Wong‐Kisiel, Lily C.

Purpose: Temporal encephaloceles are a cause of drug-resistant temporal lobe epilepsy; however, their relationship with epileptogenesis is unclear, and optimal surgical resection is uncertain. EEG source localization (ESL) may guide surgical decision-making. Methods: We reviewed patients at Mayo Clinic Rochester with drug-resistant temporal lobe epilepsy and temporal encephaloceles, who underwent limited resection and had 1-year outcomes. EEG source localization was performed using standard density scalp EEG of ictal and interictal activity. Distance from dipole and standardized low-resolution brain electromagnetic tomography (sLORETA) solutions to the encephalocele were measured. Concordance of ESL with encephalocele and surgical resection was compared with 1-year surgical outcomes. Results: Seventeen patients met criteria. The mean distances from ESL results to encephalocele center for dipole and sLORETA analyses were 23 mm (SD 9) and 22 mm (SD 11), respectively. Ten patients (55.6%) had Engel I outcomes at 1 year. Dipole-encephalocele distance and sLORETA-encephalocele distance were significantly longer in patients with Engel I outcome and patients whose encephalocele was contained by sLORETA had worse outcome as well; however, multiple logistic regression analysis found that only containment of encephalocele by the sLORETA current density was significant (P < 0.05), odds ratio 0.12 (95% confidence interval [0.021, 0.71]). Conclusions: EEG source localization of scalp EEG localizes near encephaloceles, however, typically not in the encephalocele itself; this may be due to scalp EEG sampling propagated activity or alternatively that the seizure onset zone extends beyond the herniated cortex. Surprisingly, we observed increased ESL to encephalocele distances in patients with excellent surgical outcomes. Larger cohort studies including intracranial EEG data are needed to further explore this finding.

AbstractObjectivesAlthough hemispheric surgeries are among the most effective procedures for drug‐resistant epilepsy (DRE) in the pediatric population, there is a large variability in seizure outcomes at the group level. A recently developed HOPS score provides individualized estimation of likelihood of seizure freedom to complement clinical judgement. The objective of this study was to develop a freely accessible online calculator that accurately predicts the probability of seizure freedom for any patient at 1‐, 2‐, and 5‐years post‐hemispherectomy.MethodsRetrospective data of all pediatric patients with DRE and seizure outcome data from the original Hemispherectomy Outcome Prediction Scale (HOPS) study were included. The primary outcome of interest was time‐to‐seizure recurrence. A multivariate Cox proportional‐hazards regression model was developed to predict the likelihood of post‐hemispheric surgery seizure freedom at three time points (1‐, 2‐ and 5‐ years) based on a combination of variables identified by clinical judgment and inferential statistics predictive of the primary outcome. The final model from this study was encoded in a publicly accessible online calculator on the International Network for Epilepsy Surgery and Treatment (iNEST) website (https://hops‐calculator.com/).ResultsThe selected variables for inclusion in the final model included the five original HOPS variables (age at seizure onset, etiologic substrate, seizure semiology, prior non‐hemispheric resective surgery, and contralateral fluorodeoxyglucose–positron emission tomography [FDG‐PET] hypometabolism) and three additional variables (age at surgery, history of infantile spasms, and magnetic resonance imaging [MRI] lesion). Predictors of shorter time‐to‐seizure recurrence included younger age at seizure onset, prior resective surgery, generalized seizure semiology, FDG‐PET hypometabolism contralateral to the side of surgery, contralateral MRI lesion, non‐lesional MRI, non‐stroke etiologies, and a history of infantile spasms. The area under the curve (AUC) of the final model was 73.0%.SignificanceOnline calculators are useful, cost‐free tools that can assist physicians in risk estimation and inform joint decision‐making processes with patients and families, potentially leading to greater satisfaction. Although the HOPS data was validated in the original analysis, the authors encourage external validation of this new calculator.

Abstract Introduction Epilepsy is frequently encountered in the pediatric population and some patients are treated by stimulation of the vagus nerve to reduce their seizure frequency. Vagus nerve stimulation (VNS) may induce central sleep apnea. Adaptive servo ventilation is a known treatment option for central sleep apnea in certain adult patients with heart failure and Cheyne-Stokes respiration but is infrequently utilized in the pediatric population. Report of case(s) A 17-year-old male with a history of intractable generalized epilepsy, VNS placement, obstructive sleep apnea (OSA) and central sleep apnea (CSA) presented to our tertiary care center for management of his sleep disordered breathing. Initial management of sleep disordered breathing included CPAP for OSA. After VNS placement, the patient began to have a high residual apnea-hypopnea index on data card download of his CPAP. Polysomnography (PSG) was performed on CPAP and CSA events were noted that correlated with VNS firing. BiPAP was titrated and was unsuccessful in treating the CSA. VNS adjustment did not impact the sleep disordered breathing. Repeat titration with adaptive servo ventilation successfully treated the OSA and CSA. In follow up, the patient is tolerating ASV with improvement in his nocturnal sleep disordered breathing events and his daytime functioning. Conclusion Central sleep apnea can be induced by vagus nerve stimulation. This unique case documents successful treatment of vagus nerve stimulation induced central sleep apnea by adaptive servo ventilation in an adolescent patient. Support (if any)

Abstract Background In the United States, rare disease (RD) is defined as a condition that affects fewer than 200,000 individuals. Collectively, RD affects an estimated 30 million Americans. A significant portion of RD has an underlying genetic cause; however, this may go undiagnosed. To better serve these patients, the Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD) was created under the auspices of the Center for Individualized Medicine (CIM) aiming to integrate genomics into subspecialty practice including targeted genetic testing, research, and education. Methods Patients were identified by subspecialty healthcare providers from 11 clinical divisions/departments. Targeted multi-gene panels or custom exome/genome-based panels were utilized. To support the goals of PRaUD, a new clinical service model, the Genetic Testing and Counseling (GTAC) unit, was established to improve access and increase efficiency for genetic test facilitation. The GTAC unit includes genetic counselors, genetic counseling assistants, genetic nurses, and a medical geneticist. Patients receive abbreviated point-of-care genetic counseling and testing through a partnership with subspecialty providers. Results Implementation of PRaUD began in 2018 and GTAC unit launched in 2020 to support program expansion. Currently, 29 RD clinical indications are included in 11 specialty divisions/departments with over 142 referring providers. To date, 1,152 patients have been evaluated with an overall solve rate of 14.1% and as high as 66.7% depending on the phenotype. Noteworthy, 42.7% of the solved or likely solved patients underwent changes in medical management and outcome based on genetic test results. Conclusion Implementation of PRaUD and GTAC have enabled subspecialty practices advance expertise in RD where genetic counselors have not historically been embedded in practice. Democratizing access to genetic testing and counseling can broaden the reach of patients with RD and increase the diagnostic yield of such indications leading to better medical management as well as expanding research opportunities.

AbstractFocal cortical dysplasia (FCD) type II is a highly epileptogenic developmental malformation and a common cause of surgically treated drug-resistant epilepsy. While clinical observations suggest frequent occurrence in the frontal lobe, mechanisms for such propensity remain unexplored. Here, we hypothesized that cortex-wide spatial associations of FCD distribution with cortical cytoarchitecture, gene expression and organizational axes may offer complementary insights into processes that predispose given cortical regions to harbour FCD.We mapped the cortex-wide MRI distribution of FCDs in 337 patients collected from 13 sites worldwide. We then determined its associations with (i) cytoarchitectural features using histological atlases by Von Economo and Koskinas and BigBrain; (ii) whole-brain gene expression and spatiotemporal dynamics from prenatal to adulthood stages using the Allen Human Brain Atlas and PsychENCODE BrainSpan; and (iii) macroscale developmental axes of cortical organization.FCD lesions were preferentially located in the prefrontal and fronto-limbic cortices typified by low neuron density, large soma and thick grey matter. Transcriptomic associations with FCD distribution uncovered a prenatal component related to neuroglial proliferation and differentiation, likely accounting for the dysplastic makeup, and a postnatal component related to synaptogenesis and circuit organization, possibly contributing to circuit-level hyperexcitability. FCD distribution showed a strong association with the anterior region of the antero-posterior axis derived from heritability analysis of interregional structural covariance of cortical thickness, but not with structural and functional hierarchical axes. Reliability of all results was confirmed through resampling techniques.Multimodal associations with cytoarchitecture, gene expression and axes of cortical organization indicate that prenatal neurogenesis and postnatal synaptogenesis may be key points of developmental vulnerability of the frontal lobe to FCD. Concordant with a causal role of atypical neuroglial proliferation and growth, our results indicate that FCD-vulnerable cortices display properties indicative of earlier termination of neurogenesis and initiation of cell growth. They also suggest a potential contribution of aberrant postnatal synaptogenesis and circuit development to FCD epileptogenicity.

Abstract Objective The evaluation to determine candidacy and treatment for epilepsy surgery in persons with drug‐resistant epilepsy (DRE) is not uniform. Many non‐invasive and invasive tests are available to ascertain an appropriate treatment strategy. This study examines expert response to clinical vignettes of magnetic resonance imaging (MRI)–positive lesional focal cortical dysplasia in both temporal and extratemporal epilepsy to identify associations in evaluations and treatment choice. Methods We analyzed annual report data and a supplemental epilepsy practice survey reported in 2020 from 206 adult and 136 pediatric epilepsy center directors in the United States. Non‐invasive and invasive testing and surgical treatment strategies were compiled for the two scenarios. We used chi‐square tests to compare testing utilization between the two scenarios. Multivariable logistic regression modeling was performed to assess associations between variables. Results The supplemental survey response rate was 100% with 342 responses included in the analyses. Differing testing and treatment approaches were noted between the temporal and extratemporal scenarios such as chronic invasive monitoring selected in 60% of the temporal scenario versus 93% of the extratemporal scenario. Open resection was the most common treatment choice; however, overall treatment choices varied significantly ( p < .001). Associations between non‐invasive testing, invasive testing, and treatment choices were present in both scenarios. For example, in the temporal scenario stereo‐electroencephalography (SEEG) was more commonly associated with fluorodeoxyglucose–positron emission tomography (FDG‐PET) (odds ratio [OR] 1.85; 95% confidence interval [CI] 1.06–3.29; p = .033), magnetoencephalography (MEG) (OR 2.90; 95% CI 1.60–5.28; p = <.001), high density (HD) EEG (OR 2.80; 95% CI 1.27–6.24; p = .011), functional MRI (fMRI) (OR 2.17; 95% CI 1.19–4.10; p = .014), and Wada (OR 2.16; 95% CI 1.28–3.66; p = .004). In the extratemporal scenario, choosing SEEG was associated with increased odds of neuromodulation over open resection (OR 3.13; 95% CI 1.24–7.89; p = .016). Significance In clinical vignettes of temporal and extratemporal lesional DRE, epilepsy center directors displayed varying patterns of non‐invasive testing, invasive testing, and treatment choices. Differences in practice underscore the need for comparative trials for the surgical management of DRE.

Abstract Objective Persons with drug‐resistant epilepsy may benefit from epilepsy surgery and should undergo presurgical testing to determine potential candidacy and appropriate intervention. Institutional expertise can influence use and availability of evaluations and epilepsy surgery candidacy. This census survey study aims to examine the influence of geographic region and other center characteristics on presurgical testing for medically intractable epilepsy. Methods We analyzed annual report and supplemental survey data reported in 2020 from 206 adult epilepsy center directors and 136 pediatric epilepsy center directors in the United States. Test utilization data were compiled with annual center volumes, available resources, and US Census regional data. We used Wilcoxon rank‐sum, Kruskal–Wallis, and chi‐squared tests for univariate analysis of procedure utilization. Multivariable modeling was also performed to assign odds ratios (ORs) of significant variables. Results The response rate was 100% with individual element missingness < 11% across 342 observations undergoing univariate analysis. A total of 278 complete observations were included in the multivariable models, and significant regional differences were present. For instance, compared to centers in the South, those in the Midwest used neuropsychological testing (OR = 2.87, 95% confidence interval [CI] = 1.2–6.86; p = .018) and fluorodeoxyglucose–positron emission tomography (OR = 2.74, 95% CI = = 1.14–6.61; p = .025) more commonly. For centers in the Northeast (OR = .46, 95% CI = .23–.93; p = .031) and West (OR = .41, 95% CI = .19–.87; p = .022), odds of performing single‐photon emission computerized tomography were lower by nearly 50% compared to those in the South. Center accreditation level, demographics, volume, and resources were also associated with varying individual testing rates. Significance Presurgical testing for drug‐resistant epilepsy is influenced by US geographic region and other center characteristics. These findings have potential implications for comparing outcomes between US epilepsy centers and may inject disparities in access to surgical treatment.

AbstractObjectiveSummarize the current evidence on efficacy and tolerability of vagus nerve stimulation (VNS), responsive neurostimulation (RNS), and deep brain stimulation (DBS) through a systematic review and meta‐analysis.MethodsWe followed the Preferred Reporting Items of Systematic reviews and Meta‐Analyses reporting standards and searched Ovid Medline, Ovid Embase, and the Cochrane Central Register of Controlled Trials. We included published randomized controlled trials (RCTs) and their corresponding open‐label extension studies, as well as prospective case series, with ≥20 participants (excluding studies limited to children). Our primary outcome was the mean (or median, when unavailable) percentage decrease in frequency, as compared to baseline, of all epileptic seizures at last follow‐up. Secondary outcomes included the proportion of treatment responders and proportion with seizure freedom.ResultsWe identified 30 eligible studies, six of which were RCTs. At long‐term follow‐up (mean 1.3 years), five observational studies for VNS reported a pooled mean percentage decrease in seizure frequency of 34.7% (95% confidence interval [CI]: −5.1, 74.5). In the open‐label extension studies for RNS, the median seizure reduction was 53%, 66%, and 75% at 2, 5, and 9 years of follow‐up, respectively. For DBS, the median reduction was 56%, 65%, and 75% at 2, 5, and 7 years, respectively. The proportion of individuals with seizure freedom at last follow‐up increased significantly over time for DBS and RNS, whereas a positive trend was observed for VNS. Quality of life was improved in all modalities. The most common complications included hoarseness, and cough and throat pain for VNS and implant site pain, headache, and dysesthesia for DBS and RNS.SignificanceNeurostimulation modalities are an effective treatment option for drug‐resistant epilepsy, with improving outcomes over time and few major complications. Seizure‐reduction rates among the three therapies were similar during the initial blinded phase. Recent long‐term follow‐up studies are encouraging for RNS and DBS but are lacking for VNS.