Soluble PD-L1 reprograms blood monocytes to prevent cerebral edema and facilitate recovery after ischemic stroke.

Acute cerebral ischemia triggers a profound inflammatory response. While macrophages polarized to an M2-like phenotype clear debris and facilitate tissue repair, aberrant or prolonged macrophage activation is counterproductive to recovery. The inhibitory immune checkpoint Programmed Cell Death Protein 1 (PD-1) is upregulated on macrophage precursors (monocytes) in the blood after acute cerebrovascular injury. To investigate the therapeutic potential of PD-1 activation, we immunophenotyped circulating monocytes from patients and found that PD-1 expression was upregulated in the acute period after stroke. Murine studies using a temporary middle cerebral artery (MCA) occlusion (MCAO) model showed that intraperitoneal administration of soluble Programmed Death Ligand-1 (sPD-L1) significantly decreased brain edema and improved overall survival. Mice receiving sPD-L1 also had higher performance scores short-term, and more closely resembled sham animals on assessments of long-term functional recovery. These clinical and radiographic benefits were abrogated in global and myeloid-specific PD-1 knockout animals, confirming PD-1+ monocytes as the therapeutic target of sPD-L1. Single-cell RNA sequencing revealed that treatment skewed monocyte maturation to a non-classical Ly6Clo, CD43hi, PD-L1+ phenotype. These data support peripheral activation of PD-1 on inflammatory monocytes as a therapeutic strategy to treat neuroinflammation after acute ischemic stroke.

Neurological event prediction for patients with symptomatic cerebral cavernous malformation: the BLED2 score.

OBJECTIVE: Retrospective patient cohort studies have identified risk factors associated with recurrent focal neurological events in patients with symptomatic cerebral cavernous malformations (CCMs). Using a prospectively maintained database of patients with CCMs, this study identified key risk factors for recurrent neurological events in patients with symptomatic CCM. A simple scoring system and risk stratification calculator was then created to predict future neurological events in patients with symptomatic CCMs. METHODS: This was a dual-center, prospectively acquired, retrospectively analyzed cohort study. Adult patients who presented with symptomatic CCMs causing focal neurological deficits or seizures were uniformly treated and clinically followed from the time of diagnosis onward. Baseline variables included age, sex, history of intracerebral hemorrhage, lesion multiplicity, location, eloquence, size, number of past neurological events, and duration since last event. Stepwise multivariable Cox regression was used to derive independent predictors of recurrent neurological events, and predictive accuracy was assessed. A scoring system based on the relative magnitude of each risk factor was devised, and Kaplan-Meier curve analysis was used to compare event-free survival among patients with different score values. Subsequently, 1-, 2-, and 5-year neurological event rates were calculated for every score value on the basis of the final model. RESULTS: In total, 126 (47%) of 270 patients met the inclusion criteria. During the mean (interquartile range) follow-up of 54.4 (12-66) months, 55 patients (44%) experienced recurrent neurological events. Multivariable analysis yielded 4 risk factors: bleeding at presentation (HR 1.92, p = 0.048), large size ≥ 12 mm (HR 2.06, p = 0.016), eloquent location (HR 3.01, p = 0.013), and duration ≤ 1 year since last event (HR 9.28, p = 0.002). The model achieved an optimism-corrected c-statistic of 0.7209. All factors were assigned 1 point, except duration from last event which was assigned 2 points. The acronym BLED2 summarizes the scoring system. The 1-, 2-, and 5-year risks of a recurrent neurological event ranged from 0.6%, 1.2%, and 2.3%, respectively, for patients with a BLED2 score of 0, to 48%, 74%, and 93%, respectively, for patients with a BLED2 score of 5. CONCLUSIONS: The BLED2 risk score predicts prospective neurological events in symptomatic CCM patients.

Minimally Invasive Intracerebral Hematoma Evacuation Using a Novel Cost-Effective Tubular Retractor: Single-Center Experience.

BACKGROUND: Spontaneous intracerebral hematoma (ICH) is a common disease with a dismal overall prognosis. Recent development of minimally invasive ICH evacuation techniques has shown promising results. Commercially available tubular retractors are commonly used for minimally invasive ICH evacuation yet are globally unavailable. METHODS: A novel U.S. $7 cost-effective, off-the-shelf, atraumatic tubular retractor for minimally invasive intracranial surgery is described. Patients with acute spontaneous ICH underwent microsurgical tubular retractor-assisted minimally invasive ICH evacuation using the novel retractor. Patient outcome was retrospectively analyzed and compared with open surgery and with commercial tubular retractors. RESULTS: Ten adult patients with spontaneous supratentorial ICH and median preoperative Glasgow Coma Scale score of 10 were included. ICH involved the frontal lobe, parietal lobe, occipitotemporal region, and solely basal ganglia in 3, 3, 2, and 2 patients, respectively. Mean preoperative ICH volume was 80 mL. Mean residual hematoma volume was 8.7 mL and mean volumetric hematoma reduction was 91% (median, 94%). Seven patients (70%) underwent >90% volumetric hematoma reduction. The total median length of hospitalization was 26 days. On discharge, the median Glasgow Coma Scale score was 12.5 (mean, 11.7). Thirty to 90 days' follow-up data were available for 9 patients (90%). The mean follow-up modified Rankin Scale score was 3.7 and 5 patients (56%) had a modified Rankin Scale score of 3. CONCLUSIONS: The novel cost-effective tubular retractor and microsurgical technique offer a safe and effective method for minimally invasive ICH evacuation. Cost-effective tubular retractors may continue to present a valid alternative to commercial tubular retractors.

Fulminant presentation of a SMARCB1-deficient, anterior cranial fossa tumor in adult.

BACKGROUND: Malignant atypical teratoid rhabdoid tumor (ATRT) usually develops in children. ATRTs are rare in adults, with only one case in the literature describing involvement of the anterior skull base. These primary intracranial tumors are characterized molecularly as SMARCB1 (INI1) deficient. Different types of such SMARCB1-deficient tumors exist in adulthood, usually in the form of extracranial tumors. Very few cases of such a new entity, named SMARCB1-deficient sinonasal carcinoma have been described with intracranial penetration and involvement of the anterior cranial fossa. CASE DESCRIPTION: A 36-year-old male presented with acute cognitive deterioration. Over few hours, he developed a fulminant herniation syndrome. Imaging showed a tumor in the anterior cranial fossa surrounded by massive brain edema. The tumor has destroyed the frontal bone with involvement of the nasal cavities and paranasal sinuses. The patient underwent emergent decompressive craniectomy and tumor debulking but could not be saved. Pathological analysis revealed a highly cellular tumor without rhabdoid cells but with areas of necrosis. Further immunohistochemical stains revealed that neoplastic cells were diffusely and strongly positive for epithelial membrane antigen and P63 and negative for SMARCB1 (i.e., loss of expression), confirming the diagnosis of sinonasal carcinoma. CONCLUSION: To the best of our knowledge, this is the first report of a fulminant presentation of a SMARCB1- deficient tumor in young adult, involving the anterior cranial fossa and the paranasal sinuses. The main differential diagnosis of aggressive, primary, intracranial SMARCB1-deficient tumors in adults includes ATRT, SMARCB1- deficient sinonasal carcinoma, rhabdoid meningioma, and rhabdoid glioblastoma. Atypical tumors involving the anterior skull base without a clear histopathological pattern should therefore be checked for SMARCB1 expression.