Neurostimulation in People with Drug-Resistant Epilepsy: Systematic Review and Meta-Analysis from the ILAE Surgical Therapies Commission

Abstract found on Wiley Online Library


Objective: Summarize the current evidence on efficacy and tolerability of vagus nerve stimulation (VNS), responsive neurostimulation (RNS), and deep brain stimulation (DBS) through a systematic review and meta-analysis.

Methods: We followed the PRISMA reporting standards and searched Ovid Medline, Ovid Embase, and the Cochrane Central Register of Controlled Trials. We included published randomized controlled trials (RCT) and their corresponding open-label extension studies, as well as prospective case series, with ? 20 participants (excluding studies limited to children). Our primary outcome was the mean (or median when unavailable) percentage decrease in frequency, as compared to baseline, of all epileptic seizures at last follow-up. Secondary outcomes included proportion of treatment responders and proportion with seizure freedom.

Results: We identified 30 eligible studies, six of which were RCTs. At long-term follow-up (mean 1.3 years), five observational studies for VNS reported a pooled mean percentage decrease in seizure frequency of 34.7% (95% CI: -5.1, 74.5). In the open-label extension studies for RNS, the median seizure reduction was 53%, 66%, and 75% at two, five, and nine years of follow-up, respectively. For DBS, the median reduction was 56%, 65%, and 75% at two, five, and seven years, respectively. The proportion of individuals with seizure freedom at last follow-up increased significantly over time for DBS and RNS while a positive trend was observed for VNS. Quality of life was improved in all modalities. The most common complications included hoarseness, cough and throat pain for VNS and implant site pain, headache, and dysesthesia for DBS and RNS.

Significance: Neurostimulation modalities are an effective treatment option for drug resistant epilepsy, with improving outcomes over time and few major complications. Seizure reduction rates among the three therapies were similar during the initial blinded phase. Recent long-term follow-up studies are encouraging for RNS and DBS but are lacking for VNS.

Deep Learning Resting State fMRI Lateralization of Temporal Lobe Epilepsy

Abstract found on Wiley Online Library

Objective: Localization of focal epilepsy is critical for surgical treatment of refractory seizures. There remains a great need for non-invasive techniques to localize seizures for surgical decision-making. We investigate the use of deep learning using resting state functional MRI (RS-fMRI) to identify the hemisphere of seizure onset in temporal lobe epilepsy (TLE) patients.

Methods: 2132 healthy controls and 32 pre-operative TLE patients were studied. All participants underwent structural MRI and RS-fMRI. Healthy control data was used to generate training samples for a 3D convolutional neural network (3DCNN). RS-fMRI was synthetically altered in randomly lateralized regions in the healthy control participants. The model was then trained to classify the hemisphere containing synthetic noise. Finally, the model was tested on TLE patients to assess its performance for detecting biological seizure-onset zones, and gradient-weighted class activation mapping (Grad-CAM) identified the strongest predictive regions.

Results: The 3DCNN classified healthy control hemispheres known to contain synthetic noise with 96% accuracy, and TLE hemispheres clinically identified to be seizure onset zones with 90.6% accuracy. Grad-CAM identified a range of temporal, frontal, parietal, and subcortical regions that were strong anatomical predictors of the seizure onset zone, while the resting state networks which colocalized with Grad-CAM results included default mode, medial temporal, and dorsal attention networks. Lastly, in an analysis of a subset of patients with post-surgical outcomes, the 3DCNN leveraged a more focal set of regions to achieve classification in patients with Engel class > 1 compared to Engel class 1.

Significance: Non-invasive techniques capable of localizing the seizure-onset zone could improve pre-surgical planning in patients with intractable epilepsy. We have demonstrated the ability of deep learning to identify the correct hemisphere of the seizure onset zone in TLE patients using RS-fMRI with high accuracy. This approach represents a novel technique of seizure lateralization that could improve preoperative surgical planning.

Multidisciplinary Care of Patients with Inherited Metabolic Diseases and Epilepsy: Current Perspectives

Abstract found on Dovepress

Abstract: More than 650 inherited metabolic diseases may present with epilepsy or seizures. These diseases are often multisystem, life-long and induce complex needs of patients and families. Multidisciplinary care involves all stages of disease management: diagnostics, specific or symptomatic, acute and chronic treatments, and integrated care that takes into account not only medical, but also manifold psychosocial, educational, vocational and other needs of patients and their caregivers.

Care coordination is indispensable to ensure smooth transitions of care across life and disease stages, including management of emergencies, transition from pediatric to adult services and palliative care. Care pathways are highly diverse and have to find the right balance between highly specialized and locally provided services. While multidisciplinary teams consist of many professionals, a named supervising physician in a highly specialized healthcare setting and a care coordinator are highly important. As the greatest burden of care always falls onto the shoulders of patients and/or families, patient empowerment should be a part of every care pathway and include provision of required information, involvement into common decision-making, patient’s and family’s education, support for self-management, liaison with peer support groups and emotional/ psychological support. Due to the rarity and complexity of these diseases, sufficient expertise may not be available in a national healthcare system and cross-border services (virtual or physical) in the recently developed European Reference Networks should be ensured through the proper organization of referral systems in each EU and EEA country. Finally, digital technologies are particularly important in the provision of services for patients with rare diseases and can significantly increase the availability of highly specialized services and expertise.

A Near-Global Slowing of Background Activity and Epileptic Discharges in Children With Mild to Moderately Symptomatic COVID-19 Infection: An Electro-Neurophysiological Study

Abstract found in PubMed

Background: To assess the functional involvement of the central nervous system (CNS) via quantitative electroencephalography (EEG) analysis in children with mild to moderate COVID-19 infection who were otherwise previously healthy children.

Methods: This prospective, case-control study was conducted between June and September 2020. Sleep EEG records of at least 40 min were planned for children who tested positive for COVID-19 using real-time PCR analysis and within 4-6 months post-recovery. All of the EEG analyses in this study were performed on an Ubuntu 20.04.2 LTS Operating System with the developed software using Python 3.7.6. The quantitative analysis of the epileptic discharges within the EEG records was performed using random forest after elimination of the artifacts with a model training accuracy of 98% for each sample data point. The frequency analysis was performed using the Welch method.

Results: Among the age and sex-matched groups, the global mean frequency was significantly lower among the COVID-19 patients, with a P-value of 0.004. The spike slow-wave and sharp slow-wave indices were significantly higher in the patients when compared to the controls. The mean frequency values were significantly lower in almost all of the electrodes recording the frontal, central, and occipital areas. For the temporal and parietal areas, those significantly low mean frequencies were limited to the right hemisphere.

Conclusion: A near-global involvement of background activity with decreased frequency, in addition to epileptic discharges, was recorded in mild to moderately COVID-19 infected children post-infection.

Trends in Resource Utilization and Cost of Illness in Patients with Active Epilepsy in Germany from 2003 to 2020

Abstract found in Wiley Online Library

Objective: To calculate epilepsy-related direct, indirect, and total costs in adult patients with active epilepsy (ongoing unprovoked seizures) in Germany and to analyze cost components and dynamics compared to previous studies from 2003, 2008 and 2013. This analysis was part of the Epi2020 study.

Methods: Direct and indirect costs related to epilepsy were calculated with a multicenter survey using an established and validated questionnaire with a bottom-up design and human capital approach over a 3-month period in late 2020. Epilepsy-specific costs in the German health care sector from 2003, 2008 and 2013 were corrected for inflation to allow for a valid comparison.

Results: Data on the disease-specific costs for 253 patients in 2020 were analyzed. The mean total costs were calculated at € 5,551 (± € 5,805; median: € 2,611; range: € 274 to € 21,667) per three months, comprising mean direct costs of € 1,861 (± € 1,905; median: € 1,276; range: € 327 to € 13,158) and mean indirect costs of € 3,690 (± € 5,298; median: € 0; range: € 0 to € 11,925). The main direct costs components were hospitalization (42.4%), anti-seizure medication (42.2%) and outpatient care (6.2%). Productivity losses due to early retirement (53.6%), part-time work or unemployment (30.8%) and seizure-related off-days (15.6%) were the main reasons for indirect costs. However, compared to 2013, there was no significant increase of direct costs (–10.0%), and indirect costs significantly increased (p<0.028, +35.1%), resulting in a significant increase in total epilepsy-related costs (p<0.047, +20.2%). Compared to the 2013 study population, a significant increase of cost of illness could be observed (p=0.047).

Significance: The present study shows that disease-related costs in adult patients with active epilepsy increased from 2013 to 2020. As direct costs have remained constant, this increase is attributable to an increase in indirect costs. These findings highlight the impact of productivity loss caused by early retirement, unemployment, working time reduction and seizure-related days off.

A Pharmacogenomic Assessment of Psychiatric Adverse Drug Reactions to Levetiracetam (Keppra)

Abstract found in Wiley Online Library

Objective: Levetiracetam (LEV; brand name Keppra) is an effective anti-seizure medicine, but 10-20% of people treated with LEV report psychiatric side-effects and up to 1% may have psychotic episodes. Pharmacogenomic predictors of these adverse drug reactions (ADRs) have yet to be identified. We sought to determine the contribution of both common and rare genetic variation to psychiatric and behavioural ADRs associated with LEV.

Methods: This case-control study compared cases of LEV-associated behavioural disorder (n=149) or psychotic reaction (n=37) to LEV-exposed people with no history of psychiatric ADRs (n=920). All samples were of European ancestry.

We performed GWAS analysis comparing those with LEV ADRs to controls. We estimated the polygenic risk scores (PRS) for schizophrenia and compared cases with LEV-associated psychotic reaction to controls. Rare variant burden analysis was performed using exome sequence data of cases with psychotic reactions (n=18) and controls (n=122).

Results: Univariate GWAS found no significant associations with either LEV-ADR. Polygenic risk score analysis showed that cases of leviteracetam-associated psychotic reaction had an increased polygenic risk score for schizophrenia relative to controls (p = 0.0097, estimate = 0.4886). The rare-variant analysis found no evidence of an increased burden of rare genetic variants in people who had experienced LEV-associated psychotic reaction relative to controls.

Significance: The polygenic burden for schizophrenia is a risk factor for levetiracetam-associated psychotic reaction. To assess the clinical utility of polygenic risk scores as a predictor, it should be tested in an independent and ideally prospective cohort. Larger sample sizes are required for the identification of significant univariate common genetic signals or rare genetic signals associated with psychiatric levetiracetam-adverse drug reactions.

Antiseizure Medication Treatment Pathways in US Medicare Beneficiaries with Newly Treated Epilepsy

Abstract found in Wiley Online Library


Objective: To characterize antiseizure medication (ASM) treatment pathways in Medicare beneficiaries with newly treated epilepsy.

Methods: This was a retrospective cohort study using Medicare claims. Medicare is the US’s federal health insurance program for people aged 65 and older plus younger people with disabilities or end-stage renal disease. We included beneficiaries with newly treated epilepsy (International Classification of Diseases codes for epilepsy/convulsions 2014-2017, no ASM in the previous two years). We displayed the sequence of ASM fills using sunburst plots overall, then stratified by mood disorder, age, and neurologist prescriber. We tabulated drug costs for each pathway.

Results: We included 21,458 beneficiaries. Levetiracetam comprised the greatest number of pill days (56%), followed by gabapentin (11%) and valproate (8%). There were 22,288 unique treatment pathways. The most common pathways were levetiracetam monotherapy (43%), gabapentin monotherapy (10%), or valproate monotherapy (5%). Gabapentin was the most common second- and third-line ASM. Whereas only 2% of pathways involved first-line lacosamide, those pathways accounted for 19% of cost. Gabapentin and valproate use was increased and levetiracetam use was decreased in beneficiaries with mood disorders compared to beneficiaries without mood disorders. Levetiracetam use was increased and gabapentin, valproate, lamotrigine, and topiramate use was decreased in beneficiaries aged over 65 compared with those aged 65 or less. Lamotrigine, levetiracetam, and lacosamide use was increased and gabapentin use was decreased in beneficiaries whose initial prescriber was a neurologist compared to those whose prescriber was not a neurologist.

Significance: Levetiracetam (Keppra) monotherapy was the most common pathway, though substantial heterogeneity existed. Lacosamide (Vimpat) accounted for a small percent of anti-seizure medications (ASMs) but a disproportionately large share of cost. Neurologists were more like to prescribe lamotrigine (Lamictal) compared with non-neurologists, and lamotrigine was prescribed far less frequently than may be endorsed by guidelines. Future work may explore patient- and physician-driven factors underlying ASM choices.

Seizure Latency and Epilepsy Localization as Predictors of Recurrence Following Epilepsy Surgery

Abstract found in Wiley Online Library


Objective: The primary purpose is to determine if the time between epilepsy surgery and first seizure recurrence can estimate the timing of the next seizure event for temporal and extratemporal epilepsy. A secondary endpoint aimed to compare temporal and extratemporal epilepsy surgery and examine which subgroup has a higher hazard of subsequent seizure recurrence.

Methods: Data was used from a retrospective database at Thomas Jefferson University Hospital. Records were stratified into temporal (N = 943) and extratemporal (N = 125) surgeries. Analyses were done using SAS and utilized Cox-Proportional hazards models while controlling for demographics and clinical factors. The primary predictor of time between surgery and first recurrence was treated as a nominal variable binned into six segments, while secondary endpoints used a categorical predictor of epilepsy location while controlling for seizure latency.

Results: Generally, as seizure latency following surgery increased, the time between first seizure and second seizure increased. These results were statistical meaningful in the temporal set (Wald Chi Square: 40.4715, df = 5, p<0.0001). Outcomes could also be interpreted based on predictor group, for instance, if seizure one occurred between one to two months following surgery in the temporal set, the median number of days until the next seizure was 35.5 days (95% CIs: 21 – 89 days). Secondary analysis showed that temporal lobe epilepsy had a lower hazard of a second seizure than extratemporal lobe epilepsy (89.2% reduction in hazard; 95% CIs: 0.015 – 0.795).

Significance: This analysis provides a framework to use initial seizure latency to predict the median number of days until the next seizure event, while stratifying based on epilepsy location and controlling for multiple variables. It also suggests that the hazard of seizure recurrence in temporal lobe epilepsy is lower than extratemporal lobe epilepsy.

Factors Not Considered in the Study of Drug-Resistant Epilepsy: Drug-Resistant Epilepsy: Assessment of Neuroinflammation

Abstract found on Wiley Online Library


More than one-third of people with epilepsy develop drug-resistant epilepsy (DRE). Different hypotheses have been proposed to explain the origin of DRE. Accumulating evidence suggests the contribution of neuroinflammation, modifications in the integrity of the blood-brain barrier (BBB), and altered immune responses in the pathophysiology of DRE. The inflammatory response is mainly due to the increase of cytokines and related molecules; these molecules have neuromodulatory effects that contribute to hyperexcitability in neural networks that cause seizure generation. Some patients with DRE display the presence of autoantibodies in the serum and mainly cerebrospinal fluid. These patients are refractory to the different treatments with standard antiseizure medications (ASMs), and they could be responding well to immunomodulatory therapies. This observation emphasizes that the etiopathogenesis of DRE is involved with immunology responses and associated long-term events and chronic inflammation processes. Furthermore, multiple studies have shown that functional polymorphisms as risk factors are involved in inflammation processes. Several relevant polymorphisms could be considered risk factors involved in inflammation-related DRE such as receptor for advanced glycation end products (RAGE) and interleukin 1? (IL-1?). All these evidences sustained the hypothesis that the chronic inflammation process is associated with the DRE. However, the effect of the chronic inflammation process should be investigated in further clinical studies to promote the development of novel therapeutics useful in treatment of DRE.

Multimodal Prognostic Features of Seizure Freedom in Epilepsy Surgery

Abstract found in DocWire News

OBJECTIVE: Accurate preoperative predictions of seizure freedom following surgery for focal drug resistant epilepsy remain elusive. Our objective was to systematically evaluate all meta-analyses of epilepsy surgery with seizure freedom as the primary outcome, to identify clinical features that are consistently prognostic and should be included in the future models.

METHODS: We searched PubMed and Cochrane using free-text and Medical Subject Heading (MeSH) terms according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses. This study was registered on PROSPERO. We classified features as prognostic, non-prognostic and uncertain and into seven subcategories: ‘clinical’, ‘imaging’, ‘neurophysiology’, ‘multimodal concordance’, ‘genetic’, ‘surgical technique’ and ‘pathology’. We propose a structural causal model based on these features.

RESULTS: We found 46 features from 38 meta-analyses over 22 years. The following were consistently prognostic across meta-analyses: febrile convulsions, hippocampal sclerosis, focal abnormal MRI, Single-Photon Emission Computed Tomography (SPECT) coregistered to MRI, focal ictal/interictal EEG, EEG-MRI concordance, temporal lobe resections, complete excision, histopathological lesions, tumours and focal cortical dysplasia type IIb. Severe learning disability was predictive of poor prognosis. Others, including sex and side of resection, were non-prognostic. There were limited meta-analyses investigating genetic contributions, structural connectivity or multimodal concordance and few adjusted for known confounders or performed corrections for multiple comparisons.

SIGNIFICANCE: Seizure-free outcomes have not improved over decades of epilepsy surgery and despite a multitude of models, none prognosticate accurately. Our list of multimodal population-invariant prognostic features and proposed structural causal model may serve as an objective foundation for statistical adjustments of plausible confounders for use in high-dimensional models.