Aneurysm Size is the Strongest Risk Factor for Intracranial Aneurysm Growth in the Eastern Finnish Population

Aneurysm Size is the Strongest Risk Factor for Intracranial Aneurysm Growth in the Eastern... Abstract BACKGROUND Saccular intracranial aneurysm (sIA) growth during follow-up is associated with high risk for subsequent rupture. Finnish patients have been suggested to have higher risk for subarachnoid hemorrhage, but follow-up studies of sIA growth in the Finnish population are scarce. OBJECTIVE To identify the strongest risk factors for sIA growth in Eastern Finnish population by studying 205 patients with 350 unruptured sIAs with angiographic follow-up imaging. METHODS In this population-based cohort study, we included unruptured sIA patients from the Kuopio University Hospital Intracranial Aneurysm Patient and Family database with at least 6 mo of angiographic follow-up after the diagnosis of sIAs. Angiograms were re-evaluated to detect aneurysms with growth of at least 1.0 mm. Cox regression analysis with patient- and aneurysm-related risk factors was used to calculate hazard ratios with 95% confidence intervals for growth. In addition, we tested the diagnostic value of previously introduced PHASES score for the prediction of sIA growth in Eastern Finnish population. RESULTS Of the 350 unruptured aneurysms, 36 (10.3%) showed growth during median follow-up of 1.7 yr and total follow-up of 790 yr. In the multivariate Cox regression analysis, sIA size and location in the middle cerebral artery were significant risk factors for sIA growth. In receiver operator characteristic curves, both PHASES score and sIA size had relatively low areas under the curve. CONCLUSION Our study indicates that aneurysm size is the strongest risk factor for aneurysm growth in Eastern Finnish population. Further studies are required to identify new risk factors for aneurysm growth. Finland, Intracranial Aneurysm, Risk factors, Stroke, Subarachnoid haemorrhage ABBREVIATIONS ABBREVIATIONS 3D three-dimensional aSAH aneurysmal subarachnoid haemorrhage CI confidence interval CT computed tomography CTA CT-angiography DSA Digital subtraction angiography HR hazard ratio ICA internal carotid artery MCA middle cerebral artery ROC receiver operating characteristic SAH subarachnoid hemorrhage sIA saccular intracranial aneurysm Rupture of the saccular intracranial aneurysm (sIA) wall causes aneurysmal subarachnoid hemorrhage (aSAH), a form of stroke with high rates of morbidity and mortality. Median age at the time of rupture is 55 yr, mainly affecting the working-aged population. A majority of aneurysms are small unruptured sIAs.1 Unruptured sIAs are present in some 3% of general population and the incidence of unruptured sIAs is likely to increase in future due to improving availability of noninvasive imaging modalities and longer life expectancy.1,2 The risk of sIA rupture depends on different patient- and aneurysm-related risk factors3. Selecting between active treatment and conservative follow-up is challenging; both surgical and endovascular treatment include risk for procedural morbidity and mortality.1,2,4,5 In a meta-analysis of 21 studies with a total of 4990 aneurysms, growing sIAs were associated with over 30-fold higher annual risk of rupture than stable ones.6 Growth is suggested to be a discontinuous process with episodes of rapid growth, during which the aneurysms are more prone to rupture.7,8 The risk of aneurysm growth is relatively small after 1 yr of follow-up, but increases significantly during follow-up, being as high as 45% over a period of 19 yr.7 Aneurysm growth is mediated by an inflammatory response in the cerebral artery wall9 and growth during follow-up may be a sign of an inflamed, unstable, and rupture-prone sIA wall. In previous studies, aneurysm size, irregular shape, location, multiple aneurysms, smoking, hypertension, and female sex have been shown to associate with sIA growth during follow-up.10,11 The risk for sIA rupture is higher in Finnish and Japanese populations,3 but according to the meta-analysis of Backes et al11 the risk of unruptured sIA growth is actually lower in those populations. However, studies of aneurysm growth in the Finnish population are scarce, and more information about factors predisposing to instability of aneurysm wall is needed to detect patients with higher risk for aSAH. We studied 205 patients with 350 unruptured sIAs to identify risk factors for sIA growth in Eastern Finnish population. METHODS Catchment Population During the study period of 2003 to 2016, the department of neurosurgery of Kuopio University Hospital (KUH) provided full-time acute and elective neurosurgical services for the whole Eastern Finnish catchment population. There are 4 central hospitals in the catchment area with neurological units of their own.12 The population decreased from 856 059 to 813 341 during the study period. Intracranial Aneurysm Database All diagnosed subarachnoid hemorrhage (SAH) cases in the catchment area of KUH are acutely admitted to KUH for angiography and treatment if not moribund or very aged. Since 1977, all cases with ruptured or unruptured intracranial aneurysms have been registered to the intracranial aneurysm database maintained by Neurosurgery of KUH. All new SAH cases are interviewed by a dedicated full-time nurse who collects detailed information including family history, for which the criterion is at least 2 affected first degree relatives, and clinical data from the hospital periods and follow-up visits.12-15 Diagnosis of sIAs Aneurysms in the Intracranial Aneurysm Database are usually diagnosed as incidental findings due to various reasons requiring angiographic imaging of intracranial arteries or due to a rupture of another sIA. A minority of sIAs are diagnosed as a result of screening of family members of sIA patients. Patients with suspicion of SAH routinely undergo head computed tomography (CT). In uncertain cases, lumbar puncture is used to rule out hemorrhage. Patients with suspicion of SAH in CT are routinely screened with CT-angiography (CTA) to assess the most likely site of bleeding. Digital subtraction angiography (DSA) with three-dimensional (3D) reconstruction is often performed to help with decision making for treatment, especially in potentially suitable cases for endovascular treatment. All sIA cases are assessed by experienced neurosurgeons and interventional neuroradiologists of the KUH Neurovascular Group. Study Population The basic study population includes all sIA cases from the KUH catchment area admitted to KUH between 2003 and 2016. The final study population consists of 205 patients with 350 unruptured sIAs (Figure 1) fulfilling the following criteria: At least 1 unruptured sIA in angiography. Follow-up time of at least 6 mo. Angiograms available for retrospective review in the beginning and in the end of follow-up. FIGURE 1. View largeDownload slide Flow chart showing the inclusion of followed patients. FIGURE 1. View largeDownload slide Flow chart showing the inclusion of followed patients. Location of sIAs In our Intracranial Aneurysm Database, site of aneurysm is coded into numbers, each number referring to a certain location, assessed by the neuroradiologists in the first hand. For this study, angiograms of all sIAs were reviewed during data collection by 2 authors. Aneurysms were divided into 4 categories including internal carotid artery (ICA), middle cerebral artery (MCA), anterior cerebral artery, and posterior circulation arteries. Morphology of sIAs In this study, we evaluated aneurysm size and shape in the beginning and in the end of follow-up to study sIA growth and possible changes in shape. The morphology of sIAs was assessed from 3D reconstructions of DSA, magnetic resonance angiography, or CTA. All measurements were performed on a 0.1 mm scale and included: neck width, height from the center of the neck to the tip of the dome, and the longest width perpendicular to the dome height axis. The greatest measurement of each aneurysm, whether height or width, was used in the analyses as a continuous variable. Shape was categorized as smooth or irregular as described previously.16-17 Aneurysms with blebs, daughter-sacs, or multiple lobes were considered irregular. Follow-up ended when at least 1.0 mm of growth in aneurysm width or height was detected. If the aneurysm wall remained stable, follow-up continued as long as high-quality angiograms were available for review. Last imaging date was used as the end of follow-up. PHASES Score Backes et al18 previously introduced PHASES score for the prediction of sIA growth. We studied the predictive value of the score in Eastern Finnish population. PHASES scores were calculated for each aneurysm in our cohort. The scores were further categorized to categories of 5 to 6 points, 7 points, 8 points, 9 points, 10 points, and 11 or more points. The categories were set to be as equally sized as reasonably possible. PHASES categories ranged from 30 to 68 sIAs/category. As the study population contains only Finnish patients, the scores started from 5 points on. Statistical Analysis The data were analysed with IBM SPSS statistics 23 for Windows (IBM, Armonk, New York). We used univariate and multivariate Cox regression analyses to calculate hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) for the risk factors for sIA growth, including aneurysm size, shape, and location; patient age, sex, history of smoking, history of hypertension, familial sIA disease, and previous aSAH as variables. We ran sensitivity analyses with aneurysms sized ≤5 mm (n = 300) and ≤7 mm (n = 328) to control for bias that very large aneurysms might cause. Diagnostic accuracy of PHASES score was compared to plain aneurysm size as an indicator of growth by plotting receiver operating characteristic (ROC) curves (Figure 2). FIGURE 2. View largeDownload slide ROC curve showing the diagnostic accuracy of sIA size and PHASES score for the prediction of sIA growth. FIGURE 2. View largeDownload slide ROC curve showing the diagnostic accuracy of sIA size and PHASES score for the prediction of sIA growth. Ethical Aspects The study was approved by the ethics committee of KUH. Informed consent was obtained from all patients in Intracranial Aneurysm Database. RESULTS Study Population Of the 205 included patients (Table 1), 130 (63.4%) were women. Median age at the beginning of follow-up was 48.6 yr for women and 46.7 yr for men, respectively. Men had more often positive history of smoking (72.0% vs 40.8%). Of all patients, 36.6% had positive history of hypertension, 16.1% had familial background of sIAs, and 27.8% had previously suffered aSAH. TABLE 1. Characteristics of the 205 Included Patients Patients Female Male n = 205 n = 130 (63%) n = 75 (37%) Median age 47.7 48.6 46.7 History of smoking 107 (52%) 53 (41%) 54 (72%) History of hypertension 75 (37%) 49 (38%) 26 (35%) Familial history of sIAs 33 (16%) 20 (15%) 13 (17%) Previous SAH 57 (28%) 37 (29%) 20 (27%) Patients Female Male n = 205 n = 130 (63%) n = 75 (37%) Median age 47.7 48.6 46.7 History of smoking 107 (52%) 53 (41%) 54 (72%) History of hypertension 75 (37%) 49 (38%) 26 (35%) Familial history of sIAs 33 (16%) 20 (15%) 13 (17%) Previous SAH 57 (28%) 37 (29%) 20 (27%) View Large TABLE 1. Characteristics of the 205 Included Patients Patients Female Male n = 205 n = 130 (63%) n = 75 (37%) Median age 47.7 48.6 46.7 History of smoking 107 (52%) 53 (41%) 54 (72%) History of hypertension 75 (37%) 49 (38%) 26 (35%) Familial history of sIAs 33 (16%) 20 (15%) 13 (17%) Previous SAH 57 (28%) 37 (29%) 20 (27%) Patients Female Male n = 205 n = 130 (63%) n = 75 (37%) Median age 47.7 48.6 46.7 History of smoking 107 (52%) 53 (41%) 54 (72%) History of hypertension 75 (37%) 49 (38%) 26 (35%) Familial history of sIAs 33 (16%) 20 (15%) 13 (17%) Previous SAH 57 (28%) 37 (29%) 20 (27%) View Large Main Results Of the followed 350 unruptured aneurysms (Table 2), 36 (10.3%) showed growth during median follow-up of 1.7 yr and total follow-up of 790 yr. Aneurysms were most frequently located in MCA (49.7%), which is also where growth was seen most frequently (61.1%). Median sizes were 3.6 mm for aneurysms with growth and 2.9 mm for aneurysms without growth. In the beginning of follow-up, 9/36 (25.0%) of the aneurysms that showed growth during follow-up were irregular vs 69/314 (22.0%) of the ones without growth. In the end of follow-up, 16/36 (44.4%) of the grown aneurysms were irregular. Median PHASES score was 8 for aneurysms with and without growth. TABLE 2. Characteristics of the 350 Included Aneurysms Growth No Growth n = 350 n = 36 (10%) n = 314 (90%) Aneurysm location  Internal carotid artery 7 (19%) 67 (21%)  Middle cerebral artery 22 (61%) 152 (48%)  Anterior cerebral artery 5 (14%) 61 (19%)  Posterior circulation 2 (6%) 34 (11%) Aneurysm size  Median/Mean 3.6/4.8 2.9/3.4  0-2.9 mm 14 (39%) 162 (52%)  3.0-4.9 mm 11 (31%) 103 (33%)  5.0-6.9 mm 3 (8%) 29 (9%)  7.0-9.9 mm 4 (11%) 15 (5%)   >10 mm 4 (11%) 5 (2%) Irregular shape 9 (25%) 69 (22%) Median follow-up time (yr) 2.9 1.7 Median PHASES score 8 8 Growth No Growth n = 350 n = 36 (10%) n = 314 (90%) Aneurysm location  Internal carotid artery 7 (19%) 67 (21%)  Middle cerebral artery 22 (61%) 152 (48%)  Anterior cerebral artery 5 (14%) 61 (19%)  Posterior circulation 2 (6%) 34 (11%) Aneurysm size  Median/Mean 3.6/4.8 2.9/3.4  0-2.9 mm 14 (39%) 162 (52%)  3.0-4.9 mm 11 (31%) 103 (33%)  5.0-6.9 mm 3 (8%) 29 (9%)  7.0-9.9 mm 4 (11%) 15 (5%)   >10 mm 4 (11%) 5 (2%) Irregular shape 9 (25%) 69 (22%) Median follow-up time (yr) 2.9 1.7 Median PHASES score 8 8 View Large TABLE 2. Characteristics of the 350 Included Aneurysms Growth No Growth n = 350 n = 36 (10%) n = 314 (90%) Aneurysm location  Internal carotid artery 7 (19%) 67 (21%)  Middle cerebral artery 22 (61%) 152 (48%)  Anterior cerebral artery 5 (14%) 61 (19%)  Posterior circulation 2 (6%) 34 (11%) Aneurysm size  Median/Mean 3.6/4.8 2.9/3.4  0-2.9 mm 14 (39%) 162 (52%)  3.0-4.9 mm 11 (31%) 103 (33%)  5.0-6.9 mm 3 (8%) 29 (9%)  7.0-9.9 mm 4 (11%) 15 (5%)   >10 mm 4 (11%) 5 (2%) Irregular shape 9 (25%) 69 (22%) Median follow-up time (yr) 2.9 1.7 Median PHASES score 8 8 Growth No Growth n = 350 n = 36 (10%) n = 314 (90%) Aneurysm location  Internal carotid artery 7 (19%) 67 (21%)  Middle cerebral artery 22 (61%) 152 (48%)  Anterior cerebral artery 5 (14%) 61 (19%)  Posterior circulation 2 (6%) 34 (11%) Aneurysm size  Median/Mean 3.6/4.8 2.9/3.4  0-2.9 mm 14 (39%) 162 (52%)  3.0-4.9 mm 11 (31%) 103 (33%)  5.0-6.9 mm 3 (8%) 29 (9%)  7.0-9.9 mm 4 (11%) 15 (5%)   >10 mm 4 (11%) 5 (2%) Irregular shape 9 (25%) 69 (22%) Median follow-up time (yr) 2.9 1.7 Median PHASES score 8 8 View Large Morphological Changes During Follow-up During the follow-up, growth occurred in 36/350 sIAs (10.3%; Table 2). Of those 36 sIAs, 9 were irregularly shaped in the beginning of the follow-up. During follow-up, 7 sIAs turned irregular. In the group of sIAs with no growth, any changes in sIA shape were not detected. Cox Regression Analysis In univariate Cox regression analysis (Table 3), sIA size (HR 1.13 [95% CI 1.03-1.25], P = .009) and location in MCA (HR 2.91 [95% CI 1.05-8.02], P = .039) showed statistical significance as risk factors for sIA growth. In multivariate Cox regression analysis (Table 3), sIA size (HR 1.35 [95% CI 1.19-1.52], P = .000) and location in MCA (HR 3.51 [95% CI 1.08-11.4], P = .037) were statistically significantly associated with growth. TABLE 3. Cox Regression Analysis n = 350 Univariate P-value Multivariate P-value HR (95% CI) HR (95% CI) Aneurysm size 1.13 (1.03-1.25) .009 1.35 (1.19-1.52) .000 Irregular sIA shape 0.89 (0.38-2.10) .793 0.52 (0.20-1.36) .183 Male sex 1.72 (0.87-3.39) .120 1.80 (0.76-4.29) .179 Age 0.99 (0.97-1.02) .652 0.97 (0.93-1.00) .122 Familial history of sIAs 1.52 (0.71-3.27) .284 1.14 (0.46-2.83) .781 Previous SAH 0.56 (0.23-1.38) .208 0.44 (0.17-1.17) .101 History of smoking 1.35 (0.69-2.66) .382 0.95 (0.41-2.22) .905 History of hypertension 0.69 (0.33-1.45) .328 0.61 (0.26-1.43) .257 Aneurysm location  Internal carotid artery Reference .142 Reference .164  Middle cerebral artery 2.91 (1.05-8.02) .039 3.51 (1.08-11.4) .037  Anterior cerebral artery 1.61 (0.45-5.73) .462 3.05 (0.73-12.8) .127  Posterior circulation 1.36 (0.23-7.29) .720 1.18 (0.21-6.74) .856 n = 350 Univariate P-value Multivariate P-value HR (95% CI) HR (95% CI) Aneurysm size 1.13 (1.03-1.25) .009 1.35 (1.19-1.52) .000 Irregular sIA shape 0.89 (0.38-2.10) .793 0.52 (0.20-1.36) .183 Male sex 1.72 (0.87-3.39) .120 1.80 (0.76-4.29) .179 Age 0.99 (0.97-1.02) .652 0.97 (0.93-1.00) .122 Familial history of sIAs 1.52 (0.71-3.27) .284 1.14 (0.46-2.83) .781 Previous SAH 0.56 (0.23-1.38) .208 0.44 (0.17-1.17) .101 History of smoking 1.35 (0.69-2.66) .382 0.95 (0.41-2.22) .905 History of hypertension 0.69 (0.33-1.45) .328 0.61 (0.26-1.43) .257 Aneurysm location  Internal carotid artery Reference .142 Reference .164  Middle cerebral artery 2.91 (1.05-8.02) .039 3.51 (1.08-11.4) .037  Anterior cerebral artery 1.61 (0.45-5.73) .462 3.05 (0.73-12.8) .127  Posterior circulation 1.36 (0.23-7.29) .720 1.18 (0.21-6.74) .856 View Large TABLE 3. Cox Regression Analysis n = 350 Univariate P-value Multivariate P-value HR (95% CI) HR (95% CI) Aneurysm size 1.13 (1.03-1.25) .009 1.35 (1.19-1.52) .000 Irregular sIA shape 0.89 (0.38-2.10) .793 0.52 (0.20-1.36) .183 Male sex 1.72 (0.87-3.39) .120 1.80 (0.76-4.29) .179 Age 0.99 (0.97-1.02) .652 0.97 (0.93-1.00) .122 Familial history of sIAs 1.52 (0.71-3.27) .284 1.14 (0.46-2.83) .781 Previous SAH 0.56 (0.23-1.38) .208 0.44 (0.17-1.17) .101 History of smoking 1.35 (0.69-2.66) .382 0.95 (0.41-2.22) .905 History of hypertension 0.69 (0.33-1.45) .328 0.61 (0.26-1.43) .257 Aneurysm location  Internal carotid artery Reference .142 Reference .164  Middle cerebral artery 2.91 (1.05-8.02) .039 3.51 (1.08-11.4) .037  Anterior cerebral artery 1.61 (0.45-5.73) .462 3.05 (0.73-12.8) .127  Posterior circulation 1.36 (0.23-7.29) .720 1.18 (0.21-6.74) .856 n = 350 Univariate P-value Multivariate P-value HR (95% CI) HR (95% CI) Aneurysm size 1.13 (1.03-1.25) .009 1.35 (1.19-1.52) .000 Irregular sIA shape 0.89 (0.38-2.10) .793 0.52 (0.20-1.36) .183 Male sex 1.72 (0.87-3.39) .120 1.80 (0.76-4.29) .179 Age 0.99 (0.97-1.02) .652 0.97 (0.93-1.00) .122 Familial history of sIAs 1.52 (0.71-3.27) .284 1.14 (0.46-2.83) .781 Previous SAH 0.56 (0.23-1.38) .208 0.44 (0.17-1.17) .101 History of smoking 1.35 (0.69-2.66) .382 0.95 (0.41-2.22) .905 History of hypertension 0.69 (0.33-1.45) .328 0.61 (0.26-1.43) .257 Aneurysm location  Internal carotid artery Reference .142 Reference .164  Middle cerebral artery 2.91 (1.05-8.02) .039 3.51 (1.08-11.4) .037  Anterior cerebral artery 1.61 (0.45-5.73) .462 3.05 (0.73-12.8) .127  Posterior circulation 1.36 (0.23-7.29) .720 1.18 (0.21-6.74) .856 View Large In the sensitivity analysis with aneurysms ≤7 mm (n = 328), sIA size (HR 1.49 [95% CI 1.01-2.21], P = .047) was the only statistically significant risk factor for growth. With aneurysms ≤5 mm (n = 300), none of the variables reached statistical significance (sIA size; HR 1.68 [95% CI 0.99-2.86], P = .056). Diagnostic Accuracy of PHASES Score and sIA Size We compared the diagnostic accuracy of PHASES score and plain sIA size for the prediction of sIA growth in our Eastern Finnish population (Figure 2). In our cohort, area under the curve was 0.60 for sIA size and 0.52 for PHASES score, respectively. DISCUSSION Key Results In this follow-up study of 350 unruptured sIAs, 10.3% of sIAs showed growth. sIA size was a strong independent risk factor for growth, as previous studies have also demonstrated.6,19 The PHASES score had low area under the curve (AUC = 0.52) in ROC-curves and should not be used in prediction of sIA growth in Eastern Finnish population. Currently known risk factors explain the risk for aneurysm growth poorly. Interpretation A large majority of unruptured aneurysms are relatively small and pose the biggest challenge in clinical decision making. Due to more aggressive treatment of large aneurysms, there is only a relatively small group of large aneurysms that might bias our results. To control for that bias, we ran sensitivity analyses with smaller aneurysms. In the analysis with sIAs ≤7 mm, size was a significant risk factor for growth. With sIAs ≤5 mm, none of the variables reached statistical significance. Our result suggests that sIA size is a valuable risk factor for growth, especially for aneurysms ≥5mm. In our main analysis, MCA aneurysms were over 3.5 times more prone to growth than ICA aneurysms. In a previous cohort of Finnish sIA patients, MCA aneurysms were less prone to rupture than aneurysms in other locations.16 Thus, it is surprising that MCA aneurysms in this cohort were more prone to growth, since growing aneurysms are generally at higher risk for rupture.6 However, there were only a few aneurysms with growth located elsewhere than in the MCA, which may explain why only MCA aneurysms were statistically significantly associated with growth. Irregular aneurysm shape, especially multilobularity, has previously been associated with sIA growth.10 In our analysis, irregular shape was not significantly associated with sIA growth. However, there is likely to be a substantial group of irregular aneurysms that have been selected for treatment, rather than for follow-up, leading to possible selection bias. In our study, many of the grown aneurysms were irregularly shaped after growth (16/36 vs 69/314 of the ones with no growth), suggesting that irregularity may not only be a potential risk factor for later sIA growth, but also an indicator of previous growth. Irregularity in itself should be considered as an indication for treatment,16,17 not to mention irregular sIAs with growth during follow-up. Further classification of irregular shape would be needed to study the association between sIA growth and different types of irregularity. The PHASES score was originally developed for prediction of sIA rupture.3 In the previously published study, Backes et al18 used it for the prediction of sIA growth. In PHASES score, sIA size was weighted as the strongest risk factor for sIA growth. Of the parameters included in the PHASES score, only sIA size reached statistical significance in our analysis. The ROC-curves (Figure 2) demonstrated that PHASES score (AUC 0.52) is not suitable for the prediction of sIA rupture in Finnish population. There was high variation in size of aneurysms that did not grow, causing poor AUC value for sIA size. sIA size should not be considered a diagnostic sign of future growth, but a risk factor for growth instead. However, the low AUC value of sIA size highlights the need for additional risk factors. Limitations Our study has a few limitations. First, our study is a retrospective, nonrandomized study. Since currently many unruptured aneurysms are treated to prevent rupture, the current cohorts of followed aneurysms are inevitably selected. However, conducting a follow-up study such as Juvela et al20 did when unruptured aneurysms were not treated is not feasible anymore due to current ethical and clinical realities. On the other hand, follow-up series reflecting the current clinical practice are required, since most unruptured sIAs diagnosed today are found incidentally or due to screening indicated by family history, and not because of SAH from another sIA as in Juvela's series.20,21 Second, due to rapid development of imaging modalities and due to length of the study period, there is inherent variation in the image quality, especially in the 3D reformations acquired from the aneurysms. This may have led to incorrect evaluation of aneurysm characteristics during data acquisition and morphological review, especially in cases with long follow-up and cases with different imaging modalities at different time points. If growth was seen because of changes in imaging modalities, it would most likely be present in all aneurysms of patients with multiple aneurysms. In our cohort of the patients with multiple aneurysms (n = 20), in only 2 patients did both aneurysms show growth during follow-up. Of those 4 aneurysms, only 1 had a different imaging modality in the beginning and in the end of the follow-up. Furthermore, the single-center configuration of the study compensates for this limitation since all the aneurysms were imaged with consistent guidelines and imaging techniques by a dedicated group of radiologists. Generalizability Our results indicate that even in the current selected cohort of unruptured aneurysms, a substantial proportion of aneurysms show growth during follow-up. Previous data have shown that growing aneurysms are at high risk of subsequent rupture, and our results highlight the value of aneurysm size as a risk factor for sIA growth in the Finnish population, regardless of patient-related or other aneurysm-related risk factors. Our results indicate that the currently known risk factors explain the risk for intracranial aneurysm growth poorly. Further studies are required to reveal additional risk factors to improve our diagnostic accuracy in identifying unruptured aneurysms at high risk for growth. CONCLUSION Our study indicates that aneurysm size is the strongest risk factor for aneurysm growth in Eastern Finnish population. Further studies are required to identify new risk factors for aneurysm growth. Disclosures Funding was from Petri Honkanen Foundation, Maire Taponen Foundation, Yrjö Jansson Foundation, Päivikki and Sakari Sohlberg Foundation, Emil Aaltonen Foundation, North Savo Regional Fund of Finnish Cultural Foundation, University of Eastern Finland, Kuopio University Hospital, and the Academy of Finland. The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. REFERENCES 1. Thompson BG , Brown RD , Amin-Hanjani S et al. 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Irregular shape identifies ruptured intracranial aneurysm in subarachnoid hemorrhage patients with multiple aneurysms . Stroke . 2017 ; 48 ( 7 ): 1986 - 1989 . Google Scholar CrossRef Search ADS PubMed 17. Lindgren AE , Koivisto T , Bjorkman J et al. Irregular shape of intracranial aneurysm indicates rupture risk irrespective of size in a population-based cohort . Stroke . 2016 ; 47 ( 5 ): 1219 - 1226 . Google Scholar CrossRef Search ADS PubMed 18. Backes D , Vergouwen MD , Tiel Groenestege AT et al. PHASES score for prediction of intracranial aneurysm growth . Stroke . 2015 ; 46 ( 5 ): 1221 - 1226 . Google Scholar CrossRef Search ADS PubMed 19. Matsubara S , Hadeishi H , Suzuki A , Yasui N , Nishimura H . Incidence and risk factors for the growth of unruptured cerebral aneurysms: observation using serial computerized tomography angiography . J Neurosurg . 2004 ; 101 ( 6 ): 908 - 914 . Google Scholar CrossRef Search ADS PubMed 20. Juvela S , Poussa K , Porras M . Factors affecting formation and growth of intracranial aneurysms: a long-term follow-up study . Stroke . 2001 ; 32 ( 2 ): 485 - 491 . Google Scholar CrossRef Search ADS PubMed 21. 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 . Google Scholar CrossRef Search ADS PubMed Copyright © 2018 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurosurgery Oxford University Press

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Congress of Neurological Surgeons
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Copyright © 2018 by the Congress of Neurological Surgeons
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0148-396X
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Abstract

Abstract BACKGROUND Saccular intracranial aneurysm (sIA) growth during follow-up is associated with high risk for subsequent rupture. Finnish patients have been suggested to have higher risk for subarachnoid hemorrhage, but follow-up studies of sIA growth in the Finnish population are scarce. OBJECTIVE To identify the strongest risk factors for sIA growth in Eastern Finnish population by studying 205 patients with 350 unruptured sIAs with angiographic follow-up imaging. METHODS In this population-based cohort study, we included unruptured sIA patients from the Kuopio University Hospital Intracranial Aneurysm Patient and Family database with at least 6 mo of angiographic follow-up after the diagnosis of sIAs. Angiograms were re-evaluated to detect aneurysms with growth of at least 1.0 mm. Cox regression analysis with patient- and aneurysm-related risk factors was used to calculate hazard ratios with 95% confidence intervals for growth. In addition, we tested the diagnostic value of previously introduced PHASES score for the prediction of sIA growth in Eastern Finnish population. RESULTS Of the 350 unruptured aneurysms, 36 (10.3%) showed growth during median follow-up of 1.7 yr and total follow-up of 790 yr. In the multivariate Cox regression analysis, sIA size and location in the middle cerebral artery were significant risk factors for sIA growth. In receiver operator characteristic curves, both PHASES score and sIA size had relatively low areas under the curve. CONCLUSION Our study indicates that aneurysm size is the strongest risk factor for aneurysm growth in Eastern Finnish population. Further studies are required to identify new risk factors for aneurysm growth. Finland, Intracranial Aneurysm, Risk factors, Stroke, Subarachnoid haemorrhage ABBREVIATIONS ABBREVIATIONS 3D three-dimensional aSAH aneurysmal subarachnoid haemorrhage CI confidence interval CT computed tomography CTA CT-angiography DSA Digital subtraction angiography HR hazard ratio ICA internal carotid artery MCA middle cerebral artery ROC receiver operating characteristic SAH subarachnoid hemorrhage sIA saccular intracranial aneurysm Rupture of the saccular intracranial aneurysm (sIA) wall causes aneurysmal subarachnoid hemorrhage (aSAH), a form of stroke with high rates of morbidity and mortality. Median age at the time of rupture is 55 yr, mainly affecting the working-aged population. A majority of aneurysms are small unruptured sIAs.1 Unruptured sIAs are present in some 3% of general population and the incidence of unruptured sIAs is likely to increase in future due to improving availability of noninvasive imaging modalities and longer life expectancy.1,2 The risk of sIA rupture depends on different patient- and aneurysm-related risk factors3. Selecting between active treatment and conservative follow-up is challenging; both surgical and endovascular treatment include risk for procedural morbidity and mortality.1,2,4,5 In a meta-analysis of 21 studies with a total of 4990 aneurysms, growing sIAs were associated with over 30-fold higher annual risk of rupture than stable ones.6 Growth is suggested to be a discontinuous process with episodes of rapid growth, during which the aneurysms are more prone to rupture.7,8 The risk of aneurysm growth is relatively small after 1 yr of follow-up, but increases significantly during follow-up, being as high as 45% over a period of 19 yr.7 Aneurysm growth is mediated by an inflammatory response in the cerebral artery wall9 and growth during follow-up may be a sign of an inflamed, unstable, and rupture-prone sIA wall. In previous studies, aneurysm size, irregular shape, location, multiple aneurysms, smoking, hypertension, and female sex have been shown to associate with sIA growth during follow-up.10,11 The risk for sIA rupture is higher in Finnish and Japanese populations,3 but according to the meta-analysis of Backes et al11 the risk of unruptured sIA growth is actually lower in those populations. However, studies of aneurysm growth in the Finnish population are scarce, and more information about factors predisposing to instability of aneurysm wall is needed to detect patients with higher risk for aSAH. We studied 205 patients with 350 unruptured sIAs to identify risk factors for sIA growth in Eastern Finnish population. METHODS Catchment Population During the study period of 2003 to 2016, the department of neurosurgery of Kuopio University Hospital (KUH) provided full-time acute and elective neurosurgical services for the whole Eastern Finnish catchment population. There are 4 central hospitals in the catchment area with neurological units of their own.12 The population decreased from 856 059 to 813 341 during the study period. Intracranial Aneurysm Database All diagnosed subarachnoid hemorrhage (SAH) cases in the catchment area of KUH are acutely admitted to KUH for angiography and treatment if not moribund or very aged. Since 1977, all cases with ruptured or unruptured intracranial aneurysms have been registered to the intracranial aneurysm database maintained by Neurosurgery of KUH. All new SAH cases are interviewed by a dedicated full-time nurse who collects detailed information including family history, for which the criterion is at least 2 affected first degree relatives, and clinical data from the hospital periods and follow-up visits.12-15 Diagnosis of sIAs Aneurysms in the Intracranial Aneurysm Database are usually diagnosed as incidental findings due to various reasons requiring angiographic imaging of intracranial arteries or due to a rupture of another sIA. A minority of sIAs are diagnosed as a result of screening of family members of sIA patients. Patients with suspicion of SAH routinely undergo head computed tomography (CT). In uncertain cases, lumbar puncture is used to rule out hemorrhage. Patients with suspicion of SAH in CT are routinely screened with CT-angiography (CTA) to assess the most likely site of bleeding. Digital subtraction angiography (DSA) with three-dimensional (3D) reconstruction is often performed to help with decision making for treatment, especially in potentially suitable cases for endovascular treatment. All sIA cases are assessed by experienced neurosurgeons and interventional neuroradiologists of the KUH Neurovascular Group. Study Population The basic study population includes all sIA cases from the KUH catchment area admitted to KUH between 2003 and 2016. The final study population consists of 205 patients with 350 unruptured sIAs (Figure 1) fulfilling the following criteria: At least 1 unruptured sIA in angiography. Follow-up time of at least 6 mo. Angiograms available for retrospective review in the beginning and in the end of follow-up. FIGURE 1. View largeDownload slide Flow chart showing the inclusion of followed patients. FIGURE 1. View largeDownload slide Flow chart showing the inclusion of followed patients. Location of sIAs In our Intracranial Aneurysm Database, site of aneurysm is coded into numbers, each number referring to a certain location, assessed by the neuroradiologists in the first hand. For this study, angiograms of all sIAs were reviewed during data collection by 2 authors. Aneurysms were divided into 4 categories including internal carotid artery (ICA), middle cerebral artery (MCA), anterior cerebral artery, and posterior circulation arteries. Morphology of sIAs In this study, we evaluated aneurysm size and shape in the beginning and in the end of follow-up to study sIA growth and possible changes in shape. The morphology of sIAs was assessed from 3D reconstructions of DSA, magnetic resonance angiography, or CTA. All measurements were performed on a 0.1 mm scale and included: neck width, height from the center of the neck to the tip of the dome, and the longest width perpendicular to the dome height axis. The greatest measurement of each aneurysm, whether height or width, was used in the analyses as a continuous variable. Shape was categorized as smooth or irregular as described previously.16-17 Aneurysms with blebs, daughter-sacs, or multiple lobes were considered irregular. Follow-up ended when at least 1.0 mm of growth in aneurysm width or height was detected. If the aneurysm wall remained stable, follow-up continued as long as high-quality angiograms were available for review. Last imaging date was used as the end of follow-up. PHASES Score Backes et al18 previously introduced PHASES score for the prediction of sIA growth. We studied the predictive value of the score in Eastern Finnish population. PHASES scores were calculated for each aneurysm in our cohort. The scores were further categorized to categories of 5 to 6 points, 7 points, 8 points, 9 points, 10 points, and 11 or more points. The categories were set to be as equally sized as reasonably possible. PHASES categories ranged from 30 to 68 sIAs/category. As the study population contains only Finnish patients, the scores started from 5 points on. Statistical Analysis The data were analysed with IBM SPSS statistics 23 for Windows (IBM, Armonk, New York). We used univariate and multivariate Cox regression analyses to calculate hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) for the risk factors for sIA growth, including aneurysm size, shape, and location; patient age, sex, history of smoking, history of hypertension, familial sIA disease, and previous aSAH as variables. We ran sensitivity analyses with aneurysms sized ≤5 mm (n = 300) and ≤7 mm (n = 328) to control for bias that very large aneurysms might cause. Diagnostic accuracy of PHASES score was compared to plain aneurysm size as an indicator of growth by plotting receiver operating characteristic (ROC) curves (Figure 2). FIGURE 2. View largeDownload slide ROC curve showing the diagnostic accuracy of sIA size and PHASES score for the prediction of sIA growth. FIGURE 2. View largeDownload slide ROC curve showing the diagnostic accuracy of sIA size and PHASES score for the prediction of sIA growth. Ethical Aspects The study was approved by the ethics committee of KUH. Informed consent was obtained from all patients in Intracranial Aneurysm Database. RESULTS Study Population Of the 205 included patients (Table 1), 130 (63.4%) were women. Median age at the beginning of follow-up was 48.6 yr for women and 46.7 yr for men, respectively. Men had more often positive history of smoking (72.0% vs 40.8%). Of all patients, 36.6% had positive history of hypertension, 16.1% had familial background of sIAs, and 27.8% had previously suffered aSAH. TABLE 1. Characteristics of the 205 Included Patients Patients Female Male n = 205 n = 130 (63%) n = 75 (37%) Median age 47.7 48.6 46.7 History of smoking 107 (52%) 53 (41%) 54 (72%) History of hypertension 75 (37%) 49 (38%) 26 (35%) Familial history of sIAs 33 (16%) 20 (15%) 13 (17%) Previous SAH 57 (28%) 37 (29%) 20 (27%) Patients Female Male n = 205 n = 130 (63%) n = 75 (37%) Median age 47.7 48.6 46.7 History of smoking 107 (52%) 53 (41%) 54 (72%) History of hypertension 75 (37%) 49 (38%) 26 (35%) Familial history of sIAs 33 (16%) 20 (15%) 13 (17%) Previous SAH 57 (28%) 37 (29%) 20 (27%) View Large TABLE 1. Characteristics of the 205 Included Patients Patients Female Male n = 205 n = 130 (63%) n = 75 (37%) Median age 47.7 48.6 46.7 History of smoking 107 (52%) 53 (41%) 54 (72%) History of hypertension 75 (37%) 49 (38%) 26 (35%) Familial history of sIAs 33 (16%) 20 (15%) 13 (17%) Previous SAH 57 (28%) 37 (29%) 20 (27%) Patients Female Male n = 205 n = 130 (63%) n = 75 (37%) Median age 47.7 48.6 46.7 History of smoking 107 (52%) 53 (41%) 54 (72%) History of hypertension 75 (37%) 49 (38%) 26 (35%) Familial history of sIAs 33 (16%) 20 (15%) 13 (17%) Previous SAH 57 (28%) 37 (29%) 20 (27%) View Large Main Results Of the followed 350 unruptured aneurysms (Table 2), 36 (10.3%) showed growth during median follow-up of 1.7 yr and total follow-up of 790 yr. Aneurysms were most frequently located in MCA (49.7%), which is also where growth was seen most frequently (61.1%). Median sizes were 3.6 mm for aneurysms with growth and 2.9 mm for aneurysms without growth. In the beginning of follow-up, 9/36 (25.0%) of the aneurysms that showed growth during follow-up were irregular vs 69/314 (22.0%) of the ones without growth. In the end of follow-up, 16/36 (44.4%) of the grown aneurysms were irregular. Median PHASES score was 8 for aneurysms with and without growth. TABLE 2. Characteristics of the 350 Included Aneurysms Growth No Growth n = 350 n = 36 (10%) n = 314 (90%) Aneurysm location  Internal carotid artery 7 (19%) 67 (21%)  Middle cerebral artery 22 (61%) 152 (48%)  Anterior cerebral artery 5 (14%) 61 (19%)  Posterior circulation 2 (6%) 34 (11%) Aneurysm size  Median/Mean 3.6/4.8 2.9/3.4  0-2.9 mm 14 (39%) 162 (52%)  3.0-4.9 mm 11 (31%) 103 (33%)  5.0-6.9 mm 3 (8%) 29 (9%)  7.0-9.9 mm 4 (11%) 15 (5%)   >10 mm 4 (11%) 5 (2%) Irregular shape 9 (25%) 69 (22%) Median follow-up time (yr) 2.9 1.7 Median PHASES score 8 8 Growth No Growth n = 350 n = 36 (10%) n = 314 (90%) Aneurysm location  Internal carotid artery 7 (19%) 67 (21%)  Middle cerebral artery 22 (61%) 152 (48%)  Anterior cerebral artery 5 (14%) 61 (19%)  Posterior circulation 2 (6%) 34 (11%) Aneurysm size  Median/Mean 3.6/4.8 2.9/3.4  0-2.9 mm 14 (39%) 162 (52%)  3.0-4.9 mm 11 (31%) 103 (33%)  5.0-6.9 mm 3 (8%) 29 (9%)  7.0-9.9 mm 4 (11%) 15 (5%)   >10 mm 4 (11%) 5 (2%) Irregular shape 9 (25%) 69 (22%) Median follow-up time (yr) 2.9 1.7 Median PHASES score 8 8 View Large TABLE 2. Characteristics of the 350 Included Aneurysms Growth No Growth n = 350 n = 36 (10%) n = 314 (90%) Aneurysm location  Internal carotid artery 7 (19%) 67 (21%)  Middle cerebral artery 22 (61%) 152 (48%)  Anterior cerebral artery 5 (14%) 61 (19%)  Posterior circulation 2 (6%) 34 (11%) Aneurysm size  Median/Mean 3.6/4.8 2.9/3.4  0-2.9 mm 14 (39%) 162 (52%)  3.0-4.9 mm 11 (31%) 103 (33%)  5.0-6.9 mm 3 (8%) 29 (9%)  7.0-9.9 mm 4 (11%) 15 (5%)   >10 mm 4 (11%) 5 (2%) Irregular shape 9 (25%) 69 (22%) Median follow-up time (yr) 2.9 1.7 Median PHASES score 8 8 Growth No Growth n = 350 n = 36 (10%) n = 314 (90%) Aneurysm location  Internal carotid artery 7 (19%) 67 (21%)  Middle cerebral artery 22 (61%) 152 (48%)  Anterior cerebral artery 5 (14%) 61 (19%)  Posterior circulation 2 (6%) 34 (11%) Aneurysm size  Median/Mean 3.6/4.8 2.9/3.4  0-2.9 mm 14 (39%) 162 (52%)  3.0-4.9 mm 11 (31%) 103 (33%)  5.0-6.9 mm 3 (8%) 29 (9%)  7.0-9.9 mm 4 (11%) 15 (5%)   >10 mm 4 (11%) 5 (2%) Irregular shape 9 (25%) 69 (22%) Median follow-up time (yr) 2.9 1.7 Median PHASES score 8 8 View Large Morphological Changes During Follow-up During the follow-up, growth occurred in 36/350 sIAs (10.3%; Table 2). Of those 36 sIAs, 9 were irregularly shaped in the beginning of the follow-up. During follow-up, 7 sIAs turned irregular. In the group of sIAs with no growth, any changes in sIA shape were not detected. Cox Regression Analysis In univariate Cox regression analysis (Table 3), sIA size (HR 1.13 [95% CI 1.03-1.25], P = .009) and location in MCA (HR 2.91 [95% CI 1.05-8.02], P = .039) showed statistical significance as risk factors for sIA growth. In multivariate Cox regression analysis (Table 3), sIA size (HR 1.35 [95% CI 1.19-1.52], P = .000) and location in MCA (HR 3.51 [95% CI 1.08-11.4], P = .037) were statistically significantly associated with growth. TABLE 3. Cox Regression Analysis n = 350 Univariate P-value Multivariate P-value HR (95% CI) HR (95% CI) Aneurysm size 1.13 (1.03-1.25) .009 1.35 (1.19-1.52) .000 Irregular sIA shape 0.89 (0.38-2.10) .793 0.52 (0.20-1.36) .183 Male sex 1.72 (0.87-3.39) .120 1.80 (0.76-4.29) .179 Age 0.99 (0.97-1.02) .652 0.97 (0.93-1.00) .122 Familial history of sIAs 1.52 (0.71-3.27) .284 1.14 (0.46-2.83) .781 Previous SAH 0.56 (0.23-1.38) .208 0.44 (0.17-1.17) .101 History of smoking 1.35 (0.69-2.66) .382 0.95 (0.41-2.22) .905 History of hypertension 0.69 (0.33-1.45) .328 0.61 (0.26-1.43) .257 Aneurysm location  Internal carotid artery Reference .142 Reference .164  Middle cerebral artery 2.91 (1.05-8.02) .039 3.51 (1.08-11.4) .037  Anterior cerebral artery 1.61 (0.45-5.73) .462 3.05 (0.73-12.8) .127  Posterior circulation 1.36 (0.23-7.29) .720 1.18 (0.21-6.74) .856 n = 350 Univariate P-value Multivariate P-value HR (95% CI) HR (95% CI) Aneurysm size 1.13 (1.03-1.25) .009 1.35 (1.19-1.52) .000 Irregular sIA shape 0.89 (0.38-2.10) .793 0.52 (0.20-1.36) .183 Male sex 1.72 (0.87-3.39) .120 1.80 (0.76-4.29) .179 Age 0.99 (0.97-1.02) .652 0.97 (0.93-1.00) .122 Familial history of sIAs 1.52 (0.71-3.27) .284 1.14 (0.46-2.83) .781 Previous SAH 0.56 (0.23-1.38) .208 0.44 (0.17-1.17) .101 History of smoking 1.35 (0.69-2.66) .382 0.95 (0.41-2.22) .905 History of hypertension 0.69 (0.33-1.45) .328 0.61 (0.26-1.43) .257 Aneurysm location  Internal carotid artery Reference .142 Reference .164  Middle cerebral artery 2.91 (1.05-8.02) .039 3.51 (1.08-11.4) .037  Anterior cerebral artery 1.61 (0.45-5.73) .462 3.05 (0.73-12.8) .127  Posterior circulation 1.36 (0.23-7.29) .720 1.18 (0.21-6.74) .856 View Large TABLE 3. Cox Regression Analysis n = 350 Univariate P-value Multivariate P-value HR (95% CI) HR (95% CI) Aneurysm size 1.13 (1.03-1.25) .009 1.35 (1.19-1.52) .000 Irregular sIA shape 0.89 (0.38-2.10) .793 0.52 (0.20-1.36) .183 Male sex 1.72 (0.87-3.39) .120 1.80 (0.76-4.29) .179 Age 0.99 (0.97-1.02) .652 0.97 (0.93-1.00) .122 Familial history of sIAs 1.52 (0.71-3.27) .284 1.14 (0.46-2.83) .781 Previous SAH 0.56 (0.23-1.38) .208 0.44 (0.17-1.17) .101 History of smoking 1.35 (0.69-2.66) .382 0.95 (0.41-2.22) .905 History of hypertension 0.69 (0.33-1.45) .328 0.61 (0.26-1.43) .257 Aneurysm location  Internal carotid artery Reference .142 Reference .164  Middle cerebral artery 2.91 (1.05-8.02) .039 3.51 (1.08-11.4) .037  Anterior cerebral artery 1.61 (0.45-5.73) .462 3.05 (0.73-12.8) .127  Posterior circulation 1.36 (0.23-7.29) .720 1.18 (0.21-6.74) .856 n = 350 Univariate P-value Multivariate P-value HR (95% CI) HR (95% CI) Aneurysm size 1.13 (1.03-1.25) .009 1.35 (1.19-1.52) .000 Irregular sIA shape 0.89 (0.38-2.10) .793 0.52 (0.20-1.36) .183 Male sex 1.72 (0.87-3.39) .120 1.80 (0.76-4.29) .179 Age 0.99 (0.97-1.02) .652 0.97 (0.93-1.00) .122 Familial history of sIAs 1.52 (0.71-3.27) .284 1.14 (0.46-2.83) .781 Previous SAH 0.56 (0.23-1.38) .208 0.44 (0.17-1.17) .101 History of smoking 1.35 (0.69-2.66) .382 0.95 (0.41-2.22) .905 History of hypertension 0.69 (0.33-1.45) .328 0.61 (0.26-1.43) .257 Aneurysm location  Internal carotid artery Reference .142 Reference .164  Middle cerebral artery 2.91 (1.05-8.02) .039 3.51 (1.08-11.4) .037  Anterior cerebral artery 1.61 (0.45-5.73) .462 3.05 (0.73-12.8) .127  Posterior circulation 1.36 (0.23-7.29) .720 1.18 (0.21-6.74) .856 View Large In the sensitivity analysis with aneurysms ≤7 mm (n = 328), sIA size (HR 1.49 [95% CI 1.01-2.21], P = .047) was the only statistically significant risk factor for growth. With aneurysms ≤5 mm (n = 300), none of the variables reached statistical significance (sIA size; HR 1.68 [95% CI 0.99-2.86], P = .056). Diagnostic Accuracy of PHASES Score and sIA Size We compared the diagnostic accuracy of PHASES score and plain sIA size for the prediction of sIA growth in our Eastern Finnish population (Figure 2). In our cohort, area under the curve was 0.60 for sIA size and 0.52 for PHASES score, respectively. DISCUSSION Key Results In this follow-up study of 350 unruptured sIAs, 10.3% of sIAs showed growth. sIA size was a strong independent risk factor for growth, as previous studies have also demonstrated.6,19 The PHASES score had low area under the curve (AUC = 0.52) in ROC-curves and should not be used in prediction of sIA growth in Eastern Finnish population. Currently known risk factors explain the risk for aneurysm growth poorly. Interpretation A large majority of unruptured aneurysms are relatively small and pose the biggest challenge in clinical decision making. Due to more aggressive treatment of large aneurysms, there is only a relatively small group of large aneurysms that might bias our results. To control for that bias, we ran sensitivity analyses with smaller aneurysms. In the analysis with sIAs ≤7 mm, size was a significant risk factor for growth. With sIAs ≤5 mm, none of the variables reached statistical significance. Our result suggests that sIA size is a valuable risk factor for growth, especially for aneurysms ≥5mm. In our main analysis, MCA aneurysms were over 3.5 times more prone to growth than ICA aneurysms. In a previous cohort of Finnish sIA patients, MCA aneurysms were less prone to rupture than aneurysms in other locations.16 Thus, it is surprising that MCA aneurysms in this cohort were more prone to growth, since growing aneurysms are generally at higher risk for rupture.6 However, there were only a few aneurysms with growth located elsewhere than in the MCA, which may explain why only MCA aneurysms were statistically significantly associated with growth. Irregular aneurysm shape, especially multilobularity, has previously been associated with sIA growth.10 In our analysis, irregular shape was not significantly associated with sIA growth. However, there is likely to be a substantial group of irregular aneurysms that have been selected for treatment, rather than for follow-up, leading to possible selection bias. In our study, many of the grown aneurysms were irregularly shaped after growth (16/36 vs 69/314 of the ones with no growth), suggesting that irregularity may not only be a potential risk factor for later sIA growth, but also an indicator of previous growth. Irregularity in itself should be considered as an indication for treatment,16,17 not to mention irregular sIAs with growth during follow-up. Further classification of irregular shape would be needed to study the association between sIA growth and different types of irregularity. The PHASES score was originally developed for prediction of sIA rupture.3 In the previously published study, Backes et al18 used it for the prediction of sIA growth. In PHASES score, sIA size was weighted as the strongest risk factor for sIA growth. Of the parameters included in the PHASES score, only sIA size reached statistical significance in our analysis. The ROC-curves (Figure 2) demonstrated that PHASES score (AUC 0.52) is not suitable for the prediction of sIA rupture in Finnish population. There was high variation in size of aneurysms that did not grow, causing poor AUC value for sIA size. sIA size should not be considered a diagnostic sign of future growth, but a risk factor for growth instead. However, the low AUC value of sIA size highlights the need for additional risk factors. Limitations Our study has a few limitations. First, our study is a retrospective, nonrandomized study. Since currently many unruptured aneurysms are treated to prevent rupture, the current cohorts of followed aneurysms are inevitably selected. However, conducting a follow-up study such as Juvela et al20 did when unruptured aneurysms were not treated is not feasible anymore due to current ethical and clinical realities. On the other hand, follow-up series reflecting the current clinical practice are required, since most unruptured sIAs diagnosed today are found incidentally or due to screening indicated by family history, and not because of SAH from another sIA as in Juvela's series.20,21 Second, due to rapid development of imaging modalities and due to length of the study period, there is inherent variation in the image quality, especially in the 3D reformations acquired from the aneurysms. This may have led to incorrect evaluation of aneurysm characteristics during data acquisition and morphological review, especially in cases with long follow-up and cases with different imaging modalities at different time points. If growth was seen because of changes in imaging modalities, it would most likely be present in all aneurysms of patients with multiple aneurysms. In our cohort of the patients with multiple aneurysms (n = 20), in only 2 patients did both aneurysms show growth during follow-up. Of those 4 aneurysms, only 1 had a different imaging modality in the beginning and in the end of the follow-up. Furthermore, the single-center configuration of the study compensates for this limitation since all the aneurysms were imaged with consistent guidelines and imaging techniques by a dedicated group of radiologists. Generalizability Our results indicate that even in the current selected cohort of unruptured aneurysms, a substantial proportion of aneurysms show growth during follow-up. Previous data have shown that growing aneurysms are at high risk of subsequent rupture, and our results highlight the value of aneurysm size as a risk factor for sIA growth in the Finnish population, regardless of patient-related or other aneurysm-related risk factors. Our results indicate that the currently known risk factors explain the risk for intracranial aneurysm growth poorly. Further studies are required to reveal additional risk factors to improve our diagnostic accuracy in identifying unruptured aneurysms at high risk for growth. CONCLUSION Our study indicates that aneurysm size is the strongest risk factor for aneurysm growth in Eastern Finnish population. Further studies are required to identify new risk factors for aneurysm growth. Disclosures Funding was from Petri Honkanen Foundation, Maire Taponen Foundation, Yrjö Jansson Foundation, Päivikki and Sakari Sohlberg Foundation, Emil Aaltonen Foundation, North Savo Regional Fund of Finnish Cultural Foundation, University of Eastern Finland, Kuopio University Hospital, and the Academy of Finland. The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. REFERENCES 1. Thompson BG , Brown RD , Amin-Hanjani S et al. 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Factors affecting formation and growth of intracranial aneurysms: a long-term follow-up study . Stroke . 2001 ; 32 ( 2 ): 485 - 491 . Google Scholar CrossRef Search ADS PubMed 21. 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 . Google Scholar CrossRef Search ADS PubMed Copyright © 2018 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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NeurosurgeryOxford University Press

Published: May 15, 2018

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