Ulf C. Schneider

Microglia inflict delayed brain injury after subarachnoid hemorrhage

Inflammatory changes have been postulated to contribute to secondary brain injury after aneurysmal subarachnoid hemorrhage (SAH). In human specimens after SAH as well as in experimental SAH using mice, we show an intracerebral accumulation of inflammatory cells between days 4 and 28 after the bleeding. Using bone marrow chimeric mice allowing tracing of all peripherally derived immune cells, we confirm a truly CNS-intrinsic, microglial origin of these immune cells, exhibiting an inflammatory state, and rule out invasion of myeloid cells from the periphery into the brain. Furthermore, we detect secondary neuro-axonal injury throughout the time course of SAH. Since neuronal cell death and microglia accumulation follow a similar time course, we addressed whether the occurrence of activated microglia and neuro-axonal injury upon SAH are causally linked by depleting microglia in vivo. Given that the amount of neuronal cell death was significantly reduced after microglia depletion, we conclude that microglia accumulation inflicts secondary brain injury after SAH.

Distinct clinical and radiographic characteristics of moyamoya disease amongst European Caucasians

Occlusive cerebrovascular moyamoya disease (MMD) is rare and has been characterized mainly in Asian countries, so far. In recent years, MMD has been increasingly reported worldwide, raising the question whether its clinical presentation would vary amongst different ethnic backgrounds. Here, a homogeneous series of 153 patients with MMD are reported and the specific clinical features of this rare disease amongst European Caucasians are highlighted.

Experience in using the excimer laser-assisted nonocclusive anastomosis nonocclusive bypass technique for high-flow revascularization: Mannheim-Helsinki series of 64 patients.

BACKGROUND The excimer laser–assisted nonocclusive anastomosis (ELANA) technique enables large-caliber bypass revascularization without temporary occlusion of the parent artery. OBJECTIVE To present the surgical experience of 2 bypass centers using ELANA in the treatment of complex intracranial lesions. METHODS Between July 2002 and December 2007, 64 consecutive patients (37 in Germany and 27 in Finland) were selected for high-flow bypass surgery with ELANA. Modified Rankin Scale, a bypass success rate, and the success rate of the laser arteriotomy were assessed. RESULTS In 66 surgeries for 64 intent-to-treat patients, 58 ELANA procedures were completed successfully. A favorable outcome (postoperative modified Rankin Scale score less than or equal to preoperative modified Rankin Scale) at 3 months was achieved in 43 of 56 patients (77%) with anterior circulation lesions (37 of the 43 patients had aneurysms, 4 had ischemia, and 2 received a bypass before tumor removal) and only in 2 of 8 patients (25%) with posterior circulation aneurysms. Perioperative (< 7 days) mortality for anterior and posterior circulation aneurysms was 6% and 50%, respectively. At the 3-month follow-up, 12% and 63% of patients with anterior and posterior circulation aneurysms, respectively, were dead. The success rate of the laser arteriotomy was 70%. Another 14% were retrieved manually after a nearly complete laser arteriotomy. CONCLUSION The ELANA procedure requires a meticulous and careful operative technique. Morbidity and especially mortality rates, usually unrelated to ELANA, are comparable to those of contemporary series of conventional high-flow revascularization operations. This underscores the overall complexity of treating neurovascular pathologies by high-flow bypasses.

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

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.

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

IntroductionThe 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®).MethodBetween 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.ResultsThe 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.ConclusionsThe 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.

Endothelial progenitor cells augment collateralization and hemodynamic rescue in a model of chronic cerebral ischemia.

Surgical flow augmentation for treatment of cerebral hemodynamic impairment remains controversial. Here, we investigated the benefit of endothelial progenitor cell (EPC) treatment in a rat model of chronic cerebral hypoperfusion. At repeated time points after 3-vessel occlusion (3-VO), animals were treated with 1 × 10 6 Dil-labeled (a) ex vivo-expanded embryonic-EPC (e-EPC), (b) cyclic AMP-differentiated embryonic-endothelial progenitor-derived cells (e-EPDC as biologic control) or, (c) saline. The cerebrovascular reserve capacity (CVRC) was assessed immediately before and on days 7 and 21 after 3-VO. Structural effects were assessed by latex perfusion, immunohistochemistry, and intravital fluorescence video microscopy on day 21. Three-vessel occlusion resulted in a significant impairment of the CVRC with better functional recovery after treatment with e-EPC (16.4 ± 8%) compared with e-EPDC (3.7 ± 8%) or saline (6.4 ± 9%) by day 21 (P<0.05), which was paralleled by a significant increase in the vessel diameters of the anterior Circle of Willis, a significantly higher number of leptomeningeal anastomoses and higher parenchymal capillary density in e-EPC-treated animals. Interestingly, despite in vivo interaction of e-EPC with the cerebral endothelium, e-EPC incorporation into the cerebral vasculature was not observed. Our results suggest that EPC may serve as a novel therapeutic agent in clinical trials for nonsurgical treatment of chronic cerebral hemodynamic impairment.

The use of the excimer laser-assisted anastomosis technique alleviates neuroanesthesia during cerebral high-flow revascularization.

In patients with complex intracranial aneurysms or skull base tumors, parent vessel occlusion and flow replacement by high-flow bypass surgery is a demanding therapy, both for the neurosurgeon and the neuroanesthesiologist. One reason for this is the need for prolonged temporary occlusion of a major cerebral artery, which carries a high risk of perioperative ischemia and necessitates versatile neuroprotective measures during anesthesia. Recently, a novel excimer laser-assisted nonocclusive anastomosis (ELANA) technique has been introduced, circumventing the need for temporary occlusion of cerebral vessels. We hypothesized that the use of this ELANA technique would facilitate also the neuroanesthesiologic management of these patients. To test this, we reviewed the details of the neuroanesthesiologic management of patients undergoing ELANA high-flow bypass surgery at our institution. Twenty-nine patients with giant aneurysms (n=27) or skull base tumor (n=2) who were undergoing parent vessel occlusion and permanent flow replacement by high-flow bypass surgery using the ELANA technique were investigated retrospectively. The records of the patients were analyzed for induction and maintenance of anesthesia, fluid therapy, transfusion requirements, hemodynamic parameters, and brain protective strategies. Although we are not able to provide a sufficient body of cohort data to compare the neuroanesthesiologic management of patients undergoing the conventional anastomosis technique with management using the ELANA technique, in each of our reported cases the conventional anastomosis technique would have entailed a high probability of prolonged temporary occlusion that would, in turn, have warranted intensive brain-protective strategies. The observation that use of the ELANA technique precluded the necessity of brain-protective strategies without entailing perioperative cerebral infarction suggests that the ELANA technique supports the neurosurgeon in creating difficult permanent intracranial anastomoses and also facilitates neuroanesthesiologic management of patients undergoing cerebral high-flow revascularization procedures.

Effects of VU0240551, a novel KCC2 antagonist, and DIDS on chloride homeostasis of neocortical neurons from rats and humans.

The normal function of GABAA receptor-mediated inhibition is governed by several factors, including release of GABA, subunit composition and density of the receptors and in particular by the appropriate ionic gradient. In the human epileptogenic neocortex an impaired chloride (Cl(-)) gradient has been proposed, due to decreases of potassium-coupled chloride transport (KCC2) and voltage-gated Cl(-) channels (ClC). Regarding sodium- and potassium-coupled Cl(-) transport (NKCC1) both up- and downregulations have been proposed. We investigated changes of Cl(-) homeostasis of human and rat neocortical neurons (layer 2/3) with intracellular recordings and iontophoretic Cl(-) loading employing selective compounds. After cessation of iontophoresis, the IPSPA amplitudes of rat neurons recovered with a time constant (τrec) of 6.5s (n=21). In human neurons, τrec averaged 17.8s (n=36; 23 resections). Application of the novel KCC2 blocker VU0240551 (1 μM) caused in rat neurons a reversible prolongation of τrec from 5.7 to 8.1s (n=11), corresponding to a VU0240551-sensitive Cl(-) transport rate (1/Δτrec) of 0.0504s(-1). In human neurons, τrec increased on application of 1μM VU0240551, on average from 15.1 to 20.3s (n=17). The human neurons comprised two subgroups with different τrec when segregated according to a border given by the mean+2s.d. of rat neurons. In one group, τrec averaged 8.7s (n=6) and reversibly increased to 14.6s in the presence of 1μM VU0240551, corresponding to a Cl(-) transport rate of 0.0504s(-1). The other group had an average τrec of 18.5s which increased in the presence of 1μM VU0240551 to 23.3s (n=11), indicating a much smaller rate (0.0151s(-1)). Addition of DIDS, a presumed blocker of anion exchanger (AE), increased the τrec of rat neurons from 7.5 to 8.8s (n=6) corresponding to a DIDS-sensitive rate of 0.0185s(-1). In human neurons, DIDS increased τrec from 23.3 to 50.7s (n=7), corresponding to a DIDS-sensitive rate of 0.0200s(-1). These data suggest a greatly reduced KCC2-mediated transport rate in most of the human neurons. The two subgroups observed in human tissue indicate a considerable variability of Cl(-) transport within a given tissue from almost normal to greatly impeded, predominated by a decline of KCC2 whereas AE is unaltered.

Blood pressure changes after aneurysmal subarachnoid hemorrhage and their relationship to cerebral vasospasm and clinical outcome

OBJECTIVE Cerebral vasospasm (VS) and resulting delayed ischemic brain injury constitute the most severe secondary complication after subarachnoid hemorrhage (SAH). Identification of early clinical predictors of developing vasospasm and poor outcome has remained a major challenge in neurointensive care medicine. Aim of the present study was analyze the relevance of spontaneous changes in blood pressures and their predictive value for predicting vasospasm as well as adverse clinical outcome. METHODS 98 aneurysmal SAH patients were analyzed retrospectively. Patients were divided into two study groups: (1) VS+ (developing VS) and (2) VS- (not developing VS). Repeat-angiography was routinely performed on day 8 after SAH or earlier if clinical signs were suggestive for overt vasospasm. Systolic, diastolic and mean blood pressures were averaged hourly and plotted over time. Secondly, blood pressure (BP)-progression was analyzed with respect to clinical outcomes as assessed by the Glasgow outcome scale. RESULTS Mean, systolic, and diastolic blood pressure values progressed in both VS- and VS+ cohorts over time. However, as early as 4 days after SAH a significant dissociation of RR curves was observed between the groups with patients in the VS+ group displaying a significantly higher slope coefficient of blood pressure elevation. An increase of mean arterial pressure >20% within the first 4 days was predictive of developing vasospasm. Elevation of mean arterial blood pressure in the VS+ group was mainly attributable to changes in diastolic pressure. Elevation of mean arterial blood pressure >25% within the first week after SAH was associated with unfavorable outcome. CONCLUSIONS SAH leads to spontaneous and progressive elevations in mean arterial blood pressure. Vasospasm might be anticipated by identifying early elevations of mean arterial blood pressure. Finally, spontaneous elevations of mean arterial blood pressure correlate with poorer outcomes.

Mouse cerebral magnetic resonance imaging fails to visualize brain volume changes after experimental subarachnoid hemorrhage.

BackgroundBrain atrophy after subarachnoid hemorrhage (SAH) has been detected in humans and might serve as a functional read-out parameter for neuropsychological deficits. To determine whether serial magnetic resonance imaging (MRI) can provide information on brain atrophy in animals as well, mice that had undergone experimental SAH were scanned repeatedly after the bleeding.MethodsUsing a 7-T rodent MRI, six mice were evaluated for total hemispheric, cerebrospinal fluid (CSF) and hippocampal volumes on days 1, 2, 4, 21, 28, 42 and 60 after experimental SAH or sham operation, respectively.ResultsRepeated MRI scanning demonstrated a very high reproducibility with minimum standard deviation. Nevertheless, no significant differences were found between the two groups concerning hemispherical volumes or hippocampal volumes. A transient but significant increase in CSF volume was detected on days 2 and 60 after SAH. Compared with the existing method, no MRI data on brain atrophy in mice after experimental SAH have been published.ConclusionRepeated brain MRI in mice after experimental SAH did not provide additional information on brain atrophy. Our data suggest that this is not due to a lack of sensitivity of the method. Despite all promising details about MRI, our results should initiate careful consideration (additional sequences/other questions) before its further use in this certain area, especially since it is expensive and associated with demanding logistics.