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Introduction: Aneurysmal subarachnoid hemorrhage (aSAH) during pregnancy is a rare but serious complication associated with significant maternal and fetal morbidity and mortality. Due to a limited number of published cases, development of guidelines for the management of aSAH in pregnant women has proven difficult. In the present article, we present a case and review the available literature on patients with aSAH during pregnancy., Research Question: What is the optimal management of aSAH during pregnancy?, Material and Methods: We describe the case of a pregnant woman with aSAH. In addition, a search of the PUBMED database was conducted to collect all pertinent case reports of aSAH in pregnant women published since 1990., Results: A 36 years old Caucasian primigravid woman in the 37th GW presented to our department with aSAH, due to rupture of a saccular basilar tip aneurysm. After multidisciplinary discussion, a Caesarian section (CS) and subsequent aneurysm treatment by endovascular coiling were performed without complications. On day four after ictus endovascular spasmolysis were initiated as the patient developed angiographic cerebral vasospasm and delayed cerebral ischemia (DCI). Two days later, brain tissue hypoperfusion was further aggravated by cardiopulmonary failure under induced hypertension, so that the patient died on day seven from severe cerebral infarction., Discussion and Conclusion: While there are still no formal studies that could guide the optimal management of aSAH during pregnancy, primary CS prior to definitive management of ruptured aneurysms during the third trimester seems to be the safest treatment approach for both mother and child., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier B.V. on behalf of EUROSPINE, the Spine Society of Europe, EANS, the European Association of Neurosurgical Societies.)

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).)