Resolution of Cerebral Inflammation Following Subarachnoid Hemorrhage.

BACKGROUND: Aneurismal subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke that, despite improvement through therapeutic interventions, remains a devastating cerebrovascular disorder that has a high mortality rate and causes long-term disability. Cerebral inflammation after SAH is promoted through microglial accumulation and phagocytosis. Furthermore, proinflammatory cytokine release and neuronal cell death play key roles in the development of brain injury. The termination of these inflammation processes and restoration of tissue homeostasis are of utmost importance regarding the possible chronicity of cerebral inflammation and the improvement of the clinical outcome for affected patients post SAH. Thus, we evaluated the inflammatory resolution phase post SAH and considered indications for potential tertiary brain damage in cases of incomplete resolution. METHODS: Subarachnoid hemorrhage was induced through endovascular filament perforation in mice. Animals were killed 1, 7 and 14 days and 1, 2 and 3 months after SAH. Brain cryosections were immunolabeled for ionized calcium-binding adaptor molecule-1 to detect microglia/macrophages. Neuronal nuclei and terminal deoxyuridine triphosphate-nick end labeling staining was used to visualize secondary cell death of neurons. The gene expression of various proinflammatory mediators in brain samples was analyzed by quantitative polymerase chain reaction. RESULTS: We observed restored tissue homeostasis due to decreased microglial/macrophage accumulation and neuronal cell death 1 month after insult. However, the messenger RNA expression levels of  interleukin 6  and  tumor necrosis factor α were still elevated at 1 and 2 months post SAH, respectively. The gene expression of interleukin 1ß reached its maximum on day 1, whereas at later time points, no significant differences between the groups were detected. CONCLUSIONS: By the herein presented molecular and histological data we provide an important indication for an incomplete resolution of inflammation within the brain parenchyma after SAH. Inflammatory resolution and the return to tissue homeostasis represent an important contribution to the disease's pathology influencing the impact on brain damage and outcome after SAH. Therefore, we consider a novel complementary or even superior therapeutic approach that should be carefully rethought in the management of cerebral inflammation after SAH. An acceleration of the resolution phase at the cellular and molecular levels could be a potential aim in this context.

Adenosine A1 receptor-mediated suppression of carbamazepine-resistant seizure-like events in human neocortical slices.

OBJECTIVE: The need for alternative pharmacologic strategies in treatment of epilepsies is pressing for about 30% of patients with epilepsy who do not experience satisfactory seizure control with present treatments. In temporal lobe epilepsy (TLE) even up to 80% of patients are pharmacoresistant, and surgical resection of the ictogenic tissue is only possible for a minority of TLE patients. In this study we investigate purinergic modulation of drug-resistant seizure-like events (SLEs) in human temporal cortex slices. METHODS: Layer V/VI field potentials from a total of 77 neocortical slices from 17 pharmacoresistant patients were recorded to monitor SLEs induced by application of 8 mM [K(+) ] and 50 µm bicuculline. RESULTS: Activating A1 receptors with a specific agonist completely suppressed SLEs in 73% of human temporal cortex slices. In the remaining slices, incidence of SLEs was markedly reduced. Because a subportion of slices can be pharmacosensitive, we tested effects of an A1 agonist, in slices insensitive to a high dose of carbamazepine (50 µm). Also in these cases the A1 agonist was equally efficient. Moreover, ATP and adenosine blocked or modulated SLEs, an effect mediated not by P2 receptors but rather by adenosine A1 receptors. SIGNIFICANCE: Selective activation of A1 receptors mediates a strong anticonvulsant action in human neocortical slices from pharmacoresistant patients. We propose that our human slice model of seizure-like activity is a feasible option for future studies investigating new antiepileptic drug (AED) candidates.

Implantation of a new Vagus Nerve Stimulation (VNS) Therapy® generator, AspireSR®: considerations and recommendations during implantation and replacement surgery--comparison to a traditional system.

INTRODUCTION: The most widely used neuro-stimulation treatment for drug-resistant epilepsy is Vagus Nerve Stimulation (VNS) Therapy®. Ictal tachycardia can be an indicator of a seizure and, if monitored, can be used to trigger an additional on-demand stimulation, which may positively influence seizure severity or duration. A new VNS Therapy generator model, AspireSR®, was introduced and approved for CE Mark in February 2014. In enhancement of former models, the AspireSR has incorporated a cardiac-based seizure-detection (CBSD) algorithm that can detect ictal tachycardia and automatically trigger a defined auto-stimulation. To evaluate differences in preoperative, intraoperative and postoperative handling, we compared the AspireSR to a conventional generator model (Demipulse®). METHOD: Between February and September 2014, seven patients with drug-resistant epilepsy and ictal tachycardia were implanted with an AspireSR. Between November 2013 and September 2014, seven patients were implanted with a Demipulse and served as control group. Operation time, skin incision length and position, and complications were recorded. Handling of the new device was critically evaluated. RESULTS: The intraoperative handling was comparable and did not lead to a significant increase in operation time. In our 14 operations, we had no significant short-term complications. Due to its larger size, patients with the AspireSR had significantly larger skin incisions. For optimal heart rate detection, the AspireSR had to be placed significantly more medial in the décolleté area than the Demipulse. The preoperative testing is a unique addition to the implantation procedure of the AspireSR, which may provide minor difficulties, and for which we provide several recommendations and tips. The price of the device is higher than for all other models. CONCLUSIONS: The new AspireSR generator offers a unique technical improvement over the previous Demipulse. Whether the highly interesting CBSD feature will provide an additional benefit for the patients, and will rectify the additional costs, respectively, cannot be answered in the short-term. The preoperative handling is straightforward, provided that certain recommendations are taken into consideration. The intraoperative handling is equivalent to former models-except for the placement of the generator, which might cause cosmetic issues and has to be discussed with the patient carefully. We recommend the consideration of the AspireSR in patients with documented ictal tachycardia to provide a substantial number of patients for later seizure outcome analysis.

Administration of a second generation perfluorochemical in combination with hyperbaric oxygenation does not provide additional benefit in a model of permanent middle cerebral artery occlusion in rats.

OBJECTIVE: Both, second generation perfluorochemicals (Oxycyte®) and hyperbaric oxygen (HBO) have been shown to reduce necrotic tissue volume if administered early after experimental cerebral ischemia. With the idea of exponentiation of oxygen delivery to ischemic tissue, this study was conducted to investigate the combined effect of both treatment modalities on the extent of ischemic brain damage. METHODS: Permanent focal cerebral ischemia was induced in rats by middle cerebral artery occlusion (MCAO). Animals were assigned randomly to one of the following treatment groups: Control (0.9% NaCl, 1 ml/100 g i.v.), Oxycyte® (1 ml/100 g i.v.), HBO (1 bar hyperbaric oxygenation for 1 h) and HBO + Oxycyte® (1 ml/100 g i.v. combined with 1 bar hyperbaric oxygenation for 1 h). Injection of NaCl or Oxycyte® was performed following MCAO. After injection, breathing was changed to 100% oxygen in Oxycyte®-, HBO- and HBO + Oxycyte®-groups. After eight hours the necrotic volume was calculated from serial coronal sections stained with silver-nitrate and corrected for the extent of swelling. RESULTS: Hemodynamic and metabolic parameters were not affected by infusion of Oxycyte®. Total necrosis volume was significantly reduced in HBO-treated animals (223 ± 70 mm(3)), when compared to control animals (335 ± 36 mm(3)). In animals after Oxycyte®-treatment alone (299 ± 33 mm(3)) or combined HBO + Oxycyte®-treatment (364 ± 50 mm(3)) did not show a significantly smaller necrosis volume compared to control animals (necrosis volumes are given as mean ± SD). DISCUSSION: These results suggest that combination of hyperbaric oxygenation and Oxycyte® administered immediately after onset of vascular occlusion does not provide an additional neuroprotective effect in the early phase of brain ischemia.