion criteria: (1) adequate epileptiform discharges were recorded for source localization analysis, (2) underwent surgical treatment, which was at least 6 months before the survey. Interictal ESI was performed with the LORETA method on age matched MRIs. Six neurophysiologists from the Stanford Epilepsy Program independently reviewed each case through an HIPPA-protected online survey. The same cases were presented again with additional data from the HD-EEG study. Ratings of how much the HD-EEG findings added value and in what way were recorded. RESULTS: Fifty out of 202 patients met the inclusion criteria, providing a total of 276 h of HDEEG recordings. All patients had video EEG recordings and at least one brain MRI, 88 % had neuropsychological testing, 78 % had either a PET or SPECT scan. Additional HD-EEG information was rated as helpful in 83.8 %, not useful in 14.4 % and misleading in 1.8 % of cases. In 20.4 % of cases the HD-EEG information altered decision-making in a major way, such as choosing a different surgical procedure, avoidance of invasive recording or suggesting placement of invasive electrodes in a lobe not previously planned. In 21.5 % of cases, HD-EEG changed the plan in a minor way, e.g., extra invasive electrodes near the previously planned sites in the same sub-lobar region. In 42.3 % cases, HD-EEG did not change their plan but provided confirmation. In cases with normal MRI, additional HD-EEG information was more likely to change physicians' decision making during presurgical process when compared to the cases with MRI-visible lesions (53.3 % vs. 34.3 %, p = 0.002). Among patients achieving Engel class I/II outcome, the concordance rate of HD-EEG and resection zone was 64.7 % versus 35.3 % with class III/IV (p = 0.028). CONCLUSION: HD-EEG assists presurgical planning for refractory epilepsy patients, with a higher yield in patients with non-lesional MRIs. Concordance of HD-EEG dipole analysis localization and resection site is a favorable outcome indicator.

Minimum clinically important difference (MCID) of the personal impact of epilepsy scale (PIES).

INTRODUCTION: The Personal Impact of Epilepsy Scale (PIES) assesses patient functional status in subscales of (1) seizure impact, (2) medication effects, (3) mood & social status, and (4) overall quality of life. This study was designed to determine the Minimal Clinically Important Change (MCID) in PIES subscale and total scores that demonstrate improvement. METHODS: To ascertain the correspondence of PIES score change and clinical status change (improved, same, worse) in each PIES subscale and total score, we used two distinct retrospective anchor-based assessments of clinical status (patient self-assessment and trained rater assessment) across two clinic visits. Mean PIES scores were compared between clinical status groups, controlling for days between visits and initial clinical status. Personal Impact of Epilepsy Scale score change was quantified for each group to determine MCID. A small prospective proof-of-concept study was conducted in a separate subject group. RESULTS: Patient self-report anchor analysis demonstrated lower (better) PIES scores in the "improved" group vs the "worse" group on the mood & social subscale (p < .001) and total score (p = .002), with a similar trend on the seizure subscale (p = 0.056). Clinical rater anchor analysis demonstrated lower PIES scores in the "improved" vs "worse" group in the mood & social subscale (p = .029) and a trend in total score (p = .082). For the "improved" group, the reduction in PIES scores between visits averaged across both anchor analyses was 8.14% for subscales and 8.67% for total score. DISCUSSION/CONCLUSION: Reduction of 8% on a PIES subscale or total score indicates meaningful improvement in patient clinical status, and is designated the MCID for this instrument. Personal Impact of Epilepsy Scale can be useful in day-to-day clinical care and as an outcome metric in clinical research.

EEG Evoked Potentials to Repetitive Transcranial Magnetic Stimulation in Normal Volunteers: Inhibitory TMS EEG Evoked Potentials.

The impact of repetitive magnetic stimulation (rTMS) on cortex varies with stimulation parameters, so it would be useful to develop a biomarker to rapidly judge effects on cortical activity, including regions other than motor cortex. This study evaluated rTMS-evoked EEG potentials (TEP) after 1 Hz of motor cortex stimulation. New features are controls for baseline amplitude and comparison to control groups of sham stimulation. We delivered 200 test pulses at 0.20 Hz before and after 1500 treatment pulses at 1 Hz. Sequences comprised AAA = active stimulation with the same coil for test-treat-test phases (n = 22); PPP = realistic placebo coil stimulation for all three phases (n = 10); and APA = active coil stimulation for tests and placebo coil stimulation for treatment (n = 15). Signal processing displayed the evoked EEG waveforms, and peaks were measured by software. ANCOVA was used to measure differences in TEP peak amplitudes in post-rTMS trials while controlling for pre-rTMS TEP peak amplitude. Post hoc analysis showed reduced P60 amplitude in the active (AAA) rTMS group versus the placebo (APA) group. The N100 peak showed a treatment effect compared to the placebo groups, but no pairwise post hoc differences. N40 showed a trend toward increase. Changes were seen in widespread EEG leads, mostly ipsilaterally. TMS-evoked EEG potentials showed reduction of the P60 peak and increase of the N100 peak, both possibly reflecting increased slow inhibition after 1 Hz of rTMS. TMS-EEG may be a useful biomarker to assay brain excitability at a seizure focus and elsewhere, but individual responses are highly variable, and the difficulty of distinguishing merged peaks complicates interpretation.

Visually sensitive seizures: An updated review by the Epilepsy Foundation.

Light flashes, patterns, or color changes can provoke seizures in up to 1 in 4000 persons. Prevalence may be higher because of selection bias. The Epilepsy Foundation reviewed light-induced seizures in 2005. Since then, images on social media, virtual reality, three-dimensional (3D) movies, and the Internet have proliferated. Hundreds of studies have explored the mechanisms and presentations of photosensitive seizures, justifying an updated review. This literature summary derives from a nonsystematic literature review via PubMed using the terms "photosensitive" and "epilepsy." The photoparoxysmal response (PPR) is an electroencephalography (EEG) phenomenon, and photosensitive seizures (PS) are seizures provoked by visual stimulation. Photosensitivity is more common in the young and in specific forms of generalized epilepsy. PS can coexist with spontaneous seizures. PS are hereditable and linked to recently identified genes. Brain imaging usually is normal, but special studies imaging white matter tracts demonstrate abnormal connectivity. Occipital cortex and connected regions are hyperexcitable in subjects with light-provoked seizures. Mechanisms remain unclear. Video games, social media clips, occasional movies, and natural stimuli can provoke PS. Virtual reality and 3D images so far appear benign unless they contain specific provocative content, for example, flashes. Images with flashes brighter than 20 candelas/m2 at 3-60 (particularly 15-20) Hz occupying at least 10 to 25% of the visual field are a risk, as are red color flashes or oscillating stripes. Equipment to assay for these characteristics is probably underutilized. Prevention of seizures includes avoiding provocative stimuli, covering one eye, wearing dark glasses, sitting at least two meters from screens, reducing contrast, and taking certain antiseizure drugs. Measurement of PPR suppression in a photosensitivity model can screen putative antiseizure drugs. Some countries regulate media to reduce risk. Visually-induced seizures remain significant public health hazards so they warrant ongoing scientific and regulatory efforts and public education.

Experience and consensus on stimulation of the anterior nucleus of thalamus for epilepsy.

Deep brain stimulation of the anterior nuclei of thalamus (ANT-DBS) is effective for reduction of seizures, but little evidence is available to guide practitioners in the practical use of this therapy. In an attempt to fill this gap, a questionnaire with 37 questions was circulated to 578 clinicians who were either engaged in clinical trials of or known users of DBS for epilepsy, with responses from 141, of whom 58.2% were epileptologists and 28.4% neurosurgeons. Multiple regions of the world were represented. The survey found that the best candidates for DBS were considered those with temporal or frontal seizures, refractory to at least two medicines. Motivations for renewing therapy upon battery depletion were reduced convulsive, impaired awareness, and severe seizures and improved quality of life. Targeting of leads mainly was by magnetic resonance imaging, sometimes with intraoperative imaging or microelectrode recording. The majority used transventricular approaches. Stimulation parameters mostly imitated the SANTE study parameters, except for initial stimulation amplitudes in the 2-3-V or -mA range, versus 5 V in the SANTE study. Stimulation intensity was most often increased or reduced, respectively, for lack of efficacy or side effects, but changes in active contacts, cycle time, and pulse duration were also employed. Mood or memory problems or paresthesias were the side effects most responsible for adjustments. Off-label sites stimulated included centromedian thalamus, hippocampus, neocortex, and a few others. Several physicians used DBS in conjunction with vagus nerve stimulation or responsive neurostimulation, although our study did not track efficacy for combined use. Experienced users varied more from published parameters than did inexperienced users. In conclusion, surveys of experts can provide Class IV evidence for the most prevalent practical use of ANT-DBS. We present a flowchart for one protocol combining common practices. Controlled comparisons will be needed to choose the best approach.

Analysis of Deep Brain Stimulation Lead Targeting in the Stimulation of Anterior Nucleus of the Thalamus for Epilepsy Clinical Trial.

BACKGROUND: Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is an effective therapy for patients with drug-resistant focal epilepsy. Best practices for surgical targeting of the ANT can be refined as new information becomes available regarding effective stimulation sites. OBJECTIVE: To conduct a retrospective analysis of the relationship between outcomes (seizure reduction during year 1) and DBS lead locations in subjects from the SANTÉ pivotal trial (Stimulation of ANT for Epilepsy) based upon recent clinical findings. METHODS: Postoperative images from SANTÉ subjects (n = 101) were evaluated with respect to lead trajectory relative to defined anatomic landmarks. A qualitative scoring system was used to rate each lead placement for proximity to an identified target region above the junction of the mammillothalamic tract with the ANT. Each subject was assigned a bilateral lead placement score, and these scores were then compared to clinical outcomes. RESULTS: Approximately 70% of subjects had "good" bilateral lead placements based upon location with respect to the defined target. These subjects had a much higher probability of being a clinical responder (>50% seizure reduction) than those with scores reflecting suboptimal lead placements (43.5% vs 21.9%, P < .05). CONCLUSION: Consistent with experience from more established DBS indications, our findings and other recent reports suggest that there may be specific sites within the ANT that are associated with superior clinical outcomes. It will be important to continue to evaluate these relationships and the evolution of other clinical practices (eg, programming) to further optimize this therapy.

Status epilepticus after intracranial neurosurgery: incidence and risk stratification by perioperative clinical features.

OBJECTIVE: Status epilepticus (SE) is associated with significant mortality, cost, and risk of future seizures. In one of the first studies of SE after neurosurgery, the authors assess the incidence, risk factors, and outcome of postneurosurgical SE (PNSE). METHODS: Neurosurgical admissions from the MarketScan Claims and Encounters database (2007 through 2015) were assessed in a longitudinal cross-sectional sample of privately insured patients who underwent qualifying cranial procedures in the US and were older than 18 years of age. The incidence of early (in-hospital) and late (postdischarge readmission) SE and associated mortality was assessed. Procedural, pathological, demographic, and anatomical covariates parameterized multivariable logistic regression and Cox models. Multivariable logistic regression and Cox proportional hazards models were used to study the incidence of early and late PNSE. A risk-stratification simulation was performed, combining individual predictors into singular risk estimates. RESULTS: A total of 197,218 admissions (218,217 procedures) were identified. Early PNSE occurred during 637 (0.32%) of 197,218 admissions for cranial neurosurgical procedures. A total of 1045 (0.56%) cases of late PNSE were identified after 187,771 procedure admissions with nonhospice postdischarge follow-up. After correction for comorbidities, craniotomy for trauma, hematoma, or elevated intracranial pressure was associated with increased risk of early PNSE (adjusted OR [aOR] 1.538, 95% CI 1.183-1.999). Craniotomy for meningioma resection was associated with an increased risk of early PNSE compared with resection of metastases and parenchymal primary brain tumors (aOR 2.701, 95% CI 1.388-5.255). Craniotomies for infection or abscess (aHR 1.447, 95% CI 1.016-2.061) and CSF diversion (aHR 1.307, 95% CI 1.076-1.587) were associated with highest risk of late PNSE. Use of continuous electroencephalography in patients with early (p < 0.005) and late (p < 0.001) PNSE rose significantly over the study time period. The simulation regression model predicted that patients at high risk for early PNSE experienced a 1.10% event rate compared with those at low risk (0.07%). Similarly, patients predicted to be at highest risk for late PNSE were significantly more likely to eventually develop late PNSE than those at lowest risk (HR 54.16, 95% CI 24.99-104.80). CONCLUSIONS: Occurrence of early and late PNSE was associated with discrete neurosurgical pathologies and increased mortality. These data provide a framework for prospective validation of clinical and perioperative risk factors and indicate patients for heightened diagnostic suspicion of PNSE.

The SANTÉ study at 10 years of follow-up: Effectiveness, safety, and sudden unexpected death in epilepsy.

OBJECTIVE: We evaluated the efficacy and safety of deep brain anterior thalamus stimulation after 7 and 10 years, and report the incidence of sudden unexpected death in epilepsy (SUDEP) and overall mortality in adults in the Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy (SANTÉ) study. METHODS: After the 3-month blinded and 9-month unblinded phases, subjects continued to be assessed during long-term follow-up (LTFU) and later a continued therapy access phase (CAP), to further characterize adverse events and the incidence of SUDEP. Stimulus parameter and medication changes were allowed. RESULTS: One hundred ten implanted subjects accumulated a total of 938 device-years of experience (69 subjects during the LTFU phase and 61 subjects in the CAP phase). Prior to study closure, 57 active subjects continued therapy at 14 study centers, with follow-up of at least 10 (maximum 14) years. At 7 years, median seizure frequency percent reduction from baseline was 75% (p < .001), with no outcome differences related to prior vagus nerve stimulation or resective surgery. The most severe seizure type, focal to bilateral tonic-clonic, was reduced by 71%. Adding new antiseizure medications did not impact the pattern of seizure reduction over time. There were no unanticipated serious adverse events in the study. The definite-plus-probable SUDEP rate, based on SANTÉ study experience (two deaths in 938 years) and previous pilot studies (0 deaths in 76 years), indicated a rate of 2.0 deaths for 1000 person-years. Overall mortality was 6.9 deaths per 1000 person-years. SIGNIFICANCE: The long-term efficacy and safety profiles of the deep brain stimulation (DBS) system for epilepsy are favorable and demonstrate stable outcomes. Improvement in frequency of the most severe seizure type may reduce SUDEP risk. The SUDEP rate with DBS (2.0) is comparable to other neuromodulation treatments (i.e., vagus nerve stimulation, responsive neurostimulation) for drug-resistant focal epilepsy.

Identification of seizure clusters using free text notes in an electronic seizure diary.

SIGNIFICANCE: Online seizure diaries offer a wealth of information regarding real world experience of patients living with epilepsy. Free text notes (FTN) written by patients reflect concerns and priorities of patients and provide supplemental information to structured diary data. OBJECTIVE: This project evaluated feasibility using an automated lexical analysis to identify FTN relevant to seizure clusters (SCs). METHODS: Data were extracted from EpiDiary™, a free electronic epilepsy diary with 42,799 unique users, generating 1,096,168 entries and 247,232 FTN. Both structured data as well as FTN were analyzed for presence of SC. A pilot study was conducted to validate an automated lexical analysis algorithm to identify SC in FTN in a sample of 98 diaries. The lexical analysis was then applied to the entire dataset. Outcomes included cluster prevalence and frequency, as well as the types of triggers commonly reported. RESULTS: At least one FTN was found among 13,987 (32.68%) individual diaries. An automated lexical analysis algorithm identified 5797 of FTN as SC. There were 2423 unique patients with SC that were not identified by structured data alone and were identified using lexical analysis of FTN only. Seizure clusters were identified in n = 10,331 (24.1%) of diary users through both structured data and FTN. The median number of SCs days per year was 13.7, (interquartile rank (IQR): 3.2-54.7). The median number of seizures in a cluster day was 3 (IQR 2-4). The most common missed medication linked to patients with SC was levetiracetam (n = 576, 29%) followed by lamotrigine (n = 495, 24%), topiramate (n = 208, 10.5%), carbamazepine (n = 190, 9.6%), and lacosamide (n = 170, 8.6%). These percentages generally reflected prevalence of medication use in this population. The use of rescue medications was documented in 3306 of structured entries and 4305 in FTN. CONCLUSION: This exploratory study demonstrates a novel approach applying lexical analysis to previously untapped FTN in a large electronic seizure diary database. Free text notes captured information about SC not available from the structured diary data. Diary FTN contain information of high importance to people with epilepsy, written in their own words.

Sounds of seizures.

PURPOSE: A phase I feasibility study to determine the accuracy of identifying seizures based on audio recordings. METHODS: We systematically generated 166 audio clips of 30 s duration from 83 patients admitted to an epilepsy monitoring unit between 1/2015 and 12/2016, with one clip during a seizure period and one clip during a non-seizure control period for each patient. Five epileptologists performed a blinded review of the audio clips and rated whether a seizure occurred or not, and indicated the confidence level (low or high) of their rating. The accuracy of individual and consensus ratings were calculated. RESULTS: The overall performance of the consensus rating between the five epileptologists showed a positive predictive value (PPV) of 0.91 and a negative predictive value (NPV) of 0.66. The performance improved when confidence was high (PPV of 0.96, NPV of 0.70). The agreement between the epileptologists was moderate with a kappa of 0.584. Hyperkinetic (PPV 0.92, NPV 0.86) and tonic-clonic (PPV and NPV 1.00) seizures were most accurately identified. Seizures with automatisms only and non-motor seizures could not be accurately identified. Specific seizure-related sounds associated with accurate identification included disordered breathing (PPV and NPV 1.00), rhythmic sounds (PPV 0.93, NPV 0.80), and ictal vocalizations (PPV 1.00, NPV 0.97). CONCLUSION: This phase I feasibility study shows that epileptologists are able to accurately identify certain seizure types from audio recordings when the seizures produce sounds. This provides guidance for the development of audio-based seizure detection devices and demonstrate which seizure types could potentially be detected.