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Combined Outcomes of Endovascular or Surgical Treatment of Unruptured Anterior Communicating Artery Aneurysms: Is a More Aggressive Management Strategy Warranted?
Accepted Manuscript Combined Outcomes of Endovascular or Surgical Treatment of Unruptured Anterior Communicating Artery Aneurysms: Is a More Aggressive Management Strategy Warranted? Philip G.R. Schmalz, MD, Alejandro Enriquez-Marulanda, MD, Abdulrahman Alturki, MBBS, MSc, FRCSC, Christopher J. Stapleton, MD, Ajith J. Thomas, MD, Christopher S. Ogilvy, MD PII:
S1878-8750(18)30762-9
DOI:
10.1016/j.wneu.2018.04.046
Reference:
WNEU 7882
To appear in:
World Neurosurgery
Received Date: 12 January 2018 Revised Date:
6 April 2018
Accepted Date: 7 April 2018
Please cite this article as: Schmalz PGR, Enriquez-Marulanda A, Alturki A, Stapleton CJ, Thomas AJ, Ogilvy CS, Combined Outcomes of Endovascular or Surgical Treatment of Unruptured Anterior Communicating Artery Aneurysms: Is a More Aggressive Management Strategy Warranted?, World Neurosurgery (2018), doi: 10.1016/j.wneu.2018.04.046. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1 Abstract
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Background: Updated natural history studies suggest anterior communicating artery aneurysms
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have a higher risk of rupture than formerly appreciated. As endovascular and open techniques
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advance, morbidity may fall to levels which suggest intervention even for small aneurysms.
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Objective: Assess treatment risk for smaller, unruptured anterior communicating artery
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aneurysms.
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Methods: A cross-sectional study of 149 patients with unruptured anterior communicating
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aneurysms treated over a six-year period was performed. Treatment was based on estimate of
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highest efficacy/lowest risk for each patient. Outcomes were recorded at three months and one
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year from treatment. The primary outcome measure was a modified Rankin scale (mRS) of >2 at
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one year, or persistent cognitive impairment confirmed by a neurologist.
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Results: Age averaged 61 years, range 34-84 years. Median aneurysm size was 5.5 mm (IQR 4-7
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mm). Clipping was performed in 98 patients (65.8%). Poor outcome was observed in 12 patients
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(8%). Neither aneurysm size nor treatment method predicated poor outcome. Both a history
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CAD/MI and age were most significantly associated with poor outcome (CAD/MI OR=8.11,
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95% CI 2.20-29.86, p=0.002; Age OR=1.09, 95%CI 1.019-1.17, p=0.013). Dichotomized for age
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>65 years, the odds of poor outcome increased nearly 11-fold (OR=10.93, 95% CI 2.29-52.03,
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p=0.003)
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Conclusion: Treatment risk for unruptured anterior communicating artery aneurysms for patients
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under age 65 is low. Comparing risk with natural history studies, these patients can be expected
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to outperform natural history within five years. Recognizing the risk of smaller anterior
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communicating artery aneurysms, these findings suggest treatment may be beneficial even for
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small lesions.
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Introduction
Decision-making in patients with unruptured intracranial aneurysms remains one of the
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most challenging areas in neurovascular surgery. With ubiquitous medical imaging, the
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frequency of incidental aneurysm discovery has increased and is expected to continue to rise.1 In
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order to form a coherent argument for or against intervention in patients with incidentally
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discovered aneurysms two facts must be known and compared: the risk of aneurysm rupture over
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life expectancy and the risk of intervention. With the exception of changes in modifiable risk
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factors, namely cigarette smoking, the natural history of intracranial aneurysms will remain
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immutable over time. The risks of treatment however have steadily declined from the dawn of
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aneurysm surgery to its present form.
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Today’s dual-trained cerebrovascular specialist practices in a new realm, with a great diversity of tools that are ever changing. This array of techniques can be expected to reduce
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overall treatment risk and maximize benefit by carefully selecting patients for treatment and
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treatment method based on age, comorbidities, family history, and lesion and access anatomy.
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Given the marked advances in endovascular technology, an updated understanding of treatment
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risk is necessary for comprehensive decision-making in those harboring small, unruptured
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intracranial aneurysms. This study seeks to provide an updated risk assessment for treatment of
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unruptured anterior communicating artery aneurysms via endovascular or microsurgical
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technique.
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Methods
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Data Collection
After approval from the Institutional Review Board, a prospectively maintained database
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of all patients with cerebrovascular disease treated by the senior authors at an academic medical
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center was searched for patients undergoing primary treatment for anterior communicating artery
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aneurysms from the years 2011-2016. This study was retrospective and observational in design
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and no identifiable protected health information was released, thus individual patient consent
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was not required.
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Patients presenting acutely with subarachnoid hemorrhage were excluded, however those
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with prior subarachnoid hemorrhage from a separate aneurysm were permitted in the analysis.
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Patients with previously treated anterior communicating artery aneurysms with recanalization or
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recurrence were excluded in order to capture patients at the initial “decision point.” One-hundred
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forth-nine patients met the above criteria. Baseline patient characteristics including age,
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aneurysm size and morphology, indication for imaging, smoking status, and medical
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comorbidities were recorded. Aneurysm size and morphology was determined by review of
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pretreament computed tomography- or catheter based angiography. Hypertension was defined by
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any patient taking an antihypertensive agent. Coronary artery disease or history of myocardial
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ACCEPTED MANUSCRIPT 3 infarction (CAD/MI) was determined by any patient with a clinical history of CAD/MI, a history
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of cardiac stenting, or myocardial infarction. Smoking status was defined by patient self-report to
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include current or recent smokers only. Patients with a remote or very limited history of smoking
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were considered nonsmokers. Treatment modality, including primary coil embolization, stent-
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assisted coil embolization, flow diversion (PED; Pipeline Emblization Device, Medtronic,
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Minneapolis, Minnesota) and microsurgical clipping, were obtained from operative reports. The
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use of the PED for aneurysms in this location was performed off-label, and this use is only
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incidental to the present study.
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Patient functional outcome was assessed using the modified Rankin scale (mRS) at three
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months and one year after treatment. Functional outcome at one year was used for statistical
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analysis. Cognitive outcome was assessed by patient self-report throughout the follow up period.
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When persistent cognitive impairment was reported, a confirmatory evaluation was performed by
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a cognitive neurologist (n=2). The primary outcome measure, poor outcome, was defined as a
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mRS score >2 at one-year follow-up or persistent cognitive impairment. The parameters for
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defining poor outcome were chosen to be consistent with other landmark studies such as the
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International Study of Unruptured Intracranial Aneurysms and the Barrow Ruptured Aneurysm
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Trial and can be considered to be a standard measure based on these prior studies.2,3
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Statistical Analysis
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The chi-square test was used for the comparison of categorical variables between groups
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with favorable or poor outcome. Student’s t-test and the Mann-Whitney test were used for
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analyzing continuous variables, the former used in the case of normally-distributed variables. A
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mean and standard deviation (SD) or median and interquartile range (IQR) were reported
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depending if the continuous variables were normally distributed or not, respectively. While
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outcomes data were complete, baseline patient characteristics were missing in a maximum of 3
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patients. Assuming missing data was random, a listwise deletion method was used to address
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this. A binary logistic regression analysis was then performed for each variable that was
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statistically significant in the comparison between outcomes groups, and odds ratio (OR) and
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95% confidence intervals (CI) were recorded. A statistically significant difference was
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considered if the p-value ≤0.05. All statistical analyses were performed with STATA® 13.0
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software (StataCorp LLC, College Station, Texas).
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ACCEPTED MANUSCRIPT 4 92 93
Results The database identified 2544 potentially eligible patients treated for cerebrovascular disease by the senior authors. Of these, 498 patients were identified for elective aneurysm
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treatment and were examined for eligibility. After examination, 149 patients were confirmed to
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be eligible based on exclusion criteria above. The remaining patients either did not have
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aneurysms in the anterior communicating artery, or met the aforementioned exclusion criteria.
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Sufficient follow-up data was available for all 149 patients and all eligible patients were included
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in the analysis. Age averaged 61 years, with a range of 34-84 years. Ninety-five patients were
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female (64%). Aneurysm size averaged 6 mm, with a median size of 5.5 mm (IQR 4-7 mm).
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Sixty-eight percent of aneurysms were less than 7 mm. Microsurgical clipping was performed in
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98 patients (65.8%) with the remainder treated by endovascular means (including primary coil
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embolization, stent-assisted coil embolization, and two patients treated with the Pipeline
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Embolization Device). Eighty patients were smokers (54%). A history of subarachnoid
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hemorrhage from a separate aneurysm was present in 9 patients (6%). The indication for imaging
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was based on family history of aneurysm or subarachnoid hemorrhage in 26 patients (17.4%),
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while trauma, ischemic stroke, headaches, and nonspecific neurological complaints represented
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the remaining indications for vascular imaging. An overall increasing trend was observed for
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patients treated endovascularly. Patients treated earlier underwent endovascular treatment 0-20%
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of the time. At the end of the eligibility period, the percentage of patients treated endovascularly
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had increased to more than 50% (Figure 1.) Detailed baseline patient characteristics are
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presented in Table 1.
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The primary outcome measure, poor outcome, was met in 12 patients (8%). Of all poor outcomes, 10/12 occurred in patients >65 for a poor outcome rate of 18.5% in this group.
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Outcome data, including functional outcome and cognitive impairment is presented in Table 2.
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Causes for poor functional status are detailed in Table 3. Neither aneurysm size nor treatment
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method (endovascular treatment versus microsurgery) were predictive of poor outcome, though
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this may be related to the small size of treated aneurysms and limited power with this sample
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size. Additionally, prior SAH, smoking status, or other medical comorbidities such as
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hypertension or atrial fibrillation were not associated with poor outcome. A detailed comparison
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between patients with poor and favorable outcomes is presented in Table 4. This comparison
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identified the two most predictive variables for poor outcome: age and a history of coronary
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ACCEPTED MANUSCRIPT 5 artery disease or myocardial infarction (CAD/MI). Univariate binary logistic regression analysis
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demonstrates a history of CAD/MI was significantly associated with poor outcome (OR=8.11,
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95% CI 2.20-29.86, p=0.002) as was age (OR=1.09, 95%CI 1.019-1.17, p=0.013). When
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dichotomized for age >65 years, the odds of poor outcome increased nearly 11-fold (OR=10.93,
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95% CI 2.29-52.03, p=0.003). Univariate analysis is presented in detail in Table 4. Only two
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patients under 65 had a poor outcome (one with cognitive dysfunction mRS=1, and one with a
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perforator stroke mRS=3). The overall risk for poor outcome for patients less than 65 years was
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approximately 2% (2/96).
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Discussion
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Rationale for Treatment
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Historical natural history studies have previously suggested that small, unruptured, anterior circulation aneurysms had a negligible risk of rupture.2 Recently, some natural history
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studies have suggested that the rupture risk for anterior circulation aneurysms is much higher
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than previously thought. Additionally, there is increasing evidence that rather than progressive
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growth until rupture, small aneurysms likely form and then rupture shortly after formation.4
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More nuanced studies, taking aneurysm location into account, have suggested a much greater
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risk for lesions located at the anterior communicating artery, up to 0.75-0.9% rupture risk per
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year for lesions less than 7 mm in a Japanese population.5 Further study in a Finnish population
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corroborates this finding. Though these studies are limited to selected populations, overall they
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raise the possibility that the historical 7 mm treatment threshold though helpful is insufficiently
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detailed for precise risk prediction.6 A meta-analysis encompassing multiple demographics
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suggests that anterior communicating artery aneurysms pose a risk of rupture twice as high as
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that of other intracranial aneurysms.7 These lesions have been described to behave more like
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posterior circulation lesions in their propensity to rupture.8
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While we have gained a greater understanding of the risk posed by even small anterior
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communicating artery aneurysms, the morbidity of treatment has continued to decrease, even in
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recent decades. A meta-analysis of patients treated with surgery from 1966-1996 found a
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mortality of 2.6% with permanent morbidity of 10.9%.9 Newer studies have shown much lower
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treatment risk. One study found an overall mortality and morbidity risk of less than 1% and 8%
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respectively for either open or endovascular treatment.10
ACCEPTED MANUSCRIPT 6 As surgical techniques continue to be refined, surgical risk may asymptotically approach
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negligible values and the risk/benefit calculation will continue to change. With decreasing risk, a
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greater number of aneurysms previously thought to not favor intervention may not only warrant
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treatment, the risk calculation may in fact demand it. A current understanding of this risk is
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critical for this decision-making.
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In the above analysis we show that treatment risk for unruptured anterior communicating artery aneurysms is low for those under age 65 and without a history of coronary artery disease
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or myocardial infarction. Using these data, we argue that contrary to widely published
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guidelines, even small anterior circulation aneurysms of the anterior communicating artery may
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merit intervention.
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The principal limitation of this study is its retrospective design which may underestimate the minor complication rate and may not capture overall functional and cognitive status. The
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definitions of poor outcome, mRS>2 and cognitive impairment, were chosen to be consistent
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with major studies of ruptured aneurysms. These metrics may not be appropriate for patients
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with unruptured aneurysms, though no accepted outcomes scale has been developed specifically
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for unruptured aneurysms. Additionally, despite referral to a cognitive neurologist when
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symptoms were present, this study underestimates subtler cognitive changes found if universal
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neuropsychological testing were performed on all patients. Inherent to a retrospective study
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design, minor procedural complications, such as successfully treated stent thrombosis, may not
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have been wholly captured if functional status was not impacted.
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Given the retrospective nature of this study, no formalized selection criteria were used to
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select treatment modality. In general, treatment modality was decided based on patient anatomy,
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age, comorbidities, surgeon and patient preference as well as perceived lowest risk-highest
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benefit. Furthermore, some 10-20% of endovascularly treated patients will require eventual
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retreatment, the risk of which is not captured in this study.11 While both age and a history of
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CAD/MI were associated with poor outcome, a co-occurrence of these variables is likely and
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was not accounted for in the analysis due to small sample size. Referring specifically to
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CAD/MI, those with poor outcomes did not have a cardiac etiology for poor functional status,
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thus this variable may serve as a marker for overall vascular health and stroke risk. Furthermore,
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ACCEPTED MANUSCRIPT 7 age and cardiac status are only two factors to consider in the decision-making process for
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aneurysm treatment and should not supplant a detailed understanding of overall functional status,
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patient and surgeon preference, and local practice patterns. Of note, prior studies have indicated
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that aneurysm size is a risk factor for poor treatment outcome after open surgery.12 Though there
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was no significant difference between treatment modalities as regards size, the fact that very
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small aneurysms can be difficult to treat endovascularly may have negated this historical
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difference seen with open surgery. Additionally, the overall small size of the aneurysms in this
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study limits the power of the analysis to detect a difference in risk.
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Future Decision-Making
There has been significant progress in understanding the rupture risk of intracranial
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aneurysms adding much greater nuance to our understanding of risk beyond aneurysm size.
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Recently, aneurysms located at the anterior communicating artery have been recognized to be at
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greater risk for rupture. In fact, risk scoring systems have equated lesions in this location to those
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in the posterior circulation.13 Despite this greater recognition that even smaller anterior
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communicating artery aneurysms pose a small, though significant, risk of rupture, treatment of
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small aneurysms remains controversial. In the theoretical instance that treatment of small
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aneurysms posed no risk, advocating treatment for even tiny aneurysms would pose no
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controversy. As endovascular technology and techniques, open surgical advances, and progress
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in the growing specialty of neurocritical care continue to slowly reduce treatment morbidity, a
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well founded argument can be made to expand treatment indications to smaller aneurysms.
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Overall treatment risk for unruptured aneurysms is considerably lower than at the dawn of
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aneurysm surgery.14 Furthermore, small aneurysms have shown notably lower surgical risk with
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very small lesions presenting an approximately 3% risk of major neurological morbidity for
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microsurgical clipping.12,15 With the neurosurgical community’s enthusiastic embrace of
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endovascular treatment, a growing number of dual-trained, high volume cerebrovascular
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specialists are entering practice armed with ever more sophisticated catheter technology. In the
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era of the dual-trained operator, patients can be selected for the lowest risk/greatest benefit
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intervention with a minimum of external, non-physiologic pressures towards or against treatment
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with a particular modality-either surgically or endovascularly. During the eligibility period there
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was a significant trend towards endovascular treatment over time. Though no statistical
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difference in outcome was observed between treatments, this may have contributed to the overall
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low morbidity observed. In fact, the rise of endovascular treatment has been shown to contribute
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to a decline in treatment morbidity for unruptured aneurysms.16
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We present the results of treatment of 149 patients with unruptured anterior communicating artery aneurysms. These data show that for patients harboring an unruptured
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anterior communicating artery aneurysms less than 65 years of age have an approximate 2% risk
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of poor outcome. Comparing this treatment risk to estimates of rupture for small anterior
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communicating artery shown by the UCAS and PHASES studies, which show an annual risk of
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0.3-0.9%, a patient under age 65 undergoing treatment for a small anterior communicating artery
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aneurysm can be expected to outperform natural history within five years. This finding suggests
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a more aggressive management strategy towards treatment even for small unruptured anterior
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communicating artery aneurysms. This finding is corroborated by other series which indicate
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these lesions can be treated with low morbidity, but that age is a significant factor for poor
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outcome.17,18,19 The marked increase in odds of a poor outcome for those greater than 65 (18.5%;
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OR=10.93) should give pause to cerebrovascular specialists contemplating treatment of small
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aneurysms in this age group.
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Conclusion
We present an updated treatment risk assessment for patients undergoing either
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endovascular or open surgical treatment of smaller unruptured anterior communicating artery
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aneurysms. Treatment risk for patients under age 65 and those without a history of CAD/MI was
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remarkably low, suggesting treatment of even small unruptured anterior communicating artery
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aneurysms may be warranted in younger patients. This finding should be corroborated in a
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prospective study design or ideally in a randomized trial.
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Figure Legend
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Figure 1. Modality of treatment (endovascular embolization or microsurgical clipping) as a
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percentage of all eligible patients during the study period. A clear trend towards endovascular
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treatment is apparent.
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References
ACCEPTED MANUSCRIPT 9 1. Menghini VV, Brown RD, Sicks JD, O’Fallon WM, Wiebers DO. Incidence and prevalence of intracranial aneurysms and hemorrhage in Olmsted County, Minnesota, 1965 to 1995. Neurology. 1998;51(2):405–411.
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2. Wiebers DO, Investigators IS of UIA, others. Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. The Lancet. 2003;362(9378):103–110.
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3. McDougall CG, Spetzler RF, Zabramski JM, et al. The barrow ruptured aneurysm trial. J Neurosurg. 2012;116(1):135–144.
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4. Beck J, Rohde S, Berkefeld J, Seifert V, Raabe A. Size and location of ruptured and unruptured intracranial aneurysms measured by 3-dimensional rotational angiography. Surg Neurol. 2006;65(1):18-25. doi:10.1016/j.surneu.2005.05.019.
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5. Morita A, Kirino T, Hashi K, et al. The natural course of unruptured cerebral aneurysms in a Japanese cohort. N Engl J Med. 2012;366(26):2474-2482. doi:10.1056/NEJMoa1113260.
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6. Juvela S, Korja M. Intracranial Aneurysm Parameters for Predicting a Future Subarachnoid Hemorrhage: A Long-Term Follow-up Study. Neurosurgery. 2017;81(3):432-440. doi:10.1093/neuros/nyw049.
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7. Mira JMS, Costa FADO, Horta BL, Fabião OM. Risk of rupture in unruptured anterior communicating artery aneurysms: meta-analysis of natural history studies. Surg Neurol. 2006;66:S12-S19. doi:10.1016/j.surneu.2006.06.025.
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8. Bijlenga P, Ebeling C, Jaegersberg M, et al. Risk of rupture of small anterior communicating artery aneurysms is similar to posterior circulation aneurysms. Stroke. 2013;44(11):3018– 3026.
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9. Raaymakers TW, Rinkel GJ, Limburg M, Algra A. Mortality and morbidity of surgery for unruptured intracranial aneurysms: a meta-analysis. Stroke. 1998;29(8):1531-1538.
271 272 273 274
10. O’Neill AH, Chandra RV, Lai LT. Safety and effectiveness of microsurgical clipping, endovascular coiling, and stent assisted coiling for unruptured anterior communicating artery aneurysms: a systematic analysis of observational studies. J NeuroInterventional Surg. September 2016:neurintsurg-2016-012629. doi:10.1136/neurintsurg-2016-012629.
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11. Li M-H, Gao B-L, Fang C, et al. Angiographic follow-up of cerebral aneurysms treated with Guglielmi detachable coils: an analysis of 162 cases with 173 aneurysms. Am J Neuroradiol. 2006;27(5):1107–1112.
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12. Ogilvy CS, Carter BS. Stratification of outcome for surgically treated unruptured intracranial aneurysms. Neurosurgery. 2003;52(1):82–88.
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13. Greving JP, Wermer MJ, Brown RD, et al. Development of the PHASES score for prediction of risk of rupture of intracranial aneurysms: a pooled analysis of six prospective cohort studies. Lancet Neurol. 2014;13(1):59–66.
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ACCEPTED MANUSCRIPT 10 14. King Jr JT, Berlin JA, Flamm ES. Morbidity and mortality from elective surgery for asymptomatic, unruptured, intracranial aneurysms: a meta-analysis. J Neurosurg. 1994;81(6):837–842.
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15. Bruneau M, Amin-Hanjani S, Koroknay-Pal P, et al. Surgical Clipping of Very Small Unruptured Intracranial Aneurysms: A Multicenter International Study. Neurosurgery. 2016;78(1):47-52. doi:10.1227/NEU.0000000000000991.
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16. Andaluz N, Zuccarello M. Recent trends in the treatment of cerebral aneurysms: analysis of a nationwide inpatient database. J Neurosurg. 2008;108:1163-1169.
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17. Cagnazzo F, Brinjikji W, Lanzino G. Effect of age on outcomes and practice patterns for patients with anterior communicating artery aneurysms. J Neurosurg Sci. January 2017. doi:10.23736/S0390-5616.16.03942-4.
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18. Kerezoudis P, McCutcheon BA, Murphy M, et al. Predictors of 30-day perioperative morbidity and mortality of unruptured intracranial aneurysm surgery. Clin Neurol Neurosurg. 2016;149:75-80. doi:10.1016/j.clineuro.2016.07.027.
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19. Lawson MF, Neal DW, Mocco J, Hoh BL. Rationale for Treating Unruptured Intracranial Aneurysms: Actuarial Analysis of Natural History Risk versus Treatment Risk for Coiling or Clipping Based on 14,050 Patients in the Nationwide Inpatient Sample Database. World Neurosurg. 2013;79(3-4):472-478. doi:10.1016/j.wneu.2012.01.038.
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ACCEPTED MANUSCRIPT Table 1. Baseline Patient Characteristics Variable
n=149 (100%)
Age ζ
61.01 (±9.81) 54 (36.24%)
Female
95 (63.76%)
Smoker*
80 (54.05%)
HTN*
94 (63.51%)
CAD/MI*
16 (10.81%)
Atrial fibrillation*
8 (5.41%)
Anticoagulant/antiplatelet use* ASA
42 (28.38%) 26 (68.42%) 2 (5.26%)
Clopidogrel
2 (5.26%)
Warfarin
4 (10.53%)
Warfarin+ASA
1 (2.63%)
Rivaroxaban
3 (7.89%)
Prior SAH*
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9 (6.08%)
Family history of aneurysms** Aneurysm size
26 (17.81%)
<7 mm
101 (67.79%)
7 - 12 mm
44 (29.53%)
>12 mm
5.5 (IQR 4 - 7)
Treatment Microsurgical Clipping Stent-Coil Coil Pipeline
1 2 4
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mRS at admission*
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Endovascular treatment
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Median ε
* 1 missing data
**3 missing data ζ Mean (SD) ε Median (IQR)
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Male
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Gender
98 (65.77%) 51 (34.23%) 28 (54.9%)
21 (41.17%) 2 (3.92%) 126 (85.14%) 14 (9.46%) 7 (4.73%) 1 (0.68%)
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Table 2. Outcomes Variables Outcome Good Poor* Follow up mRS >2 Cognitive impairment Follow-up mRS 0
102 (68.92%) 26 (17.57%)
1 2 3
9 (6.08%) 4 (2.7%)
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6 (4.05%) 4 6 (Expired) 1 (0.68%) Good outcome (mRS≤2 without cognitive impairment) Poor outcome (mRS 3-6 and/or cognitive impairment) * Both cognitive impairment and resultant mRS>2 were experienced by one patient for n=12 for poor outcome.
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137 (91.95%) 12 (8.05%) 11 (7.38%%) 2 (1.34%)
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n=149 (100%)
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Table 3. Causes of Poor Outcome
1 1 7 2
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Cognitive dysfunction Perforator infarction Subdural hematoma Death (sepsis)
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Complication Endovascular Embolization Wire perforation, Subarachnoid hemorrhage Stroke (delayed stent thrombosis) Stroke (without stent) Microsurgical Clipping
n=12 (100%) n 5
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Table 4. Comparison between poor and good outcomes groups Good Variable outcome: Poor outcome: 137 (91.95%) 12 (8.05%) 60.39 (±9.5) 68.08 (±10.91) Age
0.0088
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Gender
p-Value
Family history of aneurysms**
53 (38.69%) 84 (61.31%) 74 (54.41%) 86 (63.24%) 11 (8.09%) 8 (5.88%) 38 (27.94%) 9 (6.62%) 23 (17.16%)
Aneurysm size
5.5 (IQR 4 - 7 )
1 (8.33%) 11 (91.67%) 6 (50%) 8 (66.57%) 5 (41.67%) 0 (0%) 4 (33.33%) 0 (0%) 3 (25%) 4.25 (IQR 3.5 6.25)
91 (66.42%) 46 (33.58%)
7 (58.33%) 5 (41.67%)
0.571
10 (83.33%) 0 (0%) 1 (8.33%) 1 (8.33%)
0.005
Female Smoker* HTN* CAD/MI* Atrial fibrillation* Anticoagulant/antiplatelet use*
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Prior SAH*
Treatment Microsurgical Clipping Endovascular treatment
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mRS at admission*
0 1 2 4
14 (10.29%) 6 (4.41%) 0 (0%)
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116 (85.29%)
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*n(%), p-value: Chi² test ** Mean (SD), p-value: Students T-test ***Median (IQR), p-value: Mann-Whitney test
0.036 0.76 0.813 <0.001 0.388 0.691 0.358 0.497
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0.0875
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0.003 0.067 0.002 0.106 0.47
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Bold values: p-value<0.05
p-Value 0.013
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Table 5. Univariate binary logistic regression Variable OR CI95% 1.09 (1.019 - 1.17) Age (2.29 – 10.93 52.03) Age≥65 6.94 (0.87 - 55.32) Female gender 8.11 (2.20 - 29.86) CAD/MI 1.78 (0.88 - 3.61) Admission mRS 1.142 (0.79-1.64) Treatment Date
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Highlights
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Newer natural history studies show unruptured aneurysms of the ACoA pose greater risk. Surgeons may select treatment by open or endovascular means based on lowest riskhighest reward. Treatment risk for these aneurysms can be exceedingly low in selected patients. Lower treatment risk and new appreciation of rupture risk supports treatment for small aneurysms.
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Abbreviations mRS – Modified Rankin Scale CAD – Coronary Artery Disease
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MI – Myocardial Infarction OR – Odds Ratio PED – Pipeline Embolization Device
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SD – Standard Deviation IQR – Interquartile Range
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CI – Confidence Interval
UCAS – Unruptured Cerebral Aneurysm Study of Japan
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PHASES – Population, Hypertension, Age, Size, Earlier hemorrhage, Site
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Conflict of Interest and Author Agreement Statement We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.
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We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us.
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We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property.
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We further confirm that any aspect of the work covered in this manuscript that has involved either experimental animals or human patients has been conducted within the ethical guidelines of all relevant bodies. We understand that the Corresponding Author is the sole contact for the Editorial process (including Editorial Manager and direct communications with the office). He is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs. We confirm that we have provided a current, correct email address which is accessible by the Corresponding Author.
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Philip G. R. Schmalz, MD Alejandro Enriquez-Marulanda, MD Abdulrahman Alturki, MBBS, MSc, FRCSC
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Christopher J. Stapleton, MD Ajith J. Thomas, MD
Christopher S. Ogilvy, MD
S1878-8750(18)30762-9
DOI:
10.1016/j.wneu.2018.04.046
Reference:
WNEU 7882
To appear in:
World Neurosurgery
Received Date: 12 January 2018 Revised Date:
6 April 2018
Accepted Date: 7 April 2018
Please cite this article as: Schmalz PGR, Enriquez-Marulanda A, Alturki A, Stapleton CJ, Thomas AJ, Ogilvy CS, Combined Outcomes of Endovascular or Surgical Treatment of Unruptured Anterior Communicating Artery Aneurysms: Is a More Aggressive Management Strategy Warranted?, World Neurosurgery (2018), doi: 10.1016/j.wneu.2018.04.046. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1 Abstract
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Background: Updated natural history studies suggest anterior communicating artery aneurysms
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have a higher risk of rupture than formerly appreciated. As endovascular and open techniques
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advance, morbidity may fall to levels which suggest intervention even for small aneurysms.
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Objective: Assess treatment risk for smaller, unruptured anterior communicating artery
6
aneurysms.
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Methods: A cross-sectional study of 149 patients with unruptured anterior communicating
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aneurysms treated over a six-year period was performed. Treatment was based on estimate of
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highest efficacy/lowest risk for each patient. Outcomes were recorded at three months and one
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year from treatment. The primary outcome measure was a modified Rankin scale (mRS) of >2 at
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one year, or persistent cognitive impairment confirmed by a neurologist.
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Results: Age averaged 61 years, range 34-84 years. Median aneurysm size was 5.5 mm (IQR 4-7
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mm). Clipping was performed in 98 patients (65.8%). Poor outcome was observed in 12 patients
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(8%). Neither aneurysm size nor treatment method predicated poor outcome. Both a history
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CAD/MI and age were most significantly associated with poor outcome (CAD/MI OR=8.11,
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95% CI 2.20-29.86, p=0.002; Age OR=1.09, 95%CI 1.019-1.17, p=0.013). Dichotomized for age
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>65 years, the odds of poor outcome increased nearly 11-fold (OR=10.93, 95% CI 2.29-52.03,
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p=0.003)
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Conclusion: Treatment risk for unruptured anterior communicating artery aneurysms for patients
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under age 65 is low. Comparing risk with natural history studies, these patients can be expected
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to outperform natural history within five years. Recognizing the risk of smaller anterior
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communicating artery aneurysms, these findings suggest treatment may be beneficial even for
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small lesions.
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Introduction
Decision-making in patients with unruptured intracranial aneurysms remains one of the
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most challenging areas in neurovascular surgery. With ubiquitous medical imaging, the
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frequency of incidental aneurysm discovery has increased and is expected to continue to rise.1 In
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order to form a coherent argument for or against intervention in patients with incidentally
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discovered aneurysms two facts must be known and compared: the risk of aneurysm rupture over
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life expectancy and the risk of intervention. With the exception of changes in modifiable risk
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factors, namely cigarette smoking, the natural history of intracranial aneurysms will remain
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immutable over time. The risks of treatment however have steadily declined from the dawn of
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aneurysm surgery to its present form.
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Today’s dual-trained cerebrovascular specialist practices in a new realm, with a great diversity of tools that are ever changing. This array of techniques can be expected to reduce
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overall treatment risk and maximize benefit by carefully selecting patients for treatment and
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treatment method based on age, comorbidities, family history, and lesion and access anatomy.
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Given the marked advances in endovascular technology, an updated understanding of treatment
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risk is necessary for comprehensive decision-making in those harboring small, unruptured
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intracranial aneurysms. This study seeks to provide an updated risk assessment for treatment of
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unruptured anterior communicating artery aneurysms via endovascular or microsurgical
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technique.
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Methods
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Data Collection
After approval from the Institutional Review Board, a prospectively maintained database
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of all patients with cerebrovascular disease treated by the senior authors at an academic medical
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center was searched for patients undergoing primary treatment for anterior communicating artery
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aneurysms from the years 2011-2016. This study was retrospective and observational in design
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and no identifiable protected health information was released, thus individual patient consent
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was not required.
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Patients presenting acutely with subarachnoid hemorrhage were excluded, however those
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with prior subarachnoid hemorrhage from a separate aneurysm were permitted in the analysis.
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Patients with previously treated anterior communicating artery aneurysms with recanalization or
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recurrence were excluded in order to capture patients at the initial “decision point.” One-hundred
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forth-nine patients met the above criteria. Baseline patient characteristics including age,
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aneurysm size and morphology, indication for imaging, smoking status, and medical
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comorbidities were recorded. Aneurysm size and morphology was determined by review of
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pretreament computed tomography- or catheter based angiography. Hypertension was defined by
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any patient taking an antihypertensive agent. Coronary artery disease or history of myocardial
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ACCEPTED MANUSCRIPT 3 infarction (CAD/MI) was determined by any patient with a clinical history of CAD/MI, a history
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of cardiac stenting, or myocardial infarction. Smoking status was defined by patient self-report to
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include current or recent smokers only. Patients with a remote or very limited history of smoking
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were considered nonsmokers. Treatment modality, including primary coil embolization, stent-
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assisted coil embolization, flow diversion (PED; Pipeline Emblization Device, Medtronic,
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Minneapolis, Minnesota) and microsurgical clipping, were obtained from operative reports. The
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use of the PED for aneurysms in this location was performed off-label, and this use is only
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incidental to the present study.
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Patient functional outcome was assessed using the modified Rankin scale (mRS) at three
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months and one year after treatment. Functional outcome at one year was used for statistical
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analysis. Cognitive outcome was assessed by patient self-report throughout the follow up period.
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When persistent cognitive impairment was reported, a confirmatory evaluation was performed by
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a cognitive neurologist (n=2). The primary outcome measure, poor outcome, was defined as a
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mRS score >2 at one-year follow-up or persistent cognitive impairment. The parameters for
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defining poor outcome were chosen to be consistent with other landmark studies such as the
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International Study of Unruptured Intracranial Aneurysms and the Barrow Ruptured Aneurysm
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Trial and can be considered to be a standard measure based on these prior studies.2,3
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Statistical Analysis
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The chi-square test was used for the comparison of categorical variables between groups
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with favorable or poor outcome. Student’s t-test and the Mann-Whitney test were used for
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analyzing continuous variables, the former used in the case of normally-distributed variables. A
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mean and standard deviation (SD) or median and interquartile range (IQR) were reported
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depending if the continuous variables were normally distributed or not, respectively. While
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outcomes data were complete, baseline patient characteristics were missing in a maximum of 3
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patients. Assuming missing data was random, a listwise deletion method was used to address
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this. A binary logistic regression analysis was then performed for each variable that was
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statistically significant in the comparison between outcomes groups, and odds ratio (OR) and
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95% confidence intervals (CI) were recorded. A statistically significant difference was
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considered if the p-value ≤0.05. All statistical analyses were performed with STATA® 13.0
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software (StataCorp LLC, College Station, Texas).
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Results The database identified 2544 potentially eligible patients treated for cerebrovascular disease by the senior authors. Of these, 498 patients were identified for elective aneurysm
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treatment and were examined for eligibility. After examination, 149 patients were confirmed to
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be eligible based on exclusion criteria above. The remaining patients either did not have
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aneurysms in the anterior communicating artery, or met the aforementioned exclusion criteria.
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Sufficient follow-up data was available for all 149 patients and all eligible patients were included
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in the analysis. Age averaged 61 years, with a range of 34-84 years. Ninety-five patients were
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female (64%). Aneurysm size averaged 6 mm, with a median size of 5.5 mm (IQR 4-7 mm).
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Sixty-eight percent of aneurysms were less than 7 mm. Microsurgical clipping was performed in
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98 patients (65.8%) with the remainder treated by endovascular means (including primary coil
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embolization, stent-assisted coil embolization, and two patients treated with the Pipeline
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Embolization Device). Eighty patients were smokers (54%). A history of subarachnoid
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hemorrhage from a separate aneurysm was present in 9 patients (6%). The indication for imaging
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was based on family history of aneurysm or subarachnoid hemorrhage in 26 patients (17.4%),
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while trauma, ischemic stroke, headaches, and nonspecific neurological complaints represented
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the remaining indications for vascular imaging. An overall increasing trend was observed for
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patients treated endovascularly. Patients treated earlier underwent endovascular treatment 0-20%
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of the time. At the end of the eligibility period, the percentage of patients treated endovascularly
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had increased to more than 50% (Figure 1.) Detailed baseline patient characteristics are
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presented in Table 1.
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The primary outcome measure, poor outcome, was met in 12 patients (8%). Of all poor outcomes, 10/12 occurred in patients >65 for a poor outcome rate of 18.5% in this group.
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Outcome data, including functional outcome and cognitive impairment is presented in Table 2.
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Causes for poor functional status are detailed in Table 3. Neither aneurysm size nor treatment
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method (endovascular treatment versus microsurgery) were predictive of poor outcome, though
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this may be related to the small size of treated aneurysms and limited power with this sample
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size. Additionally, prior SAH, smoking status, or other medical comorbidities such as
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hypertension or atrial fibrillation were not associated with poor outcome. A detailed comparison
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between patients with poor and favorable outcomes is presented in Table 4. This comparison
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identified the two most predictive variables for poor outcome: age and a history of coronary
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ACCEPTED MANUSCRIPT 5 artery disease or myocardial infarction (CAD/MI). Univariate binary logistic regression analysis
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demonstrates a history of CAD/MI was significantly associated with poor outcome (OR=8.11,
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95% CI 2.20-29.86, p=0.002) as was age (OR=1.09, 95%CI 1.019-1.17, p=0.013). When
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dichotomized for age >65 years, the odds of poor outcome increased nearly 11-fold (OR=10.93,
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95% CI 2.29-52.03, p=0.003). Univariate analysis is presented in detail in Table 4. Only two
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patients under 65 had a poor outcome (one with cognitive dysfunction mRS=1, and one with a
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perforator stroke mRS=3). The overall risk for poor outcome for patients less than 65 years was
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approximately 2% (2/96).
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Discussion
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Rationale for Treatment
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Historical natural history studies have previously suggested that small, unruptured, anterior circulation aneurysms had a negligible risk of rupture.2 Recently, some natural history
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studies have suggested that the rupture risk for anterior circulation aneurysms is much higher
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than previously thought. Additionally, there is increasing evidence that rather than progressive
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growth until rupture, small aneurysms likely form and then rupture shortly after formation.4
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More nuanced studies, taking aneurysm location into account, have suggested a much greater
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risk for lesions located at the anterior communicating artery, up to 0.75-0.9% rupture risk per
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year for lesions less than 7 mm in a Japanese population.5 Further study in a Finnish population
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corroborates this finding. Though these studies are limited to selected populations, overall they
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raise the possibility that the historical 7 mm treatment threshold though helpful is insufficiently
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detailed for precise risk prediction.6 A meta-analysis encompassing multiple demographics
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suggests that anterior communicating artery aneurysms pose a risk of rupture twice as high as
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that of other intracranial aneurysms.7 These lesions have been described to behave more like
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posterior circulation lesions in their propensity to rupture.8
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While we have gained a greater understanding of the risk posed by even small anterior
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communicating artery aneurysms, the morbidity of treatment has continued to decrease, even in
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recent decades. A meta-analysis of patients treated with surgery from 1966-1996 found a
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mortality of 2.6% with permanent morbidity of 10.9%.9 Newer studies have shown much lower
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treatment risk. One study found an overall mortality and morbidity risk of less than 1% and 8%
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respectively for either open or endovascular treatment.10
ACCEPTED MANUSCRIPT 6 As surgical techniques continue to be refined, surgical risk may asymptotically approach
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negligible values and the risk/benefit calculation will continue to change. With decreasing risk, a
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greater number of aneurysms previously thought to not favor intervention may not only warrant
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treatment, the risk calculation may in fact demand it. A current understanding of this risk is
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critical for this decision-making.
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In the above analysis we show that treatment risk for unruptured anterior communicating artery aneurysms is low for those under age 65 and without a history of coronary artery disease
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or myocardial infarction. Using these data, we argue that contrary to widely published
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guidelines, even small anterior circulation aneurysms of the anterior communicating artery may
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merit intervention.
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The principal limitation of this study is its retrospective design which may underestimate the minor complication rate and may not capture overall functional and cognitive status. The
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definitions of poor outcome, mRS>2 and cognitive impairment, were chosen to be consistent
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with major studies of ruptured aneurysms. These metrics may not be appropriate for patients
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with unruptured aneurysms, though no accepted outcomes scale has been developed specifically
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for unruptured aneurysms. Additionally, despite referral to a cognitive neurologist when
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symptoms were present, this study underestimates subtler cognitive changes found if universal
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neuropsychological testing were performed on all patients. Inherent to a retrospective study
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design, minor procedural complications, such as successfully treated stent thrombosis, may not
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have been wholly captured if functional status was not impacted.
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Given the retrospective nature of this study, no formalized selection criteria were used to
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select treatment modality. In general, treatment modality was decided based on patient anatomy,
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age, comorbidities, surgeon and patient preference as well as perceived lowest risk-highest
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benefit. Furthermore, some 10-20% of endovascularly treated patients will require eventual
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retreatment, the risk of which is not captured in this study.11 While both age and a history of
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CAD/MI were associated with poor outcome, a co-occurrence of these variables is likely and
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was not accounted for in the analysis due to small sample size. Referring specifically to
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CAD/MI, those with poor outcomes did not have a cardiac etiology for poor functional status,
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thus this variable may serve as a marker for overall vascular health and stroke risk. Furthermore,
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ACCEPTED MANUSCRIPT 7 age and cardiac status are only two factors to consider in the decision-making process for
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aneurysm treatment and should not supplant a detailed understanding of overall functional status,
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patient and surgeon preference, and local practice patterns. Of note, prior studies have indicated
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that aneurysm size is a risk factor for poor treatment outcome after open surgery.12 Though there
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was no significant difference between treatment modalities as regards size, the fact that very
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small aneurysms can be difficult to treat endovascularly may have negated this historical
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difference seen with open surgery. Additionally, the overall small size of the aneurysms in this
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study limits the power of the analysis to detect a difference in risk.
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Future Decision-Making
There has been significant progress in understanding the rupture risk of intracranial
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aneurysms adding much greater nuance to our understanding of risk beyond aneurysm size.
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Recently, aneurysms located at the anterior communicating artery have been recognized to be at
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greater risk for rupture. In fact, risk scoring systems have equated lesions in this location to those
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in the posterior circulation.13 Despite this greater recognition that even smaller anterior
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communicating artery aneurysms pose a small, though significant, risk of rupture, treatment of
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small aneurysms remains controversial. In the theoretical instance that treatment of small
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aneurysms posed no risk, advocating treatment for even tiny aneurysms would pose no
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controversy. As endovascular technology and techniques, open surgical advances, and progress
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in the growing specialty of neurocritical care continue to slowly reduce treatment morbidity, a
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well founded argument can be made to expand treatment indications to smaller aneurysms.
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Overall treatment risk for unruptured aneurysms is considerably lower than at the dawn of
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aneurysm surgery.14 Furthermore, small aneurysms have shown notably lower surgical risk with
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very small lesions presenting an approximately 3% risk of major neurological morbidity for
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microsurgical clipping.12,15 With the neurosurgical community’s enthusiastic embrace of
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endovascular treatment, a growing number of dual-trained, high volume cerebrovascular
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specialists are entering practice armed with ever more sophisticated catheter technology. In the
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era of the dual-trained operator, patients can be selected for the lowest risk/greatest benefit
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intervention with a minimum of external, non-physiologic pressures towards or against treatment
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with a particular modality-either surgically or endovascularly. During the eligibility period there
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was a significant trend towards endovascular treatment over time. Though no statistical
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difference in outcome was observed between treatments, this may have contributed to the overall
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low morbidity observed. In fact, the rise of endovascular treatment has been shown to contribute
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to a decline in treatment morbidity for unruptured aneurysms.16
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We present the results of treatment of 149 patients with unruptured anterior communicating artery aneurysms. These data show that for patients harboring an unruptured
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anterior communicating artery aneurysms less than 65 years of age have an approximate 2% risk
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of poor outcome. Comparing this treatment risk to estimates of rupture for small anterior
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communicating artery shown by the UCAS and PHASES studies, which show an annual risk of
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0.3-0.9%, a patient under age 65 undergoing treatment for a small anterior communicating artery
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aneurysm can be expected to outperform natural history within five years. This finding suggests
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a more aggressive management strategy towards treatment even for small unruptured anterior
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communicating artery aneurysms. This finding is corroborated by other series which indicate
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these lesions can be treated with low morbidity, but that age is a significant factor for poor
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outcome.17,18,19 The marked increase in odds of a poor outcome for those greater than 65 (18.5%;
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OR=10.93) should give pause to cerebrovascular specialists contemplating treatment of small
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aneurysms in this age group.
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Conclusion
We present an updated treatment risk assessment for patients undergoing either
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endovascular or open surgical treatment of smaller unruptured anterior communicating artery
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aneurysms. Treatment risk for patients under age 65 and those without a history of CAD/MI was
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remarkably low, suggesting treatment of even small unruptured anterior communicating artery
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aneurysms may be warranted in younger patients. This finding should be corroborated in a
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prospective study design or ideally in a randomized trial.
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Figure Legend
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Figure 1. Modality of treatment (endovascular embolization or microsurgical clipping) as a
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percentage of all eligible patients during the study period. A clear trend towards endovascular
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treatment is apparent.
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References
ACCEPTED MANUSCRIPT 9 1. Menghini VV, Brown RD, Sicks JD, O’Fallon WM, Wiebers DO. Incidence and prevalence of intracranial aneurysms and hemorrhage in Olmsted County, Minnesota, 1965 to 1995. Neurology. 1998;51(2):405–411.
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2. Wiebers DO, Investigators IS of UIA, others. Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. The Lancet. 2003;362(9378):103–110.
253 254
3. McDougall CG, Spetzler RF, Zabramski JM, et al. The barrow ruptured aneurysm trial. J Neurosurg. 2012;116(1):135–144.
255 256 257
4. Beck J, Rohde S, Berkefeld J, Seifert V, Raabe A. Size and location of ruptured and unruptured intracranial aneurysms measured by 3-dimensional rotational angiography. Surg Neurol. 2006;65(1):18-25. doi:10.1016/j.surneu.2005.05.019.
258 259
5. Morita A, Kirino T, Hashi K, et al. The natural course of unruptured cerebral aneurysms in a Japanese cohort. N Engl J Med. 2012;366(26):2474-2482. doi:10.1056/NEJMoa1113260.
260 261 262
6. Juvela S, Korja M. Intracranial Aneurysm Parameters for Predicting a Future Subarachnoid Hemorrhage: A Long-Term Follow-up Study. Neurosurgery. 2017;81(3):432-440. doi:10.1093/neuros/nyw049.
263 264 265
7. Mira JMS, Costa FADO, Horta BL, Fabião OM. Risk of rupture in unruptured anterior communicating artery aneurysms: meta-analysis of natural history studies. Surg Neurol. 2006;66:S12-S19. doi:10.1016/j.surneu.2006.06.025.
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8. Bijlenga P, Ebeling C, Jaegersberg M, et al. Risk of rupture of small anterior communicating artery aneurysms is similar to posterior circulation aneurysms. Stroke. 2013;44(11):3018– 3026.
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9. Raaymakers TW, Rinkel GJ, Limburg M, Algra A. Mortality and morbidity of surgery for unruptured intracranial aneurysms: a meta-analysis. Stroke. 1998;29(8):1531-1538.
271 272 273 274
10. O’Neill AH, Chandra RV, Lai LT. Safety and effectiveness of microsurgical clipping, endovascular coiling, and stent assisted coiling for unruptured anterior communicating artery aneurysms: a systematic analysis of observational studies. J NeuroInterventional Surg. September 2016:neurintsurg-2016-012629. doi:10.1136/neurintsurg-2016-012629.
275 276 277
11. Li M-H, Gao B-L, Fang C, et al. Angiographic follow-up of cerebral aneurysms treated with Guglielmi detachable coils: an analysis of 162 cases with 173 aneurysms. Am J Neuroradiol. 2006;27(5):1107–1112.
278 279
12. Ogilvy CS, Carter BS. Stratification of outcome for surgically treated unruptured intracranial aneurysms. Neurosurgery. 2003;52(1):82–88.
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13. Greving JP, Wermer MJ, Brown RD, et al. Development of the PHASES score for prediction of risk of rupture of intracranial aneurysms: a pooled analysis of six prospective cohort studies. Lancet Neurol. 2014;13(1):59–66.
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ACCEPTED MANUSCRIPT 10 14. King Jr JT, Berlin JA, Flamm ES. Morbidity and mortality from elective surgery for asymptomatic, unruptured, intracranial aneurysms: a meta-analysis. J Neurosurg. 1994;81(6):837–842.
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15. Bruneau M, Amin-Hanjani S, Koroknay-Pal P, et al. Surgical Clipping of Very Small Unruptured Intracranial Aneurysms: A Multicenter International Study. Neurosurgery. 2016;78(1):47-52. doi:10.1227/NEU.0000000000000991.
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16. Andaluz N, Zuccarello M. Recent trends in the treatment of cerebral aneurysms: analysis of a nationwide inpatient database. J Neurosurg. 2008;108:1163-1169.
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17. Cagnazzo F, Brinjikji W, Lanzino G. Effect of age on outcomes and practice patterns for patients with anterior communicating artery aneurysms. J Neurosurg Sci. January 2017. doi:10.23736/S0390-5616.16.03942-4.
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18. Kerezoudis P, McCutcheon BA, Murphy M, et al. Predictors of 30-day perioperative morbidity and mortality of unruptured intracranial aneurysm surgery. Clin Neurol Neurosurg. 2016;149:75-80. doi:10.1016/j.clineuro.2016.07.027.
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19. Lawson MF, Neal DW, Mocco J, Hoh BL. Rationale for Treating Unruptured Intracranial Aneurysms: Actuarial Analysis of Natural History Risk versus Treatment Risk for Coiling or Clipping Based on 14,050 Patients in the Nationwide Inpatient Sample Database. World Neurosurg. 2013;79(3-4):472-478. doi:10.1016/j.wneu.2012.01.038.
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ACCEPTED MANUSCRIPT Table 1. Baseline Patient Characteristics Variable
n=149 (100%)
Age ζ
61.01 (±9.81) 54 (36.24%)
Female
95 (63.76%)
Smoker*
80 (54.05%)
HTN*
94 (63.51%)
CAD/MI*
16 (10.81%)
Atrial fibrillation*
8 (5.41%)
Anticoagulant/antiplatelet use* ASA
42 (28.38%) 26 (68.42%) 2 (5.26%)
Clopidogrel
2 (5.26%)
Warfarin
4 (10.53%)
Warfarin+ASA
1 (2.63%)
Rivaroxaban
3 (7.89%)
Prior SAH*
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9 (6.08%)
Family history of aneurysms** Aneurysm size
26 (17.81%)
<7 mm
101 (67.79%)
7 - 12 mm
44 (29.53%)
>12 mm
5.5 (IQR 4 - 7)
Treatment Microsurgical Clipping Stent-Coil Coil Pipeline
1 2 4
AC C
mRS at admission*
EP
Endovascular treatment
0
TE D
4 (2.68%)
Median ε
* 1 missing data
**3 missing data ζ Mean (SD) ε Median (IQR)
SC
Male
RI PT
Gender
98 (65.77%) 51 (34.23%) 28 (54.9%)
21 (41.17%) 2 (3.92%) 126 (85.14%) 14 (9.46%) 7 (4.73%) 1 (0.68%)
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Table 2. Outcomes Variables Outcome Good Poor* Follow up mRS >2 Cognitive impairment Follow-up mRS 0
102 (68.92%) 26 (17.57%)
1 2 3
9 (6.08%) 4 (2.7%)
AC C
EP
TE D
M AN U
6 (4.05%) 4 6 (Expired) 1 (0.68%) Good outcome (mRS≤2 without cognitive impairment) Poor outcome (mRS 3-6 and/or cognitive impairment) * Both cognitive impairment and resultant mRS>2 were experienced by one patient for n=12 for poor outcome.
SC
137 (91.95%) 12 (8.05%) 11 (7.38%%) 2 (1.34%)
RI PT
n=149 (100%)
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Table 3. Causes of Poor Outcome
1 1 7 2
AC C
EP
TE D
M AN U
3 1 1
RI PT
Cognitive dysfunction Perforator infarction Subdural hematoma Death (sepsis)
3
SC
Complication Endovascular Embolization Wire perforation, Subarachnoid hemorrhage Stroke (delayed stent thrombosis) Stroke (without stent) Microsurgical Clipping
n=12 (100%) n 5
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Table 4. Comparison between poor and good outcomes groups Good Variable outcome: Poor outcome: 137 (91.95%) 12 (8.05%) 60.39 (±9.5) 68.08 (±10.91) Age
0.0088
RI PT
Gender
p-Value
Family history of aneurysms**
53 (38.69%) 84 (61.31%) 74 (54.41%) 86 (63.24%) 11 (8.09%) 8 (5.88%) 38 (27.94%) 9 (6.62%) 23 (17.16%)
Aneurysm size
5.5 (IQR 4 - 7 )
1 (8.33%) 11 (91.67%) 6 (50%) 8 (66.57%) 5 (41.67%) 0 (0%) 4 (33.33%) 0 (0%) 3 (25%) 4.25 (IQR 3.5 6.25)
91 (66.42%) 46 (33.58%)
7 (58.33%) 5 (41.67%)
0.571
10 (83.33%) 0 (0%) 1 (8.33%) 1 (8.33%)
0.005
Female Smoker* HTN* CAD/MI* Atrial fibrillation* Anticoagulant/antiplatelet use*
M AN U
Prior SAH*
Treatment Microsurgical Clipping Endovascular treatment
TE D
mRS at admission*
0 1 2 4
14 (10.29%) 6 (4.41%) 0 (0%)
EP
Bold values: p-value<0.05
116 (85.29%)
AC C
*n(%), p-value: Chi² test ** Mean (SD), p-value: Students T-test ***Median (IQR), p-value: Mann-Whitney test
0.036 0.76 0.813 <0.001 0.388 0.691 0.358 0.497
SC
Male
0.0875
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0.003 0.067 0.002 0.106 0.47
AC C
EP
TE D
M AN U
SC
Bold values: p-value<0.05
p-Value 0.013
RI PT
Table 5. Univariate binary logistic regression Variable OR CI95% 1.09 (1.019 - 1.17) Age (2.29 – 10.93 52.03) Age≥65 6.94 (0.87 - 55.32) Female gender 8.11 (2.20 - 29.86) CAD/MI 1.78 (0.88 - 3.61) Admission mRS 1.142 (0.79-1.64) Treatment Date
AC C
EP
TE D
M AN U
SC
RI PT
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Highlights
RI PT
SC M AN U TE D EP
-
Newer natural history studies show unruptured aneurysms of the ACoA pose greater risk. Surgeons may select treatment by open or endovascular means based on lowest riskhighest reward. Treatment risk for these aneurysms can be exceedingly low in selected patients. Lower treatment risk and new appreciation of rupture risk supports treatment for small aneurysms.
AC C
-
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Abbreviations mRS – Modified Rankin Scale CAD – Coronary Artery Disease
RI PT
MI – Myocardial Infarction OR – Odds Ratio PED – Pipeline Embolization Device
SC
SD – Standard Deviation IQR – Interquartile Range
M AN U
CI – Confidence Interval
UCAS – Unruptured Cerebral Aneurysm Study of Japan
AC C
EP
TE D
PHASES – Population, Hypertension, Age, Size, Earlier hemorrhage, Site
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Conflict of Interest and Author Agreement Statement We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.
RI PT
We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us.
SC
We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property.
M AN U
We further confirm that any aspect of the work covered in this manuscript that has involved either experimental animals or human patients has been conducted within the ethical guidelines of all relevant bodies. We understand that the Corresponding Author is the sole contact for the Editorial process (including Editorial Manager and direct communications with the office). He is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs. We confirm that we have provided a current, correct email address which is accessible by the Corresponding Author.
TE D
Philip G. R. Schmalz, MD Alejandro Enriquez-Marulanda, MD Abdulrahman Alturki, MBBS, MSc, FRCSC
AC C
EP
Christopher J. Stapleton, MD Ajith J. Thomas, MD
Christopher S. Ogilvy, MD