Around 70% of patients with epilepsy respond to antiepileptic drugs.1 For patients who do not respond, surgery is an accepted treatment option.2 Seizure recurrence after resection is seen in 30-70% ...of patients and follows predictable slopes based on multiple factors, including the duration of epilepsy, history of generalised tonic seizures, frequency of preoperative seizures, and the presumptive pathological cause of epilepsy on MRI.3 Half of treatment failures after surgery lead to early recurrence of seizures, generally because of mislocalisation of seizure onset or incomplete resection of the epileptogenic substrate.4 Reccurrence of seizures later than 6 months after surgery is probably due to proepileptic cortical pathology that was unidentified in the presurgical assessment.4,5 In The Lancet Neurology, Dennis Spencer and colleagues6 discuss in a Personal View the possible roles of overlapping brain networks in focal epilepsy and its psychiatric comorbidities (eg, depression and anxiety). Visual analysis of recorded ictal patterns does not clearly identify the epileptogenic substrate, but it can be delineated by mathematical signal processing methods.7 Once validated as reliable predictors of the epileptogenic substrate, these signal processing methods will enable not only localisation of epileptogenic substrate but also testing of the hypothesis that epileptogenicity is distributed across an epileptic network. A study using single-cell gene mapping in malformations of cortical development showed somatic mutations in the mammalian target of rapamycin (mTOR) pathway in, for example, focal cortical dysplasia.8 These mutations result in the activation of the mTOR pathway that leads to synaptogenesis and play an important part in epileptogenesis.8 Similar findings for other mutations might lead to the design of highly efficacious disease-modifying drugs.
Summary
Objective
Recent evidence suggests a metabolic contribution of cytochrome P450 enzymes (CYPs) to the drug‐resistant phenotype in human epilepsy. However, the upstream molecular regulators of ...CYP in the epileptic brain remain understudied. We therefore investigated the expression and function of pregnane xenobiotic (PXR) and glucocorticoid (GR) nuclear receptors in endothelial cells established from post‐epilepsy surgery brain samples.
Methods
PXR/GR localization was evaluated by immunohistochemistry in specimens from subjects who underwent temporal lobe resections to relieve drug‐resistant seizures. We used primary cultures of endothelial cells obtained from epileptic brain tissues (EPI‐ECs; n = 8), commercially available human brain microvascular endothelial cells (HBMECs; n = 8), and human hepatocytes (n = 3). PXR/GR messenger RNA (mRNA) levels in brain ECs was initially determined by complementary DNA (cDNA) microarrays. The expression of PXR/GR proteins was quantified by Western blot. PXR and GR silencing was performed in EPI‐ECs (n = 4), and the impact on downstream CYP expression was determined.
Results
PXR/GR expression was detected by immunofluorescence in ECs and neurons in the human temporal lobe samples analyzed. Elevated mRNA and protein levels of PXR and GR were found in EPI‐ECs versus control HBMECs. Hepatocytes, used as a positive control, displayed the highest levels of PXR/GR expression. We confirmed expression of PXR/GR in cytoplasmic‐nuclear subcellular fractions, with a significant increase of PXR/GR in EPI‐ECs versus controls. CYP3A4, CYP2C9, and CYP2E1 were overexpressed in EPI‐ECs versus control, whereas CYP2D6 and CYP2C19 were downregulated or absent in EPI‐ECs. GR silencing in EPI‐ECs led to decreased CYP3A4, CYP2C9, and PXR expression. PXR silencing in EPI‐ECs resulted in the specific downregulation of CYP3A4 expression.
Significance
Our results indicate increased PXR and GR in primary ECs derived from human epileptic brains. PXR or GR may be responsible for a local drug brain metabolism sustained by abnormal CYP regulation.
Summary
Objective
Stereo‐electroencephalography (SEEG) is a procedure performed for patients with intractable epilepsy in order to anatomically define the epileptogenic zone (EZ) and the possible ...related functional cortical areas. By avoiding the need for large craniotomies and due to its intrinsic precision placement features, SEEG may be associated with fewer complications. Nevertheless, intracerebral electrodes have gained a reputation of excessive invasiveness, with a “relatively high morbidity” associated with their placement. A systematic literature review and meta‐analysis of SEEG complications has not been previously performed. The goal of this study is to quantitatively review the incidence of various surgical complications associated with SEEG electrode implantation in the literature and to provide a summary estimate. This will allow physicians to accurately counsel their patients about the potential complications related to this method of extraoperative invasive monitoring.
Methods
The systematic review was conducted following Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA). We conducted MEDLINE, Scopus, and Web of Science database searches with the search algorithm. We analyzed complication rates using a fixed‐effects model with inverse variance weighting. Calculations for the meta‐analysis and construction of forest plots were completed using an established spreadsheet. The principal summary measures were the effect summary value and 95% confidence intervals (CIs).
Results
The initial 1,901 retrieved citations were reviewed. After removing 787 duplicates, the titles and s of 1,114 publications were screened. At this stage, studies that did not mention the absence or presence of complications following SEEG or that did not fulfill the inclusion criteria in any manner were excluded. After excluding 1,057 citations, the full text was assessed in the resulting 57 articles for eligibility criteria. The most common complications were hemorrhagic (pooled prevalence 1.0%, 95% confidence interval CI 0.6–1.4%) or infectious (pooled prevalence 0.8%, 95% CI 0.3–1.2%). Five mortalities were identified (pooled prevalence 0.3%, 95% CI −0.1–0.6%). Overall, our analysis identified 121 surgical complications related to SEEG insertion and monitoring (pooled prevalence 1.3%, 95% CI 0.9–1.7%).
Significance
This review represents a comprehensive estimation of the actual incidence of complications related to SEEG. We report a rate substantially lower than the complication rates reported for other methods of extraoperative invasive monitoring. These data should alleviate the concerns of some regarding the safety of the “stereotactic” method, allowing a better decision process among the different methods of invasive monitoring and ameliorating the fear associated with the placement of depth electrodes.
The
PER
a
M
panel pooled analys
I
s of effec
T
iveness and tolerability (PERMIT) study was a pooled analysis of data from 44 real-world studies from 17 countries, in which people with epilepsy (PWE; ...focal and generalized) were treated with perampanel (PER). Retention and effectiveness were assessed after 3, 6, and 12 months, and at the last visit (last observation carried forward). Effectiveness assessments included 50% responder rate (≥ 50% reduction in seizure frequency from baseline) and seizure freedom rate (no seizures since at least the prior visit); in PWE with status epilepticus, response was defined as seizures under control. Safety and tolerability were assessed by evaluating adverse events (AEs) and discontinuation due to AEs. The Full Analysis Set included 5193 PWE. Retention, effectiveness and safety/tolerability were assessed in 4721, 4392 and 4617, respectively. Retention on PER treatment at 3, 6, and 12 months was 90.5%, 79.8%, and 64.2%, respectively. Mean retention time on PER treatment was 10.8 months. The 50% responder rate was 58.3% at 12 months and 50.0% at the last visit, and the corresponding seizure freedom rates were 23.2% and 20.5%, respectively; 52.7% of PWE with status epilepticus responded to PER treatment. Overall, 49.9% of PWE reported AEs and the most frequently reported AEs (≥ 5% of PWE) were dizziness/vertigo (15.2%), somnolence (10.6%), irritability (8.4%), and behavioral disorders (5.4%). At 12 months, 17.6% of PWEs had discontinued due to AEs. PERMIT demonstrated that PER is effective and generally well tolerated when used to treat people with focal and/or generalized epilepsy in everyday clinical practice.
We investigated how pathological changes in newborn hippocampal dentate granule cells (DGCs) lead to epilepsy. Using a rabies virus-mediated retrograde tracing system and a designer receptors ...exclusively activated by designer drugs (DREADD) chemogenetic method, we demonstrated that newborn hippocampal DGCs are required for the formation of epileptic neural circuits and the induction of spontaneous recurrent seizures (SRS). A rabies virus-mediated mapping study revealed that aberrant circuit integration of hippocampal newborn DGCs formed excessive de novo excitatory connections as well as recurrent excitatory loops, allowing the hippocampus to produce, amplify, and propagate excessive recurrent excitatory signals. In epileptic mice, DREADD-mediated-specific suppression of hippocampal newborn DGCs dramatically reduced epileptic spikes and SRS in an inducible and reversible manner. Conversely, specific activation of hippocampal newborn DGCs increased both epileptic spikes and SRS. Our study reveals an essential role for hippocampal newborn DGCs in the formation and function of epileptic neural circuits, providing critical insights into DGCs as a potential therapeutic target for treating epilepsy.
Summary
Purpose: Fast ripples are reported to be highly localizing to the epileptogenic or seizure‐onset zone (SOZ) but may not be readily found in neocortical epilepsy, whereas ripples are ...insufficiently localizing. Herein we classified interictal neocortical ripples by associated characteristics to identify a subtype that may help to localize the SOZ in neocortical epilepsy. We hypothesize that ripples associated with an interictal epileptiform discharge (IED) are more pathologic, since the IED is not a normal physiologic event.
Methods: We studied 35 patients with epilepsy with neocortical epilepsy who underwent invasive electroencephalography (EEG) evaluation by stereotactic EEG (SEEG) or subdural grid electrodes. Interictal fast ripples and ripples were visually marked during slow‐wave sleep lasting 10–30 min. Neocortical ripples were classified as type I when superimposed on epileptiform discharges such as paroxysmal fast, spike, or sharp wave, and as type II when independent of epileptiform discharges.
Key Findings: In 21 patients with a defined SOZ, neocortical fast ripples were detected in the SOZ of only four patients. Type I ripples were detected in 14 cases almost exclusively in the SOZ or primary propagation area (PP) and marked the SOZ with higher specificity than interictal spikes. In contrast, type II ripples were not correlated with the SOZ. In 14 patients with two or more presumed SOZs or nonlocalizable onset pattern, type I but not type II ripples also occurred in the SOZs. We found the areas with only type II ripples outside of the SOZ (type II‐O ripples) in SEEG that localized to the primary motor cortex and primary visual cortex.
Significance: Neocortical fast ripples and type I ripples are specific markers of the SOZ, whereas type II ripples are not. Type I ripples are found more readily than fast ripples in human neocortical epilepsy. Type II‐O ripples may represent spontaneous physiologic ripples in the human neocortex.
Objective
In the presurgical workup of magnetic resonance imaging (MRI)‐negative (MRI− or “nonlesional”) pharmacoresistant focal epilepsy (PFE) patients, discovering a previously undetected lesion ...can drastically change the evaluation and likely improve surgical outcome. Our study utilizes a voxel‐based MRI postprocessing technique, implemented in a morphometric analysis program (MAP), to facilitate detection of subtle abnormalities in a consecutive cohort of MRI− surgical candidates.
Methods
Included in this retrospective study was a consecutive cohort of 150 MRI− surgical patients. MAP was performed on T1‐weighted MRI, with comparison to a scanner‐specific normal database. Review and analysis of MAP were performed blinded to patients' clinical information. The pertinence of MAP+ areas was confirmed by surgical outcome and pathology.
Results
MAP showed a 43% positive rate, sensitivity of 0.9, and specificity of 0.67. Overall, patients with the MAP+ region completely resected had the best seizure outcomes, followed by the MAP− patients, and patients who had no/partial resection of the MAP+ region had the worst outcome (p < 0.001). Subgroup analysis revealed that visually identified subtle findings are more likely correct if also MAP+. False‐positive rate in 52 normal controls was 2%. Surgical pathology of the resected MAP+ areas contained mainly non–balloon‐cell focal cortical dysplasia (FCD). Multiple MAP+ regions were present in 7% of patients.
Interpretation
MAP can be a practical and valuable tool to: (1) guide the search for subtle MRI abnormalities and (2) confirm visually identified questionable abnormalities in patients with PFE due to suspected FCD. A MAP+ region, when concordant with the patient's electroclinical presentation, should provide a legitimate target for surgical exploration. Ann Neurol 2015;77:1060–1075
Summary
Purpose: Stereo‐electroencephalography (SEEG) enables precise recordings from deep cortical structures, multiple noncontiguous lobes, as well as bilateral explorations while avoiding large ...craniotomies. Despite a long reported successful record, its application in the United States has not been widely adopted. We report on our initial experience with the SEEG methodology in the extraoperative mapping of refractory focal epilepsy in patients who were not considered optimal surgical candidates for other methods of invasive monitoring. We focused on the applied surgical technique and its utility and efficacy in this subgroup of patients.
Methods: Between March 2009 and May 2011, 100 patients with the diagnosis of medically refractory focal epilepsy who were not considered optimal candidates for subdural grids and strips placement underwent SEEG implantation at Cleveland Clinic Epilepsy Center. Demographics, noninvasive clinical data, number and location of implanted electrodes, electrophysiologic localization of the epileptic zone, complications, and short‐term seizure outcome after resection were prospectively collected and analyzed.
Key Findings: Mean age was 32 years (range 5–68 years); 54 were male and 46 female. The mean follow‐up after resection was 15 months. In total, 1,310 electrodes were implanted. Analyses of the SEEG recordings resulted in the electrographic localization of the epileptogenic focus in 96 patients. In the group of 75 patients who underwent resection, only 53 had at least 12 months follow‐up. From this group, 33 patients (62.3%) were seizure‐free at the end of the follow‐up period. The presence of abnormal pathologic finding was strongly associated with postoperative seizure control (p = 0.005). The risk of hemorrhagic complications per electrode was 0.2%.
Significance: In patients who are not considered to be ideal candidates for subdural grids and strips implantation, the SEEG methodology is a safe, useful and reliable alternative option for invasive monitoring in patients with refractory focal epilepsy, providing an additional mean for seizure localization and control in a “difficult to localize” subgroup of patients.
PDF
