Myeloid cell replacement is neuroprotective in chronic experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is an autoimmune disease characterized by demyelination of the central nervous system (CNS). Autologous hematopoietic cell transplantation (HCT) shows promising benefits for relapsing-remitting MS in open-label clinical studies, but the cellular mechanisms underlying its therapeutic effects remain unclear. Using single-nucleus RNA sequencing, we identify a reactive myeloid cell state in chronic experimental autoimmune encephalitis (EAE) associated with neuroprotection and immune suppression. HCT in EAE mice results in an increase of the neuroprotective myeloid state, improvement of neurological deficits, reduced number of demyelinated lesions, decreased number of effector T cells and amelioration of reactive astrogliosis. Enhancing myeloid cell incorporation after a modified HCT further improved these neuroprotective effects. These data suggest that myeloid cell manipulation or replacement may be an effective therapeutic strategy for chronic inflammatory conditions of the CNS.

Patient perception and satisfaction in awake burr hole trepanation under local anesthesia for evacuation of chronic subdural hematoma.

Evacuation of chronic subdural hematoma (CSDH) will be one of the most common neurosurgical procedures in the future in the increasingly aging societies. Performing cranial surgery on awake patients may place a psychological burden on them. Aim of this study was to evaluate the psychological distress of patients during awake CSDH relief. Patients with awake evacuation of CSDH via burr hole trepanation were included in our monocentric prospective study. Patient perception and satisfaction were measured using standardized surveys 3-5 days and 6 months after surgery. Among other questionnaires, the Hospital Anxiety and Depression and the Impact of Event Scale, were used to quantify patients' stress. A total of 50 patients (mean age 72.9 years (range 51 - 92)) were included. During surgery, 28 patients reported pain (mean 4.1 (SD 3.3)). Postoperatively, 26 patients experienced pain (mean 2.7 (SD 2.6)). Patients' satisfaction with intraoperative communication was reported with a mean of 8.3 (SD 2.1). There was a significant negative correlation between intraoperatively perceived pain and satisfaction with intraoperative communication (p = 0.023). Good intraoperative communication during evacuation of CSDH in awake patients is associated with positive patient perception and correlates with pain reduction.

A cell therapy approach to restore microglial Trem2 function in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) remains one of the grand challenges facing human society. Much controversy exists around the complex and multifaceted pathogenesis of this prevalent disease. Given strong human genetic evidence, there is little doubt, however, that microglia play an important role in preventing degeneration of neurons. For example, loss of function of the microglial gene Trem2 renders microglia dysfunctional and causes an early-onset neurodegenerative syndrome, and Trem2 variants are among the strongest genetic risk factors for AD. Thus, restoring microglial function represents a rational therapeutic approach. Here, we show that systemic hematopoietic cell transplantation followed by enhancement of microglia replacement restores microglial function in a Trem2 mutant mouse model of AD.

Augmentation of a neuroprotective myeloid state by hematopoietic cell transplantation.

Multiple sclerosis (MS) is an autoimmune disease associated with inflammatory demyelination in the central nervous system (CNS). Autologous hematopoietic cell transplantation (HCT) is under investigation as a promising therapy for treatment-refractory MS. Here we identify a reactive myeloid state in chronic experimental autoimmune encephalitis (EAE) mice and MS patients that is surprisingly associated with neuroprotection and immune suppression. HCT in EAE mice leads to an enhancement of this myeloid state, as well as clinical improvement, reduction of demyelinated lesions, suppression of cytotoxic T cells, and amelioration of reactive astrogliosis reflected in reduced expression of EAE-associated gene signatures in oligodendrocytes and astrocytes. Further enhancement of myeloid cell incorporation into the CNS following a modified HCT protocol results in an even more consistent therapeutic effect corroborated by additional amplification of HCT-induced transcriptional changes, underlining myeloid-derived beneficial effects in the chronic phase of EAE. Replacement or manipulation of CNS myeloid cells thus represents an intriguing therapeutic direction for inflammatory demyelinating disease.

Diffusion tensor imaging changes in patients with glioma-associated seizures.

INTRODUCTION: Structural white matter changes associated with certain epilepsy subtypes have been demonstrated using diffusion tensor imaging (DTI). This observational study aims to identify potential water diffusion abnormalities in glioma patients with associated seizures. METHODS: Two cohorts from two centers were analyzed independently: (A) Prospectively recruited patients diagnosed with glioma who received preoperative DTI to measure mean diffusivity (MD) and fractional anisotropy (FA) in regions-of-interest (ROIs) including the marginal tumor zone (TU), adjacent peritumoral white matter as well as distant ipsilateral and contralateral white matter and cortex. Data were compared between patients with and without seizures and tested for statistical significance. (B) A retrospective cohort using an alternative technical approach sampling ROIs in contrast enhancement, necrosis, non-enhancing tumor, marginal non-enhancing tumor zone, peritumoral tissue, edema and non-tumorous tissue. RESULTS: (A) The prospective study cohort consisted of 23 patients with 12 (52.2%) presenting with a history of seizures. There were no significant seizure-associated differences in MD or FA for non-tumor white matter or cortical areas. MD-TU was significantly lower in patients with seizures (p = 0.005). (B) In the retrospective cohort consisting of 46 patients with a seizure incidence of 50.0%, significantly decreased normalized values of MD were observed for non-enhancing tumor regions of non-glioblastoma multiforme (GBM) cases in patients with seizures (p = 0.022). CONCLUSION: DTI analyses in glioma patients demonstrated seizure-associated diffusion restrictions in certain tumor-related areas. No other structural abnormalities in adjacent or distant white matter or cortical regions were detected.

Transition to a mesenchymal state in neuroblastoma confers resistance to anti-GD2 antibody via reduced expression of ST8SIA1.

Immunotherapy with anti-GD2 antibodies has advanced the treatment of children with high-risk neuroblastoma, but nearly half of patients relapse, and little is known about mechanisms of resistance to anti-GD2 therapy. Here, we show that reduced GD2 expression was significantly correlated with the mesenchymal cell state in neuroblastoma and that a forced adrenergic-to-mesenchymal transition (AMT) conferred downregulation of GD2 and resistance to anti-GD2 antibody. Mechanistically, low-GD2-expressing cell lines demonstrated significantly reduced expression of the ganglioside synthesis enzyme ST8SIA1 (GD3 synthase), resulting in a bottlenecking of GD2 synthesis. Pharmacologic inhibition of EZH2 resulted in epigenetic rewiring of mesenchymal neuroblastoma cells and re-expression of ST8SIA1, restoring surface expression of GD2 and sensitivity to anti-GD2 antibody. These data identify developmental lineage as a key determinant of sensitivity to anti-GD2 based immunotherapies and credential EZH2 inhibitors for clinical testing in combination with anti-GD2 antibody to enhance outcomes for children with neuroblastoma.

False-positive results in transcranial motor evoked potentials for outcome prognostication during surgery for supratentorial lesions.

During monitoring of motor evoked potentials (MEP) elicited by transcranial electrical stimulation (TES) for prognostication of postoperative motor deficit, significant MEP changes without postoperative deterioration of motor function represent false-positive results. We aimed to investigate this phenomenon in a large series of patients who underwent resection of supratentorial lesions. TES was applied in 264 patients during resection of motor-eloquent supratentorial lesions. MEP were recorded bilaterally from arm, leg, and/ or facial muscles. The threshold criterion was applied assessing percentage increase in threshold level, which was considered significant if being > 20% higher on affected side than on the unaffected side. Subcortical stimulation was additionally applied to estimate the distance to corticospinal tract. Motor function was evaluated at 24 h after surgery and at 3-month follow-up. Patients with false-positive results were analyzed regarding tumor location, tumor volume, and characteristics of the monitoring. MEP were recorded from 399 muscles (264 arm muscles, 75 leg muscles, and 60 facial muscles). Motor function was unchanged postoperatively in 359 muscles in 228 patients. Among these cases, the threshold level did not change significantly in 354 muscles in 224 patients, while it increased significantly in the remaining 5 muscles in 4 patients (abductor pollicis brevis in all four patients and orbicularis oris in one patient), leading to a false-positive rate of 1.1%. Tumor volume, opening the ventricle, and negative subcortical stimulation did not significantly correlate with false-positive results, while the tumor location in the parietal lobe dorsal to the postcentral gyrus correlated significantly (p = 0.012, odds ratio 11.2, 95% CI 1.8 to 69.8). False-negative results took place in 1.1% of cases in a large series of TES-MEP monitoring using the threshold criterion. Tumor location in the parietal lobe dorsal to the postcentral gyrus was the only predictor of false-positive results.

Treatment of a genetic brain disease by CNS-wide microglia replacement.

Hematopoietic cell transplantation after myeloablative conditioning has been used to treat various genetic metabolic syndromes but is largely ineffective in diseases affecting the brain presumably due to poor and variable myeloid cell incorporation into the central nervous system. Here, we developed and characterized a near-complete and homogeneous replacement of microglia with bone marrow cells in mice without the need for genetic manipulation of donor or host. The high chimerism resulted from a competitive advantage of scarce donor cells during microglia repopulation rather than enhanced recruitment from the periphery. Hematopoietic stem cells, but not immediate myeloid or monocyte progenitor cells, contained full microglia replacement potency equivalent to whole bone marrow. To explore its therapeutic potential, we applied microglia replacement to a mouse model for Prosaposin deficiency, which is characterized by a progressive neurodegeneration phenotype. We found a reduction of cerebellar neurodegeneration and gliosis in treated brains, improvement of motor and balance impairment, and life span extension even with treatment started in young adulthood. This proof-of-concept study suggests that efficient microglia replacement may have therapeutic efficacy for a variety of neurological diseases.

Cerebral venous outflow profiles are associated with the first pass effect in endovascular thrombectomy.

BACKGROUND: Recent studies found that favorable venous outflow (VO) profiles are associated with higher reperfusion rates after mechanical thrombectomy (MT) in patients with acute ischemic stroke due to large vessel occlusion (AIS-LVO). Fewer retrieval attempts and first-pass revascularization during MT lead to better functional outcomes. OBJECTIVE: To examine the hypothesis that favorable VO profiles assessed on baseline CT angiography (CTA) images correlate with successful vessel reperfusion after the first retrieval attempt and fewer retrieval attempts. METHODS: A multicenter retrospective cohort study of patients with AIS-LVO treated by MT. Baseline CTA was used to determine the cortical vein opacification score (COVES). Favorable VO was defined as COVES ≥3. Primary outcomes were successful with excellent vessel reperfusion status, defined as Thrombolysis in Cerebral Infarction (TICI) 2b/3 and 2c/3 after first retrieval attempt. RESULTS: 617 patients were included in this study, of whom 205 (33.2%) had first pass reperfusion. In univariate analysis, ordinal COVES (p=0.011) values were significantly higher in patients with first pass than in those with non-first pass reperfusion, while the number of patients exhibiting favorable pial arterial collaterals using the Maas scale on CTA did not differ (p=0.243). In multivariable logistic regression analysis, higher COVES were independently associated with TICI 2b/3 (OR=1.25, 95% CI 1.1 to 1.42; p=0.001) and TICI 2c/3 (OR=1.2, 95% CI 1.04 to 1.36; p=0.011) reperfusion after one retrieval attempt, controlling for penumbra volume and time from symptom onset to vessel reperfusion. CONCLUSIONS: Favorable VO, classified as higher COVES, is independently associated with successful and excellent first pass reperfusion in patients with AIS-LVO treated by endovascular thrombectomy.

Traumatic brain injury with concomitant injury to the spleen: characteristics and mortality of a high-risk trauma cohort from the TraumaRegister DGU®.

PURPOSE: Based on the hypothesis that systemic inflammation contributes to secondary injury after initial traumatic brain injury (TBI), this study aims to describe the effect of splenectomy on mortality in trauma patients with TBI and splenic injury. METHODS: A retrospective cohort analysis of patients prospectively registered into the TraumaRegister DGU® (TR-DGU) with TBI (AISHead ≥ 3) combined with injury to the spleen (AISSpleen ≥ 1) was conducted. Multivariable logistic regression modeling was performed to adjust for confounding factors and to assess the independent effect of splenectomy on in-hospital mortality. RESULTS: The cohort consisted of 1114 patients out of which 328 (29.4%) had undergone early splenectomy. Patients with splenectomy demonstrated a higher Injury Severity Score (median: 34 vs. 44, p < 0.001) and lower Glasgow Coma Scale (median: 9 vs. 7, p = 0.014) upon admission. Splenectomized patients were more frequently hypotensive upon admission (19.8% vs. 38.0%, p < 0.001) and in need for blood transfusion (30.3% vs. 61.0%, p < 0.001). The mortality was 20.7% in the splenectomy group and 10.3% in the remaining cohort. After adjustment for confounding factors, early splenectomy was not found to exert a significant effect on in-hospital mortality (OR 1.29 (0.67-2.50), p = 0.45). CONCLUSION: Trauma patients with TBI and spleen injury undergoing splenectomy demonstrate a more severe injury pattern, more compromised hemodynamic status and higher in-hospital mortality than patients without splenectomy. Adjustment for confounding factors reveals that the splenectomy procedure itself is not independently associated with survival.

The Potential of Self-Assessment and Associated Factors for Delayed Symptomatic Hyponatremia Following Transsphenoidal Surgery: A Single Center Experience.

(1) Background: We identified screening parameters and associated factors for delayed, symptomatic hyponatremia (DSH) following inpatient discharge after transsphenoidal surgery (TSS). (2) Methods: In this prospective, monocentric study, 108 patients who underwent TSS for pituitary pathologies were included, provided with a questionnaire and instructed to document urine specific gravity, fluid intake/urine output, body weight and clinical symptoms for every of five days following discharge from hospital. (3) Results: The overall incidence of DSH within 14 days following discharge from the hospital was 14.8% (n = 9). Symptomatic patients presented on average 8.6 days after surgery. Mild DSH was present in 3.3% of the patients, moderate in 1.6% and severe hyponatremia in 9.8% of patients. Female sex (p = 0.02) and lower BMI (p = 0.02), as well as nausea (66.7%; p < 0.01) and emesis (33.3%; p < 0.05), were associated with DSH. A significant weight delta between morning and afternoon weight two days before the event of DSH between both groups (1.26 kg (n = 5) vs. 0.79 kg (n = 52), p < 0.05) was detected. (4) Conclusions: Handing out a symptom questionnaire at discharge seems to be an easy and feasible tool for the detection of DSH after hospital discharge.

Early Prediction of Malignant Cerebellar Edema in Posterior Circulation Stroke Using Quantitative Lesion Water Uptake.

BACKGROUND: Malignant cerebellar edema (MCE) is a life-threatening complication of ischemic posterior circulation stroke that requires timely diagnosis and management. Yet, there is no established imaging biomarker that may serve as predictor of MCE. Early edematous water uptake can be determined using quantitative lesion water uptake, but this biomarker has only been applied in anterior circulation strokes. OBJECTIVE: To test the hypothesis that lesion water uptake in early posterior circulation stroke predicts MCE. METHODS: A total 179 patients with posterior circulation stroke and multimodal admission CT were included. A total of 35 (19.5%) patients developed MCE defined by using an established 10-point scale in follow-up CT, of which ≥4 points are considered malignant. Posterior circulation net water uptake (pcNWU) was quantified in admission CT based on CT densitometry and compared with posterior circulation Acute Stroke Prognosis Early CT Score (pc-ASPECTS) as predictor of MCE using receiver operating curve (ROC) analysis and logistic regression analysis. RESULTS: Acute pcNWU within the early ischemic lesion was 24.6% (±8.4) for malignant and 7.2% (±7.4) for nonmalignant infarctions, respectively (P < .0001). Based on ROC analysis, pcNWU above 14.9% identified MCE with high discriminative power (area under the curve: 0.94; 95% CI: 0.89-0.97). Early pcNWU (odds ratio [OR]: 1.28; 95% CI: 1.15-1.42, P < .0001) and pc-ASPECTS (OR: 0.71, 95% CI: 0.53-0.95, P = .02) were associated with MCE, adjusted for age and recanalization status. CONCLUSION: Quantitative pcNWU in early posterior circulation stroke is an important marker for MCE. Besides pc-ASPECTS, lesion water uptake measurements may further support identifying patients at risk for MCE at an early stage indicating stricter monitoring and consideration for further therapeutic measures.

Real-life analysis of 280 patients with surgically treated acromegaly: a single-center experience from 2008 to 2015.

OBJECTIVE: The purpose of this study was to analyze the clinical and biochemical outcome of consecutive patients with acromegaly after microscopic transsphenoidal surgery (MTS) at a single center over an 8-year period. METHODS: A retrospective analysis of patients with acromegaly treated via MTS between 2008 and 2015 at the authors' center was performed. The mean follow-up was 29 months (range 1-120 months). Parameters investigated included tumor size, pre- and postoperative insulin-like growth factor-I, growth hormone levels, pretreatment, perioperative complications, and clinical outcome. RESULTS: A total of 280 patients with acromegaly were treated surgically at the authors' center over the abovementioned time frame and were included in analyses. For 231 of these patients, complete follow-up data were available for evaluation. One hundred eighty-eight patients (81%) showed remission initially according to current criteria. So far, 23 of these patients relapsed in the further course, so that on follow-up 165 patients (71%) demonstrated full remission by surgery alone. Most patients in whom remission after surgery failed were treated with somatostatin receptor ligands and/or dopamine agonists as second-line treatment. The main postoperative complications included transient hyponatremia and diabetes insipidus (13/280; 4.6%). CSF leakage only occurred in 2 cases (2/280; 0.7%). No surgery-related death occurred. CONCLUSIONS: The data underline the effectiveness of MTS in acromegaly. Many patients with recurrent disease or incomplete tumor resection can be successfully managed pharmacologically.

Operative versus non-operative treatment of traumatic brain injuries in patients 80 years of age or older.

Traumatic brain injury (TBI) in older adults is an increasing issue in modern medicine. Nevertheless, it remains unclear which patients presenting with TBI and 80 years of age or older benefit from an operative treatment. The aim of this study was to explore the effect of an operative treatment in isolated TBI patients ≥ 80 years of age. Data were derived from the TraumaRegister DGU® from 2002 to 2016. Inclusion criteria were ≥ 80 years of age, an Abbreviated Injury ScaleHead (AIS) ≥ 3, and an AISNon-Head ≤ 1. The cohort was split in operatively and non-operatively treated patients, and outcome was assessed at discharge using the Glasgow Outcome Scale (GOS). A favorable outcome was defined as a GOS of 4 or 5. A total of 1.693 patients (431 operatively and 1.262 non-operatively treated patients) were analyzed. Mortality rate was 54.4% (687 patients) in the non-operative group and 49.4% in the operative group. Simultaneously, there were more patients discharged with a GOS 2 (persistent vegetative state) in the operative group (7.9%, 34 patients) than in the non-operative group (1.0%, 13 patients). An analysis of the operatively treated patients showed an association between a higher mortality risk and brainstem hemorrhage (p = 0.04), fixed pupils (p = 0.001), initial intubation (p = 0.03), and an AISHead of 5/6 (p = 0.03). Patients 80 years of age or older seem to benefit from an operative treatment regarding mortality rate. However, there has been a higher rate of a poor neurological outcome particularly with regard to persistent vegetative state in the operative treatment group at discharge.

The role of frameless stereotactic biopsy in contemporary neuro-oncology: molecular specifications and diagnostic yield in biopsied glioma patients.

INTRODUCTION: With the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO), diagnosis of glioma is based on molecular parameters in addition to histology potentially leading to additional demands on quality of tissue samples. This may challenge the role of minimally invasive biopsy procedures. This study aims to evaluate the diagnostic yield of glioma samples from frameless stereotactic biopsies with focus on molecular information and explore the neuromolecular profile of a glioma biopsy cohort. METHODS: In a case series analysis, 180 consecutive frameless stereotactic biopsies with the Brainlab® Varioguide system from January 2011 to October 2017 were reviewed and patients with suspected or verified glioma were identified. Neuropathological samples were reprocessed in accordance with 2016 CNS WHO standards. RESULTS: One hundred nineteen glioma patients were identified. Analysis of IDH status could be performed in 95.8% resulting in a cumulative mutation rate of 9.6%. A complete diagnosis according to 2016 CNS WHO including grading and molecular features was achieved in 110 cases (92.4%). Entities were revised in four cases. Most common diagnosis was IDH-wildtype glioblastoma (66.4%) followed by IDH-wildtype anaplastic astrocytoma (21.8%). CONCLUSIONS: A formally complete diagnosis according to 2016 CNS WHO was achieved in the majority of cases. The biopsy cohort showed a prognostically unfavorable distribution of diagnoses and molecular features. Frameless stereotactic biopsy seems to be confirmed as a useful diagnostic tool in contemporary neuro-oncology-however, certain potential limitations should be considered.

Prior malignancies in patients harboring glioblastoma: an institutional case-study of 2164 patients.

More patients are surviving long-term following a cancer diagnosis and as such are at risk for second malignancies. As the most common primary brain tumor, glioblastoma (GBM) will not infrequently occur in this population. No study has examined the incidence of prior cancer (PC) in patients harboring GBM. Here we evaluate the epidemiological features, as well as the molecular and clinical characteristics of GBM as a second cancer. Utilizing a web-based cancer data management system at our institution, we identified 2164 patients harboring GBM from 2007 to 2014. We collected baseline demographic, molecular, and clinical data. Univariate analysis was performed to compare the cohort of GBM patients with and without PC diagnosis. Survival differences were analyzed with Kaplan-Meier and log-rank testing. A Cox-proportional hazards model was fit for multivariable analysis. 170 patients (7.9%) harboring GBM had a PC diagnosis. The median interval between diagnoses was 79 months. The most common pathologies were breast (18.8%) and prostate (18.8%) cancer. Patients with a PC were older at the time of GBM diagnosis than those without PC (66 vs. 59 years, p < 0.001) and were more likely to be white (88.2 vs. 72.8%, p < 0.001). Patients with PC were more likely to harbor an EGFR (20 vs. 12.3%, p < 0.001) or MGMT mutation (17.6 vs. 11.6%, p < 0.001). Median survival was 13 months in the PC cohort and 15 months in the cohort without PC (p = NS). Age, KPS, and diagnosis year were the only factors which influenced outcome in multivariable analysis. Patients who develop GBM following a prior malignancy constitute ~8% of patients with GBM. Despite significant molecular differences these two cohorts appear to have a similar overall prognosis and clinical course. Thus, whether or not a patient harbors a malignancy prior to diagnosis of GBM should not exclude him or her from aggressive treatment or for consideration of novel investigational therapies.