Worrell, Gregory A.

OBJECTIVE Epilepsy originating from the central lobule (i.e., the primary sensorimotor cortex) is a challenging entity to treat given its involvement of eloquent cortex. The objective of this study was to review available evidence on treatment options for central lobule epilepsy. METHODS A comprehensive literature search (PubMed/Medline, EMBASE, and Scopus) was conducted for studies (1990 to date) investigating postoperative outcomes for central lobule epilepsy. The primary and secondary endpoints were seizure freedom at last follow-up and postoperative neurological deficit, respectively. The following procedures were included: open resection, multiple subpial transections (MSTs), laser and radiofrequency ablation, deep brain stimulation (DBS), responsive neurostimulation (RNS), and continuous subthreshold cortical stimulation (CSCS). RESULTS A total of 52 studies and 504 patients were analyzed. Most evidence was based on open resection, yielding a total of 400 patients (24 studies), of whom 62% achieved seizure freedom at a mean follow-up of 48 months. A new or worsened motor deficit occurred in 44% (permanent in 19%). Forty-six patients underwent MSTs, of whom 16% achieved seizure freedom and 30% had a neurological deficit (permanent in 12%). There were 6 laser ablation cases (cavernomas in 50%) with seizure freedom in 4 patients and 1 patient with temporary motor deficit. There were 5 radiofrequency ablation cases, with 1 patient achieving seizure freedom, 2 patients each with Engel class III and IV outcomes, and 2 patients with motor deficit. The mean seizure frequency reduction at the last follow-up was 79% for RNS (28 patients), 90% for CSCS (15 patients), and 73% for DBS (4 patients). There were no cases of temporary or permanent neurological deficit in the CSCS or DBS group. CONCLUSIONS This review highlights the safety and efficacy profile of resection, ablation, and stimulation for refractory central lobe epilepsy. Resection of localized regions of epilepsy onset zones results in good rates of seizure freedom (62%); however, nearly 20% of patients had permanent motor deficits. The authors hope that this review will be useful to providers and patients when tailoring decision-making for this intricate pathology.

AbstractBackgroundProgressive dysexecutive syndrome (dAD) is an atypical presentation of early onset Alzheimer’s disease (AD) with increased frontal and parietal region hypometabolism on FDG‐PET imaging compared to classic amnestic AD. We compared electroencephalogram (EEG) and FDG‐PET in dAD patients to determine if there was a correlation between EEG spectral activity and standard uptake value ratios (SUVR) in those regions.MethodFDG‐PET and resting state scalp EEG were obtained on AD‐biomarker confirmed, behavioral neurologist diagnosed cases of dAD (n = 11). We isolated awake‐eyes‐closed segments (mean duration: 113s, median:118s, range: 58‐138s) of each EEG and calculated the relative power of delta, theta, alpha, beta, and gamma bands within a wideband of 0.5‐40 Hz. In bilateral frontal and parietal regions, we averaged select channels across 6 to 14 10‐second windows per subject (fig.1). We evaluated the correlation between relative band powers and SUVRs of the regions by linear regression analysis.ResultThere is a strong negative correlation (R2 = 0.54, p < 0.01) between alpha band relative power and SUVR in bilateral frontal regions (fig 2). Delta band relative power showed a strong positive correlation (R2 = 0.54, p < 0.05) with SUVR in the left frontal region. A positive trend was noted in the delta band in the right frontal region but did not reach statistical significance. Beta band relative power was negatively correlated with frontal region SUVR bilaterally, but only the left side reached statistical significance. These findings remained significant after multiple comparisons correction. No statistically significant correlations were noted in the parietal regions. Exploratory analysis revealed negative correlations between alpha bands and temporal region SUVRs bilaterally.ConclusionIn this small sample of selected individuals with dysexecutive AD, we report a strong correlation between EEG relative spectral power and PET regional SUVR in multiple EEG frequency bands and brain regions. In the bilateral frontal regions, slower delta frequencies and faster alpha and beta frequencies were associated with lower FDG‐PET signal. Future studies are needed to determine if this spectral power pattern and other EEG properties of dAD differ from other clinical dementia phenotypes and its clinical significance.

OBJECTIVE The prevalence of epilepsy in the older adult population is increasing. While surgical intervention in younger patients is supported by level I evidence, the safety and efficacy of epilepsy surgery in older individuals is less well established. The aim of this study was to evaluate seizure freedom rates and surgical outcomes in older epilepsy patients. METHODS The authors’ institutional electronic database was queried for patients older than 50 who had undergone epilepsy surgery during 2002–2018. Cases were grouped into 50–59, 60–69, and 70+ years old. Seizure freedom at the last follow-up constituted the primary outcome of interest. The institutional analysis was supplemented by a literature review and meta-analysis (random effects model) of all published studies on this topic as well as by an analysis of complication rates, mortality rates, and cost data from a nationwide administrative database (Vizient Inc., years 2016–2019). RESULTS A total of 73 patients (n = 16 for 50–59 years, n = 47 for 60–69, and n = 10 for 70+) were treated at the authors’ institution. The median age was 63 years, and 66% of the patients were female. At a median follow-up of 24 months, seizure freedom was 73% for the overall cohort, 63% for the 50–59 group, 77% for the 60–69 group, and 70% for the 70+ group. The literature search identified 15 additional retrospective studies (474 cases). Temporal lobectomy was the most commonly performed procedure (73%), and mesial temporal sclerosis was the most common pathology (52%), followed by nonspecific gliosis (19%). The pooled mean follow-up was 39 months (range 6–114.8 months) with a pooled seizure freedom rate of 65% (95% CI 59%–72%). On multivariable meta-regression analysis, an older mean age at surgery (coefficient [coeff] 2.1, 95% CI 1.1–3.1, p < 0.001) and the presence of mesial temporal sclerosis (coeff 0.3, 95% CI 0.1–0.6, p = 0.015) were the most important predictors of seizure freedom. Finally, analysis of the Vizient database revealed mortality rates of 0.5%, 1.1%, and 9.6%; complication rates of 7.1%, 10.1%, and 17.3%; and mean hospital costs of $31,977, $34,586, and $40,153 for patients aged 50–59, 60–69, and 70+ years, respectively. CONCLUSIONS While seizure-free outcomes of epilepsy surgery are excellent, there is an expected increase in morbidity and mortality with increasing age. Findings in this study on the safety and efficacy of epilepsy surgery in the older population may serve as a useful guide during preoperative decision-making and patient counseling.

Abstract Localizing hyperexcitable brain tissue to treat focal seizures remains challenging. We want to identify the seizure onset zone from interictal EEG biomarkers. We hypothesize that a combination of interictal EEG biomarkers, including a novel low frequency marker, can predict mesial temporal involvement and can assist in prognosis related to surgical resections. Interictal direct current wide bandwidth invasive EEG recordings from 83 patients implanted with 5111 electrodes were retrospectively studied. Logistic regression was used to classify electrodes and patient outcomes. A feed-forward neural network was implemented to understand putative mechanisms. Interictal infraslow frequency EEG activity was decreased for seizure onset zone electrodes while faster frequencies such as delta (2–4 Hz) and beta-gamma (20–50 Hz) activity were increased. These spectral changes comprised a novel interictal EEG biomarker that was significantly increased for mesial temporal seizure onset zone electrodes compared to non-seizure onset zone electrodes. Interictal EEG biomarkers correctly classified mesial temporal seizure onset zone electrodes with a specificity of 87% and positive predictive value of 80%. These interictal EEG biomarkers also correctly classified patient outcomes after surgical resection with a specificity of 91% and positive predictive value of 87%. Interictal infraslow EEG activity is decreased near the seizure onset zone while higher frequency power is increased, which may suggest distinct underlying physiologic mechanisms. Narrowband interictal EEG power bands provide information about the seizure onset zone and can help predict mesial temporal involvement in seizure onset. Narrowband interictal EEG power bands may be less useful for predictions related to non-mesial temporal electrodes. Together with interictal epileptiform discharges and high-frequency oscillations, these interictal biomarkers may provide prognostic information prior to surgical resection. Computational modelling suggests changes in neural adaptation may be related to the observed low frequency power changes.

Abstract Objective Verbal memory dysfunction is common in focal, drug‐resistant epilepsy (DRE). Unfortunately, surgical removal of seizure‐generating brain tissue can be associated with further memory decline. Therefore, localization of both the circuits generating seizures and those underlying cognitive functions is critical in presurgical evaluations for patients who may be candidates for resective surgery. We used intracranial electroencephalographic (iEEG) recordings during a verbal memory task to investigate word encoding in focal epilepsy. We hypothesized that engagement in a memory task would exaggerate local iEEG feature differences between the seizure onset zone (SOZ) and neighboring tissue as compared to wakeful rest (“nontask”). Methods Ten participants undergoing presurgical iEEG evaluation for DRE performed a free recall verbal memory task. We evaluated three iEEG features in SOZ and non‐SOZ electrodes during successful word encoding and compared them with nontask recordings: interictal epileptiform spike (IES) rates, power in band (PIB), and relative entropy (REN; a functional connectivity measure). Results We found a complex pattern of PIB and REN changes in SOZ and non‐SOZ electrodes during successful word encoding compared to nontask. Successful word encoding was associated with a reduction in local electrographic functional connectivity (increased REN), which was most exaggerated in temporal lobe SOZ. The IES rates were reduced during task, but only in the non‐SOZ electrodes. Compared with nontask, REN features during task yielded marginal improvements in SOZ classification. Significance Previous studies have supported REN as a biomarker for epileptic brain. We show that REN differences between SOZ and non‐SOZ are enhanced during a verbal memory task. We also show that IESs are reduced during task in non‐SOZ, but not in SOZ. These findings support the hypothesis that SOZ and non‐SOZ respond differently to task and warrant further exploration into the use of cognitive tasks to identify functioning memory circuits and localize SOZ.

AbstractThere is a paucity of data to guide anterior nucleus of the thalamus (ANT) deep brain stimulation (DBS) with brain sensing. The clinical Medtronic Percept DBS device provides constrained brain sensing power within a frequency band (power‐in‐band [PIB]), recorded in 10‐min averaged increments. Here, four patients with temporal lobe epilepsy were implanted with an investigational device providing full bandwidth chronic intracranial electroencephalogram (cEEG) from bilateral ANT and hippocampus (Hc). ANT PIB‐based seizure detection was assessed. Detection parameters were cEEG PIB center frequency, bandwidth, and epoch duration. Performance was evaluated against epileptologist‐confirmed Hc seizures, and assessed by area under the precision‐recall curve (PR‐AUC). Data included 99 days of cEEG, and 20, 278, 3, and 18 Hc seizures for Subjects 1–4. The best detector had 7‐Hz center frequency, 5‐Hz band width, and 10‐s epoch duration (group PR‐AUC = .90), with 75% sensitivity and .38 false alarms per day for Subject 1, and 100% and .0 for Subjects 3 and 4. Hc seizures in Subject 2 did not propagate to ANT. The relative change of ANT PIB was maximal ipsilateral to seizure onset for all detected seizures. Chronic ANT and Hc recordings provide direct guidance for ANT DBS with brain sensing.

Abstract Objective This study aims to evaluate the role of scalp electroencephalography (EEG; ictal and interictal patterns) in predicting resective epilepsy surgery outcomes. We use the data to further develop a nomogram to predict seizure freedom. Methods We retrospectively reviewed the scalp EEG findings and clinical data of patients who underwent surgical resection at three epilepsy centers. Using both EEG and clinical variables categorized into 13 isolated candidate predictors and 6 interaction terms, we built a multivariable Cox proportional hazards model to predict seizure freedom 2 years after surgery. Harrell's step‐down procedure was used to sequentially eliminate the least‐informative variables from the model until the change in the concordance index (c‐index) with variable removal was less than 0.01. We created a separate model using only clinical variables. Discrimination of the two models was compared to evaluate the role of scalp EEG in seizure‐freedom prediction. Results Four hundred seventy patient records were analyzed. Following internal validation, the full Clinical + EEG model achieved an optimism‐corrected c‐index of 0.65, whereas the c‐index of the model without EEG data was 0.59. The presence of focal to bilateral tonic‐clonic seizures (FBTCS), high preoperative seizure frequency, absence of hippocampal sclerosis, and presence of nonlocalizable seizures predicted worse outcome. The presence of FBTCS had the largest impact for predicting outcome. The analysis of the models’ interactions showed that in patients with unilateral interictal epileptiform discharges (IEDs), temporal lobe surgery cases had a better outcome. In cases with bilateral IEDs, abnormal magnetic resonance imaging (MRI) predicted worse outcomes, and in cases without IEDs, patients with extratemporal epilepsy and abnormal MRI had better outcomes. Significance This study highlights the value of scalp EEG, particularly the significance of IEDs, in predicting surgical outcome. The nomogram delivers an individualized prediction of postoperative outcome, and provides a unique assessment of the relationship between the outcome and preoperative findings.

Abstract Quantitative volumetric brain MRI measurement is important in research applications, but translating it into patient care is challenging. We explore the incorporation of clinical automated quantitative MRI measurements in statistical models predicting outcomes of surgery for temporal lobe epilepsy. Four hundred and thirty-five patients with drug-resistant epilepsy who underwent temporal lobe surgery at Cleveland Clinic, Mayo Clinic and University of Campinas were studied. We obtained volumetric measurements from the pre-operative T1-weighted MRI using NeuroQuant, a Food and Drug Administration approved software package. We created sets of statistical models to predict the probability of complete seizure-freedom or an Engel score of I at the last follow-up. The cohort was randomly split into training and testing sets, with a ratio of 7:3. Model discrimination was assessed using the concordance statistic (C-statistic). We compared four sets of models and selected the one with the highest concordance index. Volumetric differences in pre-surgical MRI located predominantly in the frontocentral and temporal regions were associated with poorer outcomes. The addition of volumetric measurements to the model with clinical variables alone increased the model’s C-statistic from 0.58 to 0.70 (right-sided surgery) and from 0.61 to 0.66 (left-sided surgery) for complete seizure freedom and from 0.62 to 0.67 (right-sided surgery) and from 0.68 to 0.73 (left-sided surgery) for an Engel I outcome score. 57% of patients with extra-temporal abnormalities were seizure-free at last follow-up, compared to 68% of those with no such abnormalities (P-value = 0.02). Adding quantitative MRI data increases the performance of a model developed to predict post-operative seizure outcomes. The distribution of the regions of interest included in the final model supports the notion that focal epilepsies are network disorders and that subtle cortical volume loss outside the surgical site influences seizure outcome.

Summary: Electrical brain stimulation is an established therapy for movement disorders, epilepsy, obsessive compulsive disorder, and a potential therapy for many other neurologic and psychiatric disorders. Despite significant progress and FDA approvals, there remain significant clinical gaps that can be addressed with next generation systems. Integrating wearable sensors and implantable brain devices with off-the-body computing resources (smart phones and cloud resources) opens a new vista for dense behavioral and physiological signal tracking coupled with adaptive stimulation therapy that should have applications for a range of brain and mind disorders. Here, we briefly review some history and current electrical brain stimulation applications for epilepsy, deep brain stimulation and responsive neurostimulation, and emerging applications for next generation devices and systems.