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High-Grade Aneurysmal Subarachnoid Hemorrhage: Predictors of Functional Outcome
Original Article
High-Grade Aneurysmal Subarachnoid Hemorrhage: Predictors of Functional Outcome Natasha Ironside1, Thomas J. Buell2, Ching-Jen Chen2, Jeyan S. Kumar2, Gabriella M. Paisan3, Jennifer D. Sokolowski2, Kenneth C. Liu4, Dale Ding5
BACKGROUND: Because the prognosis of high-grade aneurysmal subarachnoid hemorrhage (aSAH), classified as World Federation of Neurosurgical Societies (WFNS) grade IVeV, is generally poor, the functional outcomes of survivors have not been thoroughly explored. The aim of this retrospective cohort study is to determine predictors of functional independence in patients who survive a highgrade aSAH.
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METHODS: We retrospectively evaluated consecutive patients with aSAH admitted to a single institution from January 2000 to April 2015. Adult (age ‡18 years) patients with WFNS grade IVeV aSAH were included for analysis. Patients without sufficient baseline data, those who died before discharge, and those without follow-up data were excluded. Univariable and multivariable logistic regression analyses were used to identify factors associated with functional independence, defined as a modified Rankin Scale score of 0e2, at last follow-up.
predictor of functional independence in the multivariable analysis (odds ratio 0.28 [0.109e0.722]; P [ 0.008). CONCLUSIONS: Because functional independence can be achieved in the majority of high-grade aSAH survivors, aggressive initial management of high-grade aSAH is warranted. Strategies that reduce the need for permanent cerebrospinal fluid diversion may improve functional outcomes in survivors of high-grade aSAH.
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RESULTS: Of the 260 patients with a WFNS grade IVeV aSAH during the study period, 139 met the inclusion criteria. After a mean follow-up of 6.3 months, functional independence was achieved in 73% of high-grade aSAH survivors (101/139 patients) and in 39% of all high-grade aSAH cases (101/260 patients). Only a lack of cerebrospinal fluid shunt placement was found to be an independent
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Key words Aneurysm - Bleed - Morbidity - Mortality - Outcome - Severe - Subarachnoid hemorrhage -
Abbreviations and Acronyms aSAH: Aneurysmal subarachnoid hemorrhage CI: Confidence interval CSF: Cerebrospinal fluid EVD: External ventricular drain GCS: Glasgow Coma Scale HH: Hunt-Hess IVH: Intraventricular hemorrhage mRS: modified Rankin Scale
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INTRODUCTION
A
neurysmal subarachnoid hemorrhage (aSAH) has an estimated incidence of 9.1 cases per 100,000 person-years worldwide.1,2 Despite declining case-fatality rates, aSAH continues cause significant neurologic morbidity and functional disability.2-4 The severity of the initial clinical presentation is the strongest prognostic indicator of long-term outcomes after aSAH.5 As a result, clinically based risk prediction scores, including the HunteHess (HH) and World Federation of Neurosurgical Societies (WFNS) grading scales, often are used to guide management decisions.6-8 Approximately 20%e30% of patients with ruptured aneurysms present with a high-grade aSAH, defined as HH or WFNS grades IV or V, and the optimal treatment paradigm for these cases remains unclear.9,10
OR: Odds ratio WFNS: World Federation of Neurosurgical Societies From the 1Department of Neurosurgery, NewYork-Presbyterian/Columbia University Medical Center, New York, New York; 2Department of Neurological Surgery, University of Virginia, Charlottesville, Virginia; 3Department of Neurological Surgery, Barrow Neurological Institute, Phoenix, Arizona; 4Department of Neurosurgery, Milton S. Hershey Medical Center, Hershey, Pennsylvania; and 5Department of Neurosurgery, University of Louisville, Louisville, Kentucky, USA To whom correspondence should be addressed: Dale Ding, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2019). https://doi.org/10.1016/j.wneu.2019.01.162 Journal homepage: www.journals.elsevier.com/world-neurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
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FUNCTIONAL OUTCOME PREDICTORS IN HIGH-GRADE ASAH
Because of the historically reported high mortality rates and poor neurologic outcomes after high-grade aSAH, the conventional stance toward the management of these patients has been relatively conservative. However, early aggressive management of high-grade aSAH has been shown to afford a reasonable long-term prognosis to some patients.9-16 Although aSAH management continues to evolve, our current understanding of factors that influence functional outcomes in patients who survive a high-grade aSAH is limited. Therefore, the aims of this single-center, retrospective cohort study are to 1) determine the interim functional outcomes of high-grade aSAH, and 2) identify predictors of functional independence in high-grade aSAH survivors. METHODS Study Design We retrospective evaluated an institutional database comprising consecutive patients with aSAH who presented to the University of Virginia between January 2000 and April 2015. This study was approved by the University of Virginia institutional review board and due to its retrospective design and data de-identification, patient consent was deemed unnecessary by the institutional review board. Patient Identification and Selection The diagnosis of SAH was based on computed tomography of the brain, magnetic resonance imaging of the brain, or the presence of cerebrospinal fluid (CSF) xanthochromia on lumbar puncture. The inclusion criteria for this study were as follows: 1) age 18 years; 2) a ruptured intracranial aneurysm as the source of SAH, based on catheter digital subtraction angiography5; 3) WFNS grade IV or V aSAH; and 4) available data regarding functional outcome following discharge from the acute hospitalization for aSAH. Patients who died during their initial hospitalization were excluded. Baseline and Initial Hospitalization Data We performed a directed review of each patient’s medical charts and neuroimaging to obtain the following baseline variables: age, sex, admission Glasgow Coma Scale (GCS) score, Fisher grade, HH grade, admission WFNS grade, aneurysm location (categorized as anterior vs. posterior circulation), aneurysm size (defined as maximum diameter), treatment modality (categorized as surgical, endovascular, or no treatment), presence of multiple aneurysms, presence of intraventricular hemorrhage (IVH), acute hydrocephalus at presentation, occurrence of angiographic cerebral vasospasm, external ventricular drain (EVD) insertion, CSF shunt placement, and follow-up duration.6,8,17 All patients with aSAH received standard-of-care management in accordance with the American Heart Association/American Stroke Association guidelines.5 Treatment of the aneurysm (surgical clipping or endovascular embolization) was decided by multidisciplinary consensus, and it was based on the aneurysm characteristics in conjunction with the neurological and clinical status of the patient. Routine surveillance for radiographic evidence of vasospasm, defined as 33% reduction in arterial diameter, was performed using computed tomography
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angiography or catheter digital subtraction angiography. Symptomatic vasospasm, defined as a focal neurologic deficit or 2-point decrease in GCS in the context of radiographic vasospasm, was treated with hypertensive-hypervolemic and/or endovascular therapy.18,19 Placement of an EVD was performed in patients with acute hydrocephalus. Persistence of symptomatic post-aSAH hydrocephalus was managed by permanent CSF diversion with shunt placement. Follow-up The primary outcome was functional independence, defined as a modified Rankin Scale (mRS) score of 0e2 (0 ¼ no symptoms at all; 1 ¼ no significant disability despite symptoms and able to carry out all usual duties and activities; 2 ¼ slight disability and unable to carry out all previous activities, but able to look after own affairs without assistance). Functional outcomes were assessed using inpatient and outpatient records obtained from our institution, referring institutions, and local primary care physicians. Functional outcome was recorded at the time of last follow-up. Statistical Analysis Statistical analyses were performed using SPSS Statistics (Version 24.0; IBM SPSS Corp., Armonk, New York, USA). Univariable comparisons of baseline data, dichotomized by the primary outcome measure, were performed using Pearson c2 test, Fisher exact test, or Student t test, as appropriate. Potential predictor variables (P 0.10) were entered into a multivariable logistic regression model, with the primary outcome as the dependent variable, to identify independent predictors. The odds ratio (OR), 95% confidence interval (CI), and P values were reported for each covariate in the multivariable model. The multivariable analysis had at least 10 participants per independent variable, which is the minimum number required for a stable multivariable logistic regression model.20 The model was assessed for goodness-of-fit using the HosmereLemeshow test.20 Statistical significance was defined as P < 0.05, and all tests were 2-tailed. Missing data was not imputed. RESULTS Baseline Characteristics of the Study Cohort Of the 888 consecutive patients with aSAH admitted to our institution between January 2000 and April 2015, 589 (66%) were WFNS grade IeIII, 260 (29.3%) were WFNS grade IVeV, and 39 (4.4%) did not have sufficient data to determine the WFNS grade. Of the 260 patients diagnosed as having WFNS grade IVeV aSAH, 121 were excluded from the present study (81 patients for death or withdrawal of care during hospitalization and 40 patients for insufficient follow-up outcomes data). The study cohort comprised 139 (53.5%) who met the inclusion criteria, including 83 (59.7%) WFNS grade IV and 56 (40.3%) WNFS grade V patients. The mean and median follow-up duration was 21.3 30.9 months and 4 [2e28] months, respectively. The mean age was 54.5 12.8 years, and 68.4% (n ¼ 95/139 patients) were female. The median GCS, HH grade, and Fisher grade at initial presentation were 7 [3e12], 4 [2e6], and 4 [4e4], respectively. Aneurysms were located in the posterior circulation in 16.6% (n ¼ 23/139 patients),
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FUNCTIONAL OUTCOME PREDICTORS IN HIGH-GRADE ASAH
the mean aneurysm diameter was 6.9 4.4 mm and 30.2% (n ¼ 42/139 patients) had multiple aneurysms. The aneurysm treatment modality was surgical in 46.8% (n ¼ 65/139 patients) and endovascular in 51.1% (n ¼ 71/139 patients). Aneurysm treatment was not performed in 2.2% (n ¼ 3/139 patients). IVH and acute hydrocephalus were present in 94.2% (n ¼ 131/139 patients) and 84.9% (n ¼ 118/139 patients), respectively, and an EVD was placed in 58.3% (n ¼ 81/139 patients). CSF shunt placement was performed in 39.6% (n ¼ 55/139 patients). CSF shunt placement was performed during the initial hospitalization in 54.5% (n ¼ 30/55 patients) and after discharge in 45.4% (n ¼ 25/55
patients). Of the 30 patients who had shunt placed after discharge, the mean time to shunt placement was 2.73 3.94 months. Functional Outcomes At last follow-up, mRS score was 0 in 34 (24.4%) patients, 1 in 38 (27.3%), 2 in 29 (20.9%), 3 in 7 (5.0%), 4 in 9 (6.5%), 5 in 19 (13.7%), and 6 in 3 (2.2%). Functional independence (mRS 0e2) was achieved in 72.7% of survivors of high-grade aSAH (n ¼ 101/139 patients) and in 38.8% of all cases of high-grade aSAH (101/260 patients). Table 1 compares the demographic, clinical, aneurysm, and treatment characteristics of patients with
Table 1. Comparison of Demographic, Clinical, Aneurysm, and Treatment Characteristics of Patients with High-Grade aSAH with mRS Score 0e2 Versus 3e6 at Follow-Up mRS 0e2 (n [ 101)
mRS 3e6 (n [ 38)
P Value*
53.1 12.08
58.1 14.2
0.043
70 (69.3)
25 (65.8)
0.691 (c2 ¼ 0.158)
GCS,y median [IQR]
8 [3e12]
7 [3e12]
0.125
HunteHess grade,y median [IQR]
4 [2e6]
4 [3e5]
0.089
Fisher grade,y median [IQR]
4 [4e4]
4 [4e4]
0.152
Variable Demographics Age, years, mean SD Female, n (%) Clinical characteristics
Intraventricular hemorrhage, n (%)
93 (92.1)
38 (100)
0.107
Acute hydrocephalus, n (%)
81 (80.2)
37 (97.4)
0.012 (c2 [ 6.347)
Vasospasm, n (%)
63 (62.4)
27 (71.1)
0.340 (c2 ¼ 0.911)
Posterior circulation location, n (%)
15 (14.9)
8 (21.1)
0.381 (c2 ¼ 0.769)
Maximum diameter, mm, mean SD
6.9 4.1
6.9 5.0
0.955
Multiple aneurysms, n (%)
31 (30.7)
11 (29.0)
0.842 (c2 ¼ 0.040)
Aneurysm characteristics
Aneurysm treatment, n (%)
0.591
Surgical clipping
45 (44.5)
20 (52.6)
Endovascular coiling
54 (53.5)
17 (44.7)
2 (2.0)
1 (2.6)
49 (48.5)
32 (84.2)
No treatment Additional interventions EVD, n (%) CSF shunt, n (%) Follow-up duration, months, mean SD Vasospasm, n (%)
<0.001
28 (27.7)
27 (71.1)
<0.001
26.6 30.9
10.3 17.3
<0.001
63 (62.4)
27 (71.1)
0.340 (c2 ¼ 0.911)
The values in bold are statistically significant (P < 0.05). aSAH, aneurysmal subarachnoid hemorrhage; mRS, modified Rankin Scale; SD, standard deviation; GCS, Glasgow Coma Scale score; IQR, interquartile range; EVD, external ventricular drain; CSF, cerebrospinal fluid. 2 *Patients were dichotomized by mRS score. Groups were compared using the Pearson c test, Fisher exact test, or Student t test. yDetermined at the time of hospital admission.
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FUNCTIONAL OUTCOME PREDICTORS IN HIGH-GRADE ASAH
Table 2. Multivariable Model for Predictors of Functional Independence (mRS 0e2) in Patients with High-Grade aSAH Variable
Odds Ratio
95% CI
P Value
Age
0.976
0.945e1.009
0.152
HunteHess grade
0.810
0.463e1.415
0.459
Acute hydrocephalus
0.407
0.046e3.612
0.420
EVD
0.430
0.141e1.309
0.137
CSF shunt
0.281
0.109e0.722
0.008
The value in bold is statistically significant (P < 0.05). mRS, modified Rankin Scale; aSAH, aneurysmal subarachnoid hemorrhage; CI, confidence interval; EVD, external ventricular drain; CSF, cerebrospinal fluid.
high-grade aSAH with an mRS score 0e2 versus 3e6 at follow-up. Patients with mRS score 0e2 were younger (mean age 53 vs. 58 years; P ¼ 0.043), less likely to have acute hydrocephalus (80% vs. 97%; P ¼ 0.012), less likely to undergo EVD insertion (49% vs. 84%; P < 0.001), and less likely to undergo CSF shunt placement (28% vs. 71%; P < 0.001). Patients with mRS 0e2 also had a longer follow-up duration (mean 27 vs. 10 months; P < 0.001).
Predictors of Functional Independence Table 2 summarizes the multivariable logistic regression analysis for predictors of functional independence. Age, admission HH grade, acute hydrocephalus at presentation, EVD insertion, and CSF shunt placement were the covariates that were included in the multivariable model. Only the lack of CSF shunt placement was found to be an independent predictor of functional independence (OR 0.28, 95% CI 0.109e0.722; P ¼ 0.008).
DISCUSSION Admission neurologic condition, often classified by the HH or WFNS grade, is a well-established predictor of follow-up outcomes in patients with aSAH.7 High-grade (i.e., HH or WFNS grade IVeV) aSAH often has been associated with a poor prognosis, and the reported rates of functional independence and mortality for these patients range from 5%e43% and 43%e87%, respectively.14-16,21,22 However, in recent years, considerable improvement in the outcome of patients with high-grade aSAH has been observed, with contemporary series reporting rates of functional independence and mortality of 30%e57% and 28%e36%, respectively.9,12,18,23-25 These improved results have been attributed to early aggressive resuscitation, the increasing use of endovascular techniques for aneurysm occlusion, and targeted postoperative neurologic intensive care.21,24,26-28 Consequently, the possibility of patient selection bias associated with the early prognostication of a poor outcome has been proposed.29 Nevertheless, a substantial proportion of patients with high-grade aSAH die during the initial hospitalization or are designated for comfort care (e.g., discharged to hospice) due to a lack of meaningful recovery. Therefore, our current understanding of outcome predictors in high-grade aSAH survivors is limited.
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In this single-center retrospective cohort study, we found 73% of patients with high-grade aSAH who survived the acute hospitalization were functionally independent (mRS 0e2) at last followup (mean duration 21.3 months). Although the proportion of functionally independent patients with high-grade aSAH appears to be unusually high at first glance, when one considers the total number of consecutive high-grade aSAH hospitalized during the study period, the adjusted functional independence rate of 39% is consistent with recent reports. Chua et al.29 analyzed a cohort of 247 HH grade IVeV patients who underwent aneurysm treatment between 1998 and 2013, and they reported a 23% increase in the rate of functional independence (defined as Glasgow Outcome Scale score of 4 or 5) for patients treated between 2007 and 2013 versus 1998 and 2003. Despite this, the rate of functional independence in the latter period of 2007e2013 was modest (45%), between 2007 and 2013.29 In A Multicenter Prospective Study of Poor Grade Aneurysmal Subarachnoid Hemorrhage (AMPAS), 51% of the patients with WFNS IVeV aSAH who underwent endovascular aneurysm treatment between 2010 and 2012 were functionally independent (mRS 0e2) at 12 months’ follow-up.24 Comparison between WFNS grade IV versus V patients revealed a significantly greater likelihood of functional independence in those with a WFNS grade IV aSAH (65% vs. 27%; P < 0.001), which suggests that subclassification of patients with high-grade aSAH may be clinically relevant.24 Han et al.30 performed a pooled meta-analysis of 806 patients with HH or WFNS IVeV aSAH who underwent ultraearly treatment (i.e., within 24 hours of hemorrhage onset) and they reported an overall rate of favorable functional outcome (mRS score 0e2 or Glasgow Outcome Scale score >3) of 47% (95% CI 40%e54%). Although ultra-early treatment may afford the potential benefits of reduced re-bleeding and early intracranial pressure control, a comparison between those undergoing ultraearly treatment to matched controls did not reveal a significant difference in the likelihood of achieving a favorable outcome (OR 1.23, 95% CI 0.75e2.02; P ¼ 0.40).11,30 Therefore, the benefit of aneurysm treatment within 24 hours remains unproven for patients with high-grade aSAH. Nevertheless, our institutional preference is to treat all ruptured aneurysms within 24 hours of admission, unless the patient is hemodynamically unstable or medically unfit for general anesthesia. Previous authors have identified older age, larger aneurysm size, ICH, and non-middle cerebral artery aneurysms to be independent predictors of poor functional outcome among patients with highgrade aSAH.26,31-34 In our cohort, we also found that older patients were less likely to be functionally independent at follow-up, although the aneurysm size and location were similar between those with mRS 0e2 versus 3e6. Only a lack of CSF shunt placement was found to be an independent predictor of functional independence. This suggests that strategies aimed at minimizing the incidence of shunt-dependent hydrocephalus and its associated complications may improve the likelihood of functional independence in patients with high-grade aSAH. In cohort of 60 patients with poor-grade aSAH, 55 (95%) of whom did not receive aneurysm treatment, Nieuwkamp et al.35 observed a mortality rate of 93% 2e4 months after aSAH. Goldberg et al.,36 in a cohort of elderly patients with high-grade aSAH, found early aggressive treatment to be associated with improved favorable outcomes at 6e12 months after
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FUNCTIONAL OUTCOME PREDICTORS IN HIGH-GRADE ASAH
aSAH. Early cerebral infarction after aSAH has been significantly correlated with poor functional outcome.37 Therefore, in addition to early aggressive resuscitation and definitive treatment of the aneurysm, targeting modifiable predictors of perioperative cerebral infarction, including the duration of intraoperative arterial occlusion and admission plasma glucose, may improve outcomes in patients with high-grade aSAH.37-39 Acute hydrocephalus in aSAH, resulting from an abrupt impairment of CSF flow at the ictus of aneurysm rupture, has been established as an important risk factor for shunt-dependent hydrocephalus.40-42 However, the mechanisms that underlie the transition between the acute obstructive and chronic communicating phases of post-aSAH hydrocephalus have yet to be fully elucidated.43 Although this has limited the identification of effective prevention strategies, nosocomial meningitis, which is associated with CSF flow disturbances and ependymal cell dysfunction, remains a modifiable risk factor for chronic hydrocephalus.44-46 In a previous study from our institution, shunt infection was found to be the strongest independent predictor of poor outcome (mRS 3e6) in patients with aSAH with shunt-dependent hydrocephalus.47 Therefore, among patients with high-grade aSAH, who are more prone to systemic complications and iatrogenic infections, strategies that minimize the risk of ventriculitis may reduce the likelihood of shunt dependency and shunt-related complications.47-49 The fact that greater WFNS grade has been associated with an increased risk of shunt-related complications further underscores the importance of targeting modifiable risk factors for shunt dependency in patients with high-grade aSAH.47 Our study has several limitations that affect the generalizability of our findings. The retrospective nature of our analysis is subject to confirmation bias in that variables were chosen based on data availability and hypothesis generation. Specifically, data regarding premorbid functional status, presence of associated IVH or intracerebral hemorrhage, change in neurologic grade, rebleeding rate, intracranial pressure characteristics, and timing of aneurysm treatment were not available for analysis. Additional limitations associated with our retrospective study design include
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reporting, recall and missing data biases due to the conditional nature of our results on the accuracy of recorded data. The presence of a selection bias is suggested by the significant differences in the duration of follow-up between the mRS 0e2 versus 3e6 groups. The documentation of admission WFNS grade, which does not account for clinical improvement after the initial resuscitation, may have contributed to the high observed rates of favorable outcome in our study population. We are also unable to ascertain the long-term outcome of highgrade aSAH, due to the modest overall follow-up duration of the study cohort. Because our data are derived from a single center, this study is subject to the treatment and referral biases of the institution. Furthermore, we were unable to account for changes in our institution’s management paradigms, advances in microsurgical and endovascular techniques and technologies, and improvements in operator experience over the 15-year time period from which the data were collected. Finally, it is important to emphasize that our findings are only relevant to patients who survive the initial hospitalization for aSAH, and as such, they should not be improperly generalized to all patients with a highgrade aSAH. CONCLUSIONS Functional independence can be achieved in the majority of patients with a high-grade aSAH who survive the acute hospitalization. Therefore, aggressive initial management of high-grade aSAH appears to be warranted, which contrasts with the historical perception that the prognosis of these patients is frequently dismal. The necessity for CSF shunt placement was the sole independent predictor of functional outcome in our study cohort, and it was associated with a lower likelihood of functional independence. Therefore, clinical improvement after the initial resuscitation is likely to be an important prognostic indicator in patients with high-grade aSAH. As such, strategies that reduce the likelihood of chronic hydrocephalus and minimize shunt-related complications may improve functional outcomes in high-grade aSAH survivors.
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FUNCTIONAL OUTCOME PREDICTORS IN HIGH-GRADE ASAH
27. Sandstrom N, Yan B, Dowling R, Laidlaw J, Mitchell P. Comparison of microsurgery and endovascular treatment on clinical outcome following poor-grade subarachnoid hemorrhage. J Clin Neurosci. 2013;20:1213-1218. 28. Komotar RJ, Schmidt JM, Starke RM, et al. Resuscitation and critical care of poor-grade subarachnoid hemorrhage. Neurosurgery. 2009;64: 397-410 [discussion: 410-411]. 29. Chua MH, Griessenauer CJ, Stapleton CJ, He L, Thomas AJ, Ogilvy CS. Documentation of improved outcomes for intracranial aneurysm management over a 15-year interval. Stroke. 2016; 47:708-712. 30. Han Y, Ye F, Long X, et al. Ultra-early treatment for poor-grade aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. World Neurosurg. 2018;115:e160-e171. 31. Schuss P, Hadjiathanasiou A, Borger V, Wispel C, Vatter H, Guresir E. Poor-grade aneurysmal subarachnoid hemorrhage: factors influencing functional outcome—a single-center series. World Neurosurg. 2016;85:125-129. 32. Mocco J, Ransom ER, Komotar RJ, et al. Preoperative prediction of long-term outcome in poorgrade aneurysmal subarachnoid hemorrhage. Neurosurgery. 2006;59:529-538 [discussion: 529538]. 33. Le Roux PD, Elliott JP, Newell DW, Grady MS, Winn HR. Predicting outcome in poor-grade patients with subarachnoid hemorrhage: a retrospective review of 159 aggressively managed cases. J Neurosurg. 1996;85:39-49. 34. Shirao S, Yoneda H, Kunitsugu I, et al. Preoperative prediction of outcome in 283 poor-grade patients with subarachnoid hemorrhage: a project of the Chugoku-Shikoku Division of the Japan Neurosurgical Society. Cerebrovasc Dis. 2010;30: 105-113. 35. Nieuwkamp DJ, Rinkel GJ, Silva R, Greebe P, Schokking DA, Ferro JM. Subarachnoid haemorrhage in patients > or ¼ 75 years: clinical course, treatment and outcome. J Neurol Neurosurg Psychiatry. 2006;77:933-937. 36. Goldberg J, Schoeni D, Mordasini P, et al. Survival and outcome after poor-grade aneurysmal subarachnoid hemorrhage in elderly patients. Stroke. 2018;49:2883-2889. 37. Juvela S, Siironen J. Early cerebral infarction as a risk factor for poor outcome after aneurysmal subarachnoid haemorrhage. Eur J Neurol. 2012;19: 332-339.
of poor outcome after aneurysmal subarachnoid hemorrhage. J Neurosurg. 2007;107:1080-1085. 40. Kanat A. Pathophysiology of acute hydrocephalus after subarachnoid hemorrhage. World Neurosurg. 2014;82:e386-387. 41. Okubo S, Strahle J, Keep RF, Hua Y, Xi G. Subarachnoid hemorrhage-induced hydrocephalus in rats. Stroke. 2013;44:547-550. 42. Kibler RF, Couch RS, Crompton MR. Hydrocephalus in the adult following spontaneous subarachnoid haemorrhage. Brain. 1961;84:45-61. 43. Sugawara T, Maehara T, Nariai T, Aoyagi M, Ohno K. Independent predictors of shuntdependent normal pressure hydrocephalus after aneurysmal subarachnoid hemorrhage. J Neurosurg Sci. 2016;60:154-158. 44. Rincon F, Gordon E, Starke RM, et al. Predictors of long-term shunt-dependent hydrocephalus after aneurysmal subarachnoid hemorrhage. Clinical article. J Neurosurg. 2010;113:774-780. 45. Yu H, Zhan R, Wen L, Shen J, Fan Z. The relationship between risk factors and prognostic factors in patients with shunt-dependent hydrocephalus after aneurysmal subarachnoid hemorrhage. J Craniofac Surg. 2014;25:902-906. 46. Xie Z, Hu X, Zan X, Lin S, Li H, You C. Predictors of shunt-dependent hydrocephalus after aneurysmal subarachnoid hemorrhage? A systematic review and meta-analysis. World Neurosurg. 2017; 106:844-860.e846. 47. Paisan GM, Ding D, Starke RM, Crowley RW, Liu KC. Shunt-dependent hydrocephalus after aneurysmal subarachnoid hemorrhage: predictors and long-term functional outcomes. Neurosurgery. 2018;83:393-402. 48. Little AS, Zabramski JM, Peterson M, et al. Ventriculoperitoneal shunting after aneurysmal subarachnoid hemorrhage: analysis of the indications, complications, and outcome with a focus on patients with borderline ventriculomegaly. Neurosurgery. 2008;62:618-627 [discussion: 618-627]. 49. Wartenberg KE, Schmidt JM, Claassen J, et al. Impact of medical complications on outcome after subarachnoid hemorrhage. Crit Care Med. 2006; 34:617-623. quiz 624. 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 29 October 2018; accepted 19 January 2019
25. Wartenberg KE. Critical care of poor-grade subarachnoid hemorrhage. Curr Opin Crit Care. 2011;17: 85-93. 26. van den Berg R, Foumani M, Schroder RD, et al. Predictors of outcome in World Federation of Neurologic Surgeons grade V aneurysmal subarachnoid hemorrhage patients. Crit Care Med. 2011;39:2722-2727.
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38. Juvela S, Siironen J, Kuhmonen J. Hyperglycemia, excess weight, and history of hypertension as risk factors for poor outcome and cerebral infarction after aneurysmal subarachnoid hemorrhage. J Neurosurg. 2005;102:998-1003. 39. McGirt MJ, Woodworth GF, Ali M, Than KD, Tamargo RJ, Clatterbuck RE. Persistent perioperative hyperglycemia as an independent predictor
Citation: World Neurosurg. (2019). https://doi.org/10.1016/j.wneu.2019.01.162 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2019.01.162
High-Grade Aneurysmal Subarachnoid Hemorrhage: Predictors of Functional Outcome Natasha Ironside1, Thomas J. Buell2, Ching-Jen Chen2, Jeyan S. Kumar2, Gabriella M. Paisan3, Jennifer D. Sokolowski2, Kenneth C. Liu4, Dale Ding5
BACKGROUND: Because the prognosis of high-grade aneurysmal subarachnoid hemorrhage (aSAH), classified as World Federation of Neurosurgical Societies (WFNS) grade IVeV, is generally poor, the functional outcomes of survivors have not been thoroughly explored. The aim of this retrospective cohort study is to determine predictors of functional independence in patients who survive a highgrade aSAH.
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METHODS: We retrospectively evaluated consecutive patients with aSAH admitted to a single institution from January 2000 to April 2015. Adult (age ‡18 years) patients with WFNS grade IVeV aSAH were included for analysis. Patients without sufficient baseline data, those who died before discharge, and those without follow-up data were excluded. Univariable and multivariable logistic regression analyses were used to identify factors associated with functional independence, defined as a modified Rankin Scale score of 0e2, at last follow-up.
predictor of functional independence in the multivariable analysis (odds ratio 0.28 [0.109e0.722]; P [ 0.008). CONCLUSIONS: Because functional independence can be achieved in the majority of high-grade aSAH survivors, aggressive initial management of high-grade aSAH is warranted. Strategies that reduce the need for permanent cerebrospinal fluid diversion may improve functional outcomes in survivors of high-grade aSAH.
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RESULTS: Of the 260 patients with a WFNS grade IVeV aSAH during the study period, 139 met the inclusion criteria. After a mean follow-up of 6.3 months, functional independence was achieved in 73% of high-grade aSAH survivors (101/139 patients) and in 39% of all high-grade aSAH cases (101/260 patients). Only a lack of cerebrospinal fluid shunt placement was found to be an independent
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Key words Aneurysm - Bleed - Morbidity - Mortality - Outcome - Severe - Subarachnoid hemorrhage -
Abbreviations and Acronyms aSAH: Aneurysmal subarachnoid hemorrhage CI: Confidence interval CSF: Cerebrospinal fluid EVD: External ventricular drain GCS: Glasgow Coma Scale HH: Hunt-Hess IVH: Intraventricular hemorrhage mRS: modified Rankin Scale
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INTRODUCTION
A
neurysmal subarachnoid hemorrhage (aSAH) has an estimated incidence of 9.1 cases per 100,000 person-years worldwide.1,2 Despite declining case-fatality rates, aSAH continues cause significant neurologic morbidity and functional disability.2-4 The severity of the initial clinical presentation is the strongest prognostic indicator of long-term outcomes after aSAH.5 As a result, clinically based risk prediction scores, including the HunteHess (HH) and World Federation of Neurosurgical Societies (WFNS) grading scales, often are used to guide management decisions.6-8 Approximately 20%e30% of patients with ruptured aneurysms present with a high-grade aSAH, defined as HH or WFNS grades IV or V, and the optimal treatment paradigm for these cases remains unclear.9,10
OR: Odds ratio WFNS: World Federation of Neurosurgical Societies From the 1Department of Neurosurgery, NewYork-Presbyterian/Columbia University Medical Center, New York, New York; 2Department of Neurological Surgery, University of Virginia, Charlottesville, Virginia; 3Department of Neurological Surgery, Barrow Neurological Institute, Phoenix, Arizona; 4Department of Neurosurgery, Milton S. Hershey Medical Center, Hershey, Pennsylvania; and 5Department of Neurosurgery, University of Louisville, Louisville, Kentucky, USA To whom correspondence should be addressed: Dale Ding, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2019). https://doi.org/10.1016/j.wneu.2019.01.162 Journal homepage: www.journals.elsevier.com/world-neurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
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FUNCTIONAL OUTCOME PREDICTORS IN HIGH-GRADE ASAH
Because of the historically reported high mortality rates and poor neurologic outcomes after high-grade aSAH, the conventional stance toward the management of these patients has been relatively conservative. However, early aggressive management of high-grade aSAH has been shown to afford a reasonable long-term prognosis to some patients.9-16 Although aSAH management continues to evolve, our current understanding of factors that influence functional outcomes in patients who survive a high-grade aSAH is limited. Therefore, the aims of this single-center, retrospective cohort study are to 1) determine the interim functional outcomes of high-grade aSAH, and 2) identify predictors of functional independence in high-grade aSAH survivors. METHODS Study Design We retrospective evaluated an institutional database comprising consecutive patients with aSAH who presented to the University of Virginia between January 2000 and April 2015. This study was approved by the University of Virginia institutional review board and due to its retrospective design and data de-identification, patient consent was deemed unnecessary by the institutional review board. Patient Identification and Selection The diagnosis of SAH was based on computed tomography of the brain, magnetic resonance imaging of the brain, or the presence of cerebrospinal fluid (CSF) xanthochromia on lumbar puncture. The inclusion criteria for this study were as follows: 1) age 18 years; 2) a ruptured intracranial aneurysm as the source of SAH, based on catheter digital subtraction angiography5; 3) WFNS grade IV or V aSAH; and 4) available data regarding functional outcome following discharge from the acute hospitalization for aSAH. Patients who died during their initial hospitalization were excluded. Baseline and Initial Hospitalization Data We performed a directed review of each patient’s medical charts and neuroimaging to obtain the following baseline variables: age, sex, admission Glasgow Coma Scale (GCS) score, Fisher grade, HH grade, admission WFNS grade, aneurysm location (categorized as anterior vs. posterior circulation), aneurysm size (defined as maximum diameter), treatment modality (categorized as surgical, endovascular, or no treatment), presence of multiple aneurysms, presence of intraventricular hemorrhage (IVH), acute hydrocephalus at presentation, occurrence of angiographic cerebral vasospasm, external ventricular drain (EVD) insertion, CSF shunt placement, and follow-up duration.6,8,17 All patients with aSAH received standard-of-care management in accordance with the American Heart Association/American Stroke Association guidelines.5 Treatment of the aneurysm (surgical clipping or endovascular embolization) was decided by multidisciplinary consensus, and it was based on the aneurysm characteristics in conjunction with the neurological and clinical status of the patient. Routine surveillance for radiographic evidence of vasospasm, defined as 33% reduction in arterial diameter, was performed using computed tomography
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angiography or catheter digital subtraction angiography. Symptomatic vasospasm, defined as a focal neurologic deficit or 2-point decrease in GCS in the context of radiographic vasospasm, was treated with hypertensive-hypervolemic and/or endovascular therapy.18,19 Placement of an EVD was performed in patients with acute hydrocephalus. Persistence of symptomatic post-aSAH hydrocephalus was managed by permanent CSF diversion with shunt placement. Follow-up The primary outcome was functional independence, defined as a modified Rankin Scale (mRS) score of 0e2 (0 ¼ no symptoms at all; 1 ¼ no significant disability despite symptoms and able to carry out all usual duties and activities; 2 ¼ slight disability and unable to carry out all previous activities, but able to look after own affairs without assistance). Functional outcomes were assessed using inpatient and outpatient records obtained from our institution, referring institutions, and local primary care physicians. Functional outcome was recorded at the time of last follow-up. Statistical Analysis Statistical analyses were performed using SPSS Statistics (Version 24.0; IBM SPSS Corp., Armonk, New York, USA). Univariable comparisons of baseline data, dichotomized by the primary outcome measure, were performed using Pearson c2 test, Fisher exact test, or Student t test, as appropriate. Potential predictor variables (P 0.10) were entered into a multivariable logistic regression model, with the primary outcome as the dependent variable, to identify independent predictors. The odds ratio (OR), 95% confidence interval (CI), and P values were reported for each covariate in the multivariable model. The multivariable analysis had at least 10 participants per independent variable, which is the minimum number required for a stable multivariable logistic regression model.20 The model was assessed for goodness-of-fit using the HosmereLemeshow test.20 Statistical significance was defined as P < 0.05, and all tests were 2-tailed. Missing data was not imputed. RESULTS Baseline Characteristics of the Study Cohort Of the 888 consecutive patients with aSAH admitted to our institution between January 2000 and April 2015, 589 (66%) were WFNS grade IeIII, 260 (29.3%) were WFNS grade IVeV, and 39 (4.4%) did not have sufficient data to determine the WFNS grade. Of the 260 patients diagnosed as having WFNS grade IVeV aSAH, 121 were excluded from the present study (81 patients for death or withdrawal of care during hospitalization and 40 patients for insufficient follow-up outcomes data). The study cohort comprised 139 (53.5%) who met the inclusion criteria, including 83 (59.7%) WFNS grade IV and 56 (40.3%) WNFS grade V patients. The mean and median follow-up duration was 21.3 30.9 months and 4 [2e28] months, respectively. The mean age was 54.5 12.8 years, and 68.4% (n ¼ 95/139 patients) were female. The median GCS, HH grade, and Fisher grade at initial presentation were 7 [3e12], 4 [2e6], and 4 [4e4], respectively. Aneurysms were located in the posterior circulation in 16.6% (n ¼ 23/139 patients),
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FUNCTIONAL OUTCOME PREDICTORS IN HIGH-GRADE ASAH
the mean aneurysm diameter was 6.9 4.4 mm and 30.2% (n ¼ 42/139 patients) had multiple aneurysms. The aneurysm treatment modality was surgical in 46.8% (n ¼ 65/139 patients) and endovascular in 51.1% (n ¼ 71/139 patients). Aneurysm treatment was not performed in 2.2% (n ¼ 3/139 patients). IVH and acute hydrocephalus were present in 94.2% (n ¼ 131/139 patients) and 84.9% (n ¼ 118/139 patients), respectively, and an EVD was placed in 58.3% (n ¼ 81/139 patients). CSF shunt placement was performed in 39.6% (n ¼ 55/139 patients). CSF shunt placement was performed during the initial hospitalization in 54.5% (n ¼ 30/55 patients) and after discharge in 45.4% (n ¼ 25/55
patients). Of the 30 patients who had shunt placed after discharge, the mean time to shunt placement was 2.73 3.94 months. Functional Outcomes At last follow-up, mRS score was 0 in 34 (24.4%) patients, 1 in 38 (27.3%), 2 in 29 (20.9%), 3 in 7 (5.0%), 4 in 9 (6.5%), 5 in 19 (13.7%), and 6 in 3 (2.2%). Functional independence (mRS 0e2) was achieved in 72.7% of survivors of high-grade aSAH (n ¼ 101/139 patients) and in 38.8% of all cases of high-grade aSAH (101/260 patients). Table 1 compares the demographic, clinical, aneurysm, and treatment characteristics of patients with
Table 1. Comparison of Demographic, Clinical, Aneurysm, and Treatment Characteristics of Patients with High-Grade aSAH with mRS Score 0e2 Versus 3e6 at Follow-Up mRS 0e2 (n [ 101)
mRS 3e6 (n [ 38)
P Value*
53.1 12.08
58.1 14.2
0.043
70 (69.3)
25 (65.8)
0.691 (c2 ¼ 0.158)
GCS,y median [IQR]
8 [3e12]
7 [3e12]
0.125
HunteHess grade,y median [IQR]
4 [2e6]
4 [3e5]
0.089
Fisher grade,y median [IQR]
4 [4e4]
4 [4e4]
0.152
Variable Demographics Age, years, mean SD Female, n (%) Clinical characteristics
Intraventricular hemorrhage, n (%)
93 (92.1)
38 (100)
0.107
Acute hydrocephalus, n (%)
81 (80.2)
37 (97.4)
0.012 (c2 [ 6.347)
Vasospasm, n (%)
63 (62.4)
27 (71.1)
0.340 (c2 ¼ 0.911)
Posterior circulation location, n (%)
15 (14.9)
8 (21.1)
0.381 (c2 ¼ 0.769)
Maximum diameter, mm, mean SD
6.9 4.1
6.9 5.0
0.955
Multiple aneurysms, n (%)
31 (30.7)
11 (29.0)
0.842 (c2 ¼ 0.040)
Aneurysm characteristics
Aneurysm treatment, n (%)
0.591
Surgical clipping
45 (44.5)
20 (52.6)
Endovascular coiling
54 (53.5)
17 (44.7)
2 (2.0)
1 (2.6)
49 (48.5)
32 (84.2)
No treatment Additional interventions EVD, n (%) CSF shunt, n (%) Follow-up duration, months, mean SD Vasospasm, n (%)
<0.001
28 (27.7)
27 (71.1)
<0.001
26.6 30.9
10.3 17.3
<0.001
63 (62.4)
27 (71.1)
0.340 (c2 ¼ 0.911)
The values in bold are statistically significant (P < 0.05). aSAH, aneurysmal subarachnoid hemorrhage; mRS, modified Rankin Scale; SD, standard deviation; GCS, Glasgow Coma Scale score; IQR, interquartile range; EVD, external ventricular drain; CSF, cerebrospinal fluid. 2 *Patients were dichotomized by mRS score. Groups were compared using the Pearson c test, Fisher exact test, or Student t test. yDetermined at the time of hospital admission.
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FUNCTIONAL OUTCOME PREDICTORS IN HIGH-GRADE ASAH
Table 2. Multivariable Model for Predictors of Functional Independence (mRS 0e2) in Patients with High-Grade aSAH Variable
Odds Ratio
95% CI
P Value
Age
0.976
0.945e1.009
0.152
HunteHess grade
0.810
0.463e1.415
0.459
Acute hydrocephalus
0.407
0.046e3.612
0.420
EVD
0.430
0.141e1.309
0.137
CSF shunt
0.281
0.109e0.722
0.008
The value in bold is statistically significant (P < 0.05). mRS, modified Rankin Scale; aSAH, aneurysmal subarachnoid hemorrhage; CI, confidence interval; EVD, external ventricular drain; CSF, cerebrospinal fluid.
high-grade aSAH with an mRS score 0e2 versus 3e6 at follow-up. Patients with mRS score 0e2 were younger (mean age 53 vs. 58 years; P ¼ 0.043), less likely to have acute hydrocephalus (80% vs. 97%; P ¼ 0.012), less likely to undergo EVD insertion (49% vs. 84%; P < 0.001), and less likely to undergo CSF shunt placement (28% vs. 71%; P < 0.001). Patients with mRS 0e2 also had a longer follow-up duration (mean 27 vs. 10 months; P < 0.001).
Predictors of Functional Independence Table 2 summarizes the multivariable logistic regression analysis for predictors of functional independence. Age, admission HH grade, acute hydrocephalus at presentation, EVD insertion, and CSF shunt placement were the covariates that were included in the multivariable model. Only the lack of CSF shunt placement was found to be an independent predictor of functional independence (OR 0.28, 95% CI 0.109e0.722; P ¼ 0.008).
DISCUSSION Admission neurologic condition, often classified by the HH or WFNS grade, is a well-established predictor of follow-up outcomes in patients with aSAH.7 High-grade (i.e., HH or WFNS grade IVeV) aSAH often has been associated with a poor prognosis, and the reported rates of functional independence and mortality for these patients range from 5%e43% and 43%e87%, respectively.14-16,21,22 However, in recent years, considerable improvement in the outcome of patients with high-grade aSAH has been observed, with contemporary series reporting rates of functional independence and mortality of 30%e57% and 28%e36%, respectively.9,12,18,23-25 These improved results have been attributed to early aggressive resuscitation, the increasing use of endovascular techniques for aneurysm occlusion, and targeted postoperative neurologic intensive care.21,24,26-28 Consequently, the possibility of patient selection bias associated with the early prognostication of a poor outcome has been proposed.29 Nevertheless, a substantial proportion of patients with high-grade aSAH die during the initial hospitalization or are designated for comfort care (e.g., discharged to hospice) due to a lack of meaningful recovery. Therefore, our current understanding of outcome predictors in high-grade aSAH survivors is limited.
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In this single-center retrospective cohort study, we found 73% of patients with high-grade aSAH who survived the acute hospitalization were functionally independent (mRS 0e2) at last followup (mean duration 21.3 months). Although the proportion of functionally independent patients with high-grade aSAH appears to be unusually high at first glance, when one considers the total number of consecutive high-grade aSAH hospitalized during the study period, the adjusted functional independence rate of 39% is consistent with recent reports. Chua et al.29 analyzed a cohort of 247 HH grade IVeV patients who underwent aneurysm treatment between 1998 and 2013, and they reported a 23% increase in the rate of functional independence (defined as Glasgow Outcome Scale score of 4 or 5) for patients treated between 2007 and 2013 versus 1998 and 2003. Despite this, the rate of functional independence in the latter period of 2007e2013 was modest (45%), between 2007 and 2013.29 In A Multicenter Prospective Study of Poor Grade Aneurysmal Subarachnoid Hemorrhage (AMPAS), 51% of the patients with WFNS IVeV aSAH who underwent endovascular aneurysm treatment between 2010 and 2012 were functionally independent (mRS 0e2) at 12 months’ follow-up.24 Comparison between WFNS grade IV versus V patients revealed a significantly greater likelihood of functional independence in those with a WFNS grade IV aSAH (65% vs. 27%; P < 0.001), which suggests that subclassification of patients with high-grade aSAH may be clinically relevant.24 Han et al.30 performed a pooled meta-analysis of 806 patients with HH or WFNS IVeV aSAH who underwent ultraearly treatment (i.e., within 24 hours of hemorrhage onset) and they reported an overall rate of favorable functional outcome (mRS score 0e2 or Glasgow Outcome Scale score >3) of 47% (95% CI 40%e54%). Although ultra-early treatment may afford the potential benefits of reduced re-bleeding and early intracranial pressure control, a comparison between those undergoing ultraearly treatment to matched controls did not reveal a significant difference in the likelihood of achieving a favorable outcome (OR 1.23, 95% CI 0.75e2.02; P ¼ 0.40).11,30 Therefore, the benefit of aneurysm treatment within 24 hours remains unproven for patients with high-grade aSAH. Nevertheless, our institutional preference is to treat all ruptured aneurysms within 24 hours of admission, unless the patient is hemodynamically unstable or medically unfit for general anesthesia. Previous authors have identified older age, larger aneurysm size, ICH, and non-middle cerebral artery aneurysms to be independent predictors of poor functional outcome among patients with highgrade aSAH.26,31-34 In our cohort, we also found that older patients were less likely to be functionally independent at follow-up, although the aneurysm size and location were similar between those with mRS 0e2 versus 3e6. Only a lack of CSF shunt placement was found to be an independent predictor of functional independence. This suggests that strategies aimed at minimizing the incidence of shunt-dependent hydrocephalus and its associated complications may improve the likelihood of functional independence in patients with high-grade aSAH. In cohort of 60 patients with poor-grade aSAH, 55 (95%) of whom did not receive aneurysm treatment, Nieuwkamp et al.35 observed a mortality rate of 93% 2e4 months after aSAH. Goldberg et al.,36 in a cohort of elderly patients with high-grade aSAH, found early aggressive treatment to be associated with improved favorable outcomes at 6e12 months after
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FUNCTIONAL OUTCOME PREDICTORS IN HIGH-GRADE ASAH
aSAH. Early cerebral infarction after aSAH has been significantly correlated with poor functional outcome.37 Therefore, in addition to early aggressive resuscitation and definitive treatment of the aneurysm, targeting modifiable predictors of perioperative cerebral infarction, including the duration of intraoperative arterial occlusion and admission plasma glucose, may improve outcomes in patients with high-grade aSAH.37-39 Acute hydrocephalus in aSAH, resulting from an abrupt impairment of CSF flow at the ictus of aneurysm rupture, has been established as an important risk factor for shunt-dependent hydrocephalus.40-42 However, the mechanisms that underlie the transition between the acute obstructive and chronic communicating phases of post-aSAH hydrocephalus have yet to be fully elucidated.43 Although this has limited the identification of effective prevention strategies, nosocomial meningitis, which is associated with CSF flow disturbances and ependymal cell dysfunction, remains a modifiable risk factor for chronic hydrocephalus.44-46 In a previous study from our institution, shunt infection was found to be the strongest independent predictor of poor outcome (mRS 3e6) in patients with aSAH with shunt-dependent hydrocephalus.47 Therefore, among patients with high-grade aSAH, who are more prone to systemic complications and iatrogenic infections, strategies that minimize the risk of ventriculitis may reduce the likelihood of shunt dependency and shunt-related complications.47-49 The fact that greater WFNS grade has been associated with an increased risk of shunt-related complications further underscores the importance of targeting modifiable risk factors for shunt dependency in patients with high-grade aSAH.47 Our study has several limitations that affect the generalizability of our findings. The retrospective nature of our analysis is subject to confirmation bias in that variables were chosen based on data availability and hypothesis generation. Specifically, data regarding premorbid functional status, presence of associated IVH or intracerebral hemorrhage, change in neurologic grade, rebleeding rate, intracranial pressure characteristics, and timing of aneurysm treatment were not available for analysis. Additional limitations associated with our retrospective study design include
REFERENCES 1. de Rooij NK, Linn FH, van der Plas JA, Algra A, Rinkel GJ. Incidence of subarachnoid haemorrhage: a systematic review with emphasis on region, age, gender and time trends. J Neurol Neurosurg Psychiatry. 2007;78:1365-1372. 2. Lovelock CE, Rinkel GJ, Rothwell PM. Time trends in outcome of subarachnoid hemorrhage: population-based study and systematic review. Neurology. 2010;74:1494-1501. 3. Rinkel GJ, Algra A. Long-term outcomes of patients with aneurysmal subarachnoid haemorrhage. Lancet Neurol. 2011;10:349-356. 4. Nieuwkamp DJ, Setz LE, Algra A, Linn FH, de Rooij NK, Rinkel GJ. Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis. Lancet Neurol. 2009;8:635-642.
reporting, recall and missing data biases due to the conditional nature of our results on the accuracy of recorded data. The presence of a selection bias is suggested by the significant differences in the duration of follow-up between the mRS 0e2 versus 3e6 groups. The documentation of admission WFNS grade, which does not account for clinical improvement after the initial resuscitation, may have contributed to the high observed rates of favorable outcome in our study population. We are also unable to ascertain the long-term outcome of highgrade aSAH, due to the modest overall follow-up duration of the study cohort. Because our data are derived from a single center, this study is subject to the treatment and referral biases of the institution. Furthermore, we were unable to account for changes in our institution’s management paradigms, advances in microsurgical and endovascular techniques and technologies, and improvements in operator experience over the 15-year time period from which the data were collected. Finally, it is important to emphasize that our findings are only relevant to patients who survive the initial hospitalization for aSAH, and as such, they should not be improperly generalized to all patients with a highgrade aSAH. CONCLUSIONS Functional independence can be achieved in the majority of patients with a high-grade aSAH who survive the acute hospitalization. Therefore, aggressive initial management of high-grade aSAH appears to be warranted, which contrasts with the historical perception that the prognosis of these patients is frequently dismal. The necessity for CSF shunt placement was the sole independent predictor of functional outcome in our study cohort, and it was associated with a lower likelihood of functional independence. Therefore, clinical improvement after the initial resuscitation is likely to be an important prognostic indicator in patients with high-grade aSAH. As such, strategies that reduce the likelihood of chronic hydrocephalus and minimize shunt-related complications may improve functional outcomes in high-grade aSAH survivors.
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