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).


1)

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.
2)

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.
3)

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.
4)

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

https://www.ahajournals.org/doi/full/10.1161/str.0b013e3182587839

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).

References

1) , 2)

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.
3)

Andaluz N, Zuccarello M. Recent trends in the treatment of cerebral aneurysms: analysis of a nationwide inpatient database. J Neurosurg. 2008 Jun;108(6):1163-9. doi: 10.3171/JNS/2008/108/6/1163. PMID: 18518722.
4)

Llull L, Mayà G, Torné R, Mellado R, Renú A, López-Rueda A, Laredo C, Culebras D, Ferrando C, Blasco J, Amaro S, Chamorro Á. Stroke Units could be a valid alternative to Intensive Care Units for low-grade aneurysmal subarachnoid haemorrhage patients. Eur J Neurol. 2020 Sep 22. doi: 10.1111/ene.14548. Epub ahead of print. PMID: 32961609.
5)

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.

Aneurysmal Subarachnoid Hemorrhage Outcome in Elderly Patients

Aneurysmal Subarachnoid Hemorrhage Outcome in Elderly Patients

Aneurysmal subarachnoid hemorrhage outcome in elderly patients are at high risk for poor functional outcomes. However, among those presenting with good Hunt and Hess Stroke Scale scores, younger-elderly patients (ages 60-65 years) tend to fare better than older-elderly patients (ages >65 years). Elderly patients presenting with high-grade aSAH fare poorly regardless of age, which can inform clinical decision-making and prognostication 1).


The purpose of a study of Goldberg et al., from Inselspital, was to provide survival and outcome data to support clinicians making decisions on treatment for this subgroup of patients.

They performed a retrospective analysis of the Bernese SAH database for poor-grade (World Federation of Neurosurgical Societies grade IV and V) elderly patients (age ≥60 years) suffering from aSAH admitted to the institution from 2005 to 2017. Patients were divided into 3 age groups (60-69, 70-79, and 80-90 years).

Survival analysis was performed to estimate mean survival and hazard ratios for death. Binary logarithmic regression was used to estimate the odds ratio for favorable (modified Rankin Scale score of 0-3) and unfavorable (modified Rankin Scale score of 4-6) outcome. Results- Increasing age was associated with an increased risk of death after aSAH. The hazard ratio increased by 6% per year of age ( P<0.001; hazard ratio, 1.06; 95% CI, 1.03-1.09) and 76% per decade ( P<0.001; hazard ratio, 1.76; 95% CI, 1.35-2.29). Mean survival was 56.3±8 months (patients aged 60-69 years), 31.6±7.6 months (70-79 years), and 7.6±5.8 months (80-90 years). Unfavorable outcomes 6 to 12 months after aSAH were strongly related to an older age. The odds ratio increased by 11% per year of age ( P<0.001; odds ratio, 1.11; 95% CI, 1.05-1.18) and 192% per decade ( P<0.001; odds ratio, 2.92; 95% CI, 1.63-5.26). Conclusions- Risk for death and unfavorable outcome increases markedly with older age in elderly patients with poor-grade aSAH. Despite high initial mortality, treatment resulted in a reasonable proportion of favorable outcomes up to 79 years of age and only a small number of patients who were moderately or severely disabled 6 to 12 months after aSAH. Mean survival and proportion of favorable outcomes decreased markedly in patients older than 80 years 2).


It is also important to investigate the critical age for defining a higher risk population among elderly patients and the clinical grade at admission in order to provide a prognostic description and help guide the management of patients aged ≥ 70 years.

A retrospective study included 165 patients aged 70-90 years who underwent surgical or endovascular treatment for a ruptured aneurysm. In addition to medical and radiological data, telephone interviews were used to obtain the 1-year functional outcome.

Multivariate analysis revealed age (p = 0.001) and the World Federation of Neurological Surgeons (WFNS) grade (p = 0.001), regardless of the treatment modalities (surgical versus endovascular), as significant risk factors for a poor outcome, while a receiver operating characteristic analysis revealed 75 years as an appropriate cutoff value for the patient age to predict a poor 1-year functional outcome (area under the curve: 0.683). For the patients aged 70-75 years with good (1-3) and poor (4-5) WFNS grades, 81.9 % and 42.9 % achieved a favorable outcome (modified Rankin Scale 0-3), respectively, whereas for the patients over the critical age (> 75 years) with good and poor WFNS grades, 54.8 % and 5.9 % achieved a favorable outcome, respectively.

The long-term outcome for elderly patients with an aneurysmal SAH is affected primarily by the clinical condition at admission and the patient’s age in relation to the critical age (> 75 years), regardless of the treatment modalities, including surgical clipping and endovascular coiling 3).

References

1) 

Catapano JS, Louie CE, Lang MJ, DiDomenico JD, Whiting AC, Labib MA, Cole TS, Fredrickson VL, Cavalcanti DD, Lawton MT. Outcomes in a case series of elderly patients with aneurysmal subarachnoid hemorrhages in the Barrow Ruptured Aneurysm Trial (BRAT). World Neurosurg. 2020 Apr 15. pii: S1878-8750(20)30704-X. doi: 10.1016/j.wneu.2020.04.007. [Epub ahead of print] PubMed PMID: 32304888.
2) 

Goldberg J, Schoeni D, Mordasini P, Z’Graggen W, Gralla J, Raabe A, Beck J, Fung C. Survival and Outcome After Poor-Grade Aneurysmal Subarachnoid Hemorrhage in Elderly Patients. Stroke. 2018 Dec;49(12):2883-2889. doi: 10.1161/STROKEAHA.118.022869. PubMed PMID: 30571422.
3) 

Park J, Woo H, Kang DH, Kim Y. Critical age affecting 1-year functional outcome in elderly patients aged ≥ 70 years with aneurysmal subarachnoid hemorrhage. Acta Neurochir (Wien). 2014 Jun 21. [Epub ahead of print] PubMed PMID: 24950994.
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