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Engelhardt and colleagues review barriers separating blood from CSF and CNS parenchyma, how pathways draining solutes from CNS to lymph nodes exclude trafficking of antigen-presenting cells and how intravital microscopy has influenced debate on immune privilege of the CNS. Discoveries leading to an improved understanding of immune surveillance of the central nervous system (CNS) have repeatedly provoked dismissal of the existence of immune privilege of the CNS. Recent rediscoveries of lymphatic vessels within the dura mater surrounding the brain, made possible by modern live-cell imaging technologies, have revived this discussion. This review emphasizes the fact that understanding immune privilege of the CNS requires intimate knowledge of its unique anatomy. Endothelial, epithelial and glial brain barriers establish compartments in the CNS that differ strikingly with regard to their accessibility to immune-cell subsets. There is a unique system of lymphatic drainage from the CNS to the peripheral lymph nodes. We summarize current knowledge on the cellular and molecular mechanisms involved in immune-cell trafficking and lymphatic drainage from the CNS, and we take into account differences in rodent and human CNS anatomy.

With a median patient survival of 15 months, glioblastoma (GBM) is still one of the deadliest malign tumors. Despite immense efforts, therapeutic regimens fail to prolong GBM patient overall survival due to various resistance mechanisms. Chemokine signaling as part of the tumor microenvironment plays a key role in gliomagenesis, proliferation, neovascularization, metastasis and tumor progression. In this review, we aimed to investigate novel therapeutic approaches targeting various chemokine axes, including CXCR2/CXCL2/IL-8, CXCR3/CXCL4/CXCL9/CXCL10, CXCR4/CXCR7/CXCL12, CXCR6/CXCL16, CCR2/CCL2, CCR5/CCL5 and CX3CR1/CX3CL1 in preclinical and clinical studies of GBM. We reviewed targeted therapies as single therapies, in combination with the standard of care, with antiangiogenic treatment as well as immunotherapy. We found that there are many antagonist-, antibody-, cell- and vaccine-based therapeutic approaches in preclinical and clinical studies. Furthermore, targeted therapies exerted their highest efficacy in combination with other established therapeutic applications. The novel chemokine-targeting therapies have mainly been examined in preclinical models. However, clinical applications are auspicious. Thus, it is crucial to broadly investigate the recently developed preclinical approaches. Promising preclinical applications should then be investigated in clinical studies to create new therapeutic regimens and to overcome therapy resistance to GBM treatment.

For decades, it has been known that the tumor microenvironment is significant for glioma progression, namely the infiltration of myeloid cells like microglia and macrophages. Hence, these cell types and their specific tasks in tumor progression are subject to ongoing research. However, the distribution of the brain resident microglia and the peripheral macrophages within the tumor tissue and their functional activity are highly debated. Results depend on the method used to discriminate between microglia and macrophages, whereby this specification is already difficult due to limited options to distinguish between these both cell populations that show mostly the same surface markers and morphology. Moreover, there are indications about various functions of microglia and macrophages but again varying on the method of discrimination. In our review, we summarize the current literature to determine which methods have been applied to differentiate the brain resident microglia from tumor-infiltrated macrophages. Furthermore, we compiled data about the proportion of microglia and macrophages in glioma tissues and ascertained if pro- or anti-tumoral effects could be allocated to one or the other myeloid cell population. Recent research made tremendous efforts to distinguish microglia from recruited macrophages. For future studies, it could be essential to verify which role these cells play in brain tumor pathology to proceed with novel immunotherapeutic strategies.

Background Microglia-driven cerebral spreading inflammation is a key contributor to secondary brain injury after SAH. Genetic depletion or deactivation of microglia has been shown to ameliorate neuronal cell death. Therefore, clinically feasible anti-inflammatory approaches counteracting microglia accumulation or activation are interesting targets for SAH treatment. Here, we tested two different methods of interference with microglia-driven cerebral inflammation in a murine SAH model: (i) inflammatory preconditioning and (ii) pharmacological deactivation. Methods 7T-MRI-controlled SAH was induced by endovascular perforation in four groups of C57Bl/6 mice: (i) Sham-operation, (ii) SAH naïve, (iii) SAH followed by inflammatory preconditioning (LPS intraperitoneally), and (iv) SAH followed by pharmacological microglia deactivation (colony-stimulating factor-1 receptor-antagonist PLX3397 intraperitoneally). Microglia accumulation and neuronal cell death (immuno-fluorescence), as well as activation status (RT-PCR for inflammation-associated molecules from isolated microglia) were recorded at day 4 and 14. Toll-like receptor4 (TLR4) status was analyzed using FACS. Results Following SAH, significant cerebral spreading inflammation occurred. Microglia accumulation and pro-inflammatory gene expression were accompanied by neuronal cell death with a maximum on day 14 after SAH. Inflammatory preconditioning as well as PLX3397-treatment resulted in significantly reduced microglia accumulation and activation as well as neuronal cell death. TLR4 surface expression in preconditioned animals was diminished as a sign for receptor activation and internalization. Conclusions Microglia-driven cerebral spreading inflammation following SAH contributes to secondary brain injury. Two microglia-focused treatment strategies, (i) inflammatory preconditioning with LPS and (ii) pharmacological deactivation with PLX3397, led to significant reduction of neuronal cell death. Increased internalization of inflammation-driving TLR4 after preconditioning leaves less receptor molecules on the cell surface, providing a probable explanation for significantly reduced microglia activation. Our findings support microglia-focused treatment strategies to overcome secondary brain injury after SAH. Delayed inflammation onset provides a valuable clinical window of opportunity.

BackgroundMoyamoya disease (MMD) is a cerebrovascular disorder characterized by fragile vascular system. Previous studies suggested that the blood-brain barrier (BBB) destabilizing cytokine angiopoietin-2 plays a critical role in increasing vascular plasticity and endothelial disintegration in MMD. The aim of this study was to assess cerebrovascular integrity in vivo in patients affected by MMD.MethodsWe retrospectively analyzed 11 patients that underwent bypass for MMD (MMD group), 11 patients that underwent bypass for atherosclerotic cerebrovascular disease (ACVD—control group I), and 5 patients that underwent clipping for unruptured aneurysms (non-ischemic—control group II). Sodium fluorescein (NaFL) extravasation was evaluated during videoangiography when checking for bypass patency. A grading system (0, +, ++, +++) was used to define the extent of extravasation. Frequency and intensity of leakage was compared among different groups.ResultsNaFL extravasation appeared in 10/11 (91%) patients with MMD and in 8/11 (73%) patients with ACVD during bypass procedures. Extravasation was observed in none of the patients undergoing clipping for unruptured aneurysms. Although both chronic ischemic patient groups showed a comparably high incidence of NaFL extravasation, the MMD group was characterized by a much greater intensity of NaFL extravasation (grade +++ in 82%) than the ACVD group (grade +++ in 27%, p < 0.05).ConclusionsWe demonstrate blood-brain barrier impairment in MMD patients for the first time in vivo. This may be due to mechanisms intrinsic to the unique pathology of MMD, probably explaining the higher association with hemorrhage and post-operative hyperperfusion.

The authors report on an observational study designed to isolate the impact of navigated transcranial magnetic stimulation (nTMS) on surgical outcome in glioblastoma treatment. We undertook a controlled observational study to identify the additive impact of presurgical nTMS in patients scheduled for surgical treatment of glioblastoma in or near motor eloquent locations. The trial data is derived from a large university hospital with a differential availability of its nTMS mapping service at its two campuses, both equally served by a single neurosurgical department. When available, the nTMS cortical mapping data and nTMS-based fiber tractography are used for surgical planning and patient counseling as well as intraoperative identification of the primary motor cortex and guidance in subcortical motor mapping. The addition of preoperative nTMS mapping data to a clinical routine already incorporating preoperative fiber tractography and intraoperative neuronavigation and electrophysiology was shown to improve surgical outcomes by increasing the extent of resection, without compromising patient safety or long-term functional outcomes in comparison to the concurrent non-TMS control group. This study is the first to prove that the improved surgical outcomes observed in previous studies after the implementation of nTMS to presurgical work-up are not caused by any overall improvement in patient care or a paradigm shift toward more aggressive resection but by the additional functional data provided by nTMS.

Abstract BACKGROUND: Navigated transcranial magnetic stimulation (nTMS) is increasingly used in presurgical brain mapping. Preoperative nTMS results correlate well with direct cortical stimulation (DCS) data in the identification of the primary motor cortex. Repetitive nTMS can also be used for mapping of speech-sensitive cortical areas. OBJECTIVE: The current cohort study compares the safety and effectiveness of preoperative nTMS with DCS mapping during awake surgery for the identification of language areas in patients with left-sided cerebral lesions. METHODS: Twenty patients with tumors in or close to left-sided language eloquent regions were examined by repetitive nTMS before surgery. During awake surgery, language-eloquent cortex was identified by DCS. nTMS results were compared for accuracy and reliability with regard to DCS by projecting both results into the cortical parcellation system. RESULTS: Presurgical nTMS maps showed an overall sensitivity of 90.2%, specificity of 23.8%, positive predictive value of 35.6%, and negative predictive value of 83.9% compared with DCS. For the anatomic Broca's area, the corresponding values were a sensitivity of 100%, specificity of 13.0%, positive predictive value of 56.5%, and negative predictive value of 100%, respectively. CONCLUSION: Good overall correlation between repetitive nTMS and DCS was observed, particularly with regard to negatively mapped regions. Noninvasive inhibition mapping with nTMS is evolving as a valuable tool for preoperative mapping of language areas. Yet its low specificity in posterior language areas in the current study necessitates further research to refine the methodology.

Congenital hydrocephalus is a life-threatening condition that might affect brain development by increasing the pressure on the brain parenchyma. Here, we describe 6 male patients from 1 family, all presenting with an isolated X-linked congenital hydrocephalus. Exome sequencing identified a likely pathogenic variant of angiomotin (AMOT) that segregated with the phenotype in the extended family. We show that the variant, affecting the first methionine, translated into a shorter AMOT protein lacking 91 amino acids from the N-terminus. Mechanistically, we unraveled that the absence of the N-terminus leads to abnormally increased AMOT protein levels due to the loss of both the N-degron degradation signal and the tankyrase-binding domain. Altered degradation of AMOT disrupted the barrier integrity of the cells. Thus, the identified AMOT variant likely underlies the clinical presentation of isolated X-linked hydrocephalus in this family, and our data underscore the importance of tight regulation of AMOT protein level in the brain. AMOT now joins the list of genes involved in congenital hydrocephalus in humans. These findings are instrumental for the genetic counseling of affected families.

Clazosentan, an endothelin receptor antagonist, significantly and dose-dependently reduced angiographic vasospasm after aneurysmal subarachnoid haemorrhage (aSAH). We investigated whether clazosentan reduced vasospasm-related morbidity and all-cause mortality. In this randomised, double-blind, placebo-controlled, phase 3 study, we randomly assigned patients with aSAH secured by surgical clipping to clazosentan (5 mg/h, n=768) or placebo (n=389) for up to 14 days (27 countries, 102 sites, inpatient and outpatient settings) using an interactive web response system. The primary composite endpoint (week 6) included all-cause mortality, vasospasm-related new cerebral infarcts, delayed ischaemic neurological deficit due to vasospasm, and rescue therapy for vasospasm. The main secondary endpoint was dichotomised extended Glasgow outcome scale (GOSE; week 12). This trial is registered with ClinicalTrials.gov, number NCT00558311. In the all-treated dataset, the primary endpoint was met in 161 (21%) of 764 clazosentan-treated patients and 97 (25%) of 383 placebo-treated patients (relative risk reduction 17%, 95% CI −4 to 33; p=0·10). Poor functional outcome (GOSE score ≤4) occurred in 224 (29%) clazosentan-treated patients and 95 (25%) placebo-treated patients (−18%, −45 to 4; p=0·10). Lung complications, anaemia, and hypotension were more common with clazosentan. Mortality (week 12) was 6% in both groups. Clazosentan at 5 mg/h had no significant effect on mortality and vasospasm-related morbidity or functional outcome. Further investigation of patients undergoing endovascular coiling of ruptured aneurysms is needed to fully understand the potential usefulness of clazosentan in patients with aSAH. Actelion Pharmaceuticals.

The average age of our population is increasing, resulting in a high incidence of chronic degenerative knee pathologies. Several treatment options, including surgical procedures are available to help mitigate these pathologies. However, the percentage of subjects with chronic post-surgical knee pain is still estimated at 16–20%. Neuromodulation techniques such as spinal cord stimulation and dorsal root ganglion stimulation (DRGS) are treatment options for subjects with chronic knee pain. The evidence for peripheral nerve stimulation (PNS) is minimal due to a limited number of neuromodulation systems capable of targeting the distal part of the lower limbs. This study aimed to investigate the safety and efficacy externally powered PNS systems for the treatment of chronic intractable knee pain targeting the saphenous nerve. Patients suffering from chronic intractable post-surgical knee pain received landmark-guided peripheral nerve stimulation of the branches of the saphenous nerve. All implants were performed with an externally powered PNS system to avoid lead migration as a result of cross-joint lead positions tunneling towards an Implantable Pulse Generator to the trunk. Data were collected retrospectively. Subject-reported outcome was measured via numerical rating scale values on a 10-point scale measuring pain intensity at rest and in motion. Additional data were collected for the subjects treated at the Charité location, including quality of life with the SF-36 form, quality of sleep with the Pittsburgh Sleep Quality Index and mood states with the short form of the General Depression Scale. Thirty-three patients received direct to permanent implant, landmark-guided peripheral nerve stimulation of the saphenous nerve branches. Six (18.2%) subjects reported non-sufficient initial benefit from the therapy and were explanted. Two subjects were explanted due to wound infections. The total study population reported included 25 patients. These subjects reported significant improvements related to pain, quality of life, mood quality, and quality of sleep. Additionally, subjects were able to reduce their opioid medication significantly after PNS therapy. Externally powered PNS at the saphenous nerve branches is a straightforward, selective and safe technique for patients with chronic knee pain. The landmark-guided implantation technique is less invasive than classical neuromodulation techniques such as spinal cord or DRGS and complication rates remain low. Short-term results are promising and show considerable reductions in pain scores and opioid intake. Long-term results are pending.