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Objective: This narrative review of the literature concerns persistent headache attributed to past non-traumatic subarachnoid hemorrhage (SAH), based off demographic and clinical features, what are pathophysiologic mechanisms by which these headaches occur, which medical and interventional treatments have the most evidence for pain alleviation, and what pre-clinical evidence is there for emerging treatments for these patients., Background: Following initial stabilization and treatment of spontaneous SAH, most commonly due to aneurysmal rupture, headache in the immediate inpatient setting and persisting after discharge are an important cause of morbidity. These headaches often receive heterogenous treatment of uncertain efficacy, and the risk factors and pathophysiology of their development has received little study., Methods: A narrative review of current literature discussing post-SAH headache was conducted using a literature search in PubMed with search term combinations including "post subarachnoid hemorrhage pain", "subarachnoid hemorrhage headache", and "post subarachnoid hemorrhage headache". Clinical studies mentioning headache after SAH and/or treatment in the abstract/title were included through March, 2022., Results and Conclusion: Post-SAH headaches are shown to decrease quality of life, have a multi-modal pathophysiology in their occurrence, and only a select few medications (reviewed herein) have been demonstrated to have efficacy in alleviation of these headaches, while also harboring possible risks including vasospasm and re-bleeding. An effective treatment paradigm of these headaches will include trials of evidence-based therapeutics, rapid reduction of opioid medications if not effective, and consideration of multi-modal pain control strategies including nerve blocks., (© 2022 American Headache Society.)

Background: Cerebral vasospasm (CV) can contribute to significant morbidity in subarachnoid hemorrhage (SAH) patients. A key unknown is how CV induction is triggered following SAH., Methods: Human aneurysmal blood and cerebral spinal fluid were collected for evaluation. To confirm mechanism, c57/bl6 wild type and c57/bl6 IL-6 female knockout (KO) mice were utilized with groups: saline injected, SAH, SAH + IL-6 blockade, SAH IL-6 KO, SAH IL-6 KO + IL-6 administration, SAH + p-STAT3 inhibition. Dual-labeled microglia/myeloid mice were used to show myeloid diapedesis. For SAH, 50 μm blood was collected from tail puncture and administered into basal cisterns. IL-6 blockade was given at various time points. Various markers of neuroinflammation were measured with western blot and immunohistochemistry. Cerebral blood flow was also measured. Vasospasm was measured via cardiac injection of India ink/gelatin. Turning test and Garcia's modified SAH score were utilized. P < 0.05 was considered significant., Results: IL-6 expression peaked 3 days following SAH (p < 0.05). Human IL-6 was increased in aneurysmal blood (p < 0.05) and in cerebral spinal fluid (p < 0.01). Receptor upregulation was periventricular and perivascular. Microglia activation following SAH resulted in increased caveolin 3 and myeloid diapedesis. A significant increase in BBB markers endothelin 1 and occludin was noted following SAH, but reduced with IL-6 blockade (p < 0.01). CV occurred 5 days post-SAH, but was absent in IL-6 KO mice and mitigated with IL-6 blockade (p < 0.05). IL-6 blockade, and IL-6 KO mitigated effects of SAH on cerebral blood flow (p < 0.05). SAH mice had impaired performance on turn test and poor modified Garcia scores compared to saline and IL-6 blockade. A distinct microglia phenotype was noted day 5 in the SAH group (overlap coefficients r = 0.96 and r = 0.94) for Arg1 and iNOS, which was altered by IL-6 blockade. Day 7, a significant increase in toll-like receptor 4 and Stat3 was noted. This was mitigated by IL-6 blockade and IL-6 KO, which also reduced Caspase 3 (p < 0.05). To confirm the mechanism, we developed a p-STAT3 inhibitor that targets the IL-6 pathway and this reduced NFΚB, TLR4, and nitrotyrosine (p < 0.001). Ventricular dilation and increased Tunel positivity was noted day 9, but resolved by IL-6 blockade (p < 0.05)., Conclusion: Correlation between IL-6 and CV has been well documented. We show that a mechanistic connection exists via the p-STAT3 pathway, and IL-6 blockade provides benefit in reducing CV and its consequences mediated by myeloid cell origin diapedesis., (© 2022. The Author(s).)

Delayed cerebral ischemia (DCI) contributes to extensive morbidity and mortality for patients with aneurysmal subarachnoid hemorrhage (SAH). Recent contributions to the basic and translational investigation of DCI have shed light on emerging concepts that may aid in the development of novel therapeutics. A clear association between cerebral vasospasm (CV) and DCI exists, but it is also known that DCI can affect brain parenchyma remote from sites of vasospasm. In this review, we highlight the most recent contributions to the understanding of the underlying pathophysiology of DCI including the emerging role of the glymphatic system. Furthermore, we discuss treatments for DCI, including both pharmacologic therapies and endovascular treatment of vasospasm. There continues to be a disconnect between interventions and targeted treatment against pathophysiology. This review is intended to serve as a catalyst for further research and discovery that can aid in improved treatment options for DCI., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is a pressing public health issue. Although most cases do not result in severe illness requiring hospitalization, there is increasing evidence that SARS-CoV-2-induced inflammation can exacerbate pre-existing diseases. We sought to describe the characteristics of patients with aneurysmal subarachnoid hemorrhage who were actively or very recently infected with SARS-CoV-2., Methods: We reviewed subarachnoid hemorrhage cases of patients who also were positive for SARS-CoV-2 at 5 high-volume cerebrovascular centers in the United States from March 2020 to January 2021. Cases of aneurysmal subarachnoid hemorrhage were analyzed., Results: A total of 10 patients were identified, consisting of 5 women (50%) and 5 men (50%). Median age was 38.5 years. Four of the 10 patients (40%) were asymptomatic with respect to SARS-CoV-2-related symptoms, 3 patients (30%) had mild-to-moderate symptoms, and 3 patients (30%) had severe coronavirus disease 2019 (COVID-19), with pneumonia and sepsis. Of the 10 cases, 4 had dissecting pseudoaneurysms (40%), 3 in the posterior circulation and 1 in the anterior circulation. Among 6 saccular/blister aneurysms, 4 (67%) were ≤4 mm in largest diameter., Conclusions: Our experience with aneurysmal subarachnoid hemorrhage in patients positive for COVID-19 reveals a possibly distinct pattern compared with traditional aneurysmal subarachnoid hemorrhage, namely a high frequency of small aneurysms, dissecting pseudoaneurysms, and young patients., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Delayed cerebral ischemia is a major predictor of poor outcomes in patients who suffer subarachnoid hemorrhage. Treatment options are limited and often ineffective despite many years of investigation and clinical trials. Modern advances in basic science have produced a much more complex, multifactorial framework in which delayed cerebral ischemia is better understood and novel treatments can be developed. Leveraging this knowledge to improve outcomes, however, depends on a holistic understanding of the disease process. We conducted a review of the literature to analyze the current state of investigation into delayed cerebral ischemia with emphasis on the major themes that have emerged over the past decades. Specifically, we discuss microcirculatory dysfunction, glymphatic impairment, inflammation, and neuroelectric disruption as pathological factors in addition to the canonical focus on cerebral vasospasm. This review intends to give clinicians and researchers a summary of the foundations of delayed cerebral ischemia pathophysiology while also underscoring the interactions and interdependencies between pathological factors. Through this overview, we also highlight the advances in translational studies and potential future therapeutic opportunities.

Background: Despite evidence to support that aneurysmal subarachnoid hemorrhage (aSAH) is best treated at high-volume centers, it is unknown whether clinical practice reflects these findings., Methods: We analyzed patients transferred to our high-volume center for aSAH between 2006 and 2017. Data collection included number of transfers, demographic data, Hunt and Hess score, Fisher score, comorbid conditions, length of stay (LOS), discharge disposition, in-hospital mortality rates, insurance status, and hospital charges. Comparisons were made across 3 time periods (2006-2009, 2010-2013, and 2014-2017) and included subgroup analyses by treatment modality (endovascular vs. microsurgical)., Results: aSAH transfers declined from 213 in 2006-2009 to 160 in 2014-2017. While there was no change in presenting Hunt and Hess scores, the percentage of modified Fisher scores of 4 increased from 2006-2009 to 2014-2017. Transferred patients had a greater comorbidity index and decreased predicted 10-year survival. Despite this, the average LOS decreased. In-hospital mortality decreased from 2006-2009 to 2014-2017, especially in the endovascular cohort. The proportions of patients who were either self-pay or Medicaid did not change. Overall inflation-adjusted hospital charges decreased from $76,975 in 2006-2009 to $59,870 in 2014-2017., Conclusions: Between 2006 and 2017, transfers to our center for aSAH declined. However, transferred patients had greater levels of complexity, more comorbidities, and were at greater risk for vasospasm based on their presenting Fisher score. Nonetheless, average LOS, in-hospital mortality, and cost declined. These changing referral patterns have implications for outcome data, quality reporting, resident education, and developing systems of care to optimize outcomes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The correlation of neuroinflammation with the development of cerebral vasospasm following subarachnoid hemorrhage has been well documented in the literature; both clinical and preclinical. The exact mechanisms by which this process occurs, however, are poorly elucidated. Recent evidence indicates that interleukin-6 is not only an important prognostic biomarker for subarachnoid hemorrhage and subsequent vasospasm development but also an integral component in the progression of injury following initial insult. In this review, we briefly highlight other pathways under investigation and focus heavily on what has been discovered regarding the role of interleukin 6 and cerebral vasospasm following subarachnoid hemorrhage. A proposed mechanistic pathway is highlighted in written and graphical format. A discussion regarding the human correlative findings and initial pre-clinical mechanistic studies is addressed. Finally, in the future investigation section, innovative developments and a clear description of areas warranting further scientific inquiry are emphasized. This review will catalyze continued discovery in this area of emerging significance and aid in the quest for effective vasospasm treatment where limited clinical therapeutics currently exist., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Traumatic subarachnoid hemorrhage (tSAH) is frequently comorbid with traumatic brain injury (TBI) and may induce secondary injury through vascular changes such as vasospasm and subsequent delayed cerebral ischemia (DCI). While aneurysmal SAH is well studied regarding vasospasm and DCI, less is known regarding tSAH and the prevalence of vasospasm and DCI, the consequences of vasospasm in this setting, when treatment is indicated, and which management strategies should be implemented. In this article, a systematic review of the literature that was conducted for cases of symptomatic vasospasm in patients with TBI is reported, association with tSAH is reported, risk factors for vasospasm and DCI are summarized, and commonalities in diagnosis and management are discussed. Clinical characteristics and treatment outcomes of 38 cases across 20 studies were identified in which patients with TBI with vasospasm underwent medical or endovascular management. Of the patients with data available for each category, the average age was 48.7 ± 20.3 years (n = 31), the Glasgow Coma Scale score at presentation was 10.6 ± 4.5 (n = 35), and 100% had tSAH (n = 29). Symptomatic vasospasm indicative of DCI was diagnosed on average at postinjury day 8.4 ± 3.0 days (n = 30). Of the patients, 56.6% (n = 30) had a new ischemic change associated with vasospasm confirming DCI. Treatment strategies are discussed, with 11 of 12 endovascularly treated and 19 of 26 medically treated patients surviving to discharge. tSAH is associated with vasospasm and DCI in moderate and severe TBI, and patients with clinical and radiographic evidence of symptomatic vasospasm and subsequent DCI may benefit from endovascular or medical management strategies. [ABSTRACT FROM AUTHOR]