Inflammatory markers for brain edema after aneurysmal subarachnoid hemorrhage

Inflammatory markers for brain edema after aneurysmal subarachnoid hemorrhage

The onset of aneurysmal subarachnoid hemorrhage (aSAH) elicits activation of the inflammatory cascade, and ongoing neuroinflammation is suspected to contribute to secondary complications, such as vasospasm and delayed cerebral ischemia.

To date, the monitoring of the inflammatory response to detect secondary complications such as DCI has not become part of the clinical routine diagnostic.

Höllig et al. estimated that the wide range of the measured values hampers their interpretation and usage as a biomarker. However, understanding the inflammatory response after aSAH and generating a multicenter database may facilitate further studies: realistic sample size calculations on the basis of a multicenter database will increase the quality and clinical relevance of the acquired results 1).


In a review, of Watson et al. analyze the extent literature regarding the relationship between neuroinflammation and cognitive dysfunction after aSAH. Pro-inflammatory cytokines appear to play a role in maintaining normal cognitive function in adults unaffected by aSAH. However, in the setting of aSAH, elevated cytokine levels may correlate with worse neuropsychological outcomes. This seemingly dichotomous relationship between neuroinflammation and cognition suggests that the action of cytokines varies, depending on their physiologic environment. Experimental therapies which suppress the immune response to aSAH appear to have a beneficial effect on cognitive outcomes. However, further studies are necessary to determine the utility of inflammatory mediators as biomarkers of neurocognitive outcomes, as well as their role in the management of aSAH 2).


Ahn et al. investigated inflammatory markers in subjects with early brain edema which does not resolve, i.e., persistent brain edema after SAH.

Computed tomography scans of SAH patients were graded at admission and at 7 days after SAH for Brain edema using the 0-4 ‘subarachnoid hemorrhage early brain edema score‘ (SEBES). SEBES ≤ 2 and SEBES ≥ 3 were considered good and poor grade, respectively. Serum samples from the same subject cohort were collected at 4 time periods (at < 24 h [T1], at 24 to 48 h [T2]. 3-5 days [T3] and 6-8 days [T4] post-admission) and concentration levels of 17 cytokines (implicated in peripheral inflammatory processes) were measured by multiplex immunoassay. Multivariable logistic regression analyses were step-wisely performed to identify cytokines independently associated with persistent CE adjusting for covariables including age, sex and past medical history (model 1), and additional inclusion of clinical and radiographic severity of SAH and treatment modality (model 2).

Of the 135 patients enrolled in the study, 21 of 135 subjects (15.6%) showed a persistently poor SEBES grade. In multivariate model 1, higher Eotaxin (at T1 and T4), sCD40L (at T4), IL-6 (at T1 and T3) and TNF-α (at T4) were independently associated with persistent CE. In multivariate model 2, Eotaxin (at T4: odds ratio [OR] = 1.019, 95% confidence interval [CI] = 1.002-1.035) and possibly PDGF-AA (at T4), sCD40L (at T4), and TNF-α (at T4) was associated with persistent CE.

They identified serum cytokines at different time points that were independently associated with persistent Brain edema. Specifically, persistent elevations of Eotaxin is associated with persistent Brain edema after SAH 3).


Leucocytosis and change in IL-6 prior to DCI reflect impending cerebral ischemia. The time-independent association of ESR with DCI after SAH may identify this as a risk factor. These data suggest that systemic inflammatory mechanisms may increase the susceptibility to the development of DCI after SAH 4)


Platelet-derived growth factor (PDGF)-AA, PDGF-AB/BB, soluble CD40 ligand, and tumor necrosis factor-α (TNF-α) increased over time. Colony-stimulating factor (CSF) 3, interleukin (IL)-13, and FMS-like tyrosine kinase 3 ligand decreased over time. IL-6, IL-5, and IL-15 peaked and decreased. Some cytokines with insignificant trends show high correlations with other cytokines and vice versa. Many correlated cytokine clusters, including a platelet-derived factor cluster and an endothelial growth factor cluster, were observed at all times. Participants with higher clinical severity at admission had elevated levels of several proinflammatory and anti-inflammatory cytokines, including IL-6, CCL2, CCL11, CSF3, IL-8, IL-10, CX3CL1, and TNF-α, compared to those with lower clinical severity 5).


1)

Höllig A, Stoffel-Wagner B, Clusmann H, Veldeman M, Schubert GA, Coburn M. Time Courses of Inflammatory Markers after Aneurysmal Subarachnoid Hemorrhage and Their Possible Relevance for Future Studies. Front Neurol. 2017 Dec 22;8:694. doi: 10.3389/fneur.2017.00694. PMID: 29312122; PMCID: PMC5744005.
2)

Watson E, Ding D, Khattar NK, Everhart DE, James RF. Neurocognitive outcomes after aneurysmal subarachnoid hemorrhage: Identifying inflammatory biomarkers. J Neurol Sci. 2018 Jun 25;394:84-93. doi: 10.1016/j.jns.2018.06.021. [Epub ahead of print] Review. PubMed PMID: 30240942.
3)

Ahn SH, Burkett A, Paz A, Savarraj JP, Hinds S, Hergenroeder G, Gusdon AM, Ren X, Hong JH, Choi HA. Systemic inflammatory markers of persistent cerebral edema after aneurysmal subarachnoid hemorrhage. J Neuroinflammation. 2022 Aug 4;19(1):199. doi: 10.1186/s12974-022-02564-1. PMID: 35927663.
4)

McMahon CJ, Hopkins S, Vail A, King AT, Smith D, Illingworth KJ, Clark S, Rothwell NJ, Tyrrell PJ. Inflammation as a predictor for delayed cerebral ischemia after aneurysmal subarachnoid haemorrhage. J Neurointerv Surg. 2013 Nov;5(6):512-7. doi: 10.1136/neurintsurg-2012-010386. Epub 2012 Sep 5. PMID: 22952245; PMCID: PMC3812893.
5)

Savarraj JPJ, Parsha K, Hergenroeder GW, Zhu L, Bajgur SS, Ahn S, Lee K, Chang T, Kim DH, Liu Y, Choi HA. Systematic model of peripheral inflammation after subarachnoid hemorrhage. Neurology. 2017 Apr 18;88(16):1535-1545. doi: 10.1212/WNL.0000000000003842. Epub 2017 Mar 17. PMID: 28314864; PMCID: PMC5395070.

Timing of endovascular treatment for aneurysmal subarachnoid hemorrhage

Timing of endovascular treatment for aneurysmal subarachnoid hemorrhage

An earlier approach may be relevant for the prevention of rebleeding and improvement of clinical outcome, but several disadvantages should be considered, such as an increased rate of periprocedural complications. Hence, a well-designed randomized controlled trial deems necessary to be able to define the optimal time of treatment. The possibility of treatment concomitant with the initial angiography should also be taken into account in this trial. This fact might represent a benefit favoring coiling over clipping in the prevention of rebleeding, and thus avoiding the inevitable delay necessary for the preparation for surgery 1).

2017

To systematically review and meta-analyse the data on impact of timing of endovascular treatment in aneurysmal subarachnoid hemorrhage (SAH) to determine if earlier treatment is associated with improved clinical outcomes and reduced case fatality.

Rawal et al., searched MEDLINE, Cochrane database, EMBASE and Web of Science to identify studies for inclusion. The measures of effect utilised were unadjusted/adjusted ORs. Effect estimates were combined using random effects models for each outcome (poor outcome, case fatality); heterogeneity was assessed using the I2 index. Subgroup and sensitivity analyses were performed to account for heterogeneity and risk of bias.

16 studies met the inclusion criteria. Treatment <1 day was associated with a reduced odds of poor outcome compared with treatment >1 day (OR=0.40 (95% CI 0.28 to 0.56; I2=0%)) but not when compared with treatment at 1-3 days (OR=1.16 (95% CI 0.47 to 2.90; I2=81%)). Treatment at <2 days and at <3 days were associated with similar odds of poor outcome compared with later treatment (OR=1.20 (95% CI 0.70 to 2.05; I2=73%; OR=0.71 (95% CI 0.36 to 1.37; I2=71%)). Early treatment was associated with similar odds of case fatality compared with later treatment, regardless of how early/late treatment were defined (OR=1.80 (95% CI 0.88 to 3.67; I2=34%) for treatment <1 day vs days 1-3; OR=1.71 (95% CI 0.72 to 4.03; I2=54%) for treatment <2 days vs later; OR=0.90 (95% CI 0.31 to 2.68; I2=48%) for treatment <3 days vs later).

In only 1 of the analyses was there a statistically significant result, which favoured treatment <1 day. The inconsistent results and heterogeneity within most analyses highlight the lack of evidence for best timing of endovascular treatment in SAH patients 2).

Patients with intracranial aneurysms treated with embolization were divided into group A (n = 277), patients with ruptured aneurysms treated within 72 hours of SAH; group B (n = 138), patients with ruptured aneurysms treated beyond 72 hours; and group C (n = 93), patients with unruptured aneurysms.

Embolization was successful in all but four patients (99.2%). The periprocedural complication rate was 36.2% in group B, significantly (p < 0.05) greater than that in group A (24.5%) or group C (11.8%). The rebleeding rate was 9.7% (6/62 patients) in groups A and B after embolization and only 0.3% (1/346 patients) in aneurysms with total or subtotal occlusion. Of these three groups of patients, 69.7% in group A, 58.7% in group B, and 76.3% in group C achieved Glasgow Outcome Scale (GOS) score of 5 or modified Rankin Scale (mRS) score of 0- to 1 at discharge. A significant difference (p < 0.05) existed in the clinical outcome between the three groups. The percentages of patients without deficits (GOS 5 or mRS 0-1) and slight disability (mRS 2) were 80.2% in group A, 81.2% in group B, and 96.7% in group C. The mortality rate was 4.3% (12/277 patients) in group A and 7.2% (10/138 patients) in group B with no significant (p = 0.21) difference. Follow-up was performed at 3 to 54 months (mean 23.2), and the recanalization rate was 28.6% (32/112 patients) in group A, 22.4% (11/49 patients) in group B, and 28.6% (16/56 patients) in group C, with no significant differences (p = 0.15). Hydrocephalus occurred in 30.5% (39/128 patients) in group B, which was significantly (p < 0.01) greater than that in group A (9.4%) or group C (2.2%).

Early embolization of ruptured cerebral aneurysms within 72 hours of rupture is safe and effective and can significantly decrease periprocedural complications compared with management beyond 72 hours. Timely management of cisternal and ventricular blood can reduce hydrocephalus incidence and improve prognosis 3).


A database of patients with aneurysmal subarachnoid hemorrhage was analyzed who were confirmed by CT, and underwent endovascular treatment between January 2005 and January 2012,. The patients were grouped into four cohorts according to the timing of treatment: ultra-early cohort (within 24 hours of onset which was confirmed by CT), early cohort (between 24 and 72 hours of onset which was confirmed by CT), intermediate cohort (between 4 and 10 days of onset which was confirmed by CT) and delayed cohort (after 11 days of onset which was confirmed by CT). Patient demographics, aneurysms features and clinical outcomes were analyzed to evaluate safety and efficacy for timing of endovascular treatment among four cohorts. In our series of 664 patients, 269 patients were grouped into ultra-early cohort, 62 patients in early cohort, 218 patients in intermediate cohort, and 115 patients in delayed cohort. The patient demographics, aneurysm characteristics and neurological conditions on admission among groups showed no statistical significance. As a result of the 9-month follow-up with 513 patients, good outcome (mRS<2) was achieved in 78% patients in “ultra-early” cohort compared with that of 57% in the “intermediate” group(p=0.000), whereas other comparisons showed no statistical significance(p<0.05) among the four groups. Dividing the patients with dichotomized mRS into “good outcome” group and “poor outcome” group (mRS<2) at the 9-month follow-up, the results showed lower Hunt-Hess scores (p=0.000) and smaller size of aneurysms (p=.001) which were correlated with the good outcome. Hypertension (p=0.776), age (p=0.327), sex (p=0.551) and location (p=0.901) showed no statistical significance between groups. Endovascular treatment of aneurysmal subarachnoid hemorrhage which was confirmed by CT within 72 hours achieved better outcomes than that confirmed after 72 hours, especially in those patients treated within 24 hours of onset in comparison with patients treated between 4 and 10 days 4).


1)

Matias-Guiu JA, Serna-Candel C. Early endovascular treatment of subarachnoid hemorrhage. Interv Neurol. 2013 Mar;1(2):56-64. doi: 10.1159/000346768. Review. PubMed PMID: 25187768; PubMed Central PMCID: PMC4031770.
2)

Rawal S, Alcaide-Leon P, Macdonald RL, Rinkel GJ, Victor JC, Krings T, Kapral MK, Laupacis A. Meta-analysis of timing of endovascular aneurysm treatment in subarachnoid haemorrhage: inconsistent results of early treatment within 1 day. J Neurol Neurosurg Psychiatry. 2017 Jan 18. pii: jnnp-2016-314596. doi: 10.1136/jnnp-2016-314596. [Epub ahead of print] PubMed PMID: 28100721.
3)

Li XY, Li CH, Wang JW, Liu JF, Li H, Gao BL. Safety and Efficacy of Endovascular Embolization of Ruptured Intracranial Aneurysms within 72 hours of Subarachnoid Hemorrhage. J Neurol Surg A Cent Eur Neurosurg. 2021 Nov 17. doi: 10.1055/s-0041-1731752. Epub ahead of print. PMID: 34788868.
4)

Qian Z, Peng T, Liu A, Li Y, Jiang C, Yang H, Wu J, Kang H, Wu Z. Early timing of endovascular treatment for aneurysmal subarachnoid hemorrhage achieves improved outcomes. Curr Neurovasc Res. 2014 Feb;11(1):16-22. PubMed PMID: 24320010.

Obesity in aneurysmal subarachnoid hemorrhage

Obesity in aneurysmal subarachnoid hemorrhage

As the number of obese people is globally increasing, reports about the putative protective effect of obesity in life-threatening diseases, such as subarachnoid hemorrhage (SAH), are gaining more interest. This theory-the obesity paradox-is challenging to study, and the impact of obesity has remained unclear in the survival of several critical illnesses, including SAH. Thus, we performed a systematic review to clarify the relation between obesity and SAH mortality. Our study protocol included systematic literature search in PubMed, Scopus, and Cochrane library databases, whereas risk-of-bias estimation and quality of each selected study were evaluated by the Critical Appraisal Skills Program and Cochrane Collaboration guidelines. A directional power analysis was performed to estimate a sufficient sample size for significant results. From 176 reviewed studies, six fulfilled our eligibility criteria for qualitative analysis. One study found paradoxical effect (odds ratio, OR = 0.83 (0.74-0.92)) between morbid obesity (body mass index (BMI) > 40) and in-hospital SAH mortality, and another study found the effect between continuously increasing BMI and both short-term (OR = 0.90 (0.82-0.99)) and long-term SAH mortalities (OR = 0.92 (0.85-0.98)). However, according to our quality assessment, methodological shortcomings expose all reviewed studies to a high-risk-of-bias. Even though two studies suggest that obesity may protect SAH patients from death in the acute phase, all reviewed studies suffered from methodological shortcomings that have been typical in the research field of obesity paradox. Therefore, no definite conclusions could be drawn 1).

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 (neuromonitoringCT 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). 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 2).


In a study involving a nationwide administrative database, milder obesity was not significantly associated with increased mortality rates, neurological complications, or poor outcomes after SAH. Morbid obesity, however, was associated with increased odds of venous thromboembolic, renal, and infectious complications, as well as of a nonroutine hospital discharge. Notably, milder obesity was associated with decreased odds of some medical complications, primarily in patients treated with coiling 3).


A total of 305 consecutive SAH patients (2002 to 2011) were retrospectively reviewed to collect demographics, BMI (kg/m(2)), comorbidities, Glascow Coma Scale, World Federation of Neurologic Surgeons Scale, aneurysm treatment, delayed cerebral ischemia, radiographic infarction, and short-term and long-term (> 24 months) morbidity, and mortality. Patients were stratified by BMI into category 1, < 25 kg/m(2); category 2, 25 -< 30 kg/m(2); and category 3, ≥ 30 kg/m(2).

Results: Categories 1, 2, and 3 had 93, 100, and 87 patients with mean BMIs of 22.4 ± 1.8, 27.6 ± 1.4, and 35.7 ± 4.6 (P < 0.05), respectively. By category, 24-month follow-up was available in 92%, 85%, and 85%. Category 3 had more hypertension, diabetes mellitus, and clipping than category 1. Short-term mortality rates were 17%, 12%, and 8%; long-term mortality rates were 34%, 26%, and 19% (P > 0.05 at all points between categories 1 vs. 3, but not 1 vs. 2 or 2 vs. 3). On univariate analysis, BMI was inversely associated with short-term (odds ratio, 0.91; 95% confidence interval 0.84-0.98; P = 0.009) and long-term (odds ratio, 0.92; 95% confidence interval 0.87-0.97; P = 0.001) mortality. On multivariate analysis including age, World Federation of Neurologic Surgeons Scale, delayed cerebral ischemia, and radiographic infarction, BMI remained significant for short-term (odds ratio, 0.91; 95% confidence interval 0.81-0.99; P = 0.047) and long-term (odds ratio, 0.92; 95% confidence interval 0.85-0.98; P = 0.021) mortality. On Kaplan-Meier survival analysis, P > 0.05 for categories 1 versus 2 and 2 versus 3, but P = 0.005 for categories 1 versus 3.

Conclusions: In our SAH population, higher BMI resulted in less short-term and long-term mortality, but no difference in functional outcome 4).


data for 741 SAH patients. A BMI greater than 25 kg/m(2) was considered overweight and greater than 30 kg/m(2) obese. The outcome according to the Glasgow Outcome Scale at discharge and after 6 months was assessed using logistic regression analysis.

Results: According to the BMI, 268 patients (36.2%) were overweight and 113 (15.2%) were obese. A favorable outcome (Glasgow Outcome Scale score >3) was achieved in 53.0% of overweight patients. In contrast, 61.4% of the 360 patients with a normal BMI had a favorable outcome (P = .021). However, in the multivariate analysis, only age (odds ratio [OR]: 1.051, 95% confidence interval [CI]: 1.04-1.07, P < .001), World Federation of Neurological Surgeons grade (OR: 2.095, 95% CI: 1.87-2.35, P < .001), occurrence of vasospasm (OR: 2.90, 95% CI: 1.94-4.34, P < .001), and aneurysm size larger than 12 mm (OR: 2.215, 95% CI: 1.20-4.10, P = .011) were independent predictors of outcome after 6 months. Of the 321 poor grade patients (World Federation of Neurological Surgeons score >3), 171 (53.3%) were overweight. Of these, 21.6% attained a favorable outcome compared with 35.3% of normal-weight patients (P = .006).

Conclusion: Although many physicians anticipate a worse outcome for obese patients, in our study, the BMI was not an independent predictor of outcome. Based on the BMI, obesity seems to be negligible for outcome after SAH compared with the impact of SAH itself, the patient’s age, occurrence of vasospasm, or aneurysm size 5).


Systolic and diastolic blood pressure were strong predictors of aneurysmal SAH, and there was a substantially increased risk associated with smoking. However, high body mass was associated with reduced risk of aneurysmal SAH 6).


1)

Rautalin I, Kaprio J, Korja M. Obesity paradox in subarachnoid hemorrhage: a systematic review. Neurosurg Rev. 2020 Dec;43(6):1555-1563. doi: 10.1007/s10143-019-01182-5. Epub 2019 Oct 29. PMID: 31664582; PMCID: PMC7680302.
2)

Veldeman M, Weiss M, Simon TP, Hoellig A, Clusmann H, Albanna W. Body mass index and leptin levels in serum and cerebrospinal fluid in relation to delayed cerebral ischemia and outcome after aneurysmal subarachnoid hemorrhage. Neurosurg Rev. 2021 Apr 17. doi: 10.1007/s10143-021-01541-1. Epub ahead of print. PMID: 33866464.
3)

Dasenbrock HH, Nguyen MO, Frerichs KU, Guttieres D, Gormley WB, Ali Aziz-Sultan M, Du R. The impact of body habitus on outcomes after aneurysmal subarachnoid hemorrhage: a Nationwide Inpatient Sample analysis. J Neurosurg. 2016 Jul 15:1-11. [Epub ahead of print] PubMed PMID: 27419827.
4)

Hughes JD, Samarage M, Burrows AM, Lanzino G, Rabinstein AA. Body Mass Index and Aneurysmal Subarachnoid Hemorrhage: Decreasing Mortality with Increasing Body Mass Index. World Neurosurg. 2015 Dec;84(6):1598-604. doi: 10.1016/j.wneu.2015.07.019. Epub 2015 Jul 15. PMID: 26187112.
5)

Platz J, Güresir E, Schuss P, Konczalla J, Seifert V, Vatter H. The impact of the body mass index on outcome after subarachnoid hemorrhage: is there an obesity paradox in SAH? A retrospective analysis. Neurosurgery. 2013 Aug;73(2):201-8. doi: 10.1227/01.neu.0000430322.17000.82. PMID: 23632760.
6)

Sandvei MS, Romundstad PR, Müller TB, Vatten L, Vik A. Risk factors for aneurysmal subarachnoid hemorrhage in a prospective population study: the HUNT study in Norway. Stroke. 2009 Jun;40(6):1958-62. doi: 10.1161/STROKEAHA.108.539544. Epub 2009 Feb 19. PMID: 19228833.
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