Predictors of Severity of Cerebral Vasospasm caused by Aneurysmal Subarachnoid Hemorrhage

Predictors of Severity of Cerebral Vasospasm caused by Aneurysmal Subarachnoid Hemorrhage Ramazan Jabbarli, MD,* Sven Gl€ asker, MD, PhD,* Johannes Weber, MD,† Christian Taschner, MD, PhD,‡ Manfred Olschewski, Dipl.-Stat.,x and Vera Van Velthoven, MD, PhD*

Background: Cerebral vasospasm is one of the leading causes of poor outcome after aneurysmal subarachnoid hemorrhage. The risk factors for the development of vasospasm have been evaluated in many clinical studies. However, it remains unclear if vasospasm severity can be predicted. The purpose of this study was to determine if different demographic and clinical factors that appear to be predictors of vasospasm can also prognosticate the severity of cerebral vasospasm. Methods: We retrospectively analyzed consecutive patients with subarachnoid hemorrhage who underwent endovascular vasospasm treatment in a single center. In order to define predictors of vasospasm severity, we studied the demographic and clinical characteristics of these patients. Vasospasm severity was defined by cerebral angiography, transcranial Doppler ultrasound, and therapeutic response on endovascular treatment. Statistical analyses were performed to determine significant predictors. Results: A total of 70 patients with vasospasm were included. Early onset of mean flow velocities .160 cm/second on transcranial Doppler ultrasound correlated with severity of angiographic vasospasm (P 5 .0469) and resistance against intra-arterial papaverine (P 5 .0277). Younger age (,51 years of age) was significantly associated with severity of vasospasm regarding extension on angiography (P 5 .0422), the need for repetitive endovascular treatment (P 5 .0084), persistence of transcranial Doppler ultrasound vasospasm after endovascular treatment (P 5 .0004), and resistance against intra-arterial papaverine (P 5 .0341). Conclusions: Younger age and early onset of vasospasm on transcranial Doppler ultrasound are important predictors for vasospasm severity. We recommend early and aggressive therapy in this subgroup. Key Words: Angioplasty—cerebral vasospasm—intra-arterial papaverine—predictor—severity— subarachnoid hemorrhage—transcranial Doppler. Ó 2013 by National Stroke Association

From the *Departments of Neurosurgery; †Neuroradiology, University Hospital of Freiburg; ‡Institute for Radiology, Canton Hospital, St. Gallen, Switzerland; and xInstitute for Medical Biometry and Medical Informatics, University of Freiburg, Freiburg, Germany. Received October 6, 2012; revision received December 15, 2012; accepted January 7, 2013. Address correspondence to Vera Van Velthoven, MD, PhD, Department of Neurology, University Hospital of Freiburg, Germany, Breisacher Strasse 64, D-79106 Freiburg/Breisgau, Germany. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2013 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.01.006

1332

After initial hemorrhage, cerebral vasospasm is the second cause of substantial disability and death in patients with aneurysmal subarachnoid hemorrhage (SAH).1 Radiographic evidence of vasospasm develops in 50% to 70% of patients with SAH, and half of those experience symptoms of delayed ischemic neurologic deficit (DIND).2-5 An important problem in the management of cerebral vasospasm is early recognition. By the time clinical symptoms of cerebral vasospasm are evident, the ischemic event may have progressed too far and the window for therapeutic intervention may have been missed.6 On the other hand, both conservative and invasive treatment modalities of vasospasm are associated with some risks, so

Journal of Stroke and Cerebrovascular Diseases, Vol. 22, No. 8 (November), 2013: pp 1332-1339

PREDICTORS OF VASOSPASM SEVERITY AFTER SAH

they cannot be routinely applied to all patients with SAH. Therefore, to improve neurologic outcome, early identification of patients at risk of cerebral infarction that would benefit from aggressive intervention is of paramount importance.6 Factors like patient age,7 sex,8-10 clinical grade on admission,11 blood volume on the initial computed tomographic (CT) scan,12-14 transcranial Doppler (TCD) ultrasound values,15 and the modality of aneurysm treatment16,17 have been suggested as predictors for the incidence of cerebral vasospasm. At the same time, the proper predictive role of these factors is still being disputed by many authors.7,10 Even less studied is the question of whether the severity of cerebral vasospasm can also be predicted. The purpose of this study was to determine if the different demographic and clinical factors that appear to be predictors of vasospasm occurrence can also prognosticate the severity of cerebral vasospasm.

Methods Patient Selection We retrospectively reviewed data from patients admitted to the University Hospital of Freiburg with acute aneurysmal SAH between January 1, 2003 and March 31, 2009. Only patients treated within 48 hours after hemorrhage were included. The presence of clinical vasospasm as seen on both daily performed TCD ultrasound and digital subtraction angiography (DSA) was a second inclusion criterion. Finally, only the patients with endovascular treatment of cerebral vasospasm were included in our investigation.

SAH Management All patients were initially admitted to our intensive care unit and received neurointensive care. Oral nimodipine (360 mg/day) was given to all patients. Baseline conservative therapy included also the maintenance of normovolemia. Posthemorrhagic hydrocephalus was treated with external ventricular or lumbar drain. As bedside monitoring of cerebral vasospasm, TCD ultrasound was performed once a day from the first day of admittance for 3 weeks after bleeding except in cases with shorter survival. According to the guidelines,6,18 absolute mean flow velocities (MFVs) .160 cm/second for anterior circulation were deemed suspicious for clinical vasospasm, and induced hypertension was initiated by maintaining mean arterial blood pressure between 110 and 120 mm Hg. In cases of clinical deterioration not explained by other complications, the patients underwent emergent DSA for vasospasm verification and endovascular therapy. A CT scan of the head was performed before the intervention both to exclude other causes of neurologic worsening

1333

(i.e., rebleeding and hydrocephalus) and to rule out ischemic infarction. Endovascular therapy was used only for cerebral vasospasm with persistent neurologic deficit resistant to conservative management. After vasospasm was angiographically verified, the vasodilator papaverine was given in all cases and infused at a concentration of 3 mg/mL at 6 to 9 L per minute, for a total dose of up to 300 mg per vascular territory according to the guidelines.19-22 In cases of resistant angiographic vasospasm despite maximal doses of intra-arterial papaverine, transluminal balloon angioplasty (TBA) was performed. After endovascular therapy, a new diagnostic DSA was initiated to evaluate the effect of treatment. In cases of persistence or recurrence of abnormal clinical and/or ultrasonographic observations, the patients underwent reangiography for the identification of angiographic vasospasm and, if needed, repeated endovascular therapy.

Data Management, Outcome Measures, and Statistical Analysis The primary endpoint of the study was the detection of predictive factors for vasospasm severity. The following demographic and clinical parameters were recorded as potential predictors: age, sex, blood group (according to ABO and Rhesus systems), number of intracranial aneurysms, initial clinical and radiologic condition, treatment modality of ruptured aneurysm, and presence of SAH-associated hydrocephalus. Patient age was considered a dichotomous variable with cutpoints of ,51 or .51 years of age according to the mean age of the cohort. The initial clinical condition of patients was graded according to Hunt and Hess.23 The severity of SAH was radiologically classified from the appearance of the initial CT scan according to Fisher et al.24 The modality of aneurysm treatment as a widely disputed predictor for vasospasm incidence was also taken into consideration. Because of currently growing consensus about multifactorial (not only vasospasmrelated) nature of DIND,25-27 the parameters of clinical outcome (course of DIND and clinical condition at discharge) were not calculated for the designation of vasospasm severity. These parameters were included in the aggregate results. The severity of cerebral vasospasm was defined on the basis of angiographic and TCD ultrasound findings. Unfortunately, there is still no unique classification of angiographic evidence of cerebral vasospasm.28-30 Establishing a goal of a detailed description of vasospastic changes in the entire intracranial vasculature, we have applied a scoring system where angiographic vasospasm was considered as the sum of vasospasm extensions in each of the basic vascular segments (the internal carotid, middle cerebral, anterior cerebral, vertebral, basilar, and posterior cerebral arteries). Vasospasm grade in each of

R. JABBARLI ET AL.

1334

Table 1. Gradation of angiographic vasospasm Grade

Description

Vessel narrowing

0 1 2 3

No evidence of vasospasm Mild vasospasm Moderate vasospasm Severe vasospasm

0 ,50% 50-75% $75%

Gradation of severity of angiographic vasospasm in the spastic segment based on the degree of vessel narrowing. For grades 0 and 1, there was no need for local endovascular treatment. Grades 2 and 3 of angiographic vasospasm were treated with intra-arterial papaverine and, if necessary, with transluminal balloon angioplasty (TBA).

these vessels was described according to a widely used gradation of angiographic vasospasm, based on the grade of constriction of the spastic segment compared with the initial DSA results (Table 1). Aside from the grade of extension of cerebral vasospasm on DSA, the fact of resistance to intra-arterial application of papaverine, the need for repetitive endovascular

therapy, and abnormal TCD ultrasound measurements both before and after the endovascular treatments were used as additional characteristics of vasospasm severity. Differences between continuous variables were analyzed using the Student t test for normally distributed data and the Mann–Whitney U test for non–normally distributed data. Associations between categorical variables were analyzed using the Chi-square or Fisher exact tests (with demonstration of odds ratio), as appropriate. P , .05 was considered statistically significant. Data analyses were performed with PRISM statistical software (version 5.0; GraphPad Software Inc; La Jolla, CA).

Results Population Characteristics A total of 505 patients with aneurysmal SAH were treated in our center between January 1, 2003 and March 31, 2009. The final analysis included 70 patients with a mean age of 51.3 years (range 23-84 years). Detailed

Table 2. Baseline characteristics and treatment outcomes of the study group (N 5 70) Age, y (n) ,51 $51 Sex, n Male Female No. of aneurysms, n 1 2 .2 Localization of ruptured aneurysm, n Anterior circulation Posterior circulation Blood group,* n ABO system A B O AB Rhesus type Positive Negative Hunt and Hess grade, n 1 2 3 4 5 Treatment modality, n Clipping Coiling Both

38 32 18 52 49 14 7 55 15

35 4 21 8 54 14 8 17 19 23 3 13 55 2

Fisher grade, n 1 2 3 4 SAH-associated hydrocephalus, n Present Absent Intra-arterial papaverine, n Sensitive Resistant No. of endovascular treatments, n Single Repetitive Course of DIND, n Improvement No improvement Not evaluabley Clinical condition at discharge (mRS65,66), n 1 2 3 4 5 6 Radiologic infarction at discharge, n No infarction Infarction in 1 arterial territory Multiple infarctions

Abbreviations: DIND, delayed ischemic neurologic deficit; mRS, modified Rankin Scale; SAH, subarachnoid hemorrhage. *There were no data regarding blood group in 2 patients. yThe course of DIND was considered as ‘‘not evaluable’’ for patients with exitus (mRS 6).

0 18 32 20 57 13 36 34 34 36 34 14 22 4 4 10 16 14 22 14 21 35

PREDICTORS OF VASOSPASM SEVERITY AFTER SAH

1335

vasospasms on TCD ultrasound (day 5.31 versus day 10; P 5.0234; Fig 1). However, there was no correlation between the presence of hydrocephalus and the severity of angiographic vasospasm (P 5 .1279). Finally, there was no correlation between vasospasm severity with the blood group and the presence of multiple aneurysms.

information about population characteristics can be seen in Table 2.

Potential Predictors The main target of this study was the relationship between vasospasm severity and parameters that are currently proposed as prognosticators of vasospasm occurrence: age, sex, initial clinical and radiologic grade, and treatment modality (Table 3). Of these potential predictors, only age had a significant correlation, indicating a more severe course of vasospasm in patients ,51 years of age. This correlation was statistically significant for all investigated vasospasm parameters. In relation to the necessity for repetitive endovascular vasospasm treatment, patient age was also significant as a continuous variable (P 5 .0022). Other demographic and clinical factors known in the literature as predictors of incidence of cerebral vasospasm had no significant predictive power for the severity of vasospasm.

TCD Ultrasound Vasospasm Young age (,51 years; P 5 .0109) and poor Hunt and Hess grade (P 5 .0023) correlated significantly with the earlier development of vasospasm on TCD ultrasound (Table 4). Conversely, the early onset of vasospasm on TCD ultrasound was significantly associated with the severity of angiographic vasospasm (P 5 .0469; Fig 2) and with papaverine resistance (P 5 .0277). There was a trend between early vasospasm on TCD ultrasound and the necessity for repetitive endovascular treatment, but this trend was not statistically significant (P 5 .1527).

Other Demographic and Clinical Parameters

Discussion

Patients with SAH-associated hydrocephalus had a significantly higher resistance against intra-arterial papaverine (P 5 .0314; odds ratio 4.27) and earlier onset of

The literature data about predictors of cerebral vasospasm is extensive, and many controversies exist

Table 3. Relationship between potential predictors and severity of vasospasm

Angiographic vasospasm Parameter Age (y) ,51 $51 Sex Male Female Hunt and Hess grade 1 2 3 4 5 Fisher grade 1 2 3 4 Treatment modality Clipping Coiling

Persistence of TCD vasospasm after endovascular therapy

Mean value P value Mean value

Resistance to intra-arterial papaverine

Necessity of repeated endovascular therapy

P value

OR (95% CI)

P value

OR (95% CI)

P value

11.76 8.25

.0422

5.73 0.45

.0004

2.93 (1.1-7.78)

.0341

6.000 (1.71-21.04)

.0084

10.78 9.94

.2831

1.93 4.09

.4391

0.69 (0.23-2.02)

.5882

1.214 (0.36-4.13)

1.0000

8.00 10.29 10.00 10.09 16.67

.3363

1.50 3.08 2.62 4.71 12.00

.8558

—

.1864

—

.8524

— 11.00 8.59 11.90

.3138

— 1.79 4.44 4.13

.3518

—

.1876

—

.8288

10.11 11.00

.5725

2.88 3.75

.8452

1.40 (0.42-4.71)

.7588

1.111 (0.24-5.1)

1.0000

Abbreviations: CI, confidence interval; OR, odds ratio; TCD, transcranial Doppler ultrasound. Mean values are given for continuous variables (extension of angiographic vasospasm and persistence of TCD vasospasm after endovascular therapy). Categorical variables are described with contingency analyses (for dichotomous predictors: age, sex, and treatment modality with ORs and CIs).

R. JABBARLI ET AL.

1336

Table 4. Relationship between appearance of abnormal transcranial Doppler ultrasound measurements with predictive factors and vasospasm severity Onset of MFV .160 cm/s on TCD Parameter

Figure 1. Relationship between subarachnoid hemorrhage (SAH)– associated hydrocephalus and vasospasm severity. (A) Correlation between SAH-associated hydrocephalus and resistance against intraarterial papaverine (odds ratio 4.267; P 5 .0314). (B) Correlation between SAH-associated hydrocephalus and onset of vasospasms detected by transcranial Doppler ultrasound (mean flow volume .160 cm/s). Mean values: no hydrocephalus, day 10; SAH-associated hydrocephalus, day 5.3 (P 5 .0234).

regarding each of the potential predictors. Even less is known about whether the severity of vasospasm can be predicted.

Age Younger age (with a widely varying age cutoff) is generally accepted as a predictor of symptomatic vasospasm.7,18,31-38 A possible explanation of this correlation is an increasing stiffness of the cerebral vasculature associated with advancing age (for example, as conditioned by atherosclerosis).39-41 However, there are also negative reports on the correlation of younger age with vasospasm incidence.10,42-44 The relationship between age as predictor and vasospasm severity has until now been scarcely investigated and conceals even more inexactness. We could show that younger age is a predictor of severity of cerebral vasospasm; a significant association was observed both on angiographic and on TCD ultrasound findings. We consider that because of a higher incidence

Mean value, day

Age (y) ,51 5.53 $51 6.97 Gender Male 8.06 Female 5.54 Hunt and Hess grade 1 12.75 2 6.94 3 5.53 4 4.30 5 3.00 Fisher grade 1 — 2 6.78 3 6.78 4 4.70 Treatment modality Clipping 6.15 Coiling 6.29 Endovascular procedures Single endovascular 8.25 treatment Repetitive endovascular 5.5 treatment Response to intra-arterial papaverine Sensitive 7.42 Resistant 4.88

P value

.0109

.1665

.0023

.1089

.7899

.1527

.0277

Abbreviations: MFV, mean flow volume; TCD, transcranial Doppler ultrasound.

and a more severe course of cerebral vasospasm, the aggressive management of vasospasm is feasible in younger adults with SAH.

Sex Female sex is a recognized risk factor for the occurrence of aneurysmal SAH.45 With the exception of a few reports,8-10 a majority of authors do not recognize female sex as a predictor of vasospasm.7,31,45-47 We did not find any correlation between patient sex and severity of vasospasm. In summary, sex does not seem to play any for either the development or severity of vasospasm.

Hunt and Hess Grade There is no consensus on the prognostic value of the initial clinical condition on vasospasm. Many authors hold the opinion that patients in poor clinical condition at

PREDICTORS OF VASOSPASM SEVERITY AFTER SAH

1337

conflict directly with the current opinion about the impact of SAH on vasospasm occurrence. We suppose that the grade of vasoconstriction (contrary to the probability to develop cerebral vasospasm) does not appear to be influenced by amount of surrounding blood. Rather, the anatomic and functional characteristics of vasculature— depending, for example, on patient age—may condition the ability to higher or lower vasospasm grade.

TCD Ultrasound Vasospasm

Figure 2. Relationship between vasospasm determined by angiography and transcranial Doppler ultrasound. The vertical axis represents the summary score of extensions of angiographic vasospasm in the intracranial vasculature according to our scoring system. The horizontal axis indicates the day of onset of mean flow volume .160 cm/s on transcranial Doppler ultrasound (linear regression model; Pearson correlation r 5 20.2033; P 5 .0469).

admission are more likely to develop cerebral vasospasm and, subsequently, a DIND.10,48,49 However, there are also reports that indicate a higher incidence of vasospasm in patients in better clinical condition.7,31,50 In our findings, the Hunt and Hess grade was not a reliable predictor of vasospasm severity. Although the clinical condition at admission correlated with the onset of vasospasm on TCD ultrasound, direct indicators of vasospasm severity, such as angiographic vasospasm, papaverine resistance, repetitive treatment, and duration of vasospasm on TCD ultrasound after endovascular treatment revealed no correlation with Hunt and Hess grade. Such negative reports are also known in regard to vasospasm incidence.47,51 Our data show that the initial clinical condition of the patient does not play the primary role in the pathogenesis of cerebral vasospasm. We think that patients with poorer initial clinical grade—because of the difficulties of proper clinical monitoring and interpretation of DIND—are de facto at higher risk of vasospasm-associated clinical deterioration because of cerebral vasospasm that has not been identified in a timely fashion and has not been sufficiently treated.

Fisher Grade The amount of subarachnoid blood on the initial CT scan is known to be the one of most powerful predictors of occurrence of cerebral vasospasm.12,13,51-53 But there are also some publications7,54-56 that could not find a significant correlation between the radiologic classification of SAH and the incidence of cerebral vasospasm. The relation between the amount of subarachnoid blood on the initial CT scan and vasospasm severity is not established yet. In our population, the Fisher grade had no predictive value for vasospasm severity; this finding does not

TCD ultrasound remains the most widely used modality for diagnosing cerebral vasospasm.47 In our report, the early onset of vasospasm in TCD ultrasound was predictive for papaverine resistance during endovascular therapy. This finding, in combination with the evidence of a correlation of early TCD ultrasound vasospasm with the extension of angiographic vasospasm, indicate that early vasospasm in TCD ultrasound should be considered a predictor of severity of vasospasm. Patients with early onset of vasospasm according to TCD ultrasound should be carefully monitored, suggesting a prophylactic diagnostic angiography in cases where no adequate clinical evaluation of patients is possible.

Hydrocephalus Among alternative clinical predictors, acute hydrocephalus has been identified by some investigators as a risk factor for symptomatic vasospasm51,57—but not all investigators agree.58,59 The positive association between the occurrence of hydrocephalus and DIND was identified in several reports17,60,61; a possible causal effect of vasospasm over hydrocephalus was up to debate as well.60,62 There is also a contrary causal speculation that elevated intracranial pressure caused by hydrocephalus in patients with SAH could negatively affect cerebral perfusion.62-64 We could show a partial correlation between SAHassociated hydrocephalus and characteristics of vasospasm severity; patients with hydrocephalus had an earlier onset of vasospasm on TCD ultrasound and a higher resistance against intra-arterial papaverine. However, the severity of angiographic vasospasm did not correlate with hydrocephalus. Positive correlations could be explained by the fact that hydrocephalic patients belonged to the group with higher clinical and radiologic grades, and it could certainly influence the final results. A larger patient contingent is needed to detect the true significance of acute hydrocephalus for vasospasm development and its severity.

Study Limitations The main limitation of our study is its retrospective design. The scoring system used for the characterization of angiographic vasospasm is not a validated scale of vasospasm assessment on DSA, but, in our opinion, it gives an

R. JABBARLI ET AL.

1338

adequate idea about vasospasm extension in the entire intracranial vasculature. In addition, a relatively small and biased population (restriction to patients who had endovascular therapy) probably weakens the statistical value of analyzed data for some correlations and limits the applicability of our conclusions for a common SAH population. However, the main endpoint of our study was not the incidence of vasospasm as such, but the possible predictability of severity of cerebral vasospasm. For this reason, we have focused on this relatively small and homogenous population and have succeeded in defining a multiparametric characterization of the severity of cerebral vasospasm; earlier studies used only a single parameter.56 In conclusion, younger age and early onset of vasospasm on TCD ultrasound seem to be important predictors for vasospasm severity. We recommend early and aggressive therapy in this subgroup. Other factors, such as sex, Hunt and Hess or Fisher grades, and the modality of treatment did not reveal any prognostic value for the severity of vasospasm in our series.

12.

13.

14.

15.

16.

17.

18.

References 1. Zwienenberg-Lee M, Hartman J, Rudisill N, et al. Effect of prophylactic transluminal balloon angioplasty on cerebral vasospasm and outcome in patients with Fisher grade III subarachnoid hemorrhage: Results of a phase II multicenter, randomized, clinical trial. Stroke 2008; 39:1759-1765. 2. Keyrouz SG, Diringer MN. Clinical review: Prevention and therapy of vasospasm in subarachnoid hemorrhage. Crit Care 2007;11:220. 3. Allen GS, Ahn HS, Preziosi TJ, et al. Cerebral arterial spasm—A controlled trial of nimodipine in patients with subarachnoid hemorrhage. N Engl J Med 1983;308:619-624. 4. Kassell NF, Torner JC, Haley EC Jr, et al. The International Cooperative Study on the Timing of Aneurysm Surgery. Part 1: Overall management results. J Neurosurg 1990; 73:18-36. 5. Kassell NF, Torner JC, Jane JA, et al. The International Cooperative Study on the Timing of Aneurysm Surgery. Part 2: Surgical results. J Neurosurg 1990;73:37-47. 6. Mascia L, Fedorko L, terBrugge K, et al. The accuracy of transcranial Doppler to detect vasospasm in patients with aneurysmal subarachnoid hemorrhage. Intensive Care Med 2003;29:1088-1094. 7. Charpentier C, Audibert G, Guillemin F, et al. Multivariate analysis of predictors of cerebral vasospasm occurrence after aneurysmal subarachnoid hemorrhage. Stroke 1999; 30:1402-1408. 8. Rosen1rn J, Eskesen V, Schmidt K. Clinical features and outcome in females and males with ruptured intracranial saccular aneurysms. Br J Neurosurg 1993;7:287-290. 9. Rosenørn J, Eskesen VN, Schmidt K. Prognosis after ruptured intracranial aneurysm in men and women [in Danish]. Ugeskr Laeger 1994;156:4707-4709. 10. Ryttlefors M, Enblad P, Ronne-Engstrom E, et al. Patient age and vasospasm after subarachnoid hemorrhage. Neurosurgery 2010;67:911-917. 11. Risselada R, Lingsma HF, Molyneux AJ, et al. Prediction of two month modified Rankin Scale with an ordinal pre-

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

diction model in patients with aneurysmal subarachnoid haemorrhage. BMC Med Res Methodol 2010;10:86. Claassen J, Bernardini GL, Kreiter K, et al. Effect of cisternal and ventricular blood on risk of delayed cerebral ischemia after subarachnoid hemorrhage: The Fisher scale revisited. Stroke 2001;32:2012-2020. Dupont SA, Wijdicks EF, Manno EM, et al. Prediction of angiographic vasospasm after aneurysmal subarachnoid hemorrhage: Value of the Hijdra sum scoring system. Neurocrit Care 2009;11:172-176. Frontera JA, Claassen J, Schmidt JM, et al. Prediction of symptomatic vasospasm after subarachnoid hemorrhage: The modified Fisher scale. Neurosurgery 2006;59:21-27. Saqqur M, Zygun D, Demchuk A. Role of transcranial Doppler in neurocritical care. Crit Care Med 2007; 35(5 Suppl):S216-S223. Ionita CC, Baker J, Graffagnino C, et al. Timing of symptomatic vasospasm in aneurysmal subarachnoid hemorrhage: The effect of treatment modality and clinical implications. J Stroke Cerebrovasc Dis 2010;19:110-115. Kawabata Y, Horikawa F, Ueno Y, et al. Clinical predictors of delayed cerebral ischemia after subarachnoid hemorrhage: First experience with coil embolization in the management of ruptured cerebral aneurysms. J Neurointerv Surg 2011;3:344-347. Boecher-Schwarz HG, Ungersboeck K, Ulrich P, et al. Transcranial Doppler diagnosis of cerebral vasospasm following subarachnoid haemorrhage: Correlation and analysis of results in relation to the age of patients. Acta Neurochir (Wien) 1994;127:32-36. Clouston JE, Numaguchi Y, Zoarski GH, et al. Intraarterial papaverine infusion for cerebral vasospasm after subarachnoid hemorrhage. AJNR Am J Neuroradiol 1995; 16:27-38. Brisman JL, Eskridge JM, Newell DW. Neurointerventional treatment of vasospasm. Neurol Res 2006;28: 769-776. Kassell NF, Helm G, Simmons N, et al. Treatment of cerebral vasospasm with intra-arterial papaverine. J Neurosurg 1992;77:848-852. Mathis JM, Jensen ME, Dion JE. Technical considerations on intra-arterial papaverine hydrochloride for cerebral vasospasm. Neuroradiology 1997;39:90-98. Hunt WE, Hess RM. Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg 1968;28:14-20. Fisher CM, Kistler JP, Davis JM. Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery 1980;6:1-9. Etminan N, Vergouwen MD, Ilodigwe D, et al. Effect of pharmaceutical treatment on vasospasm, delayed cerebral ischemia, and clinical outcome in patients with aneurysmal subarachnoid hemorrhage: A systematic review and meta-analysis. J Cereb Blood Flow Metab 2011; 31:1443-1451. Vergouwen MD, Etminan N, Ilodigwe D, et al. Lower incidence of cerebral infarction correlates with improved functional outcome after aneurysmal subarachnoid hemorrhage. J Cereb Blood Flow Metab 2011;31: 1545-1553. Muroi C, Seule M, Mishima K, et al. Novel treatments for vasospasm after subarachnoid hemorrhage. Curr Opin Crit Care 2012;18:119-126. Nathal E, L oopez-Gonzalez F, Rios C. Angiographic scale for evaluation of cerebral vasospasm. Acta Neurochir Suppl 2008;104:225-228.

PREDICTORS OF VASOSPASM SEVERITY AFTER SAH 29. Yasargil MG. Microneurosurgery: Clinical considerations, surgery of the intracranial aneurysms and results. Leipzig, Germany: Georg Thieme Verlag, 1984. 30. Macdonald RL, Weir BK. Cerebral vasospasm. Waltham (MA): Academic Press, 2001. 31. Rabb CH, Tang G, Chin LS, et al. A statistical analysis of factors related to symptomatic cerebral vasospasm. Acta Neurochir (Wien) 1994;127:27-31. 32. Macdonald RL, Wallace MC, Coyne TJ. The effect of surgery on the severity of vasospasm. J Neurosurg 1994; 80:433-439. 33. Artiola i Fortuny L, Prieto-Valiente L. Long-term prognosis in surgically treated intracranial aneurysms. Part 2: Morbidity. J Neurosurg 1981;54:35-43. 34. Artiola i Fortuny L, Prieto-Valiente L. Long-term prognosis in surgically treated intracranial aneurysms. Part 1: Mortality. J Neurosurg 1981;54:26-34. 35. Inagawa T. Cerebral vasospasm in elderly patients with ruptured intracranial aneurysms. Surg Neurol 1991; 36:91-98. 36. Torbey MT, Hauser TK, Bhardwaj A, et al. Effect of age on cerebral blood flow velocity and incidence of vasospasm after aneurysmal subarachnoid hemorrhage. Stroke 2001; 32:2005-2011. 37. Hoh BL, Topcuoglu MA, Singhal AB, et al. Effect of clipping, craniotomy, or intravascular coiling on cerebral vasospasm and patient outcome after aneurysmal subarachnoid hemorrhage. Neurosurgery 2004;55:779-786. 38. Oka K, Kuromatsu C, Takaki T, et al. Therapeutic problems in aged patients with intracranial aneurysms [in Japanese]. No Shinkei Geka 1987;15:375-379. 39. Meyer JS, Terayama Y, Takashima S. Cerebral circulation in the elderly. Cerebrovasc Brain Metab Rev 1993;5:122-146. 40. Claus JJ, Breteler MM, Hasan D, et al. Regional cerebral blood flow and cerebrovascular risk factors in the elderly population. Neurobiol Aging 1998;19:57-64. 41. Magge SN, Chen HI, Ramakrishna R, et al. Association of a younger age with an increased risk of angiographic and symptomatic vasospasms following subarachnoid hemorrhage. J Neurosurg 2010;112:1208-1215. 42. Inagawa T. Cerebral vasospasm in elderly patients treated by early operation for ruptured intracranial aneurysms. Acta Neurochir (Wien) 1992;115:79-85. 43. Yin L, Ma CY, Li ZK, et al. Predictors analysis of symptomatic cerebral vasospasm after subarachnoid hemorrhage. Acta Neurochir Suppl 2011;110:175-178. 44. Ferch R, Pasqualin A, Pinna G, et al. Temporary arterial occlusion in the repair of ruptured intracranial aneurysms: An analysis of risk factors for stroke. J Neurosurg 2002;97:836-842. 45. Kongable GL, Lanzino G, Germanson TP, et al. Genderrelated differences in aneurysmal subarachnoid hemorrhage. J Neurosurg 1996;84:43-48. 46. Yousef K, Crago E, Kuo CW, et al. Predictors of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: A cardiac focus. Neurocrit Care 2010;13: 366-372. 47. Nakae R, Yokota H, Yoshida D, et al. Transcranial Doppler ultrasonography for diagnosis of cerebral vasospasm after aneurysmal subarachnoid hemorrhage: Mean blood flow velocity ratio of the ipsilateral and contralateral middle cerebral arteries. Neurosurgery 2011;69:876-883. 48. Park S, Lee C, Choe W, et al. Cerebral vasospasm after surgical clipping versus GDC embolization in ruptured intracranial aneurysm. J Korean Neurosurg Soc 2004; 36:218-223.

1339 49. Macdonald RL, Rosengart A, Huo D, et al. Factors associated with the development of vasospasm after planned surgical treatment of aneurysmal subarachnoid hemorrhage. J Neurosurg 2003;99:644-652. 50. Teasdale GM, Drake CG, Hunt W, et al. A universal subarachnoid hemorrhage scale: Report of a committee of the World Federation of Neurosurgical Societies. J Neurol Neurosurg Psychiatry 1988;51:1457. 51. Hijdra A, van Gijn J, Nagelkerke NJ, et al. Prediction of delayed cerebral ischemia, rebleeding, and outcome after aneurysmal subarachnoid hemorrhage. Stroke 1988;19: 1250-1256. 52. Brouwers PJ, Dippel DW, Vermeulen M, et al. Amount of blood on computed tomography as an independent predictor after aneurysm rupture. Stroke 1993;24:809-814. 53. Forssell A, Larsson C, Ronnberg J, et al. CT assessment of subarachnoid haemorrhage. A comparison between different CT methods of grading subarachnoid haemorrhage. Br J Neurosurg 1995;9:21-27. 54. Reilly C, Amidei C, Tolentino J, et al. Clot volume and clearance rate as independent predictors of vasospasm after aneurysmal subarachnoid hemorrhage. J Neurosurg 2004;101:255-261. 55. Smith ML, Abrahams JM, Chandela S, et al. Subarachnoid hemorrhage on computed tomography scanning and the development of cerebral vasospasm: The Fisher grade revisited. Surg Neurol 2005;63:229-234. 56. Schaller C, Rohde V, Meyer B, et al. Amount of subarachnoid blood and vasospasm: Current aspects. A transcranial Doppler study. Acta Neurochir (Wien) 1995;136: 67-71. 57. van Gijn J, Hijdra A, Wijdicks EF, et al. Acute hydrocephalus after aneurysmal subarachnoid hemorrhage. J Neurosurg 1985;63:355-362. 58. Adams HP Jr, Kassell NF, Torner JC, et al. Predicting cerebral ischemia after aneurysmal subarachnoid hemorrhage: Influences of clinical condition, CT results, and antifibrinolytic therapy. A report of the Cooperative Aneurysm Study. Neurology 1987;37:1586-1591. 59. Qureshi AI, Sung GY, Razumovsky AY, et al. Early identification of patients at risk for symptomatic vasospasm after aneurysmal subarachnoid hemorrhage. Crit Care Med 2000;28:984-990. 60. Black PM. Hydrocephalus and vasospasm after subarachnoid hemorrhage from ruptured intracranial aneurysms. Neurosurgery 1986;18:12-16. 61. de Oliveira JG, Beck J, Setzer M, et al. Risk of shuntdependent hydrocephalus after occlusion of ruptured intracranial aneurysms by surgical clipping or endovascular coiling: A single-institution series and metaanalysis. Neurosurgery 2007;61:924-933. 62. Tanaka A, Kimura M, Nakayama Y, et al. Cerebral blood flow and autoregulation in normal pressure hydrocephalus. Neurosurgery 1997;40:1161-1165. 63. Del Bigio MR. Neuropathological changes caused by hydrocephalus. Acta Neuropathol 1993;85:573-585. 64. van Asch CJ, van der Schaaf IC, Rinkel GJ. Acute hydrocephalus and cerebral perfusion after aneurysmal subarachnoid hemorrhage. AJNR Am J Neuroradiol 2010; 31:67-70. 65. Farrell B, Godwin J, Richards S, et al. The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: Final results. J Neurol Neurosurg Psychiatry 1991;54: 1044-1054. 66. Rankin J. Cerebral vascular accidents in patients over the age of 60. II. Prognosis. Scott Med J 1957;2:200-215.