Manuscripts

Objectives: No reliable biomarkers exist for predicting and assessing vagus nerve stimulation (VNS) response. While VNS induces acute electroencephalography (EEG) desynchronization after implantation, longitudinal evaluations of EEG synchronization changes are lacking. This study constitutes the first prospective investigation evaluating EEG synchronization before and after VNS device implantation and correlating it with the clinical response to VNS.
Materials and Methods: High-density EEG recordings were obtained from 12 adults with drug-resistant epilepsy before and after VNS device implantation (one, three, and six months). EEG resting state (180 seconds), with eyes open and eyes closed (EC), was recorded in VNS ON and OFF conditions. The global weighted phase lag index (wPLI) was computed as an EEG phasesynchronization measure and correlated with the VNS response using various assessment methods, including binary classification (>50% or <50% seizure frequency reduction), percentage of seizure reduction, and the newly developed Clinical-Research Response Scale (CRRS).
Results: We observed a progressive decrease of wPLI in the delta band during the EC VNS OFF condition, which correlated with the VNS response over time, particularly when assessed using the new CRRS compared with other assessment methods. Additionally, a higher preimplant global wPLI predicted a better outcome of VNS, as did an early magnet response.
Conclusions: Overall, VNS may positively influence specific brain states, with a time-dependent evolution of EEG synchronization reflecting therapeutic efficacy. Preimplantation EEG synchronization and an early magnet response may predict VNS response. Moreover, the CRRS could constitute a more sensitive method for characterizing VNS response compared with traditional assessment methods.

Sudden unexpected death in epilepsy (SUDEP) is a critical concern for individuals suffering from epilepsy, with respiratory dysfunction playing a significant role in its pathology. Fatal seizures are often characterized by central apnea and hypercapnia (elevated CO2 levels), indicating a failure in ventilatory control. Research has shown that both human epilepsy patients and animal models exhibit a reduced hypercapnic ventilatory response in the interictal (non-seizure) period, suggesting an impaired ability to regulate breathing in response to high CO2 levels. This review examines the role of central chemoreceptors—specifically the retrotrapezoid nucleus, raphe nuclei, nucleus tractus solitarius, locus coeruleus, and hypothalamus in this pathology. These structures are critical for sensing CO2 and maintaining respiratory homeostasis. Emerging evidence also implicates neuropeptidergic pathways within these chemoreceptive regions in SUDEP. Neuropeptides like galanin, pituitary adenylate cyclase-activating peptide (PACAP), orexin, somatostatin, and bombesin-like peptides may modulate chemosensitivity and respiratory function, potentially exacerbating respiratory failure during seizures. Understanding the mechanisms linking central chemoreception, respiratory control, and neuropeptidergic signaling is essential to developing targeted interventions to reduce the risk of SUDEP in epilepsy patients.

Purpose: The Locus Coeruleus (LC) plays a vital role by releasing norepinephrine, which contributes to the antiepileptic effects of Vagus Nerve Stimulation (VNS). LC activity also influences pupil dilation. Investigating
VNS dose-dependent Pupillary Dilation Response (PDR) may provide novel neurophysiological insights into therapeutic response and allow for an objective and personalized optimization of stimulation parameters.
Methods: Fourteen VNS-implanted patients (9 responders, 5 non-responders) treated for at least 6 months were retrospectively recruited. VNS intensities were adjusted from 0.25 mA to 2.25 mA, or to the highest tolerable level. Concurrently, we tracked pupil size in the left eye and gathered patients’ subjective perception scores. Individual curve fitting was used to explore the relationship between VNS intensity and PDR.
Results: PDR increased with stimulation intensity, particularly in responders. In 6 patients, an inverted U-shaped relationship between intensity and PDR was observed 2–3 s after stimulation onset. A significant interaction was found between VNS intensity and responder status, independent of subjective perception.
Conclusions: VNS induces a dose-dependent PDR, which differs between responders and non-responders. In nearly half the patients, the dose–response relationship was characterized by an inverted U-shape with a maximal VNS effect.
Significance: We propose VNS-induced PDR as a novel biomarker of VNS response.

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.

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.