Intracranial Aneurysms

grateful!

Part I

Background

Chapter 1

Cerebrovascular Embryology and Implications for the Pathogenesis of Cerebral Aneurysms

Juan C. Mejia Munne⁎; Andrew J. Ringer†; Todd A. Abruzzo‡    ⁎ Department of Neurosurgery, University of Cincinnati (UC) College of Medicine, Cincinnati, OH, United States

† Mayfield Clinic, TriHealth Neuroscience Institute, Good Samaritan Hospital, Cincinnati, OH, United States

‡ Pediatric Interventional Neuroradiology at Department of Radiology and Medical Imaging, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States

Abstract

Although the prevalence of intracranial arterial aneurysms and the incidence of aneurysmal subarachnoid hemorrhage (SAH) vary widely among genetically distinct populations, cerebral aneurysms account for substantial morbidity and mortality across the world. Descriptions of cerebral aneurysms date back to antiquity, with many questions remaining unanswered regarding the etiology and pathogenesis of these lesions. Once thought to be congenital, intracranial arterial aneurysms are now widely accepted as acquired lesions, a result of complex interactions between cerebrovascular anatomy, vascular injury, and adaptive remodeling of the arterial wall. This chapter overviews the embryological development of the cerebral arterial circulation, and discusses the processes of vasculogenesis and angiogenesis that can generate numerous atypical anatomical variants, including the pathogenesis of cerebral aneurysms.

Keywords

Embryology; Angiogenesis; Vasculogenesis; Cerebral aneurysm

Outline

1.1Vasculogenesis and Angiogenesis

1.1.1Vasculogenesis

1.1.2Angiogenesis

1.2Embryology of the Cerebral Arterial Circulation

1.2.1Origins of the Embryonic Circulatory System

1.2.2Development of the Carotid Circulation

1.2.3Development of the Vertebrobasilar Circulation

1.3Mural Structure of Cerebral Arteries

1.4Cerebral Arterial Bifurcations as an Anatomical Vulnerability

1.5Anatomical Variants of Persistent Fetal Circulation

1.5.1Fetal PCA

1.5.2Primitive Carotid-Vertebrobasilar Anastomoses

1.5.3Persistent Trigeminal Artery

1.5.4Persistent Otic Artery

1.5.5Persistent Hypoglossal Artery

1.5.6Proatlantal Intersegmental Artery

1.5.7Congenital Absence of the ICA

1.6Conclusions

References

1.1 Vasculogenesis and Angiogenesis

1.1.1 Vasculogenesis

The process of vasculogenesis constitutes the formation of primitive embryonic capillary networks. The process is initiated when cells recruited from lateral plate mesoderm differentiate into hemangioblasts and coalesce into blood islands, which are formed locally and restricted to each embryonic segment or metamere of origin. The blood islands morph into hemangioblast cords, and the resident hemangioblasts further differentiate into two cell populations: (1) an outer layer of progenitor cells called angioblasts (endothelial cell precursors) and (2) a group of primitive blood cells enclosed by the angioblasts. The formation of endothelial tube networks results from flattening of angioblasts, hollowing of hemangioblast cords, and coalescence of cords by filopodial process extension and fusion. These networks subsequently recruit pericytes through angiopoietin-TIE 2 receptor interactions to form capillary vessels. Pericytes are derived from a diverse population of ectodermal and mesodermal cells depending on the metamere or embryonic segment of origin. The pericytes of craniocephalic metameres are derived from the cephalic neural crest, whereas the pericytes of spinal segments are derived from associated lateral plate mesoderm. Undifferentiated capillary networks, comprising a layer of endothelial cells supported by basal lamina and further ensheathed by pericytes, represent the substrate from which mature arterial and venous networks are remodeled through the process of angiogenesis.

1.1.2 Angiogenesis

Angiogenesis concerns the sprouting of new vessels (neovessels) from the preexisting blood vessels, pruning (involution or regression) of redundant vessels, and remodeling of the juvenile vascular system into mature arteries and veins. Recent progress in vascular biology has revealed that the angiogenesis of circulatory beds within end organs (i.e., liver, kidney, brain) is triggered by end-organ release of vascular endothelial cell growth factor (VEGF). This stimulates angiogenesis of embryonic capillary networks within the end organ. The earliest capillaries to form under the influence of end-organ-derived VEGF contain endothelial cells that express an arterial phenotype, specified by the Ephrin B2 transmembrane receptor ligand. Ephrin ligands mediate endothelial cell-cell interactions that influence the expression of arterial and venous phenotypes by blood vessels. The endothelium of newly formed arterial capillaries expressing Ephrin B2 induces the undifferentiated endothelial cells of neighboring capillaries to express Ephrin B4. The expression of Ephrin B4 by resident endothelial cells specifies these vessels as venous capillaries. Physiologic connection of an arterial capillary network to a venous capillary network occurs within distinct border zones. The formation of larger conducting vessels occurs by capillary-capillary fusion interactions, involving capillary vessels of the same endothelial phenotype (arterial versus venous). Further maturation of capillaries into blood vessels involves the development of the tunica media through extracellular matrix production and differentiation of pericytes into vascular smooth muscle cells.

1.2 Embryology of the Cerebral Arterial Circulation

1.2.1 Origins of the Embryonic Circulatory System

Much of our understanding of vascular embryology is owed to the research of Martin Heinrich Rathke in the 19th century. The classic Rathke diagram illustrates the primitive embryonic origins of the human cervicocerebral vasculature (Fig. 1.1). This diagram depicts how the primitive heart pumps blood into the primitive embryonic circulation, which is constituted by a pair of cephalic dorsal aortae that are fused more caudally into a single descending aorta.

Fig. 1.1 Schematic of the classic Rathke diagram depicting the primitive heart and the primitive embryonic circulation, which is constituted by a pair of cephalic dorsal aortae that are fused more caudally into a single descending aorta.

The primitive heart and dorsal aortae originate from three angiogenetic cell clusters formed by mesenchymal cells of the lateral plate mesoderm. The primitive heart begins as a U-shaped tube that encircles the cephalic pole of the embryo. The dorsal aortae originate as two linear, longitudinally oriented paramedian structures in the cephalic region of the embryo. The truncus arteriosus, which extends from the bulbus cordis portion of the heart tube, gives rise to the ventral aortic sac. The ventral aortic sac of the primitive heart connects to the embryonic dorsal aortae through a series of paired embryonic aortic arches, which are sequentially numbered in a cephalocaudal direction.

Embryological development of the six arches begins in the second or third week of gestation and is complete by the seventh week. These arches, which emerge and regress at different times, are thought to originate from undifferentiated plexiform networks that form arcades around, respectively, the named pharyngeal pouches or branchial arches (Schoenwolf, Bleyl, Brauer, & Francis-West, 2015; Stojanovska, Cascade, Chong, Quint, & Sundaram, 2012). As the embryo develops, the primitive heart is displaced from the cephalic region into the thorax. As this heart moves further caudally, the rostral aortic arch pairs are displaced and involute. The more caudal aortic arch pairs that are closer to the primitive heart are stimulated to develop from their respective branchial arcades.

1.2.2 Development of the Carotid Circulation

The embryonic maxillomandibular arches, also known as the first pair of pharyngeal/branchial arches, appear about day 22 of embryonic development. The formation of the embryonic maxillomandibular arches is soon followed by the development of the associated first aortic arch pairs (Osborn, 1999). Although these aortic arches typically involute, their remnants may persist into adulthood as the primitive maxillary artery or primitive mandibular artery. The primitive maxillary artery is related to the artery of the foramen rotundum, whereas the primitive mandibular artery is related to the vidian artery.

The embryonic hyoid arches, also known as the second pharyngeal/branchial arches, appear near day 24 of embryonic development. The corresponding second aortic arch pairs appear around day 26, typically in conjunction with regression of the first aortic arch pairs. The second aortic arches give rise to the paired primitive hyoid arteries. The stapedial arteries, which are the principal branches of the primitive hyoid arteries, mostly involute during embryonic development as their definitive vascular territories are annexed by other vessels, though remnants often persist into adulthood. The stapedial artery comprises a proximal tympanic segment, which courses in the middle ear, and two terminal trunks, which represent the definitive vascular territories of the middle meningeal artery, superficial recurrent meningeal artery, meningolacrimal artery, and portions of the internal maxillary artery. The tympanic segment of the stapedial artery often persists into adulthood as the caroticotympanic artery. A range of stapedial artery variants have been described based on differential regression of distinct stapedial artery segments. The ventral pharyngeal arteries shift from the ventral aortic sac along the third aortic arch as the heart descends, resulting in the formation of the common carotid artery bifurcation and the definitive external carotid artery (ECA).

The third aortic arches appear around day 28 in normal embryological development. Each extracranial carotid artery system includes the common carotid artery, ECA, and extracranial internal carotid artery (ICA). As the dorsal aorta regresses, this system is formed from the third aortic arch, which bridges the third and fourth aortic arches (ductus caroticus). The ventral pharyngeal arteries, which are the precursors of the definitive external carotid arteries, branch directly from the ventral aortic sac and initially contribute to supply of the first and second aortic arches.

Each intracranial ICA is formed from the ipsilateral dorsal aorta craniad to the third aortic arch. The segmental identity of each dorsal aorta corresponds to regions specified by junctional zones of the primitive aortic arches. The vertical petrous segment of the ICA forms from the dorsal aorta between the third and second aortic arches. The horizontal petrous and lacerum segments of the ICA are formed from the dorsal aorta between the second and first aortic arches. The cavernous, clinoidal, and subarachnoid segments of the ICA form from the dorsal aorta rostral to the first aortic arch. This segment of dorsal aorta terminates in a cranial division and a caudal division. The cranial division gives rise to the primitive olfactory artery, which spawns the anterior choroidal artery, anterior cerebral artery, and middle cerebral artery. The caudal division gives rise to the posterior cerebral artery (PCA). The anterior communicating artery is remodeled from a plexiform network of anastomoses between the primitive olfactory arteries. Incomplete coalescence of these anastomoses may result in fenestration of the anterior communicating artery, an anatomical variant.

The fourth aortic arches, which form around day 28 of gestation, undergo asymmetric remodeling. This includes transforming into part of the brachiocephalic artery and proximal subclavian artery on the right, and part of the definitive aortic arch on the left. The right dorsal aorta caudal to the fourth aortic arch regresses, resulting in the formation of a left-sided aortic arch according to the canonical development pathway.

The fifth aortic arches found in some animals have not been discovered in humans.

The sixth aortic arches form the primitive ductus arteriosus and are responsible for the development of the pulmonary trunk. If the left sixth arch persists, it is responsible for the persistent ductus arteriosus.

1.2.3 Development of the Vertebrobasilar Circulation

The longitudinal neural arteries coalesce from a primitive plexiform network of vessels that cover the ventral surface of the hindbrain. Each longitudinal neural artery forms a series of anastomoses with the caudal division of the ipsilateral terminal dorsal aorta, which is destined to become the communicating segment of the ICA. These anastomoses represent the primitive carotid-vertebrobasilar anastomoses. The primitive carotid-vertebrobasilar anastomoses are four pairs of transitory anastomoses, which form between the caudal division of each terminal dorsal aorta and the ipsilateral longitudinal neural artery. These anastomoses typically have an ordered sequence of formation and regression. If a carotid-vertebrobasilar anastomosis fails to regress, a fetal circulation pattern will persist into adulthood and result in a form of anatomical variation.

As the third and fourth aortic arches emerge to form the dominant circulatory pathway from the ventral aortic sac to the cranial dorsal aortae, seven cervical intersegmental arteries arise from each dorsal aorta. These intersegmental arteries form longitudinal anastomoses to each other, giving rise to the extracranial vertebral arteries. The extracranial vertebral arteries subsequently develop connections to the longitudinal neural arteries, joining the extracranial vertebral arteries to the intracranial vertebral arteries. The rostral portions of the longitudinal neural arteries form a series of anastomoses to each other across the midline, resulting in fusion of the paired vessels into a midline basilar artery. When there is incomplete coalescence of the longitudinal neural arteries and their bridging anastomoses, fenestrations may persist into adulthood as a form of anatomical variation. As the developing telencephalon expands, the posterior cerebral arteries elongate and are displaced more posteriorly. Consequently, further development of anastomoses with the basilar artery frequently leads to annexation of the posterior cerebral arteries by the basilar artery. If these anastomoses fail to sufficiently strengthen, the posterior cerebral arteries will originate from the ICAs, a form of persistent fetal anatomy.

1.3 Mural Structure of Cerebral Arteries

Cerebral aneurysms are focal lesions of arterial wall structure acquired through a process of cumulative damage. This process combines the mechanical effects of hemodynamic stress, environmental toxins (i.e., smoking), and related immuno-inflammatory responses to injury. Rates of mural damage and structural failure may be influenced by a myriad of genetically programmed traits that regulate mural structure, mural function, or extramural aspects of damage and repair processes. As a matter of definition, all aneurysms are characterized by a deficiency of the structural elements responsible for maintaining mechanical integrity of the arterial wall. Arterial wall structure is therefore central to understanding aneurysm pathogenesis.

The walls of cerebral arteries can be distinguished from extracranial arteries of comparable size. In general, the walls of cerebral arteries are thinner than their extracranial counterparts. The walls of cerebral arteries are composed of three distinct layers: the tunica intima, tunica media, and tunica adventitia. The tunica intima is the innermost layer of the arterial wall and contains the endothelial cells that form an interface with circulating blood. The tunica adventitia is the outermost layer of the arterial wall and may contain vaso vasora in thick-walled arteries, particularly in cases of advanced atherosclerotic changes. The tunica media is the muscular layer of the arterial wall that lies between the tunica intima and tunica adventitia. Compared with the general circulation, the vessels of the brain have a much smaller tunica media and a nearly absent tunica externa (Krex, Schackert, & Schackert, 2001).

The tunica intima is composed of a single layer of endothelial cells associated with a thin layer of collagen fibers that form a basal lamina. These endothelial cells are joined by tight junctions that form an impermeable barrier, thus allowing the formation of the blood-brain barrier. In contrast to large elastic arteries like the aorta, which have an abundance of elastic tissue arranged in a fenestrated pattern throughout the media, the mural elastic tissue of subarachnoid-conducting arteries is arranged into discrete, highly concentrated lamellae that form an internal elastic lamina. The internal elastic lamina lies at the boundary between the tunica intima and tunica media. It is the most important load-bearing element of the cerebral arterial wall.

The tunica media of the subarachnoid conducting arteries is prominent and well developed. It is composed mostly of vascular smooth muscle cells and their associated extracellular matrix, composed primarily of collagen. The large subarachnoid-conducing arteries within and proximal to the circle of Willis are considered large to medium sized muscular arteries. In contrast to the tunica media of large elastic arteries like the aorta, the tunica media of these arteries is relatively deficient in elastic tissue.

The tunica externa, or adventitia of cerebral arteries, varies significantly in thickness according to the size of the artery. The large central conducting subarachnoid arteries proximal to the circle of Willis have a recognizable tunica adventitia. As one progresses distally along the arterial tree, smaller arteries with thinner walls contain progressively thinner adventitia. The adventitia of cerebral arteries is primarily composed of loosely woven collagenous connective tissue. In contrast with extracranial arteries of similar size, cerebral arteries do not have a well-developed external elastic lamina. There is a paucity of vaso vasora in the poorly developed adventitia of cerebral arteries unless significant atherosclerotic wall thickening is present in the larger, more centrally located vessels.

1.4 Cerebral Arterial Bifurcations as an Anatomical Vulnerability

The common varieties of saccular cerebral aneurysms consistently form at predictable locations in close relation to arterial bifurcations within or near the circle of Willis. Thus, the importance of the cerebral arterial bifurcation as an anatomical vulnerability related to aneurysm formation has emerged as a guiding principle in our efforts to understand the pathogenesis of cerebral aneurysms. The underlying basis of this vulnerability may reflect hemodynamic factors, structural factors, or a combination of both. Most data seem to suggest that hemodynamic factors are responsible for clustering of saccular aneurysms in close relation to arterial branch points. Recent studies have suggested that some aspects of anatomical vulnerability at cerebral arterial branch points may be heritable (Mackey, Brown, Moomaw, et al., 2013). Raphes, which are bands of aligned collagen fibers where the muscle layers of branching arteries intersect, were once thought to be areas of structural weakness predisposing to aneurysm formation. However, this concept has fallen out of favor.(Finlay, Whittaker, & Canham, 1998; Forbus, 1930) Careful observations have shown that aneurysms do not typically arise at the branch points of arterial vessels where raphes are found, but immediately distal to them.

1.5 Anatomical Variants of Persistent Fetal Circulation (Fig. 1.2)

1.5.1 Fetal PCA

Three main variations have been identified with regards to the configuration of the PCA in relation to the posterior communicating artery (PComA) (Van Overbeeke, Hillen, & Tulleken, 1991). The adult configuration is characterized by a nonhypoplastic PComA having a smaller diameter than the P1 segment of the PCA (Saeki & Rhoton, 1977). The transitional configuration is distinguished by a PComA and P1 segment with the same diameter. The fetal, or embryonic, configuration of the PCA is marked by a P1 that is considerably smaller than the ipsilateral PComA.

Fig. 1.2 Internal carotid artery (ICA). (A) Schematic represents the four types of primitive ICA to vertebrobasilar anastomoses. A , artery; VA , vertebral artery; VB , vertebrobasilar; BA , basilar artery; PISA , proatlantal intersegmental artery. (B) Unsubtracted angiogram of left ICA in the right anterior oblique projection shows filling of the rostral basilar artery by a PTA. Reprinted with permission from the Mayfield Clinic.

Unilateral fetal posterior cerebral arteries are found in 4%–29% of the population (Bisaria, 1984; Horikoshi, Akiyama, Yamagata, Sugita, & Nukui, 2002; Zada, Breault, Liu, et al., 2008). In one study of patients with ICA aneurysms and fetal variant circulation, fetal PCA was the most common anatomic subtype (Horikoshi et al., 2002). This association was theorized to be due to increased flow and hemodynamic stress through the larger PComA.

1.5.2 Primitive Carotid-Vertebrobasilar Anastomoses

The transitory anastomoses that join the ICA and vertebrobasilar circulation during the first 8 weeks of fetal life are known as pre-segmental arteries. These four paired arteries derive their names from neighboring structures. From cranial to caudal, these are the primitive trigeminal, primitive otic, primitive hypoglossal, and proatlantal intersegmental arteries (Caldemeyer, Carrico, & Mathews, 1998).

During week 6 of development, anastomoses that form between the caudal division of the terminal ICA (terminal dorsal aorta) and basilar artery (fused longitudinal neural arteries) promote ordered regression of the primitive otic, hypoglossal, and then trigeminal arteries (Zhang, Xie, Yang, et al., 2009). This developing anastomosis forms the P1 segment of the PCA and establishes the PComA as a major source of blood flow to the developing hindbrain. The PComA and proatlantal intersegmental arteries supply the hindbrain until the vertebral arteries are fully developed.

Although many reports exist to associate cerebral aneurysms with persistent primitive carotid-vertebrobasilar anastomoses, no definitive evidence has been presented that these anatomical variants are independently associated with a quantifiable increased risk of cerebral aneurysm formation relative to the general population (Cloft, Razack, & Kallmes, 1999; Kimball, Ples, Miclaus, Matusz, & Loukas, 2015; Zhang et al., 2009). All of the carotid-vertebrobasilar anastomoses are necessarily associated with a branch point, and are therefore a locus of anatomical vulnerability that is no different than any other cerebral arterial bifurcation in the vicinity of the circle of Willis. It is not surprising that case reports and case series of aneurysms associated with persistent primitive carotid-vertebrobasilar anastomoses are found in the literature. Identification of a persistent primitive carotid-vertebrobasilar anastomosis does not in and of itself represent a concern for cerebral aneurysm formation. If the anatomical variant was incidentally found on a noninvasive brain imaging study, additional imaging evaluation or imaging follow-up to exclude aneurysm, particularly digital subtraction angiography, is not indicated on the basis of this finding alone.

1.5.3 Persistent Trigeminal Artery

The trigeminal artery is the last carotid-vertebrobasilar anastomosis to regress, usually around week 6 of embryonic development. Being the last to regress, it also represents the most commonly found form of the persistent carotid-vertebrobasilar circulation.

The persistent trigeminal artery (PTA) arises from the cavernous ICA and exists in two variants, medial and lateral. The extradural segment of the medial variant penetrates the sella turcica, traveling within its own groove until it pierces dura near the clivus to merge with the basilar artery (Luh, Dean, Tomsick, & Wallace, 1999). The lateral variant courses with the trigeminal root or trigeminal sensory root to the lateral sella and along the roof of the petroclinoid ligament, then joining the basilar artery between the origin of the superior cerebellar artery (SCA) and anterior inferior cerebellar artery (AICA). Trigeminal variants in which one of the major cerebellar arteries (SCA or AICA) arises directly from the cavernous ICA are rare, but sometimes found on angiography.

In most cases, trigeminal artery flow is from anterior to posterior. In most patients with this variant, the basilar artery proximal to the trigeminal-basilar junction is hypoplastic. In some cases, there is no anatomic connection between the proximal hypoplastic basilar trunk and distal trigeminal trunk fed by the trigeminal artery.

The PTA is rare, found in only 0.1%–1% of all cerebral angiograms (Ladner, Ehtesham, Davis, et al., 2014; Luh et al., 1999). In the vast majority of affected individuals, a PTA is not associated with any clinical symptoms. Neurovascular compression syndromes, including trigeminal neuralgia and ophthalmoplegia, are rarely reported.

Although some case reports and case series have alleged an association between PTA and cerebral aneurysms, most such reports are flawed by selection bias. In these reports, the PTA was discovered when the patient underwent a vascular imaging study to investigate the possibility of cerebrovascular pathology because of the associated signs and/or symptoms. These samples are highly enriched for patients with cerebral aneurysms. Even in angiographic series of patients with PTA, a consistent association between aneurysms and PTA has not been found. In one angiographic series of patients with angiographically proven PTA, the frequency of aneurysms was no greater than that found in the general population (Cloft et al., 1999). Nonetheless, since a PTA is associated with multiple branch points, aneurysms are sometimes associated with it. The PTA-associated aneurysms are typically extradural, arising at the ICA-PTA bifurcation within the cavernous sinus. Less often, PTA-associated aneurysms arise from the trunk of the PTA or at the junction of the PTA and basilar artery (Li, Li, Pan, Fang, & Wang, 2004).

1.5.4 Persistent Otic Artery

The otic artery is typically the first carotid-vertebrobasilar anastomosis to regress, and therefore represents the rarest form of persistent fetal circulation in adults (Caldemeyer et al., 1998). Arising from the petrous portion of the ICA, it travels to the internal auditory canal and represents a small portion of the blood supply to the developing vertebrobasilar territory.

Radiographically, the persistent otic artery is defined as a vessel that arises from the petrous ICA near its medial turn, transverses the internal auditory meatus, and feeds the mid-basilar artery distal to the AICA (Croft, 2004).

Few reports of persistent otic arteries exist in the literature. Patel et al. reported only the second persistent otic artery in the literature, and the first otic artery associated with an aneurysm (Patel, Gandhi, & Bederson, 2003). Despite these reports, the rarity of the persistent otic artery in the literature have led some to consider whether it even exists. Some authors have suggested that this and earlier reports of persistent otic vessels actually represent low-lying persistent trigeminal arteries (Croft, 2004).

1.5.5 Persistent Hypoglossal Artery

The persistent hypoglossal artery, the second most common carotid-vertebrobasilar anastomosis, is found in only 0.02%–0.09% of the population (Baldi, Zander, Rabellino, & Maynar, 2009). Angiographic characteristics of the persistent hypoglossal artery include several features: (1) an origin from the extracranial ICA between the C1 and C3 vertebral levels forming a reverse C-shaped configuration, (2) a course through the hypoglossal canal medial to the hypoglossal nerve, and (3) a junction with the proximal basilar artery at the level of the pontomedullary junction, close to the vertebrobasilar junction. The ipsilateral posterior inferior cerebellar artery (PICA) usually arises from the hypoglossal artery, and the ipsilateral vertebral artery is usually hypoplastic. The ipsilateral PComA is usually absent. A hypoglossal artery variant in which the PICA arises directly from the cervical ICA, and enters the posterior fossa through the hypoglossal canal is sometimes encountered.

Persistent hypoglossal arteries are typically incidental imaging findings. They can be found in conjunction with aneurysms (Hui, Schuette, & Cawley, 2011). Palsies of the glossopharyngeal and hypoglossal nerves can also be presenting symptoms of persistent hypoglossal arteries (Al-Memar & Thrush, 1998; Kempe & Smith, 1969).

1.5.6 Proatlantal Intersegmental Artery

The proatlantal intersegmental artery (PISA) has a completely extradural course. It is associated with hypoplasia of the proximal ipsilateral vertebral artery, and frequently the contralateral vertebral artery as well. Two variants of the PISA exist as first described by Padget (1954). Type I PISA arises from the ICA at the C2 to C3 vertebral level; it then courses posteriorly above the C1 transverse process to continue as the ipsilateral vertebral artery coursing along the posterior neural arch of C1, to enter the foramen magnum. It does not cross the foramen transversarium. Type II PISA arises from the ECA and passes through the C1 foramen transversarium, where it continues as the vertebral artery before entering the foramen magnum.

1.5.7 Congenital Absence of the ICA

In rare cases, there can be a congenital absence of the ICA (Alexandre, Visconti, Schiarelli, Frassanito, & Pedicelli, 2016; Ryan, Kline, & Gomez, 2000). In one series of 2194 carotid angiograms, only two cases of ICA absence were reported (Tran-Dinh, Jayasinghe, & Merry, 1986). This entity represents a spectrum of anatomical variants that express different anatomical patterns depending on the segments of the artery that are absent, and the manner in which the territory of the intracranial ICA is reconstituted. Of several different patterns of reconstitution described, each corresponded to a different level of segmental aplasia or agenesis. In most cases, the ipsilateral carotid canal will be very small and poorly developed, a diagnostic clue to the congenital nature of the process.

In one pattern of this entity, the ICA circulation is reconstituted by the basilar artery via a PComA or trigeminal artery. In another pattern, the anterior communicating artery reconstitutes the anterior and middle cerebral arteries. In yet another pattern, a rete mirabile perfused by the ascending pharyngeal artery and internal maxillary artery reconstitute the paraclinoid intradural ICA. In some cases, a primitive maxillary artery forms a trans-sellar anastomosis between the cavernous ICAs. Alternative patterns of reconstitution involving anastomoses with branches of the inferolateral trunk or stapedial artery have also been reported. In cases of the so-called aberrant ICA, there is regression of the cervical ICA with reciprocal hypertrophy of the proximal ascending pharyngeal artery and its inferior tympanic branch. The inferior tympanic artery reconstitutes the petrous ICA in the middle ear. This aberrant pattern of carotid development may be associated with symptoms of pulsatile tinnitus.

Although many patients with congenital absence of the ICA are asymptomatic because of adequate collateral cerebral blood flow, some experience transient ischemic attacks (TIAs), seizures, or headaches, particularly as they age and the acquired vascular diseases (e.g., atherosclerosis) are superimposed on a congenitally deficient cerebrovascular reserve. Cases of Horner's syndrome stemming from ICA hypoplasia have been described (Ryan et al., 2000; Tubbs & Oakes, 2005). Absence of the ICA is often associated with the presence of cerebral aneurysms, often of the anterior communicating artery, a particularly flow loaded and therefore vulnerable anatomic locus (Afifi et al., 1987; Teal, Rumbaugh, Bergeron, & Segall, 1973). Therapeutic carotid occlusion is similarly associated with an increased risk of cerebral aneurysm formation, particularly in the anterior communicating artery region. Hashimoto's experimental models of cerebral aneurysm formation in rodents and nonhuman primates have exploited the aneurysm-promoting effect of unilateral carotid occlusion.

1.5.7.1 Arterial Fenestrations

Arterial fenestrations are produced by focally incomplete fusion of the vessels within a primitive plexiform vascular network into a single discrete vascular trunk. Structurally, fenestrations are composed of pillars that segmentally divide the vessel lumen into two or more distinct channels, each having its own intimal lining. The dividing pillar is constituted by the juxtaposed walls of the incompletely fused vessels. Fenestrations are most commonly expressed in the anterior communicating artery and in the vertebrobasilar arteries, that is, vessels that form through a coalescence of primitive plexiform networks. The architecture of cerebral arterial fenestrations and arterial bifurcations are similar. Medial raphes and intimal pads are features of both structures. Duplications have been differentiated from fenestrations as persistence of entire longitudinal segments of vessels that typically regress during embryonic development. This is distinguished from the focal, short segment nature of fenestrations.

Since arterial bifurcations represent anatomical vulnerabilities for aneurysm formation and fenestrations are bifurcation structures, aneurysms can form at fenestrations. Angiographic studies have not shown a definite pathological relationship between cerebral artery fenestrations and cerebral aneurysms. In a series of 5190 aneurysms, Sanders et al. have reported that of 37 patients with 38 fenestrated arteries, 7 of them had a total of 13 aneurysms (though only 1 was at the site of fenestration) (Sanders, Sorek, & Mehta, 1993). The authors noted in their series an overall aneurysm rate of 3% at the site of fenestration—no different from the rate of aneurysm formation at the normal cerebrovascular branch points. In another study of nearly 11,000 cerebral angiograms performed between 1992 and 2011, Cooke et al. reached a similar conclusion (Cooke, Stout, Kim, et al., 2014).

1.6 Conclusions

The embryological development of the cerebral arterial circulation involves a complex process of vasculogenesis and angiogenesis that can generate numerous atypical anatomical variants. These variants represent artifacts of early embryonic development and can take many forms. The mural structure of normal cerebral arteries and their bifurcations present anatomical vulnerabilities concerning the pathogenesis of cerebral aneurysms. Some variants of embryonic development, such as arterial fenestrations, are no more vulnerable to cerebral aneurysm formation than normal cerebral artery bifurcations. Other variants of embryonic development, such as agenesis or aplasia of the ICA, are associated with a significant risk of cerebral aneurysm formation due to flow loading of collateral pathways, particularly in the anterior communicating artery region. Although some of the primitive persistent carotid-vertebrobasilar anastomoses have been alleged as risk factors for cerebral aneurysm formation, no convincing evidence of this was found in our evaluation of the literature.

References

Afifi A.K., Godersky J.C., Menezes A., Smoker W.R., Bell W.E., Jacoby C.G. Cerebral hemiatrophy, hypoplasia of internal carotid artery, and intracranial aneurysm. A rare association occurring in an infant. Archives of Neurology. 1987;44:232–235.

Alexandre A.M., Visconti E., Schiarelli C., Frassanito P., Pedicelli A. Bilateral internal carotid artery segmental agenesis: Embryology, common collateral pathways, clinical presentation, and clinical importance of a rare condition. World Neurosurgery. 2016;95:620.e9–620.e615.

Al-Memar A., Thrush D. Unilateral hypoglossal nerve palsy due to aneurysm of the stump of persistent hypoglossal artery. Journal of Neurology, Neurosurgery, and Psychiatry. 1998;64:405.

Baldi S., Zander T., Rabellino M., Maynar M. Stent-assisted coil embolization of a wide-neck aneurysm of a persistent primitive hypoglossal artery. Cardiovascular and Interventional Radiology. 2009;32:352–355.

Bisaria K.K. Anomalies of the posterior communicating artery and their potential clinical significance. Journal of Neurosurgery. 1984;60:572–576.

Caldemeyer K.S., Carrico J.B., Mathews V.P. The radiology and embryology of anomalous arteries of the head and neck. American Journal of Roentgenology. 1998;170:197–203.

Cloft H.J., Razack N., Kallmes D.F. Prevalence of cerebral aneurysms in patients with persistent primitive trigeminal artery. Journal of Neurosurgery. 1999;90:865–867.

Cooke D.L., Stout C.E., Kim W.T., et al. Cerebral arterial fenestrations. Interventional Neuroradiology. 2014;20:261–274.

Croft H.J. Persistent otic artery. American Journal of Neuroradiology. 2004;25:162 author reply 162.

Finlay H.M., Whittaker P., Canham P.B. Collagen organization in the branching region of human brain arteries. Stroke. 1998;29:1595–1601.

Forbus W. On the origin of miliary aneurysms of the superficial cerebral arteries. Bulletin of the Johns Hopkins Hospital. 1930;47:239–284.

Horikoshi T., Akiyama I., Yamagata Z., Sugita M., Nukui H. Magnetic resonance angiographic evidence of sex-linked variations in the circle of willis and the occurrence of cerebral aneurysms. Journal of Neurosurgery. 2002;96:697–703.

Hui F.K., Schuette A.J., Cawley C.M. Endovascular treatment of an aneurysm of a persistent primitive hypoglossal artery with complete resolution of brainstem compressive symptoms: Case report. Neurosurgery. 2011;68:E854–E857 discussion E857.

Kempe L.G., Smith D.R. Trigeminal neuralgia, facial spasm, intermedius and glossopharyngeal neuralgia with persistent carotid basilar anastomosis. Journal of Neurosurgery. 1969;31:445–451.

Kimball D., Ples H., Miclaus G.D., Matusz P., Loukas M. Persistent hypoglossal artery aneurysm located in the hypoglossal canal with associated subarachnoid hemorrhage. Surgical and Radiologic Anatomy. 2015;37:205–209.

Krex D., Schackert H.K., Schackert G. Genesis of cerebral aneurysms—An update. Acta Neurochirurgica. 2001;143:429–448.

Ladner T.R., Ehtesham M., Davis B.J., et al. Resolution of trigeminal neuralgia by coil embolization of a persistent primitive trigeminal artery aneurysm. BML Case Reports. 2014. ;6:e22. 2013 https://doi.org/10.1136/neurintsurg-2013-010703.rep.

Li M.H., Li W.B., Pan Y.P., Fang C., Wang W. Persistent primitive trigeminal artery associated with aneurysm: Report of two cases and review of the literature. Acta Radiologica. 2004;45:664–668.

Luh G.Y., Dean B.L., Tomsick T.A., Wallace R.C. The persistent fetal carotid-vertebrobasilar anastomoses. American Journal of Roentgenology. 1999;172:1427–1432.

Mackey J., Brown Jr. R.D., Moomaw C.J., et al. Familial intracranial aneurysms: Is anatomic vulnerability heritable? Stroke. 2013;44:38–42.

Osborn A.G. Diagnostic cerebral angiography. Philadelphia, PA: Lippincott Williams & Wilkins; 1999.

Padget D.H. Designation of the embryonic intersegmental arteries in reference to the vertebral artery and subclavian stem. The Anatomical Record. 1954;119:349–356.

Patel A.B., Gandhi C.D., Bederson J.B. Angiographic documentation of a persistent otic artery. American Journal of Neuroradiology. 2003;24:124–126.

Ryan F.H., Kline L.B., Gomez C. Congenital Horner's syndrome resulting from agenesis of the internal carotid artery. Ophthalmology. 2000;107:185–188.

Saeki N., Rhoton Jr. A.L. Microsurgical anatomy of the upper basilar artery and the posterior circle of Willis. Journal of Neurosurgery. 1977;46:563–578.

Sanders W.P., Sorek P.A., Mehta B.A. Fenestration of intracranial arteries with special attention to associated aneurysms and other anomalies. American Journal of Neuroradiology. 1993;14:675–680.

Schoenwolf G.C., Bleyl S.B., Brauer P.R., Francis-West P.H. Larsen's human embryology. 5th ed. Philadelphia, PA: Elsevier Saunders; 2015.

Stojanovska J., Cascade P.N., Chong S., Quint L.E., Sundaram B. Embryology and imaging review of aortic arch anomalies. Journal of Thoracic Imaging. 2012;27:73–84.

Teal J.S., Rumbaugh C.L., Bergeron R.T., Segall H.D. Congenital absence of the internal carotid artery associated with cerebral hemiatrophy, absence of the external carotid artery, and persistence of the stapedial artery. The American Journal of Roentgenology, Radium Therapy, and Nuclear Medicine. 1973;118:534–545.

Tran-Dinh H., Jayasinghe L.S., Merry G.M. The absence of the internal carotid artery: Report of two cases. The Australian and New Zealand Journal of Surgery. 1986;56:85–88.

Tubbs R.S., Oakes W.J. Horner's syndrome resulting from agenesis of the internal carotid artery: Report of a third case. Child's Nervous System. 2005;21:81–82.

Van Overbeeke J.J., Hillen B., Tulleken C.A.A. Comparative study of the circle of Willis in fetal and adult life. The configuration of the posterior bifurcation of the posterior communicating artery. Journal of Anatomy. 1991;176:45–54.

Zada G., Breault J., Liu C.Y., et al. Internal carotid artery aneurysms occurring at the origin of fetal variant posterior cerebral arteries: Surgical and endovascular experience. Neurosurgery. 2008;63:ONS55–ONS61 discussion ONS61–52.

Zhang C.W., Xie X.D., Yang Z.G., et al. Giant cavernous aneurysm associated with a persistent trigeminal artery and persistent otic artery. Korean Journal of Radiology. 2009;10:519–522.

Chapter 2

Biology of Cerebral Aneurysm Formation, Growth, and Rupture

Luis E. Savastano⁎; Ankur Bhambri†; David Andrew Wilkinson⁎; Aditya S. Pandey⁎    ⁎ Department of Neurosurgery, University of Michigan, Ann Arbor, MI, United States

† School of Medicine, Michigan State University, East Lansing, MI, United States

Abstract

Cerebral aneurysm rupture leads to significant morbidity and mortality. The biological understanding of aneurysmal growth and rupture may lead to opportunities of preventing subarachnoid hemorrhage. This chapter is dedicated to presenting the current understanding of the biochemical and hemodynamic changes that allow aneurysmal growth and rupture. The role of turbulent flow leading to endothelial cellular damage and subsequent changes to the internal elastic lamina leading to myoproliferation is presented. Atherosclerosis has been integral to the development of ischemic stroke and we present its association to aneurysmal growth and rupture. The roles of proinflammatory markers, including matrix metalloproteinases and interleukin-1, are discussed as such markers are more common in patients with ruptured aneurysm as compared to asymptomatic aneurysms. Finally, we present risk factors of aneurysm rupture, including patient- and aneurysm-related factors as well as triggers for aneurysmal rupture.

Keywords

Cerebral aneurysm growth; Aneurysm rupture; Cerebral aneurysm biology; Aneurysm rupture risk; Aneurysm growth risk

Outline

2.1Introduction

2.2Formation of Intracranial Aneurysms

2.2.1Epidemiological Risk Factors

2.2.2Genetic Factors

2.2.3Structural and Molecular Changes

2.3Atherosclerosis and Saccular Intracranial Aneurysms

2.4Hemodynamics and Biology

2.5Aneurysm Growth

2.6Aneurysm Wall Inflammation

2.7Aneurysm Rupture

2.7.1Risk Factors for Aneurysm Rupture

2.7.2Patient-Related Risk Factors

2.7.3Aneurysm-Related Risk Factors

2.7.4Triggers of Aneurysm Rupture

References

2.1 Introduction

Intracranial aneurysms are characterized by the variable outward ballooning of a weakened portion of an arterial wall within the cerebral vasculature. Demographically, patients usually develop such aneurysms between their early 40s and late 60s, more commonly affect females, and have an estimated prevalence of ≈ 3.2%. An unruptured intracranial aneurysm (UIA) is a perilous finding precisely because it carries a potential for rupture, which results in subsequent subarachnoid hemorrhage (SAH) and related complications. The SAH is frequently fatal and when not, often produces significant morbidity (Korja, Kivisaari, Rezai Jahromi, & Lehto, 2017). Owing to increased use of noninvasive imaging platforms which provide ever-greater resolution, UIAs are being detected more frequently and in more varied clinical settings. Incidental findings of cerebral aneurysms are inherently fraught with ambiguity as it relates to clinical management.

Aneurysmal treatment relies on microsurgical (clip reconstruction) or endovascular techniques (aneurysmal coiling or flow diversion) to prevent a communication between the aneurysm and the parent vessel. The surgical and endovascular repair is not without risk and given the low annual risk of rupture for most UIAs, careful consideration must be given to the fact that the risk of proactive treatment may outweigh the risk of rupture. Owing to significant variation in data regarding surgical and endovascular outcomes and concomitant variation in annual risk of rupture estimates, the optimal management of UIAs remains elusive. While the International Study of Unruptured Intracranial Aneurysms revealed that aneurysms greater than 7 mm are at higher risk of rupture, realization of the inclusion criteria biases of this study as well as reports of smaller aneurysm bleeding necessitates a better understanding of aneurysmal biology (Korja et al., 2017). Such understanding will likely reveal key structural and biological features and relevant patient characteristics that predispose intracranial aneurysms to form, grow, and rupture, thus facilitating the development of more precise diagnostic platforms to improve risk stratification. This knowledge will improve our ability to counsel patients regarding the pursuit of aneurysmal treatment versus observation. Further, this insight may hasten the advancement of endovascular and surgical intervention based on biological data as well as lead to noninvasive medical therapies that modify the natural history of these lesions by preventing aneurysm growth and rupture.

This chapter focuses on intracranial saccular aneurysms, typically called berry aneurysms, which generally form at branch points of large cerebral arteries and are thought to arise secondary to a combination of hemodynamic stresses and biological factors. In the following paragraphs, we will focus on the biological factors as we summarize recent insights in cerebral aneurysm formation, growth, and rupture.

2.2 Formation of Intracranial Aneurysms

The process of intracranial aneurysm formation involves pathological changes to vessel wall composition and structure occurring in the presence of predisposing genetic, environmental, and epidemiological risk factors. These changes tend to occur over the life course of a person, explaining the low incidence of aneurysm at young ages (Korja et al., 2017). The precise sequence of events leading to the development of an incipient aneurysm is not completely understood, although hemodynamic forces, arteriosclerosis, atherosclerosis, hypertension, and history of smoking are collectively implicated.

2.2.1 Epidemiological Risk Factors

Family history of UIA or SAH diagnosis, smoking history, hypertension, female gender, and autosomal polycystic kidney disease are the most salient epidemiological risk factors for intracranial aneurysm development. Of these, concomitant smoking and hypertension lead to the greatest increase in risk for eventual UIA development (OR > 8) (Vlak, Rinkel, Greebe, & Algra, 2013). In addition, first-degree relatives of patients with UIAs or previous SAH have > 3 times higher likelihood of developing UIA compared with the general population, which supports the current guidelines for familial screening when two or more first-degree relatives are diagnosed with cerebral aneurysms (Brown et al., 2008). Moreover, UIAs in these relatives tend to progress toward rupture at smaller sizes and at younger ages compared with sporadic cerebral aneurysms. Additionally, females are twice as likely to develop UIAs as males. Recent epidemiological studies on patients with connective tissue disorders (such as Marfan syndrome, Ehlers-Danlos syndrome, neurofibromatosis type 1, and Loeys-Dietz syndrome) have found little support for their association with UIA development, contrary to earlier assertions based on case study reports (Kim, Brinjikji, Lanzino, & Kallmes, 2016; van den Berg, Limburg, & Hennekam, 1996). Further, the annual risk of subsequent de novo intracranial aneurysm development in patients with history of SAH is approximately 0.2%–1.8%.

2.2.2 Genetic Factors

Identification of the genetic determinants of intracranial aneurysm formation have been challenging due to difficulty in isolating their effects given that aneurysmal formation and rupture is related to complex interactions among genetic, environmental, and epidemiological interactions. Thus, despite the strong association between family history and intracranial aneurysm development, genes responsible for this robust relationship have not been identified. Genome-wide association studies have identified some associations at chromosome 4q31.23 (EDNRA), 5q31.3, 6q24.2, 8q12.1 (SOX17), 9p21.3 (CDKN2A/CDKN2B/CDKN2BAS), 10q24.32 (CNNM2), 12q22, 13q13.1 (KL/STARD13), 18q11.2 (RBBP8), 20p12.1, and chromosome 7 near HDAC9 (7p21.1) (Yasuno et al., 2010). Many of the gene products composed of the vascular extracellular matrix, perlecan, elastin, and collagen type 1 A2 have been implicated in aneurysmal formation. However, single nucleotide polymorphisms (SNPs) at these loci account for less than 5% of the familial risk and thus have little predictive value. Limitations in these studies are due in part to geographically biased patient populations, small sample sizes, and inadequate consideration of aneurysm phenotype (Khurana, Fox, Meissner, Meyer, & Spetzler, 2006; Ko et al., 2008). Interestingly, among patients with family history, those who also have a history of smoking are three times more likely to develop an UIA, thus suggesting that gene-environment interactions may have a significant role in intracranial aneurysm pathogenesis. Additionally, several studies have identified SNPs that are associated with sporadic intracranial aneurysms. Such polymorphisms tend to occur in genes implicated in various vascular pathologies and include endothelin receptor, SOX17, and CDKN2B-AS1 (an RNA gene) (Bilguvar et al., 2010; Kremer et al., 2015). Genetic analysis with oligonucleotide microarrays has also associated the differential expression of genes involved in antigen processing and presentation with intracranial aneurysm development. Nevertheless, these associations are also limited in their predictive value (Bilguvar et al., 2010).

2.2.3 Structural and Molecular Changes

Cerebral arteries are vulnerable to aneurysm formation because of their unique structural properties (Fig. 2.1A). Compared to their systemic vascular counterparts, cerebrovascular arteries differ by having an extremely thin adventitial layer, an absent external elastic lamina, and a medial layer characterized by decreased elastic fiber density; additionally, in lieu of connective tissue these vessels are surrounded by subarachnoid cerebrospinal fluid. The internal elastic lamina (IEL), located at the circumferential junction between the intimal and medial layers, is largely responsible for preserving vessel wall geometry. Damage to the IEL and resultant loss in vessel elasticity is a seminal event in saccular intracranial aneurysm development (Jayaraman et al., 2008; Mizutani, Miki, Kojima, & Suzuki, 1999; Valen-Sendstad, Mardal, Mortensen, Reif, & Langtangen, 2011). Histological analysis has revealed that injury to the IEL is typically found at arterial branch points, which are the characteristic sites of aneurysmal formation. Such tears, initiated by hemodynamic stress, tend to occur more frequently in patients predisposed to aneurysm formation (Valen-Sendstad et al., 2011).

Fig. 2.1 Formation and growth of intracranial aneurysms. Healthy cerebral arterial walls (panel A) are formed by a well-organized construct of three concentrically arranged layers: (1) Tunica intima, the innermost layer, that consists of a single layer of endothelial cells (ECs) connected by tight junctions, a subjacent delicate basement membrane, and a robust internal elastic lamina (IEL) rich in elastin fibers; (2) tunica media, largely formed by vascular smooth muscle cells (SMCs) with paucity of elastin and collagen fibers; and (3) tunica adventitia, the outermost layer, mainly formed by a thin layer of collagen fibers, fibroblasts (FBs), and some white blood cells (WBC). The disruption of the physiological and structural homeostasis of the cerebral arteries leading to the formation of aneurysms may occur due to a combination of environmental, epidemiological, and genetic risk factors, such as smoking and hypertension, in arterial segments exposed to high hemodynamic stress and aberrant flow patterns. The latter is particularly significant at the flow dividers of arterial bifurcation and at communicating segments with uneven affluent vessels. For example, one of the most common angioarchitectures related to anterior communicating artery aneurysm is an anterior communicating artery (AComA) complex formed by a dominant left anterior cerebral artery (Left A1) and a hypoplastic right anterior cerebral artery (Right A1). Overtime, aberrant hemodynamic forces combined to a proinflammatory milieu lead to progressive structural damage characterized by endothelial dysfunction and breakdown, disruption of the IEL, and apoptosis and phenotypical changes of SMCs from a contractile to a proinflammatory/proextracellular matrix (ECM) remodeling type (panel B). All this events are further amplified by a mounting inflammatory response characterized by influx of inflammatory cell and rising levels of cytokines (e.g., TNF, monocyte chemoattractant protein-1, IL-1β, NF-κB) and matrix metalloproteinases. The focally weakened arterial wall is overwhelmed by the mechanical load and tensile stress resulting in the formation of the aneurysmal dome, that is largely formed by a remodeled ECM rich in collagen with some SMCs, paucity of inflammatory cells, and missing or discontinuous layer of ECs (panel C). The hemodynamic environment of the aneurysm sac influences aneurysmal wall remodeling, characterized by wall degradation caused by cell death and breakdown of ECM and cell proliferation, and collagen deposition. This delicate balance determines if an aneurysm dome will remain stable, grow, or rupture.

Upon IEL rupture, vascular smooth muscle cells (SMCs) begin to traverse the newly created holes and infiltrate the intima, where they subsequently undergo hyperplasia; this restructuring of the vascular architecture represents an adaptive response to structural damage (Fig. 2.1B). In addition, endothelial apoptosis leading to abnormalities of the luminal surface and exposure of subendothelial collagen has also been described. Within the medial layer, disorganization or loss of SMCs and extensive replacement of normal wall by hyaline-like matrix rich in collagen I, and in the adventitial layer, increased distension of collagenous fibers have been implicated within aneurysm formation. Moreover, aneurysms that exhibit endothelial apoptosis and medial SMC disorganization or loss have significantly weakened the vessel architecture and thus have the greatest likelihood of eventual rupture (Chatziprodromou, Tricoli, Poulikakos, & Ventikos, 2007; Hosaka & Hoh, 2014; Jayaraman et al., 2008). In addition, when compared with healthy arteries, microarray analyses have shown that the walls of intracranial aneurysms show greater expression of genes associated with apoptosis, inflammation, and humoral activity (Wang et al., 2017). All these biological factors are highly dynamic. For example, a recent study that employed radiocarbon dating to assess the age of the type I collagen fibers that predominate in the aneurysm wall concluded that type I collagen age was not dependent on aneurysm size, shape, rupture status, or patient age; it was, however, significantly decreased in smokers or those with hypertension, indicating accelerated collagen remodeling in patients predisposed to systemic vascular inflammation (Etminan et al., 2014).

2.3 Atherosclerosis and Saccular Intracranial Aneurysms

Histologic examination of the saccular intracranial aneurysm wall has shown atherosclerosis as a characteristic pathologic finding (Etminan et al., 2014). Atherosclerotic progression is associated with aneurysm growth: small aneurysms show myointimal proliferation and few foam cells and lymphocytes, whereas larger aneurysms tend to demonstrate more advanced atherosclerotic plaques with proportionally greater foamy macrophages, T lymphocytes, and major histocompatibility complex (MHC) class II expressing SMCs (Hasan et al., 2015; Starke et al., 2014). This association suggests that atherosclerosis may be etiologically involved in intracranial aneurysm formation beyond the common risk factors for these conditions such as smoking and hypertension (Nakayama, Tanaka, Kumate, Tomonaga, & Takebayashi, 1999). Indeed, previous studies have corroborated the notion that atherosclerosis is implicated in the development of abdominal aortic aneurysms intimating a common role for atherosclerosis in aneurysm pathogenesis. Thus, it is possible that the inflammation intrinsic to atherosclerosis is the driving force behind aneurysm development, growth, and eventual rupture. Additional evidence for inflammation-mediated pathogenesis comes from the fact that promoters of systemic vascular inflammation—hypertension and smoking—are risk factors for both abdominal and intracranial aneurysms (Chalouhi et al., 2012).

2.4 Hemodynamics and Biology

Intracranial aneurysms tend to develop at arterial branch points due to the increased shear stress and turbulence that prevails at these sites. Variations in the configuration of arterial bifurcations such as the presence of hypoplastic vessels, sharper angles, or more complex curvatures, further increase hemodynamic stress and thus raise the susceptibility of aneurysm formation (Krzyzewski et al., 2014). Currently, high wall shear stress and high positive spatial wall shear stress gradient focused on a small segment of the arterial wall are believed to be key players in the initiation process of aneurysm formation. Additionally, because such features tend to occur at specific locations, lesions tend to occur at relatively constant positions within the circle of Willis (Nam, Choi, Cheong, Kim, & Park, 2015). Thus, approximately 90% of cerebral aneurysms form in the anterior circulation. More precisely, about 30%–35% develop in the anterior communicating artery, 30% along the intracranial internal carotid arteries, and 20% in the middle cerebral arteries. The remaining 10% form in the posterior circulation—half of those at the basilar apex, and the rest in the remaining arteries such as the posterior inferior cerebellar arteries, the vertebrobasilar junction, and the superior and inferior cerebellar arteries.

As discussed above, novel insights into aneurysm biology have demonstrated that pathological changes within the vessel wall (e.g., digestion of supporting structural fibers by matrix metalloproteinases or MMPs) affecting wall mechanical properties and the relationship with intra-aneurysmal hemodynamic conditions, rather than size and shape of a lesion, determine the fate of an unruptured aneurysm (Aoki, Kataoka, Morimoto, Nozaki, & Hashimoto, 2007; Gaetani et al., 1999). Consequently, researchers have developed computational fluid dynamic models based on three-dimensional imaging data to better characterize these hemodynamic patterns and their impact on wall shear stress, frictional force acting on the vessel wall. Interestingly, both the high and the low wall shear stress are implicated in aneurysm pathophysiology and shear stress intensity may modulate aneurysm phenotype (Lott, Siegel, Chaudhry, & Prestigiacomo, 2009). Unfortunately, current computational models do not generally consider pathogenically important biophysical factors such as spatial gradients of wall shear stress and vessel elasticity and tension, thus limiting the strength of their predictive validity. Furthermore, such models procure data from ruptured or unruptured aneurysms rather than collecting serial data on an evolving aneurysm; consequently, their clinical utility is limited.

Chronic elevations in wall shear stress can lead to IEL degradation and consequent imbalances in the distribution of tensile forces. Such pathologic changes are accompanied by the migration of dedifferentiated SMC into the intima, where they undergo hyperplasia and elaborate extracellular matrix. More precisely, these SMCs, along with fibroblasts, synthesize substantial type I and V collagen, which is the major structural component of intracranial aneurysms (Fig. 2.1C). Such SMC phenotypic modulation may be an attempt at repair in the face of vascular damage. However, SMCs may also undergo apoptosis resulting in thinning of the medial layer. Additionally, this increased hemodynamic stress is accompanied by endothelial dysfunction and phenotypic changes such as cellular elongation and realignment. Once hemodynamic insults overwhelm the efforts to maintain structural integrity, the inflammatory response, driven by cytokines such as interleukin (IL)-1β and tumor necrosis factor (TNF), becomes a major force behind aneurysm development (Zhang et al., 2016). Proinflammatory SMCs and infiltrating macrophages begin to release MMPs capable of degrading collagen and elastin, thereby weakening the tensile strength and elasticity of the vessel wall (van der Pluijm et al., 2016; White, Haas, Phillips, & Comerota, 1993).

The intensity of wall shear stress can determine the pathophysiologic pathway responsible for subsequent aneurysm development. After initiation, the persistence of low wall shear stress, often a consequence of an intra-aneurysmal recirculation zone, promotes inflammation-mediated growth. Such inflammation is characterized by the presence of infiltrating lymphocytes, neutrophils, and macrophages. The additional macrophages amplify the production of MMPs, which further degrade the structural and morphologic integrity of the vessel thereby possibly enabling expansion and thus increased aneurysm radius (Aoki et al., 2007).

By contrast, continued high wall shear stress, often due to impinging blood flow after aneurysm initiation, results in vascular SMC-mediated development. These phenotypically modulated SMCs cause vessel wall degradation by releasing abundant MMPs. However, many SMCs and fibroblasts subsequently begin to undergo apoptosis, possibly due to loss of extracellular matrix (ECM) (Welleweerd et al., 2015). Consequently, such aneurysms develop thin walls with enough mechanical strength to preclude expansion without simultaneous rupture. Nevertheless, both types of shear stress, and aspects of both pathophysiologic pathways, may be present in the same aneurysm and the resulting consequences of this are not known; thus, it is best to consider the pathophysiologic implications of wall shear stress intensity as an idealized categorization rather than a complete assessment of continually fluctuating hemodynamic factors and the ultimate effects of their summation.

2.5 Aneurysm Growth

According to contemporary theories, when faced with an acute precipitating injury, a newly formed aneurysmal wall could rapidly grow and rupture young, or a structural repair process would happen over time significantly decreasing the future risk of bleeding for an old aneurysm. The latter aneurysm group could then stay quiescent for variable period of time, or grow and potentially rupture if forces leading to disruption prevail (Fig. 2.2). Probabilistic analysis reveals that the period of high rupture risk is approximately less than 8 weeks after the formation of aneurysm (Mitchell & Jakubowski, 2000). This may coincide with a period of heightened vessel wall inflammation immediately following aneurysm development, which combined with structural weakness, portends imminent rupture. Therefore, vulnerable aneurysms would rupture shortly after the formation and would be rarely detected as UIAs, explaining the high proportion of ruptured small aneurysm in studies analyzing patients with SAH versus the minimal prospective rupture risk calculated for small UIAs (which are likely to be old lesion) (Forget et al.,