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The efficacy of statin-treatment in aneurysmal subarachnoid hemorrhage (SAH) remains controversial. We aimed to investigate the effects of statin-treatment in non-aneurysmal (na)SAH in accordance with animal research data illustrating the pathophysiology of naSAH. We systematically searched PubMed using PRISMA-guidelines and selected experimental studies assessing the statin-effect on SAH. Detecting the accordance of the applied experimental models with the pathophysiology of naSAH, we analyzed our institutional database of naSAH patients between 1999 and 2018, regarding the effect of statin treatment in these patients and creating a translational concept. Patient characteristics such as statin-treatment (simvastatin 40 mg/d), the occurrence of cerebral vasospasm (CVS), delayed infarction (DI), delayed cerebral ischemia (DCI), and clinical outcome were recorded. In our systematic review of experimental studies, we found 13 studies among 18 titles using blood-injection-animal-models to assess the statin-effect in accordance with the pathophysiology of naSAH. All selected studies differ on study-setting concerning drug-administration, evaluation methods, and neurological tests. Patients from the Back to Bedside project, including 293 naSAH-patients and 51 patients with simvastatin-treatment, were recruited for this analysis. Patients under treatment were affected by a significantly lower risk of CVS (p < 0.01; OR 3.7), DI (p < 0.05; OR 2.6), and DCI (p < 0.05; OR 3). Furthermore, there was a significant association between simvastatin-treatment and favorable-outcome (p < 0.05; OR 3). However, dividing patients with statin-treatment in pre-SAH (n = 31) and post-SAH (n = 20) treatment groups, we only detected a tenuously significant higher chance for a favorable outcome (p < 0.05; OR 0.05) in the small group of 20 patients with statin post-SAH treatment. Using a multivariate-analysis, we detected female gender (55%; p < 0.001; OR 4.9), Hunt&Hess ≤III at admission (p < 0.002; OR 4), no anticoagulant-therapy (p < 0.0001; OR 0.16), and statin-treatment (p < 0.0001; OR 24.2) as the main factors improving the clinical outcome. In conclusion, we detected a significantly lower risk for CVS, DCI, and DI in naSAH patients under statin treatment. Additionally, a significant association between statin treatment and favorable outcome 6 months after naSAH onset could be confirmed. Nevertheless, unified animal experiments should be considered to create the basis for developing new therapeutic schemes.
MRI-detection rate and incidence of lumbar bleeding sources in 190 patients with non-aneurysmal SAH
(2017)
Background: Up to 15% of all spontaneous subarachnoid hemorrhages (SAH) have a non-aneurysmal SAH (NASAH). The evaluation of SAH patients with negative digital subtraction angiography (DSA) is sometimes a diagnostic challenge. Our goal in this study was to reassess the yield of standard MR-imaging of the complete spinal axis to rule out spinal bleeding sources in patients with NASAH.
Methods: We retrospectively analyzed the spinal MRI findings in 190 patients with spontaneous NASAH, containing perimesencephalic (PM) and non-perimesencephalic (NPM) SAH, diagnosed by computer tomography (CT) and/or lumbar puncture (LP), and negative 2nd DSA.
Results: 190 NASAH patients were included in the study, divided into PM-SAH (n = 87; 46%) and NPM-SAH (n = 103; 54%). Overall, 23 (22%) patients had a CT negative SAH, diagnosed by positive LP. MR-imaging of the spinal axis detected two patients with lumbar ependymoma (n = 2; 1,05%). Both patients complained of radicular sciatic pain. The detection rate raised up to 25%, if only patients with radicular sciatic pain received an MRI.
Conclusion: Routine radiological investigation of the complete spinal axis in NASAH patients is expensive and can not be recommended for standard procedure. However, patients with clinical signs of low-back/sciatic pain should be worked up for a spinal pathology.
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: 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.
Anti-inflammatory response of Vitamin D on extracranial vessels after subarachnoid hemorrhage
(2023)
Oral e-Poster Presentations - Booth 1: Vascular A (Aneurysms), September 25, 2023, 1:00 PM - 2:30 PM
Background: Vitamin D has been promoted to vascular regeneration in non-cerebral arteries because of its anti-inflammatory properties. Systematic inflammatory reaction as a multifactorial complication after subarachnoid hemorrhage (SAH), correlated with higher mortality and poor outcome, is the result of a multifactorial mechanism with vasoactive inflammation on extracranial vessels. We therefore hypothesized that vitamin D attenuates the systemic vascular inflammatory reaction.
Methods: We investigated the effect of vitamin D pretreatment (100 ng/kg/d; 5 days) in a blood injection SAH model in adult male C57BL6 mice. Vasomotor function (via wire myograph) of carotid and femoral artery and neurological deficits were measured. Different inflammatory factors such as tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM), were also tested.
Results: A significantly enhanced vasorelaxation was identified in Vitamin D pretreated mice (SAH-VitD versus SAH-control: p<0,001; n=10). Missing a relevant difference in vasocontraction of carotid and femoral artery comparing SAH mice with and without vitamin D treatment, there was a significantly higher endothelial related vasorelaxing effect in treated SAH mice (p<0,01, n=5). Neurological deficits in vitamin D pre-treated SAH mice were significantly decreased (p<0,05; n=10). All tested inflammatory factors were down-regulated in vitamin D pre-treated mice (SAH-VitD versus SAH-control: p<0,0001; n=10).
Conclusions: Extracranial vascular Inflammation after SAH, as one of the influencing components in the follow-up after SAH onset, was significantly attenuated by Vitamin D pretreatment. Furthermore, anti-inflammatory effect of vitamin D resulted in a decrease of extracranial vasoconstriction and neurological deficits. Further research should be focused on vitamin D to optimize therapeutic strategies for SAH patients in critical care units.
Patient care in a neurointensive care unit (neuro-ICU) is challenging. Multidrug-resistant organisms (MDROs) are increasingly common in the routine clinical practice. We evaluated the impact of infection with MDROs on outcomes in patients with subarachnoid hemorrhage (SAH). A single-center retrospective analysis of SAH cases involving patients treated in the neuro-ICU was performed. The outcome was assessed 6 months after SAH using the modified Rankin Scale [mRS, favorable (0–2) and unfavorable (3–6)]. Data were compared by matched-pair analysis. Patient characteristics were well matched in the MDRO (n = 61) and control (n = 61) groups. In this center, one nurse was assigned to a two-bed room. If a MDRO was detected, the patient was isolated, and the nurse was assigned to the patient infected with the MDRO. In the MDRO group, 29 patients (48%) had a favorable outcome, while 25 patients (41%) in the control group had a favorable outcome; the difference was not significant (p > 0.05). Independent prognostic factors for unfavorable outcomes were worse status at admission (OR = 3.1), concomitant intracerebral hematoma (ICH) (OR = 3.7), and delayed cerebral ischemia (DCI) (OR = 6.8). Infection with MRDOs did not have a negative impact on the outcome in SAH patients. Slightly better outcomes were observed in SAH patients infected with MDROs, suggesting the benefit of individual care.
Background: The prognostic factors and outcome of aneurysms appear to be dependent on its locations. Therefore, we compared left- and right- sided aneurysms in patients with aneurysmal subarachnoid hemorrhage (SAH) in terms of differences in outcome and prognostic factors.
Methods: Patients with SAH were entered into a prospectively collected database. A total of 509 patients with aneurysmal subarachnoid hemorrhage were retrospectively selected and stratified in two groups depending on side of ruptured aneurysm (right n = 284 vs. left n = 225). Midline aneurysms of the basilar and anterior communicating arteries were excluded from the analysis. Outcomes were assessed using the modified Rankin Scale (mRS; favorable (mRS 0–2) vs. unfavorable (mRS 3–6)) six months after SAH.
Results: We did not identify any differences in outcome depending on left- and right-sided ruptured aneurysms. In both groups, the significant negative predictive factors included clinical admission status (WFNS IV+V), Fisher 3- bleeding pattern in CT, the occurrence of delayed cerebral ischemia (DCI), early hydrocephalus and later shunt-dependence. The side of the ruptured aneurysm does not seem to influence patients´ outcome. Interestingly, the aneurysm side predicts the side of infarction, with a significant influence on patients´ outcome in case of left-sided infarctions. In addition, the in multivariate analysis side of aneurysm was an independent predictor for the side of cerebral infarctions.
Conclusion: The side of the ruptured aneurysms (right or left) did not influence patients’ outcome. However, the aneurysm-side predicts the side of delayed infarctions and outcome appear to be worse in patients with left-sided infarctions.
BACKGROUND: Systemic thrombolysis with recombinant tissue plasminogen activator (rt-PA) is the standard of acute stroke care. Its potential to increase the risk of secondary intracerebral hemorrhage, especially if administered late, has been ascribed to its proteolytic activity that has detrimental effects on blood-brain barrier (BBB) integrity after stroke. FTY720 has been shown to protect endothelial barriers in several disease models such as endotoxin-induced pulmonary edema and therefore is a promising candidate to counteract the deleterious effects of rt-PA. Besides that, every putative neuroprotectant that will be eventually forwarded into clinical trials should be tested in conjunction with rt-PA.
METHODS: We subjected C57Bl/6 mice to 3 h filament-induced tMCAO and postoperatively randomized them into four groups (n = 18/group) who received the following treatments directly prior to reperfusion: 1) vehicle-treatment, 2) FTY720 1 mg/kg i.p., 3) rt-PA 10 mg/kg i.v. or 4) FTY720 and rt-PA as a combination therapy. We measured functional neurological outcome, BBB disruption by quantification of EB extravasation and MMP-9 activity by gelatin zymography.
RESULTS: We observed a noticeable increase in mortality in the rt-PA/FTY720 cotreatment group (61%) as compared to the vehicle (33%), the FTY720 (39%) and the rt-PA group (44%). Overall, functional neurological outcome did not differ significantly between groups and FTY720 had no effect on rt-PA- and stroke-induced BBB disruption and MMP-9 activation.
CONCLUSIONS: Our data show that FTY720 does not improve functional outcome and BBB integrity in large hemispheric infarctions, neither alone nor in conjunction with rt-PA. These findings stand in contrast to a recently published study that showed beneficial effects of FTY720 in combination with thrombolysis in a thrombotic model of MCAO leading to circumscript cortical infarctions. They might therefore represent a caveat that the coadministration of these two drugs might lead to excess mortality in the setting of a severe stroke.
Short- and long-term effects of rehabilitation after perimesencephalic subarachnoid hemorrhage
(2021)
n about 25% of patients with spontaneous subarachnoid hemorrhage (SAH), a bleeding source cannot be identified during radiological diagnostics. Generally, the outcome of perimesencephalic or prepontine (PM) SAH is known to be significantly better than after non-PM SAH. Data about long-term follow-up concerning physical and mental health are scarce, so this study is reports on long-term results. We measured the influence of PM SAH on a quality-of-life modified Rankin (mRs) scale after six months. For long-term follow-up, a SF-36 questionnaire was used. Questionnaires were sent out between 18 and 168 months after ictus. In 37 patients, a long-term follow-up was available (up to 14 years after SAH). Data detected with the SF-36 questionnaire are compared to reference applicability to the standard population. In total, 37 patients were included for further analysis and divided in 2 subgroups; 13 patients (35%) received subsequent rehabilitation after clinical stay and 24 (65%) did not. In the short-term outcome, a significant improvement from discharge until follow-up was identified in patients with subsequent rehabilitation, but not in the matched pair group without rehabilitation. When PM SAH was compared to the standard population, a reduction in quality of life was identified in physical items (role limitations because of physical health problems, physical functioning) as well as in psychological items (role limitations because of emotional problems). Subsequent rehabilitation on PM SAH patients probably leads to an increase in independence and better mRs. While better mRs was shown at discharge in patients without subsequent rehabilitation, the mRs of rehabilitants was nearly identical after rehabilitation. Patients with good mRs also reached high levels of health-related quality of life (HRQoL) without rehabilitation. Thus, subsequent rehabilitation needs to be encouraged on an individual basis. Indication criteria for subsequent rehabilitation should be defined in further studies to improve patient treatment and efficiency in health care.
Background: Previous studies reported decreased volumes of acute stroke admissions during the COVID-19 pandemic. We aimed to examine whether aneurysmal subarachnoid hemorrhage (aSAH) volumes demonstrated similar declines in our department. Furthermore, the impact of the pandemic on disease progression should be analyzed.
Methods: We conducted a retrospective study in the neurosurgical department of the university hospital Frankfurt including patients with the diagnosis of aSAH during the first year of the COVID pandemic. One year cumulative volume for aSAH hospitalization procedures was compared to the year before (03/2020 – 02/2021 vs. 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: Compared to the 84 hospital admissions during the pre-pandemic years, the number of aSAH hospitalizations (n = 56) declined during the pandemic without reaching significance. No significant difference in the analyzed patient characteristics including clinical condition at onset, treatment, complications, and outcome, between 56 patients with aSAH admitted during the COVID pandemic and the treated patients in the last 5 years in the pre-COVID period were found. In our multivariable analysis, we detected young age (p < 0.05; OR 4.2) and no existence of early hydrocephalus (p < 0.05; OR 0.13) 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; OR 10.5) with an increased rate of cerebral vasospasm after aSAH onset (p < 0.05; OR 26). Nevertheless, past COVID-infection did not reach significance as a high-risk factor for unfavorable outcomes.
Conclusion: There was a relative decrease in the number of patients with aSAH during the COVID-19 pandemic. Despite the extremely different conditions of hospitalization, there was no impairing significant effect on the treatment and outcome of admitted patients with aSAH. A past COVID infection seemed to be an irrelevant limiting factor concerning favorable outcomes.
Background: Unruptured intracranial aneurysm (UIA) poses a therapeutic dilemma in which the risk-benefit analysis of invasive intervention has to be balanced against the natural history of the disease. To date, there is no medical treatment to prevent aneurysm development and subsequent progression to rupture. We explored the vitamin D system because of its known anti-inflammatory and anti-tissue-remodeling effect as a potential treatment for UIA.
Methods: 25-vitaminD3 levels tested between 2008-2016 and data of SAH patients admitted during the months with a peak versus nadir of VitD3-values were analyzed, retrospectively. We prospectively correlated VitD3 with size and number of aneurysms at the rupture time in patients admitted between 2017-2019. An experimental mice shear stress model and cell culture model were used to investigate the effect of 1,25-dihydroxy-vitaminD3 (1,25-VitD3) and acting mediators in this mechanism.
Results: Based on the retrospective analysis demonstrating an increased frequency of aneurysm rupture rate in patients during the low vitamin D period in winter, we started the prospective study evaluating plasma vitamin D levels at admission. VitD levels were inversely correlated with aneurysm size as well as number of aneurysms. Low number of aneurysms was significantly associated with sufficient plasma Vitamin D level as an independent factor in a multivariate analysis.
From bedside back to bench, active 1,25-VitD3 hormone attenuated the natural history of remodeling in mice basilar artery. Deletion of the vitamin-D-receptor in myeloid cells decreased the protective 1,25-VitD3 effect. Cell-culture of vascular fibroblasts confirmed the anti-tissue remodeling effect of 1,25-VitD3.
Conclusion: 1,25-VitD3 attenuates aneurysm development and subsequent progression to rupture. However, VitD-administration should be tested as optional treatment in management of patients with UIA.
Long non-coding RNAs (lncRNAs) can act as regulatory RNAs which, by altering the expression of target genes, impact on the cellular phenotype and cardiovascular disease development. Endothelial lncRNAs and their vascular functions are largely undefined. Deep RNA-Seq and FANTOM5 CAGE analysis revealed the lncRNA LINC00607 to be highly enriched in human endothelial cells. LINC00607 was induced in response to hypoxia, arteriosclerosis regression in non-human primates and also in response to propranolol used to induce regression of human arteriovenous malformations. siRNA knockdown or CRISPR/Cas9 knockout of LINC00607 attenuated VEGF-A-induced angiogenic sprouting. LINC00607 knockout in endothelial cells also integrated less into newly formed vascular networks in an in vivo assay in SCID mice. Overexpression of LINC00607 in CRISPR knockout cells restored normal endothelial function. RNA- and ATAC-Seq after LINC00607 knockout revealed changes in the transcription of endothelial gene sets linked to the endothelial phenotype and in chromatin accessibility around ERG-binding sites. Mechanistically, LINC00607 interacted with the SWI/SNF chromatin remodeling protein BRG1. CRISPR/Cas9-mediated knockout of BRG1 in HUVEC followed by CUT&RUN revealed that BRG1 is required to secure a stable chromatin state, mainly on ERG-binding sites. In conclusion, LINC00607 is an endothelial-enriched lncRNA that maintains ERG target gene transcription by interacting with the chromatin remodeler BRG1.
To clip or coil has been matter of debates for several years and is the domain of interdisciplinary decision making. However, the microsurgical outcome has still been elusive concerning wide neck aneurysms (WNA). A retrospective single center study was performed with all patients with ruptured WNA (rWNA) and unruptured WNA (uWNA) admitted to author´s institute between 2007–2017. Microsurgical outcome was evaluated according to Raymond-Roy occlusion grade and follow-up angiography was performed to analyze the stability of neck/aneurysm remnants and retreatment poverty. Of 805 aneurysms, 139 were rWNA (17.3%) and 148 uWNA (18.4%). Complete occlusion was achieved in 102 of 139 rWNA (73.4%) and 112 of 148 uWNA (75.6%). Neck remnants were observed in 36 patients with rWNA (25.9%) and 30 patients with uWNA (20.3%), 1 (0.7%) and 6 (4.1%) patients had aneurysmal remnant, respectively. Overall complication rate was 11.5%. At follow-up (939/1504 months), all remnants were stable except for one, which was further conservatively treated with marginal retreatment rate under 1%. Even the risk of de-novo aneurysm was higher than the risk for remnant growth (2.6% vs 0% in rWNA; 8.7% vs 5.3% in uWNA) without significant difference. Microsurgical clipping is effective for complete occlusion of r/uWNA with low complication. Furthermore, the risk of remnant growth is marginal even lower than the risk of de-novo rate low retreatment rate.