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Analysis of Hemorrhage Volumes After Angiogram-Negative Subarachnoid Hemorrhage
Original Article
Analysis of Hemorrhage Volumes After Angiogram-Negative Subarachnoid Hemorrhage David P. Bray, Jason A. Ellis, Sean D. Lavine, Philip M. Meyers, E. Sander Connolly, Jr.
BACKGROUND: Antiplatelet medication use is associated with worsened outcome after angiogram-negative subarachnoid hemorrhage (SAH). It has been hypothesized that these worsened outcomes may be the result of an association between antiplatelet medication use and increased hemorrhage volumes after angiogram-negative SAH. To test this hypothesis, we performed volumetric analysis of computed tomography (CT)-defined hemorrhage after angiogram-negative SAH.
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METHODS: This was a retrospective analysis of patients presenting with nontraumatic, angiogram-negative SAH in the Columbia University Subarachnoid Hemorrhage Outcomes database between 2000 and 2013. SAH volumes on admission head CT scans were measured using the MIPAV software package, version 7.20 in a semiautomated fashion.
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RESULTS: A total of 108 presenting CT scans from patients with angiogram-negative SAH were analyzed. The mean hemorrhage volume was 14.3 mL in the patients with a history of antiplatelet medication use, compared with 6.8 mL in those with no history of antiplatelet use. This difference was found to be significant (P [ 0.0029).
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CONCLUSIONS: Antiplatelet medication use is associated with increased SAH volumes in patients with angiogram-negative SAH. Increased hemorrhage volumes may contribute to poor outcomes in this patient population. Prospective studies are warranted to confirm this association.
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A
ntiplatelet drugs are among the most commonly used medications worldwide.1,2 The efficacy of these drugs, including aspirin and clopidogrel, in the prevention and treatment of thrombotic vascular disease has fueled their widespread use, especially in developed countries.3,4 Antiplatelet therapy is now a mainstay in the treatment of patients with such common conditions as unstable angina, coronary artery disease, peripheral artery disease, atrial fibrillation, and myocardial infarction.5-9 In addition, the progressive increase in the use of percutaneous coronary interventions, including stenting, adds more than 1 million patients per year to the population receiving single or dual antiplatelet therapy.10,11 Most patients with previous thromboembolic or ischemic stroke are prescribed antiplatelet therapy.12,13 Although the benefits of antiplatelet therapies are unquestionable, serious hemorrhagic complications can result from their use.14-17 Angiogram-negative subarachnoid hemorrhage (SAH), or nonaneurysmal SAH, is a unique variant of SAH for which no structural aberration can be found as a cause for the spontaneous hemorrhage.18,19 It accounts for approximately 10%e20% cases of SAH, appears to be rising in frequency, and may be associated with poor clinical outcomes, similar to those observed with aneurysmal SAH.18,20-32 Recent literature suggests that hemorrhage patterns may be correlated with clinical outcomes, although hemorrhage volume has heretofore not been rigorously evaluated as a prognostic indicator in angiogram-negative SAH.20,21,33-35 Angiogram-negative SAH is further subdivided into 2 distinct entities by bleeding pattern on the diagnostic computed tomography (CT) scan: perimesencephalic and nonperimesencephalic/ diffuse. Perimesencephalic SAH is thought to be secondary to venous bleeding and has a good prognosis.18 Nonperimesencephalic or diffuse angiogram-negative SAH may approach aneurysmal SAH in clinical severity and prognosis.21,36
Key words Aneurysm - Aspirin - Clopidogrel - Intracranial hemorrhage - Stroke
Department of Neurological Surgery, Columbia University Medical Center, New York, NY, USA
Abbreviations and Acronyms CT: Computed tomography SAH: Subarachnoid hemorrhage SHOP: Subarachnoid hemorrhage outcomes project
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WORLD NEUROSURGERY 94: 453-457, OCTOBER 2016
To whom correspondence should be addressed: David P. Bray, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2016) 94:453-457. http://dx.doi.org/10.1016/j.wneu.2016.07.019
Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2016 Elsevier Inc. All rights reserved.
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HEMORRHAGE VOLUMES AFTER ANGIOGRAM-NEGATIVE SUBARACHNOID HEMORRHAGE
Recent studies using the Columbia University Medical Center’s Subarachnoid Hemorrhage Outcomes Project (SHOP) database have demonstrated that antiplatelet therapy may be associated with poor outcomes in patients with angiogram-negative SAH.37 This and other studies have suggested that the increased use of antiplatelet medications may be linked to the rise in angiogramnegative SAH, although additional research in is needed to confirm this association.38-40 Whereas the prognostic value of hemorrhage volume and location in patients with hemorrhagic stroke has been previously suggested, we are unaware of any previous studies associating antiplatelet use with hemorrhage volumes in angiogram-negative SAH.35,41-46 Thus, in the present study we tested the hypothesis that a history of antiplatelet medication use is associated with increased hemorrhage volumes in patients with angiogram-negative SAH. METHODS Study Population All patients with nontraumatic SAH detected on head CT scan at the time of admission were prospectively enrolled in the Columbia University Medical Center’s SHOP database between 2000 and 2013. Patients were designated as “angiogram-negative” when no lesion was found on catheter angiogram. Patient demographic and historical data were also collected in the SHOP database at the time of admission. Management of SAH Our institution’s approach to management of SAH has been described previously.47 Patients presenting with a history suspicious of SAH receive a noncontrast head CT scan. On diagnosis of SAH, all antithrombotic medications are held, and reversed when applicable. Antiplatelet medications are
Figure 1. Volumetric analysis. Subarachnoid hyperdensities in the range of 50e80 Hounsfield units were used to demarcate acute blood. Pre- (A) and post-
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discontinued, and platelet transfusion is initiated. Patients with angiogram-negative SAH receive at least 2 cerebral angiograms during their admission. Variables and Volumetric Quantification Baseline data, including age, sex, admission HunteHess grade, and history of antiplatelet medication use, were collected. No specific antiplatelet medications were retrospectively recorded in the database. Available head CT scans from patients who underwent conventional catheter angiography after presenting with nontraumatic SAH were reviewed. Hemorrhage volumes were measured using the MIPAV software package, version 7.20 (National Institutes of Health, Bethesda, MD, USA) in a semiautomated fashion as validated previously (Figure 1).44,45,48 Statistical Analysis All statistical analyses were performed using Stata 14 (StataCorp, College Station, TX, USA). Student’s t test was used for continuous variables and the c2 test was used for categorical variables in univariate analyses. Multivariate analysis was performed using a multiple logistic regression model adjusting for age, sex, and admission HunteHess grade. A P value or Pearson’s coefficient 0.05 was considered significant. RESULTS A total of 1582 patients with nontraumatic SAH were enrolled in the SHOP database during the study period. Of these 1582 patients, 1351 underwent catheter cerebral angiography during their admission. No structural cause of hemorrhage was found for the 173 patients who were diagnosed with angiogram-negative SAH. Among these 173 patients, 108 had a head CT scan obtainable from our medical records database (Table 1). Fortythree of these 108 patients (40%) received an antiplatelet
(B) semiautomated thresholding of subarachnoid blood are demonstrated on a representative head CT scan.
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ORIGINAL ARTICLE DAVID P. BRAY ET AL.
HEMORRHAGE VOLUMES AFTER ANGIOGRAM-NEGATIVE SUBARACHNOID HEMORRHAGE
DISCUSSION
Table 1. Characteristics of the Study Patients No History of Antiplatelet Medication Use (n [ 65)
History of Antiplatelet Medication Use (n [ 43)
Age, years, mean (SD)
54.4 (12.18)
62.14 (12.17)
Sex, male/ female, n
34/31
Characteristic
Blood volume, mL, mean (SD)
6.83 (7.56)
Blood volume, mL, median (IQR)
3.62 (1.45e9.61)
Any extension of hemorrhag e, n (%)
28/15 14.30 (14.51)
16 (24.6)
P Value/ Pearson’s Coefficient 0.0019 0.188 0.0029
10.2 (3.76e16.1)
17 (39.5)
Admission Hunt eHess grade, n (%)
0.099
0.534
I
28 (43.1)
17 (39.5)
II
16 (24.6)
13 (30.2)
III
13 (20.0)
9 (20.9)
IV
6 (9.2)
1 (2.3)
V
2 (3.1)
3 (7.0)
SD, standard deviation; IQR, interquartile range.
medication before admission, and the other 65 (60%) did not. The patients who received antiplatelet medication were older than those who did not, but there were no statistically significant differences in sex and HunteHess grade at admission between the 2 cohorts. The mean hemorrhage volume was 14.3 14.5 mL in the patients who received antiplatelet medication before admission, compared with 6.8 7.6 mL in those with no history of antiplatelet medication use. This difference was significant (P ¼ 0.0029) (Table 1 and Figure 2). On a multivariate regression analysis adjusting for age, sex, and HunteHess grade at admission, the difference in blood volumes remained significant (P < 0.05). Of the 43 patients with angiogram-negative SAH who received antiplatelet medications, 12 (28%) had an intraventricular extension of SAH and 6 (14%) had an intraparenchymal extension, for a combined hemorrhage extension rate of 40%. One patient had both intraventricular and intraparenchymal extension of hemorrhage. In comparison, 11 of the 65 patients (17%) with angiogramnegative SAH who did not receive antiplatelet medication had an intraventricular extension of SAH, and 5 (8%) had an intraparenchymal extension, for a combined hemorrhage extension rate of 25%. This increased rate of hemorrhage extension in patients receiving antiplatelet medication trended toward significance (P ¼ 0.09) (Table 1).
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Angiogram-negative SAH is a relatively poorly understood phenomenon.18,20-32 It has been suggested that the frequency of angiogram-negative SAH is increasing, and that this rising frequency might be associated with the proliferation of antiplatelet medication use.37 Interestingly, in patients with angiogramnegative SAH, antiplatelet medication use before presentation seems to be associated with poor early outcomes, owing to a previously undefined etiology.37 Here we present data implicating hemorrhage volume as a key component in the pathophysiology of neurologic outcome. In the present study, we found higher hemorrhage volumes in patients with a history of antiplatelet medication use compared with patients with no such history before presentation with angiogram-negative SAH. This finding was confirmed to be significant by multivariate analysis adjusting for age, sex, and admission HunteHess grade. In addition, among patients with angiogram-negative SAH, those with a history of antiplatelet medication use had higher rates of intraventricular and intraparenchymal extension of hemorrhage, but the difference between the 2 cohorts showed only a trend toward statistical significance. Larger prospective studies with sufficient statistical power may yet demonstrate significance. These findings are in some ways not surprising, given that increased hemorrhage volumes, intraventricular extension, and specific bleeding patterns on presenting CT scans have been associated with worse outcomes in aneurysmal SAH.35,41-45 Previous studies have shown that the pattern of blood detected on the presenting CT scan may have prognostic value in patients with angiogram-negative SAH.19,49,50 The diffuse or nonperimesencephalic distribution of blood on the presenting CT scan has been associated with worse outcomes compared with perimesencephalic blood patterns. In one such study, Fontanella et al.21
Figure 2. Antiplatelet medications and SAH volume. Boxplots showing significantly higher SAH volumes in patients who received antiplatelet medication compared with those who did not.
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completed a retrospective review of 102 patients with angiogramnegative SAH with 8e16 years of follow-up. Patients with perimesencephalic blood patterns had no rebleeding episodes, whereas patients with diffuse SAH on the presenting CT scan had a 5.1% rate of rebleeding.21 In another study, Walcott et al.36 studied 138 patients with angiogram-negative SAH and divided the cohort into those with a perimesencephalic blood pattern and those with a nonperimesencephalic blood pattern on CT scan. In that study, radiographic vasospasm developed in 8.6% of patients with perimesencephalic SAH and in 20.6% of those with nonperimesencephalic SAH.36 We believe that the foregoing studies are entirely consistent with our finding that increased blood volume may be implicated in the worse outcomes seen in patients with nonperimesencephalic or diffuse SAH. Although only correlative, our data suggest that the use of antiplatelet medications may cause patients with an angiogram-negative SAH to develop larger hemorrhages than they otherwise would have. This may contribute to the worse outcomes noted in previous studies.37 This study has several limitations. First, owing to the standardized history collection of the SHOP database, we do not have specific information on the type and dosage of antiplatelet medication that each patient used. Moreover, platelet function can vary widely among patients receiving the same antiplatelet medication and dosage, owing to genetic polymorphisms, patient medication compliance, and drug metabolism.51 Second, all of the patients receiving antiplatelet medication in this study received a platelet transfusion after admission for SAH unless otherwise indicated. The recently published results from the PATCH (Platelet Transfusion in Cerebral Haemorrhage) trial show higher rates of adverse events and death in patients receiving
REFERENCES 1. Yusuf S, Islam S, Chow CK, Rangarajan S, Dagenais G, Diaz R, et al. Use of secondary prevention drugs for cardiovascular disease in the community in high-income, middle-income, and low-income countries (the PURE study): a prospective epidemiological survey. Lancet. 2011;378: 1231-1243. 2. Subherwal S, Patel MR, Kober L, Peterson ED, Jones WS, Gislason GH, et al. Missed opportunities: despite improvement in use of cardioprotective medications among patients with lower-extremity peripheral artery disease, underuse remains. Circulation. 2012;126:1345-1354. 3. Ferreiro JL, Angiolillo DJ. New directions in antiplatelet therapy. Circ Cardiovasc Interv. 2012;5: 433-445. 4. Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med. 2007;357:2482-2494. 5. Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE, et al. 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart
456
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antiplatelet medication and platelet transfusion after intracerebral hemorrhage compared with patients receiving standard therapy.52 Platelet transfusion could have had a confounding effect on our analysis. Further randomized controlled trials are needed to determine the role of platelet transfusion in patients with SAH associated with antiplatelet medication use. Finally, the cohort of patients who received antiplatelet medication before admission for angiogram-negative SAH had a higher mean age than those who did not. This finding is expected, because older individuals are more often prescribed antiplatelet medications for vascular disease later in life. This difference between the 2 cohorts is of minor concern, given that the hemorrhage volumes in the patients receiving antiplatelet medication were still significantly greater after multivariate analysis. To further elucidate the association between antiplatelet medications and angiogram-negative SAH, further studies are needed to relate hemorrhage volumes to specific types and doses of antiplatelet medications. In addition, correlating angiogramnegative SAH hemorrhage volumes to rates of delayed cerebral ischemia and hydrocephalus would be worthwhile. CONCLUSION Antiplatelet medication use in angiogram-negative SAH is associated with increased hemorrhage volumes at presentation. It also may be associated with higher rates of intraventricular and intraparenchymal extension of SAH. Further studies are needed to firmly establish the etiologic association between antiplatelet medication use and worse clinical outcomes in patients with angiogram-negative SAH.
Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61:e179-e347. 6. Kushner FG, Hand M, Smith SC Jr, King SB 3rd, Anderson JL, Antman EM, et al. 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2009;54:2205-2241. 7. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324:71-86. 8. Fuster V, Chesebro JH. Aspirin for primary prevention of coronary disease. Eur Heart J. 1995;16 Suppl E:16-20.
11. Shehab N, Sperling LS, Kegler SR, Budnitz DS. National estimates of emergency department visits for hemorrhage-related adverse events from clopidogrel plus aspirin and from warfarin. Arch Intern Med. 2010;170:1926-1933. 12. Mohr JP, Thompson JL, Lazar RM, Levin B, Sacco RL, Furie KL, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med. 2001;345: 1444-1451. 13. Sacco RL, Prabhakaran S, Thompson JL, Murphy A, Sciacca RR, Levin B, et al. Comparison of warfarin versus aspirin for the prevention of recurrent stroke or death: subgroup analyses from the Warfarin-Aspirin Recurrent Stroke Study. Cerebrovasc Dis. 2006;22:4-12. 14. He J, Whelton PK, Vu B, Klag MJ. Aspirin and risk of hemorrhagic stroke: a meta-analysis of randomized controlled trials. JAMA. 1998;280: 1930-1935.
9. Fuster V, Sweeny JM. Aspirin: a historical and contemporary therapeutic overview. Circulation. 2011;123:768-778.
15. Serebruany VL, Malinin AI, Eisert RM, Sane DC. Risk of bleeding complications with antiplatelet agents: meta-analysis of 338,191 patients enrolled in 50 randomized controlled trials. Am J Hematol. 2004;75:40-47.
10. Yeh RW, Mauri L, Kereiakes DJ. Dual antiplatelet therapy duration following coronary stenting. [Corrected]. J Am Coll Cardiol. 2015;65:787-790.
16. Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, et al. Aspirin and clopidogrel compared with clopidogrel alone
WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2016.07.019
ORIGINAL ARTICLE DAVID P. BRAY ET AL.
after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364:331-337. 17. Shireman TI, Howard PA, Kresowik TF, Ellerbeck EF. Combined anticoagulant-antiplatelet use and major bleeding events in elderly atrial fibrillation patients. Stroke. 2004;35:2362-2367. 18. Schwartz TH, Solomon RA. Perimesencephalic nonaneurysmal subarachnoid hemorrhage: review of the literature. Neurosurgery. 1996;39:433-440 [discussion: 440]. 19. Tatter SB, Crowell RM, Ogilvy CS. Aneurysmal and microaneurysmal “angiogram-negative” subarachnoid hemorrhage. Neurosurgery. 1995;37: 48-55.
HEMORRHAGE VOLUMES AFTER ANGIOGRAM-NEGATIVE SUBARACHNOID HEMORRHAGE
29. Brismar J, Sundbärg G. Subarachnoid hemorrhage of unknown origin: prognosis and prognostic factors. J Neurosurg. 1985;63:349-354. 30. Khan AA, Smith JD, Kirkman MA, Robertson FJ, Wong K, Dott C, et al. Angiogram negative subarachnoid haemorrhage: outcomes and the role of repeat angiography. Clin Neurol Neurosurg. 2013;115: 1470-1475.
43. Friedman JA, Goerss SJ, Meyer FB, Piepgras DG, Pichelmann MA, McIver JI, et al. Volumetric quantification of Fisher Grade 3 aneurysmal subarachnoid hemorrhage: a novel method to predict symptomatic vasospasm on admission computerized tomography scans. J Neurosurg. 2002;97:401-407.
31. Boswell S, Thorell W, Gogela S, Lyden E, Surdell D. Angiogram-negative subarachnoid hemorrhage: outcomes data and review of the literature. J Stroke Cerebrovasc Dis. 2013;22:750-757.
44. Jung SW, Lee CY, Yim MB. The relationship between subarachnoid hemorrhage volume and development of cerebral vasospasm. J Cerebrovasc Endovasc Neurosurg. 2012;14:186-191.
32. Kang DH, Park J, Lee SH, Park SH, Kim YS, Hamm IS. Does non-perimesencephalic type nonaneurysmal subarachnoid hemorrhage have a benign prognosis? J Clin Neurosci. 2009;16:904-908.
45. Ko SB, Choi HA, Carpenter AM, Helbok R, Schmidt JM, Badjatia N, et al. Quantitative analysis of hemorrhage volume for predicting delayed cerebral ischemia after subarachnoid hemorrhage. Stroke. 2011;42:669-674.
20. Cánovas D, Gil A, Jato M, de Miquel M, Rubio F. Clinical outcome of spontaneous non-aneurysmal subarachnoid hemorrhage in 108 patients. Eur J Neurol. 2012;19:457-461.
33. Whiting J, Reavey-Cantwell J, Velat G, Fautheree G, Firment C, Lewis S, et al. Clinical course of nontraumatic, nonaneurysmal subarachnoid hemorrhage: a single-institution experience. Neurosurg Focus. 2009;26:E21.
21. Fontanella M, Rainero I, Panciani PP, Schatlo B, Benevello C, Garbossa D, et al. Subarachnoid hemorrhage and negative angiography: clinical course and long-term follow-up. Neurosurg Rev. 2011;34:477-484.
34. Maslehaty H, Barth H, Petridis AK, Doukas A, Maximilian Mehdorn H. Special features of subarachnoid hemorrhage of unknown origin: a review of a series of 179 cases. Neurol Res. 2012;34: 91-97.
22. Konczalla J, Schmitz J, Kashefiolasl S, Senft C, Seifert V, Platz J. Non-aneurysmal subarachnoid hemorrhage in 173 patients: a prospective study of long-term outcome. Eur J Neurol. 2015;22: 1329-1336. 23. Konczalla J, Schuss P, Platz J, Vatter H, Seifert V, Güresir E. Clinical outcome and prognostic factors of patients with angiogram-negative and nonperimesencephalic subarachnoid hemorrhage: benign prognosis like perimesencephalic SAH or same risk as aneurysmal SAH? Neurosurg Rev. 2015; 38:121-127 [discussion: 127]. 24. Rinkel GJ, Wijdicks EF, Vermeulen M, Hageman LM, Tans JT, van Gijn J. Outcome in perimesencephalic (nonaneurysmal) subarachnoid hemorrhage: a follow-up study in 37 patients. Neurology. 1990;40:1130-1132. 25. van Gijn J, van Dongen KJ, Vermeulen M, Hijdra A. Perimesencephalic hemorrhage: a nonaneurysmal and benign form of subarachnoid hemorrhage. Neurology. 1985;35:493-497. 26. Sarabia R, Lagares A, Fernández-Alén JA, Arikan F, Vilalta J, Ibáñez J, et al. Idiopathic subarachnoid hemorrhage: a multicentre series of 220 patients. Neurocirugia (Astur). 2010;21:441-451. 27. Topcuoglu MA, Ogilvy CS, Carter BS, Buonanno FS, Koroshetz WJ, Singhal AB. Subarachnoid hemorrhage without evident cause on initial angiography studies: diagnostic yield of subsequent angiography and other neuroimaging tests. J Neurosurg. 2003;98:1235-1240. 28. Oder W, Kollegger H, Zeiler K, Dal-Bianco P, Wessely P, Deecke L. Subarachnoid hemorrhage of unknown etiology: early prognostic factors for long-term functional capacity. J Neurosurg. 1991;74: 601-605.
ischemia after subarachnoid hemorrhage: the Fisher scale revisited. Stroke. 2001;32:2012-2020.
46. Naidech AM, Rosenberg NF, Maas MB, Bendok BR, Batjer HH, Nemeth AJ. Predictors of hemorrhage volume and disability after perimesencephalic subarachnoid hemorrhage. Neurology. 2012;78:811-815. 47. Komotar RJ, Schmidt JM, Starke RM, Claassen J, Wartenberg KE, Lee K, et al. Resuscitation and critical care of poor-grade subarachnoid hemorrhage. Neurosurgery. 2009;64:397-410 [discussion: 410-411].
35. Lin N, Zenonos G, Kim AH, Nalbach SV, Du R, Frerichs KU, et al. Angiogram-negative subarachnoid hemorrhage: relationship between bleeding pattern and clinical outcome. Neurocrit Care. 2012;16:389-398.
48. Bazin PL, Cuzzocreo JL, Yassa MA, Gandler W, McAuliffe MJ, Bassett SS, et al. Volumetric neuroimage analysis extensions for the MIPAV software package. J Neurosci Methods. 2007;165:111-121.
36. Walcott BP, Stapleton CJ, Koch MJ, Ogilvy CS. Diffuse patterns of nonaneurysmal subarachnoid hemorrhage originating from the Basal cisterns have predictable vasospasm rates similar to aneurysmal subarachnoid hemorrhage. J Stroke Cerebrovasc Dis. 2015;24:795-801.
49. Rinkel GJ, Wijdicks EF, Hasan D, Kienstra GE, Franke CL, Hageman LM, et al. Outcome in patients with subarachnoid haemorrhage and negative angiography according to pattern of haemorrhage on computed tomography. Lancet. 1991;338:964-968.
37. Ellis JA, McDowell MM, Mayer SA, Lavine SD, Meyers PM, Connolly ES Jr. The role of antiplatelet medications in angiogram-negative subarachnoid hemorrhage. Neurosurgery. 2014;75:530-535 [discussion: 534-535].
50. Jafar JJ, Weiner HL. Surgery for angiographically occult cerebral aneurysms. J Neurosurg. 1993;79: 674-679.
38. Schmidt M, Johansen MB, Lash TL, Christiansen CF, Christensen S, Sørensen HT. Antiplatelet drugs and risk of subarachnoid hemorrhage: a population-based case-control study. J Thromb Haemost. 2010;8:1468-1474. 39. Garbe E, Kreisel SH, Behr S. Risk of subarachnoid hemorrhage and early case fatality associated with outpatient antithrombotic drug use. Stroke. 2013; 44:2422-2426. 40. Konczalla J, Kashefiolasl S, Brawanski N, Senft C, Seifert V, Platz J. Increasing numbers of nonaneurysmal subarachnoid hemorrhage in the last 15 years: antithrombotic medication as reason and prognostic factor? J Neurosurg. 2016;124:1731-1737.
51. Sambu N, Curzen N. Monitoring the effectiveness of antiplatelet therapy: opportunities and limitations. Br J Clin Pharmacol. 2011;72:683-696. 52. Baharoglu MI, Cordonnier C, Al-Shahi Salman R, de Gans K, Koopman MM, Brand A, et al. Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial. Lancet. 2016;387: 2605-2613.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 19 April 2016; accepted 6 July 2016
41. Broderick JP, Brott TG, Duldner JE, Tomsick T, Leach A. Initial and recurrent bleeding are the major causes of death following subarachnoid hemorrhage. Stroke. 1994;25:1342-1347. 42. Claassen J, Bernardini GL, Kreiter K, Bates J, Du YE, Copeland D, et al. Effect of cisternal and ventricular blood on risk of delayed cerebral
WORLD NEUROSURGERY 94: 453-457, OCTOBER 2016
Citation: World Neurosurg. (2016) 94:453-457. http://dx.doi.org/10.1016/j.wneu.2016.07.019 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2016 Elsevier Inc. All rights reserved.
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457
Analysis of Hemorrhage Volumes After Angiogram-Negative Subarachnoid Hemorrhage David P. Bray, Jason A. Ellis, Sean D. Lavine, Philip M. Meyers, E. Sander Connolly, Jr.
BACKGROUND: Antiplatelet medication use is associated with worsened outcome after angiogram-negative subarachnoid hemorrhage (SAH). It has been hypothesized that these worsened outcomes may be the result of an association between antiplatelet medication use and increased hemorrhage volumes after angiogram-negative SAH. To test this hypothesis, we performed volumetric analysis of computed tomography (CT)-defined hemorrhage after angiogram-negative SAH.
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METHODS: This was a retrospective analysis of patients presenting with nontraumatic, angiogram-negative SAH in the Columbia University Subarachnoid Hemorrhage Outcomes database between 2000 and 2013. SAH volumes on admission head CT scans were measured using the MIPAV software package, version 7.20 in a semiautomated fashion.
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RESULTS: A total of 108 presenting CT scans from patients with angiogram-negative SAH were analyzed. The mean hemorrhage volume was 14.3 mL in the patients with a history of antiplatelet medication use, compared with 6.8 mL in those with no history of antiplatelet use. This difference was found to be significant (P [ 0.0029).
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CONCLUSIONS: Antiplatelet medication use is associated with increased SAH volumes in patients with angiogram-negative SAH. Increased hemorrhage volumes may contribute to poor outcomes in this patient population. Prospective studies are warranted to confirm this association.
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A
ntiplatelet drugs are among the most commonly used medications worldwide.1,2 The efficacy of these drugs, including aspirin and clopidogrel, in the prevention and treatment of thrombotic vascular disease has fueled their widespread use, especially in developed countries.3,4 Antiplatelet therapy is now a mainstay in the treatment of patients with such common conditions as unstable angina, coronary artery disease, peripheral artery disease, atrial fibrillation, and myocardial infarction.5-9 In addition, the progressive increase in the use of percutaneous coronary interventions, including stenting, adds more than 1 million patients per year to the population receiving single or dual antiplatelet therapy.10,11 Most patients with previous thromboembolic or ischemic stroke are prescribed antiplatelet therapy.12,13 Although the benefits of antiplatelet therapies are unquestionable, serious hemorrhagic complications can result from their use.14-17 Angiogram-negative subarachnoid hemorrhage (SAH), or nonaneurysmal SAH, is a unique variant of SAH for which no structural aberration can be found as a cause for the spontaneous hemorrhage.18,19 It accounts for approximately 10%e20% cases of SAH, appears to be rising in frequency, and may be associated with poor clinical outcomes, similar to those observed with aneurysmal SAH.18,20-32 Recent literature suggests that hemorrhage patterns may be correlated with clinical outcomes, although hemorrhage volume has heretofore not been rigorously evaluated as a prognostic indicator in angiogram-negative SAH.20,21,33-35 Angiogram-negative SAH is further subdivided into 2 distinct entities by bleeding pattern on the diagnostic computed tomography (CT) scan: perimesencephalic and nonperimesencephalic/ diffuse. Perimesencephalic SAH is thought to be secondary to venous bleeding and has a good prognosis.18 Nonperimesencephalic or diffuse angiogram-negative SAH may approach aneurysmal SAH in clinical severity and prognosis.21,36
Key words Aneurysm - Aspirin - Clopidogrel - Intracranial hemorrhage - Stroke
Department of Neurological Surgery, Columbia University Medical Center, New York, NY, USA
Abbreviations and Acronyms CT: Computed tomography SAH: Subarachnoid hemorrhage SHOP: Subarachnoid hemorrhage outcomes project
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WORLD NEUROSURGERY 94: 453-457, OCTOBER 2016
To whom correspondence should be addressed: David P. Bray, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2016) 94:453-457. http://dx.doi.org/10.1016/j.wneu.2016.07.019
Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2016 Elsevier Inc. All rights reserved.
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ORIGINAL ARTICLE DAVID P. BRAY ET AL.
HEMORRHAGE VOLUMES AFTER ANGIOGRAM-NEGATIVE SUBARACHNOID HEMORRHAGE
Recent studies using the Columbia University Medical Center’s Subarachnoid Hemorrhage Outcomes Project (SHOP) database have demonstrated that antiplatelet therapy may be associated with poor outcomes in patients with angiogram-negative SAH.37 This and other studies have suggested that the increased use of antiplatelet medications may be linked to the rise in angiogramnegative SAH, although additional research in is needed to confirm this association.38-40 Whereas the prognostic value of hemorrhage volume and location in patients with hemorrhagic stroke has been previously suggested, we are unaware of any previous studies associating antiplatelet use with hemorrhage volumes in angiogram-negative SAH.35,41-46 Thus, in the present study we tested the hypothesis that a history of antiplatelet medication use is associated with increased hemorrhage volumes in patients with angiogram-negative SAH. METHODS Study Population All patients with nontraumatic SAH detected on head CT scan at the time of admission were prospectively enrolled in the Columbia University Medical Center’s SHOP database between 2000 and 2013. Patients were designated as “angiogram-negative” when no lesion was found on catheter angiogram. Patient demographic and historical data were also collected in the SHOP database at the time of admission. Management of SAH Our institution’s approach to management of SAH has been described previously.47 Patients presenting with a history suspicious of SAH receive a noncontrast head CT scan. On diagnosis of SAH, all antithrombotic medications are held, and reversed when applicable. Antiplatelet medications are
Figure 1. Volumetric analysis. Subarachnoid hyperdensities in the range of 50e80 Hounsfield units were used to demarcate acute blood. Pre- (A) and post-
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discontinued, and platelet transfusion is initiated. Patients with angiogram-negative SAH receive at least 2 cerebral angiograms during their admission. Variables and Volumetric Quantification Baseline data, including age, sex, admission HunteHess grade, and history of antiplatelet medication use, were collected. No specific antiplatelet medications were retrospectively recorded in the database. Available head CT scans from patients who underwent conventional catheter angiography after presenting with nontraumatic SAH were reviewed. Hemorrhage volumes were measured using the MIPAV software package, version 7.20 (National Institutes of Health, Bethesda, MD, USA) in a semiautomated fashion as validated previously (Figure 1).44,45,48 Statistical Analysis All statistical analyses were performed using Stata 14 (StataCorp, College Station, TX, USA). Student’s t test was used for continuous variables and the c2 test was used for categorical variables in univariate analyses. Multivariate analysis was performed using a multiple logistic regression model adjusting for age, sex, and admission HunteHess grade. A P value or Pearson’s coefficient 0.05 was considered significant. RESULTS A total of 1582 patients with nontraumatic SAH were enrolled in the SHOP database during the study period. Of these 1582 patients, 1351 underwent catheter cerebral angiography during their admission. No structural cause of hemorrhage was found for the 173 patients who were diagnosed with angiogram-negative SAH. Among these 173 patients, 108 had a head CT scan obtainable from our medical records database (Table 1). Fortythree of these 108 patients (40%) received an antiplatelet
(B) semiautomated thresholding of subarachnoid blood are demonstrated on a representative head CT scan.
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ORIGINAL ARTICLE DAVID P. BRAY ET AL.
HEMORRHAGE VOLUMES AFTER ANGIOGRAM-NEGATIVE SUBARACHNOID HEMORRHAGE
DISCUSSION
Table 1. Characteristics of the Study Patients No History of Antiplatelet Medication Use (n [ 65)
History of Antiplatelet Medication Use (n [ 43)
Age, years, mean (SD)
54.4 (12.18)
62.14 (12.17)
Sex, male/ female, n
34/31
Characteristic
Blood volume, mL, mean (SD)
6.83 (7.56)
Blood volume, mL, median (IQR)
3.62 (1.45e9.61)
Any extension of hemorrhag e, n (%)
28/15 14.30 (14.51)
16 (24.6)
P Value/ Pearson’s Coefficient 0.0019 0.188 0.0029
10.2 (3.76e16.1)
17 (39.5)
Admission Hunt eHess grade, n (%)
0.099
0.534
I
28 (43.1)
17 (39.5)
II
16 (24.6)
13 (30.2)
III
13 (20.0)
9 (20.9)
IV
6 (9.2)
1 (2.3)
V
2 (3.1)
3 (7.0)
SD, standard deviation; IQR, interquartile range.
medication before admission, and the other 65 (60%) did not. The patients who received antiplatelet medication were older than those who did not, but there were no statistically significant differences in sex and HunteHess grade at admission between the 2 cohorts. The mean hemorrhage volume was 14.3 14.5 mL in the patients who received antiplatelet medication before admission, compared with 6.8 7.6 mL in those with no history of antiplatelet medication use. This difference was significant (P ¼ 0.0029) (Table 1 and Figure 2). On a multivariate regression analysis adjusting for age, sex, and HunteHess grade at admission, the difference in blood volumes remained significant (P < 0.05). Of the 43 patients with angiogram-negative SAH who received antiplatelet medications, 12 (28%) had an intraventricular extension of SAH and 6 (14%) had an intraparenchymal extension, for a combined hemorrhage extension rate of 40%. One patient had both intraventricular and intraparenchymal extension of hemorrhage. In comparison, 11 of the 65 patients (17%) with angiogramnegative SAH who did not receive antiplatelet medication had an intraventricular extension of SAH, and 5 (8%) had an intraparenchymal extension, for a combined hemorrhage extension rate of 25%. This increased rate of hemorrhage extension in patients receiving antiplatelet medication trended toward significance (P ¼ 0.09) (Table 1).
WORLD NEUROSURGERY 94: 453-457, OCTOBER 2016
Angiogram-negative SAH is a relatively poorly understood phenomenon.18,20-32 It has been suggested that the frequency of angiogram-negative SAH is increasing, and that this rising frequency might be associated with the proliferation of antiplatelet medication use.37 Interestingly, in patients with angiogramnegative SAH, antiplatelet medication use before presentation seems to be associated with poor early outcomes, owing to a previously undefined etiology.37 Here we present data implicating hemorrhage volume as a key component in the pathophysiology of neurologic outcome. In the present study, we found higher hemorrhage volumes in patients with a history of antiplatelet medication use compared with patients with no such history before presentation with angiogram-negative SAH. This finding was confirmed to be significant by multivariate analysis adjusting for age, sex, and admission HunteHess grade. In addition, among patients with angiogram-negative SAH, those with a history of antiplatelet medication use had higher rates of intraventricular and intraparenchymal extension of hemorrhage, but the difference between the 2 cohorts showed only a trend toward statistical significance. Larger prospective studies with sufficient statistical power may yet demonstrate significance. These findings are in some ways not surprising, given that increased hemorrhage volumes, intraventricular extension, and specific bleeding patterns on presenting CT scans have been associated with worse outcomes in aneurysmal SAH.35,41-45 Previous studies have shown that the pattern of blood detected on the presenting CT scan may have prognostic value in patients with angiogram-negative SAH.19,49,50 The diffuse or nonperimesencephalic distribution of blood on the presenting CT scan has been associated with worse outcomes compared with perimesencephalic blood patterns. In one such study, Fontanella et al.21
Figure 2. Antiplatelet medications and SAH volume. Boxplots showing significantly higher SAH volumes in patients who received antiplatelet medication compared with those who did not.
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completed a retrospective review of 102 patients with angiogramnegative SAH with 8e16 years of follow-up. Patients with perimesencephalic blood patterns had no rebleeding episodes, whereas patients with diffuse SAH on the presenting CT scan had a 5.1% rate of rebleeding.21 In another study, Walcott et al.36 studied 138 patients with angiogram-negative SAH and divided the cohort into those with a perimesencephalic blood pattern and those with a nonperimesencephalic blood pattern on CT scan. In that study, radiographic vasospasm developed in 8.6% of patients with perimesencephalic SAH and in 20.6% of those with nonperimesencephalic SAH.36 We believe that the foregoing studies are entirely consistent with our finding that increased blood volume may be implicated in the worse outcomes seen in patients with nonperimesencephalic or diffuse SAH. Although only correlative, our data suggest that the use of antiplatelet medications may cause patients with an angiogram-negative SAH to develop larger hemorrhages than they otherwise would have. This may contribute to the worse outcomes noted in previous studies.37 This study has several limitations. First, owing to the standardized history collection of the SHOP database, we do not have specific information on the type and dosage of antiplatelet medication that each patient used. Moreover, platelet function can vary widely among patients receiving the same antiplatelet medication and dosage, owing to genetic polymorphisms, patient medication compliance, and drug metabolism.51 Second, all of the patients receiving antiplatelet medication in this study received a platelet transfusion after admission for SAH unless otherwise indicated. The recently published results from the PATCH (Platelet Transfusion in Cerebral Haemorrhage) trial show higher rates of adverse events and death in patients receiving
REFERENCES 1. Yusuf S, Islam S, Chow CK, Rangarajan S, Dagenais G, Diaz R, et al. Use of secondary prevention drugs for cardiovascular disease in the community in high-income, middle-income, and low-income countries (the PURE study): a prospective epidemiological survey. Lancet. 2011;378: 1231-1243. 2. Subherwal S, Patel MR, Kober L, Peterson ED, Jones WS, Gislason GH, et al. Missed opportunities: despite improvement in use of cardioprotective medications among patients with lower-extremity peripheral artery disease, underuse remains. Circulation. 2012;126:1345-1354. 3. Ferreiro JL, Angiolillo DJ. New directions in antiplatelet therapy. Circ Cardiovasc Interv. 2012;5: 433-445. 4. Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med. 2007;357:2482-2494. 5. Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE, et al. 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart
456
www.SCIENCEDIRECT.com
antiplatelet medication and platelet transfusion after intracerebral hemorrhage compared with patients receiving standard therapy.52 Platelet transfusion could have had a confounding effect on our analysis. Further randomized controlled trials are needed to determine the role of platelet transfusion in patients with SAH associated with antiplatelet medication use. Finally, the cohort of patients who received antiplatelet medication before admission for angiogram-negative SAH had a higher mean age than those who did not. This finding is expected, because older individuals are more often prescribed antiplatelet medications for vascular disease later in life. This difference between the 2 cohorts is of minor concern, given that the hemorrhage volumes in the patients receiving antiplatelet medication were still significantly greater after multivariate analysis. To further elucidate the association between antiplatelet medications and angiogram-negative SAH, further studies are needed to relate hemorrhage volumes to specific types and doses of antiplatelet medications. In addition, correlating angiogramnegative SAH hemorrhage volumes to rates of delayed cerebral ischemia and hydrocephalus would be worthwhile. CONCLUSION Antiplatelet medication use in angiogram-negative SAH is associated with increased hemorrhage volumes at presentation. It also may be associated with higher rates of intraventricular and intraparenchymal extension of SAH. Further studies are needed to firmly establish the etiologic association between antiplatelet medication use and worse clinical outcomes in patients with angiogram-negative SAH.
Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61:e179-e347. 6. Kushner FG, Hand M, Smith SC Jr, King SB 3rd, Anderson JL, Antman EM, et al. 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2009;54:2205-2241. 7. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324:71-86. 8. Fuster V, Chesebro JH. Aspirin for primary prevention of coronary disease. Eur Heart J. 1995;16 Suppl E:16-20.
11. Shehab N, Sperling LS, Kegler SR, Budnitz DS. National estimates of emergency department visits for hemorrhage-related adverse events from clopidogrel plus aspirin and from warfarin. Arch Intern Med. 2010;170:1926-1933. 12. Mohr JP, Thompson JL, Lazar RM, Levin B, Sacco RL, Furie KL, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med. 2001;345: 1444-1451. 13. Sacco RL, Prabhakaran S, Thompson JL, Murphy A, Sciacca RR, Levin B, et al. Comparison of warfarin versus aspirin for the prevention of recurrent stroke or death: subgroup analyses from the Warfarin-Aspirin Recurrent Stroke Study. Cerebrovasc Dis. 2006;22:4-12. 14. He J, Whelton PK, Vu B, Klag MJ. Aspirin and risk of hemorrhagic stroke: a meta-analysis of randomized controlled trials. JAMA. 1998;280: 1930-1935.
9. Fuster V, Sweeny JM. Aspirin: a historical and contemporary therapeutic overview. Circulation. 2011;123:768-778.
15. Serebruany VL, Malinin AI, Eisert RM, Sane DC. Risk of bleeding complications with antiplatelet agents: meta-analysis of 338,191 patients enrolled in 50 randomized controlled trials. Am J Hematol. 2004;75:40-47.
10. Yeh RW, Mauri L, Kereiakes DJ. Dual antiplatelet therapy duration following coronary stenting. [Corrected]. J Am Coll Cardiol. 2015;65:787-790.
16. Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, et al. Aspirin and clopidogrel compared with clopidogrel alone
WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2016.07.019
ORIGINAL ARTICLE DAVID P. BRAY ET AL.
after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364:331-337. 17. Shireman TI, Howard PA, Kresowik TF, Ellerbeck EF. Combined anticoagulant-antiplatelet use and major bleeding events in elderly atrial fibrillation patients. Stroke. 2004;35:2362-2367. 18. Schwartz TH, Solomon RA. Perimesencephalic nonaneurysmal subarachnoid hemorrhage: review of the literature. Neurosurgery. 1996;39:433-440 [discussion: 440]. 19. Tatter SB, Crowell RM, Ogilvy CS. Aneurysmal and microaneurysmal “angiogram-negative” subarachnoid hemorrhage. Neurosurgery. 1995;37: 48-55.
HEMORRHAGE VOLUMES AFTER ANGIOGRAM-NEGATIVE SUBARACHNOID HEMORRHAGE
29. Brismar J, Sundbärg G. Subarachnoid hemorrhage of unknown origin: prognosis and prognostic factors. J Neurosurg. 1985;63:349-354. 30. Khan AA, Smith JD, Kirkman MA, Robertson FJ, Wong K, Dott C, et al. Angiogram negative subarachnoid haemorrhage: outcomes and the role of repeat angiography. Clin Neurol Neurosurg. 2013;115: 1470-1475.
43. Friedman JA, Goerss SJ, Meyer FB, Piepgras DG, Pichelmann MA, McIver JI, et al. Volumetric quantification of Fisher Grade 3 aneurysmal subarachnoid hemorrhage: a novel method to predict symptomatic vasospasm on admission computerized tomography scans. J Neurosurg. 2002;97:401-407.
31. Boswell S, Thorell W, Gogela S, Lyden E, Surdell D. Angiogram-negative subarachnoid hemorrhage: outcomes data and review of the literature. J Stroke Cerebrovasc Dis. 2013;22:750-757.
44. Jung SW, Lee CY, Yim MB. The relationship between subarachnoid hemorrhage volume and development of cerebral vasospasm. J Cerebrovasc Endovasc Neurosurg. 2012;14:186-191.
32. Kang DH, Park J, Lee SH, Park SH, Kim YS, Hamm IS. Does non-perimesencephalic type nonaneurysmal subarachnoid hemorrhage have a benign prognosis? J Clin Neurosci. 2009;16:904-908.
45. Ko SB, Choi HA, Carpenter AM, Helbok R, Schmidt JM, Badjatia N, et al. Quantitative analysis of hemorrhage volume for predicting delayed cerebral ischemia after subarachnoid hemorrhage. Stroke. 2011;42:669-674.
20. Cánovas D, Gil A, Jato M, de Miquel M, Rubio F. Clinical outcome of spontaneous non-aneurysmal subarachnoid hemorrhage in 108 patients. Eur J Neurol. 2012;19:457-461.
33. Whiting J, Reavey-Cantwell J, Velat G, Fautheree G, Firment C, Lewis S, et al. Clinical course of nontraumatic, nonaneurysmal subarachnoid hemorrhage: a single-institution experience. Neurosurg Focus. 2009;26:E21.
21. Fontanella M, Rainero I, Panciani PP, Schatlo B, Benevello C, Garbossa D, et al. Subarachnoid hemorrhage and negative angiography: clinical course and long-term follow-up. Neurosurg Rev. 2011;34:477-484.
34. Maslehaty H, Barth H, Petridis AK, Doukas A, Maximilian Mehdorn H. Special features of subarachnoid hemorrhage of unknown origin: a review of a series of 179 cases. Neurol Res. 2012;34: 91-97.
22. Konczalla J, Schmitz J, Kashefiolasl S, Senft C, Seifert V, Platz J. Non-aneurysmal subarachnoid hemorrhage in 173 patients: a prospective study of long-term outcome. Eur J Neurol. 2015;22: 1329-1336. 23. Konczalla J, Schuss P, Platz J, Vatter H, Seifert V, Güresir E. Clinical outcome and prognostic factors of patients with angiogram-negative and nonperimesencephalic subarachnoid hemorrhage: benign prognosis like perimesencephalic SAH or same risk as aneurysmal SAH? Neurosurg Rev. 2015; 38:121-127 [discussion: 127]. 24. Rinkel GJ, Wijdicks EF, Vermeulen M, Hageman LM, Tans JT, van Gijn J. Outcome in perimesencephalic (nonaneurysmal) subarachnoid hemorrhage: a follow-up study in 37 patients. Neurology. 1990;40:1130-1132. 25. van Gijn J, van Dongen KJ, Vermeulen M, Hijdra A. Perimesencephalic hemorrhage: a nonaneurysmal and benign form of subarachnoid hemorrhage. Neurology. 1985;35:493-497. 26. Sarabia R, Lagares A, Fernández-Alén JA, Arikan F, Vilalta J, Ibáñez J, et al. Idiopathic subarachnoid hemorrhage: a multicentre series of 220 patients. Neurocirugia (Astur). 2010;21:441-451. 27. Topcuoglu MA, Ogilvy CS, Carter BS, Buonanno FS, Koroshetz WJ, Singhal AB. Subarachnoid hemorrhage without evident cause on initial angiography studies: diagnostic yield of subsequent angiography and other neuroimaging tests. J Neurosurg. 2003;98:1235-1240. 28. Oder W, Kollegger H, Zeiler K, Dal-Bianco P, Wessely P, Deecke L. Subarachnoid hemorrhage of unknown etiology: early prognostic factors for long-term functional capacity. J Neurosurg. 1991;74: 601-605.
ischemia after subarachnoid hemorrhage: the Fisher scale revisited. Stroke. 2001;32:2012-2020.
46. Naidech AM, Rosenberg NF, Maas MB, Bendok BR, Batjer HH, Nemeth AJ. Predictors of hemorrhage volume and disability after perimesencephalic subarachnoid hemorrhage. Neurology. 2012;78:811-815. 47. Komotar RJ, Schmidt JM, Starke RM, Claassen J, Wartenberg KE, Lee K, et al. Resuscitation and critical care of poor-grade subarachnoid hemorrhage. Neurosurgery. 2009;64:397-410 [discussion: 410-411].
35. Lin N, Zenonos G, Kim AH, Nalbach SV, Du R, Frerichs KU, et al. Angiogram-negative subarachnoid hemorrhage: relationship between bleeding pattern and clinical outcome. Neurocrit Care. 2012;16:389-398.
48. Bazin PL, Cuzzocreo JL, Yassa MA, Gandler W, McAuliffe MJ, Bassett SS, et al. Volumetric neuroimage analysis extensions for the MIPAV software package. J Neurosci Methods. 2007;165:111-121.
36. Walcott BP, Stapleton CJ, Koch MJ, Ogilvy CS. Diffuse patterns of nonaneurysmal subarachnoid hemorrhage originating from the Basal cisterns have predictable vasospasm rates similar to aneurysmal subarachnoid hemorrhage. J Stroke Cerebrovasc Dis. 2015;24:795-801.
49. Rinkel GJ, Wijdicks EF, Hasan D, Kienstra GE, Franke CL, Hageman LM, et al. Outcome in patients with subarachnoid haemorrhage and negative angiography according to pattern of haemorrhage on computed tomography. Lancet. 1991;338:964-968.
37. Ellis JA, McDowell MM, Mayer SA, Lavine SD, Meyers PM, Connolly ES Jr. The role of antiplatelet medications in angiogram-negative subarachnoid hemorrhage. Neurosurgery. 2014;75:530-535 [discussion: 534-535].
50. Jafar JJ, Weiner HL. Surgery for angiographically occult cerebral aneurysms. J Neurosurg. 1993;79: 674-679.
38. Schmidt M, Johansen MB, Lash TL, Christiansen CF, Christensen S, Sørensen HT. Antiplatelet drugs and risk of subarachnoid hemorrhage: a population-based case-control study. J Thromb Haemost. 2010;8:1468-1474. 39. Garbe E, Kreisel SH, Behr S. Risk of subarachnoid hemorrhage and early case fatality associated with outpatient antithrombotic drug use. Stroke. 2013; 44:2422-2426. 40. Konczalla J, Kashefiolasl S, Brawanski N, Senft C, Seifert V, Platz J. Increasing numbers of nonaneurysmal subarachnoid hemorrhage in the last 15 years: antithrombotic medication as reason and prognostic factor? J Neurosurg. 2016;124:1731-1737.
51. Sambu N, Curzen N. Monitoring the effectiveness of antiplatelet therapy: opportunities and limitations. Br J Clin Pharmacol. 2011;72:683-696. 52. Baharoglu MI, Cordonnier C, Al-Shahi Salman R, de Gans K, Koopman MM, Brand A, et al. Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial. Lancet. 2016;387: 2605-2613.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 19 April 2016; accepted 6 July 2016
41. Broderick JP, Brott TG, Duldner JE, Tomsick T, Leach A. Initial and recurrent bleeding are the major causes of death following subarachnoid hemorrhage. Stroke. 1994;25:1342-1347. 42. Claassen J, Bernardini GL, Kreiter K, Bates J, Du YE, Copeland D, et al. Effect of cisternal and ventricular blood on risk of delayed cerebral
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Citation: World Neurosurg. (2016) 94:453-457. http://dx.doi.org/10.1016/j.wneu.2016.07.019 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2016 Elsevier Inc. All rights reserved.
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