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Background: Delayed cerebral ischemia (DCI) is one of the main contributors to poor clinical outcome after aneurysmal subarachnoid hemorrhage (SAH). Endovascular spasmolysis with intra-arterial nimodipine (IAN) may resolve angiographic vasospasm, but its effect on infarct prevention and clinical outcome is still unclear. We report the effect of IAN on infarction rates and functional outcome in a consecutive series of SAH patients., Methods: To assess the effectiveness of IAN, we collected functional outcome data of all SAH patients referred to a single tertiary center since its availability (2011-2020). IAN was primarily reserved as a last tier option for DCI refractory to induced hypertension (iHTN). Functional outcome was assessed after 12 months according to the Glasgow Outcome Scale (GOS, favorable outcome = GOS4-5)., Results: Out of 376 consecutive SAH patients, 186 (49.5%) developed DCI. Thereof, a total of 96 (25.5%) patients remained unresponsive to iHTN and received IAN. DCI-related infarction was observed in 44 (45.8%) of IAN-treated patients with a median infarct volume of 111.6 mL (Q 1 : 51.6 to Q 3 : 245.7). Clinical outcome was available for 84 IAN-treated patients. Of those, a total of 40 (47.6%) patients reached a favorable outcome after 1 year. Interventional complications were observed in 9 (9.4%) of the IAN-treated patients., Conclusion: Intra-arterial spasmolysis using nimodipine infusion was associated with low treatment specific complications. Despite presenting a subgroup of severely affected SAH patients, almost half of IAN-treated patients were able to lead an independent life after 1 year of follow-up., Trial Registration Number: German Clinical Trial Register DRKS00030505., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cerebral autoregulation (CA) can be impaired in patients with delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). The Pressure Reactivity Index (PRx, correlation of blood pressure and intracranial pressure) and Oxygen Reactivity Index (ORx, correlation of cerebral perfusion pressure and brain tissue oxygenation, PbtO 2 ) are both believed to estimate CA. We hypothesized that CA could be poorer in hypoperfused territories during DCI and that ORx and PRx may not be equally effective in detecting such local variances., Methods: ORx and PRx were compared daily in 76 patients with aSAH with or without DCI until the time of DCI diagnosis. The ICP/PbtO 2 -probes of DCI patients were retrospectively stratified by being in or outside areas of hypoperfusion via CT perfusion image, resulting in three groups: DCI + /probe + (DCI patients, probe located inside the hypoperfused area), DCI + /probe-  (probe outside the hypoperfused area), DCI-  (no DCI)., Results: PRx and ORx were not correlated (r = - 0.01, p = 0.56). Mean ORx but not PRx was highest when the probe was located in a hypoperfused area (ORx DCI + /probe + 0.28 ± 0.13 vs. DCI + /probe-  0.18 ± 0.15, p < 0.05; PRx DCI + /probe + 0.12 ± 0.17 vs. DCI + /probe-  0.06 ± 0.20, p = 0.35). PRx detected poorer autoregulation during the early phase with relatively higher ICP (days 1-3 after hemorrhage) but did not differentiate the three groups on the following days when ICP was lower on average. ORx was higher in the DCI + /probe + group than in the other two groups from day 3 onward. ORx and PRx did not differ between patients with DCI, whose probe was located elsewhere, and patients without DCI (ORx DCI + /probe-  0.18 ± 0.15 vs. DCI-  0.20 ± 0.14; p = 0.50; PRx DCI + /probe-  0.06 ± 0.20 vs. DCI-  0.08 ± 0.17, p = 0.35)., Conclusions: PRx and ORx are not interchangeable measures of autoregulation, as they likely measure different homeostatic mechanisms. PRx represents the classical cerebrovascular reactivity and might be better suited to detect disturbed autoregulation during phases with moderately elevated ICP. Autoregulation may be poorer in territories affected by DCI. These local perfusion disturbances leading up to DCI may be more readily detected by ORx than PRx. Further research should investigate their robustness to detect DCI and to serve as a basis for autoregulation-targeted treatment after aSAH., (© 2023. The Author(s).)

Induced pluripotent stem cell-derived brain organoids enable the developmental complexities of the human brain to be deconstructed. During embryogenesis, optic vesicles (OVs), the eye primordium attached to the forebrain, develop from diencephalon. However, most 3D culturing methods generate either brain or retinal organoids individually. Here we describe a protocol to generate organoids with both forebrain entities, which we call OV-containing brain organoids (OVB organoids). In this protocol, we first induce neural differentiation (days 0-5) and collect neurospheres, which we culture in a neurosphere medium to initiate their patterning and further self-assembly (days 5-10). Then, upon transfer to spinner flasks containing OVB medium (days 10-30), neurospheres develop into forebrain organoids with one or two pigmented dots restricted to one pole, displaying forebrain entities of ventral and dorsal cortical progenitors and preoptic areas. Further long-term culture results in photosensitive OVB organoids constituting complementary cell types of OVs, including primitive corneal epithelial and lens-like cells, retinal pigment epithelia, retinal progenitor cells, axon-like projections and electrically active neuronal networks. OVB organoids provide a system to help dissect interorgan interactions between the OVs as sensory organs and the brain as a processing unit, and can help model early eye patterning defects, including congenital retinal dystrophy. To conduct the protocol, experience in sterile cell culture and maintenance of human induced pluripotent stem cells is essential; theoretical knowledge of brain development is advantageous. Furthermore, specialized expertise in 3D organoid culture and imaging for the analysis is needed., (© 2023. Springer Nature Limited.)

Many recent research projects have described typical chronic changes in the retinal vasculature for diverse neurovascular and neurodegenerative disorders such as stroke or Alzheimer's disease. Unlike cerebral vasculature, retinal blood vessels can be assessed non-invasively by retinal vessel analysis. To date, there is only a little information about potential simultaneous reactions of retinal and cerebral vessels in acute neurovascular diseases. The field of applications of retinal assessment could significantly be widened if more information about potential correlations between those two vascular beds and the feasibility of non-invasive retinal vessel analysis in acute neurovascular disease were available. Here, we present our protocol for the simultaneous assessment of retinal and cerebral vessels in an acute setting in anesthetized rats using a non-invasive retinal vessel analyzer and a superficial tissue imaging system for laser speckle contrast analysis via a closed bone window. We describe the experimental set-up in detail, outline the pitfalls of repeated retinal vessel analyses in an experimental set-up of several hours, and address issues that arise from the simultaneous use of two different assessment tools. Finally, we demonstrate the robustness and variability of the reactivity of retinal vessels to hypercapnia at baseline as well as their reproducibility over time using two anesthetic protocols common for neurovascular research. In summary, the procedures described in this protocol allow us to directly compare retinal and cerebral vascular beds and help to substantiate the role of the retina as a "window to the brain.", Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Warner, Bach-Hagemann, Schmidt, Pinkernell, Schubert, Clusmann, Albanna, Lindauer and Conzen-Dilger.)

Objective: Inflammation is increasingly recognized to be involved in the pathophysiology of aneurysmal subarachnoid hemorrhage (aSAH) and may increase the susceptibility to delayed cerebral ischemia (DCI). Macrophage migration inhibitory factor (MIF) has been shown to be elevated in serum and cerebrospinal fluid (CSF) after aSAH. Here, we determined MIF levels in serum, CSF and cerebral microdialysate (MD) at different time-points after aSAH and evaluated their clinical implications., Methods: MIF levels were measured in serum, CSF and MD obtained from 30 aSAH patients during early (EP d1-4 ), critical (CP d5-15 ) and late (LP d16-21 ) phase after hemorrhage. For subgroup analyses, patients were stratified based on demographic and clinical data., Results: MIF levels in serum increased during CP d5-15 and decreased again during LP d16-21 , while CSF levels showed little changes over time. MD levels peaked during EP d1-4 , decreased during CP d5-15 and increased again during LP d16-21 . Subgroup analyses revealed significantly higher serum levels in patients with aneurysms located in the anterior vs . posterior circulation during CP d5-15 (17.3 [15.1-21.1] vs . 10.0 [8.4-11.5] ng/ml, p = 0.009) and in patients with DCI vs . no DCI during CP d5-15 (17.9 [15.1-22.7] vs . 11.9 [8.9-15.9] ng/ml, p = 0.026) and LP d16-21 (17.4 [11.7-27.9] vs . 11.3 [9.2-12.2] ng/ml, p = 0.021). In addition, MIF levels in MD during CP d5-15 were significantly higher in patients with DCI vs . no DCI (3.6 [1.8-10.7] vs . 0.2 [0.1-0.7] ng/ml, p = 0.026), while CSF levels during the whole observation period were similar in all subgroups., Conclusion: Our findings in a small cohort of aSAH patients provide preliminary data on systemic, global cerebral and local cerebral MIF levels after aSAH and their clinical implications., Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT02142166., Competing Interests: FN was employed by Forschungszentrum Jülich GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Neumaier, Stoppe, Stoykova, Weiss, Veldeman, Höllig, Hamou, Temel, Conzen, Schmidt, Dogan, Wiesmann, Clusmann, Schubert, Haeren and Albanna.)

Background: Targeting a cerebral perfusion pressure optimal for cerebral autoregulation (CPPopt) has been gaining more attention to prevent secondary damage after acute neurological injury. Brain tissue oxygenation (PbtO 2 ) can identify insufficient cerebral blood flow and secondary brain injury. Defining the relationship between CPPopt and PbtO 2 after aneurysmal subarachnoid hemorrhage may result in (1) mechanistic insights into whether and how CPPopt-based strategies might be beneficial and (2) establishing support for the use of PbtO 2 as an adjunctive monitor for adequate or optimal local perfusion., Methods: We performed a retrospective analysis of a prospectively collected 2-center dataset of patients with aneurysmal subarachnoid hemorrhage with or without later diagnosis of delayed cerebral ischemia (DCI). CPPopt was calculated as the cerebral perfusion pressure (CPP) value corresponding to the lowest pressure reactivity index (moving correlation coefficient of mean arterial and intracranial pressure). The relationship of (hourly) deltaCPP (CPP-CPPopt) and PbtO 2 was investigated using natural spline regression analysis. Data after DCI diagnosis were excluded. Brain tissue hypoxia was defined as PbtO 2 <20 mmHg., Results: One hundred thirty-one patients were included with a median of 44.0 (interquartile range, 20.8-78.3) hourly CPPopt/PbtO2 datapoints. The regression plot revealed a nonlinear relationship between PbtO 2 and deltaCPP ( P <0.001) with PbtO 2 decrease with deltaCPP <0 mmHg and stable PbtO 2 with deltaCPP ≥0mmHg, although there was substantial individual variation. Brain tissue hypoxia (34.6% of all measurements) was more frequent with deltaCPP <0 mmHg. These dynamics were similar in patients with or without DCI., Conclusions: We found a nonlinear relationship between PbtO 2 and deviation of patients' CPP from CPPopt in aneurysmal subarachnoid hemorrhage patients in the pre-DCI period. CPP values below calculated CPPopt were associated with lower PbtO 2 . Nevertheless, the nature of PbtO 2 measurements is complex, and the variability is high. Combined multimodality monitoring with CPP/CPPopt and PbtO 2 should be recommended to redefine individual pressure targets (CPP/CPPopt) and retain the option to detect local perfusion deficits during DCI (PbtO 2 ), which cannot be fulfilled by both measurements interchangeably.

Background: Delayed cerebral ischemia (DCI) is one of the main determinants of clinical outcome after aneurysmal subarachnoid hemorrhage (SAH). The classical description of risk for DCI over time is currently based on the outdated concept of angiographic vasospasm. The goal of this study was to assess the temporal risk profile of DCI, defined by extended clinical and radiological criteria, as well as the impact the time point of DCI onset has on clinical outcome., Methods: All patients with aneurysmal SAH referred to a single tertiary care center between 2010 and 2018 were considered for inclusion. This study was designed as a retrospective cohort analysis and data were extracted from existing patient files. In conscious patients, DCI was diagnosed clinically, and in unconscious patients, diagnosis was based on perfusion computed tomography imaging and multimodal neuromonitoring. Extended Glasgow Outcome Scale scores were assessed after 12 months and compared between patients with early (< day 7) and late (≥ day 7) DCI onset., Results: The median delay from day of the hemorrhage (day 0) until detection of the first DCI event was 7.0 days, with an interquartile range of 5 days. The probability of DCI development over time demonstrated a bimodal distribution with a peak risk on day 5 (0.084; confidence interval 0.05.5-0.122) and a second peak on day 9 (0.077; confidence interval 0.045-0.120). A total of 27 patients (15.6%) suffered dominant hemispheric or severe bilateral DCI-related infarctions, resulting in the withdrawal of technical life support. Of those, the majority (20 patients, 22.2%) presented with early DCI onset (vs. late onset: 7 patients, 8.4%; p = 0.013)., Conclusions: The risk profile of DCI over time mirrors the description of angiographic vasospasm; however, it comes with an added timely delay of 1 to 2 days. Early occurrence of DCI (before day 7) is associated with a higher infarct load and DCI-related mortality. Although the exact causal relationship remains to be determined, the time point of DCI onset may serve as an independent prognostic criterion in decision-making., (© 2022. The Author(s).)

Objectives  Cerebral vasospasm in subarachnoid hemorrhage (SAH) is associated with high morbidity and mortality. There is a lack of consensus on the risk factors leading to cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage (aSAH). In this retrospective study, our objective was to determine the association of risk factors for cerebral vasospasm aSAH. Methods  A total of 259 charts of aSAH patients consecutively admitted to the surgical intensive care unit of Hamad General Hospital from January 2007 to December 2016 were reviewed and included. The patient's demographic data, including comorbidities like hypertension (HTN), was recorded. Variables of interest included measurements of the neurological deficit on admission, the severity of SAH, treatment modality, and the initial computerized tomography scan of the head for intraventricular hemorrhage, intracerebral hemorrhage, or hydrocephalus. Multivariate analysis and multiple logistic regression analyzed the relationship to identify the association of independent variables. Results  Out of the 259 patients, 34% ( n  = 87) suffered from cerebral vasospasm. The severity of SAH was associated with the development of cerebral vasospasm ( p  < 0.05). The presence of HTN and neurological deficits on admission were associated with an increased risk of cerebral vasospasm ( p  < 0.05, p  < 0.01, respectively). Hydrocephalus requiring treatment using external ventricular drains decreased the risk of cerebral vasospasm ( p  < 0.05). Intraventricular and intracerebral hemorrhage were not associated with cerebral vasospasm ( p  = 0.25, p  = 0.16). The endovascular treatment of cerebral aneurysms was associated with an increased risk of cerebral vasospasm ( p  < 0.05). Conclusion  Cerebral vasospasm is common among patients admitted with aSAH. It is significantly associated with the history of HTN, the neurological deficit on admission that corelates more strongly to the motor deficit on admission, the severity of hemorrhage (modified Fischer score), and endovascular treatment. External ventricular drainage was associated with a decrease in cerebral vasospasm. The present study's findings shed light on cerebral vasospasm's risk factors in the country and the region., Competing Interests: Conflict of Interest None declared., (Asian Congress of Neurological Surgeons. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Background: Rescue treatment for delayed cerebral ischemia (DCI) after subarachnoid hemorrhage can include induced hypertension (iHTN) and, in refractory cases, endovascular approaches, of which selective, continuous intraarterial nimodipine (IAN) is one variant. The combination of iHTN and IAN can dramatically increase vasopressor demand. In case of unsustainable doses, iHTN is often prioritized over IAN. However, evidence in this regard is largely lacking. We investigated the effects of a classical (iHTN+IAN) and modified (IAN only ) treatment protocol for refractory DCI in an observational study., Methods: Rescue treatment for DCI was initiated with iHTN (target >180 mm Hg systolic) and escalated to IAN in refractory cases. Until July 2018, both iHTN and IAN were offered in cases refractory to iHTN alone. After protocol modification, iHTN target was preemptively lowered to >120 mm Hg when IAN was initiated (IAN only ). Primary outcome was noradrenaline demand. Secondary outcomes included noradrenaline-associated complications, brain tissue oxygenation, DCI-related infarction and favorable 6-month outcome (Glasgow Outcome Scale 4-5)., Results: N=29 and n=20 patients were treated according to the classical and modified protocol, respectively. Protocol modification resulted in a significant reduction of noradrenaline demand (iHTN+IAN 0.70±0.54 µg/kg per minute and IAN only 0.26±0.20 µg/kg per minute, P <0.0001) and minor complications (15.0% versus 48.3%, unadjusted odds ratio, 0.19 [95% CI, 0.05-0.79]; P <0.05) with comparable rates of major complications (20.0% versus 20.7%, odds ratio, 0.96 [0.23-3.95]; P =0.95). Incidence of DCI-related infarction (45.0% versus 41.1%, odds ratio, 1.16 [0.37-3.66]; P =0.80) and favorable clinical outcome (55.6% versus 40.0%, odds ratio, 1.88 [0.55-6.39]; P =0.32) were similar. Brain tissue oxygenation was significantly higher with IANonly (26.6±12.8, 39.6±15.4 mm Hg; P <0.01)., Conclusions: Assuming the potential of iHTN to be exhausted in case of refractory hypoperfusion, additional IAN may serve as a last-resort measure to bridge hypoperfusion in the DCI phase. With close monitoring, preemptive lowering of pressure target after induction of IAN may be a safe alternative to alleviate total noradrenaline load and potentially reduce complication rate.

Chronic subdural hematomas (cSDHs) constitute one of the most prevalent intracranial disease entities requiring surgical treatment. Although mostly taking a benign course, recurrence after treatment is common and associated with additional morbidity and costs. Aim of this study was to develop hematoma-specific characteristics associated with risk of recurrence. All consecutive patients treated for cSDH in a single university hospital between 2015 and 2019 were retrospectively considered for inclusion. Size, volume, and midline shift were noted alongside relevant patient-specific factors. We applied an extended morphological classification system based on internal architecture in CT imaging consisting of eight hematoma subtypes. A logistic regression model was used to assess the classification's performance on predicting hematoma recurrence. Recurrence was observed in 122 (32.0%) of 381 included patients. Apart from postoperative depressed brain volume (OR 1.005; 95% CI 1.000 to 1.010; p = 0.048), neither demographic nor factors related to patient comorbidity affected recurrence. The extended hematoma classification was identified as a significant predictor of recurrence (OR 1.518; 95% CI 1.275 to 1.808; p < 0.001). The highest recurrence rates were observed in hematomas of the homogenous (isodense: 41.4%; hypodense: 45.0%) and sedimented (50.0%) types. Our results support that internal architecture subtypes might represent stages in the natural history of chronic subdural hematoma. Detection and treatment at a later stage of spontaneous repair can result in a reduced risk of recurrence. Based on their high risk of recurrence, we advocate follow-up after treatment of sedimented and homogenous hematomas., (© 2022. The Author(s).)

Purpose: Decompressive hemicraniectomy (DHC) is a potentially lifesaving procedure in refractory intracranial hypertension, which can prevent death from brainstem herniation but may cause survival in a disabled state. The spectrum of indications is expanding, and we present long-term results in a series of patients suffering from aneurysmal subarachnoid hemorrhage (SAH)., Methods: We performed a retrospective analysis of previously registered data including all patients treated for SAH between 2010 and 2018 in a single institution. Patients treated with decompressive hemicraniectomy due to refractory intracranial hypertension were identified. Clinical outcome was assessed by means of the Glasgow outcome scale after 12 months., Results: Of all 341 SAH cases, a total of 82 (24.0%) developed intracranial hypertension. Of those, 63 (18.5%) patients progressed into refractory ICP elevation and were treated with DHC. Younger age (OR 0.959, 95% CI 0.933 to 0.984; p = 0.002), anterior aneurysm location (OR 0.253, 95% CI 0.080 to 0.799; 0.019; p = 0.019), larger aneurysm size (OR 1.106, 95% CI 1.025 to 1.194; p = 0.010), and higher Hunt and Hess grading (OR 1.944, 95% CI 1.431 to 2.641; p < 0.001) were independently associated with the need for DHC. After 1 year, 10 (15.9%) patients after DHC were categorized as favorable outcome. Only younger age was independently associated with favorable outcome (OR 0.968 95% CI 0.951 to 0.986; p = 0.001)., Conclusions: Decompressive hemicraniectomy, though lifesaving, has only a limited probability of survival in a clinically favorable condition. We identified young age to be the sole independent predictor of favorable outcome after DHC in SAH., (© 2022. The Author(s).)

Background: Delayed cerebral ischemia (DCI) is a common complication of aneurysmal subarachnoid hemorrhage and contributes to unfavorable outcome. In patients with deterioration despite prophylactic nimodipine treatment, induced hypertension (iHTN) can be considered, although the safety and efficacy of induction are still a matter of debate. In this study, two iHTN treatment algorithms were compared with different approaches toward setting pressure targets., Methods: In a cohort of 325 consecutive patients with subarachnoid hemorrhage, 139 patients were treated by induced hypertension as a first tier treatment. On diagnosing DCI, blood pressure was raised via norepinephrine infusion in 20-mm Hg increments in 37 patients (iHTN incr ), whereas 102 patients were treated by immediate elevation to systolic pressure above 180 mm Hg (iHTN imm ). Treatment choice was based on personal preference of the treating physician but with a gradual shift away from incremental elevation. Both groups were evaluated for DCI-caused infarction, the need of additional endovascular rescue treatment, the occurrence of pressor-treatment-related complications, and clinical outcome assessed by the extended Glasgow outcome scale after 12 months., Results: The rate of refractory DCI requiring additional rescue therapy was comparable in both groups (48.9% in iHTN incr , 40.0% in iHTN imm ; p = 0.332). The type of induced hypertension was not independently associated with the occurrence of DCI-related infarction in a logistic regression model (odds ratio 1.004; 95% confidence interval 0.329-3.443; p = 0.942). Similar rates of pressor-treatment-related complications were observed in both treatment groups. Favorable outcome was reached in 44 (43.1%) patients in the immediate vs. 10 (27.0%) patients in the incremental treatment group (p = 0.076). However, only Hunt and Hess grading was identified as an independent predictor variable of clinical outcome (odds ratio 0.422; 95% confidence interval 0.216-0.824; p = 0.012)., Conclusions: Immediate induction of hypertension with higher pressure targets did not result in a lower rate of DCI-related infarctions but was not associated with a higher complication rate compared with an incremental approach. Future tailored blood pressure management based on patient- and time-point-specific needs will hopefully better balance the neurological advantages versus the systemic complications of induced hypertension., (© 2022. The Author(s).)

This study aims to investigate the characteristics of patients with mild aneurysmal and non-aneurysmal perimesencephalic and non-perimesencephalic subarachnoid hemorrhage (aSAH, pmSAH, npmSAH) with emphasis on admission biomarkers, clinical course, and outcome. A prospective cohort of 115 patients with aSAH (Hunt and Hess 1-3) and of 35 patients without aneurysms (16 pmSAH and 19 npmSAH) admitted between January 2014 and January 2020 was included. Demographic data, blood samples on admission, complications (hydrocephalus, shunt dependency, delayed cerebral ischemia DCI, DCI-related infarction, and mortality), and outcome after 6 months were analyzed. Demographic data was comparable between all groups except for age (aSAH 55 [48-65] vs. npmSAH 60 [56-68] vs. pmSAH 52 [42-60], p = 0.032) and loss of consciousness (33% vs. 0% vs. 0%, p = 0.0004). Admission biomarkers showed poorer renal function and highest glucose levels for npmSAH patients. Complication rate in npmSAH was high and comparable to that of aSAH patients (hydrocephalus, shunt dependency, DCI, DCI-related infarction, mortality), but nearly absent in patients with pmSAH. Favorable outcome after 6 months was seen in 92.9% of pmSAH, 83.3% of npmSAH, and 62.7% of aSAH (p = 0.0264). In this prospective cohort of SAH patients, npmSAH was associated with a complicated clinical course, comparable to that of patients with aSAH. In contrast, such complications were nearly absent in pmSAH patients, suggesting fundamental differences in the pathophysiology of patients with different types of non-aneurysmal hemorrhage. Our findings underline the importance for a precise terminology according the hemorrhage etiology as a basis for more vigilant management of npmSAH patients. NCT02142166, 05/20/2014, retrospectively registered., (© 2021. The Author(s).)

Objective: Outcome after aneurysmal subarachnoid hemorrhage (aSAH) is highly variable and largely determined by early brain injury and delayed cerebral ischemia (DCI). Soluble urokinase plasminogen activator receptor (suPAR) represents a promising inflammatory marker which has previously been associated with outcome in traumatic brain injury and stroke patients. However, its relevance in the context of inflammatory changes after aSAH is unclear. Here, we aimed to characterize the role of circulating suPAR in both serum and cerebrospinal fluid (CSF) as a novel biomarker for aSAH patients., Methods: A total of 36 aSAH patients, 10 control patients with unruptured abdominal aneurysm and 32 healthy volunteers were included for analysis. suPAR was analyzed on the day of admission in all patients. In aSAH patients, suPAR was also determined on the day of DCI and the respective time frame in asymptomatic patients. One- and two-sample t -tests were used for simple difference comparisons within and between groups. Regression analysis was used to assess the influence of suPAR levels on outcome in terms of modified Rankin score., Results: Significantly elevated suPAR serum levels (suPAR-SL) on admission were found for aSAH patients compared to healthy controls, but not compared to vascular control patients. Disease severity as documented according to Hunt and Hess grade and modified Fisher grade was associated with higher suPAR CSF levels (suPAR-CSFL). In aSAH patients, suPAR-SL increased daily by 4%, while suPAR-CSFL showed a significantly faster daily increase by an average of 22.5% per day. Each increase of the suPAR-SL by 1 ng/ml more than tripled the odds of developing DCI (OR = 3.06). While admission suPAR-CSFL was not predictive of DCI, we observed a significant correlation with modified Rankin's degree of disability at discharge., Conclusion: Elevated suPAR serum level on admission as a biomarker for early inflammation after aSAH is associated with an increased risk of DCI. Elevated suPAR-CSFL levels correlate with a higher degree of disability at discharge. These distinct relations and the observation of a continuous increase over time affirm the role of inflammation in aSAH and require further study., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schmidt, Albanna, Weiss, Veldeman, Conzen, Nikoubashman, Blume, Kluger, Clusmann, Loosen and Schubert.)

Objectives: The recommendation of induced hypertension for delayed cerebral ischemia treatment after aneurysmal subarachnoid hemorrhage has been challenged recently and ideal pressure targets are missing. A new concept advocates an individual cerebral perfusion pressure where cerebral autoregulation functions best to ensure optimal global perfusion. We characterized optimal cerebral perfusion pressure at time of delayed cerebral ischemia and tested the conformity of induced hypertension with this target value., Design: Retrospective analysis of prospectively collected data., Setting: University hospital neurocritical care unit., Patients: Thirty-nine aneurysmal subarachnoid hemorrhage patients with invasive neuromonitoring (20 with delayed cerebral ischemia, 19 without delayed cerebral ischemia)., Interventions: Induced hypertension greater than 180 mm Hg systolic blood pressure., Measurements and Main Results: Changepoint analysis was used to calculate significant changes in cerebral perfusion pressure, optimal cerebral perfusion pressure, and the difference of cerebral perfusion pressure and optimal cerebral perfusion pressure 48 hours before delayed cerebral ischemia diagnosis. Optimal cerebral perfusion pressure increased 30 hours before the onset of delayed cerebral ischemia from 82.8 ± 12.5 to 86.3 ± 11.4 mm Hg (p < 0.05). Three hours before delayed cerebral ischemia, a changepoint was also found in the difference of cerebral perfusion pressure and optimal cerebral perfusion pressure (decrease from -0.2 ± 11.2 to -7.7 ± 7.6 mm Hg; p < 0.05) with a corresponding increase in pressure reactivity index (0.09 ± 0.33 to 0.19 ± 0.37; p < 0.05). Cerebral perfusion pressure at time of delayed cerebral ischemia was lower than in patients without delayed cerebral ischemia in a comparable time frame (cerebral perfusion pressure delayed cerebral ischemia 81.4 ± 8.3 mm Hg, no delayed cerebral ischemia 90.4 ± 10.5 mm Hg; p < 0.05). Inducing hypertension resulted in a cerebral perfusion pressure above optimal cerebral perfusion pressure (+12.4 ± 8.3 mm Hg; p < 0.0001). Treatment response (improvement of delayed cerebral ischemia: induced hypertension+ [n = 15] or progression of delayed cerebral ischemia: induced hypertension- [n = 5]) did not correlate to either absolute values of cerebral perfusion pressure or optimal cerebral perfusion pressure, nor the resulting difference (cerebral perfusion pressure [p = 0.69]; optimal cerebral perfusion pressure [p = 0.97]; and the difference of cerebral perfusion pressure and optimal cerebral perfusion pressure [p = 0.51])., Conclusions: At the time of delayed cerebral ischemia occurrence, there is a significant discrepancy between cerebral perfusion pressure and optimal cerebral perfusion pressure with worsening of autoregulation, implying inadequate but identifiable individual perfusion. Standardized induction of hypertension resulted in cerebral perfusion pressures that exceeded individual optimal cerebral perfusion pressure in delayed cerebral ischemia patients. The potential benefit of individual blood pressure management guided by autoregulation-based optimal cerebral perfusion pressure should be explored in future intervention studies., Competing Interests: Dr. Wiesmann received funding from Stryker Neurovascular, Bracco Imaging, Medtronic, Penumbra, Siemens Healthcare, Abbott, AB Medica, Acandis, Asahi Intecc, Bayer, Bracco Imaging, B. Braun, Cerenovus, Codman Neurovascular, Dahlhausen, Kaneka Pharmaceuticals, Medtronic, Mentice AB, Microvention, Penumbra, Phenox, Philips Healthcare, Route 92, Siemens Healthcare, SilkRoad Medical, St. Jude, and Stryker Neurovascular. Dr. Park’s institution received funding from the National Institutes of Health (NIH, R21NS113055), and she received support for article research from the NIH. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Objective: Impaired cerebral blood flow (CBF) regulation, such as reduced reactivity to hypercapnia, contributes to the pathophysiology after aneurysmal subarachnoid hemorrhage (SAH), but temporal dynamics in the acute phase are unknown. Featuring comparable molecular regulation mechanisms, the retinal vessels participate in chronic and subacute stroke- and SAH-associated vessel alterations in patients and can be studied non-invasively. This study is aimed to characterize the temporal course of the cerebral and retinal vascular reactivity to hypercapnia in the acute phase after experimental SAH and compare the potential degree of impairment. Methods: Subarachnoid hemorrhage was induced by injecting 0.5 ml of heparinized autologous blood into the cisterna magna of male Wistar rats using two anesthesia protocols [isoflurane/fentanyl n = 25 (Sham + SAH): Iso-Group, ketamine/xylazine n = 32 (Sham + SAH): K/X-Group]. CBF (laser speckle contrast analysis) and physiological parameters were measured continuously for 6 h. At six predefined time points, hypercapnia was induced by hypoventilation controlled via blood gas analysis, and retinal vessel diameter (RVD) was determined non-invasively. Results: Cerebral reactivity and retinal reactivity in Sham groups were stable with only a slight attenuation after 2 h in RVD of the K/X-Group. In the SAH Iso-Group, cerebral and retinal CO 2 reactivity compared to baseline was immediately impaired starting at 30 min after SAH (CBF p = 0.0090, RVD p = 0.0135) and lasting up to 4 h ( p = 0.0136, resp. p = 0.0263). Similarly, in the K/X-Group, cerebral CO 2 reactivity was disturbed early after SAH (30 min, p = 0.003) albeit showing a recovery to baseline after 2 h while retinal CO 2 reactivity was impaired over the whole observation period (360 min, p = 0.0001) in the K/X-Group. After normalization to baseline, both vascular beds showed a parallel behavior regarding the temporal course and extent of impairment. Conclusion: This study provides a detailed temporal analysis of impaired cerebral vascular CO 2 reactivity starting immediately after SAH and lasting up to 6 h. Importantly, the retinal vessels participate in these acute changes underscoring the promising role of the retina as a potential non-invasive screening tool after SAH. Further studies will be required to determine the correlation with functional outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Warner, Bach-Hagemann, Albanna, Clusmann, Schubert, Lindauer and Conzen-Dilger.)

Aneurysmal subarachnoid hemorrhage (SAH) is associated with a high mortality rate and may leave surviving patients severely disabled. After the initial hemorrhage, clinical outcome is further compromised by the occurrence of delayed cerebral ischemia (DCI). Overweight and obesity have previously been associated with protective effects in the post-bleeding phase. The aim of this study was to assess the effects of a patient's body mass index (BMI) and leptin levels on the occurrence of DCI, DCI-related cerebral infarction, and clinical outcome. In total, 263 SAH patients were included of which leptin levels were assessed in 24 cases. BMI was recorded along disease severity documented by the Hunt and Hess and modified Fisher scales. The occurrence of clinical or functional DCI (neuromonitoring, CT Perfusion) was assessed. Long-term clinical outcome was documented after 12 months (extended Glasgow outcome scale). A total of 136 (51.7%) patients developed DCI of which 72 (27.4%) developed DCI-related cerebral infarctions. No association between BMI and DCI occurrence (P = .410) or better clinical outcome (P = .643) was identified. Early leptin concentration in serum (P = .258) and CSF (P = .159) showed no predictive value in identifying patients at risk of unfavorable outcomes. However, a significant increase of leptin levels in CSF occurred from 326.0 pg/ml IQR 171.9 prior to DCI development to 579.2 pg/ml IQR 211.9 during ongoing DCI (P = .049). In our data, no association between obesity and clinical outcome was detected. After DCI development, leptin levels in CSF increased either by an upsurge of active transport or disruption of the blood-CSF barrier. This trial has been registered at ClinicalTrials.gov (NCT02142166) as part of a larger-scale prospective data collection. BioSAB: https://clinicaltrials.gov/ct2/show/NCT02142166., (© 2021. The Author(s).)

Background and Purpose: Aneurysmal subarachnoid hemorrhage is a devastating disease leaving surviving patients often severely disabled. Delayed cerebral ischemia (DCI) has been identified as one of the main contributors to poor clinical outcome after subarachnoid hemorrhage. The objective of this review is to summarize existing clinical evidence assessing the diagnostic value of invasive neuromonitoring (INM) in detecting DCI and provide an update of evidence since the 2014 consensus statement on multimodality monitoring in neurocritical care., Methods: Three invasive monitoring techniques were targeted in the data collection process: brain tissue oxygen tension (ptiO2), cerebral microdialysis, and electrocorticography. Prospective and retrospective studies as well as case series (≥10 patients) were included as long as monitoring was used to detect DCI or guide DCI treatment., Results: Forty-seven studies reporting INM in the context of DCI were included (ptiO2: N=21; cerebral microdialysis: N=22; electrocorticography: N=4). Changes in brain oxygen tension are associated with angiographic vasospasm or reduction in regional cerebral blood flow. Metabolic monitoring with trend analysis of the lactate to pyruvate ratio using cerebral microdialysis, identifies patients at risk for DCI. Clusters of cortical spreading depolarizations are associated with clinical neurological worsening and cerebral infarction in selected patients receiving electrocorticography monitoring., Conclusions: Data supports the use of INM for the detection of DCI in selected patients. Generalizability to all subarachnoid hemorrhage patients is limited by design bias of available studies and lack of randomized trials. Continuous data recording with trend analysis and the combination of INM modalities can provide tailored treatment support in patients at high risk for DCI. Future trials should test interventions triggered by INM in relation to cerebral infarctions.

During embryogenesis, optic vesicles develop from the diencephalon via a multistep process of organogenesis. Using induced pluripotent stem cell (iPSC)-derived human brain organoids, we attempted to simplify the complexities and demonstrate formation of forebrain-associated bilateral optic vesicles, cellular diversity, and functionality. Around day 30, brain organoids attempt to assemble optic vesicles, which develop progressively as visible structures within 60 days. These optic vesicle-containing brain organoids (OVB-organoids) constitute a developing optic vesicle's cellular components, including primitive corneal epithelial and lens-like cells, retinal pigment epithelia, retinal progenitor cells, axon-like projections, and electrically active neuronal networks. OVB-organoids also display synapsin-1, CTIP-positive myelinated cortical neurons, and microglia. Interestingly, various light intensities could trigger photosensitive activity of OVB-organoids, and light sensitivities could be reset after transient photobleaching. Thus, brain organoids have the intrinsic ability to self-organize forebrain-associated primitive sensory structures in a topographically restricted manner and can allow interorgan interaction studies within a single organoid., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with early and delayed brain injury due to several underlying and interrelated processes, which include inflammation, oxidative stress, endothelial, and neuronal apoptosis. Treatment with melatonin, a cytoprotective neurohormone with anti-inflammatory, anti-oxidant and anti-apoptotic effects, has been shown to attenuate early brain injury (EBI) and to prevent delayed cerebral vasospasm in experimental aSAH models. Less is known about the role of endogenous melatonin for aSAH outcome and how its production is altered by the pathophysiological cascades initiated during EBI. In the present observational study, we analyzed changes in melatonin levels during the first three weeks after aSAH., Materials and Methods: Daytime (from 11:00 am to 05:00 pm) melatonin levels were measured by enzyme-linked immunosorbent assay (ELISA) in serum samples obtained from 30 patients on the day of aSAH onset (d 0 ) and in five pre-defined time intervals during the early (d 1-4 ), critical (d 5-8 , d 9-12 , d 13-15 ) and late (d 16-21 ) phase. Perioperative daytime melatonin levels determined in 30 patients who underwent elective open aortic surgery served as a control for the acute effects of surgical treatment on melatonin homeostasis., Results: There was no difference between serum melatonin levels measured in the control patients and on the day of aSAH onset (p = 0.664). However, aSAH was associated with a sustained up-regulation that started during the critical phase (d 9-12 ) and progressed to the late phase (d 16-21 ), during which almost 80% of the patients reached daytime melatonin levels above 5 pg/ml. In addition, subgroup analyses revealed higher melatonin levels on d 5-8 in patients with a poor clinical status on admission (p = 0.031), patients with anterior communicating artery aneurysms (p = 0.040) and patients without an external ventricular drain (p = 0.018), possibly pointing to a role of hypothalamic dysfunction., Conclusion: Our observations in a small cohort of patients provide first evidence for a delayed up-regulation of circulatory daytime melatonin levels after aSAH and a role of aneurysm location for higher levels during the critical phase. These findings are discussed in terms of previous results about stress-induced melatonin production and the role of hypothalamic and brainstem involvement for melatonin levels after aSAH., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: Adrenomedullin (ADM) has been identified as a promising biomarker of mortality and outcome in sepsis, heart failure and after major surgery. A recently developed assay specific for bioactive adrenomedullin (bio-ADM) has not yet been assessed in aneurysmal subarachnoid hemorrhage (aSAH). The objective of this prospective trial was to assess the time course of bio-ADM after aSAH in relation to the development of delayed cerebral ischemia (DCI) and its association with clinical outcome., Methods: Bio-ADM levels in plasma and cerebrospinal fluid (CSF) were measured during five predefined epochs, for up to 21 days in 30 aSAH patients: early, (day 0 to day 3); acute, (day 4 to day 8); early critical, (day 9 to day 12); late critical, (day 13 to day 15), and late (day 16 to day 21). DCI was diagnosed clinically or based on multimodal monitoring and imaging, and the occurrence of DCI-related cerebral infarction, and outcome after 12 months (extended Glasgow outcome scale), was noted., Results: Higher median bio-ADM levels in plasma during the acute phase were predictive of long-term unfavorable outcome (AUC = 0.97; 95% CI 0.91 to 1.00; p < 0.001). Early critical bio-ADM levels during DCI were lower in CSF and confirmed DCI occurrence (AUC = 0.80; 95% CI 0.59 to 1.00; p = 0.044)., Conclusion: The dynamics of bio-ADM levels in CSF present a fairly different course compared to plasma with observed higher bio-ADM concentrations in patients spared from DCI and/or developing favorable outcome., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Good-grade aneurysmal subarachnoid hemorrhage (Hunt and Hess 1-2) is generally associated with a favorable prognosis. Nonetheless, patients may still experience secondary deterioration due to delayed cerebral ischemia (DCI), contributing to poor outcome. In those patients, neurological assessment is challenging and invasive neuromonitoring (INM) may help guide DCI treatment., Methods: An observational analysis of 135 good-grade SAH patients referred to a single tertiary care center between 2010 and 2018 was performed. In total, 54 good-grade SAH patients with secondary deterioration evading further neurological assessment, were prospectively enrolled for this analysis. The cohort was separated into two groups: before and after introduction of INM in 2014 (pre-INM SecD : n = 28; post-INM SecD : n = 26). INM included either parenchymal oxygen saturation measurement (p ti O 2 ), cerebral microdialysis or both. Episodes of DCI (p ti O 2  < 10 mmHg or lactate/pyruvate > 40) were treated via induced hypertension or in refractory cases by endovascular means. The primary outcome was defined as the extended Glasgow outcome scale after 12 months. In addition, we recorded the amount of imaging studies performed and the occurrence of silent and overall DCI-related infarction., Results: Secondary deterioration, impeding neurological assessment, occurred in 54 (40.0%) of all good-grade SAH patients. In those patients, a comparable rate of favorable outcome at 12 months was observed before and after the introduction of INM (pre-INM SecD 14 (50.0%) vs. post-INM SecD 16, (61.6%); p = 0.253). A significant increase in good recovery (pre-INM SecD 6 (50.0%) vs. post-INM SecD 14, (61.6%); p = 0.014) was observed alongside a reduction in the incidence of silent infarctions (pre-INM SecD 8 (28.6%) vs. post-INM SecD 2 (7.7%); p = 0.048) and of overall DCI-related infarction (pre-INM SecD 12 (42.8%) vs. post-INM SecD 4 (23.1%); p = 0.027). The number of CT investigations performed during the DCI time frame decreased from 9.8 ± 5.2 scans in the pre-INM SecD group to 6.1 ± 4.0 (p = 0.003) in the post-INM SecD group., Conclusions: A considerable number of patients with good-grade SAH experiences secondary deterioration rendering them neurologically not assessable. In our cohort, the introduction of INM to guide DCI treatment in patients with secondary deterioration increased the rate of good recovery after 12 months. Additionally, a significant reduction of CT scans and infarction load was recorded, which may have an underestimated impact on quality of life and more subtle neuropsychological deficits common after SAH., (© 2020. The Author(s).)

Objective: The urea-creatinine ratio (UCR) has been proposed as potential biomarker for critical illness-associated catabolism. Its role in the context of aneurysmal subarachnoid hemorrhage (aSAH) remains to be elucidated, which was the aim of the present study., Methods: We enrolled 66 patients with aSAH with normal renal function and 36 patients undergoing elective cardiac surgery as a control group for the effects of surgery. In patients with aSAH, the predictive or diagnostic value of early (day 0-2) and critical (day 5-7) UCRs was assessed with regard to delayed cerebral ischemia (DCI), DCI-related infarction, and clinical outcome after 12 months., Results: Preoperatively, UCR was similar both groups. Within 2 days postoperatively, UCRs increased significantly in patients in the elective cardiac surgery group (P < 0.001) but decreased back to baseline on day 5-7 (P = 0.245), whereas UCRs in patients with aSAH increased to significantly greater levels on day 5-7 (P = 0.028). Greater early or critical UCRs were associated with poor clinical outcomes (P = 0.015) or DCI (P = 0.011), DCI-related infarction (P = 0.006), and poor clinical outcomes (P < 0.001) respectively. In multivariate analysis, there was an independent association between greater early UCRs and poor clinical outcomes (P = 0.026)., Conclusions: In this exploratory study of UCR in the context of aSAH, greater early values were predictive for a poor clinical outcome after 12 months, whereas greater critical values were associated with DCI, DCI-related infarctions, and poor clinical outcomes. The clinical implications as well as the pathophysiologic relevance of protein catabolism should be explored further in the context of aSAH., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Delayed cerebral ischemia (DCI) is a common complication after aneurysmal subarachnoid hemorrhage (aSAH) and can lead to infarction and poor clinical outcome. The underlying mechanisms are still incompletely understood, but animal models indicate that vasoactive metabolites and inflammatory cytokines produced within the subarachnoid space may progressively impair and partially invert neurovascular coupling (NVC) in the brain. Because cerebral and retinal microvasculature are governed by comparable regulatory mechanisms and may be connected by perivascular pathways, retinal vascular changes are increasingly recognized as a potential surrogate for altered NVC in the brain. Here, we used non-invasive retinal vessel analysis (RVA) to assess microvascular function in aSAH patients at different times after the ictus. Methods: Static and dynamic RVA were performed using a Retinal Vessel Analyzer (IMEDOS Systems GmbH, Jena) in 70 aSAH patients during the early (d 0-4 ), critical (d 5-15 ), late (d 16-23 ) phase, and at follow-up (f/u > 6 weeks) after the ictus. For comparison, an age-matched cohort of 42 healthy subjects was also included in the study. Vessel diameters were quantified in terms of the central retinal arterial and venous equivalent (CRAE, CRVE) and the retinal arterio-venous-ratio (AVR). Vessel responses to flicker light excitation (FLE) were quantified by recording the maximum arterial and venous dilation (MAD, MVD), the time to 30% and 100% of maximum dilation (tMAD 30 , tMVD 30 ; tMAD, tMVD, resp.), and the arterial and venous area under the curve (AUC art , AUC ven ) during the FLE. For subgroup analyses, patients were stratified according to the development of DCI and clinical outcomes after 12 months. Results: Vessel diameter (CRAE, CRVE) was significantly smaller in aSAH patients and showed little change throughout the whole observation period ( p < 0.0001 vs. control for all time periods examined). In addition, aSAH patients exhibited impaired arterial but not venous responses to FLE, as reflected in a significantly lower MAD [2.2 (1.0-3.2)% vs. 3.6 (2.6-5.6)% in control subjects, p = 0.0016] and AUC art [21.5 (9.4-35.8)% * s vs. 51.4 (32.5-69.7)% * s in control subjects, p = 0.0001] on d 0-4 . However, gradual recovery was observed during the first 3 weeks, with close to normal levels at follow-up, when MAD and AUC art amounted to 3.0 [2.0-5.0]% ( p = 0.141 vs. control, p = 0.0321 vs. d 5-15 ) and 44.5 [23.2-61.1]% * s ( p = 0.138 vs . control, p < 0.01 vs. d 0-4 & d 5-15 ). Finally, patients with clinical deterioration (DCI) showed opposite changes in the kinetics of arterial responses during early and late phase, as reflected in a significantly lower tMAD 30 on d 0-4 [4.0 (3.0-6.8) s vs. 7.0 (5.0-8.0) s in patients without DCI, p = 0.022) and a significantly higher tMAD on d 16-23 (24.0 (21.0-29.3) s vs . 18.0 (14.0-21.0) s in patients without DCI, p = 0.017]. Conclusion: Our findings confirm and extend previous observations that aSAH results in sustained impairments of NVC in the retina. DCI may be associated with characteristic changes in the kinetics of retinal arterial responses. However, further studies will be required to determine their clinical implications and to assess if they can be used to identify patients at risk of developing DCI. Trial Registration: ClinicalTrials.gov Identifier: NCT04094155., Competing Interests: IMEDOS Systems GmbH provided the Retinal Vessel Analyzer for research purposes only. The company did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Albanna, Conzen, Weiss, Seyfried, Kotliar, Schmidt, Kuerten, Hescheler, Bruecken, Schmidt-Trucksäss, Neumaier, Wiesmann, Clusmann and Schubert.)

Background: Intraoperative computed tomography (iCT) navigated dorsal instrumentation has been successfully introduced as a new clinical standard. The proximity of vital anatomic structures makes cervical spine instrumentation an especially delicate task. Therefore, navigated approaches might prove to be beneficial. In this study, the accuracy of conventional instrumentation was compared with iCT navigated dorsal cervical spine instrumentation with focus on cervical pedicle screws (CPSs) versus lateral mass screws (LMSs) and pathologies., Methods: We analyzed a prospective consecutive series of patients undergoing cervical dorsal instrumentation with iCT and spinal navigation and retrospectively analyzed a cohort that received conventional cervical instrumentation with C-arm fluoroscopy (control group). Accuracy was assessed with a modified Gertzbein-Robbins classification. Underlying pathologies were taken into account regarding accuracy in different entities., Results: Fifty-nine patients were treated using iCT (357 screws: 238 CPSs, 119 LMSs), and 98 patients underwent conventional instrumentation (632 screws: 69 CPSs, 563 LMSs). We achieved an initial accuracy of 93.28% (n = 220 screws) in the iCT group and 80.9% (n = 511 screws) in the control group (P < 0.001). Significant differences were found regarding the accuracy of CPS placement in cases of degenerative disorders (iCT vs. control; 94% vs. 63%; P < 0.001) and trauma (iCT vs. control; 88% vs. 72%; P < 0.05). iCT yielded favorable precision rates in regard to LMS placement (iCT vs. control; 94.2% vs. 82%; P < 0.05)., Conclusions: Accuracy of iCT navigated instrumentation was significantly higher than conventional instrumentation. An overall tendency toward the use of CPSs with iCT navigation is evident, increasing the mechanical properties of the construct. iCT appears to be especially beneficial in elective surgery cases of degenerative spinal disorders., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Metabolic demand increases with neuronal activity and adequate energy supply is ensured by neurovascular coupling (NVC). Impairments of NVC have been reported in the context of several diseases and may correlate with disease severity and outcome. Voltage-gated Ca 2+ -channels (VGCCs) are involved in the regulation of vasomotor tone. In the present study, we compared arterial and venous responses to flicker stimulation in Ca v 2.3-competent (Ca v 2.3 [+/+] ) and -deficient (Ca v 2.3 [-/-] ) mice using retinal vessel analysis. Methods: The mice were anesthetized and the pupil of one eye was dilated by application of a mydriaticum. An adapted prototype of retinal vessel analyzer was used to perform dynamic retinal vessel analysis. Arterial and venous responses were quantified in terms of the area under the curve (AUC art /AUC ven ) during flicker application, mean maximum dilation (mMD art /mMD ven ) and time to maximum dilation (tMD art /tMD ven ) during the flicker, dilation at flicker cessation (DFC art /DFC ven ), mean maximum constriction (mMC art /mMC ven ), time to maximum constriction (tMC art /tMC ven ) after the flicker and reactive magnitude (RM art /RM ven ). Results: A total of 33 retinal scans were conducted in 22 Ca v 2.3 [+/+] and 11 Ca v 2.3 [-/-] mice. Ca v 2.3 [-/-] mice were characterized by attenuated and partially reversed arterial and venous responses, as reflected in significantly lower AUC art ( p = 0.031) and AUC ven ( p = 0.047), a trend toward reduced DFC art ( p = 0.100), DFC ven ( p = 0.100), mMD ven ( p = 0.075), and RM art ( p = 0.090) and a trend toward increased tMD art ( p = 0.096). Conclusion: To our knowledge, this is the first study using a novel, non-invasive analysis technique to document impairment of retinal vessel responses in VGCC-deficient mice. We propose that Ca v 2.3 channels could be involved in NVC and may contribute to the impairment of vasomotor responses under pathophysiological conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Neumaier, Kotliar, Haeren, Temel, Lüke, Seyam, Lindauer, Clusmann, Hescheler, Schubert, Schneider and Albanna.)

Introduction: Delayed cerebral ischemia (DCI) is a common complication after aneurysmal subarachnoid hemorrhage (aSAH) that can culminate in secondary brain damage. Although it remains one of the main preventable causes of aSAH-related morbidity, there is still a lack of prognostic criteria for identification of patients at risk of developing DCI. Because elevated circulatory levels of the enzyme dipeptidyl peptidase 3 (cDPP3) were recently identified as a potential biomarker for outcome prediction in critically ill patients, we evaluated the time-course of changes in cDPP3 levels after aSAH., Materials and Methods: cDPP3 levels were quantified in serum obtained from 96 confirmed aSAH patients during the early (EP: d 1 - 4 ), critical (CP: d 5 - 8 , d 9 - 12 , d 13 - 15 ) and late (LP: d 16 - 21 ) phase after aSAH onset. Associations between cDPP3 levels and demographic or clinical parameters were evaluated. The relations between cDPP3 levels and DCI, DCI-related infarctions and long-term clinical outcomes were examined by receiver operating characteristics (ROC) curve analysis and multivariate logistic regression., Results: Significantly higher cDPP3 levels during CP (d 5 - 8 , d 9 - 12 , d 13 - 15 ) were observed in patients with poor clinical (p < 0.001 to p = 0.033) or radiological (p = 0.012 to p = 0.039) status on admission, DCI (p < 0.001 to p = 0.001), DCI-related infarctions (p = 0.002 to p = 0.007), and poorer long-term outcome (p = 0.007 to p = 0.019). ROC curve analysis indicated that higher cDPP3 levels on d 5 - 8 are predictive for a poor clinical outcome (area under the curve = 0.677, p = 0.007). In multivariate analysis, there was an independent association between cDPP3 levels on d 5 - 8 and development of DCI-related infarctions (p = 0.038)., Conclusion: Our results provide first evidence that cDPP3 could serve as a promising biomarker for early diagnosis of DCI-related infarctions in poor grade aSAH patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Endovascular treatment of ruptured cerebral aneurysms frequently requires antiplatelet medication to prevent thromboembolism. This might raise concern regarding the risk of postprocedural hemorrhage (pH), e.g. from placement of intracranial probes. We explored the risk of PH associated with standard antiplatelet therapy (sAP: acetylsalicylic acid, and/or clopidogrel) in the context of aneurysmal subarachnoid hemorrhage (aSAH)., Methods: We retrospectively reviewed a total of 146 consecutive cases with cerebral aneurysms treated between 1/2011-12/2015, and distinguished between minor (0.5 cm 3 ) - 4 cm 3 ) or major (> 4 cm 3 ) PH occurring within four weeks after intervention. A separate analysis included hemorrhages related to placement of intracranial probes and drainages in the subgroup of 99 cases with such surgical interventions (pPH). Clinical outcome was assessed via Glasgow Outcome Scale (GOS) twelve months after aSAH., Results: A total of 49 cases (33.6%) in the overall sample sustained PH, there were 19 cases of pPH. Multifactorial analyses yielded sAP as an independent predictor for minor, but not major PH (p < 0.001 vs. p = 0.829), with comparable results for pPH (p = 0.001 vs. p = 0.184). sAP did not influence the clinical outcome in either group., Conclusions: sAP was associated with a higher rate of minor PH and, more specifically, of minor pPH. However, it was neither accompanied by the occurrence of major hemorrhages nor by unfavorable clinical outcome. Future prospective studies should confirm these observations and hemorrhage risks associated with extended anticoagulation regimes after complex interventions and intra-arterial vasospasm therapy should be explored in order to facilitate interdisciplinary decision-making in aSAH., (Copyright © 2020 Elsevier B.V. All rights reserved.)