Efficacy and safety of VNS therapy or continued medication management for treatment of adults with drug-resistant epilepsy: systematic review and meta-analysis

Vagus nerve stimulation (VNS) Therapy® is an adjunctive neurostimulation treatment for people with drug-resistant epilepsy (DRE) who are unwilling to undergo resective surgery, have had unsuccessful surgery or are unsuitable for surgery. A systematic review and meta-analysis were conducted to determine the treatment effects of VNS Therapy as an adjunct to anti-seizure medications (ASMs) for the management of adults with DRE. A literature search was performed in August 2020 of the Medline®, Medline® Epub Ahead of Print, Embase, and the Cochrane library databases. Outcomes examined included reduction in seizure frequency, seizure freedom, ASM load, discontinuations, and serious adverse events (SAEs). Comparators included best medical practice, ASMs, low-stimulation or sham VNS Therapy. Four RCTs and six comparative observational studies were identified for inclusion. Against comparators, individuals treated with VNS had a significantly better odds of experiencing a ≥ 50% reduction in seizure frequency (OR: 2.27 [95% CI 1.47, 3.51]; p = 0.0002), a ≥ 75% reduction in seizure frequency (OR: 3.56 [95% CI 1.59, 7.98]; p = 0.002) and a reduced risk for increased ASM load (risk ratio: 0.36 [95% CI 0.21, 0.62]; p = 0.0002). There was no difference in the odds of discontinuation or the rate of SAEs between VNS versus comparators. This meta-analysis demonstrated the benefits of VNS Therapy in people with DRE, which included improvement in seizure frequency without an increase in the rate of SAEs or discontinuations, thereby supporting the consideration of VNS Therapy for people who are not responding to ASMs and those unsuitable or unwilling to undergo surgery.

Validating EEG, MEG and Combined MEG and EEG Beamforming for an Estimation of the Epileptogenic Zone in Focal Cortical Dysplasia

MEG and EEG source analysis is frequently used for the presurgical evaluation of pharmacoresistant epilepsy patients. The source localization of the epileptogenic zone depends, among other aspects, on the selected inverse and forward approaches and their respective parameter choices. In this validation study, we compare the standard dipole scanning method with two beamformer approaches for the inverse problem, and we investigate the influence of the covariance estimation method and the strength of regularization on the localization performance for EEG, MEG, and combined EEG and MEG. For forward modelling, we investigate the difference between calibrated six-compartment and standard three-compartment head modelling. In a retrospective study, two patients with focal epilepsy due to focal cortical dysplasia type IIb and seizure freedom following lesionectomy or radiofrequency-guided thermocoagulation (RFTC) used the distance of the localization of interictal epileptic spikes to the resection cavity resp. RFTC lesion as reference for good localization. We found that beamformer localization can be sensitive to the choice of the regularization parameter, which has to be individually optimized. Estimation of the covariance matrix with averaged spike data yielded more robust results across the modalities. MEG was the dominant modality and provided a good localization in one case, while it was EEG for the other. When combining the modalities, the good results of the dominant modality were mostly not spoiled by the weaker modality. For appropriate regularization parameter choices, the beamformer localized better than the standard dipole scan. Compared to the importance of an appropriate regularization, the sensitivity of the localization to the head modelling was smaller, due to similar skull conductivity modelling and the fixed source space without orientation constraint.

Electroclinical and Multimodality Neuroimaging Characteristics and Predictors of Post-Surgical Outcome in Focal Cortical Dysplasia Type IIIa

Focal cortical dysplasia (FCD) type IIIa is an easily ignored cause of intractable temporal lobe epilepsy. This study aimed to analyze the clinical, electrophysiological, and imaging characteristics in FCD type IIIa and to search for predictors associated with postoperative outcome in order to identify potential candidates for epilepsy surgery. We performed a retrospective review including sixty-six patients with FCD type IIIa who underwent resection for drug-resistant epilepsy. We evaluated the clinical, electrophysiological, and neuroimaging features for potential association with seizure outcome. Univariate and multivariate analyses were conducted to explore their predictive role on the seizure outcome. We demonstrated that thirty-nine (59.1%) patients had seizure freedom outcomes (Engel class Ia) with a median postsurgical follow-up lasting 29.5 months. By univariate analysis, duration of epilepsy (less than 12 years) (p = 0.044), absence of contralateral insular lobe hypometabolism on PET/MRI (pLog-rank = 0.025), and complete resection of epileptogenic area (pLog-rank = 0.004) were associated with seizure outcome. The incomplete resection of the epileptogenic area (hazard ratio = 2.977, 95% CI 1.218–7.277, p = 0.017) was the only independent predictor for seizure recurrence after surgery by multivariate analysis. The results of past history, semiology, electrophysiological, and MRI were not associated with seizure outcomes. Carefully included patients with FCD type IIIa through a comprehensive evaluation of their clinical, electrophysiological, and neuroimaging characteristics can be good candidates for resection. Several preoperative factors appear to be predictive of the postoperative outcome and may help in optimizing the selection of ideal candidates to benefit from epilepsy surgery.

Value of ultra-high field MRI in patients with suspected focal epilepsy and negative 3 T MRI (EpiUltraStudy): protocol for a prospective, longitudinal therapeutic study

Purpose Resective epilepsy surgery is a well-established, evidence-based treatment option in patients with drug-resistant focal epilepsy. A major predictive factor of good surgical outcome is visualization and delineation of a potential epileptogenic lesion by MRI. However, frequently, these lesions are subtle and may escape detection by conventional MRI (≤ 3 T). Methods We present the EpiUltraStudy protocol to address the hypothesis that application of ultra-high field (UHF) MRI increases the rate of detection of structural lesions and functional brain aberrances in patients with drug-resistant focal epilepsy who are candidates for resective epilepsy surgery. Additionally, therapeutic gain will be addressed, testing whether increased lesion detection and tailored resections result in higher rates of seizure freedom 1 year after epilepsy surgery. Sixty patients enroll the study according to the following inclusion criteria: aged ≥ 12 years, diagnosed with drug-resistant focal epilepsy with a suspected epileptogenic focus, negative conventional 3 T MRI during pre-surgical work-up. Results All patients will be evaluated by 7 T MRI; ten patients will undergo an additional 9.4 T MRI exam. Images will be evaluated independently by two neuroradiologists and a neurologist or neurosurgeon. Clinical and UHF MRI will be discussed in the multidisciplinary epilepsy surgery conference. Demographic and epilepsy characteristics, along with postoperative seizure outcome and histopathological evaluation, will be recorded. Conclusion This protocol was reviewed and approved by the local Institutional Review Board and complies with the Declaration of Helsinki and principles of Good Clinical Practice. Results will be submitted to international peer-reviewed journals and presented at international conferences. Trial registration number www.trialregister.nl: NTR7536.

Efficacy and Safety of VNS Therapy or Continued Medication Management for Treatment of Adults with Drug-Resistant Epilepsy: Systematic Review and Meta-Analysis

Vagus nerve stimulation (VNS) Therapy® is an adjunctive neurostimulation treatment for people withdrug-resistant epilepsy (DRE) who are unwilling to undergo resective surgery, have had unsuccessfulsurgery or are unsuitable for surgery. A systematic review and meta-analysis were conducted todetermine the treatment effects of VNS Therapy as an adjunct to anti-seizure medications (ASMs) forthe management of adults with DRE.A literature search was performed in August 2020 of the Medline®, Medline® Epub Ahead of Print,Embase, and the Cochrane library databases. Outcomes examined included reduction in seizurefrequency, seizure freedom, ASM load, discontinuations, and serious adverse events (SAEs).Comparators included best medical practice, ASMs, low-stimulation or sham VNS Therapy.Four RCTs and six comparative observational studies were identified for inclusion. Against comparators,individuals treated with VNS had a significantly better odds of experiencing a ≥50% reduction in seizurefrequency (OR: 2.27 [95% CI: 1.47, 3.51]; p=0.0002), a ≥75% reduction in seizure frequency (OR: 3.56[95% CI: 1.59, 7.98]; p=0.002) and a reduced risk for increased ASM load (risk ratio: 0.36 [95% CI: 0.21,0.62]; p=0.0002). There was no difference in the odds of discontinuation or the rate of SAEs betweenVNS versus comparators.This meta-analysis demonstrated the benefits of VNS Therapy in people with DRE, which includedimprovement in seizure frequency without an increase in the rate of SAEs or discontinuations, therebysupporting the consideration of VNS Therapy for people who are not responding to ASMs and thoseunsuitable or unwilling to undergo surgery.

Social Media Analytics for Pharmacovigilance of Antiepileptic Drugs

Epilepsy is a common neurological disorder worldwide and antiepileptic drug (AED) therapy is the cornerstone of its treatment. It has a laudable aim of achieving seizure freedom with minimal, if any, adverse drug reactions (ADRs). Too often, AED treatment is a long-lasting journey, in which ADRs have a crucial role in its administration. Therefore, from a pharmacovigilance perspective, detecting the ADRs of AEDs is a task of utmost importance. Typically, this task is accomplished by analyzing relevant data from spontaneous reporting systems. Despite their wide adoption for pharmacovigilance activities, the passiveness and high underreporting ratio associated with spontaneous reporting systems have encouraged the consideration of other data sources such as electronic health databases and pharmaceutical databases. Social media is the most recent alternative data source with many promising potentials to overcome the shortcomings of traditional data sources. Although in the literature some attempts have investigated the validity and utility of social media for ADR detection of different groups of drugs, none of them was dedicated to the ADRs of AEDs. Hence, this paper presents a novel investigation of the validity and utility of social media as an alternative data source for the detection of AED ADRs. To this end, a dataset of consumer reviews from two online health communities has been collected. The dataset is preprocessed; the unigram, bigram, and trigram are generated; and the ADRs of each AED are extracted with the aid of consumer health vocabulary and ADR lexicon. Three widely used measures, namely, proportional reporting ratio, reporting odds ratio, and information component, are used to measure the association between each ADR and AED. The resulting list of signaled ADRs for each AED is validated against a widely used ADR database, called Side Effect Resource, in terms of the precision of ADR detection. The validation results indicate the validity of online health community data for the detection of AED ADRs. Furthermore, the lists of signaled AED ADRs are analyzed to answer questions related to the common ADRs of AEDs and the similarities between AEDs in terms of their signaled ADRs. The consistency of the drawn answers with the existing pharmaceutical knowledge suggests the utility of the data from online health communities for AED-related knowledge discovery tasks.

Non-thermal Electroporation Ablation of Epileptogenic Zones Stops Seizures in Mice While Providing Reduced Vascular Damage and Accelerated Tissue Recovery

In epilepsy, the most frequent surgical procedure is the resection of brain tissue in the temporal lobe, with seizure-free outcomes in approximately two-thirds of cases. However, consequences of surgery can vary strongly depending on the brain region targeted for removal, as surgical morbidity and collateral damage can lead to significant complications, particularly when bleeding and swelling are located near delicate functional cortical regions. Although focal thermal ablations are well-explored in epilepsy as a minimally invasive approach, hemorrhage and edema can be a consequence as the blood-brain barrier is still disrupted. Non-thermal irreversible electroporation (NTIRE), common in many other medical tissue ablations outside the brain, is a relatively unexplored method for the ablation of neural tissue, and has never been reported as a means for ablation of brain tissue in the context of epilepsy. Here, we present a detailed visualization of non-thermal ablation of neural tissue in mice and report that NTIRE successfully ablates epileptic foci in mice, resulting in seizure-freedom, while causing significantly less hemorrhage and edema compared to conventional thermal ablation. The NTIRE approach to ablation preserves the blood-brain barrier while pathological circuits in the same region are destroyed. Additionally, we see the reinnervation of fibers into ablated brain regions from neighboring areas as early as day 3 after ablation. Our evidence demonstrates that NTIRE could be utilized as a precise tool for the ablation of surgically challenging epileptogenic zones in patients where the risk of complications and hemorrhage is high, allowing not only reduced tissue damage but potentially accelerated recovery as vessels and extracellular matrix remain intact at the point of ablation.

Efficacy and Safety of VNS Therapy or Continued Medication Management for Treatment of Adults with Drug-Resistant Epilepsy: Systematic Review and Meta-Analysis

Vagus nerve stimulation (VNS) Therapy® is an adjunctive neurostimulation treatment for people withdrug-resistant epilepsy (DRE) who are unwilling to undergo resective surgery, have had unsuccessfulsurgery or are unsuitable for surgery. A systematic review and meta-analysis were conducted todetermine the treatment effects of VNS Therapy as an adjunct to anti-seizure medications (ASMs) forthe management of adults with DRE.A literature search was performed in August 2020 of the Medline®, Medline® Epub Ahead of Print,Embase, and the Cochrane library databases. Outcomes examined included reduction in seizurefrequency, seizure freedom, ASM load, discontinuations, and serious adverse events (SAEs).Comparators included best medical practice, ASMs, low-stimulation or sham VNS Therapy.Four RCTs and six comparative observational studies were identified for inclusion. Against comparators,individuals treated with VNS had a significantly better odds of experiencing a ≥50% reduction in seizurefrequency (OR: 2.27 [95% CI: 1.47, 3.51]; p=0.0002), a ≥75% reduction in seizure frequency (OR: 3.56[95% CI: 1.59, 7.98]; p=0.002) and a reduced risk for increased ASM load (risk ratio: 0.36 [95% CI: 0.21,0.62]; p=0.0002). There was no difference in the odds of discontinuation or the rate of SAEs betweenVNS versus comparators.This meta-analysis demonstrated the benefits of VNS Therapy in people with DRE, which includedimprovement in seizure frequency without an increase in the rate of SAEs or discontinuations, therebysupporting the consideration of VNS Therapy for people who are not responding to ASMs and thoseunsuitable or unwilling to undergo surgery.

Neuromodulation for Refractory Epilepsy

Three neuromodulation therapies, all using implanted device and electrodes, have been approved to treat adults with drug-resistant focal epilepsy, namely, the vagus nerve stimulation in 1995, deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) in 2018 (2010 in Europe), and responsive neurostimulation (RNS) in 2014. Indications for VNS have more recently extended to children down to age of 4. Limited or anecdotal data are available in other epilepsy syndromes and refractory/super-refractory status epilepticus. Overall, neuromodulation therapies are palliative, with only a minority of patients achieving long-term seizure freedom, justifying favoring such treatments in patients who are not good candidates for curative epilepsy surgery. About half of patients implanted with VNS, ANT-DBS, and RNS have 50% or greater reduction in seizures, with long-term data suggesting increased efficacy over time. Besides their impact on seizure frequency, neuromodulation therapies are associated with various benefits and drawbacks in comparison to antiseizure drugs. Yet, we lack high-level evidence to best position each neuromodulation therapy in the treatment pathways of persons with difficult-to-treat epilepsy.

Variations in Seizure Frequency During Pregnancy and Postpartum by Epilepsy Type

Objective:To assess whether increased seizure frequency during pregnancy and post-partum is influenced by epilepsy type, seizure location, and antiseizure medications.Methods:Clinical data was collected in a longitudinal prospective database of pregnant women with epilepsy at Brigham and Women’s Hospital. Within each individual participant, baseline seizure frequency was calculated for the 9 months preconception, and it was determined if seizure frequency increased during pregnancy or the postpartum period. Seizure frequency was calculated for each 4-week interval during pregnancy. Generalized estimating equations for logistic regression were applied.Results:Ninety-nine patients contributing 114 pregnancies were included from 2013-2018. Increased seizure frequency occurred more often during pregnancies of women with focal versus generalized epilepsy (21.1% vs 5.3%, OR 4.70; 95% CI (1.00, 22.00); p = 0.0497). Among women with focal epilepsy, increased seizure frequency occurred more often in those with frontal lobe epilepsy (OR 8.00; 95 % CI (2.19, 29.21); p = 0.0017). There was no difference in seizure worsening in the postpartum period between focal and generalized (11.1% vs 9.1%, p=0.4478), or frontal and other focal (18.8% vs 6.0%; p=0.1478) epilepsy groups. Pregnancies on polytherapy had higher odds of seizure worsening compared to monotherapy (OR = 8.36, 95% CI = (2.07, 33.84), p = 0.0029), regardless of the medication or epilepsy type. A lack of preconception seizure freedom was also associated with increased seizure frequency during pregnancy (OR = 6.418; p = 0.0076).Conclusion:Women with focal epilepsy have higher likelihood of seizure worsening during pregnancy compared to women with generalized epilepsy; frontal lobe epilepsy poses an especially elevated risk. Polytherapy and lack of preconception seizure freedom are additional predictors for an increased likelihood of seizure worsening.