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

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.

Author Correction: Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution.

In this Letter, Dominic Grün and Sagar have been added to the author list (affiliated with Max-Planck-Institute of Immunology and Epigenetics (MPI-IE), Freiburg, Germany). The author list, 'Author contribution' and 'Acknowledgements' sections have been corrected online. See accompanying Amendment.

Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution.

Microglia have critical roles not only in neural development and homeostasis, but also in neurodegenerative and neuroinflammatory diseases of the central nervous system1-4. These highly diverse and specialized functions may be executed by subsets of microglia that already exist in situ, or by specific subsets of microglia that develop from a homogeneous pool of cells on demand. However, little is known about the presence of spatially and temporally restricted subclasses of microglia in the central nervous system during development or disease. Here we combine massively parallel single-cell analysis, single-molecule fluorescence in situ hybridization, advanced immunohistochemistry and computational modelling to comprehensively characterize subclasses of microglia in multiple regions of the central nervous system during development and disease. Single-cell analysis of tissues of the central nervous system during homeostasis in mice revealed specific time- and region-dependent subtypes of microglia. Demyelinating and neurodegenerative diseases evoked context-dependent subtypes of microglia with distinct molecular hallmarks and diverse cellular kinetics. Corresponding clusters of microglia were also identified in healthy human brains, and the brains of patients with multiple sclerosis. Our data provide insights into the endogenous immune system of the central nervous system during development, homeostasis and disease, and may also provide new targets for the treatment of neurodegenerative and neuroinflammatory pathologies.

Semiautomated electric source imaging determines epileptogenicity of encephaloceles in temporal lobe epilepsy.

OBJECTIVE: We aimed to assess the ability of semiautomated electric source imaging (ESI) from long-term video-electroencephalographic (EEG) monitoring (LTM) to determine the epileptogenicity of temporopolar encephaloceles (TEs) in patients with temporal lobe epilepsy. METHODS: We conducted a retrospective study involving 32 temporal lobe epilepsy patients with TEs as potentially epileptogenic lesions in structural magnetic resonance imaging scans. Findings were validated through invasive intracerebral stereo-EEG in six of 32 patients and postsurgical outcome after tailored resection of the TE in 17 of 32 patients. LTM (mean duration = 6 days) was performed using the 10/20 system with additional T1/T2 for all patients and sphenoidal electrodes in 23 of 32 patients. Semiautomated detection and clustering of interictal epileptiform discharges (IEDs) were carried out to create IED types. ESI was performed on the averages of the two most frequent IED types per patient, utilizing individual head models, and two independent inverse methods (sLORETA [standardized low-resolution brain electromagnetic tomography], MUSIC [multiple signal classification]). ESI maxima concordance and propagation in spatial relation to TEs were quantified for sources with good signal quality (signal-to-noise ratio > 2, explained signal > 60%). RESULTS: ESI maxima correctly colocalized with a TE in 20 of 32 patients (62.5%) either at the onset or half-rising flank of at least one IED type per patient. ESI maxima showed propagation from the temporal pole to other temporal or extratemporal regions in 14 of 32 patients (44%), confirming propagation originating in the area of the TE. The findings from both inverse methods validated each other in 14 of 20 patients (70%), and sphenoidal electrodes exhibited the highest signal amplitudes in 17 of 23 patients (74%). The concordance of ESI with the TE predicted a seizure-free postsurgical outcome (Engel I vs. >I) with a diagnostic odds ratio of 2.1. SIGNIFICANCE: Semiautomated ESI from LTM often successfully identifies the epileptogenicity of TEs and the IED onset zone within the area of the TEs. Additionally, it shows potential predictive power for postsurgical outcomes in these patients.

Herniation World Federation of Neurosurgical Societies Scale Improves Prediction of Outcome in Patients With Poor-Grade Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Favorable outcomes are seen in up to 50% of patients with World Federation of Neurosurgical Societies (WFNS) grade V aneurysmal subarachnoid hemorrhage. Therefore, the usefulness of the current WFNS grading system for identifying the worst scenarios for clinical studies and for making treatment decisions is limited. We previously modified the WFNS scale by requiring positive signs of brain stem dysfunction to assign grade V. This study aimed to validate the new herniation WFNS grading system in an independent prospective cohort. METHODS: We conducted an international prospective multicentre study in poor-grade aneurysmal subarachnoid hemorrhage patients comparing the WFNS classification with a modified version-the herniation WFNS scale (hWFNS). Here, only patients who showed positive signs of brain stem dysfunction (posturing, anisocoric, or bilateral dilated pupils) were assigned hWFNS grade V. Outcome was assessed by modified Rankin Scale score 6 months after hemorrhage. The primary end point was the difference in specificity of the WFNS and hWFNS grading with respect to poor outcomes (modified Rankin Scale score 4-6). RESULTS: Of the 250 patients included, 237 reached the primary end point. Comparing the WFNS and hWFNS scale after neurological resuscitation, the specificity to predict poor outcome increased from 0.19 (WFNS) to 0.93 (hWFNS) (McNemar, P<0.001) whereas the sensitivity decreased from 0.88 to 0.37 (P<0.001), and the positive predictive value from 61.9 to 88.3 (weighted generalized score statistic, P<0.001). For mortality, the specificity increased from 0.19 to 0.93 (McNemar, P<0.001), and the positive predictive value from 52.5 to 86.7 (weighted generalized score statistic, P<0.001). CONCLUSIONS: The identification of objective positive signs of brain stem dysfunction significantly improves the specificity and positive predictive value with respect to poor outcome in grade V patients. Therefore, a simple modification-presence of brain stem signs is required for grade V-should be added to the WFNS classification. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT02304328.

Mitigation of Blood Load Impact in Patients with Subarachnoid Hemorrhage by Cisternal Lavage.

OBJECT: The initial amount of subarachnoid and ventricular blood is an important prognostic factor for outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). In this comparative study of an unselected aSAH-population, we assess the modifiability of these factors by implementation of blood clearance by cisternal lavage. METHODS: All patients with aSAH treated in our department between October 2011 and October 2019 (8 years, n = 458) were included in our study. In the first 4-year period (BEFORE, n = 237), patients were treated according to international guidelines. In the second 4-year period (AFTER, n = 221), cisternal lavage methods were available and applied in 72 high-risk patients (32.5%). The cisternal and ventricular blood load was recorded by the Hijdra score. Multivariable regression models were used to assess the prognostic significance of risk factors, including blood load, in relation to common aSAH characteristics in both study groups. RESULTS: Worse neurological outcomes (mRS > 3) occurred in the BEFORE population with 41.45% versus 30.77% in the AFTER cohort, 6 months after aSAH (HR: 1.59, 95% CI 1.08-2.34, p = 0.01). Admission WFNS grade, comorbidities (Charlson Comorbidity Index), herniation signs, concomitant intracerebral hemorrhage, and the development of delayed cerebral infarction were strongly associated with poor outcome in both study groups. Intraventricular and cisternal blood load and, particularly, a cast fourth ventricle (Cast 4) represented strong prognosticators of poor neurological outcome in the BEFORE cohort. This effect was lost after implementation of cisternal lavage (AFTER cohort). CONCLUSION: Cisternal and ventricular blood load - in particular: a Cast 4 - represent important prognosticators in patients with aSAH. They are, however, amenable to modification by blood clearing therapies.

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.

Mossy fiber sprouting into the hippocampal region CA2 in patients with temporal lobe epilepsy.

Hippocampal sclerosis (HS) in Temporal Lobe Epilepsy (TLE) shows neuronal death in cornu ammonis (CA)1, CA3, and CA4. It is known that granule cells and CA2 neurons survive and their axons, the mossy fibers (MF), lose their target cells in CA3 and CA4 and sprout to the granule cell layer and molecular layer. We examined in TLE patients and in a mouse epilepsy model, whether MF sprouting is directed to the dentate gyrus or extends to distant CA regions and whether sprouting is associated with death of target neurons in CA3 and CA4. In 319 TLE patients, HS was evaluated by Wyler grade and International League against Epilepsy (ILAE) types using immunohistochemistry against neuronal nuclei (NeuN). Synaptoporin was used to colocalize MF. In addition, transgenic Thy1-eGFP mice were intrahippocampally injected with kainate and sprouting of eGFP-positive MFs was analyzed together with immunocytochemistry for regulator of G-protein signaling 14 (RGS14). In human HS Wyler III and IV as well as in ILAE 1, 2, and 3 specimens, we found synaptoporin-positive axon terminals in CA2 and even in CA1, associated with the extent of granule cell dispersion. Sprouting was seen in cases with cell death of target neurons in CA3 and CA4 (classical severe HS ILAE type 1) but also without this cell death (atypical HS ILAE type 2). Similarly, in epileptic mice eGFP-positive MFs sprouted to CA2 and beyond. The presence of MF terminals in the CA2 pyramidal cell layer and in CA1 was also correlated with the extent of granule cell dispersion. The similarity of our findings in human specimens and in the mouse model highlights the importance and opens up new chances of using translational approaches to determine mechanisms underlying TLE.

Epilepsy surgery: Late seizure recurrence after initial complete seizure freedom.

OBJECTIVE: This study was undertaken to improve understanding of late relapse following epilepsy surgery in pharmacoresistant epilepsy. METHODS: Retrospective comparison was made of 99 of 1278 patients undergoing surgery during 1999-2015 with seizure relapses after at least 2 years of complete seizure freedom with matched controls experiencing continued long-term seizure freedom. Univariate and multivariate analyses were performed. RESULTS: With a mean follow-up of 9.7 years, mean time to seizure relapse was 56.6 months. In multivariate analysis, incomplete resection based on magnetic resonance imaging (MRI), bilateral lesions on preoperative MRI, and epilepsy onset in the first year of life carried a significantly higher risk of late relapse. In patients with late relapse, additional functional imaging with positron emission tomography had been performed significantly more often. Although the differences were not significant in multivariate analysis, doses of antiepileptic drugs were higher in the relapse group preoperatively and in the first 24 months and complete withdrawal was more frequent in the control group (68% vs. 51%). Regarding seizure frequency, most patients had mild seizure relapse (single relapse seizure or <1/month). SIGNIFICANCE: In our predominantly lesional cohort, complete resection of the MRI lesion is the most important factor to maintain long-term seizure freedom. Two patterns of recurrence were identified: (1) incomplete resected lesions with seizure generation in proximity to the initial resection and (2) epileptogenic networks not detected preoperatively or evolving in the postoperative interval and manifesting with new clinical and diagnostic features.

Impact of Stereotactic Ventriculocisternostomy on Delayed Cerebral Infarction and Outcome After Subarachnoid Hemorrhage.

Background and Purpose- Delayed cerebral infarction (DCI) is an important cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (aSAH). Stereotactic catheter ventriculocisternostomy (STX-VCS) and fibrinolytic/spasmolytic lavage is a new method for DCI prevention. Here, we assess the effects of implementing STX-VCS in an unselected aSAH patient population of a tertiary referral center. Methods- Retrospective cohort study of all consecutive aSAH patients admitted to a neurosurgical referral center during a 7-year period (April 2012 to April 2019). Midterm STX-VCS was introduced and offered to patients at high risk for DCI. We compared the incidence and burden of DCI, neurological outcome, and the use of induced hypertension and endovascular rescue therapy in this consecutive aSAH population 3.5 years before versus 3.5 years after STX-VCS became available. Results- Four hundred thirty-six consecutive patients were included: 222 BEFORE and 214 AFTER. Fifty-seven of 214 (27%) patients received STX-VCS. Stereotactic procedures resulted in one (2%) subdural hematoma. Favorable neurological outcome at 6 months occurred in 118 (53%) patients BEFORE and 139 (65%) patients AFTER (relative risk, 0.79 [95% CI, 0.66-0.95]). DCI occurred in 40 (18.0%) patients BEFORE and 17 (7.9%) patients AFTER (relative risk, 0.68 [95% CI, 0.57-0.86]), and total DCI volumes were 8933 (100%) and 3329 mL (36%), respectively. Induced hypertension was used in 97 (44%) and 30 (15%) patients, respectively (relative risk, 0.55 [95% CI, 0.46-0.65]). Thirty (13.5%) patients BEFORE versus 5 (2.3%) patients AFTER underwent endovascular rescue therapies (relative risk, 0.17 [95% CI, 0.07-0.42]). Conclusions- Selecting high-risk patients for STX-VCS reduced the DCI incidence, burden, and related mortality in a consecutive aSAH patient population. This was associated with an improved neurological outcome.

Oligodendrocyte lineage and myelination are compromised in the gray matter of focal cortical dysplasia type IIa.

OBJECTIVES: Focal cortical dysplasias (FCDs) are local malformations of the human neocortex and a leading cause of medically intractable epilepsy. FCDs are characterized by local architectural disturbances of the neocortex and often by a blurred gray-white matter boundary indicating abnormal white matter myelination. We have recently shown that myelination is also compromised in the gray matter of dysplastic areas, since transcripts encoding factors for oligodendrocyte differentiation and myelination are downregulated and myelin fibers appear fractured and disorganized. METHODS: Here, we characterized the gray matter-associated myelination pathology in detail by in situ hybridization, immunohistochemistry, and electron microscopy with markers for myelin, mature oligodendrocytes, and oligodendrocyte precursor cells in tissue sections of FCD IIa and control cortices. In addition, we isolated oligodendrocyte precursor cells from resected dysplastic tissue and performed proliferation assays. RESULTS: We show that the proportion of myelinated gray matter is similar in the dysplastic cortex to that in controls and myelinated fibers extend up to layer III. On the ultrastructural level, however, we found that the myelin sheaths of layer V axons are thinner in dysplastic specimens than in controls. In addition, the density of oligodendrocyte precursor cells and of mature oligodendrocytes was reduced. Finally, we show for the first time that oligodendrocyte precursor cells isolated from resected dysplastic cortex have a reduced proliferation capacity in comparison to controls. SIGNIFICANCE: These results indicate that proliferation and differentiation of oligodendrocyte precursor cells and the formation of myelin sheaths are compromised in FCD and might contribute to the epileptogenicity of this cortical malformation.

Atypical meningioma: progression-free survival in 161 cases treated at our institution with surgery versus surgery and radiotherapy.

Although atypical meningioma recurs frequently in spite of total resection and/or radiotherapy, no consensus on optimal adjuvant management was found. However, several retrospective studies analysed the additional effect of adjuvant radiotherapy in atypical meningioma with inconsistent results. Therefrom, the purpose of this study was to evaluate prognostic factors influencing the recurrence/progression and progression-free survival (PFS) rates of atypical meningioma, particularly focused on the role of postoperative adjuvant radiotherapy. Between February 2001 and March 2015, 161 atypical meningioma resections were performed in our Department of Neurosurgery, of which, 128 cases underwent surgical treatment alone and 33 cases underwent surgery and radiotherapy. Kaplan-Meier analysis was used to provide median point estimates and PFS rates. The Cox-regression model was used in the univariate and multivariate analysis to identify significant factors associated with treatment. The extent of resection (Simpson grade I and II) significantly influenced the risk of recurrence (hazard ratio = 1.8, CI (95%) 1.3-2.6, p-value = 0.0004). There was no significant benefit for progression-free survival after adjuvant radiotherapy (hazard ratio = 1.48, CI (95%) 0.76-2.86, p-value = 0.22). Additionally, meningioma located at the anterior and posterior fossa showed a significantly longer PFS compared to other locations (p-value = 0.03). Adjuvant postoperative radiotherapy had no significant impact on recurrence/progression rate or PFS. The extent of resection according to Simpson grade remains the most important prognostic factor associated with lower recurrence/progression rates and longer PFS in patients with atypical meningioma. The location of the tumours at the anterior or posterior fossa was an independent factor associated with improved PFS.

Stereotactic Catheter Ventriculocisternostomy for Clearance of Subarachnoid Hemorrhage: A Matched Cohort Study.

BACKGROUND AND PURPOSE: Delayed cerebral infarction (DCI) is a major source of morbidity and mortality after aneurysmal subarachnoid hemorrhage. We report a novel intervention-stereotactic catheter ventriculocisternostomy (STX-VCS) and fibrinolytic/spasmolytic lavage therapy-for DCI prevention. Outcomes of 20 consecutive patients are compared with 60 matched controls. METHODS: On the basis of individual treatment decisions, STX-VCS was performed in 20 high-risk aneurysmal subarachnoid hemorrhage patients admitted to our department between September 2015 and October 2016. Three controls matched for age, sex, aneurysm treatment method, and admission Hunt and Hess grade were assigned to each case treated by STX-VCS. DCI was the primary outcome. Mortality and mRS at rehabilitation discharge were secondary outcome parameters. The association between STX-VCS and DCI, mortality, and mRS was assessed by conditional logistic regression. RESULTS: Stereotactic procedures were performed without surgical complications. Continuous cisternal lavage was feasible in 17 of 20 patients (85%). One adverse event because of cisternal lavage was without sequelae. DCI occurred in 25 of 60 (42%) controls and 3 of 20 (15%) patients with STX-VCS (odds ratio, 0.15; 95% confidence interval, 0.04-0.64). Mortality occurred in 20 of 60 (33%) controls and 1 of 20 (5%) patients with STX-VCS, respectively (odds ratio, 0.08; 95% confidence interval, 0.01 - 0.66). Favorable outcome (mRS≤3) at rehabilitation discharge was observed in 12 of 20 patients with STX-VCS (60%) versus 21 of 60 (35%) matched controls (odds ratio, 0.26; 95% confidence interval, 0.8-0.86). CONCLUSIONS: STX-VCS was feasible and safe in patients with severe aneurysmal subarachnoid hemorrhage. Initial results indicate that DCI and mortality can be reduced, and neurological outcome may be improved with this method.

Giant central thoracic disc herniations: surgical outcome in 17 consecutive patients treated by mini-thoracotomy.

PURPOSE: Safe treatment of giant central thoracic disc herniations (cTDHs) remains a surgical challenge due to frequent calcifications, intradural extension and, importantly, the rare exposure of spine surgeons to these lesions. We report our 10-year experience in the management of giant cTDH by mini-thoracotomy and offer a detailed description of the technique. METHODS: 17 patients harboring 17 giant cTDH operated on via a mini-thoracotomy at the authors' institution between 2004 and 2014 were reviewed. All patients presented with myelopathy of varying magnitude. Mean patient age was 47 years. The mean follow-up period was 5.5 years. Median canal compromise of the cTDH was 66 %. cTDH were densely calcified in 7 (41 %), partially calcified in 6 (35 %) and soft in 4 (24 %) patients. Intradural extension of cTDH was noted in six patients (35 %). Benzels' modified myelopathy score of the Japanese Orthopedic Association was adjusted for the evaluation of thoracic myelopathy (mJOA) to assess functional outcomes. RESULTS: Successful removal of the offending cTDH was achieved in all patients. The overall mJOA Score improved from 7.9/13 to 11.1/13. Two patients with giant and densely calcified cTDH experienced a transient post-operative neurological decline. There was a statistically significant correlation between size of cTDH and intradural extension. CONCLUSION: Patients with myelopathy due to giant cTDH can be safely treated by the mini-thoracotomy approach. Postoperative neurological worsening and severe complications or incisional pain are rare. In contrast to complex posterior or thoracoscopic approaches, the mini-thoracotomy is technically straightforward and thus easy to learn for experienced spine surgeons.

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.

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.

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.

Functional hemispheric disconnection procedures for chronic epilepsy: history, indications, techniques, complications and current practice in Europe. A consensus statement on behalf of the EANS functional neurosurgery section.

Introduction: The surgical procedure for severe, drug-resistant, unilateral hemispheric epilepsy is challenging. Over the last decades the surgical landscape for hemispheric disconnection procedures changed from anatomical hemispherectomy to functional hemispherotomy with a reduction of complications and stable good seizure outcome. Here, a task force of European epilepsy surgeons prepared, on behalf of the EANS Section for Functional Neurosurgery, a consensus statement on different aspects of the hemispheric disconnection procedure. Research question: To determine history, indication, timing, techniques, complications and current practice in Europe for hemispheric disconnection procedures in drug-resistant epilepsy. Material and methods: Relevant literature on the topic was collected by a literature search based on the PRISMA 2020 guidelines. Results: A comprehensive overview on the historical development of hemispheric disconnection procedures for epilepsy is presented, while discussing indications, timing, surgical techniques and complications. Current practice for this procedure in European epilepsy surgery centers is provided. At present, our knowledge of long-term seizure outcomes primarily stems from open surgical disconnection procedures. Although minimal invasive surgical techniques in epilepsy are rapidly developing and reported in case reports or small case series, long-term seizure outcome remain uncertain and needs to be reported. Discussion and conclusion: This is the first paper presenting a European consensus statement regarding history, indications, techniques and complications of hemispheric disconnection procedures for different causes of chronic, drug-resistant epilepsy. Furthermore, it serves as the pioneering document to report a comprehensive overview of the current surgical practices regarding this type of surgery employed in renowned epilepsy surgery centers across Europe.

Outcome of Epilepsy Surgery in MRI-Negative Patients Without Histopathologic Abnormalities in the Resected Tissue.

BACKGROUND AND OBJECTIVE: Patients with presumed nonlesional focal epilepsy-based on either MRI or histopathologic findings-have a lower success rate of epilepsy surgery compared with lesional patients. In this study, we aimed to characterize a large group of patients with focal epilepsy who underwent epilepsy surgery despite a normal MRI and had no lesion on histopathology. Determinants of their postoperative seizure outcomes were further studied. METHODS: We designed an observational multicenter cohort study of MRI-negative and histopathology-negative patients who were derived from the European Epilepsy Brain Bank and underwent epilepsy surgery between 2000 and 2012 in 34 epilepsy surgery centers within Europe. We collected data on clinical characteristics, presurgical assessment, including genetic testing, surgery characteristics, postoperative outcome, and treatment regimen. RESULTS: Of the 217 included patients, 40% were seizure-free (Engel I) 2 years after surgery and one-third of patients remained seizure-free after 5 years. Temporal lobe surgery (adjusted odds ratio [AOR]: 2.62; 95% CI 1.19-5.76), shorter epilepsy duration (AOR for duration: 0.94; 95% CI 0.89-0.99), and completely normal histopathologic findings-versus nonspecific reactive gliosis-(AOR: 4.69; 95% CI 1.79-11.27) were significantly associated with favorable seizure outcome at 2 years after surgery. Of patients who underwent invasive monitoring, only 35% reached seizure freedom at 2 years. Patients with parietal lobe resections had lowest seizure freedom rates (12.5%). Among temporal lobe surgery patients, there was a trend toward favorable outcome if hippocampectomy was part of the resection strategy (OR: 2.94; 95% CI 0.98-8.80). Genetic testing was only sporadically performed. DISCUSSION: This study shows that seizure freedom can be reached in 40% of nonlesional patients with both normal MRI and histopathology findings. In particular, nonlesional temporal lobe epilepsy should be regarded as a relatively favorable group, with almost half of patients achieving seizure freedom at 2 years after surgery-even more if the hippocampus is resected-compared with only 1 in 5 nonlesional patients who underwent extratemporal surgery. Patients with an electroclinically identified focus, who are nonlesional, will be a promising group for advanced molecular-genetic analysis of brain tissue specimens to identify new brain somatic epilepsy genes or epilepsy-associated molecular pathways.