Louis Wagner

The long-term effect of vagus nerve stimulation on quality of life in patients with pharmacoresistant focal epilepsy: The PuLsE (Open Prospective Randomized Long-term Effectiveness) trial

To evaluate whether vagus nerve stimulation (VNS) as adjunct to best medical practice (VNS + BMP) is superior to BMP alone in improving long‐term health‐related quality of life (HRQoL).

A prospective, multicenter study of cardiac-based seizure detection to activate vagus nerve stimulation.

PURPOSE This study investigates the performance of a cardiac-based seizure detection algorithm (CBSDA) that automatically triggers VNS (NCT01325623). METHODS Thirty-one patients with drug resistant epilepsy were evaluated in an epilepsy monitoring unit (EMU) to assess algorithm performance and near-term clinical benefit. Long-term efficacy and safety were evaluated with combined open and closed-loop VNS. RESULTS Sixty-six seizures (n=16 patients) were available from the EMU for analysis. In 37 seizures (n=14 patients) a ≥ 20% heart rate increase was found and 11 (n=5 patients) were associated with ictal tachycardia (iTC, 55% or 35 bpm heart rate increase, minimum of 100 bpm). Multiple CBSDA settings achieved a sensitivity of ≥ 80%. False positives ranged from 0.5 to 7.2/h. 27/66 seizures were stimulated within ± 2 min of seizure onset. In 10/17 of these seizures, where triggered VNS overlapped with ongoing seizure activity, seizure activity stopped during stimulation. Physician-scored seizure severity (NHS3-scale) showed significant improvement for complex partial seizures (CPS) at EMU discharge and through 12 months (p<0.05). Patient-scored seizure severity (total SSQ score) showed significant improvement at 3 and 6 months. Quality of life (total QOLIE-31-P score) showed significant improvement at 12 months. The responder rate (≥ 50% reduction in seizure frequency) at 12 months was 29.6% (n=8/27). Safety profiles were comparable to prior VNS trials. CONCLUSIONS The investigated CBSDA has a high sensitivity and an acceptable specificity for triggering VNS. Despite the moderate effects on seizure frequency, combined open- and closed-loop VNS may provide valuable improvements in seizure severity and QOL in refractory epilepsy patients.

Evaluating Contextual Processing in Diffusion MRI: Application to Optic Radiation Reconstruction for Epilepsy Surgery

Diffusion MRI and tractography allow for investigation of the architectural configuration of white matter in vivo, offering new avenues for applications like presurgical planning. Despite the promising outlook, there are many pitfalls that complicate its use for (clinical) application. Amongst these are inaccuracies in the geometry of the diffusion profiles on which tractography is based, and poor alignment with neighboring profiles. Recently developed contextual processing techniques, including enhancement and well-posed geometric sharpening, have shown to result in sharper and better aligned diffusion profiles. However, the research that has been conducted up to now is mainly of theoretical nature, and so far these techniques have only been evaluated by visual inspection of the diffusion profiles. In this work, the method is evaluated in a clinically relevant application: the reconstruction of the optic radiation for epilepsy surgery. For this evaluation we have developed a framework in which we incorporate a novel scoring procedure for individual pathways. We demonstrate that, using enhancement and sharpening, the extraction of an anatomically plausible reconstruction of the optic radiation from a large amount of probabilistic pathways is greatly improved in three healthy controls, where currently used methods fail to do so. Furthermore, challenging reconstructions of the optic radiation in three epilepsy surgery candidates with extensive brain lesions demonstrate that it is beneficial to integrate these methods in surgical planning.

Stability metrics for optic radiation tractography: towards damage prediction after resective surgery

Highlights • The alignment of streamlines is quantified by fiber-to-bundle coherence measures.• Reliable ML-TP distance measurement by removal of spurious (deviating) streamlines.• Parameter estimation to remove spurious streamlines and to retain the Meyers loop.• The validity of ML-TP distance is estimated by pre and postoperative OR comparisons.• The stability metrics are promising to relate OR damage to a visual field deficit.

Deep brain stimulation of the anterior nucleus of the thalamus for drug-resistant epilepsy

Despite the use of first-choice anti-epileptic drugs and satisfactory seizure outcome rates after resective epilepsy surgery, a considerable percentage of patients do not become seizure free. ANT-DBS may provide for an alternative treatment option in these patients. This literature review discusses the rationale, mechanism of action, clinical efficacy, safety, and tolerability of ANT-DBS in drug-resistant epilepsy patients. A review using systematic methods of the available literature was performed using relevant databases including Medline, Embase, and the Cochrane Library pertaining to the different aspects ANT-DBS. ANT-DBS for drug-resistant epilepsy is a safe, effective and well-tolerated therapy, where a special emphasis must be given to monitoring and neuropsychological assessment of both depression and memory function. Three patterns of seizure control by ANT-DBS are recognized, of which a delayed stimulation effect may account for an improved long-term response rate. ANT-DBS remotely modulates neuronal network excitability through overriding pathological electrical activity, decrease neuronal cell loss, through immune response inhibition or modulation of neuronal energy metabolism. ANT-DBS is an efficacious treatment modality, even when curative procedures or lesser invasive neuromodulative techniques failed. When compared to VNS, ANT-DBS shows slightly superior treatment response, which urges for direct comparative trials. Based on the available evidence ANT-DBS and VNS therapies are currently both superior compared to non-invasive neuromodulation techniques such as t-VNS and rTMS. Additional in-vivo research is necessary in order to gain more insight into the mechanism of action of ANT-DBS in localization-related epilepsy which will allow for treatment optimization. Randomized clinical studies in search of the optimal target in well-defined epilepsy patient populations, will ultimately allow for optimal patient stratification when applying DBS for drug-resistant patients with epilepsy.

Automated identification of intracranial depth electrodes in computed tomography data

Intracranial depth electrodes are commonly used to identify the regions of the brain that are responsible for epileptic seizures. Knowledge of the exact location of the electrodes is important as to properly interpret the EEG in relation to the anatomy. In order to provide fast and accurate identification of these electrodes, a procedure has been developed for automatic detection and localization in computed tomography data. Results indicate that in the vast majority of cases the depth electrodes can be automatically found. The localization of the electrodes versus the anatomy showed an acceptably small error when compared to manual positioning. Furthermore, interactive visualization software is developed to show the detected electrodes together with pre-operative MRI images, which enables the physician to confirm that the electrode is placed at the expected anatomical location.

Modeling of intracerebral interictal epileptic discharges: Evidence for network interactions

OBJECTIVE The interictal epileptic discharges (IEDs) occurring in stereotactic EEG (SEEG) recordings are in general abundant compared to ictal discharges, but difficult to interpret due to complex underlying network interactions. A framework is developed to model these network interactions. METHODS To identify the synchronized neuronal activity underlying the IEDs, the variation in correlation over time of the SEEG signals is related to the occurrence of IEDs using the general linear model. The interdependency is assessed of the brain areas that reflect highly synchronized neural activity by applying independent component analysis, followed by cluster analysis of the spatial distributions of the independent components. The spatiotemporal interactions of the spike clusters reveal the leading or lagging of brain areas. RESULTS The analysis framework was evaluated for five successfully operated patients, showing that the spike cluster that was related to the MRI-visible brain lesions coincided with the seizure onset zone. The additional value of the framework was demonstrated for two more patients, who were MRI-negative and for whom surgery was not successful. CONCLUSIONS A network approach is promising in case of complex epilepsies. SIGNIFICANCE Analysis of IEDs is considered a valuable addition to routine review of SEEG recordings, with the potential to increase the success rate of epilepsy surgery.

Long-term drug-resistant temporal lobe epilepsy associated with a mixed ganglioglioma and dysembryoplastic neuroepithelial tumor in an elderly patient

Background: Mixed ganglioglioma and dysembryoplastic neuroepithelial tumor (DNET) is an extremely rare neuropathological diagnosis. The sparse number of patients described are children or young adults with long-term drug-resistant epilepsy. Case Description: We report on a rare case of this tumor in a 61-year-old patient with an epilepsy duration of almost 60 years. This patient received an epilepsy surgery work-up with the intention to cure his drug-resistant epilepsy by performing a complete lesionectomy. The available literature on these mixed tumors is reviewed. Conclusion: A contrast-enhancing mixed ganglioglioma and DNET can mimic a malignant tumor and appears not only in children and young adults, but also in the elderly patients with chronic epilepsy. A long-lasting epilepsy, in this case almost 60 years, can be completely cured by a complete lesionectomy.

Deterioration of dyslexia after non-dominant temporal lobectomy for drug-resistant epilepsy

We present a patient with drug-resistant right-sided temporal lobe epilepsy, caused by a ganglioglioma of the parahippocampal gyrus. Preoperatively, the patient was also known to have dyslexia. A right-sided anterior temporal lobectomy, including complete lesionectomy, was performed. Several months after the otherwise uncomplicated procedure, the patient complained about visual memory disturbances, accompanied by increased reading and spelling problems. Postoperative neuropsychological examination revealed deterioration of the visual memory functions, compared to the preoperative assessment, and consequently provided a possible explanation for worsening of the pre-existing dyslexia. In this case report, we hypothesize on the cause of this unusual deterioration and present recommendations to be included in the preoperative epilepsy surgery evaluation for patients with verbal or reading disorders such as dyslexia.

Single cell firing patterns in the anterior nucleus of the thalamus relate to therapy response in deep brain stimulation for refractory epilepsy

Introduction: Patients with medically refractory epilepsy treated with deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) vary highly in their therapy response. Proper positioning of the DBS lead is crucial to maximize efficacy and minimize side effects. For a correct implantation, the ANT is anatomically located using pre-operative 3T MRI and perioperative microelectrode recordings (MER). Neurons in the ANT have highly variable, yet characteristic patterns of firing in bursts. During DBS lead implantation, we noted differences among patients’ characteristic burst patterns along the electrode trajectory. In this study, we investigate whether electrophysiological characteristics of the target region could predict therapy response to DBS and could thus be used to improve ANT targeting during DBS surgery. Objectives: To determine whether perioperative neurophysiological characteristics relate to therapy response in DBS for patients with medically refractory epilepsy. Patients and methods: We included ten consecutive epilepsy patients planned for DBS surgery at Maastricht University Medical Center. All patients were diagnosed with medically refractory epilepsy and had incapacitating seizures. Patients failed trials of at least two reasonably tolerated and adequately chosen antiepileptic drug schedules. Using pre-operative 3T MRI, we planned an extraventricular approach to target. The ANT was defined as a grey matter structure at the top of the mamillothalamic tract. Along this trajectory, we performed stereotactic single cell MERs. The anatomical location of the recordings were verified using preoperative 3T MR images. We compared characteristics of the neural signals at different depths along the trajectory between DBS responders and non-responders. Responders were defined as patients with a seizure frequency reduction of more than 50% at one year follow-up. Results: Using MER data from 19 electrode trajectories of ten patients (one unilateral and nine bilateral trajectories), we found high-amplitude neuronal bursts around the target area or ANT. Responders to DBS (n = 5) had higher normalized mean firing rates and mean burst rates near the target area compared to non-responders (n = 5), with a clearer delineation between the target region and surroundings. Electrode trajectories and lead localization did not differ between responders and non-responders. Conclusion: Single cell firing patterns in the ANT relate to therapy response in DBS for patients with medically refractory epilepsy. Analysis of single cell firing patterns using MER may guide targeting or contribute to predicting therapy response to ANT DBS. Further exploration into the use of electrophysiological recordings is warranted to improve targeting or predict outcome in DBS for epilepsy patients.