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PHASES and ELAPSS Scores Are Associated with Aneurysm Growth: A Study of 431 Unruptured Intracranial Aneurysms
Original Article
PHASES and ELAPSS Scores Are Associated with Aneurysm Growth: A Study of 431 Unruptured Intracranial Aneurysms Waleed Brinjikji1, Vitor M. Pereira1, Rujimas Khumtong1, Alex Kostensky1, Michael Tymianski2, Timo Krings1, Ivan Radovanovich2
BACKGROUND: Understanding risk factors for intracranial aneurysm growth is important for patient management. We performed a retrospective study examining risk factors for the growth of unruptured intracranial aneurysms followed at our institution, evaluating both traditional risk factors and the PHASES (Population, Hypertension, Age, Size, Earlier Subarachnoid Hemorrhage, Site) score.
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METHODS: We retrospectively reviewed a consecutive series of unruptured intracranial aneurysms followed at our institution for a minimum of 6 months over a 15-year period. The primary outcome of this study was aneurysm growth, defined as a ‡1-mm increase in maximum diameter. Risk factors studied included PHASES score, ELAPSS (Earlier Subarachnoid Hemorrhage, Location of Aneurysm, Age, Population, Size, and Shape) score, demographics, multiple aneurysms, previous subarachnoid hemorrhage, family history of aneurysm or subarachnoid hemorrhage, smoking, hypertension, and aneurysm shape, size, and location. The c2 test was used for comparison of categorical variables, and the Student t test was used for continuous variables.
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RESULTS: The study cohort comprised 352 patients with a total of 431 unruptured intracranial aneurysms. The mean duration of follow-up was 4.8 years, and there was a total of 2100 aneurysm-years of follow-up. Forty aneurysms (9.3%) grew, for an annualized growth rate of 2.0% of
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Key words Aneurysm - Growth - Risk Factor -
Abbreviations and Acronyms ACA: Anterior cerebral artery AComA: Anterior communicating artery CI: Confidence interval ELAPSS: Earlier Subarachnoid Hemorrhage, Location of Aneurysm, Age >60 Years, Population, Size of Aneurysm, Shape of Aneurysm ICA: Interior carotid artery MCA: Middle cerebral artery OR: Odds ratio PCA: Posterior cerebral artery PComA: Posterior communicating artery
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aneurysms/year. Current smoking status was the sole modifiable risk factor associated with growth (growth rate of 5.1%/year compared with 1.5%/year for never smokers; P [ 0.0004). Increasing size (odds ratio [OR], 1.22; 95% confidence interval [CI], 1.11e1.33; P < 0.0001), ELAPSS score (OR, 1.10; 95% CI, 1.09e1.11; P < 0.0001), and PHASES score (OR, 1.24; 95% CI, 1.20e1.28; P < 0.0001) were associated with growth as well. Age, location, previous subarachnoid hemorrhage, and hypertension were not independently associated with aneurysm growth. CONCLUSIONS: Our retrospective study suggests that aneurysm size, smoking status, PHASES score, and ELAPSS score are associated with aneurysm growth.
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INTRODUCTION
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nruptured intracranial aneurysms are present in 2%e8% of the general population.1,2 However, the incidence of subarachnoid hemorrhage (SAH) is substantially lower, at approximately 10e30 per 100,000 per year.3 In addition to their long-term risk of rupture, unruptured aneurysms can produce substantial morbidity secondary to cranial nerve palsies, headache, and even anxiety.4 Overall, there has been a trend toward increasing treatment of unruptured intracranial aneurysms with surgical clipping and endovascular coiling.5 With improvements
PHASES: Population, Hypertension, Age, Size, Earlier Subarachnoid Hemorrhage, Site SAH: Subarachnoid hemorrhage From the 1Joint Department of Medical Imaging, and 2Department of Neurosurgery, Toronto Western Hospital, Toronto, Ontario, Canada To whom correspondence should be addressed: Waleed Brinjikji, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2018) 114:e425-e432. https://doi.org/10.1016/j.wneu.2018.03.003 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2018 Elsevier Inc. All rights reserved.
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in operative and endovascular techniques as well as postoperative care, the morbidity and mortality related to such treatments has decreased over time.6 At many centers, aneurysm growth is considered an indication for treatment because of its association with an increased risk of rupture and is a marker of aneurysm instability. Because many longitudinal observational studies might not follow patients long enough to witness aneurysm rupture but will see aneurysm growth over their short follow-up periods, there has been interest in assessing variables associated with aneurysm growth. However, risk factors for aneurysm growth are relatively understudied compared with those of aneurysm rupture. To better understand risk factors for aneurysm growth, we performed a retrospective study on the natural history of unruptured aneurysms followed at our institution to determine the growth rate of these lesions, as well as risk factors for growth. We hypothesized that factors known to be associated with aneurysm rupture, such as the PHASES (Population, Hypertension, Age, Size, Earlier Subarachnoid Hemorrhage, Site) score, hypertension, older age, increasing aneurysm size, previous SAH, and middle cerebral artery (MCA)/ anterior cerebral artery (ACA)/posterior communicating artery (PComA)/posterior cerebral artery (PCA) aneurysm, as well as the ELAPSS (Earlier Subarachnoid Hemorrhage, Location of Aneurysm, Age >60 Years, Population, Size of Aneurysm, Shape of Aneurysm) score, would be associated with aneurysm growth. METHODS Patient Population Following Institutional Review Board approval, we retrospectively searched our institution’s vascular malformation and intracranial aneurysm database for patients with unruptured intracranial aneurysms seen at our institution between 2000 and 2016. Inclusion criteria were adult age group, unruptured saccular intracranial aneurysm, at least 2 imaging studies spaced at least 6 months apart, and satisfactory imaging quality for assessment of aneurysm size. Patients with fusiform or dissecting aneurysms were excluded, as were patients with poor imaging quality or insufficient follow-up. Imaging Both the baseline and most recent imaging studies of each patient were assessed by 1 of 2 observers who were blinded to clinical data and patient risk factors. If aneurysm rupture occurred during follow-up, the last imaging study before rupture was used. Imaging assessment was done per patient within a single session by the same observer. Imaging data collected included aneurysm location (i.e., petrocavernous, paraophthalmic, PComA/anterior choroidal, carotid terminus, ACA/AComA, MCA, PCA, basilar trunk, basilar tip, or posterior inferior cerebellar artery), aneurysm morphology (i.e., regular vs. irregular), aneurysm relationship to parent vessel (i.e., sidewall vs. bifurcation) and aneurysm size. Regularly shaped aneurysms were defined as those with a smooth contour and no lobulation or daughter sac. Irregularly shaped aneurysms were defined as those with a daughter sac or lobulation. Aneurysm size was measured using an independent PACS workstation, which allowed for multiplanar reformatting, on an
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axis perpendicular to the parent vessel. Neck size and aspect ratio were also calculated. Growth, the primary outcome of this study, was defined as an size increase of 1 mm between imaging studies. All aneurysms in which growth was noted were reviewed by a third neuroradiologist. Data Collection In addition to imaging findings, data on demographics, patient risk factors, and the PHASES score were collected for each patient. Patient data collected included age, sex, aneurysm multiplicity, previous SAH, family history of aneurysm or SAH, hypertension, smoking status (current, former, never), ELAPSS score, and overall PHASES score. PHASES score, ELAPSS score, age, and aneurysm size were modeled as both continuous and categorical variables for the purpose of statistical analysis. Data were also collected on follow-up time, defined as the interval between the first and last imaging studies. The PHASES and ELAPSS scores are summarized in Table 1. Statistical Analysis Growth rate was calculated on both a per-aneurysm and pere aneurysm-year basis. The equation for calculating the pereaneurysm-year rate was as follows: number of growing aneurysms/ (number of aneurysms followed total number of years followed). Thus, this statistic is an indicator of the proportion of aneurysms that grew with each year of follow-up. Although statistical comparisons were made on both a per-aneurysm and pere aneurysm-year basis, the growth rate per aneurysm-year was the primary outcome, because some cohorts may have had shorter follow-up times than others. Growth rates for categorical variables were compared using c2 analysis. The associations between continuous variables and growth were studied using logistic regression. A multivariate logistic regression analysis was performed to examine the associations between PHASES score risk factors and aneurysm growth, to determine which variables were independently associated with aneurysm growth. KaplaneMeier growth-free survival curves were plotted to examine the associations between quartiles of the PHASES score and aneurysm growth. A multivariate logistic regression analysis was also performed to examine the associations between the ELAPSS score risk factors and aneurysm growth. KaplaneMeier growth-free survival curves were plotted to examine associations among ELAPSS score groups (i.e., <5, 5e9, 10e19, 15e19, and 20þ). RESULTS Patient Population Of a total of 1062 unruptured intracranial aneurysm patients included in our prospective institutional database, 142 aneurysms were excluded because of treatment before a 6-month follow-up period and 485 aneurysms were excluded because of insufficient imaging follow-up. In all, a total of 352 patients (271 [76.9%] females) with 431 unruptured aneurysms met our inclusion criteria (Figure 1). The main reason for exclusion of patients was treatment soon after presentation or insufficient follow-up data. The mean patient age was 55.8 0.6 years. Twenty-eight patients
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2018.03.003
ORIGINAL ARTICLE WALEED BRINJIKJI ET AL.
PHASES AND ELAPSS SCORES ASSOCIATED WITH ANEURYSM GROWTH
Table 1. Summary of ELAPSS and PHASES Scores ELAPSS Score Points
PHASES Score Points
Yes
0
1
No
1
0
ICA
0
0
ACA/AComA
0
4
MCA
3
2
PComA/PCA
5
4
0
NA
Earlier SAH
Location of aneurysm
Age (years) 60 >60 (per 5 years)
1
NA
<70
NA
0
70
NA
1
North America, China, Europe
0
0
Japan
1
3
Finland
7
5
1e2.9
0
0
3e4.9
4
0
5e6.9
10
0
7e9.9
13
3
10e19.9
22
6
20
22
10
Regular
0
NA
Irregular
4
NA
Yes
NA
1
No
NA
0
Population
Aneurysm size, mm
Aneurysm shape
Hypertension
ELAPSS, Earlier Subarachnoid Hemorrhage, Location of Aneurysm, Age >60 Years, Population, Size of Aneurysm, Shape of Aneurysm; PHASES, Population, Hypertension, Age, Size, Earlier Subarachnoid Hemorrhage, Site; SAH, subarachnoid hemorrhage; ICA, internal carotid artery; ACA, anterior cerebral artery; AcomA, anterior communicating artery; MCA, middle cerebral artery; PComA, posterior communicating artery; PCA, posterior cerebral artery.
(7.9%) had a previous history of SAH. The mean aneurysm size at baseline was 3.9 0.1 mm. The mean duration of follow-up was 4.8 0.5 years, and there was a total of 2100 aneurysm-years of follow-up. Summary data on patient characteristics are provided in Table 2.
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Figure 1. Flow chart of patient inclusion.
Patient Risk Factors for Aneurysm Growth A total of 40 aneurysms grew during the course of this study (9.7%). The overall aneurysm growth rate was 2.0% of aneurysms per aneurysm-year. The median time to growth was 2.6 years. Smoking status was the sole patient risk factor associated with aneurysm growth as current smokers had a growth rate of 5.1% of aneurysms/aneurysm-year, compared with 1.5% for former
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Table 2. Patient Characteristics Variable
Outcome
Number of patients Number of aneurysms Follow-up (years), mean (SD) Number of patient-years Number of aneurysm-years Age (years), mean (SD)
352 431 4.8 (9.5) 1760 2109 55.8 (12.2)
Age (years), number (%) <70
316 (88.6)
>70
36 (11.4)
Sex, number (%) Male
81 (23.1)
Female
271 (76.9)
Multiple aneurysms, number (%) Yes
128 (36.1)
No
224 (63.9)
Previous SAH, number (%) Yes
28 (7.9)
No
324 (92.1)
Family history, number (%) Yes
90 (25.6)
Aneurysms
23 (6.8)
SAH
67 (18.9)
No
151 (43.1)
Unknown
111 (31.3)
Hypertension, number (%) Yes
172 (48.7)
No
180 (51.3)
Smoking, number (%) Never
138 (38.9)
Current
115 (32.7)
Former
70 (20.3)
Unknown
29 (8.2)
SD, standard deviation; SAH, subarachnoid hemorrhage.
smokers and 1.6% for never smokers (P ¼ 0.0004). When modeling age as a continuous variable, there was no association between age and growth (P ¼ 0.59). When dividing patients into age groups (<70 vs. 70 years), there was a trend toward a higher growth rate in older patients (4.6% vs. 1.8%; P ¼ 0.06). There was no difference in growth rates by sex (P ¼ 0.65), previous SAH (P ¼ 0.81), aneurysm multiplicity (P ¼ 0.19), history of hypertension (P ¼ 0.19), and family history of aneurysm or SAH (P ¼ 0.31).
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Aneurysm and Anatomic Risk Factors for Aneurysm Growth There was no association between aneurysm location and aneurysm growth rates. Aneurysms in the anterior circulation had a growth rate of 2.2%/aneurysm-year compared to 1.6%/aneurysmyear for posterior circulation (P ¼ 0.69). When dividing aneurysm location based on the PHASES study (ICA, MCA, ACA/AComA/ PComA/posterior circulation), there was no significant difference in growth rates (2.3%, 1.5%, and 2.2%, respectively; P ¼ 0.69). Each 1-mm increase in aneurysm size was associated with an increasing odds ratio (OR) of 1.22 (95% confidence interval [CI], 1.11e1.33; P < 0.0001) for aneurysm growth. Aneurysms <3 mm had a growth rate of 1.1%/year, compared with 5.7% for aneurysms 7e9.9 mm and 19.1% for aneurysms 13 mm. Aneurysm shape (P ¼ 0.19) and relationship to the parent vessel (P ¼ 0.09) were not significantly associated with growth. Neck size was associated with growth; each 1-mm increase in neck size was associated with an OR for growth of 1.42 (95% CI, 1.31e1.53; P ¼ 0.0002). There was a trend toward increased growth rates with increasing aspect ratio, with each 1-unit increase associated with an OR for growth of 1.52 (95% CI, 0.98e2.06; P ¼ 0.08). These data are summarized in Table 3. PHASES Score and Aneurysm Growth The median PHASES score was 3 (interquartile range, 1e5). The maximum PHASES score was 12, and the minimum was 0. When modeling PHASES score as a continuous variable, an increasing PHASES score was associated with a higher odds of aneurysm growth, with each 1-point increase associated with an OR of 1.24 (95% CI, 1.20e1.28; P < 0.0001) for aneurysm growth. Dividing PHASES scores into quartiles of 0e1, 2e3, 4e5, and 6, patients with PHASES score 6 had the highest aneurysm growth rate (9.0%/year). This was significantly higher than the growth rates for the other 3 quartiles: 1.5%/year, 1.6%/year, and 1.4%/year, respectively (P < 0.0001). On multivariate logistic regression analysis adjusting for aneurysm location, size, previous history of SAH, age, and hypertension, the sole variable independently associated with aneurysm growth was size (P ¼ 0.0006). Aneurysm location (P ¼ 0.70), previous history of SAH (P ¼ 0.88), age (P ¼ 0.88), and hypertension (P ¼ 0.68) were not associated with aneurysm growth. KaplaneMeier survival curves for aneurysm growth by PHASES quartile are shown in Figure 2. ELAPSS Score and Aneurysm Growth The median ELAPSS score was 6 (interquartile range, 4e11). The maximum ELAPSS score was 29, and the minimum was 0. When modeling ELAPSS score as a continuous variable, increasing ELAPSS score was associated with a higher odds of aneurysm growth, with each 1-point increase associated with an OR of 1.10 (95% CI, 1.09e1.11; P < 0.0001) for aneurysm growth. Dividing ELAPSS scores into groups of <5, 5e9, 10e19, 15e19, and 20, patients with an ELAPSS score 20 had the highest aneurysm growth rate (11.3%/year). This was significantly higher than the growth rates for the other 4 groups (0.8%/year, 2.1%/year, 2.9%/year, and 1.7%/year, respectively; P < 0.0001). The median time to growth by ELAPSS score group was 3.5 years for <5, 2.5 years for 5e9, 2.3 years for 10e19, 2.9 years for 15e19, and 1.3 years for 20.
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ORIGINAL ARTICLE WALEED BRINJIKJI ET AL.
PHASES AND ELAPSS SCORES ASSOCIATED WITH ANEURYSM GROWTH
Table 3. Risk Factors for Aneurysm Growth Number of Aneurysms
Number (%) of Aneurysms Growing
Annualized Aneurysm Growth Rate, % Growing/Year
P Value, per Aneurysm-Year
P Value, per Patient
431
40 (9.3)
2.00
—
—
<70
390
36 (9.2)
1.80
>70
41
6 (13.6)
4.60
Factor All patients Age (years)
0.06
0.35
0.65
0.52
0.51
0.51
0.69
0.89
0.72
0.54
0.19
0.19
0.81
0.91
0.31
0.01
Sex Male
99
7 (7.1)
1.60
Female
332
33 (9.9)
2.10
Aneurysm location Petrocavernous ICA
53
5 (9.4)
2.10
Paraophthalmic ICA
82
9 (11.0)
2.70
PComA/anterior choroidal ICA
36
3 (8.4)
3.80
ICA terminus
27
1 (3.7)
1.00
ACA/AComA
75
8 (10.8)
2.20
MCA
124
10 (8.1)
2.90
PCA
5
0 (0.0)
0.00
Basilar trunk
13
0 (0.0)
0.00
Basilar tip
11
3 (27.3)
2.00
PICA
5
1 (20.0)
5.60
Anterior
396
36 (9.1)
2.20
Posterior
35
4 (11.4)
1.60
162
15 (9.3)
2.30
Anterior versus posterior
Aneurysm location (PHASES) ICA MCA
124
10 (8.1)
1.50
ACA/PComA/posterior circulation
145
15 (10.3)
2.22
Multiple aneurysms Yes
206
16 (7.8)
1.50
No
225
24 (10.7)
2.40
Yes
33
3 (9.1)
2.30
No
398
37 (9.3)
2.00
Yes
110
7 (6.4)
1.70
No
180
19 (10.6)
2.80
Previous SAH
Family history
Hypertension ICA, internal carotid artery; PComA, posterior communicating artery; ACA, anterior cerebral artery; AcomA, anterior communicating artery; MCA, middle cerebral artery; PCA, posterior cerebral artery; PICA, posterior inferior cerebellar artery; PHASES, Population, Hypertension, Age, Size, Earlier Subarachnoid Hemorrhage, Site; SAH, subarachnoid hemorrhage; ELAPSS, Earlier Subarachnoid Hemorrhage, Location of Aneurysm, Age >60 Years, Population, Size of Aneurysm, Shape of Aneurysm. Continues
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Table 3. Continued Number of Aneurysms
Number (%) of Aneurysms Growing
Annualized Aneurysm Growth Rate, % Growing/Year
Yes
213
23 (10.8)
2.50
No
218
17 (7.8)
1.60
Former
84
10 (11.9)
1.50
Never
168
12 (7.1)
1.60
Current
150
18 (12.0)
5.10
Regular
386
33 (8.6)
0.50
Irregular
45
7 (15.6)
3.50
Sidewall
226
23 (10.2)
2.60
Bifurcation
205
17 (8.3)
1.50
<3
184
10 (5.4)
1.10
3e4.9
157
14 (8.9)
2.22
5e6.9
49
5 (10.2)
1.56
7e9.9
28
5 (17.9)
5.68
10e12.9
6
2 (33.3)
11.76
13þ
7
4 (57.1)
19.05
0e1
135
8 (5.9)
1.50
2e3
112
10 (8.9)
1.60
4e5
135
10 (7.5)
1.40
6þ
50
12 (25.0)
9.00
<5
128
6 (4.7)
0.80
5e9
170
15 (8.8)
2.10
10e14
76
8 (10.5)
2.90
15e19
34
4 (11.8)
1.70
20
23
7 (30.4)
11.3
Factor
P Value, per Aneurysm-Year
P Value, per Patient
0.19
0.28
0.0004
0.28
0.19
0.16
0.09
0.35
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
Smoking status
Shape
Relationship to parent vessel
Size (mm)
PHASES score
ELAPSS score
ICA, internal carotid artery; PComA, posterior communicating artery; ACA, anterior cerebral artery; AcomA, anterior communicating artery; MCA, middle cerebral artery; PCA, posterior cerebral artery; PICA, posterior inferior cerebellar artery; PHASES, Population, Hypertension, Age, Size, Earlier Subarachnoid Hemorrhage, Site; SAH, subarachnoid hemorrhage; ELAPSS, Earlier Subarachnoid Hemorrhage, Location of Aneurysm, Age >60 Years, Population, Size of Aneurysm, Shape of Aneurysm.
On multivariate logistic regression analysis adjusting for aneurysm location, size, previous history of SAH, age, and hypertension, the sole variable independently associated with aneurysm growth was size (P ¼ 0.0009). Aneurysm location (P ¼ 0.67), previous history of SAH (P ¼ 0.83), age (P ¼ 0.22), and shape (P ¼ 0.12) were not associated with aneurysm growth. KaplaneMeier survival curves for aneurysm growth by ELAPSS group are shown in Figure 3.
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DISCUSSION Our analysis of more than 400 aneurysms with 2100 aneurysmyears of follow-up has demonstrated a number of interesting findings. Aneurysm growth occurred in approximately 10% of cases over the roughly 5-year follow-up period, for an overall growth rate of 2.0%/year. Predictors of aneurysm growth included aneurysm size and current smoking status. Although the PHASES
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ORIGINAL ARTICLE WALEED BRINJIKJI ET AL.
PHASES AND ELAPSS SCORES ASSOCIATED WITH ANEURYSM GROWTH
aneurysms growing at a median of 1.3 years and lower-risk aneurysms growing at a median of 3.5 years. Thus, our data suggest that in general, imaging surveillance for evaluating growth of unruptured aneurysms can be extended to 2- to 3-year intervals, with closer, annual follow-up for higher-risk aneurysms. These findings are corroborated by findings from a large multiinstitutional study by Rinkel et al.11 that found a median time to growth of 1.9 years.
Figure 2. KaplaneMeier curve by PHASES score.
and ELAPSS scores were also associated with growth, the sole individual component of the scores that was independently associated with aneurysm growth was size. This study highlights the fact that aneurysm growth is not uncommon, and in the case of larger aneurysms and aneurysms in current smokers, growth rates are rather high. These findings are important, highlighting important clinical and anatomic risk factors for the progression of intracranial aneurysms that can be used in counseling patients with unruptured aneurysms. Clinical Implications Understanding risk factors for aneurysm growth and obtaining an estimate for overall aneurysm growth rates is important, because some growing aneurysms are at increased risk for future rupture. In a study of 1002 patients with 1325 unruptured aneurysms, Inoue et al.7 reported an annual rupture risk after aneurysm growth of 18.5%/person-year. In a multivariate analysis, Mehan et al.8 found that aneurysm growth was associated with an OR of 55.9 for rupture. The series reported by Juvela et al.,9 which has the longest follow-up of any population-based study on the natural history of unruptured aneurysms, demonstrated that 45% of aneurysms receiving follow-up had some growth >1 mm over the lifetime of the patient. Of these, 66% ruptured.9 A large metaanalysis found that growing aneurysms were >30-fold more likely to rupture than stable ones, with an overall rupture rate of these aneurysms of 3.1%/year, a rate similar to that reported in patients with a PHASES score of 8.10 Another important finding from our study was the time to growth of the included unruptured aneurysms. Typically, imaging surveillance for follow-up of an unruptured aneurysm is performed to evaluate for changes in size and morphology. Follow-up times are highly variable across institutions. According to American Heart Association recommendations, for patients with unruptured intracranial aneurysms managed noninvasively, the first follow-up study should be performed at 6e12 months after initial discovery, followed by subsequent imaging at 1e2 years. In our study, we found a median time to growth of 2.6 years, with higher-risk
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Growth Risk Factors and Predictive Models A number of previous studies have reported growth rates and examined risk factors for aneurysm growth. In a meta-analysis of 21 longitudinal studies examining the natural history of unruptured aneurysms, the overall growth rate was 2.5% of aneurysms/ year, and risk factors found to be statistically associated with aneurysm growth included larger aneurysm size, posterior circulation location, irregular aneurysm shape, smoking, and female sex.10 Other previous large studies have reported annual aneurysm growth rates of approximately 1.5%e2.5% of aneurysms/year, similar to our findings, and have identified other risk factors for growth, including bifurcation location and hypertension.7,8,12,13 Models that have been used to predict aneurysm growth include the PHASES and ELAPSS scores. The PHASES score, designed primarily to study aneurysm rupture, has been associated with aneurysm growth.14 In a study of 557 patients with 734 unruptured aneurysms and 2.2 years of follow-up, Backes et al.15 found that each point increase in PHASES score was associated with a hazard ratio for aneurysm growth of 1.32. Similar to our study, the authors found that aneurysm size was the only PHASES score variable that was independently associated with growth while hypertension, age, earlier SAH from another aneurysm and aneurysm site were not independently associated with growth.15 Backes et al. later developed the ELAPSS score based on longitudinal data on aneurysm growth from multiple centers. The ELAPSS score was designed specifically to study aneurysm growth. Although many of the factors included in this score are similar to those of the PHASES score, there are some important differences.
Figure 3. KaplaneMeier curve by ELAPSS score.
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PHASES AND ELAPSS SCORES ASSOCIATED WITH ANEURYSM GROWTH
First, hypertension is not included in the ELAPSS score, but is included in the PHASES score. Previous SAH from another aneurysm is a risk factor for aneurysm rupture, but not for growth. Regarding aneurysm location, ACA/AComA aneurysms are at risk for rupture, but not for growth. Finally, the ELAPSS score includes aneurysm shape as a variable, but the PHASES score does not. Growth rates for aneurysms with an ELAPSS score of <5 were on the order of 1%e2%/year, compared with upward of 12%/year for aneurysms with a score 25. Our study, which had substantially longer follow-up than the ELAPSS study, confirms the results of the ELAPSS study; aneurysms with a score <5 had a growth rate of <1%/year, whereas those with a score >20 had a growth rate of 11%/year. We found that size was the sole independent predictor of growth out of all the variables included in the ELAPSS score. In addition, our study highlights the fact that smoking history, which is not included in the PHASES score or ELAPSS score, is an important variable to consider when exploring the natural history of an unruptured aneurysm. Limitations Our study has some limitations. First, there was no predefined protocol regarding the type and timing of imaging used in followup. Aneurysm growth was assessed with various imaging modalities, including computed tomography angiography, digital subtraction angiography, and magnetic resonance angiography, which could have introduced some error or bias. Our study only
REFERENCES 1. Li MH, Chen SW, Li YD, Chen YC, Cheng YS, Hu DJ, et al. Prevalence of unruptured cerebral aneurysms in Chinese adults aged 35 to 75 years: a cross-sectional study. Ann Intern Med. 2013;159: 514-521. 2. Vlak MH, Algra A, Brandenburg R, Rinkel GJ. Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and metaanalysis. Lancet Neurol. 2011;10:626-636. 3. Ziemba-Davis M, Bohnstedt BN, Payner TD, Leipzig TJ, Palmer E, Cohen-Gadol AA. Incidence, epidemiology, and treatment of aneurysmal subarachnoid hemorrhage in 12 midwest communities. J Stroke Cerebrovasc Dis. 2014;23:1073-1082. 4. Brown RD Jr, Broderick JP. Unruptured intracranial aneurysms: epidemiology, natural history, management options, and familial screening. Lancet Neurol. 2014;13:393-404. 5. Brinjikji W, Rabinstein AA, Lanzino G, Kallmes DF, Cloft HJ. Effect of age on outcomes of treatment of unruptured cerebral aneurysms: a study of the National Inpatient Sample 2001-2008. Stroke. 2011;42:1320-1324. 6. Brinjikji W, Rabinstein AA, Lanzino G, Kallmes DF, Cloft HJ. Patient outcomes are better for unruptured cerebral aneurysms treated at centers that preferentially treat with endovascular coiling: a study of the national inpatient sample
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included patients from a single institution, which might limit the generalizability of our results. There was substantial selection bias in this study; the patients included composed just 35% of all those with unruptured aneurysms evaluated at our institution. Higherrisk aneurysms were more likely to undergo treatment. As such, this could result in underestimation of the risk of growth, because patients at greater risk of growth or rupture likely were not included. A number of patients were lost to follow-up as well.
CONCLUSIONS Overall growth rates of intracranial aneurysms are not negligible; approximately 10% of the aneurysms followed in this study grew over a mean follow-up period of 5 years. Risk factors for the growth of intracranial aneurysms included increasing PHASES and ELAPSS score, larger aneurysm size, and smoking status. When considering the individual components of the PHASES and ELAPSS scores, however, size was the sole independent predictor of aneurysm growth. The median time to growth was 2.6 years, suggesting that imaging follow-up can be performed at 2- to 3-year intervals. These findings should be considered when counseling patients regarding the natural history of intracranial aneurysms and could be used to guide decisions regarding the frequency of follow-up imaging for patients with unruptured aneurysms who are managed conservatively.
2001-2007. AJNR Am J Neuroradiol. 2011;32: 1065-1070. 7. Inoue T, Shimizu H, Fujimura M, Saito A, Tominaga T. Annual rupture risk of growing unruptured cerebral aneurysms detected by magnetic resonance angiography. J Neurosurg. 2012;117: 20-25. 8. Mehan WA Jr, Romero JM, Hirsch JA, Sabbag DJ, Gonzalez RG, Heit JJ, et al. Unruptured intracranial aneurysms conservatively followed with serial CT angiography: could morphology and growth predict rupture? J Neurointerv Surg. 2014;6:761-766. 9. Juvela S, Poussa K, Porras M. Factors affecting formation and growth of intracranial aneurysms: a long-term follow-up study. Stroke. 2001;32: 485-491. 10. Brinjikji W, Zhu YQ, Lanzino G, Cloft HJ, Murad MH, Wang Z, et al. Risk factors for growth of intracranial aneurysms: a systematic review and meta-analysis. AJNR Am J Neuroradiol. 2016;37: 615-620. 11. Backes D, Rinkel GJE, Greving JP, Velthuis BK, Murayama Y, Takao H, et al. ELAPSS score for prediction of risk of growth of unruptured intracranial aneurysms. Neurology. 2017;88:1600-1606.
13. Villablanca JP, Duckwiler GR, Jahan R, Tateshima S, Martin NA, Frazee J, et al. Natural history of asymptomatic unruptured cerebral aneurysms evaluated at CT angiography: growth and rupture incidence and correlation with epidemiologic risk factors. Radiology. 2013;269:258-265. 14. Greving JP, Wermer MJ, Brown RD Jr, Morita A, Juvela S, Yonekura M, 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: 59-66. 15. Backes D, Vergouwen MD, Tiel Groenestege AT, Bor AS, Velthuis BK, Greving JP, et al. PHASES score for prediction of intracranial aneurysm growth. Stroke. 2015;46:1221-1226.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 6 February 2018; accepted 1 March 2018 Citation: World Neurosurg. (2018) 114:e425-e432. https://doi.org/10.1016/j.wneu.2018.03.003 Journal homepage: www.WORLDNEUROSURGERY.org
12. Juvela S, Poussa K, Lehto H, Porras M. Natural history of unruptured intracranial aneurysms: a long-term follow-up study. Stroke. 2013;44: 2414-2421.
Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2018 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2018.03.003
PHASES and ELAPSS Scores Are Associated with Aneurysm Growth: A Study of 431 Unruptured Intracranial Aneurysms Waleed Brinjikji1, Vitor M. Pereira1, Rujimas Khumtong1, Alex Kostensky1, Michael Tymianski2, Timo Krings1, Ivan Radovanovich2
BACKGROUND: Understanding risk factors for intracranial aneurysm growth is important for patient management. We performed a retrospective study examining risk factors for the growth of unruptured intracranial aneurysms followed at our institution, evaluating both traditional risk factors and the PHASES (Population, Hypertension, Age, Size, Earlier Subarachnoid Hemorrhage, Site) score.
-
METHODS: We retrospectively reviewed a consecutive series of unruptured intracranial aneurysms followed at our institution for a minimum of 6 months over a 15-year period. The primary outcome of this study was aneurysm growth, defined as a ‡1-mm increase in maximum diameter. Risk factors studied included PHASES score, ELAPSS (Earlier Subarachnoid Hemorrhage, Location of Aneurysm, Age, Population, Size, and Shape) score, demographics, multiple aneurysms, previous subarachnoid hemorrhage, family history of aneurysm or subarachnoid hemorrhage, smoking, hypertension, and aneurysm shape, size, and location. The c2 test was used for comparison of categorical variables, and the Student t test was used for continuous variables.
-
RESULTS: The study cohort comprised 352 patients with a total of 431 unruptured intracranial aneurysms. The mean duration of follow-up was 4.8 years, and there was a total of 2100 aneurysm-years of follow-up. Forty aneurysms (9.3%) grew, for an annualized growth rate of 2.0% of
-
Key words Aneurysm - Growth - Risk Factor -
Abbreviations and Acronyms ACA: Anterior cerebral artery AComA: Anterior communicating artery CI: Confidence interval ELAPSS: Earlier Subarachnoid Hemorrhage, Location of Aneurysm, Age >60 Years, Population, Size of Aneurysm, Shape of Aneurysm ICA: Interior carotid artery MCA: Middle cerebral artery OR: Odds ratio PCA: Posterior cerebral artery PComA: Posterior communicating artery
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aneurysms/year. Current smoking status was the sole modifiable risk factor associated with growth (growth rate of 5.1%/year compared with 1.5%/year for never smokers; P [ 0.0004). Increasing size (odds ratio [OR], 1.22; 95% confidence interval [CI], 1.11e1.33; P < 0.0001), ELAPSS score (OR, 1.10; 95% CI, 1.09e1.11; P < 0.0001), and PHASES score (OR, 1.24; 95% CI, 1.20e1.28; P < 0.0001) were associated with growth as well. Age, location, previous subarachnoid hemorrhage, and hypertension were not independently associated with aneurysm growth. CONCLUSIONS: Our retrospective study suggests that aneurysm size, smoking status, PHASES score, and ELAPSS score are associated with aneurysm growth.
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INTRODUCTION
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nruptured intracranial aneurysms are present in 2%e8% of the general population.1,2 However, the incidence of subarachnoid hemorrhage (SAH) is substantially lower, at approximately 10e30 per 100,000 per year.3 In addition to their long-term risk of rupture, unruptured aneurysms can produce substantial morbidity secondary to cranial nerve palsies, headache, and even anxiety.4 Overall, there has been a trend toward increasing treatment of unruptured intracranial aneurysms with surgical clipping and endovascular coiling.5 With improvements
PHASES: Population, Hypertension, Age, Size, Earlier Subarachnoid Hemorrhage, Site SAH: Subarachnoid hemorrhage From the 1Joint Department of Medical Imaging, and 2Department of Neurosurgery, Toronto Western Hospital, Toronto, Ontario, Canada To whom correspondence should be addressed: Waleed Brinjikji, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2018) 114:e425-e432. https://doi.org/10.1016/j.wneu.2018.03.003 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2018 Elsevier Inc. All rights reserved.
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in operative and endovascular techniques as well as postoperative care, the morbidity and mortality related to such treatments has decreased over time.6 At many centers, aneurysm growth is considered an indication for treatment because of its association with an increased risk of rupture and is a marker of aneurysm instability. Because many longitudinal observational studies might not follow patients long enough to witness aneurysm rupture but will see aneurysm growth over their short follow-up periods, there has been interest in assessing variables associated with aneurysm growth. However, risk factors for aneurysm growth are relatively understudied compared with those of aneurysm rupture. To better understand risk factors for aneurysm growth, we performed a retrospective study on the natural history of unruptured aneurysms followed at our institution to determine the growth rate of these lesions, as well as risk factors for growth. We hypothesized that factors known to be associated with aneurysm rupture, such as the PHASES (Population, Hypertension, Age, Size, Earlier Subarachnoid Hemorrhage, Site) score, hypertension, older age, increasing aneurysm size, previous SAH, and middle cerebral artery (MCA)/ anterior cerebral artery (ACA)/posterior communicating artery (PComA)/posterior cerebral artery (PCA) aneurysm, as well as the ELAPSS (Earlier Subarachnoid Hemorrhage, Location of Aneurysm, Age >60 Years, Population, Size of Aneurysm, Shape of Aneurysm) score, would be associated with aneurysm growth. METHODS Patient Population Following Institutional Review Board approval, we retrospectively searched our institution’s vascular malformation and intracranial aneurysm database for patients with unruptured intracranial aneurysms seen at our institution between 2000 and 2016. Inclusion criteria were adult age group, unruptured saccular intracranial aneurysm, at least 2 imaging studies spaced at least 6 months apart, and satisfactory imaging quality for assessment of aneurysm size. Patients with fusiform or dissecting aneurysms were excluded, as were patients with poor imaging quality or insufficient follow-up. Imaging Both the baseline and most recent imaging studies of each patient were assessed by 1 of 2 observers who were blinded to clinical data and patient risk factors. If aneurysm rupture occurred during follow-up, the last imaging study before rupture was used. Imaging assessment was done per patient within a single session by the same observer. Imaging data collected included aneurysm location (i.e., petrocavernous, paraophthalmic, PComA/anterior choroidal, carotid terminus, ACA/AComA, MCA, PCA, basilar trunk, basilar tip, or posterior inferior cerebellar artery), aneurysm morphology (i.e., regular vs. irregular), aneurysm relationship to parent vessel (i.e., sidewall vs. bifurcation) and aneurysm size. Regularly shaped aneurysms were defined as those with a smooth contour and no lobulation or daughter sac. Irregularly shaped aneurysms were defined as those with a daughter sac or lobulation. Aneurysm size was measured using an independent PACS workstation, which allowed for multiplanar reformatting, on an
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axis perpendicular to the parent vessel. Neck size and aspect ratio were also calculated. Growth, the primary outcome of this study, was defined as an size increase of 1 mm between imaging studies. All aneurysms in which growth was noted were reviewed by a third neuroradiologist. Data Collection In addition to imaging findings, data on demographics, patient risk factors, and the PHASES score were collected for each patient. Patient data collected included age, sex, aneurysm multiplicity, previous SAH, family history of aneurysm or SAH, hypertension, smoking status (current, former, never), ELAPSS score, and overall PHASES score. PHASES score, ELAPSS score, age, and aneurysm size were modeled as both continuous and categorical variables for the purpose of statistical analysis. Data were also collected on follow-up time, defined as the interval between the first and last imaging studies. The PHASES and ELAPSS scores are summarized in Table 1. Statistical Analysis Growth rate was calculated on both a per-aneurysm and pere aneurysm-year basis. The equation for calculating the pereaneurysm-year rate was as follows: number of growing aneurysms/ (number of aneurysms followed total number of years followed). Thus, this statistic is an indicator of the proportion of aneurysms that grew with each year of follow-up. Although statistical comparisons were made on both a per-aneurysm and pere aneurysm-year basis, the growth rate per aneurysm-year was the primary outcome, because some cohorts may have had shorter follow-up times than others. Growth rates for categorical variables were compared using c2 analysis. The associations between continuous variables and growth were studied using logistic regression. A multivariate logistic regression analysis was performed to examine the associations between PHASES score risk factors and aneurysm growth, to determine which variables were independently associated with aneurysm growth. KaplaneMeier growth-free survival curves were plotted to examine the associations between quartiles of the PHASES score and aneurysm growth. A multivariate logistic regression analysis was also performed to examine the associations between the ELAPSS score risk factors and aneurysm growth. KaplaneMeier growth-free survival curves were plotted to examine associations among ELAPSS score groups (i.e., <5, 5e9, 10e19, 15e19, and 20þ). RESULTS Patient Population Of a total of 1062 unruptured intracranial aneurysm patients included in our prospective institutional database, 142 aneurysms were excluded because of treatment before a 6-month follow-up period and 485 aneurysms were excluded because of insufficient imaging follow-up. In all, a total of 352 patients (271 [76.9%] females) with 431 unruptured aneurysms met our inclusion criteria (Figure 1). The main reason for exclusion of patients was treatment soon after presentation or insufficient follow-up data. The mean patient age was 55.8 0.6 years. Twenty-eight patients
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2018.03.003
ORIGINAL ARTICLE WALEED BRINJIKJI ET AL.
PHASES AND ELAPSS SCORES ASSOCIATED WITH ANEURYSM GROWTH
Table 1. Summary of ELAPSS and PHASES Scores ELAPSS Score Points
PHASES Score Points
Yes
0
1
No
1
0
ICA
0
0
ACA/AComA
0
4
MCA
3
2
PComA/PCA
5
4
0
NA
Earlier SAH
Location of aneurysm
Age (years) 60 >60 (per 5 years)
1
NA
<70
NA
0
70
NA
1
North America, China, Europe
0
0
Japan
1
3
Finland
7
5
1e2.9
0
0
3e4.9
4
0
5e6.9
10
0
7e9.9
13
3
10e19.9
22
6
20
22
10
Regular
0
NA
Irregular
4
NA
Yes
NA
1
No
NA
0
Population
Aneurysm size, mm
Aneurysm shape
Hypertension
ELAPSS, Earlier Subarachnoid Hemorrhage, Location of Aneurysm, Age >60 Years, Population, Size of Aneurysm, Shape of Aneurysm; PHASES, Population, Hypertension, Age, Size, Earlier Subarachnoid Hemorrhage, Site; SAH, subarachnoid hemorrhage; ICA, internal carotid artery; ACA, anterior cerebral artery; AcomA, anterior communicating artery; MCA, middle cerebral artery; PComA, posterior communicating artery; PCA, posterior cerebral artery.
(7.9%) had a previous history of SAH. The mean aneurysm size at baseline was 3.9 0.1 mm. The mean duration of follow-up was 4.8 0.5 years, and there was a total of 2100 aneurysm-years of follow-up. Summary data on patient characteristics are provided in Table 2.
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Figure 1. Flow chart of patient inclusion.
Patient Risk Factors for Aneurysm Growth A total of 40 aneurysms grew during the course of this study (9.7%). The overall aneurysm growth rate was 2.0% of aneurysms per aneurysm-year. The median time to growth was 2.6 years. Smoking status was the sole patient risk factor associated with aneurysm growth as current smokers had a growth rate of 5.1% of aneurysms/aneurysm-year, compared with 1.5% for former
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Table 2. Patient Characteristics Variable
Outcome
Number of patients Number of aneurysms Follow-up (years), mean (SD) Number of patient-years Number of aneurysm-years Age (years), mean (SD)
352 431 4.8 (9.5) 1760 2109 55.8 (12.2)
Age (years), number (%) <70
316 (88.6)
>70
36 (11.4)
Sex, number (%) Male
81 (23.1)
Female
271 (76.9)
Multiple aneurysms, number (%) Yes
128 (36.1)
No
224 (63.9)
Previous SAH, number (%) Yes
28 (7.9)
No
324 (92.1)
Family history, number (%) Yes
90 (25.6)
Aneurysms
23 (6.8)
SAH
67 (18.9)
No
151 (43.1)
Unknown
111 (31.3)
Hypertension, number (%) Yes
172 (48.7)
No
180 (51.3)
Smoking, number (%) Never
138 (38.9)
Current
115 (32.7)
Former
70 (20.3)
Unknown
29 (8.2)
SD, standard deviation; SAH, subarachnoid hemorrhage.
smokers and 1.6% for never smokers (P ¼ 0.0004). When modeling age as a continuous variable, there was no association between age and growth (P ¼ 0.59). When dividing patients into age groups (<70 vs. 70 years), there was a trend toward a higher growth rate in older patients (4.6% vs. 1.8%; P ¼ 0.06). There was no difference in growth rates by sex (P ¼ 0.65), previous SAH (P ¼ 0.81), aneurysm multiplicity (P ¼ 0.19), history of hypertension (P ¼ 0.19), and family history of aneurysm or SAH (P ¼ 0.31).
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Aneurysm and Anatomic Risk Factors for Aneurysm Growth There was no association between aneurysm location and aneurysm growth rates. Aneurysms in the anterior circulation had a growth rate of 2.2%/aneurysm-year compared to 1.6%/aneurysmyear for posterior circulation (P ¼ 0.69). When dividing aneurysm location based on the PHASES study (ICA, MCA, ACA/AComA/ PComA/posterior circulation), there was no significant difference in growth rates (2.3%, 1.5%, and 2.2%, respectively; P ¼ 0.69). Each 1-mm increase in aneurysm size was associated with an increasing odds ratio (OR) of 1.22 (95% confidence interval [CI], 1.11e1.33; P < 0.0001) for aneurysm growth. Aneurysms <3 mm had a growth rate of 1.1%/year, compared with 5.7% for aneurysms 7e9.9 mm and 19.1% for aneurysms 13 mm. Aneurysm shape (P ¼ 0.19) and relationship to the parent vessel (P ¼ 0.09) were not significantly associated with growth. Neck size was associated with growth; each 1-mm increase in neck size was associated with an OR for growth of 1.42 (95% CI, 1.31e1.53; P ¼ 0.0002). There was a trend toward increased growth rates with increasing aspect ratio, with each 1-unit increase associated with an OR for growth of 1.52 (95% CI, 0.98e2.06; P ¼ 0.08). These data are summarized in Table 3. PHASES Score and Aneurysm Growth The median PHASES score was 3 (interquartile range, 1e5). The maximum PHASES score was 12, and the minimum was 0. When modeling PHASES score as a continuous variable, an increasing PHASES score was associated with a higher odds of aneurysm growth, with each 1-point increase associated with an OR of 1.24 (95% CI, 1.20e1.28; P < 0.0001) for aneurysm growth. Dividing PHASES scores into quartiles of 0e1, 2e3, 4e5, and 6, patients with PHASES score 6 had the highest aneurysm growth rate (9.0%/year). This was significantly higher than the growth rates for the other 3 quartiles: 1.5%/year, 1.6%/year, and 1.4%/year, respectively (P < 0.0001). On multivariate logistic regression analysis adjusting for aneurysm location, size, previous history of SAH, age, and hypertension, the sole variable independently associated with aneurysm growth was size (P ¼ 0.0006). Aneurysm location (P ¼ 0.70), previous history of SAH (P ¼ 0.88), age (P ¼ 0.88), and hypertension (P ¼ 0.68) were not associated with aneurysm growth. KaplaneMeier survival curves for aneurysm growth by PHASES quartile are shown in Figure 2. ELAPSS Score and Aneurysm Growth The median ELAPSS score was 6 (interquartile range, 4e11). The maximum ELAPSS score was 29, and the minimum was 0. When modeling ELAPSS score as a continuous variable, increasing ELAPSS score was associated with a higher odds of aneurysm growth, with each 1-point increase associated with an OR of 1.10 (95% CI, 1.09e1.11; P < 0.0001) for aneurysm growth. Dividing ELAPSS scores into groups of <5, 5e9, 10e19, 15e19, and 20, patients with an ELAPSS score 20 had the highest aneurysm growth rate (11.3%/year). This was significantly higher than the growth rates for the other 4 groups (0.8%/year, 2.1%/year, 2.9%/year, and 1.7%/year, respectively; P < 0.0001). The median time to growth by ELAPSS score group was 3.5 years for <5, 2.5 years for 5e9, 2.3 years for 10e19, 2.9 years for 15e19, and 1.3 years for 20.
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2018.03.003
ORIGINAL ARTICLE WALEED BRINJIKJI ET AL.
PHASES AND ELAPSS SCORES ASSOCIATED WITH ANEURYSM GROWTH
Table 3. Risk Factors for Aneurysm Growth Number of Aneurysms
Number (%) of Aneurysms Growing
Annualized Aneurysm Growth Rate, % Growing/Year
P Value, per Aneurysm-Year
P Value, per Patient
431
40 (9.3)
2.00
—
—
<70
390
36 (9.2)
1.80
>70
41
6 (13.6)
4.60
Factor All patients Age (years)
0.06
0.35
0.65
0.52
0.51
0.51
0.69
0.89
0.72
0.54
0.19
0.19
0.81
0.91
0.31
0.01
Sex Male
99
7 (7.1)
1.60
Female
332
33 (9.9)
2.10
Aneurysm location Petrocavernous ICA
53
5 (9.4)
2.10
Paraophthalmic ICA
82
9 (11.0)
2.70
PComA/anterior choroidal ICA
36
3 (8.4)
3.80
ICA terminus
27
1 (3.7)
1.00
ACA/AComA
75
8 (10.8)
2.20
MCA
124
10 (8.1)
2.90
PCA
5
0 (0.0)
0.00
Basilar trunk
13
0 (0.0)
0.00
Basilar tip
11
3 (27.3)
2.00
PICA
5
1 (20.0)
5.60
Anterior
396
36 (9.1)
2.20
Posterior
35
4 (11.4)
1.60
162
15 (9.3)
2.30
Anterior versus posterior
Aneurysm location (PHASES) ICA MCA
124
10 (8.1)
1.50
ACA/PComA/posterior circulation
145
15 (10.3)
2.22
Multiple aneurysms Yes
206
16 (7.8)
1.50
No
225
24 (10.7)
2.40
Yes
33
3 (9.1)
2.30
No
398
37 (9.3)
2.00
Yes
110
7 (6.4)
1.70
No
180
19 (10.6)
2.80
Previous SAH
Family history
Hypertension ICA, internal carotid artery; PComA, posterior communicating artery; ACA, anterior cerebral artery; AcomA, anterior communicating artery; MCA, middle cerebral artery; PCA, posterior cerebral artery; PICA, posterior inferior cerebellar artery; PHASES, Population, Hypertension, Age, Size, Earlier Subarachnoid Hemorrhage, Site; SAH, subarachnoid hemorrhage; ELAPSS, Earlier Subarachnoid Hemorrhage, Location of Aneurysm, Age >60 Years, Population, Size of Aneurysm, Shape of Aneurysm. Continues
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PHASES AND ELAPSS SCORES ASSOCIATED WITH ANEURYSM GROWTH
Table 3. Continued Number of Aneurysms
Number (%) of Aneurysms Growing
Annualized Aneurysm Growth Rate, % Growing/Year
Yes
213
23 (10.8)
2.50
No
218
17 (7.8)
1.60
Former
84
10 (11.9)
1.50
Never
168
12 (7.1)
1.60
Current
150
18 (12.0)
5.10
Regular
386
33 (8.6)
0.50
Irregular
45
7 (15.6)
3.50
Sidewall
226
23 (10.2)
2.60
Bifurcation
205
17 (8.3)
1.50
<3
184
10 (5.4)
1.10
3e4.9
157
14 (8.9)
2.22
5e6.9
49
5 (10.2)
1.56
7e9.9
28
5 (17.9)
5.68
10e12.9
6
2 (33.3)
11.76
13þ
7
4 (57.1)
19.05
0e1
135
8 (5.9)
1.50
2e3
112
10 (8.9)
1.60
4e5
135
10 (7.5)
1.40
6þ
50
12 (25.0)
9.00
<5
128
6 (4.7)
0.80
5e9
170
15 (8.8)
2.10
10e14
76
8 (10.5)
2.90
15e19
34
4 (11.8)
1.70
20
23
7 (30.4)
11.3
Factor
P Value, per Aneurysm-Year
P Value, per Patient
0.19
0.28
0.0004
0.28
0.19
0.16
0.09
0.35
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
Smoking status
Shape
Relationship to parent vessel
Size (mm)
PHASES score
ELAPSS score
ICA, internal carotid artery; PComA, posterior communicating artery; ACA, anterior cerebral artery; AcomA, anterior communicating artery; MCA, middle cerebral artery; PCA, posterior cerebral artery; PICA, posterior inferior cerebellar artery; PHASES, Population, Hypertension, Age, Size, Earlier Subarachnoid Hemorrhage, Site; SAH, subarachnoid hemorrhage; ELAPSS, Earlier Subarachnoid Hemorrhage, Location of Aneurysm, Age >60 Years, Population, Size of Aneurysm, Shape of Aneurysm.
On multivariate logistic regression analysis adjusting for aneurysm location, size, previous history of SAH, age, and hypertension, the sole variable independently associated with aneurysm growth was size (P ¼ 0.0009). Aneurysm location (P ¼ 0.67), previous history of SAH (P ¼ 0.83), age (P ¼ 0.22), and shape (P ¼ 0.12) were not associated with aneurysm growth. KaplaneMeier survival curves for aneurysm growth by ELAPSS group are shown in Figure 3.
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DISCUSSION Our analysis of more than 400 aneurysms with 2100 aneurysmyears of follow-up has demonstrated a number of interesting findings. Aneurysm growth occurred in approximately 10% of cases over the roughly 5-year follow-up period, for an overall growth rate of 2.0%/year. Predictors of aneurysm growth included aneurysm size and current smoking status. Although the PHASES
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2018.03.003
ORIGINAL ARTICLE WALEED BRINJIKJI ET AL.
PHASES AND ELAPSS SCORES ASSOCIATED WITH ANEURYSM GROWTH
aneurysms growing at a median of 1.3 years and lower-risk aneurysms growing at a median of 3.5 years. Thus, our data suggest that in general, imaging surveillance for evaluating growth of unruptured aneurysms can be extended to 2- to 3-year intervals, with closer, annual follow-up for higher-risk aneurysms. These findings are corroborated by findings from a large multiinstitutional study by Rinkel et al.11 that found a median time to growth of 1.9 years.
Figure 2. KaplaneMeier curve by PHASES score.
and ELAPSS scores were also associated with growth, the sole individual component of the scores that was independently associated with aneurysm growth was size. This study highlights the fact that aneurysm growth is not uncommon, and in the case of larger aneurysms and aneurysms in current smokers, growth rates are rather high. These findings are important, highlighting important clinical and anatomic risk factors for the progression of intracranial aneurysms that can be used in counseling patients with unruptured aneurysms. Clinical Implications Understanding risk factors for aneurysm growth and obtaining an estimate for overall aneurysm growth rates is important, because some growing aneurysms are at increased risk for future rupture. In a study of 1002 patients with 1325 unruptured aneurysms, Inoue et al.7 reported an annual rupture risk after aneurysm growth of 18.5%/person-year. In a multivariate analysis, Mehan et al.8 found that aneurysm growth was associated with an OR of 55.9 for rupture. The series reported by Juvela et al.,9 which has the longest follow-up of any population-based study on the natural history of unruptured aneurysms, demonstrated that 45% of aneurysms receiving follow-up had some growth >1 mm over the lifetime of the patient. Of these, 66% ruptured.9 A large metaanalysis found that growing aneurysms were >30-fold more likely to rupture than stable ones, with an overall rupture rate of these aneurysms of 3.1%/year, a rate similar to that reported in patients with a PHASES score of 8.10 Another important finding from our study was the time to growth of the included unruptured aneurysms. Typically, imaging surveillance for follow-up of an unruptured aneurysm is performed to evaluate for changes in size and morphology. Follow-up times are highly variable across institutions. According to American Heart Association recommendations, for patients with unruptured intracranial aneurysms managed noninvasively, the first follow-up study should be performed at 6e12 months after initial discovery, followed by subsequent imaging at 1e2 years. In our study, we found a median time to growth of 2.6 years, with higher-risk
WORLD NEUROSURGERY 114: e425-e432, JUNE 2018
Growth Risk Factors and Predictive Models A number of previous studies have reported growth rates and examined risk factors for aneurysm growth. In a meta-analysis of 21 longitudinal studies examining the natural history of unruptured aneurysms, the overall growth rate was 2.5% of aneurysms/ year, and risk factors found to be statistically associated with aneurysm growth included larger aneurysm size, posterior circulation location, irregular aneurysm shape, smoking, and female sex.10 Other previous large studies have reported annual aneurysm growth rates of approximately 1.5%e2.5% of aneurysms/year, similar to our findings, and have identified other risk factors for growth, including bifurcation location and hypertension.7,8,12,13 Models that have been used to predict aneurysm growth include the PHASES and ELAPSS scores. The PHASES score, designed primarily to study aneurysm rupture, has been associated with aneurysm growth.14 In a study of 557 patients with 734 unruptured aneurysms and 2.2 years of follow-up, Backes et al.15 found that each point increase in PHASES score was associated with a hazard ratio for aneurysm growth of 1.32. Similar to our study, the authors found that aneurysm size was the only PHASES score variable that was independently associated with growth while hypertension, age, earlier SAH from another aneurysm and aneurysm site were not independently associated with growth.15 Backes et al. later developed the ELAPSS score based on longitudinal data on aneurysm growth from multiple centers. The ELAPSS score was designed specifically to study aneurysm growth. Although many of the factors included in this score are similar to those of the PHASES score, there are some important differences.
Figure 3. KaplaneMeier curve by ELAPSS score.
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PHASES AND ELAPSS SCORES ASSOCIATED WITH ANEURYSM GROWTH
First, hypertension is not included in the ELAPSS score, but is included in the PHASES score. Previous SAH from another aneurysm is a risk factor for aneurysm rupture, but not for growth. Regarding aneurysm location, ACA/AComA aneurysms are at risk for rupture, but not for growth. Finally, the ELAPSS score includes aneurysm shape as a variable, but the PHASES score does not. Growth rates for aneurysms with an ELAPSS score of <5 were on the order of 1%e2%/year, compared with upward of 12%/year for aneurysms with a score 25. Our study, which had substantially longer follow-up than the ELAPSS study, confirms the results of the ELAPSS study; aneurysms with a score <5 had a growth rate of <1%/year, whereas those with a score >20 had a growth rate of 11%/year. We found that size was the sole independent predictor of growth out of all the variables included in the ELAPSS score. In addition, our study highlights the fact that smoking history, which is not included in the PHASES score or ELAPSS score, is an important variable to consider when exploring the natural history of an unruptured aneurysm. Limitations Our study has some limitations. First, there was no predefined protocol regarding the type and timing of imaging used in followup. Aneurysm growth was assessed with various imaging modalities, including computed tomography angiography, digital subtraction angiography, and magnetic resonance angiography, which could have introduced some error or bias. Our study only
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included patients from a single institution, which might limit the generalizability of our results. There was substantial selection bias in this study; the patients included composed just 35% of all those with unruptured aneurysms evaluated at our institution. Higherrisk aneurysms were more likely to undergo treatment. As such, this could result in underestimation of the risk of growth, because patients at greater risk of growth or rupture likely were not included. A number of patients were lost to follow-up as well.
CONCLUSIONS Overall growth rates of intracranial aneurysms are not negligible; approximately 10% of the aneurysms followed in this study grew over a mean follow-up period of 5 years. Risk factors for the growth of intracranial aneurysms included increasing PHASES and ELAPSS score, larger aneurysm size, and smoking status. When considering the individual components of the PHASES and ELAPSS scores, however, size was the sole independent predictor of aneurysm growth. The median time to growth was 2.6 years, suggesting that imaging follow-up can be performed at 2- to 3-year intervals. These findings should be considered when counseling patients regarding the natural history of intracranial aneurysms and could be used to guide decisions regarding the frequency of follow-up imaging for patients with unruptured aneurysms who are managed conservatively.
2001-2007. AJNR Am J Neuroradiol. 2011;32: 1065-1070. 7. Inoue T, Shimizu H, Fujimura M, Saito A, Tominaga T. Annual rupture risk of growing unruptured cerebral aneurysms detected by magnetic resonance angiography. J Neurosurg. 2012;117: 20-25. 8. Mehan WA Jr, Romero JM, Hirsch JA, Sabbag DJ, Gonzalez RG, Heit JJ, et al. Unruptured intracranial aneurysms conservatively followed with serial CT angiography: could morphology and growth predict rupture? J Neurointerv Surg. 2014;6:761-766. 9. Juvela S, Poussa K, Porras M. Factors affecting formation and growth of intracranial aneurysms: a long-term follow-up study. Stroke. 2001;32: 485-491. 10. Brinjikji W, Zhu YQ, Lanzino G, Cloft HJ, Murad MH, Wang Z, et al. Risk factors for growth of intracranial aneurysms: a systematic review and meta-analysis. AJNR Am J Neuroradiol. 2016;37: 615-620. 11. Backes D, Rinkel GJE, Greving JP, Velthuis BK, Murayama Y, Takao H, et al. ELAPSS score for prediction of risk of growth of unruptured intracranial aneurysms. Neurology. 2017;88:1600-1606.
13. Villablanca JP, Duckwiler GR, Jahan R, Tateshima S, Martin NA, Frazee J, et al. Natural history of asymptomatic unruptured cerebral aneurysms evaluated at CT angiography: growth and rupture incidence and correlation with epidemiologic risk factors. Radiology. 2013;269:258-265. 14. Greving JP, Wermer MJ, Brown RD Jr, Morita A, Juvela S, Yonekura M, 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: 59-66. 15. Backes D, Vergouwen MD, Tiel Groenestege AT, Bor AS, Velthuis BK, Greving JP, et al. PHASES score for prediction of intracranial aneurysm growth. Stroke. 2015;46:1221-1226.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 6 February 2018; accepted 1 March 2018 Citation: World Neurosurg. (2018) 114:e425-e432. https://doi.org/10.1016/j.wneu.2018.03.003 Journal homepage: www.WORLDNEUROSURGERY.org
12. Juvela S, Poussa K, Lehto H, Porras M. Natural history of unruptured intracranial aneurysms: a long-term follow-up study. Stroke. 2013;44: 2414-2421.
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