Multiomic spatial landscape of innate immune cells at human central nervous system borders

The innate immune compartment of the human central nervous system (CNS) is highly diverse and includes several immune-cell populations such as macrophages that are frequent in the brain parenchyma (microglia) and less numerous at the brain interfaces as CNS-associated macrophages (CAMs). Due to their scantiness and particular location, little is known about the presence of temporally and spatially restricted CAM subclasses during development, health and perturbation. Here we combined single-cell RNA sequencing, time-of-flight mass cytometry and single-cell spatial transcriptomics with fate mapping and advanced immunohistochemistry to comprehensively characterize the immune system at human CNS interfaces with over 356,000 analyzed transcriptomes from 102 individuals. We also provide a comprehensive analysis of resident and engrafted myeloid cells in the brains of 15 individuals with peripheral blood stem cell transplantation, revealing compartment-specific engraftment rates across different CNS interfaces. Integrated multiomic and high-resolution spatial transcriptome analysis of anatomically dissected glioblastoma samples shows regionally distinct myeloid cell-type distributions driven by hypoxia. Notably, the glioblastoma-associated hypoxia response was distinct from the physiological hypoxia response in fetal microglia and CAMs. Our results highlight myeloid diversity at the interfaces of the human CNS with the periphery and provide insights into the complexities of the human brain's immune system.</p

Cross-Species Single-Cell Analysis Reveals Divergence of the Primate Microglia Program

Summary Microglia, the brain-resident immune cells, are critically involved in many physiological and pathological brain processes, including neurodegeneration. Here we characterize microglia morphology and transcriptional programs across ten species spanning more than 450 million years of evolution. We find that microglia express a conserved core gene program of orthologous genes from rodents to humans, including ligands and receptors associated with interactions between glia and neurons. In most species, microglia show a single dominant transcriptional state, whereas human microglia display significant heterogeneity. In addition, we observed notable differences in several gene modules of rodents compared with primate microglia, including complement, phagocytic, and susceptibility genes to neurodegeneration, such as Alzheimer’s and Parkinson’s disease. Our study provides an essential resource of conserved and divergent microglia pathways across evolution, with important implications for future development of microglia-based therapies in humans

A new clinico-pathological classification system for mesial temporal sclerosis

We propose a histopathological classification system for hippocampal cell loss in patients suffering from mesial temporal lobe epilepsies (MTLE). One hundred and seventy-eight surgically resected specimens were microscopically examined with respect to neuronal cell loss in hippocampal subfields CA1–CA4 and dentate gyrus. Five distinct patterns were recognized within a consecutive cohort of anatomically well-preserved surgical specimens. The first group comprised hippocampi with neuronal cell densities not significantly different from age matched autopsy controls [no mesial temporal sclerosis (no MTS); n = 34, 19%]. A classical pattern with severe cell loss in CA1 and moderate neuronal loss in all other subfields excluding CA2 was observed in 33 cases (19%), whereas the vast majority of cases showed extensive neuronal cell loss in all hippocampal subfields (n = 94, 53%). Due to considerable similarities of neuronal cell loss patterns and clinical histories, we designated these two groups as MTS type 1a and 1b, respectively. We further distinguished two atypical variants characterized either by severe neuronal loss restricted to sector CA1 (MTS type 2; n = 10, 6%) or to the hilar region (MTS type 3, n = 7, 4%). Correlation with clinical data pointed to an early age of initial precipitating injury (IPI < 3 years) as important predictor of hippocampal pathology, i.e. MTS type 1a and 1b. In MTS type 2, IPIs were documented at a later age (mean 6 years), whereas in MTS type 3 and normal appearing hippocampus (no MTS) the first event appeared beyond the age of 13 and 16 years, respectively. In addition, postsurgical outcome was significantly worse in atypical MTS, especially MTS type 3 with only 28% of patients having seizure relief after 1-year follow-up period, compared to successful seizure control in MTS types 1a and 1b (72 and 73%). Our classification system appears suitable for stratifying the clinically heterogeneous group of MTLE patients also with respect to postsurgical outcome studies

Mastication after craniotomy: pilot assessment of postoperative oral health-related quality of life

Background!#!Neurosurgical approaches to the brain often require the mobilization of the temporal muscle. Many patients complain of postoperative pain, atrophy, reduced mouth opening, and masticatory problems. Although the pterional, frontolateral-extended-pterional, and temporal craniotomies are the most frequently used approaches in neurosurgery, a systematic assessment of the postoperative oral health-related quality of life has never been performed so far. This study evaluates the oral health-related quality of life of patients after pterional, frontolateral-extended-pterional, or temporal craniotomy using a validated and standardized dental questionnaire, compares the results with the normal values of the general population, and investigates whether this questionnaire is sensitive to changes caused by surgical manipulation of the temporal muscle.!##!Methods!#!The 'Oral Health Impact Profile' (OHIP14) is a validated questionnaire to assess the oral health-related quality of life. It asks the patients to assess their oral health situation within the past 7 days in 14 questions. Possible answers range from 0 (never) to 4 (very often). Sixty patients with benign intracranial processes operated through a lateral cranial approach were included. The questionnaire was answered before surgery (baseline) and 3 months and 15 months after surgery.!##!Results!#!Overall, postoperative OHIP scores increase significantly after 3 months and decrease after 15 months, but not to preoperative values. No factors can be identified which show a considerable relationship with the postoperative OHIP score.!##!Conclusions!#!Postoperative impairment of mouth opening and pain during mastication can be observed 3 to 15 months after surgery and sometimes cause feedback from patients and their dentists. However, in line with existing literature, these complaints decrease with time. The study shows that the OHIP questionnaire is sensitive to changes caused by surgical manipulation of the temporal muscle and can therefore be used to investigate the influence of surgical techniques on postoperative complaints. Postoperatively, patients show worse OHIP scores than the general population, demonstrating that neurosurgical cranial approaches negatively influence the patient's oral health-related wellbeing. Larger studies using the OHIP questionnaire should evaluate if postoperative physical therapy, speech therapy, or specialized rehabilitation devices can improve the masticatory impairment after craniotomy.!##!Trial registration!#!Clinical trial register: DRKS00011096

PEEK Cages versus PMMA Spacers in Anterior Cervical Discectomy: Comparison of Fusion, Subsidence, Sagittal Alignment, and Clinical Outcome with a Minimum 1-Year Follow-Up

Purpose. To compare radiographic and clinical outcomes after anterior cervical discectomy in patients with cervical degenerative disc disease using PEEK cages or PMMA spacers with a minimum 1-year follow-up. Methods. Anterior cervical discectomy was performed in 107 patients in one or two levels using empty PEEK cages (51 levels), Sulcem PMMA spacers (49 levels) or Palacos PMMA spacers (41 levels) between January, 2005 and February, 2009. Bony fusion, subsidence, and sagittal alignment were retrospectively assessed in CT scans and radiographs at follow-up. Clinical outcome was measured using the VAS, NDI, and SF-36. Results. Bony fusion was assessed in 65% (PEEK cage), 57% (Sulcem), and 46% (Palacos) after a mean follow-up of 2.5 years. Mean subsidence was 2.3–2.6 mm without significant differences between the groups. The most pronounced loss of lordosis was found in PEEK cages (−4.1°). VAS was 3.1 (PEEK cage), 3.6 (Sulcem), and 2.7 (Palacos) without significant differences. Functional outcome in the PEEK cage and Palacos group was superior to the Sulcem group. Conclusions. The substitute groups showed differing fusion rates. Clinical outcome, however, appears to be generally not correlated with fusion status or subsidence. We could not specify a superior disc substitute for anterior cervical discectomy. This trial is registered with DRKS00003591

Development of a bleeding scale and hemostasis algorithm in cranial neurosurgery

Effective hemostasis is crucial in neurosurgery as anatomical and functional considerations reduce tolerance for any bleeding. The classification of bleeding severities is a necessary step to enable neurosurgeons to counteract bleeding during surgery.Even though bleeding scales are used for a variety of surgical specialties, they cannot be transferred to cranial neurosurgery without adaption, and no consensus on the nature of such a classification exists to date. Moreover, there is plethora of topical hemostasis products with diverse mechanisms of action and application available. Clinical studies investigating those products used in neurosurgery did not define standardized procedures. This article demonstrates the systematic establishment of both a bleeding scale and a hemostasis algorithm to close this gap in the assessment of intracranial bleeding.The expert panel consisting of 7 members from different neurosurgical centers developed a qualitative bleeding scale with the peculiarities of neurosurgical procedures, based on the experience of each member in daily practice. The hemostasis algorithm is a recommendation for neurosurgeons to aid in the decision-making process to control any sort of bleeding, taking into account the rational use of available hemostatics, depending on type and location of bleeding, as well as the mechanism of action of such agents. Effectiveness of hemostasis, surgery times and economic costs can be optimized by applying the algorithm in daily practice

Kallosotomien bei Sturzanfällen und epileptischen Spasmen

&lt;jats:title&gt;Zusammenfassung&lt;/jats:title&gt;&lt;jats:p&gt;Die Kallosotomie ist eine palliative Operation, die seit fast 80 Jahren bei Patienten mit therapierefraktären, bilateralen Anfällen eingesetzt wird, wenn ein resektives Verfahren nicht möglich ist. Neuere, minimal-invasive Techniken wie die MRT-gesteuerte laserinduzierte Thermokoagulation sind vermutlich vergleichbar bezüglich Outcome und Komplikationsraten, die Datenlage ist aber insgesamt noch spärlich. In vielen Fallserien war die Kallosotomie v. a. in der Reduktion von Sturzanfällen effektiv, in geringerem Ausmaß auch für epileptische Spasmen. Eine vollständige Anfallsfreiheit wird nur sehr selten erreicht. Chirurgische Komplikationen wie Blutungen oder Infektionen treten in etwa 5 % auf. Die wichtigste, jedoch sehr seltene Nebenwirkung der Kallosotomie ist ein Diskonnektionssyndrom mit Apraxie, taktiler und visueller Anomie, Neglect oder SMA(supplementär-motorisches Areal)-Syndrom. Besonders bei Kindern ist das Diskonnektionssyndrom in aller Regel transient. Ob eine anteriore oder eine komplette Kallosotomie durchgeführt wird, variiert von Zentrum zu Zentrum. Komplette Kallosotomien sind hinsichtlich der Anfallsreduktion effizienter, gehen aber mit einem höheren Risiko für Komplikationen und Nebenwirkungen einher. Eine Option ist eine zweistufige Kallosotomie, bei der zunächst eine anteriore Diskonnektion durchgeführt wird und in den Fällen ohne hinreichenden postoperativen Nutzen in einem zweiten Schritt vervollständigt wird.&lt;/jats:p&gt

Minimally Invasive Technique for PMMA Augmentation of Fenestrated Screws

Purpose. To describe the minimally invasive technique for cement augmentation of cannulated and fenestrated screws using an injection cannula as well as to report its safety and efficacy. Methods. A total of 157 cannulated and fenestrated pedicle screws had been cement-augmented during minimally invasive posterior screw-rod spondylodesis in 35 patients from January to December 2012. Retrospective evaluation of cement extravasation and screw loosening was carried out in postoperative plain radiographs and thin-sliced triplanar computed tomography scans. Results. Twenty-seven, largely prevertebral cement extravasations were detected in 157 screws (17.2%). None of the cement extravasations was causing a clinical sequela like a new neurological deficit. One screw loosening was noted (0.6%) after a mean follow-up of 12.8 months. We observed no cementation-associated complication like pulmonary embolism or hemodynamic insufficiency. Conclusions. The presented minimally invasive cement augmentation technique using an injection cannula facilitates convenient and safe cement delivery through polyaxial cannulated and fenestrated screws during minimally invasive screw-rod spondylodesis. Nevertheless, the optimal injection technique and design of fenestrated screws have yet to be identified. This trial is registered with German Clinical Trials DRKS00006726

Stereotactic cisternal lavage in patients with aneurysmal subarachnoid hemorrhage with urokinase and nimodipine for the prevention of secondary brain injury (SPLASH): study protocol for a randomized controlled trial

Background!#!Delayed cerebral infarction (DCI) is a major cause of death and poor neurological outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). Direct intrathecal therapies with fibrinolytic and spasmolytic drugs have appeared promising in clinical trials. However, access to the subarachnoid space for intrathecal drug administration is an unsolved problem so far, especially in patients with endovascular aneurysm securing. We investigate a therapy protocol based on stereotactic catheter ventriculocisternostomy (STX-VCS), a new approach to overcome this problem. The primary objective of this study is to assess whether cisternal lavage with urokinase, nimodipine, and Ringer's solution administered via a stereotactically implanted catheter into the basal cisterns (= investigational treatment (IT)) is safe and improves neurological outcome in patients with aSAH.!##!Methods!#!This is a randomized, controlled, parallel-group, open-label phase II trial. Fifty-four patients with severe aSAH (WFNS grade ≥ 3) will be enrolled at one academic tertiary care center in Southern Germany. Patients will be randomized at a ratio of 1:1 to receive either standard of care only or standard of care plus the IT. The primary endpoint is the proportion of subjects with a favorable outcome on the Modified Rankin Scale (defined as mRS 0-3) at 6 months after aSAH. Further clinical and surrogate outcome parameters are defined as secondary endpoints.!##!Discussion!#!New approaches for the prevention and therapy of secondary brain injury in patients with aSAH are urgently needed. We propose this RCT to assess the clinical safety and efficacy of a novel therapy protocol for intrathecal administration of urokinase, nimodipine, and Ringer's solution.!##!Trial registration!#!Deutsches Register Klinischer Studien (German Clinical Trials Register), DRKS00015645 . Registered on 8 May 2019