Abstract
Purpose
Investigating the associations between cerebral small vessel disease (cSVD) burden and cerebral vasospasm (CVS), delayed cerebral ischemia (DCI) and clinical outcomes in patients with aneurysmal subarachnoid hemorrhage (aSAH).
Methods
Consecutive aSAH patients with initial (<7 days after onset) and 3-month follow-up brain magnetic resonance imaging (MRI) and clinical evaluation at 6 months were included. The cSVD burden score was built using MRI criteria. CVS was defined according to transcranial Doppler examination and computed tomography (CT) or digital subtraction angiography. DCI was defined by the appearance of hyperintense fluid-attenuated inversion recovery lesions, with territorial or cortico-subcortical distribution, between initial MRI and 3-month MRI. The modified Rankin scale of ≤2 at 6 months was considered a favorable outcome. Using univariate and multivariable analyses, we investigated the associations between cSVD and CVS, DCI and clinical outcome.
Results
A total of 113 patients were included in the study sample (median age 49.1 years (IQR 42.1–60.8), 70/113 females). The burden of cSVD was mild with a median of 0 (IQR 0–1). When comparing patients with no/mild versus those with moderate/severe cSVD burden, we did not find a univariable difference regarding vasospasm occurrence (60% versus 46.1%, p = 0.54), DCI (20.2% versus 23%, p = 0.66) or favorable outcome at 3 months (94% versus 83.3%, p = 0.20). There was a univariable trend towards more frequent favorable outcome in patients with no/milde white matter hyperintensities versus those with moderate/severe white matter hyperintensities (92% versus 85%, p = 0.09). In multivariable models, cSVD markers were not associated with CVS occurrence and severity, DCI or clinical outcome.
Conclusions
In patients with mild aSAH, the burden of cSVD as assessed by MRI is minimal and is not associated with CVS, DCI or clinical outcome.
Keywords: Cerebral small vessel disease, aneurysmal subarachnoid hemorrhage, cerebral vasospasm, delayed cerebral ischemia, clinical outcome
Introduction
Cerebral small vessel disease (cSVD) relates to the chronic alteration of smaller arterioles, capillaries and venules of the brain, and plays a key role in brain ageing and neurodegeneration.1 Its burden can be assessed by the visual assessment of resulting structural brain damage imaged routinely using clinical level magnetic resonance (MR) imaging (MRI) markers that includes white matter hyperintensities (WMHs), lacunes of presumed vascular origin, cerebral microbleeds (CMBs) and global cortical atrophy.2 These cSVD markers have been consistently shown to strongly influence outcome in patients with ischemic stroke as well as primary intracerebral hemorrhage, hypothetically due to their cumulative impact on brain network efficiency, but also due to their associations with recurrence risk and independent higher susceptibility to ischemia.3,4
On the other hand, aneurysmal subarachnoid hemorrhage (aSAH), a disease of larger sized vessels, is amongst the deadliest forms of stroke and, despite its relative scarcity, causes major healthcare consequences and represents an important socio-economic burden.5 Much of its morbi-mortality is due to cerebral vasospasm (CVS), maximal 7–10 days after onset, triggered by the presence of blood in the subarachnoid spaces, and associated with delayed cerebral ischemia (DCI),6 persistent neurological deficits and long-term neurological disability.7
Recent data have highlighted the role of white matter structural integrity in the early prognostication of patients with aSAH.8 These data showed that a decrease of tissue microstructural integrity was associated with poor functional outcomes and DCI occurrence in aSAH patients, raising the question of potential associations between acute consequences of CVS and chronic alteration of microvasculature function as well as pre-existing cSVD-related brain damage. Similar findings in acute ischemic stroke9 further reinforce the suggested role of cSVD in determining outcome in patients with acute cerebro-vascular insult, and prompt the question of the broader role of cSVD with regards to aSAH patients’ evolution.
In this context, the association between small vessel disease (SVD) burden and CVS and DCI as well as functional outcomes in aSAH patients has never been assessed.
In a retrospective analysis of prospectively collected data, we tested the hypothesis that aSAH patients with higher cSVD burden (assessed by clinical level MRI biomarkers) would experience more frequent CVS occurrence, more frequent DCI and poorer 6-month clinical outcome.
Patients and methods
Study design
This study was a retrospective review of prospectively collected data from consecutive patients presenting with aSAH at a single academic hospital. Baseline and follow-up clinical imaging protocol for the included patients is summarized in Figure 1.
Figure 1.
Baseline and follow-up clinical imaging protocol for included patients.
aSAH: aneurysmal subarachnoid hemorrhage; CT: computed tomography; DCI: delayed cerebral ischemia; GOSE: Extended Glasgow Outcome Scale; MRI: magnetic resonance imaging; mRs: modified Rankin scale.
Patient selection
Adult patients with subarachnoid hemorrhage of aneurysmal etiology after adequate work-up treated between January 2011 and May 2017 at our center were screened for eligibility. All patients were treated according to a standard institutional protocol along the recruitment period. For the present analysis, we restricted the patient sample to patients meeting the following criteria: (a) saccular degenerative aneurysm; (b) initial imaging work-up including MRI within 7 days of symptoms onset; (c) follow-up MRI at ≈3 months; and (d) clinical evaluation at 6 months. Patients with other or unknown etiology for the subarachnoid bleed, with infectious or traumatic aneurysms, or deceased before 3 months following ictus were excluded. Clinical severity was assessed using the Hunt and Hess scale, a grading system ranging from 1 (asymptomatic) to 5 (coma, decerebrate posturing).10
Imaging acquisition and analysis
Initial imaging characteristics were rated on a baseline computed tomography (CT) scan, using the modified Fisher CT scale,11 as well as the Hijdra scale.12 CT scans were also rated for presence of hydrocephalus at admission (temporal horn dilatation) and intraparenchymal and/or sylvian fissure hematoma. Aneurysmal etiology was based on CT angiography as well digital subtraction angiography.
All included patients underwent, at the attending senior neuroradiologist’s discretion, a standardized 1.5T MRI examination on a 1.5-Tesla Signa MR Unit (General Electric Healthcare, Milwaukee, WI, USA) using an 8-channel phased array coil including at least two-dimensional axial fluid-attenuated inversion recovery (FLAIR), axial T2 gradient recalled echo (GRE) (T2*), axial diffusion weighted imaging, sagittal T1 and three-dimensional time of flight MR angiography (TOF MRA).
The diagnosis of subarachnoid hemorrhage was ascertained by the presence of a FLAIR hyperintensity in the basal cisterns, the cortical sulci and/or sylvian fissures with conclusive accompanying symptomatology, as per current practice guidelines.13
The aneurysmal etiology was established based on the presence of a saccular aneurysm, corresponding bleed location and/or abundance, and in the absence of concurrent cause.
cSVD markers were reviewed blinded to clinical data by two trained observers in consensus, according to the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE).19 WMHs of presumed vascular origin were classified into periventricular and deep and rated using the 0–3 Fazekas scale.2 Cerebral microbleeds’ (CMBs) presence and number were evaluated on axial T2*-GRE using current consensus criteria.2 Enlarged perivascular spaces (EPVSs) were assessed on axial T2-weighted MR images, when available, alternatively on T2*, in the basal ganglia and centrum semiovale, using a validated 4-point visual rating scale,14 with a prespecified dichotomized classification of EPVS degree as high (score >2) or low (score ≤2) in accordance with previous cSVD studies.15 Global atrophy was rated on sagittal brain T1-weighted imaging, according to a previously validated 0–3 scale,16 where 3 represents severe atrophy. We dichotomized patients into those with no or mild atrophy (0–1) and those with moderate to severe atrophy (2–3). Lacunes were defined according to the STRIVE criteria, as round or ovoid fluid-filled cavities between 3 and 15 mm in diameter.2
The cSVD burden score was built using the above-mentioned markers, as per the previously validated SVD score by Staals and colleagues.1 As in previous works, cSVD burden was defined as none, mild, moderate or severe for scores of 0–4, respectively.
Images were assessed by two raters (GB, neuroradiologist with 9 years’ experience in radiology; AV, radiology resident with 4 years’ experience).
Imaging follow-up
Cerebral vasospasm assessment
Per institutional protocol, all patients admitted for aSAH are monitored daily by transcranial Doppler. Vasospasm was defined for the anterior circulation as a Lindegaard ratio (i.e. the ratio of the middle cerebral artery (MCA) mean flow velocity to upper cervical internal carotid mean flow velocity) >3 with mean flow velocity >120 cm/s for the MCA and mean flow velocity >90 cm/s for the anterior cerebral artery (ACA).17 Severe vasospasm was defined for the MCA as a Lindegaard ratio >5 and/or appearance of a focal neurological deficit with no concurrent cause, and for the ACA as mean flow velocity ≥100 cm/s. For the posterior circulation a modified Lindegaard ratio (i.e. the ratio of basilar artery mean flow velocity to extra-cranial vertebral artery) >2 with mean flow velocity >80 cm/s, considered severe if modified Lindegaard ratio >3 and/or appearance of a focal neurological deficit with no concurrent cause.18
Delayed cerebral ischemia
At our institution, follow-up at 3 months includes a 1.5T MRI with at least an axial FLAIR and 3D TOF MRA, using the same sequence parameters as the baseline MRI. At the 3-month follow-up MRI, DCI was defined as the interval appearance of hyperintense FLAIR lesions, with territorial or cortico-subcortical distribution.13
Clinical follow-up
Patients were received at an outpatient consultation at 6 months following ictus, and functional status was prospectively ascertained and collected as per the modified Rankin scale (mRs), defined as favorable if the score ≤2.
Statistical analysis
Continuous variables were summarized using means (SDs) or medians (interquartile ranges (IQRs)) where appropriate, and discrete variables were summarized using counts (percentages). Chi-square test, Fisher exact test, t test and Mann–Whitney test were used as appropriate for the univariate analysis, with a p-value < 0.05 as the threshold for statistical significance. Separate multivariable logistic regression models were used to determine factors that were independently associated with CVS occurrence, DCI at 3 months and favorable outcome at 6 months, with a prespecified adjustment for age and the baseline modified Fisher scale and then backward elimination was used to remove non-significant variables (p > 0.05). The effect of cSVD score on each of these outcomes was evaluated after dichotomization into no/mild and moderate/severe categories. Sensitivity analyses used the same approach, with cSVD modelled as a continuous variable.
Ethics
All aspects of the study were in respect to the General Data Protection Regulation and actual French law and ethics in health related research. As for all observational studies with retrospective analysis of routinely acquired data, written informed consent was waived, and patients could oppose the use of their health-related data.
Manuscript preparation
The manuscript was prepared in accordance with the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) statement.9
Results
Patient characteristics
Amongst 351 patients screened for inclusion, 113 were included in the study sample. Patients were most commonly excluded for the absence of baseline MRI (n = 122). See Figure 2 for the detailed flowchart of patient selection.
Figure 2.
Study flow chart.
aSAH: aneurysmal SAH; MR: magnetic resonance; SAH: subarachnoid hemorrhage.
Excluded patients did not differ from included patients, except for older age (53.9 years versus 49.1; p = 0.008) and for being less frequently active smokers (p < 0.001). Initial clinical and imaging severity, assessed using Hunt–Hess grading or Fisher scale, were similar.
Detailed characteristics of included patients are presented in Table 1.
Table 1.
Patients’ baseline characteristics.
| Baseline characteristics | All patients (n = 113) |
|---|---|
| Age (years) | 49.1 (42.1–60.8) |
| Female sex | 70 (61.9%) |
| Diabetes | 6 (5.3%) |
| High blood pressure | 49 (43.4%) |
| Smoking status | |
| Active | 13 (11.5%) |
| Previous | 43 (38.1%) |
| Never | 57 (50.4%) |
| Dyslipidemia | 20 (17.7%) |
| Vascular diseasea | 6 (5.3%) |
| Initial severity | |
| Aneurysm location | |
| Anterior | 102 (90.3%) |
| Posterior | 11 (9.7%) |
| Initial GCS | 15 (14–15) |
| Hunt & Hess scale | |
| 1 | 53 (46.9%) |
| 2 | 33 (29.2%) |
| 3 | 22 (19.5%) |
| 4 | 1 (0.9%) |
| 5 | 4 (3.5%) |
| Modified Fisher scale | |
| 1 | 10 (8.8%) |
| 2 | 13 (11.5%) |
| 3 | 17 (15%) |
| 4 | 73 (64.6%) |
| Cisternal Hijdra grade | 17 (6–24) |
| Ventricular Hijdra grade | 0 (0–0) |
| Acute hydrocephalus | 31 (27.4%) |
Variables are presented as absolute number (% of total) or median (inter quartile range).
Vascular disease: other vascular condition linked to vascular risk factors (acute myocardial infarction or coronary disease, lower limb symptomatic atherosclerosis, atherosclerotic aortic aneurysm).
GCS: Glasgow coma scale.
cSVD burden
Amongst 113 patients (median age 49.1 years (IQR 42.1–60.8), 70 (61.9%) women), the burden of cSVD was mild with a median Fazekas score of 1/6 (IQR 0–2) and a prevalence of lacunes and CMBs of 3.5% (4/113) and (11/102) 10.8%, respectively. The median total cSVD burden score in the sample was 0 (IQR 0–1) and 12 patients (10.6%) had a total cSVD score of 2 or more. Overall, 31 patients had a cSVD score of 1 or more. Details are presented in Table 2.
Table 2.
Baseline magnetic resonance imaging cerebral small vessel disease markers distribution.
| Variable | Distribution |
|---|---|
| Frequent/severe EPVSs | 7 (6.2%) |
| Lacunes | 4 (3.5%) |
| Fazekas total | 1 (0–2) |
| Microbleeds | 11/102 (10.8%) |
| Total cSVD burden score | 0 (0–1) |
Variables are presented as absolute number (% of total) or median (interquartile range).
cSVD: cerebral small vessel disease; EPVS: enlarged perivascular space.
Associations between cSVD burden and outcomes
When comparing patients with no/mild (n = 101) versus those with moderate/severe (n = 12) cSVD burden, we did not find a difference regarding vasospasm occurrence (60% versus 46.1%, p = 0.54), DCI at 3 months (20.2% versus 23%, p = 0.66) or favorable outcome at 6 months (94% versus 83.3%, p = 0.20) (Table 3).
Table 3.
Univariate analysis of the association between cerebral small vessel disease score and outcomes.
| Patients |
|||
|---|---|---|---|
| Outcomes | cSVD score: no/mild (n = 101) | cSVD score: moderate/ severe (n = 12) | p-value |
| Cerebral vasospasm | 61 (60%) | 6 (46.1%) | 0.538 |
| Delayed cerebral ischemia | 20 (20.2%) | 3 (23%) | 0.655 |
| Unfavorable outcome | 94 (94%) | 10 (83.3%) | 0.199 |
cSVD: cerebral small vessel disease.
In multivariable models, cSVD markers were not associated with CVS, DCI or clinical outcome (Table 4), and only older age showed a positive association with decreased odds of favorable outcome.
Table 4.
Multivariable analyses of the association between cerebral small vessel disease score and outcomes.
| Variable | Cerebral vasospasm (n = 67) | Delayed cerebral ischemia (n = 23) | Unfavorable outcome (n = 9) |
|---|---|---|---|
| Agea | 1.02 (0.99–1.05); 0.246 | 0.96 (0.92–0.99); 0.019 | 1.14 (1.05–1.28); <0.001 |
| Modified Fisher scale <3 | 0.41 (0.15–1.05); 0.058 | 0.62 (0.13–2.21); 0.484 | 2.11 (0.25–3.68); 0.076 |
| Lacunes | 1.98 (0.2–20.17); 0.729 | 1.14 (0.09–28.71); 0.921 | 0 (0–1.68); 0.098 |
| Microbleeds | 0.83 (0.2–3.13); 0.542 | 1.47 (0.32–10.69); 0.891 | |
| Moderate/severe WMHs | 0.41 (0.15–1.05); 0.353 | 0.62 (0.13–2.21); 0.337 | 2.11 (0.25–48.68); 0.932 |
Values are presented as adjusted odds ratio (95% confidence interval); p-value.
Continuous variable, odds ratio is per unit increase in regressor.
WMH: white matter hyperintensity.
In sensitivity analyses, using only WMHs as marker of cSVD, there was a trend towards more frequent favorable outcome in patients with no/mild WMHs (92% versus 85%, p = 0.086) which was not confirmed in multivariable analysis after adjustment for age.
Discussion
In this retrospective observational study of patients with aSAH, we showed that the prevalence of pre-existing SVD as assessed by routine MRI markers was low and its severity not associated with either CVS occurrence or DCI or 6 months’ functional outcome.
There have been scattered reports mentioning cSVD markers in aSAH patients,19 but none with the aim of investigating prevalence and potential relationship with angiographic, parenchymal and clinical outcome.
As expected, given the specificities of aSAH patients being disproportionally younger than patients with ischemic stroke or primary intracerebral hemorrhage, we found the burden of cSVD to be much less important in our cohort, despite the shared risk factors and important proportion of patients with history of high blood pressure or smoking, two major determinants of cSVD.1 The reason for the discrepancy between shared risk factors and conversely low burden of cSVD may be explained by the divergent natural history of smaller versus larger vessels insult. It is indeed known that before being conspicuous on clinical level MRI, cSVD may be for instance responsible for altered white matter microstructure as assessed with diffusion tensor imaging,20 while remaining occult using routine sequences.9 In line, sporadic cSVD-related brain insult is known to be preceding overt clinical manifestations or found to be advanced when those manifestations occur,15 at variance with intracranial aneurysms that typically affect younger, usually asymptomatic, patients hence with a shorter exposition to these common risk factors.
cSVD, and especially WMHs and lacunes of presumed vascular origin, have been linked to multifactorial chronic cerebral hypoperfusion and hypothesized to be associated with lower vascular reserve,21 mediating the greater susceptibility to ischemia in ischemic stroke patients as well as in the general population as the burden of WMHs increases.
Conversely, in aSAH patients, the link between CVS and DCI is yet to be fully elucidated, with many proposed therapeutics demonstrating encouraging angiographic results (on CVS) but limited, if any, effect on DCI or clinical outcome.22,23 This discrepancy suggests a missing link in our understanding of the pathophysiology of DCI, a phenomenon closely linked to distal vascular reserve. Subject to the undermentioned limitations, cSVD does not seem to play a key role in linking CVS, DCI and outcome.
Our results should be interpreted with caution. Indeed, two reasons may explain the absence of observed association between cSVD and DCI or outcome. First, it may well not exist. Second, our study may not be adequate to detect a difference due to multiple factors: target population (mild aSAH, mild CVS, mild cSVD burden), limited sample size explained by the need to obtain MRI at baseline, or chance only. We note that a marginal association was found between presence of lacunes and higher odds of favorable outcome (p = 0.098) in our sample. Similarly this result is subject to limitations, and a larger study would be needed to confirm this association or its absence.
The reason for proceeding with this study in the first place was triggered by the intense debate of the imbrication of small and large vessel pathology in patients with ischemic and hemorrhagic stroke,24 and the absence of previous material available to evaluate cSVD burden in patients with aSAH and hence their potential associations. Here we provide a preliminary pilot study, suggesting that despite the pathophysiological rationale, there does not seem to be an association between baseline cSVD and vasospasm occurrence, DCI or functional outcome in patients with aSAH, at least as assessed using the mRs and in the setting used for this work.
The strengths of this study derive from the reporting of the prevalence and severity of SVD markers in aSAH patients in a relatively large sample of patients who received a baseline MRI. Limitations, inherent to the design and the disease under scrutiny, are its retrospective nature, the fact that the sample is derived from a single center, and the need for a baseline MRI biasing the sample towards less severe patients, thus contributing to the limitation of generalizability of our findings to similarly mild aSAH patients.
Conclusion
In patients with clinically mild aSAH, the burden of pre-existing cSVD as assessed by MRI is minimal, and is not associated with CVS, DCI or clinical outcome. Larger studies are needed to confirm these preliminary results.
Footnotes
A Villain and G Boulouis contributed equally to this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Data sharing
Any additional unpublished data are made available upon request from the corresponding author.
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