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Frontiers in Neurology 2024
PubMed: 38867887
DOI: 10.3389/fneur.2024.1419224 -
Neurological Research and Practice Nov 2023As a complication of subarachnoid hemorrhage (SAH), vasospasm substantially contributes to its morbidity and mortality. We aimed at analyzing predictors of outcome for...
As a complication of subarachnoid hemorrhage (SAH), vasospasm substantially contributes to its morbidity and mortality. We aimed at analyzing predictors of outcome for these patients including the role of endovascular treatment (ET). Our database was screened for patients with SAH treated in our Neuro-ICU from 2009 to 2019. Clinical parameters including functional outcome (modified Rankin Scale, mRS of 0-2 or 3-6 at discharge and after a median follow-up of 18 months) and details about ET were gathered on 465 patients, 241 (52%) of whom experienced vasospasm. Descriptive analyses were performed to identify explanatory variables for the dichotomized mRS score. A logistic regression model was fitted on 241 patients with vasospasm including age, Hunt and Hess Score, extraventricular drainage (EVD), forced hypertension, ET and delayed cerebral ischemia (DCI). The model found a Hunt and Hess Score of 5 (OR = 0.043, p = 0.008), requirement of EVD (OR = 0.161, p < 0.001), forced hypertension (OR = 0.242, p = 0.001), ET (OR = 0.431, p = 0.043) and DCI (OR = 0.229, p < 0.001) to be negative predictors of outcome while age was not. Use of intraarterial nimodipine alone (OR = 0.778, p = 0.705) or including balloon angioplasty (OR = 0.894, p = 0.902) and number of ETs per patient (OR = 0.757, p = 0.416) were not significant in a separate model with otherwise identical variables. While DCI is clearly associated with poor outcome, the influence of ET on outcome remains inconclusive. Limited by their retrospective nature and an indication bias, these data encourage a randomized assessment of ET.
PubMed: 37915071
DOI: 10.1186/s42466-023-00283-3 -
Journal of Cerebrovascular and... Sep 2023Cerebral collateral circulation may affect subarachnoid hemorrhage (SAH) induced cerebral vasospasm and delayed cerebral ischemia. In this study our aim was to...
OBJECTIVE
Cerebral collateral circulation may affect subarachnoid hemorrhage (SAH) induced cerebral vasospasm and delayed cerebral ischemia. In this study our aim was to investigate the relationship between collateral status, vasospasm and delayed cerebral ischemia (DCI) in both aneurysmal and nonaneurysmal SAH.
METHODS
Patients diagnosed as SAH with and without aneurysm were included and their data investigated retrospectively. After the patients diagnosed as SAH according to cerebral computed tomography (CT)/magnetic resonance imaging (MRI), they underwent cerebral angiography to check for cerebral aneurysm. The diagnosis of DCI was made according to the neurological examination and control CT/MRI. All the patients had their control cerebral angiography on days 7 to 10 in order to assess vasospasm and also collateral circulation. The American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) Collateral Flow Grading System was modified to measure collateral circulation.
RESULTS
A total of 59 patients data were analyzed. Patients with aneurysmal SAH had higher Fisher scores and DCI was more common. Although there was no statistically significant difference between the patients with and without DCI in terms of demographics and mortality, patients with DCI had worse collateral circulation and more severe vasospasm. These patients had higher Fisher scores and more cerebral aneurysm overall.
CONCLUSIONS
According to our data, patients with higher Fisher scores, more severe vasospasm, and poor cerebral collateral circulation may experience DCI more frequently. Additionally aneurysmal SAH had higher Fisher scores and DCI was seen more common. To improve the clinical results for SAH patients, we believe that physicians should be aware of the DCI risk factors.
PubMed: 37232069
DOI: 10.7461/jcen.2023.E2022.11.005 -
Stroke and Vascular Neurology May 2024Subarachnoid haemorrhage (SAH) and intraventricular haemorrhage (IVH) are associated with poor patient outcomes. Intraventricular fibrinolysis is effective in clearing...
BACKGROUND
Subarachnoid haemorrhage (SAH) and intraventricular haemorrhage (IVH) are associated with poor patient outcomes. Intraventricular fibrinolysis is effective in clearing IVH and improving patient survival and neurological outcome. By similar rationale, cisternal irrigation has been proposed as a potential method to accelerate haematoma clearance in SAH. We aimed to provide a comprehensive review and meta-analysis evaluating the effect of intraventricular and cisternal irrigation on clinical outcomes in patients with SAH and IVH.
METHODS
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed preparing this systematic review and study selection was performed by multiple investigators. We extracted ORs from the individual studies and aggregated these using a random effects model. The quality of evidence was evaluated using Grading of Recommendations, Assessment, Development and Evaluations assessment and ROBINS-I or RoB-2.
RESULTS
24 articles were included. In SAH, we found that cisternal irrigation with fibrinolytic agents was associated with reduced mortality (OR: 0.68, 95% CI 0.46 to 1.00), higher probability of favourable functional outcome (OR: 1.80, 95% CI 1.30 to 2.51), and reduced risks of DCI (OR: 0.28, 95% CI 0.18 to 0.42) and cerebral vasospasm (OR: 0.28, 95% CI 0.18 to 0.42), compared with conventional therapy. Cisternal irrigation with vasodilatory agents was associated with lower mortality (OR: 0.32, 95% CI 0.13 to 0.79) and reduced risk of cerebral vasospasm (OR: 0.37, 95% CI 0.17 to 0.79). The evidence for irrigation therapy of IVH was sparse and insufficient to show any significant effect.
CONCLUSION
In this study, we found that cisternal irrigation could improve the prognosis in patients with SAH compared with conventional therapy. There is no evidence to support cisternal irrigation treatment of IVH.
PubMed: 38782496
DOI: 10.1136/svn-2023-003062 -
Neurosurgical Review Apr 2024Recent studies suggest that differential DNA methylation could play a role in the mechanism of cerebral vasospasm (CVS) and delayed cerebral ischemia (DCI) after... (Review)
Review
Recent studies suggest that differential DNA methylation could play a role in the mechanism of cerebral vasospasm (CVS) and delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). Considering the significance of this matter and a lack of effective prophylaxis against DCI, we aim to summarize the current state of knowledge regarding their associations with DNA methylation and identify the gaps for a future trial. PubMed MEDLINE, Scopus, and Web of Science were searched by two authors in three waves for relevant DNA methylation association studies in DCI after aSAH. PRISMA checklist was followed for a systematic structure. STROBE statement was used to assess the quality and risk of bias within studies. This research was funded by the National Science Centre, Poland (grant number 2021/41/N/NZ2/00844). Of 70 records, 7 peer-reviewed articles met the eligibility criteria. Five studies used a candidate gene approach, three were epigenome-wide association studies (EWAS), one utilized bioinformatics of the previous EWAS, with two studies using more than one approach. Methylation status of four cytosine-guanine dinucleotides (CpGs) related to four distinct genes (ITPR3, HAMP, INSR, CDHR5) have been found significantly or suggestively associated with DCI after aSAH. Analysis of epigenetic clocks yielded significant association of lower age acceleration with radiological CVS but not with DCI. Hub genes for hypermethylation (VHL, KIF3A, KIFAP3, RACGAP1, OPRM1) and hypomethylation (ALB, IL5) in DCI have been indicated through bioinformatics analysis. As none of the CpGs overlapped across the studies, meta-analysis was not applicable. The identified methylation sites might potentially serve as a biomarker for early diagnosis of DCI after aSAH in future. However, a lack of overlapping results prompts the need for large-scale multicenter studies. Challenges and prospects are discussed.
Topics: Humans; Subarachnoid Hemorrhage; DNA Methylation; Cerebral Infarction; Brain Ischemia; Biomarkers; Vasospasm, Intracranial; Cadherin Related Proteins
PubMed: 38594575
DOI: 10.1007/s10143-024-02381-5 -
Critical Care and Resuscitation :... Dec 2023Ascorbate, the biologically active form of vitamin C, is the primary neural anti-oxidant. Ascorbate concentrations have never been quantified following aneurysmal...
BACKGROUND
Ascorbate, the biologically active form of vitamin C, is the primary neural anti-oxidant. Ascorbate concentrations have never been quantified following aneurysmal subarachnoid haemorrhage (aSAH).
OBJECTIVE
To quantify plasma and cerebrospinal fluid (CSF) ascorbate concentrations in patients following SAH.
DESIGN SETTING PARTICIPANTS MAIN OUTCOME MEASURES
Cohort study in which plasma and CSF ascorbate concentrations were measured longitudinally in 12 aSAH patients admitted to a quaternary referral intensive care unit and compared to one-off samples obtained from 20 pregnant women prior to delivery in a co-located obstetric hospital. Data are median [interquartile range] or median (95 % confidence intervals).
RESULTS
Forty-eight plasma samples were obtained from the 12 aSAH patients (eight females, age 62 [53-68] years). Eight participants with extra-ventricular drains provided 31 paired CSF-plasma samples. Single plasma and CSF samples were obtained from 20 pregnant women (age 35 [31-37] years). Initial plasma and CSF ascorbate concentrations post aSAH were less than half those in pregnant controls (plasma: aSAH: 31 [25-39] μmol/L vs. comparator: 64 [59-77] μmol/L; P < 0.001 and CSF: 116 [80-142] μmol/L vs. 252 [240-288] μmol/L; P < 0.001). Post aSAH there was a gradual reduction in the CSF:plasma ascorbate ratio from ∼4:1 to ∼1:1. Six (50 %) patients developed vasospasm and CSF ascorbate concentrations were lower in these patients (vasospasm: 61 (25, 97) vs. no vasospasm: 110 (96, 125) μmol/L; P = 0.01).
CONCLUSION
Post aSAH there is a marked reduction in CSF ascorbate concentration that is most prominent in those who develop vasospasm.
PubMed: 38234324
DOI: 10.1016/j.ccrj.2023.10.003 -
MedRxiv : the Preprint Server For... Oct 2023Subarachnoid hemorrhage (SAH) is a devastating type of stroke, leading to high mortality and morbidity rates. Cerebral vasospasm and delayed cerebral ischemia (DCI) are...
Subarachnoid hemorrhage (SAH) is a devastating type of stroke, leading to high mortality and morbidity rates. Cerebral vasospasm and delayed cerebral ischemia (DCI) are common complications following SAH and contribute significantly to the poor outcomes observed in these patients. Intrathecal (IT) nicardipine delivered via an existing external ventricular drain has been shown to be correlated with reduced DCI and improved patient outcomes. The current study aims to characterize population pharmacokinetic (popPK) properties of intermittent IT nicardipine. Following informed consent, serial cerebrospinal fluid (CSF) samples were obtained from 16 SAH patients (50.4 ± 9.3 years old; 12 females) treated with IT nicardipine every 6 hours (n=8) or every 8 hours (n=8), which were subject to high-performance liquid chromatography for measurement of its CSF concentration. Our popPK analysis showed that the CSF PK of IT nicardipine in the cohort was adequately described by a two-compartment model with a lag time, with reliable parameter estimates (relative standard error < 50%). The intracranial pressure influenced both the total clearance and the central volume. Calculated PK parameters were similar between q6h and q8h dosing regimens. Despite a small cohort of SAH patients, we successfully developed a popPK model to describe the nicardipine disposition kinetics in the CSF following IT administration. These findings may help inform future clinical trials designed to examine the optimal dosing of IT nicardipine.
PubMed: 37905152
DOI: 10.1101/2023.10.17.23297116 -
Hypertension (Dallas, Tex. : 1979) Apr 2024Increased vasoreactivity due to reduced endothelial NO bioavailability is an underlying feature of cardiovascular disease, including hypertension. In small resistance...
BACKGROUND
Increased vasoreactivity due to reduced endothelial NO bioavailability is an underlying feature of cardiovascular disease, including hypertension. In small resistance arteries, declining NO enhances vascular smooth muscle (VSM) reactivity partly by enabling rapid depolarizing Ca-based spikes that underlie vasospasm. The endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) is metabolized by DDAH1 (dimethylarginine dimethylaminohydrolase 1) and elevated in cardiovascular disease. We hypothesized ADMA might enable VSM spikes and vasospasm by reducing NO bioavailability, which is opposed by DDAH1 activity and L-arginine.
METHODS
Rat isolated small mesenteric arteries and myogenic rat-isolated intraseptal coronary arteries (RCA) were studied using myography, VSM intracellular recording, Ca imaging, and DDAH1 immunolabeling. Exogenous ADMA was used to inhibit NO synthase and a selective DDAH1 inhibitor, N-(2-methoxyethyl) arginine, to assess the functional impact of ADMA metabolism.
RESULTS
ADMA enhanced rat-isolated small mesenteric arteries vasoreactivity to the α-adrenoceptor agonist, phenylephrine by enabling T-type voltage-gated calcium channel-dependent depolarizing spikes. However, some endothelium-dependent NO-vasorelaxation remained, which was sensitive to DDAH1-inhibition with N-(2-methoxyethyl) arginine. In myogenically active RCA, ADMA alone stimulated depolarizing Ca spikes and marked vasoconstriction, while NO vasorelaxation was abolished. DDAH1 expression was greater in rat-isolated small mesenteric arteries endothelium compared with RCA, but low in VSM of both arteries. L-arginine prevented depolarizing spikes and protected NO-vasorelaxation in rat-isolated small mesenteric artery and RCA.
CONCLUSIONS
ADMA increases VSM electrical excitability enhancing vasoreactivity. Endothelial DDAH1 reduces this effect, and low levels of DDAH1 in RCAs may render them susceptible to endothelial dysfunction contributing to vasospasm, changes opposed by L-arginine.
Topics: Rats; Animals; Cardiovascular Diseases; Coronary Vessels; Arginine; Nitric Oxide Synthase; Amidohydrolases; Nitric Oxide
PubMed: 38226470
DOI: 10.1161/HYPERTENSIONAHA.123.22454 -
Scientific Reports Aug 2023Perimesencephalic nonaneurysmal subarachnoid hemorrhage (NASAH) is a rare type of subarachnoid hemorrhage (SAH), usually associated with minor complications compared to...
Perimesencephalic nonaneurysmal subarachnoid hemorrhage (NASAH) is a rare type of subarachnoid hemorrhage (SAH), usually associated with minor complications compared to aneurysmal SAH. Up to date, data is scarce and consensus on therapeutic management and follow-up diagnostics of NASAH is often missing. This survey aims to evaluate the clinical management among neurosurgical departments in Germany. 135 neurosurgical departments in Germany received a hardcopy questionnaire. Encompassing three case vignettes with minor, moderate and severe NASAH on CT-scans and questions including the in-hospital treatment with initial observation, blood pressure (BP) management, cerebral vasospasm (CV) prophylaxis and the need for digital subtraction angiography (DSA). 80 departments (59.2%) answered the questionnaire. Whereof, centers with a higher caseload state an elevated complication rate (Chi < 0.001). Initial observation on the intensive care unit is performed in 51.3%; 47.5%, 70.0% in minor, moderate and severe NASAH, respectively. Invasive BP monitoring is performed more often in severe NASAH (52.5%, 55.0%, 71.3% minor, moderate, severe). CV prophylaxis and transcranial doppler ultrasound (TCD) are performed in 41.3%, 45.0%, 63.8% in minor, moderate and severe NASAH, respectively. Indication for a second DSA is set in the majority of centers, whereas after two negative ones, a third DSA is less often indicated (2nd: 66.2%, 72.5%, 86.2%; 3rd: 3.8%, 3.8%, 13.8% minor, moderate, severe). This study confirms the influence of bleeding severity on treatment and follow-up of NASAH patients. Additionally, the existing inconsistency of treatment pathways throughout Germany is highlighted. Therefore, we suggest to conceive new treatment guidelines including this finding.
Topics: Humans; Subarachnoid Hemorrhage; Subarachnoid Space; Tomography, X-Ray Computed; Vasospasm, Intracranial; Angiography, Digital Subtraction; Cerebral Angiography
PubMed: 37550334
DOI: 10.1038/s41598-023-39195-2 -
MedRxiv : the Preprint Server For... Mar 2024In Alzheimer's disease (AD), the most common cause of dementia, females have higher prevalence and faster progression, but sex-specific molecular findings in AD are...
In Alzheimer's disease (AD), the most common cause of dementia, females have higher prevalence and faster progression, but sex-specific molecular findings in AD are limited. Here, we comprehensively examined and validated 7,006 aptamers targeting 6,162 proteins in cerebral spinal fluid (CSF) from 2,077 amyloid/tau positive cases and controls to identify sex-specific proteomic signatures of AD. In discovery (N=1,766), we identified 330 male-specific and 121 female-specific proteomic alternations in CSF (FDR <0.05). These sex-specific proteins strongly predicted amyloid/tau positivity (AUC=0.98 in males; 0.99 in females), significantly higher than those with age, sex, and APOE-ε4 (AUC=0.85). The identified sex-specific proteins were well validated (r≥0.5) in the Stanford study (N=108) and Emory study (N=148). Biological follow-up of these proteins led to sex differences in cell-type specificity, pathways, interaction networks, and drug targets. Male-specific proteins, enriched in astrocytes and oligodendrocytes, were involved in postsynaptic and axon-genesis. The male network exhibited direct connections among 152 proteins and highlighted PTEN, NOTCH1, FYN, and MAPK8 as hubs. Drug target suggested melatonin (used for sleep-wake cycle regulation), nabumetone (used for pain), daunorubicin, and verteporfin for treating AD males. In contrast, female-specific proteins, enriched in neurons, were involved in phosphoserine residue binding including cytokine activities. The female network exhibits strong connections among 51 proteins and highlighted JUN and 14-3-3 proteins (YWHAG and YWHAZ) as hubs. Drug target suggested biperiden (for muscle control of Parkinson's disease), nimodipine (for cerebral vasospasm), quinostatin and ethaverine for treating AD females. Together, our findings provide mechanistic understanding of sex differences for AD risk and insights into clinically translatable interventions.
PubMed: 38559166
DOI: 10.1101/2024.03.15.24304164