Introduction Cerebral collateral circulation has been studied extensively in ischemic stroke where it has been shown to be a predictor of reperfusion, final infarct size, and outcome. Little is known about the significance of the collaterals in the setting of aneurysmal subarachnoid hemorrhage (aSAH). We sought to evaluate the effect of cerebral vasospasm on the development of cerebral collaterals following aneurysmal subarachnoid hemorrhage and the effects of the latter on delayed cerebral ischemia (DCI).
Methods We retrospectively evaluated 64 aSAH patients with evidence of DCI between day 5 and 7, enrolled in a prospectively maintained observational cohort study. Angiograms were evaluated by four blinded neurointerventionalists. We compared good collateral grades to poor collateral grades, additionally we compared enrolled individuals with any collaterals versus patients who had no collaterals.
Results Inter-rater reliability for collateral grades was substantial (weighted kappa 0.632). Mild vasospasm was more frequent in patients with poor collateral grades compared with patients with good collateral grades (32% vs 4% P=0.012). There was no difference between the collateral groups with regards to DCI, functional, or cognitive outcome. Patients adjudicated to have any collaterals were more likely to have severe vasospasm (62% vs 33% P=0.023) and less likely to have mild vasospasm (37% vs 9% P=0.007). In a multivariable model, vasospasm severity remained associated with collateral status, while aneurysm location was not.
Conclusions The severity of vasospasm following aSAH was associated with the development of collaterals. There was no difference between collateral grades with regards to DCI or outcome.
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Delayed cerebral ischemia (DCI) following aSAH has been strongly associated with poor functional and cognitive outcome, however, cerebral vasospasm as a primary mechanism underlying DCI has been called into question and alternative mechanisms have been postulated.1–8
Despite the prevalence of radiographic vasospasm being up to 70% of patients, DCI occurs only in approximately 30% of patients. A number of hypotheses may underlie this dissociation: mild or even moderate degrees of vasospasm may not necessarily be hemodynamically significant; vasospasm is associated but not causally related to DCI; and current measures of vasospasm severity typically do not take collateral flow or brain tissue perfusion information into account.
Cerebral collateral circulation has been extensively studied in the ischemic stroke literature, in which the collateral vessel status has been shown to be an independent predictor of reperfusion, final infarct size, and clinical outcome.9 Observations from recent ischemic stroke literature suggest that highly variable cerebral perfusion via the collateral circulation may primarily determine infarct growth dynamics, and we believe this has implications for patients with significant vasospasm after aSAH.10 However, current literature provides scant evidence on the significance of the cerebral collateral circulation in patients with aSAH who develop clinically significant vasospasm. Here, we investigated symptomatic vasospasm in patients with aSAH and the association with collateral circulation, in order to assess the clinical importance of this phenomenon.
Our primary hypothesis was that severity of symptomatic vasospasm is correlated with the presence of collateral circulation. Additionally, we hypothesized that the development of delayed cerebral ischemia (DCI) would be more frequent in patients with poor collateral grades, and third that the presence of good collaterals might be associated with more favorable clinical outcome 3 months after the aSAH.
We retrospectively evaluated 64 consecutively admitted aSAH patients with clinical and radiological evidence of symptomatic vasospasm, admitted to the Neurological Intensive Care Unit between August 2005 and June 2014 and enrolled in the propectively maintained SAH Outcomes Project (SHOP). The study was approved by the Columbia University Medical Center Institutional Review Board and informed consent was acquired from the patient or a surrogate in all cases. Patients included in the study had clinical evidence of DCI, CT angiographic evidence of vasospasm in the anterior circulation, and had undergone repeat diagnostic cerebral angiograms between day 5 and 7 after aneurysmal rupture. Patients under 18 years of age, or with non-aneurysmal SAH secondary to trauma, arteriovenous malformation rupture, and perimesencephalic bleeds were excluded.
Clinical management was in accordance with the American Heart Association and the Neurocritical Care Society aSAH guidelines.11 12 On admission, all patients underwent diagnostic cerebral angiograms followed by securement of the ruptured aneurysm via either endovascular coiling or surgical clipping within 24 to 48 hours of ictus. Hypertensive euvolemic therapy (HHT) was initiated for patients with acute onset of DCI as well as for poor grade patients with severe angiographic vasospasm.13 All patients enrolled in this study developed DCI between day 5 and 7 after aneurysmal rupture, and subsequently underwent a repeat diagnostic cerebral angiography with the intent to treat with intra-arterial vasodilator (calcium channel blocker, verapamil) infusion at the discretion of the neuroendovascular surgeon, and in accordance with our institutional standard of care.14
Digital subtraction angiograms (DSA) were independently reviewed by a neurointensivist and two neurointerventionalists, all of whom were blinded and had received extensive training in evaluating varying degrees of vasospasm and collaterals. The reviewers compared the initial angiogram on admission to the repeat DSA on days 5 to 7 in order to determine the presence, location, severity of vasospasm, and collateral circulation status. A fourth, senior neurointerventionalist was invoked as the tiebreaker when there was a discrepancy between the three readers on collateral vessel grade. Raters were blinded to all other imaging and clinical data throughout the entire review process. Weekly clinical meetings allowed for prospective adjudication of pertinent clinical and radiographic data points. Documentation of level of functioning was performed via scheduled 3-monthly follow-on interviews with the patients and/or their families.
Clinical and radiological variables
The diagnosis of aSAH was established by CT and CT angiography (CTA) or by the presence of blood and/or xanthochromia of the CSF if the initial CT scan was inconclusive. All patients received digital subtraction angiography (DSA) to characterize the underlying ruptured aneurysm. Neuroradiologic grades were classified by the modified Fisher grade.15 Delayed cerebral ischemia from cerebral vasospasm was defined as: clinical deterioration (i.e., a new focal deficit, decrease in level of consciousness, or both); and/or a new infarct on CT that was not visible on the admission or immediate postoperative CT scan, thought to be secondary to vasospasm.15
The presence and quality of cerebral collateral circulation was based on a comparison between the initial admission angiogram and the repeat DSA on days 5 to 7. The quality of the collateral circulation was assessed using a modification of the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) Collateral Flow Grading System.16 This scale assigns patients to Grade 0 (no collateral vessels visible), Grade 1 (slow collateral blood flow to the periphery of the ischemic site, supplied by the vasospastic vessel, with persistence of some of the defect), Grade 2 (rapid collateral blood flow to the periphery of the ischemic site, supplied by the vasospastic vessel, with persistence of some of the defect), Grade 3 (collateral flow with slow but complete angiographic blood flow of the ischemic bed by the late venous phase), and Grade 4 (complete and rapid collateral blood flow to the vascular bed in the entire ischemic territory by retrograde perfusion) (figure 1).
Cerebral vasospasm was based on a comparison between the initial admission angiogram and the repeat DSA on days 5 to 7. Vasospasm was defined as luminal narrowing relative to the normal widths of vessels on DSA, before or after the advent of vasospasm, respectively. Mild cerebral vasospasm was defined as <30% luminal narrowing, moderate cerebral vasospasm as between 30% and 50% luminal narrowing, and severe cerebral vasospasm as >50% luminal narrowing. Intra-arterial verapamil infusion were administered at the discretion of the neuroendovascular surgeon and in accordancewith our institutional protocols.14
The primary outcome measure was the association of collaterals with the degree of vasospasm. The secondary outcome was the development of DCI in patients with poor collateral grades.17 The modified Rankin Scale (mRS) was assessed by in-person interview or structured telephone interview at 3 months' post discharge.18 19 Poor outcome was defined as requiring some help, requiring much help, constant nursing care, or death (mRS scores 3 to 6), while good outcome was attributed to patients with an mRS scores of 0 to 2.11 20 21
Data analyses were performed with the IBM Statistical Package for the Social Sciences (SPSS, version 23). P≤0.05 were considered significant.
The inter-observer agreement was measured using a weighted kappa.22 Logistic regression analysis was used to identify the association of collateral grades and outcome and to determine differences between patients with and without cerebral collateral circulation. Two models were created comparing poor collaterals grades (ASITN/SIR 0,1,2) with good collaterals (ASITN/SIR 3,4) and another model compared any collaterals (ASITN/SIR 1,2,3,4) with no collaterals (ASITN/SIR 0). Multivariable models were generated using candidate variables with univariate associations. Tests for interactions were performed for all significant variables retained in baseline multivariable models.
The inter-observer agreement between reviewers was determined using Cohen’s kappa statistics.22 23 Kappa (κ) is standardized to lie on a −1 to 1 scale, where 1 is perfect agreement, 0 is exactly what would be expected by chance, and negative values indicate agreement less than chance. According to Landis and Koch, a κ value <0 indicates no agreement and 0–0.20 as slight, 0.21–0.40 as fair, 0.41–0.60 as moderate, 0.61–0.80 as substantial, and 0.81–1 as almost perfect agreement.23 The agreement on interpreter opinions are considered to be acceptable beginning at a correlation co-efficient of 0.41–0.60.22
In this cohort of aSAH patients enrolled between the years of 2005 and 2015, 64 patients met our inclusion criteria. Inter-rater reliability for the collateral grades, measured using the weighted kappa statistic was 0.632, implying substantial agreement. Good collateral grades (ASITN/SIR 3–4) were seen in 35% of our patients while 64% had poor collateral grades (ASITN/SIR 0–2). There was no statistically significant difference between the good collateral group and the poor collateral groups in terms of demographics, past medical history, baseline clinical Hunt Hess grades, radiographic characteristics as well as complications.
In a univariate comparison, patients with poor collateral grades were more likely to have mild vasospasm compared with patients with good collateral grades (32% vs 4% P=0.012)(table 1). Additionally, anteriorly located aneurysms were significantly more prevalent in patients with good collateral grades than in patients with poor collateral grades (78% vs 51%, P=0.033). There was no difference in outcomes between the collateral groups with regards to DCI, functional, or cognitive outcome.
In a second statistical model, we compared patients with any collaterals to patients with no collaterals. Patients with severe vasospasm were more likely to have any collaterals (62% vs 33% P=0.023). Patients with mild vasospasm were less likely to have collaterals (37% vs 9% P=0.007). In this model, again, anteriorly located aneurysms were associated with the development of collaterals (74% vs 47% P=0.028) (table 2). Multivariable models were generated using only those variables as input variables that were statistically significantly different between the collateral groups in univariate comparisons. Here, vasospasm severity remained associated with collateral status, while aneurysm location did not(table 3).
In this study of 64 aSAH patients with radiographic and clinical cerebral vasospasm, we found that vasospasm severity was associated with the development of collaterals. Our study did not show an association between collateral grades and the development of DCI or functional outcome.
A number of observations have motivated this controversy: delayed infarction may occur in patients without proximal vasospasm;2 24 pharmacological agents that reduce rates of moderate to severe vasospasm have not been shown to improve outcomes; 25–27 and one of the few treatments with proven efficacy in this setting (eg, oral nimodipine) has not been shown to improve cerebral vasospasm.28 Contrary to the above findings, there is a strong correlation between the severity of cerebral vasospasm and the incidence of cerebral infarction.27
The exact underlying mechanism of injury leading to DCI is still poorly understood and likely multifactorial and interdependent. The vast majority of research on the etiology of vasospasm and DCI in aSAH has focused on spasmogenic and neuroinflammatory substances generated from the lysis of subarachnoid blood, or released from the arterial wall acutely after SAH. Substances such as serotonin,29 arginine vasopressin (AVP),30 and hypoxia inducible factor-1 (HIF-1)31 have been implicated, as well as an alteration of the endothelial nitrous oxide pathway,32 and endothelin-1 receptor activation.33 34 Additionally, pro-inflammatory cascades involving IL-6, IL-1, and tumor necrosis factor-alpha35 have been shown to be critical in the development and maintenance of cerebral vasospasm following SAH.36–38
Currently, the role of proximal vasospasm in DCI remains controversial.7 Neurologic or cognitive decline may occur in the absence of vasospasm, and, conversely, some patients with cerebral vasospasm do not show overt clinical deterioration. The CONSCIOUS (Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage) trials were randomized, double-blind, placebo-controlled trials examining the effect of intravenous Clazosentan, an endothelin receptor antagonist. Clazosentan significantly decreased moderate and severe vasospasm in CONSCIOUS-1, however, CONSCIOUS-3 was halted prematurely when it failed to improve outcome.27
Conflicting pharmacologic data also lends to the current controversy regarding the contribution of cerebral vasospasm toward DCI. Agents that reduce rates of moderate to severe vasospasm have not been shown to improve outcome, whereas nimodipine has been shown to improve outcome without an impact on cerebral vasospasm.28 In a landmark multi-institution, prospective, double-blind, randomized, placebo-controlled trial examining the effect of nimodipine in subarachnoid hemorrhage revealed improved outcomes in the nimodipine group.39 40 Although the exact mechanism of action of Nimodipine is still incompletely understood, nimodipine has been postulated to mediate its effects by dilation of collateral circulation.41–43
The cerebral collateral circulation is an ancillary complex circuit of vascular channels that becomes recruited to augment cerebral blood flow when the primary network fails secondary to thromboembolism and or hemodynamic insufficiency.44 Pathophysiological recruitment of cerebral collateral circulation has been extensively studied in the ischemic stroke literature, and has been shown to have dramatic effects on reperfusion, final infarct size, and clinical outcome, with collateral vessel status independently predicting all three outcomes.9 45–47 Here, we investigated symptomatic vasospasm in patients with aSAH and the association with collateral circulation, in order to assess the clinical importance of this phenomenon.
The discrepancy between the incidence of angiographic and clinical vasospasm may be explained by differences in the location and degree of arterial narrowing, and the adequacy of collateral circulation.48 Current measures of vasospasm severity often do not incorporate collateral flow or perfusion information, perhaps best assessed through combining angiographic and perfusion imaging.4 Studies have shown that patients have variable hemodynamic reserve and respond differently to flow limitation, a topic of particular interest in the ischemic stroke literature.10 These observations suggest that highly variable cerebral perfusion via the collateral circulation may primarily determine infarct growth dynamics, and we believe this has implications for patients with significant vasospasm after aSAH.
Studies examining the relationships between collateral circulation, vasospasm, and DCI in the context of subarachnoid hemorrhage are limited. In animal models examining SAH, studies have shown that vasospasm was associated with better outcomes in participants with good collaterals, compared with those with absent collaterals.49 Another study examined the extent of collateralization, and the ability to predict symptomatic cerebral vasospasm among pediatric patients. In this population, despite the presence of moderate to severe cerebral vasospasm, patients rarely became symptomatic and tended to have good outcomes. This was believed to be due to the presence of robust cerebral collateral blood flow.50
The recruitment of secondary collaterals, such as leptomeningeal anastomoses, requires time to develop once primary routes have failed.44 Perhaps, severe vasospasm initiates an accelerated chronology of secondary leptomeningeal recruitment, as was demonstrated in our population. Furthermore, patients in our study with mild vasospasm were less likely to have collateral circulation (37% vs 9% P=0.007). It is postulated that local cerebral ischemia may trigger the release of angiogenic peptides that in turn form collaterals.51 Thus, perhaps only patients with severe vasospasm preferentially release such angiogenic peptides, while those same substances are withheld in patients with mild or moderate vasospasm.
Although the significance of this finding remains unclear, we found that patients with severe vasospasm were more likely to have collateral circulation (62% vs 33% P=0.023). Studies examining regional cerebral blood flow have demonstrated diminution of cortical cerebral blood flow where there is an underlying subcortical infarction.44 Thus, it is possible that regional areas of subcortical ischemia in areas of severe vasospasm may trigger more distal leptomeningeal collateral recruitment in certain patients. Furthermore, although a direct causation has not been demonstrated but chronic hypoperfusion due to arterial flow restriction has been postulated to trigger the development of collaterals.44 The presence of secondary collateral pathways is considered a surrogate marker of cerebral hemodynamics failure with resultant clinical symptoms developing secondary to collateral failure. Similarly, we hypothesize that the presence of collateral circulation may be a marker of impaired hemodynamic function in those patients with severe vasospasm.
Our study has a number of limitations including its retrospective, observational design. While kappa statistics describing inter-rater variability have been used in clinical research, they have primarily been validated in sociology-related studies.
While the kappa is one of the most commonly used statistics to test interrater reliability, it has limitations. Judgments about what level of kappa should be acceptable for health research are questioned. Cohen’s kappa have been suggested to be too lenient for health-related studies, hence it is recommended that only scores above 0.61 (corresponding to substantial to almost perfect agreement) be considered acceptable in healthcare studies. Despite our efforts to standardize the training of the reviewers (reviewing cases with varying degree of vasospasm with the neuroendovascular surgeon) and to minimize the likelihood of major discrepancies (presence of a tie-breaker) we cannot definitely say that there was no misinterpretation of the degree of collateral circulation as there is not a validated ‘gold standard’ against which to judge. Although the determination of angiographic vasospasm was performed by reviewers who were blind to outcome, the study was underpowered to detect a relation to outcome, hence it remains unknown whether the presence of collaterals is clinically relevant to DCI risk and outcome. Future studies will likely have to be multicenter studies in order to reach sufficient power to examine the relations to outcomes.
Our study demonstrated that the severity of vasospasm following aSAH is associated with the development of collaterals in patients with radiographic vasospasm. We could not, however, demonstrate a correlation between collateral grades with neither the development of DCI or outcome.52 53
Contributors Study concept and design: FA-M. Acquisition, analysis, or interpretation of data: all authors. Drafting the article: FA-M. Critically revising the article: FA-M. Administrative, technical, or material support: FA-M. Statistical analysis: FA-M. Study supervision: FA-M.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.
Competing interests None declared.
Patient consent Detail has been removed from this case description/these case descriptions to ensure anonymity. The editors and reviewers have seen the detailed information available and are satisfied that the information backs up the case the authors are making.
Ethics approval Columbia University Institutional Board Review Committee.
Provenance and peer review Not commissioned; externally peer reviewed.
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