From conservative to interventional management in unruptured intracranial aneurysms.

OBJECTIVE: Indication for treatment of unruptured intracranial aneurysms (UIAs) is based on several factors, such as patient age, previous medical history, and UIA location and size. For patients harboring UIAs initially managed noninvasively, the treatment strategy during follow-up (FU) can be changed to include surgical or endovascular intervention. This study aims to identify characteristic patterns and potential predictors of UIAs that require revision of the initial management strategy. METHODS: The authors identified intracranial aneurysm (IA) cases newly diagnosed between 2006 and 2022 and initially assigned conservative management. These cases were retrospectively reviewed for 1) patient and UIA characteristics at the time of diagnosis (patient age, comorbidities, previous medical history, potential risk factors, as well as UIA angioarchitecture, location, and size), and 2) any changes in treatment strategy (reason for change, time until intervention, modality of intervention). RESULTS: Among 1041 IA cases diagnosed in the study period, 144 were initially assigned conservative management. In 10 (6.9%) of these 144 cases, the treatment indication was modified to microsurgical clipping (n = 6) or endovascular embolization (n = 4) after a median FU of 26 months (IQR 8.5-64.5 months). In these 10 cases, the indication for intervention was attributable to IA growth (n = 7), a change in IA configuration (n = 2), or both (n = 1). Exploratory analyses of the effects of UIA size on diagnosis in terms of the hazard for a change of decision suggested an effect starting from 3 mm. No conservatively managed UIAs (n = 144) ruptured during the study period (median FU 24.5 months, IQR 7.75-55.75 months). CONCLUSIONS: The likelihood of a shift to invasive UIA treatment is relatively low if a conservative therapeutic strategy was initially established. However, for cases with changes to the treatment strategy, the change is most often attributable to UIA growth over time. UIAs measuring < 3 mm at initial diagnosis are less likely to be later treated interventionally than those > 3 mm at diagnosis. Therefore, conservatively managed patients with UIAs should be closely monitored with regular radiographic FUs, particularly if the UIA measured > 3 mm at the time of diagnosis.

Effect of cranial entry site on the rate of proximal catheter misplacement in ventriculoperitoneal shunt insertion.

OBJECTIVE: The insertion of a ventriculoperitoneal shunt (VPS) is a common neurosurgical procedure, but the optimal entry site of the ventricular catheter is still under debate. In this study, the authors compare the parietal (Keen's) and frontal (Kocher's) entry sites in terms of the rate of revision surgery due to ventricular catheter misplacement, VPS dysfunction, and VPS infection. METHODS: The authors retrospectively analyzed the data on consecutive adults (age ≥ 18 years) who had undergone primary VPS insertion between 2010 and 2020 at two neurosurgical centers. One center regularly inserts the ventricular catheter frontally (frontal group); the other center, parietally (parietal group). The primary outcome of interest was the rate of ventricular catheter misplacement necessitating revision surgery. Secondary outcomes were functional outcome as measured by the modified Rankin Scale (mRS), rate of revision surgery for VPS dysfunction and infection, as well as early (≤ 30 days) and late (> 30 days) mortality rates. Propensity score matching was performed based on baseline variables, such as normal pressure hydrocephalus, postinfectious hydrocephalus, and idiopathic intracranial hypertension, which were identified as predictors of ventricular catheter misplacement using logistic regression analysis. RESULTS: Among 539 consecutive patients, 301 (55.8%) were in the frontal group and 238 (44.2%) in the parietal group. Postoperative rates of revision surgery due to misplacement were comparable in the two catheter entry site groups (frontal 14 [4.7%] vs parietal 11 [4.6%], p = 0.987). Rates of revision surgery for VPS dysfunction (14 [4.7%] vs 10 [4.2%], respectively, p = 0.802) and infection (22 [7.3%] vs 10 [4.2%], p = 0.13) exhibited no significant differences. Favorable functional outcomes (mRS score ≤ 2; 164 [76.3%] vs 174 [79.5%], respectively, p = 0.058) and early mortality rates (5 [1.7%] vs 6 [2.5%], p = 0.483) were similar between the groups. After propensity score matching, the primary and secondary outcome measures remained comparable between the groups. CONCLUSIONS: The entry site of the ventricular catheter in VPS surgery does not seem to affect proximal revision rates. Further, revision rates due to VPS dysfunction, VPS infection, and morbidity were comparable as well.

Safety and functional outcome analysis of ventriculoperitoneal shunt placement for hydrocephalus within the critical phase of possible delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

Shunt-dependent hydrocephalus (HC) is a common sequela following aneurysmal subarachnoid hemorrhage (aSAH). However, there is still poor evidence regarding the optimal timing of ventriculoperitoneal shunt (VPS) placement, particularly in the context of early aSAH-associated complications such as delayed cerebral ischemia (DCI). The purpose of this study was to compare the impact of early (< 21 days after aSAH) versus late (≥ 21 days after aSAH) VPS placement on the functional clinical outcome. We retrospectively analyzed data from 82 patients with VPS placement after aSAH enrolled in our institutional database between 2011 and 2021. We compared two groups, early VPS placement (< 21 days after aSAH) versus late VPS placement (≥ 21 days after aSAH) in terms of demographics, SAH grading, radiological parameters, externalized cerebrospinal fluid diversions, DCI, VPS variables, and functional outcome. We identified 53 patients with early and 29 patients with late VPS implantation. Baseline variables, such as the modified Rankin Scale (mRS), the World Federation of Neurological Surgeons Scale, the Glasgow Coma Scale, and Fisher grade were not significantly different between the groups. Postoperatively, the mRS (p = 0.0037), the Glasgow Outcome Scale (p = 0.0037), and the extended Glasgow Outcome Scale (p = 0.0032) showed significantly better functional results in patients with early cerebrospinal fluid diversion. The rate of DCI did not differ significantly between the groups (p = 0.53). There was no difference in the rate of VPS placement associated complications (p = 0.44) or overall mortality (p = 0.39). Early shunt implantation, within 21 days after aSAH and therefore during the timeframe of possible DCI, might not be harmful in patients developing HC after aSAH.

Incidence, therapy, and outcome in the management of chronic subdural hematoma in Switzerland: a population-based multicenter cohort study.

Background: Chronic subdural hematoma (cSDH) is a disease affecting mainly elderly individuals. The reported incidence ranges from 2.0/100,000 to 58 per 100,000 person-years when only considering patients who are over 70 years old, with an overall incidence of 8.2-14.0 per 100,000 persons. Due to an estimated doubling of the population above 65 years old between 2000 and 2030, cSDH will become an even more significant concern. To gain an overview of cSDH hospital admission rates, treatment, and outcome, we performed this multicenter national cohort study of patients requiring surgical treatment of cSDH. Methods: A multicenter cohort study included patients treated in 2013 in a Swiss center accredited for residency. Demographics, medical history, symptoms, and medication were recorded. Imaging at admission was evaluated, and therapy was divided into burr hole craniostomy (BHC), twist drill craniostomy (TDC), and craniotomy. Patients' outcomes were dichotomized into good (mRS, 0-3) and poor (mRS, 4-6) outcomes. A two-sided t-test for unpaired variables was performed, while a chi-square test was performed for categorical variables, and a p-value of <0.05 was considered to be statistically significant. Results: A total of 663 patients were included. The median age was 76 years, and the overall incidence rate was 8.2/100,000. With age, the incidence rate increased to 64.2/100,000 in patients aged 80-89 years. The most prevalent symptoms were gait disturbance in 362 (58.6%) of patients, headache in 286 (46.4%), and focal neurological deficits in 252 (40.7%). CSDH distribution was unilateral in 478 (72.1%) patients, while 185 presented a bilateral hematoma with no difference in the outcome. BHC was the most performed procedure for 758 (97.3%) evacuations. CSDH recurrence was noted in 104 patients (20.1%). A good outcome was seen in almost 81% of patients. Factors associated with poor outcomes were age, GCS and mRS on admission, and the occurrence of multiple deficits present at the diagnosis of the cSDH. Conclusion: As the first multicenter national cohort-based study analyzing the disease burden of cSDH, our study reveals that the hospital admission rate of cSDH was 8.2/100,000, while with age, it rose to 64.2/100,000. A good outcome was seen in 81% of patients, who maintained the same quality of life as before the surgery. However, the mortality rate was 4%.

Topographic distribution of inflammation factors in a healing aneurysm.

BACKGROUND: Healing of intracranial aneurysms following endovascular treatment relies on the organization of early thrombus into mature scar tissue and neointima formation. Activation and deactivation of the inflammation cascade plays an important role in this process. In addition to timely evolution, its topographic distribution is hypothesized to be crucial for successful aneurysm healing. METHODS: Decellularized saccular sidewall aneurysms were created in Lewis rats and coiled. At follow-up (after 3 days (n = 16); 7 days (n = 19); 21 days (n = 8)), aneurysms were harvested and assessed for healing status. In situ hybridization was performed for soluble inflammatory markers (IL6, MMP2, MMP9, TNF-α, FGF23, VEGF), and immunohistochemical analysis to visualize inflammatory cells (CD45, CD3, CD20, CD31, CD163, HLA-DR). These markers were specifically documented for five regions of interest: aneurysm neck, dome, neointima, thrombus, and adjacent vessel wall. RESULTS: Coiled aneurysms showed enhanced patterns of thrombus organization and neointima formation, whereas those without treatment demonstrated heterogeneous patterns of thrombosis, thrombus recanalization, and aneurysm growth (p = 0.02). In coiled aneurysms, inflammation markers tended to accumulate inside the thrombus and in the neointima (p < 0.001). Endothelial cells accumulated directly in the neointima (p < 0.0001), and their presence was associated with complete aneurysm healing. CONCLUSION: The presence of proinflammatory cells plays a crucial role in aneurysm remodeling after coiling. Whereas thrombus organization is hallmarked by a pronounced intra-thrombotic inflammatory reaction, neointima maturation is characterized by direct invasion of endothelial cells. Knowledge concerning topographic distribution of regenerative inflammatory processes may pave the way for future treatment modalities which enhance aneurysm healing after endovascular therapy.

Anatomical Variations of the Common Carotid Arteries and Neck Structures of the New Zealand White Rabbit and Their Implications for the Development of Preclinical Extracranial Aneurysm Models.

BACKGROUND: Rabbit models involving neck arteries are of growing importance for the development of preclinical aneurysm models. An optimal understanding of the anatomy is primordial to allow the conception of models while minimizing mortality and morbidity. The aim of this study is to give reliable anatomical landmarks to allow a standardized approach to the neck vessels. METHODS: We performed a necropsy on nine specimens from ongoing experimental studies. We measured the distance between the origins of the right and left common carotid artery (rCCA/lCCA) and between the rCCA and the manubrium sterni (MS). The structures at risk were described. RESULTS: Female New Zealand White rabbits (NZWR) weighing 3.7 ± 0.3 kg and aged 25 ± 5 weeks were included. The rCCA origin was located 9.6 ± 1.2 mm laterally and 10.1 ± 3.3 mm caudally to the MS. In all specimens, the lCCA originated from the aortic arch, together with the brachiocephalic trunk (BCT), and 6.2 ± 3.1 mm proximally to the rCCA origin. The external and internal jugular veins, trachea and laryngeal nerve were the main structures at risk. CONCLUSIONS: The data help to localize both CCAs and their origin to guide surgical approaches with the manubrium sterni as a main landmark. Special attention has to be paid to the trachea, jugular veins and laryngeal nerves.

Usefulness and Reliability of the Bispectral Index during Balanced Anesthesia for Neurovascular Surgery in New Zealand White Rabbits.

Few data about the electroencephalogram and its calculated indices, such as the bispectral index (BIS), have been reported in rabbits. We aimed to evaluate whether a clinically stable anesthesia was mirrored by consistent and stable BIS values and to investigate the effects of modified cerebral blood supply, due to bilateral carotid clamping and re-opening, on BIS values. We also investigated the effects of fentanyl, as an antinociceptive drug, on the BIS. Sixty-eight rabbits undergoing general anesthesia for surgical creation of carotid bifurcation aneurysms were enrolled. The BIS values were recorded at nine selected time points (TPs) during each procedure and before and after fentanyl administration. The BIS values over time were compared with two-way repeated-measures analysis of variance followed by Tukey test, while the Wilcoxon signed rank test was performed to compare values at clamping and re-opening of the carotids as well as before and after fentanyl administration. The BIS values were significantly lower during anesthesia than at the end of anesthesia and at tracheal extubation; no significant differences were found among other TPs. Adequate depth of anesthesia was mirrored by consistent BIS values among rabbits, and alteration of cerebral blood supply did not modify BIS values, except once. Following fentanyl, BIS values did not change in a clinically relevant way.

Incidence and Outcome of Peri-interventional Vasospasm During Endovascular or Microsurgical Treatment of Unruptured Intracranial Aneurysms.

BACKGROUND: Peri-interventional vasospasm (PIVS) is associated with high risk of delayed cerebral vasospasm (DCVS), delayed cerebral ischemia, and poor outcome after aneurysmal subarachnoid hemorrhage. However, the incidence rate associated with treatment of unruptured intracranial aneurysm (UIA) remains unclear. OBJECTIVE: To define the incidence and clinical significance of PIVS in UIA repair based on intraoperative/peri-interventional digital subtraction angiography. METHODS: A consecutive series of 205 patients who underwent UIA treatment by means of microsurgical clipping (n = 109) or endovascular coil embolization (n = 96) was assessed for the occurrence of PIVS. In all cases, PIVS was detected, measured, and classified using intraoperative/peri-interventional digital subtraction angiography. Severity of PIVS, association of PIVS with the development of DCVS, and neurological outcome were analyzed. RESULTS: Intraoperative PIVS was present in n = 14/109 (13%) patients with microsurgical clipping. Of these, caliber irregularities were mild (n = 10), moderate (n = 3), and severe (n = 1). In endovascularly treated patients, 6/96 (6%) developed PIVS, which were either mild (n = 3) or moderate (n = 3). Management in all cases included immediate intensive blood pressure management and application of topical papaverine or intra-arterial nimodipine immediately on detection of PIVS. No patient developed DCVS or lasting neurological deficits attributable to PIVS. CONCLUSION: This series revealed a relatively high overall incidence of PIVS (10%). However, no association of PIVS with the development of DCVS or poor outcome was found. In contrast to ruptured intracranial aneurysms, PIVS in unruptured intracranial aneurysms-if immediately and adequately addressed-seems to be benign and without sequelae for patient's functional outcome.

Risk of intracranial aneurysm recurrence after microsurgical clipping based on 3D digital subtraction angiography.

OBJECTIVE: Current knowledge of recurrence rates after intracranial aneurysm (IA) surgery relies on 2D digital subtraction angiography (DSA), which fails to detect more than 75% of small aneurysm remnants. Accordingly, the discrimination between recurrence and growth of a remnant remains challenging, and actual assessment of recurrence risk of clipped IAs could be inaccurate. The authors report, for the first time, 3D-DSA-based long-term durability and risk factor data of IA recurrence and remnant growth after microsurgical clipping. METHODS: Prospectively collected data for 305 patients, with a total of 329 clipped IAs that underwent baseline 3D-DSA, were evaluated. The incidence of recurrent IA was described by Kaplan-Meier curves. Risk factors for IA recurrence were analyzed by multivariable Cox proportional hazards and logistic regression models. RESULTS: The overall observed proportion of IA recurrence after clipping was 2.7% (9 of 329 IAs) at a mean follow-up of 46 months (0.7% per year). While completely obliterated IAs did not recur during follow-up, incompletely clipped aneurysms (76 of 329) demonstrated remnant growth in 11.8% (3.4% per year). Young age and large initial IA size significantly increased the risk of IA recurrence. CONCLUSIONS: The findings support those in previous studies that hypothesized that completely clipped IAs have an extremely low risk of recurrence. Conversely, the results highlight the significant risk posed by incompletely clipped IAs. Young patients with initial large IAs and incomplete obliteration have an especially high risk for IA recurrence and therefore should be monitored more closely.

The Effect of Losartan on Neuroinflammation as Well as on Endothelin-1- and Serotonin-Induced Vasoconstriction in a Double-Haemorrhage Rat Model.

Poor patient outcome after aneurysmal subarachnoid haemorrhage (SAH) is due to a multifactorial process. Delayed cerebral vasospasm, ischemic neurological deficits, and infarction are the most feared acute sequelae triggered by enhanced synthesis of serotonin and endothelin-1 (ET-1). During the past decades, multiple drugs have been analysed for protective effects without resounding success. Therefore, the authors wanted to analyse the potential beneficial role of Losartan (LOS). Male Sprague Dawley rats were randomised into either a group receiving two injections of blood into the cisterna magna (SAH group) or a group receiving two injections of isotonic sodium chloride (sham group). The animals were culled on day five and basilar artery ring segments were used for in vitro tension studies. Sarafotoxin S6c caused a dose-dependent vasorelaxation in sham and SAH segments, which was more pronounced in sham segments. LOS, applied in a concentration of 10−3 M, was able to significantly reduce serotonin- (p < 0.01) and ET-1- (p < 0.05, p < 0.01) mediated vasoconstriction in sham segments. These findings, along with the well-known beneficial effects of LOS on restoring the impaired endothelin-B1-receptor function after SAH, as well as on the neuroprotectional and antiepileptogenic aspects, might be implemented in advancing tailored concepts to sufficiently ameliorate patients' functional outcome after SAH.

Using a Cell-Tracer Injection to Investigate the Origin of Neointima-Forming Cells in a Rat Saccular Side Wall Model.

Microsurgical clipping creates a subsequent barrier of blood flow into intracranial aneurysms, whereas endovascular treatment relies on neointima and thrombus formation. The source of endothelial cells covering the endoluminal layer of the neointima remains unclear. Therefore, the aim of the present study was to investigate the origin of neointima-forming cells after cell-tracer injection in the already well-established Helsinki rat microsurgical sidewall aneurysm model. Sidewall aneurysms were created by suturing decellularized or vital arterial pouches end-to-side to the aorta in male Lewis rats. Before arteriotomy with aneurysm suture, a cell-tracer injection containing CM-Dil dye was performed into the clamped aorta to label endothelial cells in the adjacent vessel and track their proliferation during follow-up (FU). Treatment followed by coiling (n = 16) or stenting (n = 15). At FU (7 days or 21 days), all rats underwent fluorescence angiography, followed by aneurysm harvesting and macroscopic and histological evaluation with immunohistological cell counts for specific regions of interest. None of the 31 aneurysms had ruptured upon follow-up. Four animals died prematurely. Macroscopically residual perfusion was observed in 75.0% coiled and 7.0% of stented rats. The amount of cell-tracer-positive cells was significantly elevated in decellularized stented compared to coiled aneurysms with respect to thrombus on day 7 (p = 0.01) and neointima on day 21 (p = 0.04). No significant differences were found in thrombus or neointima in vital aneurysms. These findings confirm worse healing patterns in coiled compared to stented aneurysms. Neointima formation seems particularly dependent on the parent artery in decellularized aneurysms, whereas it is supported by the recruitment from aneurysm wall cells in vital cell-rich walls. In terms of translation, stent treatment might be more appropriate for highly degenerated aneurysms, whereas coiling alone might be adequate for aneurysms with mostly healthy vessel walls.

Interrater and intrarater agreement superior for three-dimensional digital subtraction angiography (3D-DSA) over 2D-DSA classification for detecting remnants after intracranial aneurysm clipping, a GRRAS Reliability and Agreement Study.

BACKGROUND: Growing evidence suggests that three-dimensional digital subtraction angiography (3D-DSA) is superior to 2D-DSA in detection of intracranial aneurysm (IA) remnants after clipping. With a simple, practical quantitative scale proposed to measure maximal remnant dimension on 3D-DSA, this study provides a rigorous interrater and intrarater reliability and agreement study comparing this newly established scale with a commonly used (Sindou) 2D-DSA scale. METHOD: Records of 43 patients with clipped IAs harboring various sized remnants who underwent 2D- and 3D-DSA between 2012 and 2018 were evaluated. Using the 2D and 3D scales, six raters scored these remnants and repeated the scoring task 8 weeks later. Interrater and intrarater agreement for both grading schemes were calculated using kappa (κ) statistics. RESULTS: Interrater agreement was highly significant, yielding κ-values at 95% CI (p = 0.000) of 0.225 for the first [0.185; 0.265] and 0.368 s [0.328; 0.408] time points for 2D-DSA and values of 0.700 for the first [0.654; 0.745] and 0.776 s [0.729; 0.822] time points for 3D-DSA. Intrarater agreement demonstrated κ-values between 0.139 and 0.512 for 2D-DSA and between 0.487 and 0.813 for 3D-DSA scores. CONCLUSION: Interrater and intrarater agreement was minimal or weak for 2D-DSA scores, but strong for 3D-DSA scores. We propose that baseline 3D-DSA characterization may prove more reliable when categorizing clipped IA remnants for purposes of risk stratification and lifelong follow-up.

Parent artery-initiated and stent-mediated neointima formation in a rat saccular side wall model.

BACKGROUND: Unlike clipping that forms an immediate barrier of blood flow into intracranial aneurysms, endovascular treatments rely on thrombus organization and neointima formation. Therefore, a continuous endothelial cell layer is crucial to prevent blood flow in the former aneurysm. This study investigates the origin of endothelial cells in the neointima of endovascular treated aneurysms, specifically whether cells from the parent artery play a role in neointima formation. METHODS: In male rats, decellularized and vital side wall aneurysms were treated by coil (n=16) or stent embolization (n=15). The cell tracer CM-Dil dye was injected into the clamped aorta before aneurysm suture to mark initial endothelial cells in the parent artery and enable tracking of their proliferation during follow-up. Aneurysms were analyzed for growth, thrombus formation, and recurrence. Histological evaluation followed with cell counts for specific regions-of-interest. RESULTS: During follow-up, none of the 31 aneurysms ruptured. Macroscopic residual perfusion was observed in 12/16 rats after coiling and in 1/15 after stenting. Amounts of CM-Dil +cells in coiled versus stented decellularized aneurysms significantly decreased in the thrombus on day 7 (p=0.01) and neointima on day 21 (p=0.04). For vital aneurysms, the number of CM-Dil +cells in the neointima on day 21 showed no significant difference. CONCLUSIONS: Healing patterns were worse in coil-treated than stent-treated aneurysms. Cell migration forming a neointima seemed mainly dependent on the adjacent vessel in decellularized aneurysms, but appeared buoyed by recruitment from aneurysm wall cells in vital aneurysms. Therefore, a cell-rich parent artery might be crucial.

Levosimendan as a therapeutic strategy to prevent neuroinflammation after aneurysmal subarachnoid hemorrhage?

BACKGROUND: Poor patient outcomes after aneurysmal subarachnoid hemorrhage (SAH) occur due to a multifactorial process, mainly involving cerebral inflammation (CI), delayed cerebral vasospasm (DCVS), and delayed cerebral ischemia, followed by neurodegeneration. CI is mainly triggered by enhanced synthesis of serotonin (5-HT), prostaglandin F2alpha (PGF2a), and cytokines such as interleukins. Levosimendan (LV), a calcium-channel sensitizer, has already displayed anti-inflammatory effects in patients with severe heart failure. Therefore, we wanted to elucidate its potential anti-inflammatory role on the cerebral vasculature after SAH. METHODS: Experimental SAH was induced by using an experimental double-hemorrhage model. Sprague Dawley rats were harvested on day 3 and day 5 after the ictus. The basilar artery was used for isometric investigations of the muscular media tone. Vessel segments were either preincubated with LV or without, with precontraction performed with 5-HT or PGF2a followed by application of acetylcholine (ACh) or LV. RESULTS: After preincubation with LV 10-4 M and 5-HT precontraction, ACh triggered a strong vasorelaxation in sham segments (LV 10-4 M, Emax 65%; LV 10-5 M, Emax 48%; no LV, Emax 53%). Interestingly, SAH D3 (LV 10-4, Emax 76%) and D5 (LV 10-4, Emax 79%) segments showed greater vasorelaxation compared with sham. An LV series after PGF2a precontraction showed significantly enhanced relaxation in the sham (P=0.004) and SAH groups (P=0.0008) compared with solvent control vessels. CONCLUSIONS: LV application after SAH seems to beneficially influence DCVS by antagonizing 5-HT- and PGF2a-triggered vasoconstriction. Considering this spasmolytic effect, LV might have a role in the treatment of SAH, additionally in selected patients suffering takotsubo cardiomyopathy.

Preclinical and clinical role of interleukin-6 in the development of delayed cerebral vasospasm and neuronal cell death after subarachnoid hemorrhage: towards a potential target therapy?

Delayed cerebral vasospasm (DCVS), early brain injury (EBI), and delayed cerebral ischemia (DCI) are devastating complications after aneurysmal subarachnoid hemorrhage (SAH). Interleukin (IL)-6 seems to be an important interleukin in the inflammatory response after SAH, and many studies describe a strong correlation between IL-6 and worse outcome. The aim of this study was to systematically review preclinical and clinical studies that evaluated systemic and cerebral IL-6 levels after SAH and their relation to DCVS, neuronal cell death, and DCI. We conducted two systematic literature searches using PubMed to identify preclinical and clinical studies evaluating the role of IL-6 after SAH. Suitable articles were selected based on predefined eligibility criteria following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A total of 61 and 30 preclinical and clinical articles, respectively, were included in the systematic reviews. Of the preclinical studies in which IL-6 was measured in cerebrospinal fluid (CSF), parenchyma, and systemically, 100%, 94.4%, and 81.3%, respectively, showed increased expression of IL-6 after SAH. Preclinical results were mirrored by clinical findings in which elevated levels of IL-6 in CSF and plasma were found after SAH, correlating with DCVS, DCI, and worse outcome. Only two preclinical studies analyzed the direct inhibition of IL-6, which resulted in reduced DCVS and neuronal cell death. IL-6 is a marker of intracranial inflammation and plays a role in the pathophysiology of DCVS and DCI after SAH in preclinical animal models and clinical studies. Its inhibition might have therapeutic potential to improve the outcome of SAH patients.

A standardized model for in vitro testing of sutures and patches for watertight dural closure.

OBJECTIVE: CSF leaks are common complications of spinal and cranial surgeries. Several dural grafts and suture techniques are available to achieve watertight dural closure, but the effectiveness of these techniques remains unclear. The authors developed a standardized in vitro model to test available grafts and suture techniques alone or in combination to find the technique with the most watertight dural closure. METHODS: A fluid chamber with a dural fixation device, infusion pump, pressure gauge, and porcine pericardium as a dural equivalent was assembled to provide the reusable device for testing. The authors performed dural closure in 4 different fashions, as follows: A) using running versus simple interrupted suture technique and different suture materials to close a 3-cm incision; B) selecting commonly used sealants and dural patches in combination with a running suture; C) performing duraplasty (1.5 × 1.5-cm square defect) with different dural substitutes in a stand-alone fashion; and D) performing duraplasty with different dural substitutes in a double-layer fashion. Each technique was tested 6 times. The hydrostatic burst pressure (BP) was measured and compared using the Kruskal-Wallis test or the Mann-Whitney U-test. Values are reported as mean ± SD. RESULTS: There was no significant difference between the running and simple interrupted suture technique (p = 0.79). Adding a patch or sealant to a suture resulted in a 1.7- to 14-fold higher BP compared to solitary suture closure (36.2 ± 24.27 cm H2O and 4.58 ± 1.41 cm H2O, respectively; p < 0.001). The highest BP was achieved by adding DuraSeal or TachoSil (82.33 ± 12.72 cm H2O and 74.17 ± 12.64 cm H2O, respectively). For closing a square defect, using a double-layer duraplasty significantly increased BP by a factor of 4-12 compared to a single-layer duraplasty (31.71 ± 12.62 cm H2O vs 4.19 ± 0.88 cm H2O, respectively; p < 0.001). The highest BP was achieved with the combination of Lyomesh and TachoSil (43.67 ± 11.45 cm H2O). CONCLUSIONS: A standardized in vitro model helps to objectify the watertightness of dural closure. It allows testing of sutures and dural grafts alone or in combination. In the authors' testing, a running 6-0 monofilament polypropylene suture combined with DuraSeal or TachoSil was the technique achieving the highest BP. For the duraplasty of square defects, the double-layer technique showed the highest efficacy.

Aspirin treatment prevents inflammation in experimental bifurcation aneurysms in New Zealand White rabbits.

BACKGROUND: Aneurysm wall degeneration is linked to growth and rupture. To address the effect of aspirin (ASA) on aneurysm formation under various wall conditions, this issue was analyzed in a novel rabbit bifurcation model. METHODS: Bifurcation aneurysms created in 45 New Zealand White rabbits were randomized to vital (n=15), decellularized (n=13), or elastase-degraded (n=17) wall groups; each group was assigned to a study arm with or without ASA. At follow-up 28 days later, aneurysms were evaluated for patency, growth, and wall inflammation at macroscopic and histological levels. RESULTS: 36 rabbits survived to follow-up at the end of the trial. None of the aneurysms had ruptured. Patency was visualized in all aneurysms by intraoperative fluorescence angiography and confirmed in 33 (92%) of 36 aneurysms by MRI/MRA. Aneurysm size was significantly increased in the vital (without ASA) and elastase-degraded (with and without ASA) groups. Aneurysm thrombosis was considered complete in three (50%) of six decellularized aneurysms without ASA by MRI/MRA. Locoregional inflammation of the aneurysm complex was significantly reduced in histological analysis among all groups treated with ASA. CONCLUSION: ASA intake prevented inflammation of both the periadventitial tissue and aneurysm wall, irrespective of initial wall condition. Although ASA prevented significant growth in aneurysms with vital walls, this preventive effect did not have an important role in elastase-degraded pouches. In possible translation to the clinical situation, ASA might exert a potential preventive effect during early phases of aneurysm formation in patients with healthy vessels but not in those with highly degenerative aneurysm walls.

Clinical Studies and Pre-clinical Animal Models on Facial Nerve Preservation, Reconstruction, and Regeneration Following Cerebellopontine Angle Tumor Surgery-A Systematic Review and Future Perspectives.

Background and purpose: Tumorous lesions developing in the cerebellopontine angle (CPA) get into close contact with the 1st (cisternal) and 2nd (meatal) intra-arachnoidal portion of the facial nerve (FN). When surgical damage occurs, commonly known reconstruction strategies are often associated with poor functional recovery. This article aims to provide a systematic overview for translational research by establishing the current evidence on available clinical studies and experimental models reporting on intracranial FN injury. Methods: A systematic literature search of several databases (PubMed, EMBASE, Medline) was performed prior to July 2020. Suitable articles were selected based on predefined eligibility criteria following the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines. Included clinical studies were reviewed and categorized according to the pathology and surgical resection strategy, and experimental studies according to the animal. For anatomical study purposes, perfusion-fixed adult New Zealand white rabbits were used for radiological high-resolution imaging and anatomical dissection of the CPA and periotic skull base. Results: One hundred forty four out of 166 included publications were clinical studies reporting on FN outcomes after CPA-tumor surgery in 19,136 patients. During CPA-tumor surgery, the specific vulnerability of the intracranial FN to stretching and compression more likely leads to neurapraxia or axonotmesis than neurotmesis. Severe FN palsy was reported in 7 to 15 % after vestibular schwannoma surgery, and 6% following the resection of CPA-meningioma. Twenty-two papers reported on experimental studies, out of which only 6 specifically used intracranial FN injury in a rodent (n = 4) or non-rodent model (n = 2). Rats and rabbits offer a feasible model for manipulation of the FN in the CPA, the latter was further confirmed in our study covering the radiological and anatomical analysis of perfusion fixed periotic bones. Conclusion: The particular anatomical and physiological features of the intracranial FN warrant a distinguishment of experimental models for intracranial FN injuries. New Zealand White rabbits might be a very cost-effective and valuable option to test new experimental approaches for intracranial FN regeneration. Flexible and bioactive biomaterials, commonly used in skull base surgery, endowed with trophic and topographical functions, should address the specific needs of intracranial FN injuries.

Statins Improve Clinical Outcome After Non-aneurysmal Subarachnoid Hemorrhage: A Translational Insight From a Systematic Review of Experimental Studies.

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.