16 Natural History and Management Options of Unruptured Intracranial Aneurysms

Hugo Andrade-Barazarte, Behnam Rezai Jahromi, Felix Goehre, Ajmal Zemmar, Weixing Bai, Zhiyuan Sheng, Guangmin Duan, Zhongcan Cheng, Tianxiao Li, and Juha Hernesniemi

Abstract

Intracranial aneurysms (IAs) are acquired lesions with a prevalence of 1–3% in the general population. During the last decades, diagnosis of unruptured intracranial aneurysms (UIAs) has increased due to the use of noninvasive imaging for techniques. UIAs may remain clinically asymptomatic for a long period or rupture, causing an aneurysmal subarachnoid hemorrhage (SAH). Management of UIAs is challenging and it depends on risks factors for possible aneurysm rupture. Currently, the PHASES study represents the largest and most comprehensive data set on risk of aneurysm rupture and includes independent predictors for aneurysm rupture such as: population, arterial hypertension, patient age, aneurysm size, previous SAH from another aneurysm and aneurysm site. Besides these factors, current smoking, alcohol consumption, familial history of SAH, female sex, and presence of multiple IAs are also considered risk factors for SAH.

Intracranial aneurysms (IAs) are acquired lesions with a prevalence of 1 to 3% in the general population.1 A current theory for aneurysm formation acknowledges the presence of underlying endothelial dysfunction that leads to pathological remodeling with degenerative changes of vascular walls.² Additionally, general genome-wide linkage studies have identified several loci on chromosomes 1p34.3–p36.13, 7q11, 19q13.3, and Xp22 that may predispose to IA formation.^{1,​ 3,​ 4} During the last decades, diagnosis of unruptured intracranial aneurysms (UIAs) has increased due to the widespread use of magnetic resonance angiography (MRA) and computed tomography angiography (CTA) as screening tools (Fig. 16.1).⁵ UIAs may remain clinically asymptomatic for a long period or rupture, causing an aneurysmal subarachnoid hemorrhage (SAH),⁶ leading to severe neurological deficit and death in up to 40%.^{7,​ 8,​ 9,​ 10,​ 11,​ 12,​ 13}

When an aneurysm presents with rupture, the decision is clear and the goal is to secure the aneurysm by either endovascular or surgical methods to prevent rebleeding.^{14,​ 15} However, UIAs may be managed either conservatively with serial imaging or by preventive repair (endovascular treatment or microsurgery). Therefore, these therapeutic options should be tailored and individualized to each patient according to risk factors, natural history, and possible treatment-related complications.

Data regarding natural history and management of UIAs have different levels of evidence and in several circumstances are restricted to specific geographic populations, which limits its complete applicability to estimate further risks/benefits. Thus, a multidisciplinary consensus is required to estimate the short- or long-term risks of rupture of an individual aneurysm and provide further management options.

This chapter discusses available clinical data on the natural history and management options for UIAs.

16.2 Selected Papers on Natural History of UIAs

●Korja M, Lehto H, Juvela S. Lifelong rupture risk of intracranial aneurysms depends on risk factors: a prospective Finnish cohort study. Stroke 2014;45(7):1958–1963

●Morita A, Kirino T, Hashi K, et al; UCAS Japan Investigators. The natural course of unruptured cerebral aneurysms in a Japanese cohort. N Engl J Med 2012;366(26):2474–2482

●Greving JP, Wermer MJ, Brown RD Jr, et al. Development of the PHASES score for prediction of risk of rupture of intracranial aneurysms: a pooled analysis of six prospective cohort studies. Lancet Neurol 2014;13(1):59–66

●Hackenberg KAM, Hänggi D, Etminan N. Unruptured intracranial aneurysms. Stroke 2018;49(9):2268–2275

●Juvela S, Poussa K, Lehto H, Porras M. Natural history of unruptured intracranial aneurysms: a long-term follow-up study. Stroke 2013;44(9):2414–2421

16.3 Natural History of UIAs

Despite available evidence, the true natural history of UIAs is poorly understood and whether treatment should be offered to prevent a future rupture remains controversial.¹⁶ The temptation to treat UIAs is based on the fear of SAH and the need to prevent a conceivable rupture.¹⁷ However, treatment decisions should be based on comparisons between the risks associated with preventive treatments and natural history of the disease, instead of preventive treatments compare to outcomes after SAH.

Currently, the PHASES study represents the largest and most comprehensive data set on risk of aneurysm rupture.¹⁸ This study is based on six prospective UIA cohort studies comprising of 8,382 patients and 10,272 UIAs from Europe (including Finland), North America, and Japan. In this meta-analysis, the mean observed 1-year risk of rupture was 1.4% (95% confidence interval [CI]: 1.1–1.6), and the 5-year risk of rupture was 3.4% (95% CI: 2.9–4.0).¹⁸ Furthermore, this study identified six independent predictors for aneurysm rupture including (1) population, (2) arterial hypertension, (3) patient age, (4) aneurysm size, (5) previous SAH from another aneurysm, and (6) aneurysm site.

The PHASES score failed to preclude other additional known risk factors for aneurysm rupture due to lack of data or heterogeneous definitions of the data in the underlying studies.6 Table 16.1 shows PHASES score parameters and characteristics.

Table 16.1 PHASES score parameters and rupture risk

16.4 Lifelong Rupture Risk of Intracranial Aneurysms Depends on Risk Factors

Data derived from population-based or case control studies identified risk factors that could be used to further estimate the relative rupture risk of patients with UIAs.^{6,​19,​ 20,​ 21,​ 22,​ 23,​ 24,​} These risk factors can be divided into patient-related factors (modifiable and nonmodifiable) and aneurysm-related factors.

In addition to the patient-related modifiable factors (hypertension) identified by the PHASES study, current smoking and alcohol consumption are also considered risk factors for SAH.^{6,​ 19,​ 21,​ 25} In a Finnish lifelong study, current smokers had an odds ratio (OR) of 3.05 (CI: 1.19–7.83) for a lifetime risk of SAH in comparison with never/ex-smokers. In addition to the current smoking activity, a large case control study with 4,701 patients reported the smoking intensity and duration associated with SAH.²⁶ Showing the direct correlation between smoking and SAH, several nation-wide population studies reported the decreasing incidence of SAH associated with decreasing smoking habits.^{23,​ 24} Alcohol consumption and drug abuse are also considered modifiable risk factors for SAH; however, a specific threshold regarding their detrimental effect has not been yet identified.

The PHASES study recognized some patient-related nonmodifiable risk factors for SAH such as earlier SAH from another aneurysm, age, and geographical location.¹⁸ In addition to these factors, several studies have identified familial history of SAH or UIAs (defined as two or more first-degree relatives with SAH or UIA), female sex, and presence of multiple IAs as important risk factors for SAH.^{6,​ 20,​ 25} The familial intracranial aneurysm (FIA) study demonstrated that patients with FIA carrying UIAs less than 6 mm in diameter have a 17-fold higher risk as compared to sporadic UIA carriers.²⁷ Additionally, several long-term prospective population-based studies have identified women to have a higher risk of SAH.^{6,​ 24,​ 25,​ 28,​ 29} A long-term prospective population-based study published by Korja et al identified that multiple aneurysms are more common in women.³⁰ It is important to mention that aneurysm multiplicity is assumed but is not an established risk factor for rupture; therefore, more data derived from non-Japanese populations are needed to further estimate their effect.^{31,​ 32}

Two large prospective population-based studies (Finland and Japan) reported an inverse age regression for rupture, especially an increased long-term risk of rupture in patients younger than 50 years.6^{,​ 32} These findings are in contrast with the findings of the PHASES score, which recognized an increased risk of rupture in patients older than 70 years.¹⁸

Moreover, Finland and Japan are considered to have a higher incidence of SAH, but it remains unclear whether the increased risk is truly derived from ethnicity or rather exposure to environmental risk factors because of geographical location.^{23,​ 33} Currently, several studies reported that Finland have a similar incidence of SAH as compared to other Nordic countries.

16.4.1 Aneurysm-Related Risk Factors

According to the largest and most comprehensive follow-up studies of UIAs, the most important risk factors for aneurysm rupture are UIA size (> 7 mm) and location (anterior communicating, posterior communicating, or vertebrobasilar artery).^{8,​ 34,​ 35} Additionally, an increasing number of studies including two large meta-analyses highlighted the relevance of aneurysm irregularity as an independent risk factor for rupture.^{32,​ 36} Moreover, retrospective studies have identified several morphological parameters as potential predictors of rupture including volume of the aneurysm,³⁷ aspect ratio,³⁸ bottleneck factor,³⁹ height-to-width ratio,³⁹ and volume-to-ostium area ratio (VOR).⁴⁰ A long-term follow-up prospective study by Juvela and Korja confirmed aneurysm volume, VOR, and the bottleneck factor separately as continuous variables predicted aneurysm rupture.²² Additionally, aneurysm growth during the follow-up is associated with smoking but not with aneurysm indexes or parameters.²²

Furthermore, UIA growth occurs in approximately 12 to 18% of patients with UIA during 2.2- to 2.7-year follow-up or approximately 45% of UIAs within 19 years and it is considered a well-established surrogate for UIA rupture.⁶

A pooled analysis comprising 10 prospective cohort studies with a total of 1,507 patients and 1,909 UIAs followed during 5,782 patient-years (median: 2.5 years; range: 0.5–14.3 years) identified earlier SAH, aneurysm location, age greater than 60 years, population, aneurysm size, and shape (ELAPSS) as independent predictors for UIA growth.⁴¹ The ELAPSS score is helpful to identify possible aneurysm growth, thus being beneficial while considering UIA follow-up imaging.⁴¹

16.5 Serial Imaging Surveillance

The ELAPSS score is useful to identify patients harboring UIAs that are at risk of growth. This score allows us to estimate the 3- and 5-year risk of aneurysm growth, thus being beneficial while scheduling follow-up intervals (Table 16.2 shows the ELAPSS score).⁴¹ In a cohort of 382 patients diagnosed with UIAs followed by serial imaging (CTA and MRA), Chien et al identified that initial size and multiplicity were significant factors related to aneurysm growth. Additionally, they reported a 1.09-fold increase in risk of growth for every 1-mm increase in initial size (95% CI: 1.04–1.15; p = 0.001). Moreover, aneurysms in patients with multiple aneurysms were 2.43-fold more likely to grow than those in patients with single aneurysms (95% CI: 1.36–4.35; p = 0.003). The growth rate (speed) for UIAs  ≥ 7 mm (0.085 mm/mo) was significantly higher than that for UIAs less than 3 mm (0.030 mm/mo).⁴² In addition, UIAs have different tendency to grow when they are associated with different risk factors. Chien et al identified that growth (defined by size increase  > 0.5–1.0 mm) in small aneurysms was difficult to detect with a 1-year follow-up imaging study.⁴² Therefore, this subgroup of lesions would benefit from longer follow-up. Whereas, there are high-risk situations where patients with risk factors (smokers and suffering of hypothyroidism) in which the UIA might become greater than 7 mm within 1 year, meaning that a 6-month follow-up study is critical to identify fast-growing lesions in high-risk patients.⁴²

Table 16.2 Demonstrating the ELAPSS score variables and points

It is important to mention that the most consistent predictor of aneurysm growth is the duration of follow-up. As previously demonstrated by Juvela et al, the longer UIAs are followed, the more likely they are to enlarge.8

16.6 Selected Papers on Management Options for UIAs

●Backes D, Rinkel GJE, Greving JP, et al. ELAPSS score for prediction of risk of growth of unruptured intracranial aneurysms. Neurology 2017;88(17):1600–1606

●Etminan N, Brown RD Jr, Beseoglu K, et al. The unruptured intracranial aneurysm treatment score: a multidisciplinary consensus. Neurology 2015;85(10):881–889

●Bijlenga P, Gondar R, Schilling S, et al. PHASES score for the management of intracranial aneurysm: a cross-sectional population-based retrospective study. Stroke 2017;48(8):2105–2112

●Kotowski M, Naggara O, Darsaut TE, et al. Safety and occlusion rates of surgical treatment of unruptured intracranial aneurysms: a systematic review and meta-analysis of the literature from 1990 to 2011. J Neurol Neurosurg Psychiatry 2013;84(1):42–48

●Naggara ON, White PM, Guilbert F, Roy D, Weill A, Raymond J. Endovascular treatment of intracranial unruptured aneurysms: systematic review and meta-analysis of the literature on safety and efficacy. Radiology 2010;256(3):887–897

16.7 Management Options for UIAs

Treatment decision for UIAs (either by endovascular or by surgical modality) should be adopted in a multidisciplinary team conformed by neurosurgeons and interventional neuroradiologists and should take into consideration all relevant patient- and aneurysm-related factors for rupture risk.⁴³ Additionally, it should be based on risks and benefits to the patient when considering any management option.⁴³

Due to the large variety and different levels of evidence in the management of UIAs, these decisions can often be challenging. Therefore, treatment options and follow-ups should be individualized based on previous characteristics of patients and aneurysms.

The PHASES score allows risk estimation for the possible 5-year rupture risk based on six independent parameters.¹⁸ Therefore, treatment options and conservative management should be balanced according to rupture risk in the presence of certain risks factors (age, smoking, hypertension, hypothyroidism) and therapeutic risks of preventive repairs (endovascular and surgical complications). A recent prospective population-based study from Bijlenga et al, which included 841 patients with UIAs and ruptured IAs, identified that patients with PHASES scores less than 3 were mostly followed up with serial imaging, whereas patients with PHASES scores greater than 4 were more likely to be treated. Additionally, this group was able to identify a threshold of an absolute PHASES score of 3 to 4 to distinguish between low and high rupture risk UIA in their patients’ cohort.⁴⁴

The UIA treatment score (UIATS) is a consensus among a large multidisciplinary group of UIA specialists as an attempt to provide the best management options to UIAs.⁴³ This score takes in consideration patient-, aneurysm-, and treatment-related risk factors in the decision-making for or against preventive repair. The UIATS comprised two columns that contain all relevant factors for or against UIA repair. These two columns provide absolute numerical values that at the end can be used to assess the treatment recommendation or if treatment is recommended.⁴³

If preventive repair is chosen, the most effective, simple, and least complicated treatment modality should be discussed within a multidisciplinary team. Additionally, it should consider patient age, comorbidities, aneurysm rupture risk, and rate of complications. Also, aneurysm-related factors for complications such as size, shape, location, and presence of calcification along the neck and parent artery.^{45,​ 46,​ 47}

Among treatment modalities, simple coiling seems to be the preferred technique for endovascular repair and clipping the preferred technique for surgical repair.

It is generally accepted that older patients with higher comorbidity index would benefit from treatment by endovascular coiling as the first-line option. On the contrary, young patients with superficial aneurysms (e.g., middle cerebral artery aneurysms) and wide-neck aneurysms should undergo surgical clipping due to the higher obliteration rate and treatment durability (Fig. 16.2).⁴⁸

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