Cardiac Complications After Subarachnoid Hemorrhage

Cardiac Complications After Subarachnoid Hemorrhage

Subarachnoid hemorrhage (SAH) is a serious condition, and a myocardial injury or dysfunction could contribute to the outcome.

Acute cardiac complications frequently occur after subarachnoid hemorrhage (SAH). These complications include electrocardiogram (ECG) abnormalities, the release of cardiac biomarkers, and the development of acute stress-induced heart failure resembling Takotsubo cardiomyopathy 1) 2) 3) 4) 5) 6)

non-ST elevation myocardial infarction, ST-elevation myocardial infarction and cardiac arrest, but their clinical relevance is unclear.

Lång et al. assessed the prevalence and prognostic impact of cardiac involvement in a cohort with SAH in a prospective observational multicenter study. They included 192 patients treated for non traumatic subarachnoid hemorrhage. They performed ECG recordings, echocardiogram, and blood sampling within 24 h of admission and on days 3 and 7 and at 90 days. The primary endpoint was the evidence of cardiac involvement at 90 days, and the secondary endpoint was to examine the prevalence of a myocardial injury or dysfunction. The median age was 54.5 (interquartile range [IQR] 48.0-64.0) years, 44.3% were male and the median World Federation of Neurosurgical Societies grading for subarachnoid hemorrhage score was 2 (IQR 1-4). At day 90, 22/125 patients (17.6%) had left ventricular ejection fractions ≤ 50%, and 2/121 patients (1.7%) had evidence of a diastolic dysfunction as defined by mitral peak E-wave velocity by peak e’ velocity (E/e’) > 14. There was no prognostic impact from echocardiographic evidence of cardiac complications on neurological outcomes. The overall prevalence of cardiac dysfunction was modest. They found no demographic or SAH-related factors associated with 90 days cardiac dysfunction 7).

Among patients suffering from cardiac events at the time of aneurysmal subarachnoid hemorrhage, those with myocardial infarction and in particular those with a troponin level greater than 1.0 mcg/L had a 10 times increased risk of death 8).


Zaroff JG, Rordorf GA, Newell JB, Ogilvy CS, Levinson JR. Cardiac outcome in patients with subarachnoid hemorrhage and electrocardiographic abnormalities. Neurosurgery. 1999;44:34–39. doi: 10.1097/00006123-199901000-00013.

Tung P, Kopelnik A, Banki N, et al. Predictors of neurocardiogenic injury after subarachnoid hemorrhage. Stroke. 2004;35:548–551. doi: 10.1161/01.STR.0000114874.96688.54.

Banki N, Kopelnik A, Tung P, et al. Prospective analysis of prevalence, distribution, and rate of recovery of left ventricular systolic dysfunction in patients with subarachnoid hemorrhage. J Neurosurg. 2006;105:15–20. doi: 10.3171/jns.2006.105.1.15.

Lee VH, Connolly HM, Fulgham JR, Manno EM, Brown JRD, Wijdicks EFM. Tako-tsubo cardiomyopathy in aneurysmal subarachnoid hemorrhage: an underappreciated ventricular dysfunction. J Neurosurg. 2006;105:264–270. doi: 10.3171/jns.2006.105.2.264.

Oras J, Grivans C, Bartley A, Rydenhag B, Ricksten SE, Seeman-Lodding H. Elevated high-sensitive troponin T on admission is an indicator of poor long-term outcome in patients with subarachnoid haemorrhage: a prospective observational study. Crit Care (Lond, Engl) 2016;20:11. doi: 10.1186/s13054-015-1181-5.

van der Bilt IA, Hasan D, Vandertop WP, et al. Impact of cardiac complications on outcome after aneurysmal subarachnoid hemorrhage: a meta-analysis. Neurology. 2009;72:635–642. doi: 10.1212/01.wnl.0000342471.07290.07.

Lång M, Jakob SM, Takala R, Lyngbakken MN, Turpeinen A, Omland T, Merz TM, Wiegand J, Grönlund J, Rahi M, Valtonen M, Koivisto T, Røsjø H, Bendel S. The prevalence of cardiac complications and their impact on outcomes in patients with non-traumatic subarachnoid hemorrhage. Sci Rep. 2022 Nov 22;12(1):20109. doi: 10.1038/s41598-022-24675-8. PMID: 36418906.

Ahmadian A, Mizzi A, Banasiak M, Downes K, Camporesi EM, Thompson Sullebarger J, Vasan R, Mangar D, van Loveren HR, Agazzi S. Cardiac manifestations of subarachnoid hemorrhage. Heart Lung Vessel. 2013;5(3):168-78. PubMed PMID: 24364008; PubMed Central PMCID: PMC3848675.

Subarachnoid hemorrhage scales

Subarachnoid hemorrhage scales

see also Poor grade aneurysmal subarachnoid hemorrhage

Hijdra sum score

Hunt and Hess Stroke Scale

World Federation of Neurological Surgeons Grading System

Modified Fisher scale


Graeb Score or LeRoux scores improve the prediction of shunt dependency and in parts of case fatality rate (CFR) in aneurysmal SAH patients therefore confirming the relevance of the extent and distribution of intraventricular hemorrhage for the clinical course in SAH 1)


Czorlich P, Ricklefs F, Reitz M, Vettorazzi E, Abboud T, Regelsberger J, Westphal M, Schmidt NO. Impact of intraventricular hemorrhage measured by Graeb and LeRoux score on case fatality risk and chronic hydrocephalus in aneurysmal subarachnoid hemorrhage. Acta Neurochir (Wien). 2015 Mar;157(3):409-15. doi: 10.1007/s00701-014-2334-z. Epub 2015 Jan 21. PubMed PMID: 25599911.

Nicotine replacement therapy in aneurysmal subarachnoid hemorrhage

Nicotine replacement therapy in aneurysmal subarachnoid hemorrhage

Smoking prevalence is twice as high among patients admitted to hospital because of the acute condition of aneurysmal subarachnoid hemorrhage (aSAH) as in the general population.

Despite vasoactive properties, administration of NRT among active smokers with acute SAH appeared to be safe, with similar rates of vasospasm and DCI, and a slightly higher rate of seizures. The association of NRT with lower mortality could be due to chance, uncontrolled factors, or a neuroprotective effect of nicotine in active smokers hospitalized with SAH, and should be tested prospectively 1).

Smoking was also associated with paradoxical superior outcomes on some measures, and future research to confirm and further understand the basis of this relationship is needed 2).

Current evidence suggests that NRT does not induce vasospasm, and is associated with improved outcomes in smokers hospitalized for SAH. Protocol registered in PROSPERO, available at: 3) 4).

The use of NRT in the acute phase of aSAH does not seem to have an impact on the intensity of headaches or analgesic consumption 5).

Limited safety data may prompt caution regarding seizures and delirium in patients with subarachnoid hemorrhage 6).

Eisenring et al. investigated the international practice of NRT use for aSAH among neurosurgeons.

The online SurveyMonkey software was used to administer a 15-question, 5-min online questionnaire. An invitation link was sent to those 1425 of 1988 members of the European Association of Neurosurgical Societies (EANS) who agreed to participate in surveys to assess treatment strategies for withdrawal of tobacco smoking during aSAH. Factors contributing to physicians’ posture towards NRT were assessed.

A total of 158 physicians from 50 nations participated in the survey (response rate 11.1%); 68.4% (108) were affiliated with university hospitals and 67.7% (107) practiced at high-volume neurovascular centers with at least 30 treated aSAH cases per year. Overall, 55.7% (88) of physicians offered NRT to smokers with aSAH, 22.1% (35) offered non-NRT support including non-nicotine medication and counseling, while the remaining 22.1% (35) did not actively support smoking cessation. When smoking was not possible, 42.4% (67) of physicians expected better clinical outcomes when prescribing NRT instead of nicotine deprivation, 36.1% (57) were uncertain, 13.9% (22) assumed unaffected outcomes, and 7.6% (12) assumed worse outcomes. Only 22.8% (36) physicians had access to a local smoking cessation team in their practice, of whom half expected better outcomes with NRT as compared to deprivation.

A small majority of the surveyed physicians of the EANS offered NRT to support smoking cessation in hospitalized patients with aSAH. However, less than half believed that NRT could positively impact clinical outcomes as compared to deprivation. This survey demonstrated the lack of consensus regarding the use of NRT for hospitalized smokers with aSAH 7).


Seder DB, Schmidt JM, Badjatia N, Fernandez L, Rincon F, Claassen J, Gordon E, Carrera E, Kurtz P, Lee K, Connolly ES, Mayer SA. Transdermal nicotine replacement therapy in cigarette smokers with acute subarachnoid hemorrhage. Neurocrit Care. 2011 Feb;14(1):77-83. doi: 10.1007/s12028-010-9456-9. PMID: 20949331.

Dasenbrock HH, Rudy RF, Rosalind Lai PM, Smith TR, Frerichs KU, Gormley WB, Aziz-Sultan MA, Du R. Cigarette smoking and outcomes after aneurysmal subarachnoid hemorrhage: a nationwide analysis. J Neurosurg. 2018 Aug;129(2):446-457. doi: 10.3171/2016.10.JNS16748. Epub 2017 Oct 27. PMID: 29076779.

Turgeon RD, Chang SJ, Dandurand C, Gooderham PA, Hunt C. Nicotine replacement therapy in patients with aneurysmal subarachnoid hemorrhage: Systematic review of the literature, and survey of Canadian practice. J Clin Neurosci. 2017 Aug;42:48-53. doi: 10.1016/j.jocn.2017.03.014. Epub 2017 Mar 22. PMID: 28342700.

Carandang RA, Barton B, Rordorf GA, Ogilvy CS, Sims JR. Nicotine replacement therapy after subarachnoid hemorrhage is not associated with increased vasospasm. Stroke. 2011 Nov;42(11):3080-6. doi: 10.1161/STROKEAHA.111.620955. Epub 2011 Aug 25. PMID: 21868740.

Charvet A, Bouchier B, Dailler F, Ritzenthaler T. Nicotine Replacement Therapy Does Not Reduce Headaches Following Subarachnoid Hemorrhage: A Propensity Score-Matched Study. Neurocrit Care. 2022 Sep 1. doi: 10.1007/s12028-022-01576-2. Epub ahead of print. PMID: 36050538.

Parikh NS, Salehi Omran S, Kamel H, Elkind MSV, Willey JZ. Smoking-cessation pharmacotherapy for patients with stroke and TIA: Systematic review. J Clin Neurosci. 2020 Aug;78:236-241. doi: 10.1016/j.jocn.2020.04.026. Epub 2020 Apr 22. PMID: 32334957; PMCID: PMC8908464.

Eisenring CV, Hamilton PL, Herzog P, Oertel MF, Jacot-Sadowski I, Burn F, Cornuz J, Schatlo B, Nanchen D. Nicotine Replacement Therapy for Smokers with Acute Aneurysmal Subarachnoid Hemorrhage: An International Survey. Adv Ther. 2022 Sep 19. doi: 10.1007/s12325-022-02300-4. Epub ahead of print. PMID: 3612

Aneurysmal subarachnoid hemorrhage complications

Aneurysmal subarachnoid hemorrhage complications

Vasospasm is an important cause for mortality following aneurysmal subarachnoid hemorrhage aSAH affecting as many as 70% of patients. It usually occurs between 4th and 21st days of aSAH and is responsible for delayed ischemic neurological deficit (DIND) and cerebral infarction

It is one of the factors that can most significantly worsen the prognosis despite different treatments.

Transcranial doppler (TCD) evidence of vasospasm is predictive of delayed cerebral ischemia (DCI) with high accuracy. Although high sensitivity and negative predictive value make TCD an ideal monitoring device, it is not a mandated standard of care in aneurysmal subarachnoid hemorrhage (aSAH) due to the paucity of evidence on clinically relevant outcomes, despite recommendation by national guidelines. High-quality randomized trials evaluating the impact of TCD monitoring on patient-centered and physician-relevant outcomes are needed 1).

A greater proportion of aneurysmal subarachnoid hemorrhage patients, are surviving their initial hemorrhagic event but remain at increased risk of a number of complications, including delayed cerebral ischemia, epilepsy, nosocomial infections, cognitive impairment, shunt dependent hydrocephalus, and shunt related complications 2).

Intracranial complications including delayed cerebral ischemia (vasospasm), aneurysm rebleeding, and hydrocephalus form the targets for initial management. However, the extracranial consequences including hypertensionhyponatremia, and cardiopulmonary abnormalities can frequently arise during the management phase and have shown to directly affect clinical outcome.

Although the intracranial complications of SAH can take priority in the initial management, the extracranial complications should be monitored for and recognized as early as possible because these complications can develop at varying times throughout the course of the condition. Therefore, a variety of investigations, as described by this article, should be undertaken on admission to maximize early recognition of any of the extracranial consequences. Furthermore, because the extracranial complications have a direct effect on clinical outcome and can lead to and exacerbate the intracranial complications, monitoring, recognizing, and managing these complications in parallel with the intracranial complications is important and would allow optimization of the patient’s management and thus help improve their overall outcome 3).

Aneurysmal subarachnoid hemorrhage is complicated by intracerebral hemorrhage in 20—40 %, by intraventricular hemorrhage in 13-28%, and by subdural blood in 2-5% (usually due to posterior communicating aneurysm when over convexity, or distal anterior intracerebral artery (DACA) aneurysm with interhemispheric subdural).

The intracranial effects of aSAH causing death and disability are from vasospasm, direct effects of the initial bleed, increased intracranial pressure (ICP) and rebleeding 4).

Early brain injury and hydrocephalus (HCP) are important mediators of poor outcome in subarachnoid hemorrhage (SAH) patients. Injection of SAH patients’ CSF into the rat ventricle leads to HCP as well as subependymal injury compared with injection of control CSF 5).

Fever is a common occurrence (70%) especially in poor grades, contributes to adverse outcome and may not always respond to conventional treatment.

Persistent hyperglycemia (>200 mg/dl for >2 consecutive days) increases the likelihood of poor outcome after aSAH.

Management of patients following aSAH includes four major considerations:

(1) prediction of patients at highest risk for development of DCI,

(2) prophylactic measures to reduce its occurrence,

(3) monitoring to detect early signs of cerebral ischemia,

(4) treatments to correct vasospasm and cerebral ischemia once it occurs 6).

see Vasospasm after aneurysmal subarachnoid hemorrhage.

Brain edema after aneurysmal subarachnoid hemorrhage

see Delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage

see Aneurysm rebleeding

Subarachnoid hemorrhage (SAH) is often accompanied by pulmonary complications, which may lead to poor outcomes and death.

Sympathetic activation of the cardiovascular system in aneurysmal subarachnoid hemorrhage not only triggers the release of atrial and brain natriuretic peptides it can also lead to increased pulmonary venous pressures and permeability causing hydrostatic pulmonary edema 7).

see Neurogenic pulmonary edema.

Cardiac manifestations of intracranial subarachnoid hemorrhage patients include mild electrocardiogram variability, Takotsubo cardiomyopathy, non-ST elevation myocardial infarction, ST-elevation myocardial infarction and cardiac arrest, but their clinical relevance is unclear.

Among patients suffering from cardiac events at the time of aneurysmal subarachnoid hemorrhage, those with myocardial infarction and in particular those with a troponin level greater than 1.0 mcg/L had a 10 times increased risk of death 8).

Acute kidney injury

see Hyponatremia after aneurysmal subarachnoid hemorrhage

Hypokalemia is a common electrolyte disorder in the intensive care unit. Its cause often is complex, involving both potassium losses from the body and shifts of potassium into cells.

We present a case of severe hypokalemia of sudden onset in a patient being treated for subarachnoid hemorrhage in the surgical intensive care unit in order to illustrate the diagnosis and management of severe hypokalemia of unclear cause. The patient received agents that promote renal potassium losses and treatments associated with a shift of potassium into cells. Ibanez et al. outline the steps in diagnosis and management, focusing on the factors regulating the transcellular distribution of potassium in the body 9).

see Hydrocephalus after aneurysmal subarachnoid hemorrhage.

The clinical outcome after aneurysm rupture is at least in part determined by the severity of IVH. Knowledge of the effect of IVH may help guide physicians in the care of patients with aneurysmal bleeding 10).

see Cognitive disorder after subarachnoid hemorrhage.

Aneurysmal subarachnoid hemorrhage neuropsychiatric disturbance.

Overall rates of VTE (Deep-Vein Thrombosis Deep-vein thrombosis or PE), Deep-vein thrombosis, and PE were 4.4%, 3.5%, and 1.2%, respectively. On multivariate analysis, the following factors were associated with increased VTE risk: increasing age, black race, male sex, teaching hospital, congestive heart failure, coagulopathy, neurologic disorders, paralysis, fluid and electrolyte disorders, obesity, and weight loss. Patients that underwent clipping versus coiling had similar VTE rates. VTE was associated with pulmonary/cardiac complication (odds ratio [OR] 2.8), infectious complication (OR 2.8), ventriculostomy (OR 1.8), and vasospasm (OR 1.3). Patients with VTE experienced increased non-routine discharge (OR 3.3), and had nearly double the mean length of stay (p<0.001) and total inflation-adjusted hospital charges (p<0.001). To our knowledge, this is the largest study evaluating the incidence and risk factors associated with the development of VTE after aSAH. The presence of one or more of these factors may necessitate more aggressive VTE prophylaxis 11).

Short course (<48h) administration of EACA in patients with aneurysmal subarachnoid hemorrhage is associated with an 8.5 times greater risk of Deep-Vein Thrombosis (Deep-vein thrombosis) formation 12).

Routine compressive venous Doppler ultrasonography is an efficient, noninvasive means of identifying Deep-Vein Thrombosis (Deep-vein thrombosis) as a screening modality in both symptomatic and asymptomatic patients following aneurysmal SAH. The ability to confirm or deny the presence of Deep-vein thrombosis allows one to better identify the indications for chemoprophylaxis. Prophylaxis for venous thromboembolism in neurosurgical patients is common. Emerging literature and anecdotal experience have exposed risks of complications with prophylactic anticoagulation protocols. The identification of patients at high risk-for example, those with asymptomatic Deep-vein thrombosis-will allow physicians to better assess the role of prophylactic anticoagulation 13).

Deep-Vein Thrombosis (Deep-vein thrombosis) formation most commonly occurs in the first 2 weeks following aSAH, with detection in a cohort peaking between Days 5 and 9. Chemoprophylaxis is associated with a significantly lower incidence of Deep-vein thrombosis 14).

Patient should be ideally monitored in the NICU for at least 1st 24 h after surgery. Anticonvulsants, osmotherapy and nimodipine must be continued. Hydrocephalus, vasospasm, seizures, and electrolyte disturbances can occur necessitating close observation and prompt management. One of the major challenges in the management of aSAH is identifying potential or ongoing perfusion deficits. Ischemic insults can occur following ictus, or due to raised ICP, hypotension and vasospasm. Early identification and appropriate treatment of postictal intracranial (ICP, TCD flow velocities) and cardiovascular (cardiac output, ECG, BP, CVP) changes is possible in dedicated NICU and is crucial for improving outcomes. Heuer et al. observed that raised ICP (>20 mmHg) occurred in >50% of patients after aSAH and was associated with poor outcomes. Factors associated with raised ICP included poor clinical and radiological grades of aSAH, intraoperative brain swelling, parenchymal and intraventricular bleed and rebleeding.

see Seizure after aneurysmal subarachnoid hemorrhage.

Cytotoxic Lesions of the Corpus Callosum.

Koizumi et al. evaluated the incidence of NOMI in patients with subarachnoid hemorrhage (SAH) due to ruptured aneurysms, and they present the clinical characteristics and describe the outcomes to emphasize the importance of recognizing NOMI.

Observations: Overall, 7 of 276 consecutive patients with SAH developed NOMI. Their average age was 71 years, and 5 patients were men. Hunt and Kosnik grades were as follows: grade II, 2 patients; grade III, 3 patients; grade IV, 1 patient; and grade V, 1 patient. Fisher grades were as follows: grade 1, 1 patient; grade 2, 1 patient; and grade 3, 5 patients. Three patients were treated with endovascular coiling, 3 with microsurgical clipping, and 1 with conservative management. Five patients had abdominal symptoms prior to the confirmed diagnosis of NOMI. Four patients fell into shock. Two patients required emergent laparotomy followed by second-look surgery. Four patients could be managed conservatively. The overall mortality of patients with NOMI complication was 29% (2 of 7 cases).

NOMI had a high mortality rate. Neurosurgeons should recognize that NOMI can occur as a fatal complication after SAH 15).


Kumar G, Shahripour RB, Harrigan MR. Vasospasm on transcranial Doppler is predictive of delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J Neurosurg. 2015 Oct 23:1-8. [Epub ahead of print] PubMed PMID: 26495942.

Connolly ES Jr, Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, Higashida RT, et al: Guidelines for the manage- ment of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Asso- ciation/American Stroke Association. Stroke 43:1711–1737, 2012

Hall A, O’Kane R. The Extracranial Consequences of Subarachnoid Hemorrhage. World Neurosurg. 2018 Jan;109:381-392. doi: 10.1016/j.wneu.2017.10.016. Epub 2017 Oct 16. Review. PubMed PMID: 29051110.

Kassell MJ. Aneurysmal subarachnoid hemorrhage: An update on the medical complications and treatments strategies seen in these patients. Curr Opin Anaesthesiol. 2011;24:500–7.

Li P, Chaudhary N, Gemmete JJ, Thompson BG, Hua Y, Xi G, Pandey AS. Intraventricular Injection of Noncellular Cerebrospinal Fluid from Subarachnoid Hemorrhage Patient into Rat Ventricles Leads to Ventricular Enlargement and Periventricular Injury. Acta Neurochir Suppl. 2016;121:331-4. doi: 10.1007/978-3-319-18497-5_57. PubMed PMID: 26463970.

Dusick JR, Gonzalez NR. Management of arterial vasospasm following aneurysmal subarachnoid hemorrhage. Semin Neurol. 2013 Nov;33(5):488-97. doi: 10.1055/s-0033-1364216. Epub 2014 Feb 6. PubMed PMID: 24504612.

Lo BW, Fukuda H, Nishimura Y, Macdonald RL, Farrokhyar F, Thabane L, Levine MA. Pathophysiologic mechanisms of brain-body associations in ruptured brain aneurysms: A systematic review. Surg Neurol Int. 2015 Aug 11;6:136. doi: 10.4103/2152-7806.162677. eCollection 2015. PubMed PMID: 26322246.

Ahmadian A, Mizzi A, Banasiak M, Downes K, Camporesi EM, Thompson Sullebarger J, Vasan R, Mangar D, van Loveren HR, Agazzi S. Cardiac manifestations of subarachnoid hemorrhage. Heart Lung Vessel. 2013;5(3):168-78. PubMed PMID: 24364008; PubMed Central PMCID: PMC3848675.

Ybanez N, Agrawal V, Tranmer BI, Gennari FJ. Severe hypokalemia in a patient with subarachnoid hemorrhage. Am J Kidney Dis. 2014 Mar;63(3):530-5. doi: 10.1053/j.ajkd.2013.07.005. Epub 2013 Aug 20. PubMed PMID: 23972266.

Mayfrank L, Hütter BO, Kohorst Y, Kreitschmann-Andermahr I, Rohde V, Thron A, Gilsbach JM. Influence of intraventricular hemorrhage on outcome after rupture of intracranial aneurysm. Neurosurg Rev. 2001 Dec;24(4):185-91. PubMed PMID: 11778824.

Kshettry VR, Rosenbaum BP, Seicean A, Kelly ML, Schiltz NK, Weil RJ. Incidence and risk factors associated with in-hospital venous thromboembolism after aneurysmal subarachnoid hemorrhage. J Clin Neurosci. 2014 Feb;21(2):282-6. doi: 10.1016/j.jocn.2013.07.003. Epub 2013 Oct 13. PubMed PMID: 24128773.

Foreman PM, Chua M, Harrigan MR, Fisher WS 3rd, Tubbs RS, Shoja MM, Griessenauer CJ. Antifibrinolytic therapy in aneurysmal subarachnoid hemorrhage increases the risk for deep venous thrombosis: A case-control study. Clin Neurol Neurosurg. 2015 Sep 10;139:66-69. doi: 10.1016/j.clineuro.2015.09.005. [Epub ahead of print] PubMed PMID: 26378393.

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Liang CW, Su K, Liu JJ, Dogan A, Hinson HE. Timing of Deep-Vein Thrombosis formation after aneurysmal subarachnoid hemorrhage. J Neurosurg. 2015 Oct;123(4):891-6. doi: 10.3171/2014.12.JNS141288. Epub 2015 Jul 10. PubMed PMID: 26162047; PubMed Central PMCID: PMC4591180.

Koizumi H, Yamamoto D, Maruhashi T, Kataoka Y, Inukai M, Asari Y, Kumabe T. Relationship between subarachnoid hemorrhage and nonocclusive mesenteric ischemia as a fatal complication: patient series. J Neurosurg Case Lessons. 2022 Jul 18;4(3):CASE22199. doi: 10.3171/CASE22199. PMID: 36046708; PMCID: PMC9301345.

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).


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.

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.

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.

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.

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).


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).


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.

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.

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.

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 (NCT02142166) as part of a larger-scale prospective data collection. BioSAB: 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).


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.

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.

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.

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.

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.

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.

Seizure after aneurysmal subarachnoid hemorrhage

Seizure after aneurysmal subarachnoid hemorrhage

Epilepsy is a common and serious complication of subarachnoid hemorrhage (SAH), giving rise to increased morbidity and mortality. It’s difficult to identify patients at high risk of epilepsy and the application of antiepileptic drugs (AEDs) following SAH is a controversial topic. Therefore, it’s pressingly needed to gain a better understanding of the risk factors, underlying mechanisms, and the optimization of therapeutic strategies for epilepsy after SAH. Neuroinflammation, characterized by microglial activation and the release of inflammatory cytokines has drawn growing attention due to its influence on patients with epilepsy after SAH. In a review, Wang et al. discussed the risk factors for epilepsy after SAH and emphasize the critical role of microglia. Then they discussed how various molecules arising from pathophysiological changes after SAH activates specific receptors such as TLR4NLRP3RAGEP2X7R and initiate the downstream inflammatory pathways. Additionally, they focused on the significant responses implicated in epilepsy including neuronal excitotoxicity, the disruption of the blood-brain barrier (BBB), and the change of immune responses. As the application of AEDs for seizure prophylaxis after SAH remains controversial, the regulation of neuroinflammation targeting the key pathological molecules could be a promising therapeutic method. While neuroinflammation appears to contribute to epilepsy after SAH, more comprehensive experiments on their relationships are needed 1).

Literature has reported seizure rates to be as high as 27% in this population 2).

More recently published studies have found seizure rates to be significantly lower than previously described (1–10%) 3) 4).

Seizure activity has been associated with secondary neurologic injury including reduced cerebral blood flow and intracranial hypertension 5).

see Anticonvulsant in aneurysmal subarachnoid hemorrhage.


Wang J, Liang J, Deng J, Liang X, Wang K, Wang H, Qian D, Long H, Yang K, Qi S. Emerging Role of Microglia-Mediated Neuroinflammation in Epilepsy after Subarachnoid Hemorrhage. Mol Neurobiol. 2021 Jan 26. doi: 10.1007/s12035-021-02288-y. Epub ahead of print. PMID: 33501625.

Lin YJ, Chang WN, Chang HW, Ho JT, Lee TC, Wang HC, Tsai NW, Tsai MH, Lu CH. Risk factors and outcome of seizures after spontaneous aneurysmal subarachnoid hemorrhage. Eur J Neurol. 2008 May;15(5):451-7. doi: 10.1111/j.1468-1331.2008.02096.x. Epub 2008 Mar 5. PubMed PMID: 18325027.

Rosengart AJ, Huo JD, Tolentino J, Novakovic RL, Frank JI, Goldenberg FD, Macdonald RL. Outcome in patients with subarachnoid hemorrhage treated with antiepileptic drugs. J Neurosurg. 2007 Aug;107(2):253-60. PubMed PMID: 17695377.

Chumnanvej S, Dunn IF, Kim DH. Three-day phenytoin prophylaxis is adequate after subarachnoid hemorrhage. Neurosurgery. 2007 Jan;60(1):99-102; discussion 102-3. PubMed PMID: 17228257.

Rhoney DH, Tipps LB, Murry KR, Basham MC, Michael DB, Coplin WM. Anticonvulsant prophylaxis and timing of seizures after aneurysmal subarachnoid hemorrhage. Neurology. 2000 Jul 25;55(2):258-65. PubMed PMID: 10908901.

Osteopontin in subarachnoid hemorrhage

Osteopontin in subarachnoid hemorrhage

Experimental studies reported that osteopontin (OPN), is induced in the brain after subarachnoid hemorrhage (SAH).

OPN may increase MAPK phosphatase-1 that inactivates MAPKs, upstream and downstream of vascular endothelial growth factor A, by binding to L-arginyl-glycyl-L-aspartate-dependent integrin receptors, suggesting a novel mechanism of OPN-induced post-SAH BBB protection 1).

The relationships between osteopontin (OPN) expression and chronic shunt-dependent hydrocephalus (SDHC) have never been investigated. In 166 SAH patients (derivation and validation cohorts, 110 and 56, respectively), plasma OPN levels were serially measured at days 1-3, 4-6, 7-9, and 10-12 after aneurysmal obliteration. The OPN levels and clinical factors were compared between patients with and without subsequent development of chronic SDHC. Plasma OPN levels in the SDHC patients increased from days 1-3 to days 4-6 and remained high thereafter, while those in the non-SDHC patients peaked at days 4-6 and then decreased over time. Plasma OPN levels had no correlation with serum levels of C-reactive protein (CRP), a systemic inflammatory marker. Univariate analyses showed that age, modified Fisher scaleacute hydrocephaluscerebrospinal fluid drainage, and OPN and CRP levels at days 10-12 were significantly different between patients with and without SDHC. Multivariate analyses revealed that higher plasma OPN levels at days 10-12 were an independent factor associated with the development of SDHC, in addition to the more frequent use of cerebrospinal fluid drainage and higher modified Fisher grade at admission. Plasma OPN levels at days 10-12 maintained similar discrimination power in the validation cohort and had good calibration on the Hosmer-Lemeshow goodness-of-fit test. Prolonged higher expression of OPN may contribute to the development of post-SAH SDHC, possibly by excessive repairing effects promoting fibrosis in the subarachnoid space 2).

Abate et al. included 44 patients with the following criteria: (1) age 18 and 80 years, (2) diagnosis of SAH from cerebral aneurysm rupture, (3) insertion of an external ventricular drain. Plasma and CSF were sampled at day 1, 4, and 8. OPN levels, in CSF and plasma, displayed a weak correlation on day 1 and were higher, in CSF, in all time points. Only in poor prognosis patients, OPN levels in CSF significantly increased at day 4 and day 8. Plasma OPN at day 1 and 4 was predictor of poor outcome. In conclusion, plasma and CSF OPN displays a weak correlation, on day 1. The higher levels of OPN found in the CSF compared to plasma, suggest OPN production within the CNS after SAH. Furthermore, plasma OPN, at day 1 and 4, seems to be an independent predictor of poor outcome 3).

The aim of the study was to investigate the relationships between plasma OPN levels and outcome after aneurysmal SAH in a clinical setting. This is a prospective study consisting of 109 aneurysmal SAH patients who underwent aneurysmal obliteration within 48 h of SAH. Plasma OPN concentrations were serially determined at days 1-3, 4-6, 7-9, and 10-12 after onset. Various clinical factors as well as OPN values were compared between patients with 90-day good and poor outcomes. Plasma OPN levels were significantly higher in SAH patients compared with control patients and peaked at days 4-6. Poor-outcome patients had significantly higher plasma OPN levels through all sampling points. Receiver-operating characteristic curves demonstrated that OPN levels at days 10-12 were the most useful predictor of poor outcome at cutoff values of 915.9 pmol/L (sensitivity, 0.694; specificity, 0.845). Multivariate analyses using the significant variables identified by day 3 showed that plasma OPN ≥ 955.1 pmol/L at days 1-3 (odds ratio, 10.336; 95% confidence interval, 2.563-56.077; p < 0.001) was an independent predictor of poor outcome, in addition to increasing age, preoperative World Federation of Neurological Surgeons grades IV-V, and modified Fisher grade 4. Post hoc analyses revealed no correlation between OPN levels and serum levels of C-reactive protein, a non-specific inflammatory parameter, at days 1-3. Acute-phase plasma OPN could be used as a useful prognostic biomarker in SAH 4).


Suzuki H, Hasegawa Y, Kanamaru K, Zhang JH. Mechanisms of osteopontin-induced stabilization of blood-brain barrier disruption after subarachnoid hemorrhage in rats. Stroke. 2010 Aug;41(8):1783-90. doi: 10.1161/STROKEAHA.110.586537. Epub 2010 Jul 8. PMID: 20616319; PMCID: PMC2923856.

Asada R, Nakatsuka Y, Kanamaru H, Kawakita F, Fujimoto M, Miura Y, Shiba M, Yasuda R, Toma N, Suzuki H; pSEED group. Higher Plasma Osteopontin Concentrations Associated with Subsequent Development of Chronic Shunt-Dependent Hydrocephalus After Aneurysmal Subarachnoid Hemorrhage. Transl Stroke Res. 2021 Jan 9. doi: 10.1007/s12975-020-00886-x. Epub ahead of print. PMID: 33423213.

Abate MG, Moretto L, Licari I, Esposito T, Capuano L, Olivieri C, Benech A, Brucoli M, Avanzi GC, Cammarota G, Dianzani U, Clemente N, Panzarasa G, Citerio G, Carfagna F, Cappellano G, Della Corte F, Vaschetto R. Osteopontin in the Cerebrospinal Fluid of Patients with Severe Aneurysmal Subarachnoid Hemorrhage. Cells. 2019 Jul 10;8(7):695. doi: 10.3390/cells8070695. PMID: 31295895; PMCID: PMC6678172.

Nakatsuka Y, Shiba M, Nishikawa H, Terashima M, Kawakita F, Fujimoto M, Suzuki H; pSEED group. Acute-Phase Plasma Osteopontin as an Independent Predictor for Poor Outcome After Aneurysmal Subarachnoid Hemorrhage. Mol Neurobiol. 2018 Jan 20. doi: 10.1007/s12035-018-0893-3. [Epub ahead of print] PubMed PMID: 29353454.

Aneurysmal Subarachnoid Hemorrhage Guidelines

Aneurysmal Subarachnoid Hemorrhage Guidelines

Connolly ES Jr, Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, Higashida RT, Hoh BL, Kirkness CJ, Naidech AM, Ogilvy CS, Patel AB, Thompson BG, Vespa P; American Heart Association Stroke Council; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; Council on Cardiovascular Surgery and Anesthesia; Council on Clinical Cardiology. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/american Stroke Association. Stroke. 2012 Jun;43(6):1711-37. doi: 10.1161/STR.0b013e3182587839. Epub 2012 May 3. PubMed PMID: 22556195 1).

Hospital Characteristics and Systems of Care

According to current Aneurysmal Subarachnoid Hemorrhage Guidelines (aSAH) patients are mostly managed in intensive care units (ICU) regardless of baseline severity.

Low-volume hospitals (eg, <10 aSAH cases per year) should consider early transfer of patients with aSAH to high-volume centers (eg, >35 aSAH cases per year) with experienced cerebrovascular surgeons, endovascular specialists, and multidisciplinary neuro-intensive care services (Class I; Level of Evidence B). (Revised recommendation from previous guidelines)

Annual monitoring of complication rates for surgical and interventional procedures is reasonable (Class IIa; Level of Evidence C). (New recommendation)

A hospital credentialing process to ensure that proper training standards have been met by individual physicians treating brain aneurysms is reasonable (Class IIa; Level of Evidence C). (New recommendation) 2).

The adjusted odds of definitive repair were significantly higher in urban teaching hospitals than in urban nonteaching hospitals (odds ratio, 1.62) or rural hospitals (odds ratio, 3.08).7 In another study from 1993 to 2003, teaching status and larger hospital size were associated with higher charges and longer stay but also with better outcomes (P<0.05) and lower mortality rates (P<0.05), especially in patients who underwent aneurysm clipping (P<0.01). Endovascular treatment, which was more often used in the elderly, was also associated with significantly higher mortality rates in smaller hospitals (P<0.001) and steadily increasing morbidity rates (45%). Large academic centers were associated with better results, particularly for surgical clip placement 3).

Llull et al. from a Comprehensive Stroke Center in Barcelona assessed the prognostic and economic implications of initial admission of low-grade aSAH patients into a Stroke Unit (SU) compared to initial ICU admission.

They reviewed prospectively registered data from consecutive aSAH patients with a WFNS grade lower than 3 admitted at a Comprehensive Stroke Center between April-2013 and September-2018. Clinical and radiological baseline traits, in-hospital complications, length of hospital stay (LOS) and poor outcome at 90 days (modified Rankin Scale >2) were compared between the ICU and SU groups in the whole population and in a propensity score matched cohort.

From 131 patients, 74 (56%) were initially admitted in the ICU and 57 (44%) in the SU. In-hospital complication rates were similar in the ICU and SU groups and included rebleeding (10% vs 7%, p=0.757), angiographic vasospasm (61% vs 60%, p=0.893), delayed cerebral ischemia (12% vs 12%, p=0.984), pneumonia (6% vs 4%, p=0.697) and death (10% vs 5%, p=0.512). LOS did not differ across both groups [median (IQR) 22 (16-30) vs 19 (14-26) days, p=0.160]. In adjusted multivariate models, the location of initial admission was not associated with long-term poor outcome either in the whole population (OR=1.16, 95%CI=0.32-4.19, p=0.825) or in the matched cohort (OR=0.98, 95%CI=0.24-4.06, p=0.974).

A dedicated SU cared by a multidisciplinary team might be an optimal alternative to ICU to initially admit patients with low-risk aSAH 4).

Bederson JB, Connolly ES Jr, Batjer HH, Dacey RG, Dion JE, Diringer MN, Duldner JE Jr, Harbaugh RE, Patel AB, Rosenwasser RH; American Heart Association. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke. 2009 Mar;40(3):994-1025. doi: 10.1161/STROKEAHA.108.191395. Epub 2009 Jan 22. Review. Erratum in: Stroke. 2009 Jul;40(7):e518. PubMed PMID: 19164800. 5).


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Bederson JB, Connolly ES Jr, Batjer HH, Dacey RG, Dion JE, Diringer MN, Duldner JE Jr, Harbaugh RE, Patel AB, Rosenwasser RH; American Heart Association. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke. 2009 Mar;40(3):994-1025. doi: 10.1161/STROKEAHA.108.191395. Epub 2009 Jan 22. Review. Erratum in: Stroke. 2009 Jul;40(7):e518. PubMed PMID: 19164800.