Functional Outcomes and Delayed Cerebral Ischemia Following Nonperimesencephalic Angiogram-Negative Subarachnoid Hemorrhage Similar to Aneurysmal Subarachnoid Hemorrhage

Functional Outcomes and Delayed Cerebral Ischemia Following Nonperimesencephalic... Abstract BACKGROUND The angiogram-negative subarachnoid hemorrhage (SAH) literature includes patients with perimesencephalic hemorrhage, which is recognized to have a much better outcome than aneurysmal SAH. OBJECTIVE To evaluate the clinical outcomes of Nonperimesencephalic Angiogram-Negative SAH (NPAN-SAH). METHODS A prospective, spontaneous SAH database of 1311 patients that accrued between April 2006 and December 2014 was screened. All patients with NPAN-SAH and 2 consecutive negative cerebral angiograms were included. RESULTS We identified 191 (11%) from a total of 1311 patients with spontaneous SAH. Amongst angiogram-negative patients, 83 (4.9%) were adjudicated to have NPAN-SAH. Patient characteristics were similar across the groups, except NPAN-SAH patients were more likely to be men and had higher rates of diabetes. In a multivariable logistic regression model, NPAN-SAH patients were less likely to develop vasospasm, after adjusting for Fisher grade, sex, and diabetes (odds ratio [OR]: 0.197, 95% confidence interval [CI; 0.07-0.55], P = .002). In another adjusted model accounting for Hunt and Hess clinical grade, NPAN-SAH patients were also less likely to develop vasospasm (OR: 0.2, 95% CI [0.07-0.57], P = .002). We found no statistical significance between 2 groups for rebleed, developing hydrocephalus, seizures, or delayed cerebral ischemia. NPAN-SAH patients were equally associated with poor functional outcome (modified Rankin scale ≥3; OR: 1.16, 95% CI [0.615-2.20], P = .6420), and death (OR: 1.22, 95% CI [0.362-4.132], P = .7455) compared to aneurysmal SAH. CONCLUSION Although the risk of vasospasm may be lower, patients with NPAN-SAH are equally associated with delayed cerebral ischemia, poor outcome, and death as compared to patients with aneurysmal SAH. Furthers studies may be necessary to further clarify these findings Angiogram negative, Subarachnoid hemorrhage, Cerebral vasospasm, Delayed cerebral ischemia, Functional recovery ABBREVIATIONS ABBREVIATIONS SAH subarachnoid hemorrhage NPAN-SAH nonperimesencephalic angiogram-negative SAH OR odds ratio CI confidence interval mRS modified Rankin scale Subarachnoid hemorrhage (SAH) affects over 30 000 people in the United States and, despite advances in management, it remains associated with an overall mortality of approximately 50%, with 10% of patients dying prior to reaching the hospital, and 45% dying over the course of 30 d.1-3 In 15% to 20%, vascular abnormalities are not demonstrated on noninvasive vascular imaging nor digital-subtracted angiogram. This condition is referred to as angiogram-negative SAH.1,4,5 The angiogram-negative SAH literature includes perimesencephalic hemorrhage, which has a very different natural history and is well known to have an overall better outcome than aneurysmal SAH. Recent studies have successfully shown that pattern of bleeding—as opposed to volume of blood—seems to be the primary determinant of the risk of neurological injury after SAH. Nonperimesencephalic Angiogram-Negative SAH (NPAN-SAH) accounts for almost 5% of all patients who present with SAH.4,5 Several theories have been put forth to clarify the etiology of NPAN-SAH; however, the underlying etiology cannot be identified in many cases and the natural history of NPAN-SAH has not been not well characterized. Herein, we examined the clinical significance of NPAN-SAH by determining its incidence, associations, and impact on long-term functional term outcomes using a large cohort of SAH patients. We hypothesize that their long-term outcomes would be similar to patients with angiogram-positive SAH. METHODS Design and Study Population We sought to evaluate 90-d outcomes and complications of NPAN-SAH using a prospective observational cohort of all SAH patients over the age of 18 yr with spontaneous SAH admitted to the Neurosciences ICU between April 2006 and December 2015. Patients with the perimesencephalic pattern of SAH, secondary SAH related to conditions such as vasculitis, trauma, or rupture of an arteriovenous malformation were excluded.6 Consent was obtained for all enrolled patients through the patients themselves or their next of kin. All study protocols were approved by the Institutional Review Board in accordance with federal guidelines. Clinical and Radiological Variables The diagnosis was established by appropriate clinical exam findings, admission CT brain scan showing SAH or by the presence of xanthochromia on lumbar puncture, and a cerebral aneurysm on vascular imaging such as CTA or catheter angiography thought to be responsible for the blood pattern on CT. All patients received cerebrovascular imaging in the form of digital subtraction angiography or CTA. The modified Fisher scale was calculated and recorded on the admission CT in order to estimate the risk of delayed cerebral ischemia based on the distribution and quantity of subarachnoid blood. All patients were assigned a Hunt and Hess grade based on the clinical severity assessed within 24 hours.7 Delayed cerebral ischemia (DCI) was defined as (1) Glasgow Coma Scale by ≥2 points or development of new motor deficits between postbleed days 5 and 12, with no other identifiable neurologic or systemic etiologies for the clinical deterioration (ie, diminishing level of consciousness, new focal neurological deficits, or both), and/or (2) a new evidence of infarction on CT that was not present on the admission neuroimaging, when the cause was adjudicated to be vasospasm.8,9 Angiogram-negative SAH was defined as 2 negative angiograms spaced 1 week apart in patients with SAH. Perimesencephalic SAH included the presence of SAH isolated to the perimesencephalic cisterns with extension into the ambient cisterns or basal parts of the sylvian fissures. Perimesencephalic SAH does not include blood extending into the lateral sylvian fissure, anterior interhemispheric fissure, or lateral ventricles. NPAN-SAH was characterized by the presence of blood primarily in the suprasellar, sylvian (basal and lateral), and interhemisperic cisterns.1,10-15 Clinical Management Management was in accordance with the Neurocritical Care Society and American Heart Association SAH guidelines.16,17 Electrocardiograms and cardiac troponin I testing were performed on admission and subsequently when clinically indicated. Oral nimodipine was administered to all patients and intravenous hydration was instituted to maintain euvolemia. Induced hypertensive therapy, with a titrated systolic blood pressure goal of 180 to 220 mm Hg, was initiated for delayed ischemic neurological deficits secondary to cerebral vasospasm or when severe angiographic vasospasm was diagnosed in poor grade patients.18 Data Collection Baseline demographics characteristics as well as past medical history, and baseline clinical status using the modified Rankin scale (mRS) were collected. Hospitalization course was prospectively recorded and all data points were documented and adjudicated in scheduled meetings with the Neurocritical care team and clinical providers. Outcome Assessment The primary outcome measure was the development of poor outcome defined as moderate to severe disability or death or (mRS of 3-6) at discharge and 3 mo19,20 In each group, patients were evaluated for rehemorrhage, seizures, hydrocephalus, external ventricular drain, permanent shunt, ischemic complications, as well as length of hospital stay, and poor outcome at 3 mo. Statistical Analyses We compared patients who had NPAN-SAH and those who had aneurysmal SAH using Pearson Chi-Square (or Fisher's exact test where appropriate). The odds ratios (OR) and 95% confidence intervals (95% CI) was estimated using crude and adjusted logistic regression models to identify the relationship between NPAN-SAH and poor functional outcome at discharge. To avoid any inaccuracies that may arise secondary to collinearity due to the inclusion of both Hunt and Hess and modified Fisher grades, we created 2 models adjusting for each individually.21 A P-value of .05 was used as the level of statistical significance. RESULTS Frequency and Clinical Features of NPAN-SAH We identified 1311 patients with spontaneous SAH, and 191 (11%) were found to have 2 negative angiograms. A total of 83 patients (4.9%) of all patients were adjudicated to have NPAN pattern of SAH. Patient demographics and clinical characteristics were similar across the groups except with a higher proportion of men and diabetes in the NPAN-SAH group (see Table 1). The median modified fisher grade was 3 in both the NPAN-SAH and aneurysmal SAH groups. The clinical presentations in the NPAN-SAH group was less severe that the aneurysmal SAH group, manifested as a median Hunt and Hess grade of 2 for NPAN-SAH and 3 for the aneurysmal SAH group, assigned at the time of the admission noncontrast Computed tomography of the head (See Table 2). TABLE 1. Baseline Characteristics compared between NPAN-SAH and Angiogram-Positive SAH   NPAN-SAH  Angiogram-positive SAH    Characteristic  (n = 83)  (n = 1120)  P-value  Demographics          Female gender  42  (50.6%)  797  (71.2%)  <.0001  Age  56.0  (20.0, 90.0)  54.0  (13.0, 98.0)  .0985  Non-Caucasian ethnicity  40  (47.6%)  625  (55.8%)  .2880  Comorbidities          Cocaine use  0  (0.0%)  72  (6.9%)  .0036  Human immunodeficiency virus  1  (1.2%)  8  (0.7%)  .3573  Kidney disease  1  (1.2%)  23  (2.1%)  .3150  Diabetes mellitus  16  (19.1%)  78  (7.2%)  .0001  Chronic obstructive pulmonary disease  2  (2.4%)  54  (5.0%)  .1414  Peripheral artery disease  2  (2.4%)  22  (2.0%)  .2800  Myocardial infarction  4  (4.8%)  32  (3.0%)  .1452  Congestive heart disease  2  (2.4%)  17  (1.6%)  .2523  Atrial fibrillation  3  (3.6%)  28  (2.6%)  .2107  Hypertension  37  (44.1%)  522  (47.9%)  .4920  Coagulopathy  1  (1.2%)  5  (0.5%)  .2973    NPAN-SAH  Angiogram-positive SAH    Characteristic  (n = 83)  (n = 1120)  P-value  Demographics          Female gender  42  (50.6%)  797  (71.2%)  <.0001  Age  56.0  (20.0, 90.0)  54.0  (13.0, 98.0)  .0985  Non-Caucasian ethnicity  40  (47.6%)  625  (55.8%)  .2880  Comorbidities          Cocaine use  0  (0.0%)  72  (6.9%)  .0036  Human immunodeficiency virus  1  (1.2%)  8  (0.7%)  .3573  Kidney disease  1  (1.2%)  23  (2.1%)  .3150  Diabetes mellitus  16  (19.1%)  78  (7.2%)  .0001  Chronic obstructive pulmonary disease  2  (2.4%)  54  (5.0%)  .1414  Peripheral artery disease  2  (2.4%)  22  (2.0%)  .2800  Myocardial infarction  4  (4.8%)  32  (3.0%)  .1452  Congestive heart disease  2  (2.4%)  17  (1.6%)  .2523  Atrial fibrillation  3  (3.6%)  28  (2.6%)  .2107  Hypertension  37  (44.1%)  522  (47.9%)  .4920  Coagulopathy  1  (1.2%)  5  (0.5%)  .2973  View Large TABLE 2. Comparison of Clinical Assessments and Hospitalization Complications NPAN-SAH and Angiogram-Positive SAH   NPAN-SAH  Angio-positive SAH    Characteristic  (n = 83)  (n = 1120)  P-value  Clinical assessments          Hunt and Hess Grade 24 h (median)  2.0    3.0    .0711  Admission Hunt and Hess Grade (median)  2.0    3.0    .0273  Glasgow Coma Scale  15    14    .0247  Thick SAH (Fisher Grade 3 or modified Fisher 3-4)  3.0    3.0    .6023  Aneurysm size (mm)  0.0    11.0  (1.0, 18.0)  <.0001  SAH hospitalization complications            Seizure  2  (2.4%)  131  (12.0%)  .0023  Global cerebral edema  14  (17.7%)  297  (27.3%)  .0643  Rebleed  1  (1.2%)  91  (8.2%)  .0077  Ictal infarction  4  (4.8%)  31  (2.9%)  .1414  Delayed cerebral infarction  11  (13.1%)  371  (33.2%)  .0001  Intracranial hemorrhage  5  (6.0%)  192  (17.2%)  .0081  Vasospasm  4  (4.8%)  232  (20.8%)  <.0001  Hydrocephalus  27  (32.1%)  423  (37.8%)  .3013    NPAN-SAH  Angio-positive SAH    Characteristic  (n = 83)  (n = 1120)  P-value  Clinical assessments          Hunt and Hess Grade 24 h (median)  2.0    3.0    .0711  Admission Hunt and Hess Grade (median)  2.0    3.0    .0273  Glasgow Coma Scale  15    14    .0247  Thick SAH (Fisher Grade 3 or modified Fisher 3-4)  3.0    3.0    .6023  Aneurysm size (mm)  0.0    11.0  (1.0, 18.0)  <.0001  SAH hospitalization complications            Seizure  2  (2.4%)  131  (12.0%)  .0023  Global cerebral edema  14  (17.7%)  297  (27.3%)  .0643  Rebleed  1  (1.2%)  91  (8.2%)  .0077  Ictal infarction  4  (4.8%)  31  (2.9%)  .1414  Delayed cerebral infarction  11  (13.1%)  371  (33.2%)  .0001  Intracranial hemorrhage  5  (6.0%)  192  (17.2%)  .0081  Vasospasm  4  (4.8%)  232  (20.8%)  <.0001  Hydrocephalus  27  (32.1%)  423  (37.8%)  .3013  View Large NPAN-SAH and Incidence of DCI and Clinical Course The proportion of vasospasm and delayed cerebral infarction in patients with NPAN-SAH were 4.8% and 13.1%, respectively (Table 1). In a multivariable logistic regression model, NPAN-SAH patients were less likely to develop vasospasm, after adjusting for Fisher grade, sex, and diabetes (OR: 0.197, 95% CI [0.07-0.55], P = .002; see Table 3). In another adjusted model accounting for Hunt and Hess clinical grade, NPAN-SAH patients were also less likely to develop vasospasm (OR: 0.2, 95% CI [0.07-0.57], P = .002). TABLE 3. Crude and Adjusted Models for the Association Between NPAN-SAH and Angiogram-Positive SAH in Patient Outcomes         Adjusted for modified      Adjusted for modified  Adjusted for Hunt and  Fisher ≥3, female    Univariable model  Fisher ≥3  Hess Grade ≥3  gender and DM  Characteristic  OR 95% CI)  P-value  OR (95% CI)  P-value  OR (95% CI)  P-value  OR (95% CI)  P-value  Global cerebral edema  0.55 (0.30, 0.99)  .049  0.52(0.28, 0.96)  .039  0.62 (0.34, 1.13)  .121  0.58 (0.31, 1.08)  .089  Rebleed  0.13 (0.02, 0.98)  .047  0.13 (0.02, 0.98)  .048  0.157 (0.02, 1.15)  .068  0.14 (0.02, 1.0)  .050  Seizure  0.44 (0.13, 1.42)  .170  0.45(0.14, 1.47)  .186  0.498 (0.15, 1.62)  .247  0.47 (0.14, 1.54)  .212  Hydrocephalus  0.78 (0.48, 1.25)  .304  0.74 (0.44, 1.23)  .251  1.0 (0.58, 1.72)  .992  0.79 (0.47, 1.33)  .380  Vasospasm  0.19 (0.07, 0.52)  .001  0.19 (0.07, 0.52)  .001  0.2 (0.07, 0.57)  .002  0.197 (0.07, 0.55)  .002  Delayed cerebral ischemia  1.64 (0.57, 4.76)  .360  1.71 (0.59, 4.97)  .320  1.754 (0.6, 5.10)  .303  1.62 (0.54, 4.87)  .384          Adjusted for modified      Adjusted for modified  Adjusted for Hunt and  Fisher ≥3, female    Univariable model  Fisher ≥3  Hess Grade ≥3  gender and DM  Characteristic  OR 95% CI)  P-value  OR (95% CI)  P-value  OR (95% CI)  P-value  OR (95% CI)  P-value  Global cerebral edema  0.55 (0.30, 0.99)  .049  0.52(0.28, 0.96)  .039  0.62 (0.34, 1.13)  .121  0.58 (0.31, 1.08)  .089  Rebleed  0.13 (0.02, 0.98)  .047  0.13 (0.02, 0.98)  .048  0.157 (0.02, 1.15)  .068  0.14 (0.02, 1.0)  .050  Seizure  0.44 (0.13, 1.42)  .170  0.45(0.14, 1.47)  .186  0.498 (0.15, 1.62)  .247  0.47 (0.14, 1.54)  .212  Hydrocephalus  0.78 (0.48, 1.25)  .304  0.74 (0.44, 1.23)  .251  1.0 (0.58, 1.72)  .992  0.79 (0.47, 1.33)  .380  Vasospasm  0.19 (0.07, 0.52)  .001  0.19 (0.07, 0.52)  .001  0.2 (0.07, 0.57)  .002  0.197 (0.07, 0.55)  .002  Delayed cerebral ischemia  1.64 (0.57, 4.76)  .360  1.71 (0.59, 4.97)  .320  1.754 (0.6, 5.10)  .303  1.62 (0.54, 4.87)  .384  View Large There was no statistical difference between the 2 groups in developing DCI after adjusting for Fisher grade, sex, and diabetes (OR: 1.62, 95% CI [0.54-4.8], P = .384) and Hunt and Hess clinical grade (OR: 1.754, 95% CI [0.6-5.1], P = .303). Additionally, after adjusting for demographics and baseline variables, NPAN-SAH patients were equally associated with rebleeding, global cerebral edema, hydrocephalus, and seizures. NPAN-SAH and Functional Outcome After adjusting for known predictors of poor outcome, including Hunt and Hess clinical grade, global cerebral edema, hydrocephalus, rebleeding, seizures, vasospasm, and DCI, NPAN-SAH patients were equally associated with poor outcome (mRS ≥ 3; OR:1.16, 95% CI [0.615-2.20], P = .6420), and death (OR: 1.22, 95% CI [0.362-4.132], P = .7455) compared to aneurysmal SAH (see Table 4). TABLE 4. Multivariable Logistic Regression Models for the Association Between NPAN-SAH and Long-Term Functional Outcomes   OR      (95% CI)  P value  Poor mRS at 3 moa  1.16 (0.615-2.20)  .6420  Deatha  1.22 (0.362-4.132)  .7455    OR      (95% CI)  P value  Poor mRS at 3 moa  1.16 (0.615-2.20)  .6420  Deatha  1.22 (0.362-4.132)  .7455  aAdjusted for HH, GCE, rebleed, delayed cerebral ischemia seizure, vasospasm, and hydrocephalus. View Large DISCUSSION Patients with NPAN-SAH were found to have a lower proportion of vasospasm, but similar odds of developing DCI, seizure, poor outcome, and death compared with aneurysmal SAH. We also found that the proportions of angiogram-negative SAH and NPAN-SAH were similar to the reported rates in the literature.4,5 NPAN-SAH and Incidence of Vasospasm, DCI Despite the fact that there was no statistically significant difference between aneurysmal SAH and NPAN-SAH in terms of Hunt and Hess grade, Fisher grade, or the development DCI, the proportion of vasospasm in the NPAN-SAH patients was 4.8%, considerably lower than the 20.8% that was observed in the aneurysmal SAH group. One possible explanation is that DCI following SAH is not solely due to cerebrovascular vasospasm but rather is now recognized to be due to interplay of several pathways contributing to its pathogenesis, including cortical spreading ischemia, microcirculatory vasoconstriction and thrombosis, and early brain injury cascades.22,23 NPAN-SAH and Clinical Course Another area in which our study found differences when compared to previous studies related to the development of hydrocephalus as a consequence of the SAH. Thirty-two percent of our NPAN-SAH group developed hydrocephalus, values which were closer to our aneurysmal SAH group (37.8%) than to any cohort analyzing NPAN-SAH patients. Other studies found incidence rates between 6% and 19% but failed to describe the incidence of hydrocephalus in the NPAN-SAH subgroup.4,5,24 Our incidence is similar to the incidence reported by DH Kang et al22 at 37.9%.22 Hemorrhage within the subarachnoid space has been postulated to obstruct and impair cerebrospinal fluid flow and absorption, precipitating the development of a pressure gradient and consequently hydrocephalus. Hence, it is likely that due to the similar blood distribution between the aneurysmal SAH and NPAN groups, the same degree of subarachnoid space compartmentalization may occur resulting in similar rates of hydrocephalus. Furthermore, NPAN-SAH patients were equally associated with rebleeding and seizures as aneurysmal SAH patients. The close proximity of the hemorrhage to the medial temporal lobes may explain the equivalent association of seizures in patients with NPAN and aneurysmal SAH explaining why there was no difference in the 2 subgroups in our study. NPAN-SAH and Outcome Previously published studies of angiogram-negative SAH included perimesencephalic SAH, which is characterized by a more favorable outcome. This could bias the results considering the perimesencephalic SAH subgroup is not typically representative of NPAN-SAH.4 The clinical course of NPAN-SAH remains poorly characterized where some studies described a favorable outcome while others described complicated clinical courses punctuated by both vasospasm and DCI.15,22,24 These studies however compared NPAN to perimesencephalic SAH instead of comparing them to matched controls of aneurysmal SAH.5 Additionally, due to the small numbers of enrolled patients, these studies lacked sufficient power to more precisely delineate the prognosis.22 While other studies have found that, in general, idiopathic SAH patients tend to have good functional outcomes, we once again stress the fact that perimesencephalic SAH patients were included in that group. In 2009, Gupta et al15 analyzed 292 patients admitted with SAH, 59 of whom were determined to have a NPAN-SAH. This study excluded patients who died and examined the outcomes of the survivors, hence determining that NPAN-SAH patients tend to have an overall better prognosis when compared to aneurysmal SAH patients. Exclusion of NPAN patients who were deceased was a major bias of that study, which the authors acknowledged.15 Theories abound regarding why NPAN-SAH—despite having lower grade hemorrhages compared to aneurysmal SAH—have equally associated poor outcomes and death, and remain speculative in nature. While NPAN-SAH may be venous in origin, another postulated etiology is from an arterial leak from perforators just prior to their entry into substance of the brainstem. Limitations Several limitations to our study deserve mention. Although we utilized a prospectively maintained database, our study was retrospective in nature, lacked randomization, and was conducted in a single center. We did not study CT head results regarding which patients with DCI developed cortical vs subcortical strokes, which deserves further investigation. And while our finding that a higher percentage of diabetics were seen in the NPAN-SAH group was certainly significant, it did not produce a difference in outcome once adjusted for diabetes. However, since our institution is a busy tertiary referral center which receives patients with a broad variety of comorbidities, demographics, and manifestations of this devastating neurological disease, we feel that our results may be generalizable. CONCLUSION Although the risk of vasospasm may be lower, patients with NPAN-SAH are equally associated with DCI, poor outcome, and death as compared to patients with aneurysmal SAH hence caution should be applied. These results and others collectively suggest that NPAN-SAH patients behave more comparably to angiogram-positive SAH in both clinical course and outcome. Further studies may be necessary to clarify these findings. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. This work was presented at the Neurocritical Care Society 13th Annual Meeting in Scottsdale, Arizona, October 7-10, 2015. REFERENCES 1. van Gijn J, Kerr RS, Rinkel GJ. Subarachnoid haemorrhage. Lancet (London, England) . 2007; 369( 9558): 306- 318. Google Scholar CrossRef Search ADS PubMed  2. Hop JW, Rinkel GJ, Algra A, van Gijn J. Case-fatality rates and functional outcome after subarachnoid hemorrhage: a systematic review. Stroke . 1997; 28( 3): 660- 664. Google Scholar CrossRef Search ADS PubMed  3. Broderick JP, Brott TG, Duldner JE, Tomsick T, Leach A. 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Google Scholar CrossRef Search ADS PubMed  20. de Haan R, Limburg M, Bossuyt P, van der Meulen J, Aaronson N. The clinical meaning of Rankin 'handicap' grades after stroke. Stroke . 1995; 26( 11): 2027- 2030. Google Scholar CrossRef Search ADS PubMed  21. Bender R, Lange S. Adjusting for multiple testing—when and how? J Clin Epidemiol . 2001; 54( 4): 343- 349. Google Scholar CrossRef Search ADS PubMed  22. Kang DH, Park J, Lee SH, Park SH, Kim YS, Hamm IS. Does non-perimesencephalic type non-aneurysmal subarachnoid hemorrhage have a benign prognosis? J Clin Neurosci . 2009; 16( 7): 904- 908. Google Scholar CrossRef Search ADS PubMed  23. Brathwaite S, Macdonald RL. Current management of delayed cerebral ischemia: update from results of recent clinical trials. Translat Stroke Res . 2014; 5( 2): 207- 226. Google Scholar CrossRef Search ADS   24. 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. Neurolog Res . 2012; 34( 1): 91- 97. Google Scholar CrossRef Search ADS   COMMENTS The authors have prepared a manuscript on the functional outcomes and delayed cerebral ischemia following non-perimesencephalic angiogram negative subarachnoid hemorrhage (NPAN-SAH) that appear similar to aneurysmal SAH on imaging. It is well known that patients with perimesencephalic hemorrhage have a much better outcome than aneurysmal SAH. This manuscript evaluates the clinical outcomes of NPAN-SAH in a prospective manner. The authors identified 191 (11%) from a total of 1311 patients with spontaneous SAH. The authors found that although the risk of vasospasm may be lower, patients with NPAN-SAH are equally associated with DCI, poor outcome and death as compared to patients with aneurysmal SAH. This is an interesting paper and may reflect the difference in etiology as many surgeons believe that the classical perimesencephalic hemorrhage is of venous origin and a true aneurysmal subarachnoid hemorrhage and this non-perimesencephalic SAH are arterial. This may warrant long-term imaging in the non-perimesencephalic SAH cohort and more so than in the classic mesencephalic hemorrhage, which often only have 2 angiograms and if they are negative are often not seen again. It will be interesting to see if these non-perimesencephalic SAH develop aneurysms long-term. Gavin W. Britz Houston, Texas This is an interesting article addressing an important clinical issue; non-aneurysmal subarachnoid hemorrhage seems to come in 1 distinct "flavors", perimesencephalic and non-perimesencephalic (or as the authors call it "non-perimesencephalic angiogram-negative SAH, NPAN-SAH). The authors correctly intuited that these 2 conditions present differently and are associated with different outcomes, and with their study have now documented this more clearly and in the process raised some issues worthy of further investigation. In particular, the finding that the distribution of subarachnoid blood in the suprasellar, interhemisperic cisterns and sylvian (basal and lateral) fissures, in close proximity to the Circle of Willis, likely plays a role in approximating the risk of delayed cerebral ischemia to that of SAH regardless of the presence or absence of the aneurysm is incredibly interesting, and begs the question of how delayed cerebral ischemia is linked biologically to vasospasm, in spite of the growing evidence that vasospasm (a radiographic diagnosis) is not inherently/causally linked to delayed cerebral ischemia (a clinical and sometimes radiographic diagnosis). This contribution is also important because it reminds all of us who care for patients with non-aneurysmal SAH that a clean angiogram does not mean the patient is "out of the woods". James Towner G. Edward Vates Rochester, New York The authors have performed a systematic retrospective review of a large number of subarachnoid hemorrhages (SAH) at a single institution. They found that nearly 5% of these SAH were found to be non-perimesencephalic angiogram negative (NPAN-SAH). Somewhat surprisingly, the NPAN-SAH group showed similar overall outcome to the patients that harbored ruptured aneurysms. The authors showed that the NPAN-SAH group had a higher proportion of men, history of diabetes, and a lower incidence of cocaine use on presentation. Despite a significantly lower risk of cerebral vasospasm, the NPAN-SAH group showed similar rates of delayed cerebral ischemia (DCI) as the aneurysm group. This finding is surprising and somewhat hard to explain by the data shown. We do believe that patients with DCI should be better evaluated for the source of their ischemia. Better evaluation of axial imaging may shed light on the types of DCI that a patient experiences. (The size and location of the infarcts, whether cortical or subcortical). Certainly, this finding of equivalent degrees of DCI and poor outcome despite remarkably lower frequency of vasospasm deserves a closer look in additional studies. The authors found equivalent clinical (mRS) outcomes. One possible reason could be that men do less well following SAH than women, which would skew the results in favor of the aneurysmal group. Also, the finding that a higher percentage of diabetics were seen in the NPAN-SAH group is possibly important. A careful and deeper evaluation of patients that did poorly should be obtained in following studies (Is poor outcome related to other risk factors? Is the hospitalization period complicated with general/neurological complications?). Overall, we congratulate the authors for a valuable study and while raising many questions does suggest that a SAH and NPAN-SAH have similar features post-intensive care unit and that the non-aneurysmal patients should be managed aggressively so as to allay the inherent risks of these dangerous bleeds. Erez Nossek David J. Langer New York, New York Copyright © 2017 by the Congress of Neurological Surgeons http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurosurgery Oxford University Press

Functional Outcomes and Delayed Cerebral Ischemia Following Nonperimesencephalic Angiogram-Negative Subarachnoid Hemorrhage Similar to Aneurysmal Subarachnoid Hemorrhage

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Oxford University Press
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Copyright © 2017 by the Congress of Neurological Surgeons
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0148-396X
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1524-4040
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10.1093/neuros/nyx188
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Abstract

Abstract BACKGROUND The angiogram-negative subarachnoid hemorrhage (SAH) literature includes patients with perimesencephalic hemorrhage, which is recognized to have a much better outcome than aneurysmal SAH. OBJECTIVE To evaluate the clinical outcomes of Nonperimesencephalic Angiogram-Negative SAH (NPAN-SAH). METHODS A prospective, spontaneous SAH database of 1311 patients that accrued between April 2006 and December 2014 was screened. All patients with NPAN-SAH and 2 consecutive negative cerebral angiograms were included. RESULTS We identified 191 (11%) from a total of 1311 patients with spontaneous SAH. Amongst angiogram-negative patients, 83 (4.9%) were adjudicated to have NPAN-SAH. Patient characteristics were similar across the groups, except NPAN-SAH patients were more likely to be men and had higher rates of diabetes. In a multivariable logistic regression model, NPAN-SAH patients were less likely to develop vasospasm, after adjusting for Fisher grade, sex, and diabetes (odds ratio [OR]: 0.197, 95% confidence interval [CI; 0.07-0.55], P = .002). In another adjusted model accounting for Hunt and Hess clinical grade, NPAN-SAH patients were also less likely to develop vasospasm (OR: 0.2, 95% CI [0.07-0.57], P = .002). We found no statistical significance between 2 groups for rebleed, developing hydrocephalus, seizures, or delayed cerebral ischemia. NPAN-SAH patients were equally associated with poor functional outcome (modified Rankin scale ≥3; OR: 1.16, 95% CI [0.615-2.20], P = .6420), and death (OR: 1.22, 95% CI [0.362-4.132], P = .7455) compared to aneurysmal SAH. CONCLUSION Although the risk of vasospasm may be lower, patients with NPAN-SAH are equally associated with delayed cerebral ischemia, poor outcome, and death as compared to patients with aneurysmal SAH. Furthers studies may be necessary to further clarify these findings Angiogram negative, Subarachnoid hemorrhage, Cerebral vasospasm, Delayed cerebral ischemia, Functional recovery ABBREVIATIONS ABBREVIATIONS SAH subarachnoid hemorrhage NPAN-SAH nonperimesencephalic angiogram-negative SAH OR odds ratio CI confidence interval mRS modified Rankin scale Subarachnoid hemorrhage (SAH) affects over 30 000 people in the United States and, despite advances in management, it remains associated with an overall mortality of approximately 50%, with 10% of patients dying prior to reaching the hospital, and 45% dying over the course of 30 d.1-3 In 15% to 20%, vascular abnormalities are not demonstrated on noninvasive vascular imaging nor digital-subtracted angiogram. This condition is referred to as angiogram-negative SAH.1,4,5 The angiogram-negative SAH literature includes perimesencephalic hemorrhage, which has a very different natural history and is well known to have an overall better outcome than aneurysmal SAH. Recent studies have successfully shown that pattern of bleeding—as opposed to volume of blood—seems to be the primary determinant of the risk of neurological injury after SAH. Nonperimesencephalic Angiogram-Negative SAH (NPAN-SAH) accounts for almost 5% of all patients who present with SAH.4,5 Several theories have been put forth to clarify the etiology of NPAN-SAH; however, the underlying etiology cannot be identified in many cases and the natural history of NPAN-SAH has not been not well characterized. Herein, we examined the clinical significance of NPAN-SAH by determining its incidence, associations, and impact on long-term functional term outcomes using a large cohort of SAH patients. We hypothesize that their long-term outcomes would be similar to patients with angiogram-positive SAH. METHODS Design and Study Population We sought to evaluate 90-d outcomes and complications of NPAN-SAH using a prospective observational cohort of all SAH patients over the age of 18 yr with spontaneous SAH admitted to the Neurosciences ICU between April 2006 and December 2015. Patients with the perimesencephalic pattern of SAH, secondary SAH related to conditions such as vasculitis, trauma, or rupture of an arteriovenous malformation were excluded.6 Consent was obtained for all enrolled patients through the patients themselves or their next of kin. All study protocols were approved by the Institutional Review Board in accordance with federal guidelines. Clinical and Radiological Variables The diagnosis was established by appropriate clinical exam findings, admission CT brain scan showing SAH or by the presence of xanthochromia on lumbar puncture, and a cerebral aneurysm on vascular imaging such as CTA or catheter angiography thought to be responsible for the blood pattern on CT. All patients received cerebrovascular imaging in the form of digital subtraction angiography or CTA. The modified Fisher scale was calculated and recorded on the admission CT in order to estimate the risk of delayed cerebral ischemia based on the distribution and quantity of subarachnoid blood. All patients were assigned a Hunt and Hess grade based on the clinical severity assessed within 24 hours.7 Delayed cerebral ischemia (DCI) was defined as (1) Glasgow Coma Scale by ≥2 points or development of new motor deficits between postbleed days 5 and 12, with no other identifiable neurologic or systemic etiologies for the clinical deterioration (ie, diminishing level of consciousness, new focal neurological deficits, or both), and/or (2) a new evidence of infarction on CT that was not present on the admission neuroimaging, when the cause was adjudicated to be vasospasm.8,9 Angiogram-negative SAH was defined as 2 negative angiograms spaced 1 week apart in patients with SAH. Perimesencephalic SAH included the presence of SAH isolated to the perimesencephalic cisterns with extension into the ambient cisterns or basal parts of the sylvian fissures. Perimesencephalic SAH does not include blood extending into the lateral sylvian fissure, anterior interhemispheric fissure, or lateral ventricles. NPAN-SAH was characterized by the presence of blood primarily in the suprasellar, sylvian (basal and lateral), and interhemisperic cisterns.1,10-15 Clinical Management Management was in accordance with the Neurocritical Care Society and American Heart Association SAH guidelines.16,17 Electrocardiograms and cardiac troponin I testing were performed on admission and subsequently when clinically indicated. Oral nimodipine was administered to all patients and intravenous hydration was instituted to maintain euvolemia. Induced hypertensive therapy, with a titrated systolic blood pressure goal of 180 to 220 mm Hg, was initiated for delayed ischemic neurological deficits secondary to cerebral vasospasm or when severe angiographic vasospasm was diagnosed in poor grade patients.18 Data Collection Baseline demographics characteristics as well as past medical history, and baseline clinical status using the modified Rankin scale (mRS) were collected. Hospitalization course was prospectively recorded and all data points were documented and adjudicated in scheduled meetings with the Neurocritical care team and clinical providers. Outcome Assessment The primary outcome measure was the development of poor outcome defined as moderate to severe disability or death or (mRS of 3-6) at discharge and 3 mo19,20 In each group, patients were evaluated for rehemorrhage, seizures, hydrocephalus, external ventricular drain, permanent shunt, ischemic complications, as well as length of hospital stay, and poor outcome at 3 mo. Statistical Analyses We compared patients who had NPAN-SAH and those who had aneurysmal SAH using Pearson Chi-Square (or Fisher's exact test where appropriate). The odds ratios (OR) and 95% confidence intervals (95% CI) was estimated using crude and adjusted logistic regression models to identify the relationship between NPAN-SAH and poor functional outcome at discharge. To avoid any inaccuracies that may arise secondary to collinearity due to the inclusion of both Hunt and Hess and modified Fisher grades, we created 2 models adjusting for each individually.21 A P-value of .05 was used as the level of statistical significance. RESULTS Frequency and Clinical Features of NPAN-SAH We identified 1311 patients with spontaneous SAH, and 191 (11%) were found to have 2 negative angiograms. A total of 83 patients (4.9%) of all patients were adjudicated to have NPAN pattern of SAH. Patient demographics and clinical characteristics were similar across the groups except with a higher proportion of men and diabetes in the NPAN-SAH group (see Table 1). The median modified fisher grade was 3 in both the NPAN-SAH and aneurysmal SAH groups. The clinical presentations in the NPAN-SAH group was less severe that the aneurysmal SAH group, manifested as a median Hunt and Hess grade of 2 for NPAN-SAH and 3 for the aneurysmal SAH group, assigned at the time of the admission noncontrast Computed tomography of the head (See Table 2). TABLE 1. Baseline Characteristics compared between NPAN-SAH and Angiogram-Positive SAH   NPAN-SAH  Angiogram-positive SAH    Characteristic  (n = 83)  (n = 1120)  P-value  Demographics          Female gender  42  (50.6%)  797  (71.2%)  <.0001  Age  56.0  (20.0, 90.0)  54.0  (13.0, 98.0)  .0985  Non-Caucasian ethnicity  40  (47.6%)  625  (55.8%)  .2880  Comorbidities          Cocaine use  0  (0.0%)  72  (6.9%)  .0036  Human immunodeficiency virus  1  (1.2%)  8  (0.7%)  .3573  Kidney disease  1  (1.2%)  23  (2.1%)  .3150  Diabetes mellitus  16  (19.1%)  78  (7.2%)  .0001  Chronic obstructive pulmonary disease  2  (2.4%)  54  (5.0%)  .1414  Peripheral artery disease  2  (2.4%)  22  (2.0%)  .2800  Myocardial infarction  4  (4.8%)  32  (3.0%)  .1452  Congestive heart disease  2  (2.4%)  17  (1.6%)  .2523  Atrial fibrillation  3  (3.6%)  28  (2.6%)  .2107  Hypertension  37  (44.1%)  522  (47.9%)  .4920  Coagulopathy  1  (1.2%)  5  (0.5%)  .2973    NPAN-SAH  Angiogram-positive SAH    Characteristic  (n = 83)  (n = 1120)  P-value  Demographics          Female gender  42  (50.6%)  797  (71.2%)  <.0001  Age  56.0  (20.0, 90.0)  54.0  (13.0, 98.0)  .0985  Non-Caucasian ethnicity  40  (47.6%)  625  (55.8%)  .2880  Comorbidities          Cocaine use  0  (0.0%)  72  (6.9%)  .0036  Human immunodeficiency virus  1  (1.2%)  8  (0.7%)  .3573  Kidney disease  1  (1.2%)  23  (2.1%)  .3150  Diabetes mellitus  16  (19.1%)  78  (7.2%)  .0001  Chronic obstructive pulmonary disease  2  (2.4%)  54  (5.0%)  .1414  Peripheral artery disease  2  (2.4%)  22  (2.0%)  .2800  Myocardial infarction  4  (4.8%)  32  (3.0%)  .1452  Congestive heart disease  2  (2.4%)  17  (1.6%)  .2523  Atrial fibrillation  3  (3.6%)  28  (2.6%)  .2107  Hypertension  37  (44.1%)  522  (47.9%)  .4920  Coagulopathy  1  (1.2%)  5  (0.5%)  .2973  View Large TABLE 2. Comparison of Clinical Assessments and Hospitalization Complications NPAN-SAH and Angiogram-Positive SAH   NPAN-SAH  Angio-positive SAH    Characteristic  (n = 83)  (n = 1120)  P-value  Clinical assessments          Hunt and Hess Grade 24 h (median)  2.0    3.0    .0711  Admission Hunt and Hess Grade (median)  2.0    3.0    .0273  Glasgow Coma Scale  15    14    .0247  Thick SAH (Fisher Grade 3 or modified Fisher 3-4)  3.0    3.0    .6023  Aneurysm size (mm)  0.0    11.0  (1.0, 18.0)  <.0001  SAH hospitalization complications            Seizure  2  (2.4%)  131  (12.0%)  .0023  Global cerebral edema  14  (17.7%)  297  (27.3%)  .0643  Rebleed  1  (1.2%)  91  (8.2%)  .0077  Ictal infarction  4  (4.8%)  31  (2.9%)  .1414  Delayed cerebral infarction  11  (13.1%)  371  (33.2%)  .0001  Intracranial hemorrhage  5  (6.0%)  192  (17.2%)  .0081  Vasospasm  4  (4.8%)  232  (20.8%)  <.0001  Hydrocephalus  27  (32.1%)  423  (37.8%)  .3013    NPAN-SAH  Angio-positive SAH    Characteristic  (n = 83)  (n = 1120)  P-value  Clinical assessments          Hunt and Hess Grade 24 h (median)  2.0    3.0    .0711  Admission Hunt and Hess Grade (median)  2.0    3.0    .0273  Glasgow Coma Scale  15    14    .0247  Thick SAH (Fisher Grade 3 or modified Fisher 3-4)  3.0    3.0    .6023  Aneurysm size (mm)  0.0    11.0  (1.0, 18.0)  <.0001  SAH hospitalization complications            Seizure  2  (2.4%)  131  (12.0%)  .0023  Global cerebral edema  14  (17.7%)  297  (27.3%)  .0643  Rebleed  1  (1.2%)  91  (8.2%)  .0077  Ictal infarction  4  (4.8%)  31  (2.9%)  .1414  Delayed cerebral infarction  11  (13.1%)  371  (33.2%)  .0001  Intracranial hemorrhage  5  (6.0%)  192  (17.2%)  .0081  Vasospasm  4  (4.8%)  232  (20.8%)  <.0001  Hydrocephalus  27  (32.1%)  423  (37.8%)  .3013  View Large NPAN-SAH and Incidence of DCI and Clinical Course The proportion of vasospasm and delayed cerebral infarction in patients with NPAN-SAH were 4.8% and 13.1%, respectively (Table 1). In a multivariable logistic regression model, NPAN-SAH patients were less likely to develop vasospasm, after adjusting for Fisher grade, sex, and diabetes (OR: 0.197, 95% CI [0.07-0.55], P = .002; see Table 3). In another adjusted model accounting for Hunt and Hess clinical grade, NPAN-SAH patients were also less likely to develop vasospasm (OR: 0.2, 95% CI [0.07-0.57], P = .002). TABLE 3. Crude and Adjusted Models for the Association Between NPAN-SAH and Angiogram-Positive SAH in Patient Outcomes         Adjusted for modified      Adjusted for modified  Adjusted for Hunt and  Fisher ≥3, female    Univariable model  Fisher ≥3  Hess Grade ≥3  gender and DM  Characteristic  OR 95% CI)  P-value  OR (95% CI)  P-value  OR (95% CI)  P-value  OR (95% CI)  P-value  Global cerebral edema  0.55 (0.30, 0.99)  .049  0.52(0.28, 0.96)  .039  0.62 (0.34, 1.13)  .121  0.58 (0.31, 1.08)  .089  Rebleed  0.13 (0.02, 0.98)  .047  0.13 (0.02, 0.98)  .048  0.157 (0.02, 1.15)  .068  0.14 (0.02, 1.0)  .050  Seizure  0.44 (0.13, 1.42)  .170  0.45(0.14, 1.47)  .186  0.498 (0.15, 1.62)  .247  0.47 (0.14, 1.54)  .212  Hydrocephalus  0.78 (0.48, 1.25)  .304  0.74 (0.44, 1.23)  .251  1.0 (0.58, 1.72)  .992  0.79 (0.47, 1.33)  .380  Vasospasm  0.19 (0.07, 0.52)  .001  0.19 (0.07, 0.52)  .001  0.2 (0.07, 0.57)  .002  0.197 (0.07, 0.55)  .002  Delayed cerebral ischemia  1.64 (0.57, 4.76)  .360  1.71 (0.59, 4.97)  .320  1.754 (0.6, 5.10)  .303  1.62 (0.54, 4.87)  .384          Adjusted for modified      Adjusted for modified  Adjusted for Hunt and  Fisher ≥3, female    Univariable model  Fisher ≥3  Hess Grade ≥3  gender and DM  Characteristic  OR 95% CI)  P-value  OR (95% CI)  P-value  OR (95% CI)  P-value  OR (95% CI)  P-value  Global cerebral edema  0.55 (0.30, 0.99)  .049  0.52(0.28, 0.96)  .039  0.62 (0.34, 1.13)  .121  0.58 (0.31, 1.08)  .089  Rebleed  0.13 (0.02, 0.98)  .047  0.13 (0.02, 0.98)  .048  0.157 (0.02, 1.15)  .068  0.14 (0.02, 1.0)  .050  Seizure  0.44 (0.13, 1.42)  .170  0.45(0.14, 1.47)  .186  0.498 (0.15, 1.62)  .247  0.47 (0.14, 1.54)  .212  Hydrocephalus  0.78 (0.48, 1.25)  .304  0.74 (0.44, 1.23)  .251  1.0 (0.58, 1.72)  .992  0.79 (0.47, 1.33)  .380  Vasospasm  0.19 (0.07, 0.52)  .001  0.19 (0.07, 0.52)  .001  0.2 (0.07, 0.57)  .002  0.197 (0.07, 0.55)  .002  Delayed cerebral ischemia  1.64 (0.57, 4.76)  .360  1.71 (0.59, 4.97)  .320  1.754 (0.6, 5.10)  .303  1.62 (0.54, 4.87)  .384  View Large There was no statistical difference between the 2 groups in developing DCI after adjusting for Fisher grade, sex, and diabetes (OR: 1.62, 95% CI [0.54-4.8], P = .384) and Hunt and Hess clinical grade (OR: 1.754, 95% CI [0.6-5.1], P = .303). Additionally, after adjusting for demographics and baseline variables, NPAN-SAH patients were equally associated with rebleeding, global cerebral edema, hydrocephalus, and seizures. NPAN-SAH and Functional Outcome After adjusting for known predictors of poor outcome, including Hunt and Hess clinical grade, global cerebral edema, hydrocephalus, rebleeding, seizures, vasospasm, and DCI, NPAN-SAH patients were equally associated with poor outcome (mRS ≥ 3; OR:1.16, 95% CI [0.615-2.20], P = .6420), and death (OR: 1.22, 95% CI [0.362-4.132], P = .7455) compared to aneurysmal SAH (see Table 4). TABLE 4. Multivariable Logistic Regression Models for the Association Between NPAN-SAH and Long-Term Functional Outcomes   OR      (95% CI)  P value  Poor mRS at 3 moa  1.16 (0.615-2.20)  .6420  Deatha  1.22 (0.362-4.132)  .7455    OR      (95% CI)  P value  Poor mRS at 3 moa  1.16 (0.615-2.20)  .6420  Deatha  1.22 (0.362-4.132)  .7455  aAdjusted for HH, GCE, rebleed, delayed cerebral ischemia seizure, vasospasm, and hydrocephalus. View Large DISCUSSION Patients with NPAN-SAH were found to have a lower proportion of vasospasm, but similar odds of developing DCI, seizure, poor outcome, and death compared with aneurysmal SAH. We also found that the proportions of angiogram-negative SAH and NPAN-SAH were similar to the reported rates in the literature.4,5 NPAN-SAH and Incidence of Vasospasm, DCI Despite the fact that there was no statistically significant difference between aneurysmal SAH and NPAN-SAH in terms of Hunt and Hess grade, Fisher grade, or the development DCI, the proportion of vasospasm in the NPAN-SAH patients was 4.8%, considerably lower than the 20.8% that was observed in the aneurysmal SAH group. One possible explanation is that DCI following SAH is not solely due to cerebrovascular vasospasm but rather is now recognized to be due to interplay of several pathways contributing to its pathogenesis, including cortical spreading ischemia, microcirculatory vasoconstriction and thrombosis, and early brain injury cascades.22,23 NPAN-SAH and Clinical Course Another area in which our study found differences when compared to previous studies related to the development of hydrocephalus as a consequence of the SAH. Thirty-two percent of our NPAN-SAH group developed hydrocephalus, values which were closer to our aneurysmal SAH group (37.8%) than to any cohort analyzing NPAN-SAH patients. Other studies found incidence rates between 6% and 19% but failed to describe the incidence of hydrocephalus in the NPAN-SAH subgroup.4,5,24 Our incidence is similar to the incidence reported by DH Kang et al22 at 37.9%.22 Hemorrhage within the subarachnoid space has been postulated to obstruct and impair cerebrospinal fluid flow and absorption, precipitating the development of a pressure gradient and consequently hydrocephalus. Hence, it is likely that due to the similar blood distribution between the aneurysmal SAH and NPAN groups, the same degree of subarachnoid space compartmentalization may occur resulting in similar rates of hydrocephalus. Furthermore, NPAN-SAH patients were equally associated with rebleeding and seizures as aneurysmal SAH patients. The close proximity of the hemorrhage to the medial temporal lobes may explain the equivalent association of seizures in patients with NPAN and aneurysmal SAH explaining why there was no difference in the 2 subgroups in our study. NPAN-SAH and Outcome Previously published studies of angiogram-negative SAH included perimesencephalic SAH, which is characterized by a more favorable outcome. This could bias the results considering the perimesencephalic SAH subgroup is not typically representative of NPAN-SAH.4 The clinical course of NPAN-SAH remains poorly characterized where some studies described a favorable outcome while others described complicated clinical courses punctuated by both vasospasm and DCI.15,22,24 These studies however compared NPAN to perimesencephalic SAH instead of comparing them to matched controls of aneurysmal SAH.5 Additionally, due to the small numbers of enrolled patients, these studies lacked sufficient power to more precisely delineate the prognosis.22 While other studies have found that, in general, idiopathic SAH patients tend to have good functional outcomes, we once again stress the fact that perimesencephalic SAH patients were included in that group. In 2009, Gupta et al15 analyzed 292 patients admitted with SAH, 59 of whom were determined to have a NPAN-SAH. This study excluded patients who died and examined the outcomes of the survivors, hence determining that NPAN-SAH patients tend to have an overall better prognosis when compared to aneurysmal SAH patients. Exclusion of NPAN patients who were deceased was a major bias of that study, which the authors acknowledged.15 Theories abound regarding why NPAN-SAH—despite having lower grade hemorrhages compared to aneurysmal SAH—have equally associated poor outcomes and death, and remain speculative in nature. While NPAN-SAH may be venous in origin, another postulated etiology is from an arterial leak from perforators just prior to their entry into substance of the brainstem. Limitations Several limitations to our study deserve mention. Although we utilized a prospectively maintained database, our study was retrospective in nature, lacked randomization, and was conducted in a single center. We did not study CT head results regarding which patients with DCI developed cortical vs subcortical strokes, which deserves further investigation. And while our finding that a higher percentage of diabetics were seen in the NPAN-SAH group was certainly significant, it did not produce a difference in outcome once adjusted for diabetes. However, since our institution is a busy tertiary referral center which receives patients with a broad variety of comorbidities, demographics, and manifestations of this devastating neurological disease, we feel that our results may be generalizable. CONCLUSION Although the risk of vasospasm may be lower, patients with NPAN-SAH are equally associated with DCI, poor outcome, and death as compared to patients with aneurysmal SAH hence caution should be applied. These results and others collectively suggest that NPAN-SAH patients behave more comparably to angiogram-positive SAH in both clinical course and outcome. Further studies may be necessary to clarify these findings. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. This work was presented at the Neurocritical Care Society 13th Annual Meeting in Scottsdale, Arizona, October 7-10, 2015. REFERENCES 1. van Gijn J, Kerr RS, Rinkel GJ. Subarachnoid haemorrhage. Lancet (London, England) . 2007; 369( 9558): 306- 318. Google Scholar CrossRef Search ADS PubMed  2. Hop JW, Rinkel GJ, Algra A, van Gijn J. Case-fatality rates and functional outcome after subarachnoid hemorrhage: a systematic review. Stroke . 1997; 28( 3): 660- 664. Google Scholar CrossRef Search ADS PubMed  3. Broderick JP, Brott TG, Duldner JE, Tomsick T, Leach A. 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Special features of subarachnoid hemorrhage of unknown origin: a review of a series of 179 cases. Neurolog Res . 2012; 34( 1): 91- 97. Google Scholar CrossRef Search ADS   COMMENTS The authors have prepared a manuscript on the functional outcomes and delayed cerebral ischemia following non-perimesencephalic angiogram negative subarachnoid hemorrhage (NPAN-SAH) that appear similar to aneurysmal SAH on imaging. It is well known that patients with perimesencephalic hemorrhage have a much better outcome than aneurysmal SAH. This manuscript evaluates the clinical outcomes of NPAN-SAH in a prospective manner. The authors identified 191 (11%) from a total of 1311 patients with spontaneous SAH. The authors found that although the risk of vasospasm may be lower, patients with NPAN-SAH are equally associated with DCI, poor outcome and death as compared to patients with aneurysmal SAH. This is an interesting paper and may reflect the difference in etiology as many surgeons believe that the classical perimesencephalic hemorrhage is of venous origin and a true aneurysmal subarachnoid hemorrhage and this non-perimesencephalic SAH are arterial. This may warrant long-term imaging in the non-perimesencephalic SAH cohort and more so than in the classic mesencephalic hemorrhage, which often only have 2 angiograms and if they are negative are often not seen again. It will be interesting to see if these non-perimesencephalic SAH develop aneurysms long-term. Gavin W. Britz Houston, Texas This is an interesting article addressing an important clinical issue; non-aneurysmal subarachnoid hemorrhage seems to come in 1 distinct "flavors", perimesencephalic and non-perimesencephalic (or as the authors call it "non-perimesencephalic angiogram-negative SAH, NPAN-SAH). The authors correctly intuited that these 2 conditions present differently and are associated with different outcomes, and with their study have now documented this more clearly and in the process raised some issues worthy of further investigation. In particular, the finding that the distribution of subarachnoid blood in the suprasellar, interhemisperic cisterns and sylvian (basal and lateral) fissures, in close proximity to the Circle of Willis, likely plays a role in approximating the risk of delayed cerebral ischemia to that of SAH regardless of the presence or absence of the aneurysm is incredibly interesting, and begs the question of how delayed cerebral ischemia is linked biologically to vasospasm, in spite of the growing evidence that vasospasm (a radiographic diagnosis) is not inherently/causally linked to delayed cerebral ischemia (a clinical and sometimes radiographic diagnosis). This contribution is also important because it reminds all of us who care for patients with non-aneurysmal SAH that a clean angiogram does not mean the patient is "out of the woods". James Towner G. Edward Vates Rochester, New York The authors have performed a systematic retrospective review of a large number of subarachnoid hemorrhages (SAH) at a single institution. They found that nearly 5% of these SAH were found to be non-perimesencephalic angiogram negative (NPAN-SAH). Somewhat surprisingly, the NPAN-SAH group showed similar overall outcome to the patients that harbored ruptured aneurysms. The authors showed that the NPAN-SAH group had a higher proportion of men, history of diabetes, and a lower incidence of cocaine use on presentation. Despite a significantly lower risk of cerebral vasospasm, the NPAN-SAH group showed similar rates of delayed cerebral ischemia (DCI) as the aneurysm group. This finding is surprising and somewhat hard to explain by the data shown. We do believe that patients with DCI should be better evaluated for the source of their ischemia. Better evaluation of axial imaging may shed light on the types of DCI that a patient experiences. (The size and location of the infarcts, whether cortical or subcortical). Certainly, this finding of equivalent degrees of DCI and poor outcome despite remarkably lower frequency of vasospasm deserves a closer look in additional studies. The authors found equivalent clinical (mRS) outcomes. One possible reason could be that men do less well following SAH than women, which would skew the results in favor of the aneurysmal group. Also, the finding that a higher percentage of diabetics were seen in the NPAN-SAH group is possibly important. A careful and deeper evaluation of patients that did poorly should be obtained in following studies (Is poor outcome related to other risk factors? Is the hospitalization period complicated with general/neurological complications?). Overall, we congratulate the authors for a valuable study and while raising many questions does suggest that a SAH and NPAN-SAH have similar features post-intensive care unit and that the non-aneurysmal patients should be managed aggressively so as to allay the inherent risks of these dangerous bleeds. Erez Nossek David J. Langer New York, New York Copyright © 2017 by the Congress of Neurological Surgeons

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NeurosurgeryOxford University Press

Published: Mar 1, 2018

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