Thiemo Florian Dinger1*, Jonas Peschke1, Mehdi Chihi1, Meltem Gümüs1, Maryam Said1, Alejandro Nicolas Santos1, Jan Rodemerk1, Anna Michel1, Marvin Darkwah Oppong1, Yan Li2, Cornelius Deuschl, Karsten Henning Wrede1, Philipp René Dammmann1, Benedikt Frank3, Christoph Kleinschnitz3, Michael Forsting2, Ulrich Sure1, Ramazan Jabbarli1
- University Hospital of Essen, Department of Neurosurgery and Spine Surgery, and Center for Translational Neuroscience and Behavioral Science (C-TNBS), University of Duisburg-Essen, Essen, Nortrhine-Westphalia, Germany
- University Hospital Essen, Institute for Diagnostic and Interventional Radiology and Neuroradiology, University of Duisburg-Essen, Essen, Nortrhine-Westphalia, Germany
- University Hospital of Essen, Department of Neurology and Center for Translational Neuroscience and Behacioral Science (C-TNBS), University of Duisburg-Essen, Essen, Nortrhine-Westphalia, Germany
* Corresponding author – Thiemo-Florian.Dinger@Uk-Essen.de
PMID: 36333955
DOI: 10.1111/ene.15625
Abstract
Objective: According to the International Study of Unruptured Intracranial Aneurysms, small (<7 mm) unruptured intracranial aneurysms (IA) of the anterior circulation (aC) carry a neglectable 5-years rupture risk. In contrast, some studies report frequencies of more than 20% of all ruptured IA being small IA of the aC. This contradiction was addressed in this study by analyzing the rates and risk factors for rupture of small IA within the aC.
Methods: Of the institutional observational cohort with 3767 saccular intradural IA diagnosed between 01/2003 and 06/2016, 1676 small IA of the aC were included. Different demographic, clinical, laboratory and radiographic characteristics were collected. A rupture risk score was established using all independent prognostic factors. The score performance was checked using receiver operating characteristic curve analysis.
Results: Of all registered small IA of the aC, 20.1% were ruptured. The constructed SIAAC score (range: -4 to +13 points) contained five major risk factors: IA location (anterior communicating artery: +5 points, ≥A2 branch of the anterior cerebral artery: +2 points) and size (+1 point for 2mm, with an additional point for each 1mm increase), arterial hypertension, alcohol abuse, and chronic renal failure (each: +1 point). In addition, three putative protective factors were also included in the score: -2 points for hypothyroidism, -1 point each for dyslipidemia and peripheral arterial disease. There was an increasing rate of the ruptured IA with increasing total SIAAC points value: from 0% (≤-1 points) through >50% (≥8 points), and up to 100% in patients scoring ≥12 points. The SIAAC score achieved excellent discrimination (AUCSIAAC=0.803) and performed better than the PHASES score (AUCPHASES=0.743).
Conclusions: Small IA of the aC carry a considerable rupture risk. After external validation, the proposed rupture risk score might provide a basis for better decision-making regarding the treatment of small unruptured IA of the aC.
Abbreviations: aC: anterior circulation; ACA: anterior cerebral artery; ACoA: anterior communicating artery; AST: aspartate transaminase; AUC: area under the curve; dACA: distal anterior cerebral artery; DSA: digital subtraction angiography; IA: intracranial aneurysms; ICA: internal carotid artery; ISUIA: International Study of Unruptured Intracranial Aneurysms; MCA: middle cerebral artery; MVA: multivariable analyses; (a)OR: (adjusted) odds ratio; PC: posterior circulation; RIA: ruptured intracranial aneurysms; ROC: receiver operating characteristic; SAH: subarachnoid hemorrhage; SIAAC: small IA of the aC; UIA: unruptured intracranial aneurysms; UIATS: unruptured intracranial aneurysm treatment score; UVA: using univariate analysis
Introduction
In 2003 the International Study of Unruptured Intracranial Aneurysms (ISUIA) was published1. This multicenter study enrolled 4060 patients, of whom 1692 were treated conservatively with a mean follow-up time of 4.1 years. This study laid the foundation for today’s therapy recommendation of unruptured intracranial aneurysms (UIA). In ISUIA, intracranial aneurysms (IA) of internal carotid (ICA), anterior cerebral (ACA), and middle cerebral artery (MCA) were summarized into the subgroup of anterior circulation (aC) aneurysms.
Besides its acknowledgeable achievements, one interpretation by the ISUIA authors is still a matter of debate. Regarding the aC subgroup, small IA (<7mm) showed a cumulative 5-year rupture risk of 0%1. Therefore, patients with small aC IA are mostly recommended conservative treatment. But this summation of aC IA might cause a simplification bias. As subsequent studies on small IA showed, location makes a difference in the aC subgroup concerning IA rupture risk2. Additionally, it could also be found that in at least some IA populations, the relative amount of small aC IA of all ruptured IA (RIA) exceeds 20%2,3. This data implies that the rupture risk of small aC IA might be underestimated.
This controversy leaves patients with small IA of the aC and their physicians with a high level of uncertainty. On one side, they have to face severe individual and socioeconomic consequences of subarachnoid hemorrhage (SAH) in case of IA rupture4. On the other side, there is a considerable risk for complications during IA treatment. Coiling or clipping of UIA have an approximated mortality risk of 1-4% and a risk for major morbidity of around 4%5.
These two aspects become even more important, knowing that we face and will face the challenges of an aging population. For example, it could be demonstrated that elderly patients (≥65y) have a 1.65 higher adjusted odds ratio (aOR) than their younger counterparts for in-hospital mortality regarding endovascular coiling of UIA6. Additionally, the incidental detection of small IA will increase due to increased accessibility to magnetic resonance imaging and improving resolution of cranial imaging techniques7.
Especially for the subgroup of patients with small IA, there is an emerging urge for more individual risk stratification to improve treatment recommendations. This study aims to clarify the controversial data on the rupture risk of small IA of the aC.
Materials and Methods
Between January 2003 and June 2016, all patients with IA confirmed by digital subtraction angiography (DSA) at the University Hospital of Essen, Germany, were enlisted in our institutional database. The study was approved by the Institutional Review Board (Institutional ethical review committee, Medical Faculty, University of Duisburg-Essen, registration number: 15-6331-BO) and registered in the German clinical trial registry (DRKS, Unique identifier: DRKS00008749).
Definition of study aims
The study’s aim was to identify parameters related to the rupture status of small IA of the aC and summarize the most relevant prognostic factors into a cumulative risk score for IA rupture. Therefore, the patients’ data were screened for socio-demographic and radiological characteristics, pre-existing medical conditions, and routine blood examinations.
Definition and documentation of IA
IA patients were identified based on DSA reports of the neurocranium. IA were defined by a size ≥ 1mm and a saccular form. Two experienced neuroradiologists at our university hospital independently reviewed the DSA images. IA were defined as small if the largest sack diameter measured less than 7mm. This definition was the most commonly approved in the literature1,3,8. Altogether, the exclusion criteria were: (i) missing DSA confirmation, (ii) size < 1mm or > 6mm, (iii) location: posterior circulation or extradural, and (iv) non-saccular morphology (Figure 1).
Data extraction
All patients’ electronic charts were screened for demographic, clinical, and laboratory data. IA sizes, locations, morphologies, and numbers were extracted from DSA data. IA location was subsumed into the following groups: MCA, ICA, anterior communicating artery (ACoA; A1 segment including ACoA), distal anterior cerebral artery dACA (originating from A2-branch of ACA or more distal), and posterior circulation (PC; including posterior communicating, posterior cerebral, basilar and vertebral arteries).
As previously described in detail9, the patients’ records were screened to extract demographic and clinical (imaging, pre-existing medical conditions, AB0/Rh blood group, and blood examinations) information summarized in Table 1. For blood examinations consisting of multiple entries, only the results at admission were included in the analysis if not stated otherwise. In addition, blood values known to be altered by SAH (electrolytes, blood cells, and their properties, creatine kinase, etc.) 10–15 were excluded from the analysis of IA rupture predictors and only analyzed to verify the described changes in our study.
Statistical analysis
All statistical analyses were performed on SPSS (version 28.0.0.0; IBM Corporation) and OriginPro 2020 (version 9.7.0.188; OriginLab Corporation). Statistical significance was defined by p<0.05. All parameters were checked for a significant correlation with the rupture status of IA using univariate analysis (UVA). To check for significance, the Mann-Whitney-U test was used for continuous variables and the Chi-Square test for dichotomized data. Multivariable analyses (MVA) were performed for statistically significant factors identified in UVA. For the MVA of the putative risk and safety factors comparing unruptured and ruptured IA, binary logistic regression analyses were used. Missing data were handled by multiple imputations.
Risk and protective factors identified by MVA were selected to develop the rupture risk score for small IA of the aC (SIAAC). The risk points were determined by dividing the aOR by the smallest coefficient and then rounded to the nearest whole number. Based on this SIAAC risk score, each small IA of the aC was evaluated. Afterward, the SIAAC risk score was assessed for internal validation using ROC (receiver operating characteristic) curve. Finally, the SIACC risk score was compared against the established PHASES score8. The performance of the proposed rupture risk score for small IA of the aC (SIAAC) and a comparison with the established PHASES score were done using receiver operating characteristic (ROC) curve analysis.
Results
2,442 patients formed the complete database after excluding all cases/IA with insufficient imaging, non-saccular, extradural, and IA < 1mm (Figure 1). A total of 3,767 IA could be included.
Therefore, a total of 1,676 IA of the aC, smaller than 7mm, were extracted (1,228 patients) from the institutional database (Figure 1). In this subpopulation, the relative number of female patients was 70.2%. The mean age was 53.9 years, and 29.5% of the patients were admitted with SAH. Table 1 gives a general overview of the aC subpopulation.
Rupture of small aC IA – demographic aspects
A reduced predominance of female patients could be observed in the small aC IA population for RIA cp. to UIA. The UIA subgroup had a percentage of 73.6% females, whereas the RIA counterpart had a statistically significantly smaller majority of 62.2% (p<0.001; OR=0.59; Table 2). This difference did not stay significant in the MVA (Table 3). The other demographic risk factors, age (RIA: 54.5 years vs. UIA: 53.7 years) and ethnicity, did not significantly differ between the two subgroups (p=0.319 and p=0.815, respectively; Table 2).
Rupture of small aC IA – size & location of IA
The mean IA size in the RIA group was 4.3 mm, and in the UIA group significantly smaller, with a mean IA size of 3.8 mm (p<0.001; Table 2). Analyzing the group of IA measuring 1 mm, the relative amount of RIA was 4.0% (Figure 2). As depicted in Figure 2, with increasing IA size, the percentage of RIA continuously increased. Regarding the 2mm group, 11.0% of the IA were ruptured, in the 3mm group 18.6%, and in the 4mm group 28.6%. The relative RIA amount reached 32.6% and 36.8% for the 5mm and 6mm groups, respectively (Figure 2).
Comparing IA location of small RIA vs. UIA of the aC, significant changes could be detected. Figure 3 depicts in descending order the proportion of RIA vs. UIA for each location. For IA located at the ACoA, more than half of these aneurysms were ruptured at the time of diagnosis (54.2%). The second-highest proportion of RIA was found at the dACA location with 31.5%. The least rupture-prone locations for small IA were the MCA and ICA, with 14.7% and 9.5% of RIA, respectively. With an OR of 7.49 the ACoA location was the most significant rupture risk factor analyzing IA location (p<0.001; Table 2).
Rupture of small aC IA – pre-existing medical conditions
Arterial hypertension statistically correlated with rupture of small IA of the aC (OR: 1.51; p=0.002; Table 2). Other statistically significant risk factors for the rupture of small aC IA were alcohol abuse (OR: 3.02; p<0.001) and chronic kidney insufficiency (OR: 2.03; p<0.001). The known general risk factors for IA rupture, tobacco consumption (OR: 1.19; p=0.220), and diabetes (OR=0.96; p=0.861) did not show a statistical difference between the UIA and RIA groups.
Putative protective factors that showed a statistically significant correlation with UIA vs. RIA were dyslipidemia (OR: 0.63; p=0.009), peripheral arterial diseases (OR: 0.42; p<0.001), and hypothyroidism (OR: 0.35; p<0.001).
Rupture of small aC IA – blood examination
Regarding small IA of the aC, the blood group phenotypes did not differ significantly between the UIA and RIA groups (Table 2).
Of all blood examinations that had no previously described SAH-caused alterations, it could be shown that a pathological elevation of the liver enzyme aspartate transaminase (AST; p=0.001) correlated significantly with the rupture of small IA of the aC (Table 2).
Rupture of small aC IA – multivariable analysis
In the MVA, female sex did not stay significant (p=0.258; Table 3). In contrast, IA size and location correlated significantly with rupture state (aOR: 1.45 with p<0.001; aOR: 7.22 & p=0.001, respectively; Table 3). Regarding the pre-existing medical conditions, arterial hypertension (aOR: 1.46, p=0.013), alcohol abuse (aOR: 2.07, p=0.014), and chronic renal failure (aOR: 1.70, p=0.005) stayed statistically significant risk factors of RIA of the aC (Table 3). Dyslipidemia (aOR: 0.57, p=0.004), hypothyroidism (aOR: 0.35, p<0.001), and peripheral arterial disease (aOR: 0.61, p=0.023) did remain statistically significant in MVA as putative protective factors of rupture for small IA of the aC (Table 3).
Proposed rupture risk score for small IA of the aC– SIAAC
As demonstrated in Table 4, five potential risk and three protective factors could be identified regarding the rupture of small IA of the aC in MVA (Table 3). Each manifestation of a variable had a different aOR-adjusted value. In detail, the following values were calculated: -2 points for hypothyroidism, -1 point each for dyslipidemia and peripheral arterial disease, +1 point each for alcohol abuse, chronic renal failure, and arterial hypertension. Regarding IA size, for a 2mm IA +1 point was calculated with an additional point for each 1mm increase in size. IA located at the dACA were assigned with +2 points, and those situated at the ACoA with +5 points. Therefore, the SIAAC score ranges from a total of -4 to +13 points. The most common risk score value was 2 points, representing 16.1% of all small IA of the aC. More than 90% of all IA had at least a score of +1 point. No IA scored -4, -3, or the maximum of 13 points. A -2 and -1 points score was associated with a 0% proportion of RIA. In contrast, a SIAAC score of +12 points was associated with a 100% rupture rate (Figure 4).
The proposed score for small IA of the aC (SIAAC score) was tested for his performance on the study population with an increasing number of RIA identified and an area under the curve (AUC) of 0.803 (Figure 4, A&B), representing excellent discrimination. Additionally, the SIAAC score was compared against the established PHASES score8 (Figure 4, B). As a result, it could be shown that the SIAAC score performed better than the PHASES score (AUCPHASES:0.743).
Discussion
With the help of this study, a better subdivision into more and less rupture-prone small IA of the aC seems to be possible. Especially the location (i.e., ACoA) presents a particular risk factor for IA rupture, strongly distinguishing the risk profile of small IA in the ACoA complex from other locations of the aC. Therefore, clustering all small aC IA as it was done in the ISUIA seems to lead to a very heterogeneous group regarding the rupture risk1. Unfortunately, the ISUIA data and clustering approach have already been integrated into widely used scores to predict IA rupture or determine the treatment, also for small aC IA8.
By analyzing 1,767 small IA of the aC from 1,228 consecutive patients, a rupture rate of 22.9% was found. Comparable results have been published recently by other groups2,3,16. For example, the UCAS Japan showed for IA <5mm an RIA incidence of 20.1%2.
Currently, small IA of aC are generally considered eligible for conservative management. At the same time, a considerable portion of small IA of aC carry significant rupture risk and, therefore, might profit from interventional treatment. In order to give these patients individualized treatment recommendations, the proper assessment of a rupture risk for this specific IA subpopulation is essential. By analyzing known and putative IA risk factors for the population of small IA of the aC, a panel of factors could be identified in MVA with high internal validity.
That IA size is of importance even for small IA to stratify the danger they pose has already been demonstrated previously by others17. We made a similar observation in our cohort, with size remaining a significant risk factor for IA rupture.
Also, the location seems to play an important role when evaluating the rupture risk of small IA of the aC. IA located at the ACoA had by far the highest amount of documented ruptures with a total of 54.2% and only 45.8% of UIA. Already, Bijlenga and colleagues showed that in a cohort of 932 patients with small IA, the ACoA location was an independent SAH risk factor16.
These results suggest that patients with small aC UIA, especially those located at the ACoA, followed by small UIA in the dACA, require a more differentiated approach during treatment decisions since the rupture risk is not negligible. In our study, arterial hypertension, IA size, and chronic renal failure significantly correlated with a higher proportion of RIA. Arterial hypertension, resulting in augmented wall shear stress and finally in IA wall inflammation and degeneration, is a widely accepted risk factor and also seems to play an essential role for small aC IA18. In addition to regulating blood pressure, kidneys have other vital functions, such as erythropoiesis, regulation of acid-base and electrolyte balance, and excretion of toxins and water. Regarding the rupture of IA, it is known that intramural inflammation is a crucial factor18,19. This inflammatory process could be prolonged in patients with chronic kidney failure due to reduced renal excretion of pro-inflammatory cytokines20. In general, for IA rupture, it could be demonstrated that 0.8-23.1% of all SAH patients had at least a mild renal dysfunction21,22. Compared to the prevalence of non-end stage renal dysfunction in the general population, it seems to be overrepresented in SAH cohorts23.
Modifiable risk factors are of particular interest due to their potential therapeutic impact on the rupture risk. However, in our study, the best-known risk factor, tobacco consumption, was not associated with an increased SAH risk for small aC IA. Also, Ikawa and colleagues could not detect an increased rupture risk of small IA in smokers2. These results suggest that tobacco-induced alterations are of reduced importance regarding rupture of small IA of the aC.
The picture is different for alcohol abuse. Multiple studies could identify excessive/regular alcohol intake as an independent risk factor for SAH independently of IA size, comparable to tobacco consumption24,25. However, in contrast to smoking, this study demonstrated for the first time that alcohol might play a distinct role concerning SAH caused by small IA located at the aC. Although the underlying pathophysiology mostly remains unknown, it is hypothesized that ethanol-induced endothelial damage leads to inflammation and rupture25.
Potential protective factors regarding rupture of small aC IA were hypothyroidism, dyslipidemia, and peripheral arterial disease.
A dysregulated lipid metabolism with elevated blood cholesterol is a primary contributing factor to atherosclerosis. Furthermore, it is hypothesized that the increased stiffness of atherosclerotic arteries protects against rupture26–28. These mentioned studies revealed a negative correlation between atherosclerosis with IA rupture. Wang and colleagues detected a lower risk of rupture for ACoA IA in patients with intracranial atherosclerosis28. It is hypothesized that aneurysmal blood flow is reduced by calcified IA walls, thereby limiting local wall shear stress28.
Interestingly, there is a link between hypothyroidism and an increased level of atherosclerosis29. But besides its contribution to the development of atherosclerosis, there are multiple additional associations between hypothyroidism and IA rupture30. First, thyroid hormones have a proangiogenic function, and an induced remodeling of intracranial vessels might temporarily destabilize the wall structure30–32. Thereby, hypothyroidism could reduce remodeling. Second, a lower level of thyroid hormones induces cerebral hypometabolism, which leads to decreased oxidative stress, a key player in IA growth18,30,33. Third, patients with (subclinical) hypothyroidism generally show a reduced activity level and arterial hypotension30,33. These conditions are likely to protect against IA rupture. Finally, in a previous study, we could demonstrate that hypothyroidism was a protective factor for the clinical course of SAH patients in general34.
All statistically significant factors identified by MVA were used to develop the rupture prediction score SIAAC. This score was created because more and more data demonstrated the need for specific risk stratification of small IA of the aC2,3,16. Known rupture prediction scores are the unruptured intracranial aneurysm treatment score (UIATS) and the PHASES score8,35. The first score is based on a multidisciplinary consensus, and the second is based on a systematic literature review including 8,382 participants from six prospective cohort studies. Interestingly, one study included in the systematic literature review for the PHASES score was ISUIA1. However, none of these studies focused on small IA of the aC and might thereby underestimate their rupture risk. With the newly developed SIAAC score, small IA of the aC can be solely assessed for rupture risk.
Limitations
The main limitation of this study is its retrospective, monocentric design. The completeness and reliability of data are limited due to the retrospective assessment. Another weakness is that blood samples of SAH patients were taken directly at the arrival of the patients in the emergency room. Still, some patients had longer transfer times to our department than others. This potential bias could not be statistically corrected.
Further studies of the natural course of small IA of the aC are needed to improve their specific risk assessment and therapy recommendations. Also, the presented data and the proposed rupture risk score lack external validation.
Conclusion
Patients with small IA of the aC have a non-neglectable rupture risk. Therefore, especially patients with increased alcohol consumption, IA located at the ACoA, AHT, and renal diseases should be offered IA treatment. In addition, small aC IA of patients with dyslipidemia, peripheral arterial disease, and hypothyroidism are more secure from rupture than without these factors. Hopefully, with the developed rupture risk score solely for small IA of the aC, safer therapy recommendations are possible for these patients.
Supplementary Materials: None
Author Contributions: XXX (When the author list is definite.
Funding: This manuscript was supported by the Open-Access Fund of the Medical Library of the University of Duisburg-Essen, Germany.
Data Availability Statement: The data presented in this study are available on request from the corresponding author. The data are not publicly available because some are sensitive patient information.
Conflicts of Interest: Outside the submitted work, Prof. Wrede received personal fees from Biogen for expert opinion on aneurysms and vestibular schwannomas. All the other authors report no conflicts.
| Parameter class | aC subpopulation |
| IA size limitation | <7mm |
| Putative RF | (n= 1228) |
| Demographic | |
| Age (years) | 53.90 (45-63) |
| Female | 862 (70.2) |
| Ethnicity (Caucasian) | 1163 (94.7) |
| Imaging (findings) | |
| MIA | 693 (56.4) |
| Size IA (mm) | 3.96 (3.0-5.0)† |
| ICA | 654 (39.0)† |
| ACoA | 550 (32.8)† |
| dACA | 380 (22.7)† |
| MCA | 92 (5.5)† |
| Pre-existing medical conditions | |
| AHT | 785 (63.9) |
| Alcohol abuse | 57 (4.6)* |
| Cardiac diseases | 197 (16.0)* |
| Chronic inflammation | 80 (6.5)* |
| Diabetes | 125 (10.2) |
| Dyslipidemia | 213 (17.3) |
| Gynecologic diseases | 40 (3.3)* |
| Hepatic diseases | 53 (4.3) |
| Hyperthyroidism | 16 (1.3) |
| Hyperuricaemia | 24 (2.0) |
| Hypothyroidism | 197 (16.0) |
| Hx of SAH | 4 (0.3) |
| Musculoskeletal diseases | 147 (12.0) |
| Obesity | 93 (7.6) |
| Oncologic diseases | 137 (11.1) |
| Peripheral arterial diseases | 183 (14.9) |
| Pulmonary diseases | 121 (9.9) |
| Renal failure (chronic) | 154 (12.5) |
| SAH (acute) | 362 (29.5) |
| Smoker | 307 (25.0) |
| Blood group | |
| 0 | 358 (29.2)* |
| A | 414 (33.7)* |
| B | 97 (7.9)* |
| AB | 51 (4.2)* |
| Blood examination | |
| ALT (U/L) | 27.7 (16.0-31.0)* |
| AST (U/L) | 27.2 (17.8-28.0)* |
| (d)BIL (mg/dL) | 0.2 (0.1-0.2)* |
| (t)BIL (mg/dL) | 0.5 (0.3-0.6)* |
| Calcium (mmol/L) | 2.3 (2.2-2.4)* |
| Chloride (mmol/L) | 107.0 (104.0-109.0)* |
| CK (U/L) | 146.7 (59.0-129.0)* |
| Creatinine (mg/dL) | 1.0 (0.8-1.1)* |
| CRP (mg/dL) | 3.0 (0.4-2.9)* |
| γ-GT (U/L) | 39.4 (15.0-40.0)* |
| HB (mg/dL) | 13.5 (12.6-14.5)* |
| HC | 0.40 (0.37-0.43)* |
| LDH (U/L) | 207.9 (175.0-229.0)* |
| MCH (pg) | 30.2 (29.2-31.4)* |
| MCV (fL) | 89.4 (86.0-92.8)* |
| Phosphate (mmol/L) | 3.4 (2.9-3.9)* |
| PLT (/nL) | 254.6 (210.0-295.0)* |
| Potassium (mmol/L) | 4.2 (4.0-4.5)* |
| RBC (/pL) | 4.5 (4.2-4.8)* |
| Sodium (mmol/L) | 140.9 (139.0-143.0)* |
| TP (g/dL) | 6.9 (6.5-7.4)* |
| Urea (mg/dL) | 14.5 (11.0-17.4)* |
| WBC (/nL) | 9.9 (6.8-11.9)* |
*Data could not be obtained for all patients. † Based on the total number of 1676 small intracranial aneurysms of the anterior circulation.
Table 1
The table shows the distribution of (potential) risk factors for rupture in the population of (patients with) intracranial aneurysms at the anterior circulation (aC).
Abbreviations: ACoA: anterior communicating artery; AHT: arterial hypertension; ALT: alanine transaminase; AST: aspartate transaminase; dACA: distal anterior cerebral artery; (d)BIL: direct (conjugated) bilirubin; (t)BIL: total bilirubin; CK: creatine kinase; CRP: c-reactive protein; γ-GT: γ-glutamyltransferase; HB: hemoglobin; HC: hematocrit; IA: intracranial aneurysm; ICA: internal carotid artery; LDH: Lactate dehydrogenase; MCA: middle cerebral artery; MCH: mean corpuscular/cellular hemoglobin; MCHC: mean corpuscular/cellular hemoglobin concentration; MCV: mean corpuscular volume; MIA: multiple intracranial aneurysms; PLT: platelet count; RBC: red blood cell count; SAH: subarachnoid hemorrhage; TP: total protein; WBC: white blood cell count.
| Parameter class | RIA | UIA | p-value | OR | 95% CI | |
| Putative RF | ||||||
| Demographic | ||||||
| Age (years) | 54.47 ± 14.57 | 53.66 ± 12.18 | 0.319a | N/A | N/A | |
| Female | 225 (62.2) | 637 (73.6) | <0.001b | 0.59 | 0.46-0.77 | |
| Ethnicity (non-Caucasian) | 20 (5.5) | 45 (5.2) | 0.815b | 1.07 | 0.62-1.83 | |
| Imaging (findings) | ||||||
| MIA | 94 (26.1) | 599 (69.2) | <0.001b | 0.17 | 0.12-0.21 | |
| Size IA (mm) | 4.3 ± 1.3 | 3.8 ± 1.4 | <0.001a | N/A | N/A | |
| ICA | 52 (13.6) | 498 (38.5) | <0.001a | 0.25 | 0.18-0.34 | |
| ACoA | 206 (53.8) | 174 (13.5) | <0.001a | 7.49 | 5.79-9.68 | |
| dACA | 29 (7.6) | 63 (4.9) | 0.043a | 1.60 | 1.01-2.52 | |
| MCA | 96 (25.1) | 558 (43.2) | <0.001a | 0.44 | 0.34-0.57 | |
| Pre-existing medical conditions | ||||||
| AHT | 255 (70.4) | 530 (61.2) | 0.002b | 1.51 | 1.16-1.97 -2.48 | |
| Alcohol abuse | 31 (8.6) | 26 (3.0) | <0.001b | 3.02 | 1.77-5.17 | |
| Cardiac diseases | 64 (17.7) | 133 (15.4) | 0.316b | 1.18 | 0.85-1.64 | |
| Chronic inflammation | 27 (7.5) | 53 (6.3) | 0.439b | 1.21 | 0.75-1.96 | |
| Diabetes | 36 (9.9) | 89 (10.3) | 0.861b | 0.96 | 0.64-1.45 | |
| Dyslipidemia | 47 (13.0) | 166 (19.2) | 0.009b | 0.63 | 0.44-0.89 | |
| Gynecologic diseases | 19 (5.4) | 21 (3.0) | 0.062b | 1.83 | 0.97-3.45 | |
| Hepatic diseases | 22 (6.1) | 31 (3.6) | 0.053b | 1.74 | 0.99-3.05 | |
| Hyperthyroidism | 6 (1.7) | 10 (1.2) | 0.483b | 1.44 | 0.52-4.00 | |
| Hyperuricaemia | 9 (2.5) | 15 (1.7) | 0.388b | 1.45 | 0.63-3.33 | |
| Hypothyroidism | 28 (7.7) | 169 (19.5) | <0.001b | 0.35 | 0.23-0.53 | |
| Musculoskeletal diseases | 52 (14.4) | 95 (11.0) | 0.097b | 1.36 | 0.95-1.95 | |
| Obesity | 33 (9.1) | 60 (6.9) | 0.190 | 1.35 | 0.86-2.10 | |
| Oncologic disease | 34 (9.4) | 103 (11.9) | 0.203b | 0.77 | 0.51-1.15 | |
| Peripheral arterial diseases | 30 (8.3) | 153 (17.7) | <0.001b | 0.42 | 0.28-0.64 | |
| Pulmonary diseases | 38 (10.5) | 83 (9.6) | 0.629b | 1.11 | 0.74-1.66 | |
| Renal failure (chronic) | 67 (18.5) | 87 (10.1) | <0.001b | 2.03 | 1.44-2.87 | |
| Smoker | 99 (27.3) | 208 (24.0) | 0.220b | 1.19 | 0.90-1.57 | |
| Blood group | ||||||
| 0 | 104 (42.3) | 254 (37.7) | 0.206b | 1.21 | 0.90-1.63 | |
| A | 107 (43.5) | 307 (45.5) | 0.580b | 0.92 | 0.67-1.24 | |
| B | 22 (8.9) | 75 (11.1) | 0.341b | 0.78 | 0.48-1.29 | |
| AB | 13 (5.3) | 38 (5.6) | 0.836b | 0.93 | 0.49-1.78 | |
| Blood examination | ||||||
| ALT (>55 U/L) | 21 (7.8) | 38 (5.4) | 0.160b | 1.49 | 0.86-2.58 | |
| AST (>40 U/L) | 41 (15.2) | 58 (8.2) | 0.001b | 2.01 | 1.31-3.08 | |
| (t)BIL (>1.2 mg/dL) | 13 (4.9) | 18 (2.6) | 0.074b | 1.94 | 0.94-4.02 | |
| Calcium (mmol/L) | 2.25 ± 0.16 | 2.34 ± 0.15 | <0.001a | N/A | N/A | |
| Chloride (mmol/L) | 108.4 ± 6.3 | 106.5 ± 4.3 | <0.001a | N/A | N/A | |
| CK (U/L) | 163.5 ± 16.0 | 137.4 ± 20.5 | 0.502a | N/A | N/A | |
| Creatinine (>1.3 mg/dL) | 13 (4.9) | 49 (6.9) | 0.235b | 0.68 | 0.37-1.28 | |
| CRP (>2 mg/dL) | 96 (36.4) | 159 (27.8) | 0.013b | 1.48 | 1.09-2.02 | |
| γ-GT (>60 U/L) | 46 (17.1) | 84 (11.9) | 0.034b | 1.53 | 1.03-2.25 | |
| HB (mg/dL) | 13.1 ± 1.8 | 13.6 ± 1.4 | <0.001a | N/A | N/A | |
| HC (%) | 38.4 ± 4.7 | 40.5 ± 3.9 | <0.001a | N/A | N/A | |
| LDH (U/L) | 218.2 ± 61.0 | 204.0 ± 53.2 | <0.001a | N/A | N/A | |
| MCH (pg) | 30.3 ± 2.3 | 30.2 ± 2.0 | 0.845a | N/A | N/A | |
| MCV (fL) | 88.5 ± 6.1 | 89.7 ± 5.4 | 0.003a | N/A | N/A | |
| Phosphate (mmol/L) | 3.22 ± 0.84 | 3.47 ± 0.69 | <0.001a | N/A | N/A | |
| PLT (/nL) | 237.2 ± 67.3 | 261.2 ± 71.2 | <0.001a | N/A | N/A | |
| Potassium (mmol/L) | 3.99 ± 0.55 | 4.32 ± 0.42 | <0.001a | N/A | N/A | |
| RBC (/pL) | 4.35 ± 0.55 | 4.52 ± 0.48 | <0.001a | N/A | N/A | |
| Sodium (mmol/L) | 140.2 ± 3.6 | 141.1 ± 3.1 | <0.001a | N/A | N/A | |
| TP (g/dL) | 6.61 ± 0.89 | 6.96 ± 0.68 | <0.001a | N/A | N/A | |
| Urea (mg/dL) | 14.3 ± 6.6 | 14.6 ± 5.2 | 0.382a | N/A | N/A | |
| WBC (/nL) | 12.1 ± 4.2 | 9.0 ± 3.9 | <0.001a | N/A | N/A | |
Table 2
Univariate analysis of putative demographic and clinical risk factors for the rupture of small aneurysms (<7mm) of the anterior circulation. Putative risk factors with a statistically significant correlation are highlighted in grey.
a. Student’s t-test b. Chi-Square test
Abbreviations: ACoA: anterior communicating artery; AHT: arterial hypertension; ALT: alanine transaminase; AST: aspartate transaminase; dACA: distal anterior cerebral artery; (t)BIL: total bilirubin; CI: confidence interval; CK: creatine kinase; CRP: c-reactive protein; γ-GT: γ-glutamyltransferase; HB: hemoglobin; HC: hematocrit; IA: intracranial aneurysm; ICA: internal carotid artery; LDH: Lactate dehydrogenase; MCA: middle cerebral artery; MCH: mean corpuscular/cellular hemoglobin; MCV: mean corpuscular volume; MIA: multiple intracranial aneurysms; N/A: not applicable; OR: odds ratio; PLT: platelet count; RBC: red blood cell count; RIA: ruptured intracranial aneurysm; TP: total protein; UIA: unruptured intracranial aneurysm; WBC: white blood cell count.
Multivariable binary logistic regression model for the rupture risk of small aneurysms (<7mm) of the anterior circulation. Statistically significant risk factors (RF), adjusted odds ratio (aOR), and the 95% confidence interval (CI) are highlighted in grey. Abbreviations: (d)ACA: distal anterior cerebral artery; ACoA: anterior communicating artery; AHT: arterial hypertension; AST: aspartate transaminase; ICA: internal carotid artery; MCA: middle cerebral artery.
Proposed rupture risk score for small intracranial aneurysms of the anterior circulation (SIAAC score). In order to calculate the proposed score, the points for each risk and protective factor are summed up (possible range from – 4 to +13). For example, a 4 mm IA (3 pts.) located at the ACoA (5 pts.) from patient suffering from arterial hypertension (1 pt.) and hypothyroidism (-2 pts.) would score a total of 6 points.
Abbreviation: (d): distal anterior cerebral artery; ACoA: anterior communicating artery; ICA: internal carotid artery; MCA: middle cerebral artery;
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