Insular Role in Blood Pressure and Systemic Vascular Resistance Regulation.

OBJECTIVES: The insula is a brain area involved in the modulation of autonomic responses. Previous studies have focused mainly on its heart rate regulatory function, but its role in vascular control is not well defined. Ictal/postictal blood pressure (BP) fluctuations may have a role in the pathogenesis of sudden unexpected death in epilepsy. This study aims to characterize the insular influence on vascular regulation through direct high-frequency electrical stimulation (E-stim) of different insular regions during stereo-electroencephalographic studies. MATERIALS AND METHODS: An observational, prospective study was conducted, involving people with epilepsy who underwent E-stim of depth electrodes implanted in the insular cortex. Patients with anatomical or electrophysiological insular abnormalities, E-stim producing after discharges, or any elicited symptoms were excluded. Variations of BP and systemic vascular resistance (SVR) during the insular stimuli were analyzed, comparing them with those observed during E-stim of control contacts implanted in cortical noneloquent regions and sham stimulations. RESULTS: Fourteen patients were included, five implanted in the right insula and nine in the left. We analyzed 14 stimulations in the right insula, 18 in the left insula, 18 in control electrodes, and 13 sham stimulations. Most right insular responses were hypertensive, whereas most left ones were hypotensive. E-stim of the right insula produced a significant BP and SVR increase, whereas the left insula induced a significant BP decrease without SVR changes. The most remarkable changes were elicited in both posterior insulas, although the magnitude of BP changes was generally low. Control and sham stimulations did not induce BP or SVR changes. CONCLUSION: Our findings on insular stimulation suggest an interhemispheric difference in its vascular regulatory function, with a vasopressor effect of the right insula and a vasodilator effect of the left one.

Characterization of the Insular Role in Cardiac Function through Intracranial Electrical Stimulation of the Human Insula.

OBJECTIVE: The link between brain function and cardiovascular dynamics is an important issue yet to be elucidated completely. The insula is a neocortical brain area that is thought to have a cardiac chronotropic regulatory function, but its role in cardiac contractility is unknown. We aimed to analyze the variability in heart rate and cardiac contractility after functional activation of different insular regions through direct electrical stimulation (E-stim) in humans. METHODS: This was an observational, prospective study, including patients admitted for stereo-electroencephalographic recording because of refractory epilepsy, in whom the insular cortex was implanted. Patients with anatomical or electrophysiological insular abnormalities and those in whom E-stim produced subjective symptoms were excluded. Variations in heart rate (HR), stroke volume (SV), and cardiac output (CO) were analyzed during insular E-stim and compared with control E-stim of non-eloquent brain regions and sham stimulations. RESULTS: Ten patients were included, 5 implanted in the right insula (52 E-stim) and 5 in the left (37 E-stim). Demographic and clinical characteristics of both groups were similar. E-stim of both right and left insulas induced a significant decrease of the CO and HR, and an increase of the SV. E-stim of control electrodes and sham stimulations were not associated with variations in cardiac function. Blood pressure and respiratory rate remained unaltered. INTERPRETATION: Our results suggest a direct chronotropic and inotropic cardiac depressor function of the right and left insulas. The evidence of an insular direct cardiac regulatory function might open a path in the prevention or treatment of heart failure, arrhythmias, and sudden unexpected death in epilepsy. ANN NEUROL 2021;89:1172-1180.

Degenerate time-dependent network dynamics anticipate seizures in human epileptic brain.

Epileptic seizures are known to follow specific changes in brain dynamics. While some algorithms can nowadays robustly detect these changes, a clear understanding of the mechanism by which these alterations occur and generate seizures is still lacking. Here, we provide crossvalidated evidence that such changes are initiated by an alteration of physiological network state dynamics. Specifically, our analysis of long intracranial electroencephalography (iEEG) recordings from a group of 10 patients identifies a critical phase of a few hours in which time-dependent network states become less variable ("degenerate"), and this phase is followed by a global functional connectivity reduction before seizure onset. This critical phase is characterized by an abnormal occurrence of highly correlated network instances and is shown to be particularly associated with the activity of the resected regions in patients with validated postsurgical outcome. Our approach characterizes preseizure network dynamics as a cascade of 2 sequential events providing new insights into seizure prediction and control.

Prediction error connectivity: A new method for EEG state analysis.

Several models have been proposed to explain brain regional and interregional communication, the majority of them using methods that tap the frequency domain, like spectral coherence. Considering brain interareal communication as binary interactions, we describe a novel method devised to predict dynamics and thus highlight abrupt changes marked by unpredictability. Based on a variable-order Markov model algorithm developed in-house for data compression, the prediction error connectivity (PEC) estimates network transitions by calculating error matrices (EMs). We analysed 20 h of EEG signals of virtual networks generated with a neural mass model. Subnetworks changed through time (2 of 5 signals), from normal to normal or pathological states. PEC was superior to spectral coherence in detecting all considered transitions, especially in broad and ripple bands. Subsequently, EMs of real data were classified using a support vector machine in order to capture the transition from interictal to preictal state and calculate seizure risk. A single seizure was randomly selected for training. Through this approach it was possible to establish a threshold that the calculated risk consistently overcame minutes before the events. Using either spectral coherence or PEC we created 1000 models that successfully predicted 6 seizures (100% sensibility), a whole cluster recorded in a patient with hippocampal epilepsy. However, PEC resulted superior to coherence in terms of true seizure free time and amount of false warnings. Indeed, the best PEC model predicted 96% of interictal time (vs. 83% of coherence) of about 20 h of stereo-EEG. This analysis was extended to patients with neo/mesocortical temporal, neocortical frontal, parietal and occipital lobe epilepsy. Again PEC showed high performance, allowing the prediction of 31 events distributed across 10 days with ROC AUCs that reached 98% (average 93 ±â€¯5%) in 6 different patients. Moreover, considering another state transition, PEC could classify and forecast up to 88% (average 85 ±â€¯3%) of the REM phase both in deep and scalp EEG. In conclusion, PEC is a novel approach that relies on pattern analysis in the time-domain. We believe that this method can be successfully employed both for the study of brain connectivity, and also implemented in real-life solutions for seizure detection and prediction.

Effect of lacosamide on depression and anxiety symptoms in patients with focal refractory epilepsy: A prospective multicenter study.

INTRODUCTION: Depression is the main psychiatric comorbidity in epilepsy with an estimated prevalence between 20% and 55% and one of the main determinants of quality of life. The aim of this study was to investigate the effect of lacosamide (LCM) on mood and anxiety symptoms in patients with focal onset seizures (FOS). The secondary objective was to evaluate if the potential modifications in variables were related to seizure control or to the intrinsic effect of LCM. MATERIAL AND METHODS: We performed a prospective multicenter study in 8 tertiary epilepsy centers in adults with FOS in which LCM was initiated as add-on therapy. Patients' mood and quality of life were evaluated through questionnaires and scales such as the Beck Depression Inventory-II (BDI-II), the State-Trait Anxiety Inventory (STAI-S/T), the Hospital Anxiety and Depression Scale (HADS), and the Quality of Life in Epilepsy-10 (QOLIE-10). Initiation of psychotropic medication was not allowed during the observation period. Patients with diagnosis of major depression or bipolar disorder were excluded. Evaluations were scheduled before LCM treatment, at 3 and 6months. RESULTS: Forty-nine patients were included (51% female) with an average age of 39.5years (range 18-65). At the start of treatment with LCM, 65.3% of the patients were on treatment with one antiepileptic drug (AED). Based on BDI-II, 38.8% of patients had depressive symptoms and 46.9% according to HADS Depression (HADS-D), 63.3% of patients presented pathological levels of anxiety (STAI-S/T), and 44.9% according to HADS Anxiety (HADS-A). Quality of Life in Epilepsy-10 showed that 57.1% of patients had a relevant reduction in their quality of life. After LCM, the score on the BDI-II depression scale decreased significantly (p<0.001). Based on the STAI and HADS-anxiety scales, patients who had a pathological anxiety at baseline, significantly improved. The QOLIE-10 improved significantly over the observation period (p<0.001). At 6months, 28.3% of patients were seizure-free (67.4% were responders). The improvements on depression and anxiety scores were not statistically related to seizure control. CONCLUSION: Lacosamide seems to have a positive effect on depressive and anxiety symptoms. Although the efficacy of LCM in seizure control was demonstrated, the antidepressant and anxiolytic effect on mood and anxiety seems to be an independent factor.

Validation of direct cortical stimulation in presurgical evaluation of epilepsy.

OBJECTIVE: Direct cortical stimulation (DCS) is standard for intracranial presurgical evaluation in drug-resistant epilepsy (DRE). Few studies have reported levels of concordance between spontaneous seizure generators and triggered seizures during DCS. The present work reports validity measures of DCS for detecting the seizure onset zone (SOZ) during stereoelectroencephalography (SEEG). METHODS: We evaluated all patients who underwent SEEG evaluation at our epilepsy center between 2013 and 2019. Data were analyzed using contingency tables. Validity measures of the diagnostic test were computed for all patients evaluated with DCS and for seizure free patients. RESULTS: Fifty-eight consecutive patients were evaluated through DCS. One hundred seventy-three clinical seizures were elicited with DCS. Electroclinical identical to spontaneous seizures were considered true positive (TP) seizures. They showed a high specificity (96.9%) for detecting the SOZ in patients that remained seizure free one year after treatment. Sensitivity was low (23.0%), and a high percentage of false-negative stimulations was documented in the SOZ. The accuracy was 87.9%. CONCLUSIONS: DCS is a technique with high specificity but a low sensitivity for the localization of the SOZ. The DCS validity measures need to be known when considered for surgical decisions. The interpretation of DCS-triggered seizures and the differentiation of true-positive vs false-positive seizures should be carefully evaluated. SIGNIFICANCE: DCS seizure triggering is highly specific for SOZ localization.

SUDEP in Spain: An Epilepsy Monitoring Unit based case series.

PURPOSE: SUDEP is the first cause of mortality related to epilepsy. However, in Spain there are no published cases or series from Epilepsy Monitoring Units that could expose the characteristics of SUDEP in our population. METHOD: We reviewed all patients treated at our Spanish Epilepsy Reference Centre who died between 2010-2018. SUDEP cases were classified as definite, probable, possible or near-SUDEP. Epilepsy type, demographics and case detection issues were described. RESULTS: From 1250 evaluated patients, 102 died during the study period. Seven patients were diagnosed with SUDEP or near-SUDEP: two definite SUDEP, one definite SUDEP plus, two probable SUDEP and two near-SUDEP. Specific problems for detection and registration of SUDEP inherent to the Spanish healthcare system and the legal framework were defined. Only 43% of cases were known by the referral neurologist. SUDEP incidence was 1.3 per 1000 patient/year, comprising 0.56% of all deaths in our cohort. Two cases were female, the average age was 36 years (18-61). All patients had focal epilepsy and suffered from generalized tonic-clonic seizures. All witnessed cases occurred after a focal to bilateral tonic-clonic seizure. Four cases occurred during sleep and all non-witnessed cases were found in prone position. One case occurred during video-EEG monitoring. CONCLUSIONS: Our casuistic represents the first Epilepsy Monitoring Unit based case series of SUDEP conducted in Spain. The incidence in our population agrees with the reported in other countries. However, in our population, SUDEP is probably underdiagnosed due to administrative and legal issues.

Ictal spitting in non-dominant temporal lobe epilepsy: an anatomo-electrophysiological correlation.

We report a patient presenting drug-resistant, non-dominant temporal lobe epilepsy with ictal spitting and prosopometamorphopsia, both extremely rare semiologies. Second-phase pre-surgical monitoring was performed using SEEG due to lesion-negative imaging and the rare semiology. The seizure onset zone was delimited to the right anterior hippocampus and the temporobasal cortex, with the propagation zone within the entorhinal cortex. Interestingly, direct electrical stimulation to the entorhinal cortex, which was reproduced in a number of trials, evoked spitting without leading to seizures or post-discharges. After the resection of the epileptogenic zone, the patient remained seizure-free without AEDs for a follow-up period of five years (Engel Class 1a). The neuropathology revealed a focal cortical dysplasia type FCD-Ia. Spectral analysis of intracranial ictal EEG (iEEG) data suggested a possible role of the basal temporal and entorhinal cortex as a necessary node in ictal spitting. [Published with video sequences on www.epilepticdisorders.com].

Detection of recurrent activation patterns across focal seizures: Application to seizure onset zone identification.

OBJECTIVE: We introduce a method that quantifies the consistent involvement of intracranially monitored regions in recurrent focal seizures. METHODS: We evaluated the consistency of two ictal spectral activation patterns (mean power change and power change onset time) in intracranial recordings across focal seizures from seven patients with clinically marked seizure onset zone (SOZ). We examined SOZ discrimination using both patterns in different frequency bands and periods of interest. RESULTS: Activation patterns were proved to be consistent across more than 80% of recurrent ictal epochs. In all patients, whole-seizure mean activations were significantly higher for SOZ than non-SOZ regions (P<0.05) while activation onset times were significantly lower for SOZ than for non-SOZ regions (P<0.001) in six patients. Alpha-beta bands (8-20Hz) achieved the highest patient-average effect size on the whole-seizure period while gamma band (20-70Hz) achieved the highest discrimination values between SOZ and non-SOZ sites near seizure onset (0-5s). CONCLUSIONS: Consistent spectral activation patterns in focal epilepsies discriminate the SOZ with high effect sizes upon appropriate selection of frequency bands and activation periods. SIGNIFICANCE: The present method may be used to improve epileptogenic identification as well as pinpoint additional regions that are functionally altered during ictal events.

Relevance of stroke subtype in vascular risk prediction.

OBJECTIVE: To ascertain the risk of a new vascular event (NVE) occurring after ischemic stroke and evaluate differences in risk based on stroke subtype. METHODS: This was a prospective observational study of consecutive patients with nonfatal stroke recruited at a single tertiary stroke center with follow-up ranging from 2 to 5 years (average, 31 ± 15.9 months). An NVE (vascular death, nonfatal stroke or myocardial infarction, and hospitalization for other atherothrombotic events) was defined according to criteria used in a previously developed large multicenter register of atherothrombotic patients (Reduction of Atherothrombosis for Continued Health Registry [REACH]). We analyzed age, sex, and atherosclerotic burden (AB) based on a number of vascular risk factors, affected vascular areas, and stroke subtype according to Stop Stroke Study Trial of Org 10172 in acute stroke treatment (SSS-TOAST) criteria in cardioaortic, large artery atherosclerosis (LAA), unclassified (more than one causal mechanism), small-artery disease (SAD), and undetermined (without cause) stroke categories. RESULTS: The final cohort consisted of 748 patients. An NVE occurred in 162 patients (21.7%), equivalent to a rate of 0.084 events per patient/year. Multivariate analysis revealed that higher NVE risk was associated with AB and 3 stroke subtypes, namely cardioaortic (hazard ratio [HR] = 2.58; 95% confidence interval [CI] 1.27-5.22), LAA (HR = 4.17; 95% CI 2.03-8.56), and unclassified (HR = 5.70; 95% CI 2.49-13.08). Patients with SAD or stroke of undetermined cause had lower NVE risk. CONCLUSIONS: Patients who survive stroke are at increased risk for NVEs. The risk for NVE varies according to stroke subtype.