Deep brain stimulation of the anterior nucleus of the thalamus in drug-resistant epilepsy in the MORE multicenter patient registry

Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background and objectives: The efficacy of deep brain stimulation of the anterior nucleus of the thalamus (ANT DBS) in patients with drug-resistant epilepsy (DRE) was demonstrated in the double-blind Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy randomized controlled trial. The Medtronic Registry for Epilepsy (MORE) aims to understand the safety and longer-term effectiveness of ANT DBS therapy in routine clinical practice. Methods: MORE is an observational registry collecting prospective and retrospective clinical data. Participants were at least 18 years old, with focal DRE recruited across 25 centers from 13 countries. They were followed for at least 2 years in terms of seizure frequency (SF), responder rate (RR), health-related quality of life (Quality of Life in Epilepsy Inventory 31), depression, and safety outcomes. Results: Of the 191 patients recruited, 170 (mean [SD] age of 35.6 [10.7] years, 43% female) were implanted with DBS therapy and met all eligibility criteria. At baseline, 38% of patients reported cognitive impairment. The median monthly SF decreased by 33.1% from 15.8 at baseline to 8.8 at 2 years (p 10 implantations) had 42.8% reduction in median monthly SF by 2 years in comparison with 25.8% in low-volume center. In patients with cognitive impairment, the reduction in median monthly SF was 26.0% by 2 years compared with 36.1% in patients without cognitive impairment. The most frequently reported adverse events were changes (e.g., increased frequency/severity) in seizure (16%), memory impairment (patient-reported complaint, 15%), depressive mood (patient-reported complaint, 13%), and epilepsy (12%). One definite sudden unexpected death in epilepsy case was reported. Discussion: The MORE registry supports the effectiveness and safety of ANT DBS therapy in a real-world setting in the 2 years following implantation. Classification of evidence: This study provides Class IV evidence that ANT DBS reduces the frequency of seizures in patients with drug-resistant focal epilepsy.The MORE registry was sponsored and funded by Medtronic, plc.info:eu-repo/semantics/publishedVersio

Functional Variant in Complement C3 Gene Promoter and Genetic Susceptibility to Temporal Lobe Epilepsy and Febrile Seizures

BACKGROUND: Human mesial temporal lobe epilepsies (MTLE) represent the most frequent form of partial epilepsies and are frequently preceded by febrile seizures (FS) in infancy and early childhood. Genetic associations of several complement genes including its central component C3 with disorders of the central nervous system, and the existence of C3 dysregulation in the epilepsies and in the MTLE particularly, make it the C3 gene a good candidate for human MTLE. METHODOLOGY/PRINCIPAL FINDINGS: A case-control association study of the C3 gene was performed in a first series of 122 patients with MTLE and 196 controls. Four haplotypes (HAP1 to 4) comprising GF100472, a newly discovered dinucleotide repeat polymorphism [(CA)8 to (CA)15] in the C3 promoter region showed significant association after Bonferroni correction, in the subgroup of MTLE patients having a personal history of FS (MTLE-FS+). Replication analysis in independent patients and controls confirmed that the rare HAP4 haplotype comprising the minimal length allele of GF100472 [(CA)8], protected against MTLE-FS+. A fifth haplotype (HAP5) with medium-size (CA)11 allele of GF100472 displayed four times higher frequency in controls than in the first cohort of MTLE-FS+ and showed a protective effect against FS through a high statistical significance in an independent population of 97 pure FS. Consistently, (CA)11 allele by its own protected against pure FS in a second group of 148 FS patients. Reporter gene assays showed that GF100472 significantly influenced C3 promoter activity (the higher the number of repeats, the lower the transcriptional activity). Taken together, the consistent genetic data and the functional analysis presented here indicate that a newly-identified and functional polymorphism in the promoter of the complement C3 gene might participate in the genetic susceptibility to human MTLE with a history of FS, and to pure FS. CONCLUSIONS/SIGNIFICANCE: The present study provides important data suggesting for the first time the involvement of the complement system in the genetic susceptibility to epileptic seizures and to epilepsy

Seven-Tesla MRI of Hippocampal Sclerosis: An In Vivo Feasibility Study With Histological Correlations.

INTRODUCTION Temporal lobe epilepsy (TLE) is the most frequent form of focal epilepsy in adults. Because approximately half of these patients develop drug resistance, epilepsy surgery designed to remove the epileptogenic zone is an excellent option in selected patients. Histopathological analyses of hippocampal specimens in TLE patients revealed 4 types of Ammon's horn sclerosis, which are correlated with long-term epileptological outcome. The aim of this study was the correlation of noninvasive, high-resolution, morphological magnetic resonance imaging (MRI) at an ultra-high-field (7 T) of the hippocampus in TLE patients with histopathological findings. METHODS High-resolution, T2-weighted FSE MRI in 14 patients with drug-resistant temporal lobe epilepsy was performed on a 7-T Magnetom using a 32-channel coil. Four independent investigators assessed the delineation and semiquantitative evaluation of volume, signal intensity, internal architecture, and overall grading of the hippocampal subfields CA1-4, as well as the presence of the dentate granule cell layer (DGCL), on MRI scans. Results were compared with semiquantitative evaluation of neuronal loss and astrogliosis in the histological sections of the surgical specimens. RESULTS Seven-tesla MR examinations were evaluable in 13 cases. Volume loss and signal intensity, as well as overall grading, showed a strong correlation between MRI and histology in individual CA regions. Furthermore, sensitivity and specificity values up to 100% were found for the detection of pathology in the CA subfields. The prediction of Ammon's horn sclerosis type was correct in up to 12 of 13 cases, whereas the dentate gyrus could not be delineated on MRI. DISCUSSION High-resolution, ultra-high-field MRI is a promising tool for the detection of subtle changes in the hippocampus in patients with temporal lobe epilepsy. Large cohorts will be necessary to confirm the predictive value of 7-T MRI in the preoperative evaluation of TLE patients

The Impact of Nonconvulsive Status Epilepticus after Cardiac Surgery on Outcome

Neurological complications after heart surgery are associated with tremendous morbidity and mortality. Nonconvulsive status epilepticus (NCSE), which can only be verified by EEG, may cause secondary brain damage. Its frequency and its impact on outcomes after cardiac surgery is still unclear. We collected the neurological files and clinical data of all our patients after heart surgery who, in the course of their ICU stay, had been seen by a neurologist who ordered an EEG. Within 18 months, 1457 patients had cardiac surgery on cardiopulmonary bypass. EEG was requested for 89 patients. Seizures were detected in 39 patients and NCSE was detected in 11 patients. Open heart surgery was performed in all 11 NSCE patients, of whom eight showed concomitant brain insults. None had a history of epilepsy. Despite the inhibition of seizure activity with antiseizure medication, clinical improvement was only noted in seven NCSE patients, three of whom were in cerebral performance category 2 and four in category 3 at hospital discharge. The four patients without neurological benefit subsequently died in the ICU. The occurrence of NCSE after open cardiac surgery is significant and frequently associated with brain injury. It seems prudent to perform EEG studies early to interrupt seizure activity and mitigate secondary cerebral injury

Scientific Reports / Insights into Intrinsic Brain Networks based on Graph Theory and PET in right- compared to left-sided Temporal Lobe Epilepsy

The human brain exhibits marked hemispheric differences, though it is not fully understood to what extent lateralization of the epileptic focus is relevant. Preoperative [18F]FDG-PET depicts lateralization of seizure focus in patients with temporal lobe epilepsy and reveals dysfunctional metabolic brain connectivity. The aim of the present study was to compare metabolic connectivity, inferred from inter-regional [18F]FDG PET uptake correlations, in right-sided (RTLE; n=30) and left-sided TLE (LTLE; n=32) with healthy controls (HC; n=31) using graph theory based network analysis. Comparing LTLE and RTLE and patient groups separately to HC, we observed higher lobar connectivity weights in RTLE compared to LTLE for connections of the temporal and the parietal lobe of the contralateral hemisphere (CH). Moreover, especially in RTLE compared to LTLE higher local efficiency were found in the temporal cortices and other brain regions of the CH. The results of this investigation implicate altered metabolic networks in patients with TLE specific to the lateralization of seizure focus, and describe compensatory mechanisms especially in the CH of patients with RTLE. We propose that graph theoretical analysis of metabolic connectivity using [18F]FDG-PET offers an important additional modality to explore brain networks.(VLID)467617

Peripheral metabolism of (R)-[C-11]verapamil in epilepsy patients

Purpose (R)-[C-11]verapamil is a new PET tracer for P-glycoprotein-mediated transport at the blood-brain barrier. For kinetic analysis of (R)-[C-11]verapamil PET data the measurement of a metabolite-corrected arterial input function is required. The aim of this study was to assess peripheral (R)-[C-11]verapamil metabolism in patients with temporal lobe epilepsy and compare these data with previously reported data from healthy volunteers. Methods Arterial blood samples were collected from eight patients undergoing (R)-[C-11]verapamil PET and selected samples were analysed for radiolabelled metabolites of (R)-[C-11]verapamil by using an assay that measures polar N-demethylation metabolites by solid-phase extraction and lipophilic N-dealkylation metabolites by HPLC. Results Peripheral metabolism of (R)-[C-11]verapamil was significantly faster in patients compared to healthy volunteers (AUC of (R)-[C-11]verapamil fraction in plasma: 29.4 +/- 3.9 min for patients versus 40.8 +/- 5.0 min for healthy volunteers; p <0.0005, Student's t-test), which resulted in lower (R)-[C-11]verapamil plasma concentrations (AUC of (R)-[C-11]verapamil concentration, normalised to injected dose per body weight: 25.5 +/- 2.1 min for patients and 30.5 +/- 5.9 min for healthy volunteers; p=0.038). Faster metabolism appeared to be mainly due to increased N-demethylation as the polar [C-11]metabolite fraction was up to two-fold greater in patients. Conclusions Faster metabolism of (R)-[C-11]verapamil in epilepsy patients may be caused by hepatic cytochrome P450 enzyme induction by antiepileptic drugs. Based on these data caution is warranted when using an averaged arterial input function derived from healthy volunteers for the analysis of patient data. Moreover, our data illustrate how antiepileptic drugs may decrease serum levels of concomitant medication, which may eventually lead to a loss of therapeutic efficacy

In vivo P-glycoprotein function before and after epilepsy surgery

OBJECTIVES: To study the functional activity of the multidrug efflux transporter P-glycoprotein (Pgp) at the blood-brain barrier of patients with temporal lobe epilepsy using (R)-[(11)C]verapamil (VPM)-PET before and after temporal lobe surgery to assess whether postoperative changes in seizure frequency and antiepileptic drug load are associated with changes in Pgp function. METHODS: Seven patients with drug-resistant temporal lobe epilepsy underwent VPM-PET scans pre- and postsurgery. Patients were followed up for a median of 6 years (range 4–7) after surgery. Pgp immunoreactivity in surgically resected hippocampal specimens was determined with immunohistochemistry. RESULTS: Optimal surgical outcome, defined as seizure freedom and withdrawal of antiepileptic drugs, was associated with higher temporal lobe Pgp function before surgery, higher Pgp-positive staining in surgically resected hippocampal specimens, and reduction in global Pgp function postoperatively, compared with nonoptimal surgery outcome. CONCLUSIONS: The data from our pilot study suggest that Pgp overactivity in epilepsy is dynamic, and complete seizure control and elimination of antiepileptic medication is associated with reversal of overactivity, although these findings will require confirmation in a larger patient cohort