Summary:Purpose: This pilot study prospectively evaluated the efficacy of long-term deep brain stimulation (DBS) in medial temporal lobe (MTL) structures in patients with MTL epilepsy.Methods: Twelve consecutive patients with refractory MTL epilepsy were included in this study. The protocol included invasive video-EEG monitoring for ictal-onset localization and evaluation for subsequent stimulation of the ictal-onset zone. Side effects and changes in seizure frequency were carefully monitored.Results: Ten of 12 patients underwent long-term MTL DBS. Two of 12 patients underwent selective amygdalohippocampectomy. After mean follow-up of 31 months (range, 12-52 months), one of 10 stimulated patients are seizure free (>1 year), one of 10 patients had a >90% reduction in seizure frequency; five of 10 patients had a seizure-frequency reduction of ≥50%; two of 10 patients had a seizure-frequency reduction of 30-49%; and one of 10 patients was a nonresponder. None of the patients reported side effects. In one patient, MRI showed asymptomatic intracranial hemorrhages along the trajectory of the DBS electrodes. None of the patients showed changes in clinical neurological testing. Patients who underwent selective amygdalohippocampectomy are seizure-free (>1 year), AEDs are unchanged, and no side effects have occurred.Conclusions: This open pilot study demonstrates the potential efficacy of long-term DBS in MTL structures that should now be further confirmed by multicenter randomized controlled trials.

This study shows that the characteristics of spontaneous seizures in the intrahippocampal KA model display many similarities to other SE models and human temporal lobe epilepsy.

The objective of this article was to review and summarize the available reports on the profile of the novel anticonvulsant drug levetiracetam (LEV) in a clinical setting. Therefore, a careful search was conducted in the MEDLINE database and combined with guidelines from regulatory agencies, proceedings of professional scientific meetings, and information provided by the manufacturers. This article is devoted to the clinical pharmacology and clinical trials of LEV investigating its efficacy and safety as add-on therapy or monotherapy for various seizure types. Finally, results from postmarketing surveillance of LEV are briefly discussed. In general, LEV is shown to be a safe, broad-spectrum anticonvulsant drug with highly beneficial pharmacokinetic properties, a favorable long-term retention rate, and a high responder rate, indicating that LEV is an efficient therapeutic option for the treatment of several types of epilepsy. CLINICAL PHARMACOLOGYLevetiracetam (LEV) is a white to off-white powder with a bitter taste and faint odor that is highly soluble in water (0.104 g/mL). It is structurally unrelated to other anticonvulsant drugs (ACDs), with an empirical formula of C 8 H 14 N 2 O 2 and a molecular weight of 170.21.

The objective of this article was to review and summarize the available reports on the preclinical profile of the novel anticonvulsant drug levetiracetam (LEV). Therefore, a careful search was conducted in the MEDLINE database and combined with guidelines from regulatory agencies, proceedings of professional scientific meetings, and information provided by the manufacturers. This article provides detailed information on the anticonvulsant effects of LEV in various animal models of epilepsy and on its pharmacology in laboratory animals. The mechanism of action of LEV is reviewed, with special regard to its recently discovered binding site, the synaptic vesicle protein 2A. In general, LEV is shown to be a safe, broad-spectrum anticonvulsant drug with highly beneficial pharmacokinetic properties and a distinct mechanism of action. The clinical studies with LEV will be discussed in the second part of this review article to be published subsequently.

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Summary:Purpose: This experimental animal study evaluates the effect of high frequency deep brain stimulation (HFS DBS) on seizures in the Alternate Day Rapid Kindling model for temporal lobe epilepsy (TLE). The target for HFS is the hippocampus, as this structure is often presumed to be the seizure focus in human TLE.Methods: Rats (n = 12) were fully kindled in the hippocampus according to the Alternate Day Rapid Kindling protocol. Characteristics of the evoked afterdischarges (AD) were determined in the baseline period using AD threshold, AD latency, and AD duration as parameters. Rats were divided into a treated group (n = 7) that received 130 Hz HFS for 1 week, and a control group (n = 5) that did not receive HFS. Rats were retested in the following week. After 1 additional week of rest, the HFS group was continuously stimulated again for 1 week, during which AD evoked by kindling stimuli were characterized again.Results: HFS had a direct effect on evoked AD: during HFS, it increased AD threshold to 203 ± 13% of controls (p < 0.01) and increased AD latency to 191 ± 19% (p < 0.05). It decreased AD duration to 71 ± 9% (p < 0.05) of controls. The effect outlasted the HFS stimulation as in the week following HFS similar differences, but smaller in size, could still be established.Conclusion: Continuous HFS (130 Hz) in the hippocampus of epileptic rats modulates the characteristics of evoked AD in a way that reflects a reduction in excitability of the target region.

Summary:Purpose: Adult hippocampal neurogenesis is enhanced in several models for temporal lobe epilepsy (TLE). In this study, we used low-dose whole brain radiation to suppress hippocampal neurogenesis and then studied the effect of this treatment on epileptogenesis in a kindling model for TLE.Methods: Half of the rats were exposed to a radiation dose of 8 Gy one day before the initiation of a rapid kindling protocol. Afterdischarge threshold (ADT), afterdischarge duration (ADD), clinical seizure severity, and inflammation were compared between groups. On the first and third day after radiation, rats were injected with 5 -bromo-2 -deoxyuridine (BrdU) to evaluate neurogenesis. Seven and 21 days after radiation, numbers of doublecortin (DCX) positive neuroblasts in subgranular zone and granule cell layer were compared between groups.Results: We showed that radiation significantly suppressed neurogenesis and neuroblast production during kindling acquisition. Radiation prevented an increase in ADT that became significantly lower in radiated rats. On the third and fourth kindling acquisition day radiated rats developed more severe seizures more rapidly, which resulted in a significantly higher mean severity score on these days. Differences in ADD could not be demonstrated.Discussion: Our results demonstrate that brain radiation with a relatively low dose effectively suppressed the generation of new granule cells and transiently enhanced excitability during kindling acquisition. Although seizure-induced neurogenesis was lower in the radiated rats we could not detect a strong effect on the final establishment of the permanent fully kindled state, which argues against a prominent role of seizure-induced neurogenesis in epileptogenesis.

Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THIS TOPIC?  Decentralized clinical trials (DCTs) have the possibility to improve clinical trial conduct. However, regulatory requirements and perceived low degree of regulatory acceptance may impact the implementation of DCTs. WHAT QUESTION DID THIS STUDY ADDRESS?  What are the opportunities and challenges for the authorization and implementation of DCTs in Europe from a regulators' perspective? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?  Regulators expect that DCTs will facilitate the recruitment of underserved patients. Data collected in DCTs are furthermore expected to be more representative of the realworld. However, concerns regarding investigator oversight and safety monitoring may challenge DCT implementation. Regulators suggested that further experience with DCTs can be exerted through hybrid clinical trials, combining decentralized and on-site activities. HOW MIGHT THIS CHANGE CLINICAL PHARMA-COLOGY OR TRANSLATIONAL SCIENCE? This research helps progress the implementation of DCTs by providing insights into the opportunities and challenges for its implementation from a European regulator's perspective. The themes described in this research should be considered when designing a DCT and could help to educate regulators on DCTs.