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Propranolol as a potentially novel treatment of arteriovenous malformations: from bench to bedside
(2022)
Background: Propranolol is a non-selective blocker of the β-adrenergic receptor and has been used for treatment of proliferative infantile hemangiomas. The vasoconstrictive and antiangiogenic effects of propranolol led us to explore its potential application for the treatment of AVMs.
Methods: AVM tissue was cultured after surgical resection in the presence of 100μM propranolol or solvent DMSO. After incubation for 72 hours, tissue was harvested for testing. The expression levels of SDF1α, CXCR4, VEGF and HIF-1 was measured by rt-PCR. Furthermore, data of patients in 2 vascular centres harboring AVM was retrospectively interrogated for a time period of 20 years. The database included information about hemorrhage, AVM size and antihypertensive medication. Descriptive analyses were performed, focusing on the risk of hemorrhage, size of the lesion at presentation and clinical follow-up in patients on β-blocker medication versus those who were not.
Results: Among 483 patients, 73 (15%) were under β-blocker-treatment. 48% AVMs presented with hemorrhage at diagnosis. Patients under β-blocker-treatment had a lower risk of hemorrhage at the time of diagnosis in a univariate analysis (p<0,0001;OR13). Patients under β-blocker-treatment showed a significant higher chance for a lower Spetzler-Martin-grade ≤III (p<0,0001;OR6,5) and a lower risk for the presence of an associated aneurysm (p<0,0001;OR3,6).
Multivariate analysis including Spetzler-Martin-Grading, young age ≤50, presence of associated aneurysm and β-blocker-treatment showed reduced risk for hemorrhage under β-blocker-treatment (p<0,01,OR0,2).
The expression of CXCR4 was suppressed by propranolol most likely through the HIF-1-pathways. The gene-expression of vasculogenesis factors was decreased in with propranolol incubated AVMs.
Conclusion: β-Blocker medication seems to be associated with a decreased risk of AVM-related hemorrhage and AVM-size at presentation or during follow-up. Propranolol inhibits SDF1α-induced vasculogenesis by suppressing the expression of CXCR4 most likely through the HIF-1-pathways. Therefore, SDF1α/CXCR4 axis plays an important role in the vasculogenesis and migration of inflammatory cells in AVM lesions.
Background: To investigate whether patients with critical emergency conditions are seeking or receiving the medical care that they require we characterized the reality of care for patients presenting with Neuro-emergencies during the first phase of the COVID-19 pandemic.
Methods: In this observational, longitudinal cohort study, all neurosurgical admissions that presented to our Department between February 1st and April 15th during the COVID-19 pandemic and during the same time-period in 2019 were identified and categorized according to the presence of a Neuro-emergency, the route of admission, management, and the category of disease. Further, the clinical course of patients with chronic subdural hematoma (cSDH) was investigated as a Neuro-emergency representative for a wide variety of semi-urgent symptoms.
Results: During the pandemic, the percentage of Neuro-emergencies among all neurosurgical admissions remained similar as in 2019 but a larger proportion presented through the emergency department than through the outpatient clinic or by referral (*p=0.009). The total number of Neuro-emergencies was significantly reduced (*p=0.0007) across all types of disease, particularly in severe vascular (*p=0.036) but also in spinal (*p=0.007) and hydrocephalus (*p=0.048) emergencies. Strikingly, elderly patients with cSDH and mild to moderate symptoms presented less frequently, with more severe symptoms (*p=0.046) and were less likely to reach favorable outcome (*p=0.003).
Conclusions: Despite pandemic-related restrictive measures and reallocation of resources, patients with Neuro-emergencies should be encouraged to present regardless of the severity of symptoms because deferred presentation may result in adverse outcome. Thus, conservation of critical healthcare resources remains essential in spite fighting COVID-19.
Background: Following elective craniotomy patients routinely receive monitoring on ICU. However, the benefit of ICU monitoring in these patients is discussed controversially. Due to the current COVID-19 pandemic, there are further limitations of ICU capacities. This study aimed to compare this strategy with a standardized management of post-craniotomy patients on ICU.
Methods: Two postoperative strategies were compared in a matched-pair analysis: The first cohort included patients treated between May-August 2021 according to the “No ICU – unless” concept (NIU group), where patients were managed on the normal ward postoperatively. The second cohort contained patients routinely admitted to the ICU between February-April 2021 (control group). Outcome parameters contained complications, length of stay, duration to first postoperative mobilization, number of unplanned imaging, number/type of ICU interventions and pre- and postoperative mRS. Patient characteristics were analyzed using electronic medical records.
Results: The NIU group consisted of 96 patients, the control group of 75 patients. Complication rates were comparable in both cohorts (16% in NIU vs. 17% in control; p=0.123). Groups did not differ significantly in the number of imaging (10% in NIU vs. 13% in control; p=0.67), in the type of interventions on ICU (antihypertensive therapy 5% (NIU) vs. 6% (control); p=0.825) or in the time to first postoperative mobilization (average 1.1± 1.6 days vs. 0.9± 1.2 days; p=0.402). Length of hospital stay was shorter in the NIU group without reaching statistical significance (average 5.8 vs. 6.8 days; p=0.481). There was no significant change in the distribution of preoperative (p=0.960) and postoperative (p=0.425) mRS scores.
Conclusion: Postoperative ICU management does not reduce postoperative complications and has no effect on the surgical outcome of elective craniotomies. The majority of postoperative complications are detected after a 24-hour observation period. This approach may represent a potential strategy to prevent overutilization of ICU capacities while maintaining sufficient postoperative care for neurosurgical patients.
Background: During the COVID-19 pandemic, decreased volumes of acute stroke admissions were reported. We aimed to examine whether subarachnoid hemorrhage (SAH) volumes demonstrated similar declines in our department. Furthermore, the impact of pandemic on disease progression should be analyzed.
Methods: We conducted a retrospective study in neurosurgical department of university hospital Frankfurt including patients with the diagnosis of aneurysmal SAH during the first year of COVID-pandemic. One year cumulative volume for SAH hospitalization procedures were compared to the one-year period before (03/2020–02/2021 versus 03/2019–02/2020) and the last 5 pre-COVID-pandemic years (2015-2020). All relevant patient characteristics concerning family history, disease history, clinical condition at admission, active/past COVID-infection, treatment management, complications and outcome were analyzed.
Results: There was a decline in SAH hospitalizations, with 84 admissions in the year immediately before and 56 admissions during the pandemic, without reaching a significance. No significant difference in analyzed patient characteristics including clinical condition at onset, treatment, complications and outcome, between 56 SAH patients admitted during COVID pandemic and treated patients in the last 5 years in pre-COVID period were found. Using a multivariable analysis, we detected young age (p<0.05;OR4,2) and no existence of early hydrocephalus (p<0.05;OR0,13) as important factors for a favorable outcome (mRS≤0-2) after aSAH during the COVID-pandemic. A past COVID-infection was detected in young patients suffering from aSAH (Age< 50years, p<0.05;OR10,5) with increased rate of cerebral vasospasm after SAH onset (p<0.05;OR26). Nevertheless, past COVID-infection did not reach a significance as a high risk factor for unfavorable outcome.
Conclusion: There was a relative decrease in the volume of SAH during the COVID-19 pandemic. Despite of extremely different conditions of hospitalization, there was no impairing significant effect on treatment and outcome of admitted SAH patients. A past COVID-infection seemed not to be a relevant limiting factor concerning favorable outcome.
Background: The most frequent therapy of hydrocephalus is the implantation of ventriculoperitoneal shunts for diverting cerebrospinal fluid from the ventricles into the peritoneum. We compared two adjustable valves, the proGAV and proGAV 2.0, for complications which resulted in revision operations.
Methods: Four hundred patients who underwent primary shunt implantation between 2014 and 2020 were analyzed for overall revision rate, one-year revision rate, revision free survival and overall survival observing patient age group, gender, etiology of hydrocephalus, implantation site, prior diversion of cerebrospinal fluid and cause of revision.
Results: All data were available of all 400 patients (female/male 208/192). Overall, 99 patients underwent revision surgery after primary implantation. ProGAV valve was implanted in 283 patients, proGAV 2.0 in 117 patients. There was no significant difference between the two shunt valves concerning revision rate (p=0.8069), one-year revision rate (p=0.9077), revision free survival (p=0.6921) and overall survival (p=0.3232). Furthermore, regarding one-year revision rate, we observed no significant difference between the two shunt valves in pediatric patients (40.7% vs 27.6%; p=0.2247). Revision operation had to be performed more frequently in pediatric patients (46.6% vs 24.8%; p=0.0093) with a significant higher number of total revisions with proGAV than proGAV 2.0 (55.9% vs. 27.6%; p=0.0110) most likely due to longer follow up in the proGAV -group.
Conclusion: According to the target variables we analyzed, aside from lifetime revision rate in pediatric patients there is no significant difference between the two shunt valves. From our subjective point of view, implantation of the newer proGAV 2.0 valve is preferable due to higher adjustment comfort for both patients and physicians.
Oral e-Poster Presentations - Booth 1: Vascular 3, September 27, 2023, 10:00 AM - 10:40 AM
Background: Despite current clinical guidelines recommending suboccipital decompressive craniectomy (SDC) in patients with space-occupying cerebellar infarction when neurological deterioration occurs, the precise definition of such deterioration remains unclear. The current study aimed at characterizing whether clinical outcomes can be predicted by the GCS score immediately prior to SDC, and whether higher GCS scores are associated with better clinical outcomes. We aimed to characterize whether clinical outcomes can be predicted by the GCS score immediately prior to SDC, and if higher GCS scores are associated with better clinical outcomes.
Methods: In a single-center, retrospective analysis of 51 patients treated with SDC for space-occupying cerebellar infarction clinical and imaging data were evaluated at the timepoints of symptom onset, hospital admission and preoperatively. Clinical outcome was measured by mRS at the last available follow-up. Preoperative GCS scores were stratified into three groups (GCS 3-8, 9-11 and 12-15). Univariate and multivariate Cox regression analyses were performed using clinical and radiological parameters as predictors of clinical outcome.
Results: In Cox-regression analysis using mRS of 1-2 as a positive clinical outcome we found a significant increase in the proportional hazard ratio (HR) of 6.581 [CI 1.839-36.414]; p=0.031 for GCS scores of 12-15 prior to SDC. Clinical outcomes (mRS 3-6) were associated with infarct volume above 6.0 cm3 (HR 2.473 [CI 1.209-5.057]; p=0.013), tonsillar herniation (HR: 0.279 [CI 0.083-0.933]; p=0.038), brainstem compression (HR 0.304 [CI 0.123-0.749]; p=0.010) and a preoperative GCS score of 3-8 (HR 2.386 [CI 1.160-4.906]; p=0.018).
Conclusions: SDC should be considered in patients with infarct volumes above 6.0 cm3 with GCS scores higher than previously described in the literature, as these patients may show better long-term outcome than those in which surgery is delayed until a GCS score of 11 or lower.
Oral e-Poster Presentations - Booth 3: Spine 2 (Tumors), September 26, 2023, 4:10 PM - 4:50 PM
Background: Spinal metastasis remains a persistent and oftentimes urgent challenge in the neurosurgical operating room. We aim to understand metastatic spread to the spinal bone on a molecular level in endothelial cells and tumor cells to facilitate improved therapeutic approaches and diagnostics.
Methods: We established a murine syngeneic spinal bone metastasis model. In vivo dissemination was first evaluated using fluorescent beads, followed by murine cancer cell lines (B16, LLC1). We investigated short-term seeding and long-term growth to identify correlations between seeding and tumor formation. EphrinB2-Eph4 interaction has been described as a crucial mediator of spinal bone metastasis. Transient (pharmacological) and permanent (genetical) ephrinB2-Eph4 interventions were performed.
Results: Dissemination of microbeads to distinct spinal segments depended on segment and particle size. Disseminated tumor cells on the contrary showed less frequent arrest in the bone and equal distribution among segments. EphrinB2 intervention changed the dissemination behavior towards the lumbar segment. Interestingly, only transient intervention retained this distribution, permanent ephrinB2 depletion on endothelial cells (efnb2iΔEC) resulted in equal dispersion of metastases. Histological staining revealed a reduction of Endomucin (Emcn) positive structures in combination with a reduction of Type H (Emcn high/CD31 high) endothelial cells in naïve efnb2iΔEC animals. In tumor tissue, these Type H endothelial cells were unaffected. However, an increase in CD31-expressing endothelial cells was observed under endothelial ephrinB2 depletion. These CD31-expressing endothelial cells have been recently described as Type E (Emcn low/CD31 high) and implicated in angiogenesis and osteogenesis.
Conclusions: We here describe a subpopulation of endothelial cells in efnb2iΔEC mice that seems to resemble pro-angiogenic and possibly pro-adhesive type E endothelial cells. Based on these finding we propose a compensatory pro-angiogenic mechanism in efnb2iΔEC mice that is highjacking pre-existing developmental pathways, which is critical for late-stage spinal metastatic growth independent of the initial seeding and extravasation of metastatic cells.