Effects of midazolam on high-frequency oscillations in amygdala and hippocampus of epilepsy patients.

High-frequency oscillations (HFOs) are associated with normal brain function, but are also increasingly recognized as potential biomarkers of epileptogenic tissue. Considering the important role of interneuron activity in physiological HFO generation, we studied their modulation by midazolam (MDZ), an agonist of γ-aminobutyric acid type A (GABAA)-benzodiazepine receptors. Here, we analyzed 80 intracranial electrode contacts in amygdala and hippocampus of 13 patients with drug-refractory focal epilepsy who had received MDZ for seizure termination during presurgical monitoring. Ripples (80-250 Hz) and fast ripples (FRs; 250-400 Hz) were compared before and after seizures with MDZ application, and according to their origin either within or outside the individual seizure onset zone (SOZ). We found that MDZ distinctly suppressed all HFOs (ripples and FRs), whereas the reduction of ripples was significantly less pronounced inside the SOZ compared to non-SOZ contacts. The rate of FRs inside the SOZ was less affected, especially in hippocampal contacts. In a few cases, even a marked increase of FRs following MDZ administration was seen. Our results demonstrate, for the first time, a significant HFO modulation in amygdala and hippocampus by MDZ, thus giving insights into the malfunction of GABA-mediated inhibition within epileptogenic areas and its role in HFO generation.

Epileptogenicity of white matter lesions in cerebral small vessel disease: a systematic review and meta-analysis.

BACKGROUND: The epileptogenic properties of white matter lesions (WML) in cerebral small vessel disease (CSVD) are not yet understood. The aim of our systematic review and meta-analysis was to estimate the association between the extent of WML in CSVD and epilepsy, analyze whether these WML are associated with an increased risk of seizure recurrence, and evaluate if treatment with anti-seizure medication (ASM) is justified in first-seizure patients with WML and no cortical lesions. METHODS: Following a pre-registered study protocol (PROSPERO-ID CRD42023390665), we systematically searched Pubmed and Embase for relevant literature comparing WML load between patients with epilepsy and controls as well as studies on seizure recurrence risk and ASM therapy in the presence vs. absence of WML. We calculated pooled estimates using a random effects model. RESULTS: Eleven studies comprising 2983 patients were included in our study. Presence of WML (OR 2.14, 95% CI 1.38-3.33) and presence of relevant WML as assessed by visual rating scales (OR 3.96, 95% CI 2.55-6.16) but not WML volume (OR 1.30, 95% CI 0.91-1.85) were significantly associated with seizures. These results stayed robust in sensitivity analyses restricted to studies on patients with late-onset seizures/epilepsy. Only two studies assessed the association between WML and risk of seizure recurrence with conflicting results. Currently, there are no studies on the efficacy of ASM therapy in the presence of WML in CSVD. CONCLUSIONS: This meta-analysis suggests an association between presence of WML in CSVD and seizures. More research is needed addressing the association between WML and risk of seizure recurrence and ASM therapy focusing on a population of patients with a first unprovoked seizure.

Face-induced gamma oscillations and event-related potentials in patients with epilepsy: an intracranial EEG study.

BACKGROUND: To examine the pathological effect of a mesial temporal seizure onset zone (SOZ) on local and inter-regional response to faces in the amygdala and other structures of the temporal lobe. METHODS: Intracranial EEG data was obtained from the amygdala, hippocampus, fusiform gyrus and parahippocampal gyrus of nine patients with drug-refractory epilepsy during visual stimulation with faces and mosaics. We analyzed event-related potentials (ERP), gamma frequency power, phase-amplitude coupling and phase-slope-index and compared the results between patients with versus without a mesial temporal SOZ. RESULTS: In the amygdala and fusiform gyrus, faces triggered higher ERP amplitudes compared to mosaics in both patient groups and higher gamma power in patients without a mesial temporal SOZ. In the hippocampus, famous faces triggered higher gamma power for both groups combined but did not affect ERPs in either group. The differentiated ERP response to famous faces in the parahippocampal gyrus was more pronounced in patients without a mesial temporal SOZ. Phase-amplitude coupling and phase-slope-index results yielded bidirectional modulation between amygdala and fusiform gyrus, and predominately unidirectional modulation between parahippocampal gyrus and hippocampus. CONCLUSIONS: A mesial temporal SOZ was associated with an impaired response to faces in the amygdala, fusiform gyrus and parahippocampal gyrus in our patients. Compared to this, the response to faces in the hippocampus was impaired in patients with, as well as without, a mesial temporal SOZ. Our results support existing evidence for face processing deficits in patients with a mesial temporal SOZ and suggest the pathological effect of a mesial temporal SOZ on the amygdala to play a pivotal role in this matter in particular.

Resective epilepsy surgery in patients aged 50years and older - a retrospective study regarding seizure outcome, memory performance, and psychopathology.

PURPOSE: To assess clinical and demographic characteristics in two cohorts of elderly patients with drug-resistant focal epilepsy, undergoing resective epilepsy surgery (RES). Further, to determine seizure, neuropsychological, and mental health outcomes after RES and evaluate possible influencing factors. METHODS: Consecutive patients aged ≥50 years with temporal lobe epilepsy (TLE) who underwent curative RES in the Hamburg epilepsy surgery program (2004-2017) were identified. Data were retrospectively analyzed. Seizure outcome was classified according to ILAE and Engel outcome scales in patients with first-time surgeries and with reoperations. Previously reported predictors of the seizure outcome were evaluated using regression analyses. Changes in verbal memory were assessed for patients with complete pre- and postoperative datasets (n=30) using repeated-measures analysis of variance. For evaluation of possible predictors of psychopathologic changes after RES a regression analysis was conducted. RESULTS: Fifty-one elderly patients underwent RES of the temporal lobe, including twelve aged ≥60 years, and five with reoperations. After one year, 65% of the patients with first-time surgeries were seizure free and 91% had a favorable outcome. At last follow-up, 49% were seizure free since surgery. Three reoperated patients had an Engel I outcome. Seizure outcome was not dependent on age at surgery, duration of epilepsy, or other evaluated variables. There was no significant decline in the memory performance after surgery. Significant improvements in mental health were found. CONCLUSION: RES for drug-resistant TLE is safe, effective, and improves mental health also in patients aged ≥ 50 years. Thus, it should be evaluated as the treatment of choice also in this age group.

Electrocorticographic and neurochemical findings after local cortical valproate application in patients with pharmacoresistant focal epilepsy.

Because oral pharmacological treatment of neocortical focal epilepsy is limited due to common systemic side effects and relatively low drug concentrations reached at the epileptic foci locally, application of antiepileptic agents directly onto the neocortical focus may enhance treatment tolerability and efficacy. We describe the effects of cortically applied sodium valproate (VPA) in two patients with pharmacoresistant neocortical focal epilepsy who were selected for epilepsy surgery after a circumscribed epileptic focus had been determined by invasive presurgical evaluation using subdural electrodes. Local VPA modified epileptic activity as electrocorticographically recorded from the chronic focus in both patients. In addition, VPA induced local increase of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) in cortical tissue samples, whereas the excitatory glutamate was possibly decreased. In this clinical pilot study, we could show antiepileptic effects of cortically applied VPA in humans by electrocorticographic and neurochemical parameters.

Decision-making in temporal lobe epilepsy surgery based on invasive stereo-electroencephalography (sEEG).

In medical refractory temporal lobe epilepsy (TLE), the epileptogenic zone can be difficult to identify and therefore difficult to treat, especially in the absence of clear MRI pathologies and specific results from presurgical evaluation. Invasive monitoring with stereo-electroencephalography (sEEG) is a tool for a better determination of the epileptogenic zone. Here, we investigate the impact of sEEG on decision-making in temporal lobe epilepsy surgery. We reviewed patients with TLE who underwent further investigation with sEEG in our epilepsy unit. We examined specifically how sEEG findings influenced our decision regarding indication for a surgical procedure and resection volume. From 2013 to 2017, we performed 152 temporal resections in epilepsy patients. Twenty-one of these patients were designated for further preoperative investigation with sEEG due to incongruent findings in presurgical evaluation. Six patients were implanted bitemporally. In five cases, the hypothesis for the epileptogenic zone and localization had to be changed due to sEEG findings and resulted in a different tailored resection than intended. In three cases, sEEG findings led to the cancelation of the originally intended temporal resection as the epileptogenic zone was not definable or bilateral. In another three cases, the prognosis for reduction of seizures postoperatively had to be reduced due to the sEEG findings. However, the resection was performed after interdisciplinary discussion and informed consent of the patient. The examination by sEEG led to a change of plan for further treatment in 13 patients (61.9%) suffering TLE in total. Invasive monitoring with sEEG electrodes had a strong impact on decision-making for further treatment in patients suffering from temporal lobe epilepsy with incongruent findings in presurgical examination designated for epilepsy surgery. This applies to resection volumes as well as to prediction of seizure outcome.

Reduction of epileptiform activity through local valproate-implants in a rat neocortical epilepsy model.

PURPOSE: Pharmacotherapy of epilepsies is limited due to low concentrations at epileptogenic foci, side effects of high systemic doses and that some potentially efficient substances do not pass the blood-brain barrier. To overcome these limitations, we tested the efficacy of local valproate (VPA)-containing polymer implants in a model of necocortical injected tetanus toxin (TeT) in the rat. METHODS: Tetanus toxin was injected intracortically and cobalt (II) chloride (CoCl2) was applied on the cortical surface. Video-electrocorticography recordings with intracortical electrodes were performed. VPA-containing polymers were implanted above the cortical focus. Antiepileptic effects were evaluated as reductions of epileptiform potentials (EPs) per hour in comparison to saline (NaCl)-containing polymer implants. RESULTS: Triple 50ng TeT injections plus CoCl2 application (20/10mg) showed consistent EPs. NaCl-implanted animals (n=6) showed a mean of 10.5EPs/h after the first week, the EP frequency increased to 53.5EPs/h after the second week. VPA-implant animals (n=5) showed a reduction in EP frequency from 71.6 to 4.8EPs/h after the second week. The EP frequency after the second week was higher in the NaCl-implanted animals than in the VPA-implanted (p=0.0303). The mean EPs/h increase in NaCl-implanted rats (+42.9EPs/h) was different (p=0.0087) from the mean EPs/h decrease in VPA-implanted rats (-66.8EPs/h). CONCLUSION: Despite former publications no clear seizures could be reproduced but it was possible to establish focal EPs, which proved to be a reliable marker for epileptic activity. Local antiepileptic therapy with VPA has shown efficacy in decreasing EP frequency.

Locally applied valproate enhances survival in rats after neocortical treatment with tetanus toxin and cobalt chloride.

PURPOSE: In neocortical epilepsies not satisfactorily responsive to systemic antiepileptic drug therapy, local application of antiepileptic agents onto the epileptic focus may enhance treatment efficacy and tolerability. We describe the effects of focally applied valproate (VPA) in a newly emerging rat model of neocortical epilepsy induced by tetanus toxin (TeT) plus cobalt chloride (CoCl2). METHODS: In rats, VPA (n = 5) or sodium chloride (NaCl) (n = 5) containing polycaprolactone (PCL) implants were applied onto the right motor cortex treated before with a triple injection of 75 ng TeT plus 15 mg CoCl2. Video-EEG monitoring was performed with intracortical depth electrodes. RESULTS: All rats randomized to the NaCl group died within one week after surgery. In contrast, the rats treated with local VPA survived significantly longer (P < 0.01). In both groups, witnessed deaths occurred in the context of seizures. At least 3/4 of the rats surviving the first postoperative day developed neocortical epilepsy with recurrent spontaneous seizures. CONCLUSIONS: The novel TeT/CoCl2 approach targets at a new model of neocortical epilepsy in rats and allows the investigation of local epilepsy therapy strategies. In this vehicle-controlled study, local application of VPA significantly enhanced survival in rats, possibly by focal antiepileptic or antiepileptogenic mechanisms.