Premature newborns with intraventricular hemorrhage do not have vasospasm pattern by cranial Doppler ultrasound: A pilot study.

Preterm neonates are at risk for neurodevelopmental impairment, especially those with intraventricular hemorrhage (IVH). Cerebral vasospasm (VSP) is a common complication after subarachnoid hemorrhage (SAH) in adult population, but it is unknown if preterm neonates with IVH may develop it. We prospectively enrolled premature newborns < 32 weeks with IVH and without IVH. All patients received serial transcranial sonography through the temporal window of the middle cerebral artery, anterior cerebral artery, posterior cerebral artery, and the internal carotid artery with transcranial Doppler sonography days 2, 4, and 10 of life. Cerebral blood velocities (CBFVs) were measured including median velocity flow (MV), peak systolic velocity (PSV), and maximum end-diastolic velocity (EDV). Resistance index and pulsatility index were calculated. VSP was defined as an increase of 50% in the baseline velocity per day and/or a Lindegaard ratio higher than 3. Fifty subjects were enrolled. None of the patients with IVH showed elevation of MV or a Lindegaard ratio > 3. There were no differences between IVH and without IVH groups regarding resistance index and pulsatility index.    Conclusion: Preterm infants with IVH do not present a pattern of VSP analyzed by Doppler transcranial ultrasound in this pilot study. What is Known: • In adult population with subarachnoid hemorrhage the most treatable cause of cerebral ischemia is due cerebral vasospasm but is unknown if premature newborn may have vasospasm due the extravasation of blood in the context of intraventricular hemorrhage What is New: •In this pilot study we did not find in premature newborn with intraventricular hemorrhage signs of vasoespam measured by transcranial color doppler ultrasound.

Cerebral Hemodynamics and Levosimendan Use in Patients with Cerebral Vasospasm and Subarachnoid Hemorrhage: An Observational Perfusion CT-Based Imaging Study.

BACKGROUND: Delayed cerebral ischemia associated with cerebral vasospasm (CVS) in aneurysmal subarachnoid hemorrhage significantly affects patient prognosis. Levosimendan has emerged as a potential treatment, but clinical data are lacking. The aim of this study is to decipher levosimendan's effect on cerebral hemodynamics by automated quantitative measurements of brain computed tomography perfusion (CTP). METHODS: We conducted a retrospective analysis of a database of a neurosurgical intensive care unit. All patients admitted from January 2018 to July 2022 for aneurysmal subarachnoid hemorrhage and treated with levosimendan for CVS who did not respond to other therapies were included. Quantitative measurements of time to maximum (Tmax), relative cerebral blood volume (rCBV), and relative cerebral blood flow (rCBF) were automatically compared with coregistered CTP before and after levosimendan administration in oligemic regions. RESULTS: Of 21 patients included, CTP analysis could be performed in 16. Levosimendan improved Tmax from 14.4 s (interquartile range [IQR] 9.1-21) before treatment to 7.1 s (IQR 5.5-8.1) after treatment (p < 0.001). rCBV (94% [IQR 79-103] before treatment and 89% [IQR 72-103] after treatment, p = 0.63) and rCBF (85% [IQR 77-90] before treatment and 87% [IQR 73-98] after treatment, p = 0.98) remained stable. The subgroup of six patients who did not develop cerebral infarction attributed to delayed cerebral ischemia showed an approximately 10% increase (rCBV 85% [IQR 79-99] before treatment vs. 95% [IQR 88-112] after treatment, p = 0.21; rCBF 81% [IQR 76-87] before treatment vs. 89% [IQR 84-99] after treatment, p = 0.4). CONCLUSIONS: In refractory CVS, levosimendan use was associated with a significant reduction in Tmax in oligemic regions. However, this value remained at an abnormal level, indicating the presence of a persistent CVS. Further analysis raised the hypothesis that levosimendan causes cerebral vasodilation, but other studies are needed because our design does not allow us to quantify the effect of levosimendan from that of the natural evolution of CVS.

Smartphone pupillometry for detection of cerebral vasospasm after aneurysmal subarachnoid hemorrhage.

OBJECTIVES: Vasospasm is a complication of aneurysmal subarachnoid hemorrhage (aSAH) that can change the trajectory of recovery and is associated with morbidity and mortality. Earlier detection of vasospasm could improve patient outcomes. Our objective is to evaluate the accuracy of smartphone-based quantitative pupillometry in the detection of radiographic vasospasm and delayed cerebral ischemia (DCI) after aSAH. MATERIALS AND METHODS: We prospectively collected pupillary light reflex (PLR) parameters from patients with aSAH admitted to a neurocritical care unit at a single hospital twice daily using quantitative smartphone pupillometry recordings. PLR parameters included: Maximum pupil diameter, minimum pupil diameter, percent change in pupil diameter, latency in beginning of pupil constriction to light, mean constriction velocity, maximum constriction velocity, and mean dilation velocity. Two-tailed t-tests for independent samples were performed to determine changes in average concurrent PLR parameter values between the following comparisons: (1) patients with and without radiographic vasospasm (defined by angiography with the need for endovascular intervention) and (2) patients with and without DCI. RESULTS: 49 subjects with aSAH underwent 323 total PLR recordings. For PLR recordings taken with (n=35) and without (n=241) radiographic vasospasm, significant differences were observed in MIN (35.0 ± 7.5 pixels with vasospasm versus 31.6 ± 6.2 pixels without; p=0.002). For PLR recordings taken with (n=43) and without (n=241) DCI, significant differences were observed in MAX (48.9 ± 14.3 pixels with DCI versus 42.5 ± 9.2 pixels without; p<0.001). CONCLUSIONS: Quantitative smartphone pupillometry has the potential to be used to detect radiographic vasospasm and DCI after aSAH.

Effects of induced arterial hypertension for vasospasm on unruptured and unsecured cerebral aneurysms (growth and rupture). A retrospective case-control study.

OBJECTIVES: Unruptured cerebral aneurysms (UCAs) often coexist with the ruptured one but are typically left unsecured during the weeks following aneurysmal subarachnoid hemorrhage (aSAH). We compared the rate of UCAs rupture or volume growth (≥5 mm3) between patients exposed to induced arterial hypertension (iHTN) for vasospasm and those not exposed (control group). MATERIALS AND METHODS: From 2013 to 2021, we retrospectively included consecutive adult patients with aSAH who had ≥1 UCA. Custom software for digital subtraction angiography (DSA) image analysis characterized UCAs volume, going beyond merely considering UCAs long axis. RESULTS: We analyzed 118 patients (180 UCAs): 45 in the iHTN group (64 UCAs) and 73 in the control group (116 UCAs). Systolic blood pressure in the iHTN group was significantly higher than in the control group for several days after aSAH. During the 107 day-monitoring period [interquartile range(IQR):92;128], no UCA rupture occurred in either group. UCA volume analysis was performed in 44 patients (60 UCAs): none of the UCAs in the iHTN group and 3 out of 42 (7%) in the control group had a >5 mm3 volume growth (p=0.55). Other morphologic parameters did not exhibit any variations that might indicate an increased risk of rupture in the iHTN group compared to the control group. CONCLUSION: iHTN did not increase the risk of rupture or volume growth of UCAs within several weeks following aSAH. These reassuring results encourage not to refrain, because of the existence of UCAs, from iHTN as an option to prevent cerebral infarction during cerebral vasospasm.

[Reversible cerebral vasoconstriction syndrome : A rare cause of stroke]. / Reversibles zerebrales Vasokonstriktionssyndrom : Eine seltene Schlaganfallursache.

Reversible cerebral vasoconstriction syndrome (RCVS) is a complex and etiologically diverse neurovascular disorder that typically presents with severe thunderclap headaches (TCH) as the primary symptom, accompanied by reversible vasoconstriction of the cerebral arteries. The clinical course may include focal neurological deficits or epileptic seizures. There are two types: idiopathic RCVS and secondary RCVS, the latter triggered by various substances, medical interventions, or diseases. In clinical practice, various medical specialists may initially encounter this condition, underscoring the importance of accurate recognition and diagnosis of RCVS. The clinical course often appears monophasic and self-limiting, with recurrences reported in only 1.7% of cases annually. Complications such as cerebral hemorrhages and cerebral ischemia can lead to death in 5-10% of cases. This article utilizes a case study to explore RCVS, its complications, and the diagnostic procedures involved.

NLRP3 inhibition attenuates early brain injury and delayed cerebral vasospasm after subarachnoid hemorrhage.

BACKGROUND: The NLRP3 inflammasome is a critical mediator of several vascular diseases through positive regulation of proinflammatory pathways. In this study, we defined the role of NLRP3 in both the acute and delayed phases following subarachnoid hemorrhage (SAH). SAH is associated with devastating early brain injury (EBI) in the acute phase, and those that survive remain at risk for developing delayed cerebral ischemia (DCI) due to cerebral vasospasm. Current therapies are not effective in preventing the morbidity and mortality associated with EBI and DCI. NLRP3 activation is known to drive IL-1ß production and stimulate microglia reactivity, both hallmarks of SAH pathology; thus, we hypothesized that inhibition of NLRP3 could alleviate SAH-induced vascular dysfunction and functional deficits. METHODS: We studied NLRP3 in an anterior circulation autologous blood injection model of SAH in mice. Mice were randomized to either sham surgery + vehicle, SAH + vehicle, or SAH + MCC950 (a selective NLRP3 inhibitor). The acute phase was studied at 1 day post-SAH and delayed phase at 5 days post-SAH. RESULTS: NLRP3 inhibition improved outcomes at both 1 and 5 days post-SAH. In the acute (1 day post-SAH) phase, NLRP3 inhibition attenuated cerebral edema, tight junction disruption, microthrombosis, and microglial reactive morphology shift. Further, we observed a decrease in apoptosis of neurons in mice treated with MCC950. NLRP3 inhibition also prevented middle cerebral artery vasospasm in the delayed (5 days post-SAH) phase and blunted SAH-induced sensorimotor deficits. CONCLUSIONS: We demonstrate a novel association between NLRP3-mediated neuroinflammation and cerebrovascular dysfunction in both the early and delayed phases after SAH. MCC950 and other NLRP3 inhibitors could be promising tools in the development of therapeutics for EBI and DCI.

Characterization of thunderclap headache in a reversible cerebral vasoconstriction syndrome case series.

OBJECTIVES: To empirically address how thunderclap headache (TCH) is described in a relevant real-world setting. BACKGROUND: TCH refers to a highly recognizable description of a severe headache that reaches maximum severity within 1 minute and endures for at least 5 minutes. The use of a numerical rating scale (NRS) to appraise TCH severity, as well as assessment of TCH progression in patients with pre-existing headache at the time of TCH onset has not been previously evaluated. METHODS: This was a retrospective case series of adults with a diagnosis of reversible cerebral vasoconstriction syndrome (RCVS), identified through a search of the electronic health record. Individuals meeting International Classification of Headache Disorders, 3rd Edition criteria for acute headache attributed to RCVS were included. Attacks described using a verbal descriptor scale (VDS), NRS, or both were recorded to evaluate acute headache characteristics. RESULTS: In all, 56 individuals with available descriptions of 120 acute headaches were included in the study analysis. Patients were female (35, 62.5%) with a median age of 46 (range: 19-67). The majority of patients reported a RCVS trigger (39, 69.6%). Acute headaches were characterized using a VDS (52, 43.3%), NRS (51, 42.5%), or both (17, 14.1%). Acute headaches were always described as severe when a VDS was utilized, and with a median NRS of 10 (range: 4-10). Four patients (7%) did not have a single headache characterized as either severe or with a NRS 8 or greater. In the 10 cases for which there was a pre-TCH baseline headache, it was either rated as mild or with a median NRS of 3 (range: 2-6). CONCLUSIONS: TCH in RCVS can be recognized using either VDS or NRS, with a broader range of peak intensities than previously recognized. TCH remains recognizable despite pre-existing baseline headache.

Posterior Reversible Encephalopathy Syndrome.

PURPOSE OF REVIEW: This review provides an updated discussion on the clinical presentation, diagnosis and radiographic features, mechanisms, associations and epidemiology, treatment, and prognosis of posterior reversible encephalopathy syndrome (PRES). Headache is common in PRES, though headache associated with PRES was not identified as a separate entity in the 2018 International Classification of Headache Disorders. Here, we review the relevant literature and suggest criteria for consideration of its inclusion. RECENT FINDINGS: COVID-19 has been identified as a potential risk factor for PRES, with a prevalence of 1-4% in patients with SARS-CoV-2 infection undergoing neuroimaging, thus making a discussion of its identification and treatment particularly timely given the ongoing global pandemic at the time of this writing. PRES is a neuro-clinical syndrome with specific imaging findings. The clinical manifestations of PRES include headache, seizures, encephalopathy, visual disturbances, and focal neurologic deficits. Associations with PRES include renal failure, preeclampsia and eclampsia, autoimmune conditions, and immunosuppression. PRES is theorized to be a syndrome of disordered autoregulation and endothelial dysfunction resulting in preferential hyperperfusion of the posterior circulation. Treatment typically focuses on treating the underlying cause and removal of the offending agents.

Non-steroidal anti-inflammatory drugs in the pathophysiology of vasospasms and delayed cerebral ischemia following subarachnoid hemorrhage: a critical review.

Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening condition associated with the development of early brain injury (EBI) and delayed cerebral ischemia (DCI). Pharmacological treatment of vasospasm following aSAH currently mainly comprises nimodipine administration. In the past few years, many drugs that can potentially benefit cases of subarachnoid hemorrhage have become available. The objective of this review is to critically assess the effects of non-steroidal anti-inflammatory drugs (NSAIDs) following aSAH. A systematic literature review was conducted following PRISMA guidelines. The search was aimed at studies addressing aSAH and NSAIDs during the 2010 to 2019 period, and it yielded 13 articles. Following the application of search criteria, they were divided into two groups, one containing 6 clinical articles and the other containing 7 experimental articles on animal models of aSAH. Inflammatory cerebral changes after aneurysm rupture contribute to the development of EBI, DCI and cerebral vasospasm. It appears that NSAIDs (especially coxibs) are even more effective in reducing vasospasm than nimodipine. Other beneficial effects of NSAIDs include reduction in mortality, improved functional outcome and increased hypoaggregability. However, despite these positive effects, there is only one randomized, double-blind, placebo-controlled trial showing a tendency towards a better outcome with lower incidence of vasospasm or mortality in patients following aSAH.

Reversible Cerebral Vasoconstriction Syndrome Following Exposure to Oleoresin Capsicum "Pepper Spray".

OBJECTIVES: To report a case associating the use of Oleoresin Capsicum Pepper Spray (OCPS) during law enforcement training with development of Reversible Cerebral Vasoconstriction Syndrome (RCVS). MATERIALS AND METHODS: RCVS is radiographically characterized by multifocal smooth narrowing of cerebral arteries heralded by clinical manifestations of recurrent thunderclap headaches. 70% of cases with RCVS have a clear precipitating factor and agents commonly implicated were cannabis, selective serotonin reuptake inhibitors, nasal decongestants, cocaine, postpartum state, eclampsia and strenuous physical/sexual activity.1 RESULTS: 24-year-old female police officer with no past medical history who presented with thunderclap headaches after exposure to pepper spray to her face during work training. Neurological examination was unremarkable. CT angiogram (CTA) of the head and neck and subsequent conventional angiogram revealed multifocal mild arterial narrowing of bilateral middle cerebral arteries (MCA), bilateral posterior cerebral arteries (PCA) and left anterior cerebral artery (ACA) concerning for RCVS. Eight weeks later, she had a repeat MRA head and neck demonstrating complete resolution of the previously noted narrowing of her cerebral arteries. CONCLUSIONS: OCPS is widely used in law enforcement training as well as by general population as a self- defense tool. It is generally assumed to be safe, although the consequences of its use can never be predicted with certainty.2 As our case highlights, use of OCPS may be associated with development of RCVS and awareness needs to be raised regarding this rare but serious complication.

Pediatric Case of Life-Threatening Stroke Caused by Reversible Cerebral Vasoconstriction Syndrome with Spontaneous Cervical Internal Carotid Artery Vasospasm: A Case Report.

Pediatric reversible cerebral vasoconstriction syndrome (RCVS) and spontaneous cervical internal carotid artery (ICA) vasospasm are rare conditions; the former is commonly associated with a favorable prognosis. A healthy 13-year-old girl presented with thunderclap headache, followed by left hemiparesis, during a curling match. Six days after onset, left hemiparesis worsened to hemiplegia. Magnetic resonance imaging showed progressive cerebral infarction caused by severe right middle cerebral artery and cervical ICA stenosis. She became comatose because of impending uncal herniation. Emergent surgical decompression was performed. Then, 59 days after onset, her multiple stenoses improved, which was consistent with RCVS concomitant with spontaneous cervical ICA vasospasm. This is the first case of RCVS that concurrently developed spontaneous cervical ICA vasospasm. The patient developed life-threatening stroke due to the hemodynamic impairment of the affected intracranial and cervical arteries. Spontaneous extracranial supra-aortic artery vasospasm can be a poor prognostic predictor of RCVS.

Reversible Cerebral Vasoconstriction Syndrome in Patients with Coronavirus Disease: A Multicenter Case Series.

BACKGROUND AND OBJECTIVES: RCVS (Reversible Cerebral Vasoconstrictive Syndrome) is a condition associated with vasoactive agents that alter endothelial function. There is growing evidence that endothelial inflammation contributes to cerebrovascular disease in patients with coronavirus disease 2019 (COVID-19). In our study, we describe the clinical features, risk factors, and outcomes of RCVS in a multicenter case series of patients with COVID-19. MATERIALS AND METHODS: Multicenter retrospective case series. We collected clinical characteristics, imaging, and outcomes of patients with RCVS and COVID-19 identified at each participating site. RESULTS: Ten patients were identified, 7 women, ages 21 - 62 years. Risk factors included use of vasoconstrictive agents in 7 and history of migraine in 2. Presenting symptoms included thunderclap headache in 5 patients with recurrent headaches in 4. Eight were hypertensive on arrival to the hospital. Symptoms of COVID-19 included fever in 2, respiratory symptoms in 8, and gastrointestinal symptoms in 1. One patient did not have systemic COVID-19 symptoms. MRI showed subarachnoid hemorrhage in 3 cases, intraparenchymal hemorrhage in 2, acute ischemic stroke in 4, FLAIR hyperintensities in 2, and no abnormalities in 1 case. Neurovascular imaging showed focal segment irregularity and narrowing concerning for vasospasm of the left MCA in 4 cases and diffuse, multifocal narrowing of the intracranial vasculature in 6 cases. Outcomes varied, with 2 deaths, 2 remaining in the ICU, and 6 surviving to discharge with modified Rankin scale (mRS) scores of 0 (n=3), 2 (n=2), and 3 (n=1). CONCLUSIONS: Our series suggests that patients with COVID-19 may be at risk for RCVS, particularly in the setting of additional risk factors such as exposure to vasoactive agents. There was variability in the symptoms and severity of COVID-19, clinical characteristics, abnormalities on imaging, and mRS scores. However, a larger study is needed to validate a causal relationship between RCVS and COVID-19.

Nicardipine Prolonged Release Implants for Prevention of Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage: A Meta-Analysis.

OBJECTIVES: A paucity of treatments to prevent delayed cerebral ischemia (DCI) has stymied recovery after aneurysmal subarachnoid hemorrhage (aSAH). Nicardipine has long been recognized as a potent cerebrovascular vasodilator with a history off-label use to prevent vasospasm and DCI. Multiple centers have developed nicardipine prolonged release implants (NPRI) that are directly applied during clip ligation to locally deliver nicardipine throughout the vasospasm window. Here we perform a systematic review and meta-analysis to assess whether NPRI confers protection against DCI and improves functional outcomes after aSAH. MATERIALS AND METHODS: A systematic search of PubMed, Ovid Embase, and Cochrane databases was performed for studies reporting the use of NPRI after aSAH published after January 1, 1980. We included all studies assessing the association of NPRI with DCI and or functional outcomes. Findings from studies with control arms were analyzed using a random effects model. A separate network meta-analysis was performed, including controlled NPRI studies, single-arm NPRI reports, and the control-arms of modern aSAH randomized clinical trials as additional comparators. RESULTS: The search identified 214 unique citations. Three studies with 284 patients met criteria for the random effects model. The pooled summary odds ratio for the association of NPRI and DCI was 0.21 (95% CI 0.09-0.49, p = 0.0002) with no difference in functional outcomes (OR 1.80, 95% CI 0.63 - 5.16, p = 0.28). 10 studies of 866 patients met criteria for the network meta-analysis. The pooled summary odds ratio for the association of NPRI and DCI was 0.30 (95% CI 0.13-0.89,p = 0.017) with a trend towards improved functional outcomes (OR 1.68, 0.63 - 4.13 95% CI, p = 0.101). CONCLUSIONS: In these meta-analyses, NPRI decreases the incidence of DCI with a non-significant trend towards improvement in functional outcomes. Randomized trials on the role of intrathecal calcium channel blockers are warranted to evaluate these observations in a prospective manner.

COVID-19 Associated Reversible Cerebral Vasoconstriction Syndrome Successfully Treated with Nimodipine and Aspirin.

There have been limited cases linking SARS-CoV-2 infection with the development of reversible cerebral vasoconstriction syndrome (RCVS). We hereby report a rare case of RCVS in the setting of mild SARS-CoV-2 respiratory infection successfully treated with nimodipine and aspirin. SARS-CoV-2 attacks the ACE2-receptors, which are expressed in various body organs including the lungs, kidneys, and blood vessels. Vasoconstriction can result from down-regulation of the ACE2-receptors that can lead to sympathetic hypertonia of the cerebral blood vessel walls and/or over-activation of the renin-angiotensin axis.

The effect of remote ischemic conditioning on blood coagulation function and cerebral blood flow in patients with aneurysmal subarachnoid hemorrhage.

OBJECTIVE: To explore the effect of remote ischemic conditioning (RIC) on blood coagulation function and cerebral blood flow in patients with aneurysmal subarachnoid hemorrhage. PATIENTS AND METHODS: According to inclusion and exclusion standards, from October 2017 to June 2018, 30 consecutive patients of aneurysmal subarachnoid hemorrhage admitted to Intensive Care Unit, Department of Neurosurgery at Xuanwu Hospital, were given remote ischemic conditioning 5 times intervention to each patient within 7 days, and blood coagulation function testing, including prothrombin activity (PTA), prothrombin time (PT), activated partial prothrombin time (APTT), fibrinogen (Fib), D-dimer, and thromboelastogram (TEG, including R, K, Angle, MA, EPL, LY30, A, CI, G, and A30) were performed for each patient before and after the RIC intervention, as well as venous ultrasound monitoring before and after the RIC intervention for detection of deep vein thrombosis (DVT). Transcranial Doppler evaluation (TCD), including cerebral blood flow of bilateral ACA, MCA, PCA and intracranial segments of VA, as well as BA and the ratios of MCA cerebral blood flow/terminal segment of ipsilateral ICA cerebral blood flow, was performed before and after RIC intervention; and fresh infarction was evaluated by head CT or MRI recheck after RIC intervention. Thirty cases without RIC intervention of matched age, gender, and Hunt Hess grade with aneurysmal subarachnoid hemorrhage were selected to compare coagulation function and cerebral blood flow using TCD with RIC group. RESULTS: (1) Comparing the data before and after the RIC intervention, there was no significant difference for APTT, Fib, and D-dimer (P > 0.05), while PTA decreased and PT increased slightly after intervention as well as INR (P < 0.05) but all still in normal reference values. (2) Comparing the data before and after the RIC intervention, within TEG parameters, only the R value increased with significant difference (P < 0.05) but still in normal reference value, while K, Angle, MA, EPL, LY30, A, CI, G, and A30 had no significant difference (P > 0.05). (3) Comparing the data before and after the RIC intervention, DVT was not detected on the pressurized limbs of patients. (4) Comparing the data before and after the RIC intervention, the cerebral blood flow of bilateral MCA, L-ACA, L-VA, and BA increased (P < 0.05), while the elevation ranges were all in 25%, and the other parameters showed no significant difference. (5) Head CT or MRI showed no fresh cerebral infarction after the RIC intervention. (6) Compared with the group without RIC intervention, the coagulation function and the cerebral blood flow evaluated by TCD of the RIC group showed no statistical difference (P > 0.05) except APTT and D-dimer decreased after RIC but still in normal reference values. CONCLUSION: RIC showed no obvious effect on blood coagulation function and cerebral blood flow in patients with aneurysmal subarachnoid hemorrhage both after the intervention and compared with the non-intervention group. DVT was not detected on the pressurized limbs of patients and no fresh cerebral infarction was detected. This preliminary study confirmed the safety of RIC on blood coagulation function and cerebral blood flow in patients with aneurysmal subarachnoid hemorrhage, and the application of RIC on patients with aneurysmal subarachnoid hemorrhage needs further study to confirm and validate the safety and effectiveness.

Dysfunction of the endothelium and constriction of the isolated rat's middle cerebral artery in low sodium environment in the presence of vasopressin.

Hyponatraemia, a water-electrolyte disorder diagnosed in patients with subarachnoid haemorrhage (SAH), increases a risk of persistent vasospasm. In majority of cases, hyponatraemia results from inappropriate secretion of vasopressin (AVP). The effect of AVP-associated hyponatraemia on cerebral vasculature is unknown. The present study aimed to elucidate the role of AVP in the response of the middle cerebral artery (MCA) of the rat to hyponatraemia. Isolated, cannulated, and pressurized rat MCAs were perfused/superfused with physiological (Na+  = 144 mmol/L) buffer or low-sodium (Na+  = 121 mmol/L) buffer containing either AVP or angiotensin II (ANG II). ANG II was used to check if the effect of low plasma sodium concentration combined with AVP on the MCA tone is unique to vasopressin. At physiological Na+ concentration, vasopressin (1.4 × 10-11  mol/L) or angiotensin II (10-9  mol/L) resulted in relaxation of the MCA. Substitution of low-sodium for the normal sodium buffer with the same concentration of AVP, resulted in the constriction of the MCA. This effect was absent after removal of the endothelium, administration of vasopressin V1 receptor antagonist or concomitant inhibition of endothelin-1 receptors and synthesis of thromboxane A2. In contrast, no constriction of the MCA in low-sodium buffer was observed when AVP was replaced with ANG II. Our data suggest that presence of vasopressin and low sodium ion concentration results in the change of endothelium phenotype from pro-vasodilatory to pro-vasoconstrictory. This phenomenon may be an overlooked factor contributing to vasospasm in SAH patients with hyponatraemia caused by inappropriate antidiuretic hormone secretion (SIADH).

Narrative Review: Headaches After Reversible Cerebral Vasoconstriction Syndrome.

PURPOSE OF REVIEW: Reversible cerebral vasoconstriction syndrome (RCVS) is a disorder with distinct features: recurrent thunderclap headaches with reversible vasoconstriction of intracranial arteries. Substantial studies regarding outcomes after RCVS were conducted, showing favorable functional outcomes in most patients despite the potentially life-threatening complications of RCVS, including ischemic stroke, intracranial hemorrhage, or convexity subarachnoid hemorrhage. However, patients may report headaches after the resolution of RCVS while relative studies were scarce. RECENT FINDINGS: Two prospective studies from different cohorts consistently revealed that RCVS recurred in at least 5% of patients. Patients with prior migraine history and patients whose thunderclap headaches are elicited by sexual activity or exertion are at higher risk for RCVS recurrence. On the other hand, several retrospective studies and case reports reported that chronic headaches are common in RCVS patients after the resolution of acute bouts. The chronic headaches after RCVS are sometimes disabling in certain patients. Headaches after RCVS are not uncommon but usually overseen. Medical attention and examinations are warranted in patient with RCVS who reported recurrence of thunderclap headaches or chronic headaches after RCVS.

Delayed Cerebral Ischemia After Subarachnoid Hemorrhage: Experimental-Clinical Disconnect and the Unmet Need.

BACKGROUND: Delayed cerebral ischemia (DCI) is among the most dreaded complications following aneurysmal subarachnoid hemorrhage (SAH). Despite advances in neurocritical care, DCI remains a significant cause of morbidity and mortality, prolonged intensive care unit and hospital stay, and high healthcare costs. Large artery vasospasm has classically been thought to lead to DCI. However, recent failure of clinical trials targeting vasospasm to improve outcomes has underscored the disconnect between large artery vasospasm and DCI. Therefore, interest has shifted onto other potential mechanisms such as microvascular dysfunction and spreading depolarizations. Animal models can be instrumental in dissecting pathophysiology, but clinical relevance can be difficult to establish. METHODS: Here, we performed a systematic review of the literature on animal models of SAH, focusing specifically on DCI and neurological deficits. RESULTS: We find that dog, rabbit and rodent models do not consistently lead to DCI, although some degree of delayed vascular dysfunction is common. Primate models reliably recapitulate delayed neurological deficits and ischemic brain injury; however, ethical issues and cost limit their translational utility. CONCLUSIONS: To facilitate translation, clinically relevant animal models that reproduce the pathophysiology and cardinal features of DCI after SAH are urgently needed.

Genetic Variability and Trajectories of DNA Methylation May Support a Role for HAMP in Patient Outcomes After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND/OBJECTIVE: Preclinical evidence suggests that iron homeostasis is an important biological mechanism following aneurysmal subarachnoid hemorrhage (aSAH); however, this concept is underexplored in humans. This study examined the relationship between patient outcomes following aSAH and genetic variants and DNA methylation in the hepcidin gene (HAMP), a key regulator of iron homeostasis. METHODS: In this exploratory, longitudinal observational study, participants with verified aSAH were monitored for acute outcomes including cerebral vasospasm (CV) and delayed cerebral ischemia (DCI) and evaluated post-discharge at 3 and 12 months for long-term outcomes of death and functional status using the Modified Rankin Scale (mRS; poor = 3-6) and Glasgow Outcome Scale (GOS; poor = 1-3). Participants were genotyped for two genetic variants, and DNA methylation data were collected from serial cerebrospinal fluid over 14 days post-aSAH at eight methylation sites within HAMP. Participants were grouped based on their site-specific DNA methylation trajectory, with and without correcting for cell-type heterogeneity (CTH), and the associations between genetic variants and inferred DNA methylation trajectory groups and patient outcomes were tested. To correct for multiple testing, an empirical significance threshold was computed using permutation testing. RESULTS: Genotype data for rs10421768 and rs7251432 were available for 241 and 371 participants, respectively, and serial DNA methylation data were available for 260 participants. Acute outcome prevalence included CV in 45% and DCI in 37.1% of the overall sample. Long-term outcome prevalence at 3 and 12 months included poor GOS in 23% and 21%, poor mRS in 31.6% and 27.3%, and mortality in 15.1% and 18.2%, respectively, in the overall sample. Being homozygous for the rs7251432 variant allele was significantly associated with death at 3 months (p = 0.003) and was the only association identified that passed adjustment for multiple testing mentioned above. Suggestive associations (defined as trending toward significance, p value < 0.05, but not meeting empirical significance thresholds) were identified between the homozygous variant allele for rs7251432 and poor GOS and mRS at 3 months (both p = 0.04) and death at 12 months (p = 0.02). For methylation trajectory groups, no associations remained significant after correction for multiple testing. However, for methylation trajectory groups not adjusted for CTH, suggestive associations were identified between cg18149657 and poor GOS and mRS at 3 months (p = 0.003 and p = 0.04, respectively) and death at 3 months (p = 0.04), and between cg26283059 and DCI (p = 0.01). For methylation trajectory groups adjusted for CTH, suggestive associations were identified between cg02131995 and good mRS at 12 months (p = 0.02), and between cg26283059 and DCI (p = 0.01). CONCLUSIONS: This exploratory pilot study offers preliminary evidence that HAMP may play a role in patient outcomes after aSAH. Replication of this study and mechanistic investigation of the role of HAMP in patient outcomes after aSAH are needed.

RAR-Related Orphan Receptor Gamma T (RoRγt)-Related Cytokines Play a Role in Neutrophil Infiltration of the Central Nervous System After Subarachnoid Hemorrhage.

BACKGROUND: How inflammatory cells are recruited into the central nervous system is a topic of interest in a number of neurological injuries. In aneurysmal subarachnoid hemorrhage (SAH), neutrophil accumulation in the central nervous system 3 days after the hemorrhage is a critical step in the development of delayed cerebral injury (DCI). The mechanism by which neutrophils enter the central nervous system is still unclear. METHODS AND RESULTS: To identify human effectors of neutrophil recruitment, cerebrospinal fluid (CSF) samples were taken from a small, selected sample of SAH patients with external ventricular drainage devices (10 patients). Among a battery of CSF cytokines tested 3 days after SAH, five cytokines were associated with poor 90-day outcome (modified Rankin Score 3-6). A parallel study in a mouse model of mild SAH showed elevation in three cytokines in the CNS compared to sham. IL-17 and IL-2 were increased in both patients and the mouse model. IL-17 was investigated further because of its known role in neutrophil recruitment. Inhibition of RAR-Related Orphan Receptor Gamma T, the master transcription factor of IL-17, with the inverse agonist GSK805 suppressed neutrophils entry into the CNS after SAH compared to control. Using an IL-17 reporter mouse, we investigated the source of IL-17 and found that myeloid cells were a common IL-17-producing cell type in the meninges after SAH, suggesting an autocrine role for neutrophil recruitment. CONCLUSIONS: Taken together, IL-17 appears to be in important factor in the recruitment of neutrophils into the meninges after SAH and could be an important target for therapies to ameliorate DCI.