Clinical manifestations

Presentation and course

Unruptured cerebral aneurysms are typically asymptomatic and discovered incidentally during neuroimaging workup for other conditions. Among the most common reasons for aneurysm detection in The International Study of Unruptured Intracranial Aneurysms (ISUIA) were imaging workups for: subarachnoid hemorrhage, headaches, cerebral ischemia, cranial nerve deficit, and undefined spells (51). Comparable results from a Japanese cohort in the Unruptured Cerebral Aneurysm Study (UCAS) indicate that over 90% of aneurysms were discovered incidentally due to headaches or dizziness (47%), screening (44%), subarachnoid hemorrhage (4%), symptoms caused by mass effect or embolic episodes (3%), and other indications for diagnostic imaging (2%) (20). In a cohort specifically selected for small incidental aneurysms, the reasons for imaging detection included: nonspecific spells or symptoms of focal cerebral ischemia (43%), head or neck pathology (24%), headaches (16%), head trauma (6%), screening (4%), cancer staging (2%), and other reasons (5%) (27).

Prognosis and complications

Overall, cerebral aneurysms are quoted to rupture at a rate of 1% to 2% per year. A contemporary meta-analysis including 19 studies with 6556 unruptured aneurysms found an overall rupture risk of 1.2% with age greater than 60 years, female gender, Japanese or Finnish descent, aneurysm size greater than 5 mm, posterior circulation aneurysm, and symptomatic aneurysm being significant risk factors.

Despite decades of study resulting in countless publications, the natural history of unruptured intracranial aneurysms remains a controversial topic. Our modern understanding of the matter is significantly derived from the prospective International Study of Unruptured Intracranial Aneurysms (ISUIA) and the Japanese Unruptured Cerebral Aneurysm Study (UCAS) (51; 20). The ISUIA study suggests that small anterior circulation aneurysms less than 7 mm in size have a very low risk of rupture. Indeed, after excluding patients with a prior history of subarachnoid hemorrhage and those with posterior communicating artery aneurysms, the ISUIA investigators reported a 0% 5-year cumulative rupture rate for small anterior circulation aneurysms. Aneurysms 7 to 12 mm in size had 5-year cumulative rupture rates of 2.6% in the anterior circulation (excluding cavernous and posterior communicating artery aneurysms) and 14.5% in the posterior circulation (including posterior communicating aneurysms). Additional size stratification in the UCAS study generally corroborates the ISUIA finding of low rupture risk for small aneurysms. Overall 3- to 4-mm and 5- to 6-mm aneurysms in UCAS ruptured at rates of 0.36% and 0.5% per year, respectively. This is in contrast to the overall annual rupture rates for aneurysms sized 7 to 9 mm, 10 to 24 mm, and 25 mm or more, which were 1.69%, 4.37%, and 33.4%, respectively.

Although the yearly rupture rate is low, the life expectancy of the patient should be taken into consideration. Younger patients should be treated more aggressively given the cumulative risk of rupture over a longer life span. Additionally, there is a paradoxical nature of aneurysm rupture. Although the risk of rupture of an aneurysm less than 7 mm is low, the majority of the ruptured aneurysms seen in the community are all less than 7 mm.

Clinical vignette

Case 1. A 51 year-old woman with no significant past medical history was self-referred to our center for further work-up of an abnormal brain MRI. The MRI was obtained as part of a research protocol for which she was a volunteer control subject. She was given a report indicating an abnormal flow-void in the region of the left middle cerebral artery (MCA) bifurcation suspicious for an aneurysm.

The patient had no history of headaches or neurologic dysfunction. She did not smoke and only occasionally drank alcohol. She did not have a family history of cerebral aneurysms. On examination the patient was found to be neurologically intact. An elective 4-vessel catheter cerebral angiogram was obtained confirming the presence of a 7-mm left middle cerebral artery (MCA) bifurcation aneurysm as well as a small (4 mm) contralateral MCA aneurysm.

After multidisciplinary evaluation of the angiogram by both a neurosurgeon and an interventional neuroradiologist, it was determined that the aneurysms were poor candidates for endovascular coiling. Based on the patient’s relatively young age and data suggesting a 1% to 2% yearly risk of rupture for the larger aneurysm, she was counselled to have the left MCA aneurysm surgically clipped. The patient was also counseled that the right MCA aneurysm had a low risk of rupture but should be closely followed. She agreed with this plan and underwent an elective left-sided craniotomy with uneventful aneurysm clipping. Intraoperative catheter angiography confirmed complete exclusion of the aneurysm from the circulation.

The patient obtained an MRA of the head 1 year postoperatively, which indicated that the untreated right MCA aneurysm was stable in size. She remained asymptomatic after 2-years of follow-up but elected to have the right MCA aneurysm definitively treated to reduce her anxiety regarding the possibility of rupture. Thus, she was electively admitted to the hospital at which time a preoperative catheter cerebral angiogram was obtained followed by a right-sided craniotomy for clipping of the aneurysm on the following morning. Intraoperative angiography confirmed complete occlusion of the aneurysm and the patient was discharged home on the second postoperative day with no complications.

Case 2. A 65 year-old female, with a history of hypertension, smoking, and family history of ruptured brain aneurysm in her mother, presented to the office with an incidental finding of a 3 mm right internal carotid artery aneurysm after a workup for chronic headaches.

Catheter cerebral angiogram demonstrated a 3 to 4 mm right internal carotid artery aneurysm in the location of the carotid cave, a potential intradural space for formation of aneurysm.

After review of the images and discussion with the patient, including discussion of a 1% per year risk of rupture, the patient elected to proceed with treatment. Treatment options for an aneurysm in this location included microsurgical clipping and endovascular treatment. Endovascular treatment options included stent assisted coiling of the aneurysm or placement of a flow diverting stent. Given the difficulties and morbidity associated with open microsurgical treatment of an aneurysm in this location, the patient elected to proceed with endovascular treatment with stent assisted coiling of the aneurysm.

The patient was placed on dual antiplatelet agents consisting of 81 mg of aspirin and 75 mg of Plavix daily. Intraoperative angiography demonstrating final images of the stent assisted coiled aneurysm.

The patient did well from the procedure and went home the following day.

Biological basis

Etiology and pathogenesis

The vast majority of cerebral aneurysms occur spontaneously; however, traumatic, infectious, and malignancy-associated etiologies are also recognized (23). Hypertension and cigarette smoking are significant modifiable risk factors associated with the occurrence of spontaneous cerebral aneurysms. Although intracranial aneurysms are considered acquired lesions, familial presentations are recognized. Furthermore, their association with heritable connective tissue disorders such as Ehlers-Danlos syndrome type IV, autosomal dominant polycystic kidney disease, and possibly Marfan syndrome implicate genetic predisposition as an etiologic component (10; 07; 24). Indeed, a number of studies, including a large meta-analysis, confirm a complex and substantial genetic contribution to the genesis of spontaneous cerebral aneurysms (24; 02).

Normal intracranial arteries are composed of 3 layers, including an intima, media, and adventitia. The intima consists of a luminal monolayer of endothelial cells connected by tight junctions and surrounded by a subendothelial extracellular matrix of connective tissue. Elastic fibers form the internal elastic lamina, which separates the intima from the media. The media is composed of concentric layers of smooth muscle cells and collagen whereas the outermost adventitia is composed of a complex network of collagen, elastic fibers, and fibroblasts (23; 34).

Saccular or “berry” aneurysms are abnormal focal outpouchings of cerebral arteries that typically occur at vessel bifurcations. Histological analyses indicate that loss of the internal elastic lamina beginning at the aneurysm neck is a near universal feature of cerebral aneurysms (35; 14; 15). Frösen and colleagues distinguished 4 histological types of saccular cerebral aneurysm walls including: (1) type A, endothelialized wall with linearly organized smooth muscle cells; (2) type B, thickened wall with disorganized smooth muscle cells; (3) type C, hypocellular wall with either myointimal hyperplasia or organizing luminal thrombosis; and (4) type D, extremely thin thrombosis-lined hypocellular wall (14). The authors hypothesized that the histological subtypes (A-D) reflect consecutive stages of wall degeneration linked to increasing rupture risk.

Hemodynamic stress and the subsequent arterial wall response have been correlated to the initiation and progression of cerebral saccular aneurysms. High wall shear stress, which is typically seen at arterial branch points, may explain the proclivity for aneurysm formation in such locations (01). Conversely, low wall shear stress is associated with aneurysm wall remodeling that leads to growth and rupture (29; 06). Molecular-cellular mechanisms of remodeling that are found to be active in cerebral aneurysms, and especially in those that rupture, include proteolysis of extracellular matrix components, apoptosis of smooth muscle cells, and inflammatory cell infiltration (34).

Epidemiology

Technological advancements in noninvasive cerebral vascular imaging and the proliferation of their use among clinicians and researchers have led to increased detection of unruptured intracranial aneurysms. Unruptured intracranial aneurysms are thought to have an average prevalence of 2% to 3% in the general population. Among 2000 subjects from a population-based cohort in the Netherlands who underwent brain MRI, 1.8% were found to harbor incidental brain aneurysms (47). A similar study from a Chinese population screened 4813 subjects with MRA and found aneurysms in 7% (26). MRA-detected aneurysms were found in 1.9% of 1006 volunteers in a Norwegian study (31). In a comprehensive review including 68 studies reporting on 94,912 subjects from 21 countries, the overall prevalence of unruptured intracranial aneurysms was estimated to be 3.2% (48). In this study, the prevalence ratio was 1.57 in women compared to men. They also reported that the majority of unruptured intracranial aneurysms are small (66% less than 5 mm) and found in the anterior circulation (95%). Unruptured intracranial aneurysms are uncommon in children. In the pediatric population there appears to be a higher incidence of posterior circulation aneurysms (40% to 45%) and a 2-fold male predominance (09).

Prevention

Modifiable risk factors associated with unruptured intracranial aneurysms include hypertension and cigarette smoking. Thus, treatment or prevention of hypertension as well as avoidance of smoking may be reasonably considered protective against cerebral aneurysm formation. Although excessive alcohol intake has been associated with cerebral aneurysm rupture, it is unclear if there is any relation to the initiation of aneurysm formation (21). On the other hand, pharmacological therapy with statins has been suggested as a possible strategy to prevent cerebral aneurysm formation; however, such a regimen has yet to be rigorously evaluated (46). Additionally, evidence supports the continuation of aspirin in patients diagnosed with a cerebral aneurysm (39). Aspirin inhibits inflammation, which has been implicated in the formation of cerebral aneurysms. Clinical studies provide evidence that it can protect against rupture of aneurysms (40).

Differential diagnosis

Confusing conditions

Unruptured cerebral aneurysms are diagnosed based on neuroimaging findings. On noninvasive imaging, aneurysms, especially large and giant aneurysms (greater than 25 mm) may mimic other pathologies seen in the brain. Extremely small and blister-like cerebral aneurysms may be easily overlooked on CT- or MR-based imaging modalities and are best seen with high resolution catheter angiography (49; 50). Infundibula are also best resolved and differentiated from aneurysms on catheter angiography. In contrast, partially thrombosed aneurysms, which are often large or giant, may be unseen on catheter angiography and can present with mass effect mimicking neoplasia on MRI or CT. Cavernous and clinoidal internal carotid artery segment aneurysms can appear similar to sellar tumors because of their proximity to the sellar turcica.

Diagnostic workup

Symptomatic patients presenting with headache, cranial nerve palsy, evidence of intracranial mass effect, or ischemia are commonly initially screened with noncontrast head CT or brain MRI. Noninvasive vascular imaging with CTA or MRA is warranted if a vascular etiology is suspected. Similarly, asymptomatic unruptured aneurysms may be initially screened in this manner. CTA may be somewhat more sensitive than MRA (77% to 97% vs. 69% to 93%), with the capability of detecting aneurysms as small as 2 mm in diameter as compared to 3 to 5mm for MRA (05). Catheter cerebral angiography is the gold standard diagnostic imaging modality for the detection of aneurysms and should be performed if treatment either by endovascular or open surgery is contemplated.

Screening for unruptured intracranial aneurysms is not generally recommended. In populations at increased risk for harboring intracranial aneurysms, such a protocol utilizing either CTA or MRA may be justified, however. Such populations include those with predisposing genetic syndromes such as autosomal dominant polycystic kidney disease, Ehlers-Danlos syndrome, and sickle cell disease. Similarly, in patients with familial intracranial aneurysm syndrome in whom 2 or more first-degree relatives have a history of aneurysmal subarachnoid hemorrhage, screening may be reasonable. Finally, late radiological follow-up for patients with a history of treated aneurysmal subarachnoid hemorrhage should be considered because the annual rate of new aneurysm formation may be as high as 2% (05).

Management

Patients with unruptured intracranial aneurysms may be managed conservatively with close clinical and radiographic follow-up, or they may be treated surgically. Surgical options include traditional open microsurgery or endovascular methodologies. Although direct microsurgical clipping of the aneurysm’s neck and endovascular coiling of the aneurysmal sac represent the most common surgical options, alternative microsurgical and endovascular strategies beyond the scope of this article are also available.

The decision of whether to treat or observe an unruptured aneurysm can be complex and is probably best made after counsel by an experienced neurovascular team. Treatment decisions are individualized and take into account the risks of both observation and intervention as well as patient preference. The ISUIA investigators concluded that for small aneurysms less than 7 mm in size in patients without a history of subarachnoid hemorrhage, it would be difficult to improve on the natural history of the aneurysm with intervention (51).The UCAS and Small Unruptured Intracranial Aneurysm Verification Study (SUAVe) suggest that an even lower aneurysm size threshold may be reasonable in specific groups, including patients with communicating (anterior or posterior) artery aneurysms and patients with multiple aneurysms or other comorbidities (37; 20). Treatment decisions are understandably influenced by the fact that a significant number of patients present with subarachnoid hemorrhage from small aneurysms less than 5 mm in diameter in actual clinical practice (37).

The treatment of incidental cavernous internal carotid artery aneurysms is probably not warranted as both the risk of rupture and subarachnoid hemorrhage in the face of rupture are quite low (51). Symptomatic as well as enlarging aneurysms of all sizes should be strongly considered for treatment as the risk of rupture for such aneurysms may be significant (05; 19). Similarly, large (10 to 25 mm) and giant (larger than 25 mm) intradural aneurysms have been shown to have high annual rates of rupture and, thus, should also be strongly considered for treatment rather than observation (51; 20). The caveat for pursuing treatment for large and giant aneurysms is that intervention may also carry a relatively high risk of morbidity.

Outcomes

The outcomes after unruptured cerebral aneurysm treatment are difficult to quantitatively define based on the currently available literature. Complication rates for microsurgical clipping and endovascular coiling are similar and can range from 5% to 10%. Treatment-related mortality is generally quoted as 1% or less. Treatment morbidity is most often the result of either brain ischemic or hemorrhagic sequelae. Additional major and minor procedure-related complications such as infection, seizure, access-related morbidity (such as groin hematoma), and others are also possible but thought to be of low risk. Observational data suggests that the better outcomes may be achieved at high-volume cerebrovascular treatment centers (43).

Special considerations

Pregnancy

Although older literature may suggest otherwise, the risk of aneurysmal subarachnoid hemorrhage appears to not be significantly increased during pregnancy, labor, or the puerperium (41; 44; 22). Although the absolute risk of aneurysm rupture may be quite low, relative rupture rates seem to increase steadily from the first through the third trimester, with the greatest risk occurring during labor and delivery (41).

Operative intervention is generally not recommended for asymptomatic unruptured cerebral aneurysms during pregnancy. On the other hand, successful operative management with both open surgery and endovascular techniques has been described for the treatment of aneurysmal subarachnoid hemorrhage during pregnancy (12; 30; 42). An early review of the literature reporting on 106 antepartum women with aneurysmal intracranial hemorrhage found an 11% maternal mortality in the cohort that underwent surgery and a 63% maternal mortality in the cohort that did not have surgery (12). This same study reported a fetal mortality rate of 5% in the group having surgery and a 27% fetal mortality in the group that did not have surgery. The benefit to operative intervention was clearly evident even from this relatively small retrospective review.

With regard to the treatment of unruptured aneurysms, it is at best a matter of opinion to delay treatment of those that are symptomatic or enlarging until the second trimester in order to reduce the teratogenic effects of anesthetic agents or radiation (41; 36).

Anesthesia

General anesthesia with endotracheal intubation is typically preferred during both the open surgical and endovascular treatment of unruptured cerebral aneurysms. Administration of neuroprotective anesthetics that can be titrated to achieve temporary burst suppression may be beneficial in some cases (25). Neuromuscular blockade is an important component of the anesthetic regimen that facilitates precision microsurgery as well as microcatheter navigation and coil placement. Specialized anesthetic and monitoring techniques may also be utilized during hypothermic and chemically-induced cardiac standstill to facilitate microsurgical clipping or endovascular embolization (18; 28; 04).