Electroencephalogram synchronization measure as a predictive biomarker of Vagus nerve stimulation response in refractory epilepsy: A retrospective study.

There are currently no established biomarkers for predicting the therapeutic effectiveness of Vagus Nerve Stimulation (VNS). Given that neural desynchronization is a pivotal mechanism underlying VNS action, EEG synchronization measures could potentially serve as predictive biomarkers of VNS response. Notably, an increased brain synchronization in delta band has been observed during sleep-potentially due to an activation of thalamocortical circuitry, and interictal epileptiform discharges are more frequently observed during sleep. Therefore, investigation of EEG synchronization metrics during sleep could provide a valuable insight into the excitatory-inhibitory balance in a pro-epileptogenic state, that could be pathological in patients exhibiting a poor response to VNS. A 19-channel-standard EEG system was used to collect data from 38 individuals with Drug-Resistant Epilepsy (DRE) who were candidates for VNS implantation. An EEG synchronization metric-the Weighted Phase Lag Index (wPLI)-was extracted before VNS implantation and compared between sleep and wakefulness, and between responders (R) and non-responders (NR). In the delta band, a higher wPLI was found during wakefulness compared to sleep in NR only. However, in this band, no synchronization difference in any state was found between R and NR. During sleep and within the alpha band, a negative correlation was found between wPLI and the percentage of seizure reduction after VNS implantation. Overall, our results suggest that patients exhibiting a poor VNS efficacy may present a more pathological thalamocortical circuitry before VNS implantation. EEG synchronization measures could provide interesting insights into the prerequisites for responding to VNS, in order to avoid unnecessary implantations in patients showing a poor therapeutic efficacy.

Modified Vertical Parasagittal Sub-Insular Hemispherotomy-Case Series and Technical Note.

(1) Background: Hemispherotomy is the generally accepted treatment for hemispheric drug-resistant epilepsy (DRE). Lateral or vertical approaches are performed according to the surgeon's preference. Multiple technical variations have been proposed since Delalande first described his vertical technique. We propose a sub-insular variation of the vertical parasagittal hemispherotomy (VPH) and describe our case series of patients operated on using this procedure. (2) Methods: Data from a continuous series of patients with hemispheric DRE who were operated on by the senior author (CR) using the modified sub-insular VPH technique were analyzed retrospectively. Pre-operative demographic and epilepsy characteristics, functional outcome, and surgical complications were extracted from medical charts. (3) Results: Twenty-five patients were operated on between August 2008 and August 2023; 23 have at least 3 months of follow-up. Of this group, 20 (86.9%) patients are seizure-free. Only two patients developed postoperative hydrocephalus (8.7%). All patients who were able to walk autonomously preoperatively and 20 (86.9%) of those with follow-up were able to walk without assistance. A total of 17 (74%) patients were able to perform adapted social activities at the latest follow-up. (4) Conclusions: Modified sub-insular VPH is a successful surgical technique for hemispheric DRE with seizure freedom rates similar to the largest series reported in the literature. Compared to other series, patients who were operated on with our modified technique had a lower rate of postoperative hydrocephalus and excellent long-term motor and cognitive outcomes.

Clinical added value of interictal automated electrical source imaging in the presurgical evaluation of MRI-negative epilepsy: A real-life experience in 29 consecutive patients.

OBJECTIVE: During the presurgical evaluation, manual electrical source imaging (ESI) provides clinically useful information in one-third of the patients but it is time-consuming and requires specific expertise. This prospective study aims to assess the clinical added value of a fully automated ESI analysis in a cohort of patients with MRI-negative epilepsy and describe its diagnostic performance, by evaluating sublobar concordance with stereo-electroencephalography (SEEG) results and surgical resection and outcome. METHODS: All consecutive patients referred to the Center for Refractory Epilepsy (CRE) of St-Luc University Hospital (Brussels, Belgium) for presurgical evaluation between 15/01/2019 and 31/12/2020 meeting the inclusion criteria, were recruited to the study. Interictal ESI was realized on low-density long-term EEG monitoring (LD-ESI) and, whenever available, high-density EEG (HD-ESI), using a fully automated analysis (Epilog PreOp, Epilog NV, Ghent, Belgium). The multidisciplinary team (MDT) was asked to formulate hypotheses about the epileptogenic zone (EZ) location at sublobar level and make a decision on further management for each patient at two distinct moments: i) blinded to ESI and ii) after the presentation and clinical interpretation of ESI. Results leading to a change in clinical management were considered contributive. Patients were followed up to assess whether these changes lead to concordant results on stereo-EEG (SEEG) or successful epilepsy surgery. RESULTS: Data from all included 29 patients were analyzed. ESI led to a change in the management plan in 12/29 patients (41%). In 9/12 (75%), modifications were related to a change in the plan of the invasive recording. In 8/9 patients, invasive recording was performed. In 6/8 (75%), the intracranial EEG recording confirmed the localization of the ESI at a sublobar level. So far, 5/12 patients, for whom the management plan was changed after ESI, were operated on and have at least one-year postoperative follow-up. In all cases, the EZ identified by ESI was included in the resection zone. Among these patients, 4/5 (80%) are seizure-free (ILAE 1) and one patient experienced a seizure reduction of more than 50% (ILAE 4). CONCLUSIONS: In this single-center prospective study, we demonstrated the added value of automated ESI in the presurgical evaluation of MRI-negative cases, especially in helping to plan the implantation of depth electrodes for SEEG, provided that ESI results are integrated into the whole multimodal evaluation and clinically interpreted.

Stereoelectroencephalography Implantation Using Frameless Neuronavigation and Varioguide: Prospective Analysis of Accuracy and Safety in a Case Series of 11 Patients.

BACKGROUND: Stereoencephalography (SEEG) is becoming a widespread diagnostic procedure for drug-resistant epilepsy investigation. Techniques include frame-based and robot-assisted implantation, and more recently, frameless neuronavigated systems (FNSs). Despite its recent use, the accuracy and safety of FNS are still under investigation. OBJECTIVE: To assess in a prospective study the accuracy and safety of a specific FNS use for SEEG implantation. METHODS: Twelve patients who underwent SEEG implantation using FNS (Varioguide [Brainlab]) were included in this study. Data were collected prospectively and included demographic data, postoperative complications, functional results, and implantation characteristics (i.e., duration and number of electrodes). Further analysis included accuracy at entry point and target using measurements of the euclidean distance between planned and actual trajectories. RESULTS: Eleven patients underwent SEEG-FNS implantation from May 2019 to March 2020. One patient did not undergo surgery because of a bleeding disorder. The mean target deviation was 4.06 mm, and mean entry point deviation was 4.2 mm, with insular electrodes significantly more deviated. Results excluding insular electrodes showed a mean target deviation of 3.66 mm and a mean entry point deviation of 3.77 mm. No severe complications occurred; a few mild to moderate adverse events were reported (1 superficial infection, 1 seizure cluster, and 3 transient neurologic impairments). The mean implantation duration by electrodes was 18.5 minutes. CONCLUSIONS: Implantation of depth electrodes for SEEG using FNS seems to be safe, but larger prospective studies are needed to validate these results. Accuracy is sufficient for noninsular trajectories but warrant caution for insular trajectories with statistically significantly less accuracy.

Second surgery after vertical paramedian hemispherotomy for epilepsy recurrence.

Background: Vertical Paramedian Hemispherotomy (VPH) is considered an effective surgical treatment for drug-resistant epilepsy with 80% of patients experiencing seizure freedom or worthwhile improvement. Identifying persistent connective tracts is challenging in failed VPH. Methods: We reviewed our series of consecutive patients undergoing VPH for hemispheric drug-resistant epilepsy and included cases with recurrent epileptic seizures undergoing second surgery with at least 6 months of postoperative follow-up. The cases were extensively assessed to propose a targeted complementary resection. Results: Two children suffering from seizure recurrence following hemispherotomy leading to second surgery were included. After complete assessment, persisting amygdala residue was suspected responsible for the epilepsy recurrence in both patients. Complementary resection of the amygdala residue led to seizure freedom for both patients (Engel IA/ILAE Class 1) without complication. Different diagnostic tools are used to assess patients after failed hemispherotomy including routine EEG, prolonged video EEG, MRI (particularly DTI sequences), SPECT or PET scans and clinical evaluation. These tools allow to rule out epileptic foci in the contralateral hemisphere and to localize a potentially persisting epileptogenic zone. Assessment of these patients should be as systematic and integrated as the initial workup. Although our two patients suffered from Rasmussen's encephalitis, seizure recurrence after VPH has been described in other pathologies. Conclusion: Lying deep and medially in the surgical corridor of VPH, the amygdala can be incompletely resected and cause recurrent epilepsy. Complementary selective resection of the amygdala residue may safely lead to success in epilepsy control.

Vagus Nerve Stimulation Elicits Sleep EEG Desynchronization and Network Changes in Responder Patients in Epilepsy.

Neural desynchronization was shown as a key mechanism of vagus nerve stimulation (VNS) action in epilepsy, and EEG synchronization measures are explored as possible response biomarkers. Since brain functional organization in sleep shows different synchrony and network properties compared to wakefulness, we aimed to explore the effects of acute VNS on EEG-derived measures in the two different states of vigilance. EEG epochs were retrospectively analyzed from twenty-four VNS-treated epileptic patients (11 responders, 13 non-responders) in calm wakefulness and stage N2 sleep. Weighted Phase Lag Index (wPLI) was computed as connectivity measure of synchronization, for VNS OFF and VNS ON conditions. Global efficiency (GE) was computed as a network measure of integration. Ratios OFF/ON were obtained as desynchronization/de-integration index. Values were compared between responders and non-responders, and between EEG states. ROC curve and area-under-the-curve (AUC) analysis was performed for response classification. In responders, stronger VNS-induced theta desynchronization (p < 0.05) and decreased GE (p < 0.05) were found in sleep, but not in wakefulness. Theta sleep wPLI Ratio OFF/ON yielded an AUC of 0.825, and 79% accuracy as a response biomarker if a cut-off value is set at 1.05. Considering all patients, the VNS-induced GE decrease was significantly more important in sleep compared to awake EEG state (p < 0.01). In conclusion, stronger sleep EEG desynchronization in theta band distinguishes responders to VNS therapy from non-responders. VNS-induced reduction of network integration occurs significantly more in sleep than in wakefulness.

Automated electrical source imaging with scalp EEG to define the insular irritative zone: Comparison with simultaneous intracranial EEG.

OBJECTIVE: To evaluate the accuracy of automatedinterictallow-density electrical source imaging (LD-ESI) to define the insular irritative zone (IZ) by comparing the simultaneous interictal ESI localization with the SEEG interictal activity. METHODS: Long-term simultaneous scalp electroencephalography (EEG) and stereo-EEG (SEEG) with at least one depth electrode exploring the operculo-insular region(s) were analyzed. Automated interictal ESI was performed on the scalp EEG using standardized low-resolution brain electromagnetic tomography (sLORETA) and individual head models. A two-step analysis was performed: i) sublobar concordance betweencluster-based ESI localization and SEEG-based IZ; ii) time-locked ESI-/SEEG analysis. Diagnostic accuracy values were calculated using SEEG as reference standard. Subgroup analysis wascarried out, based onthe involvement of insular contacts in the seizure onset and patterns of insular interictal activity. RESULTS: Thirty patients were included in the study. ESI showed an overall accuracy of 53% (C.I. 29-76%). Sensitivity and specificity were calculated as 53% (C.I. 29-76%), 55% (C.I. 23-83%) respectively. Higher accuracy was found in patients with frequent and dominant interictal insular spikes. CONCLUSIONS: LD-ESI defines with good accuracy the insular implication in the IZ, which is not possible with classical interictalscalpEEG interpretation. SIGNIFICANCE: Automated LD-ESI may be a valuable additional tool to characterize the epileptogenic zone in epilepsies with suspected insular involvement.

Neonatal presentation of genetic epilepsies: Early differentiation from acute provoked seizures.

OBJECTIVE: Although most seizures in neonates are due to acute brain injury, some represent the first sign of neonatal onset genetic epilepsies. Delay in recognition and lack of expert assessment of neonates with epilepsy may result in worse developmental outcomes. As in older children and adults, seizure semiology in neonates is an essential determinant in diagnosis. We aimed to establish whether seizure type at presentation in neonates can suggest a genetic etiology. METHODS: We retrospectively analyzed the clinical and electroencephalographic (EEG) characteristics of seizures in neonates admitted in two Level IV neonatal intensive care units, diagnosed with genetic epilepsy, for whom a video-EEG recording at presentation was available for review, and compared them on a 1:2 ratio with neonates with seizures due to stroke or hypoxic-ischemic encephalopathy. RESULTS: Twenty neonates with genetic epilepsy were identified and compared to 40 neonates with acute provoked seizures. Genetic epilepsies were associated with pathogenic variants in KCNQ2 (n = 12), KCNQ3 (n = 2), SCN2A (n = 2), KCNT1 (n = 1), PRRT2 (n = 1), and BRAT1 (n = 2). All neonates with genetic epilepsy had seizures with clinical correlates that were either tonic (18/20) or myoclonic (2/20). In contrast, 17 of 40 (42%) neonates with acute provoked seizures had electrographic only seizures, and the majority of the remainder had clonic seizures. Time to first seizure was longer in neonates with genetic epilepsies (median = 60 h of life) compared to neonates with acute provoked seizures (median = 15 h of life, p < .001). Sodium channel-blocking antiseizure medications were effective in 13 of 14 (92%) neonates with tonic seizures who were trialed at onset or during the course of the epilepsy. SIGNIFICANCE: Seizure semiology is an easily accessible sign of genetic epilepsies in neonates. Early identification of the seizure type can prompt appropriate workup and treatment. Tonic seizures are associated with channelopathies and are often controlled by sodium channel-blocking antiseizure medications.

Recommendations for the treatment of epilepsy in adult and pediatric patients in Belgium: 2020 update.

To guide health care professionals in Belgium in selecting the appropriate antiepileptic drugs (AEDs) for their epilepsy patients, a group of Belgian epilepsy experts developed recommendations for AED treatment in adults and children (initial recommendations in 2008, updated in 2012). As new drugs have become available, others have been withdrawn, new indications have been approved and recommendations for pregnant women have changed, a new update was pertinent. A group of Belgian epilepsy experts (partly overlapping with the group in charge of the 2008/2012 recommendations) evaluated the most recent international guidelines and relevant literature for their applicability to the Belgian situation (registration status, reimbursement, clinical practice) and updated the recommendations for initial monotherapy in adults and children and add-on treatment in adults. Recommendations for add-on treatment in children were also included (not covered in the 2008/2012 publications). Like the 2008/2012 publications, the current update also covers other important aspects related to the management of epilepsy, including the importance of early referral in drug-resistant epilepsy, pharmacokinetic properties and tolerability of AEDs, comorbidities, specific considerations in elderly and pregnant patients, generic substitution and the rapidly evolving field of precision medicine.

Ictal EEG source imaging and connectivity to localize the seizure onset zone in extratemporal lobe epilepsy.

PURPOSE: To evaluate the yield of Functional Connectivity (FC) in addition to low-density ictal Electrical Source Imaging (ESI) in extratemporal lobe epilepsy (ETLE), using an automated algorithm for analysis. METHOD: Long-term EEG monitoring of consecutive ETLE patients who underwent surgery was reviewed by epileptologists, and seizure onsets characterized by rhythmical activity were identified. A spectrogram-based algorithm was developed to select objectively the parameters of ESI analysis. Two methods for SOZ localization were compared: i) ESI power, based on LORETA exclusively; ii) ESI + FC, including a Granger causality-based connectivity analysis. Results were determined at a sublobar level. The resection zone, in relation to 1-year follow-up surgical outcome, was considered as reference standard for diagnostic accuracy analyses. RESULTS: Ninety-four seizures from 24 patients were analyzed. At seizure-level, ESI power showed 36 % sensitivity and 72 % specificity (accuracy: 45 %). ESI + FC significantly improved the accuracy, with 52 % sensitivity and 84 % specificity (accuracy: 61 %, p = 0.04). Results of ESI + FC were equally valuable in patients with lateralized or bilateral/generalized visual interpretation of ictal EEG. In a patient level sub-analysis, upon blinded clinical interpretation, ESI + FC showed a correct localization in 67 % of patients and substantial inter-rater agreement (kappa = 0.64), against 27 % achieved by ESI power, with fair inter-rater agreement (kappa = 0.37). CONCLUSION: FC significantly improves SOZ localization compared to ESI solely in ETLE. Ictal ESI + FC could represent a novel option in the armamentarium of presurgical evaluation, aiding also in patients with visually non-localizable scalp ictal EEG. Prospective studies evaluating the clinical added value of automated low-density ictal ESI may be justified.

Vagus Nerve Stimulation-Induced Laryngeal Motor Evoked Potentials: A Possible Biomarker of Effective Nerve Activation.

Vagus nerve stimulation (VNS) therapy is associated with laryngeal muscle activation and induces voice modifications, well-known side effects of the therapy resulting from co-activation of the recurrent laryngeal nerve. In this study, we describe the non-invasive transcutaneous recording of laryngeal motor evoked potentials (LMEPs), which could serve as a biomarker of effective nerve activation and individual titration in patients with drug-resistant epilepsy. We recruited drug-resistant epileptic patients treated for at least 6 months with a VNS. Trains of 600-1200 VNS pulses were delivered with increasing current outputs. We placed six skin electrodes on the ventral surface of the neck, in order to record LMEPs whenever the laryngeal muscular threshold was reached. We studied the internal consistency and the variability of LMEP recordings, and compared different methods for amplitude calculation. Recruitment curves were built based on the stimulus-response relationship. We also determined the electrical axis of the LMEPs dipole in order to define the optimal electrode placement for LMEPs recording in a clinical setting. LMEPs were successfully recorded in 11/11 patients. The LMEPs threshold ranged from 0.25 to 1 mA (median 0.50 mA), and onset latency was between 5.37 and 8.77 ms. The signal-to-noise ratio was outstanding in 10/11 patients. In these cases, excellent reliability (Intraclass correlation coefficient, ICC > 0.90 across three different amplitude measurements) was achieved with 10 sample averages. Moreover, our recordings showed very good internal consistency (Cronbach's alpha > 0.95 for 10 epochs). Area-under-the-curve and peak-to-peak measurement proved to be complementary methods for amplitude calculation. Finally, we determined that an optimal derivation requires only two recording electrodes, aligned on a horizontal axis around the laryngeal prominence. In conclusion, we describe here an optimal methodology for the recording of VNS-induced motor evoked responses from the larynx. Although further clinical validation is still necessary, LMEPs might be useful as a non-invasive marker of effective nerve activation, and as an aid for the clinician to perform a more rational titration of VNS parameters.

Habituation of phase-locked local field potentials and gamma-band oscillations recorded from the human insula.

Salient nociceptive and non-nociceptive stimuli elicit low-frequency local field potentials (LFPs) in the human insula. Nociceptive stimuli also elicit insular gamma-band oscillations (GBOs), possibly preferential for thermonociception, which have been suggested to reflect the intensity of perceived pain. To shed light on the functional significance of these two responses, we investigated whether they would be modulated by stimulation intensity and temporal expectation - two factors contributing to stimulus saliency. Insular activity was recorded from 8 depth electrodes (41 contacts) implanted in the left insula of 6 patients investigated for epilepsy. Thermonociceptive, vibrotactile, and auditory stimuli were delivered using two intensities. To investigate the effects of temporal expectation, the stimuli were delivered in trains of three identical stimuli (S1-S2-S3) separated by a constant 1-s interval. Stimulation intensity affected intensity of perception, the magnitude of low-frequency LFPs, and the magnitude of nociceptive GBOs. Stimulus repetition did not affect perception. In contrast, both low-frequency LFPs and nociceptive GBOs showed a marked habituation of the responses to S2 and S3 as compared to S1 and, hence, a dissociation with intensity of perception. Most importantly, although insular nociceptive GBOs appear to be preferential for thermonociception, they cannot be considered as a correlate of perceived pain.

Gamma-Band Oscillations Preferential for Nociception can be Recorded in the Human Insula.

Transient nociceptive stimuli elicit robust phase-locked local field potentials (LFPs) in the human insula. However, these responses are not preferential for nociception, as they are also elicited by transient non-nociceptive vibrotactile, auditory, and visual stimuli. Here, we investigated whether another feature of insular activity, namely gamma-band oscillations (GBOs), is preferentially observed in response to nociceptive stimuli. Although nociception-evoked GBOs have never been explored in the insula, previous scalp electroencephalography and magnetoencephalography studies suggest that nociceptive stimuli elicit GBOs in other areas such as the primary somatosensory and prefrontal cortices, and that this activity could be closely related to pain perception. Furthermore, tracing studies showed that the insula is a primary target of spinothalamic input. Using depth electrodes implanted in 9 patients investigated for epilepsy, we acquired insular responses to brief thermonociceptive stimuli and similarly arousing non-nociceptive vibrotactile, auditory, and visual stimuli (59 insular sites). As compared with non-nociceptive stimuli, nociceptive stimuli elicited a markedly stronger enhancement of GBOs (150-300 ms poststimulus) at all insular sites, suggesting that this feature of insular activity is preferential for thermonociception. Although this activity was also present in temporal and frontal regions, its magnitude was significantly greater in the insula as compared with these other regions.

New-Onset Refractory Status Epilepticus: More Investigations, More Questions.

A 27-year-old previously healthy woman was admitted to the hospital with recurrent seizures. Status epilepticus developed that became refractory to third-line therapy with propofol and barbiturates. The patient had a very extensive diagnostic workup including autoimmune, viral and genetic investigations. A tentative immune therapy was proposed with high doses of steroids and plasma exchanges. Our patient had an inherited heterozygous single nucleotide variant in the sequence c.1280A>G [p.Lys427Arg] of the SMC3 gene that was insufficient to explain the seizures. Surprisingly, IgM antibodies against Japanese encephalitis virus were positive on the serum drawn 11 days after symptom onset, as detected by ELISA and the immunofluorescence antibody (IFA) technique. IgG antibodies were also positive using the IFA technique, but not with ELISA. The same investigations as well as the detection of the viral genome by the q-RT-PCR technique were negative on cerebrospinal fluid. Despite the suspicion of a viral infection, we concluded that our patient had a new-onset refractory status epilepticus of cryptogenic origin. Termination of the status epilepticus was obtained after 47 days, with a possible benefit from the introduction of ketamine.

Post-resection electrocorticography has no added value in epilepsy surgery.

Intra-operative electrocorticography (ECoG) has been traditionally used in the surgical management of medically refractory partial epilepsies to identify the limits of the epileptogenic zone. This retrospective study had as goal to evaluate whether tailored surgery based on the presurgical evaluation completed by intra-operative post-resection ECoG improves outcome. We reviewed 94 cases of epilepsy surgery with intra-operative ECoG and determined how many had an ECoG-guided surgical procedure in addition to the initial planned surgery. We also reviewed the presence of specific recurrent ECoG patterns of interictal epileptiform discharges (IED) in the exposed cortical surface, such as: electrographic seizures, bursts, intermittent spike waves, polyspikes or fast rhythms and continuous or quasi-continuous spiking. When performing a post-resection ECoG-tailored surgery, outcome did not improve in lesional or non-lesional epilepsy. Postoperative residual IED did not correlate with a poorer outcome. In our study, the persistence of post-resection IED on ECoG is not correlated with outcome in patients with lesional or non-lesional epilepsy.

Nociceptive Local Field Potentials Recorded from the Human Insula Are Not Specific for Nociception.

The insula, particularly its posterior portion, is often regarded as a primary cortex for pain. However, this interpretation is largely based on reverse inference, and a specific involvement of the insula in pain has never been demonstrated. Taking advantage of the high spatiotemporal resolution of direct intracerebral recordings, we investigated whether the human insula exhibits local field potentials (LFPs) specific for pain. Forty-seven insular sites were investigated. Participants received brief stimuli belonging to four different modalities (nociceptive, vibrotactile, auditory, and visual). Both nociceptive stimuli and non-nociceptive vibrotactile, auditory, and visual stimuli elicited consistent LFPs in the posterior and anterior insula, with matching spatial distributions. Furthermore, a blind source separation procedure showed that nociceptive LFPs are largely explained by multimodal neural activity also contributing to non-nociceptive LFPs. By revealing that LFPs elicited by nociceptive stimuli reflect activity unrelated to nociception and pain, our results confute the widespread assumption that these brain responses are a signature for pain perception and its modulation.